Academic Appointments

Administrative Appointments

  • Review Editor, Alcoholism: Clinical and Experimental Research (2004 - Present)
  • Review Editor, Frontiers in Human Neuroscience (2009 - Present)
  • Section Editor, Neurobiology of Aging (2009 - 2013)
  • Editor-in-Chief, Neuropsychology Review (2009 - 2015)
  • Review Editor, Hippocampus (2003 - Present)

Honors & Awards

  • Henri Begleiter Award for Excellence in Research, Research Society on Alcoholism (2019)
  • Doctorate Honoris Causa, EPHE, Sorbonne, France (2018)
  • Fellow, American College of Neuropsychopharmacology (2015)
  • Distinguished Career Award, International Neuropsychological Society (2014)
  • Bowles Lectureship Award, University of North Carolina (2013)
  • Keller Honorary Lectureship Award, NIAAA (2013)
  • Distinguished Researcher Award, Research Society on Alcoholism (2011)
  • Fellow, American Psychological Association (2008)

Boards, Advisory Committees, Professional Organizations

  • Editorial Advisory Committee Member, Alcohol Research: Current Reviews of NIAAA (2007 - 2019)
  • NIAAA Advisory Council Member, NIAAA of the NIH (2017 - Present)
  • Program Committee Member, Society of Biological Psychiatry (2019 - Present)

Professional Education

  • Ph.D., University of Connecticut, Experimental Psychology (1975)
  • M.A., University of Connecticut, Experimental Psychology (1973)
  • B.A., University of Connecticut, Experimental Psychology (1969)

Research & Scholarship

Current Research and Scholarly Interests

Application of neuroimaging modalities and component process analysis of cognitive, sensory, and motor functions to identify brain structural and functional mechanisms disrupted in diseases affecting the brain: alcoholism, HIV infection, dementia, and normal aging from adolescence through adulthood. Structural and functional MRI, MR spectroscopy, and MR diffusion tensor imaging are applied in animal models of alcoholism in parallel with the human studies. Multi-site research projects examine 1) the development of the adolescent brain and neuropsychological function and how initiation of hazardous drinking and consumption of other drugs of abuse alter the normal trajectory of brain structure and function (National Consortium on Alcohol and NeuroDevelopment in Adolescence:; 2) the effects of high alcohol exposure on brain structure and function in animal models (Integrated Neuroscience Initiative on Alcoholism:; 3) potential interaction of alcoholism and dementia.


2018-19 Courses

Stanford Advisees


All Publications

  • Accelerated aging and motor control deficits are related to regional deformation of central cerebellar white matter in alcohol use disorder. Addiction biology Zhao, Q., Pfefferbaum, A., Podhajsky, S., Pohl, K. M., Sullivan, E. V. 2019


    The World Health Organization estimates a 12-month prevalence rate of 8+% for an alcohol use disorder (AUD) diagnosis in people age 15years and older in the United States and Europe, presenting significant health risks that have the potential of accelerating age-related functional decline. According to neuropathological studies, white matter systems of the cerebellum are vulnerable to chronic alcohol dependence. To pursue the effect of AUD on white matter structure and functions in vivo, this study used T1-weighted, magnetic resonance imaging (MRI) to quantify the total corpus medullare of the cerebellum and a finely grained analysis of its surface in 135 men and women with AUD (mean duration of abstinence, 248d) and 128 age- and sex-matched control participants; subsets of these participants completed motor testing. We identified an AUD-related volume deficit and accelerated aging in the total corpus medullare. Novel deformation-based surface morphometry revealed regional shrinkage of surfaces adjacent to lobules I-V, lobule IX, and vermian lobule X. In addition, accelerated aging was detected in the regional surface areas adjacent to lobules I-V, lobule VI, lobule VIIB, and lobules VIII, IX, and X. Sex differences were not identified for any measure. For both volume-based and surface-based analyses, poorer performance in gait and balance, manual dexterity, and grip strength were linked to greater regional white matter structural deficits. Our results suggest that local deformation of the corpus medullare has the potential of identifying structurally and functionally segregated networks affected in AUD.

    View details for PubMedID 30932270

  • Dissociable Contributions of Precuneus and Cerebellum to Subjective and Objective Neuropathy in HIV. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology Zahr, N. M., Pohl, K. M., Pfefferbaum, A., Sullivan, E. V. 2019


    Neuropathy, typically diagnosed by the presence of either symptoms or signs of peripheral nerve dysfunction, remains a frequently reported complication in the antiretroviral (ART)-treated HIV population. This study was conducted in 109 healthy controls and 57 HIV-infected individuals to investigate CNS regions associated with neuropathy. An index of objective neuropathy was computed based on 4 measures: deep tendon ankle reflex, vibration sense (great toes), position sense (great toes), and 2-point discrimination (feet). Subjective neuropathy (self-report of pain, aching, or burning; pins and needles; or numbness in legs or feet) was also evaluated. Structural MRI data were available for 126/166 cases. The HIV relative to the healthy control group was impaired on all 4 signs of neuropathy. Within the HIV group, an objective neuropathy index of 1 (bilateral impairment on 1 measure) or 2 (bilateral impairment on at least 2/4 measures) was associated with older age and a smaller volume of the cerebellar vermis. Moderate to severe symptoms of neuropathy were associated with more depressive symptoms, reduced quality of life, and a smaller volume of the parietal precuneus. This study is consistent with the recent contention that ART-treated HIV-related neuropathy has a CNS component. Distinguishing subjective symptoms from objective signs of neuropathy allowed for a dissociation between the precuneus, a brain region involved in conscious information processing and the vermis, involved in fine tuning of limb movements. Graphical Abstract In HIV patients, objective signs of neuropathy correlated with smaller cerebellar vermis (red) volumes whereas subjective symptoms of neuropathy were associated with smaller precuneus (blue) volumes.

    View details for PubMedID 30741374

  • Relations between cognitive and motor deficits and regional brain volumes in individuals with alcoholism. Brain structure & function Fama, R., Le Berre, A. P., Sassoon, S. A., Zahr, N. M., Pohl, K. M., Pfefferbaum, A., Sullivan, E. V. 2019


    Despite the common co-occurrence of cognitive impairment and brain structural deficits in alcoholism, demonstration of relations between regional gray matter volumes and cognitive and motor processes have been relatively elusive. In pursuit of identifying brain structural substrates of impairment in alcoholism, we assessed executive functions (EF), episodic memory (MEM), and static postural balance (BAL) and measured regional brain gray matter volumes of cortical, subcortical, and cerebellar structures commonly affected in individuals with alcohol dependence (ALC) compared with healthy controls (CTRL). ALC scored lower than CTRL on all composite scores (EF, MEM, and BAL) and had smaller frontal, cingulate, insular, parietal, and hippocampal volumes. Within the ALC group, poorer EF scores correlated with smaller frontal and temporal volumes; MEM scores correlated with frontal volume; and BAL scores correlated with frontal, caudate, and pontine volumes. Exploratory analyses investigating relations between subregional frontal volumes and composite scores in ALC yielded different patterns of associations, suggesting that different neural substrates underlie these functional deficits. Of note, orbitofrontal volume was a significant predictor of memory scores, accounting for almost 15% of the variance; however, this relation was evident only in ALC with a history of a non-alcohol substance diagnosis and not in ALC without a non-alcohol substance diagnosis. The brain-behavior relations observed provide evidence that the cognitive and motor deficits in alcoholism are likely a result of different neural systems and support the hypothesis that a number of identifiable neural systems rather than a common or diffuse neural pathway underlies cognitive and motor deficits observed in chronic alcoholism.

    View details for DOI 10.1007/s00429-019-01894-w

    View details for PubMedID 31161472

  • Convergence of three parcellation approaches demonstrating cerebellar lobule volume deficits in Alcohol Use Disorder. NeuroImage. Clinical Sullivan, E. V., Zahr, N. M., Saranathan, M., Pohl, K. M., Pfefferbaum, A. 2019; 24: 101974


    Recent advances in robust and reliable methods of MRI-derived cerebellar lobule parcellation volumetry present the opportunity to assess effects of Alcohol Use Disorder (AUD) on selective cerebellar lobules and relations with indices of nutrition and motor functions. In pursuit of this opportunity, we analyzed high-resolution MRI data acquired in 24 individuals with AUD and 20 age- and sex-matched controls with a 32-channel head coil using three different atlases: the online automated analysis pipeline volBrain Ceres, SUIT, and the Johns Hopkins atlas. Participants had also completed gait and balance examination and hematological analysis of nutritional and liver status, enabling testing of functional meaningfulness of each cerebellar parcellation scheme. Compared with controls, each quantification approach yielded similar patterns of group differences in regional volumes: All three approaches identified AUD-related deficits in total tissue and total gray matter, but only Ceres identified a total white matter volume deficit. Convergent volume differences occurred in lobules I-V, Crus I, VIIIB, and IX. Coefficients of variation (CVs) were <20% for 46 of 56 regions measured and in general were graded: Ceres

    View details for DOI 10.1016/j.nicl.2019.101974

    View details for PubMedID 31419768

  • Accelerated and Premature Aging Characterizing Regional Cortical Volume Loss in Human Immunodeficiency Virus Infection: Contributions From Alcohol, Substance Use, and Hepatitis C Coinfection. Biological psychiatry. Cognitive neuroscience and neuroimaging Pfefferbaum, A., Zahr, N. M., Sassoon, S. A., Kwon, D., Pohl, K. M., Sullivan, E. V. 2018


    BACKGROUND: Life expectancy of successfully treated human immunodeficiency virus (HIV)-infected individuals is approaching normal longevity. The growing HIV population ≥50 years of age is now at risk of developing HIV-associated neurocognitive disorder, acquiring coinfection with the hepatitis C virus (HCV), and engaging in hazardous drinking or drug consumption that can adversely affect trajectories of the healthy aging of brain structures.METHODS: This cross-sectional/longitudinal study quantified regional brain volumes from 1101 magnetic resonance imaging scans collected over 14 years in 549 participants (25 to 75 years of age): 68 HIV-infected individuals without alcohol dependence, 60 HIV-infected individuals with alcohol dependence, 222 alcohol-dependent individuals, and 199 control subjects. We tested 1) whether localized brain regions in HIV-infected individuals exhibited accelerated aging, or alternatively, nonaccelerated premature aging deficits; and 2) the extent to which alcohol or substance dependence or HCV coinfection altered brain aging trajectories.RESULTS: The HIV-infected cohort exhibited steeper declining volume trajectories than control subjects, consistently in the frontal cortex. Nonaccelerated volume deficits occurred in the temporal, parietal, insular, and cingulate regions of all three diagnostic groups. Alcohol and drug dependence comorbidities and HCV coinfection exacerbated HIV-related volume deficits. Accelerated age interactions in frontal and posterior parietal volumes endured in HIV-infected individuals free of alcohol or substance dependence and HCV infection comorbidities. Functionally, poorer HIV-associated neurocognitive disorder scores and Veterans Aging Cohort Study indices correlated with smaller regional brain volumes in the HIV-infected individuals without alcohol dependence and alcohol-dependent groups.CONCLUSIONS: HIV infection itself may confer a heightened risk of accelerated brain aging, potentially exacerbated by HCV coinfection and substance dependency. Confirmation would require a prospective study with a preinfection baseline.

    View details for PubMedID 30093343

  • Liability of Youthful Alcohol Misuse. Biological psychiatry. Cognitive neuroscience and neuroimaging Sullivan, E. V. 2018; 3 (7): 575–76

    View details for PubMedID 30047474

  • The Role of Aging, Drug Dependence, and Hepatitis C Comorbidity in Alcoholism Cortical Compromise JAMA PSYCHIATRY Sullivan, E. V., Zahr, N. M., Sassoon, S. A., Thompson, W. K., Kwon, D., Pohl, K. M., Pfefferbaum, A. 2018; 75 (5): 474–83


    The prevalence of alcohol misuse increased substantially over a decade in adults, particularly in those aged 65 years or older. Ramifications for brain structural integrity are significant, especially in older adults.To combine cross-sectional, longitudinal data to test age-alcoholism interactions and examine the association between prevalent comorbidities (drug dependence and hepatitis C virus [HCV] infection) and cortical volume deficits in alcohol dependence.During 14 years, 826 structural magnetic resonance images were acquired in 222 individuals with alcohol dependence and 199 age-matched control participants (aged 25-75 years at initial study), parcellated with a common atlas, and adjusted for brain volume. Longitudinal data were available on 116 participants with alcoholism and 96 control participants. DSM-IV criteria determined alcohol and drug diagnoses; serology testing determined HCV status. The study was conducted at SRI International and Stanford University School of Medicine from April 11, 2003, to March 3, 2017.Magnetic resonance imaging-derived regional cortical volumes corrected for supratentorial volume and sex.Of the 222 participants with alcoholism, 156 (70.3%) were men; mean (SD) age was 48.0 (10.0) years; the mean age for the 199 control participants was 47.6 (14.0) years. Participants with alcohol dependence had volume deficits in frontal (t = -5.732, P < .001), temporal (t = -3.151, P = .002), parietal (t = -5.063, P < .001), cingulate (t = -3.170, P = .002), and insular (t = -4.920, P < .001) cortices; deficits were prominent in frontal subregions and were not sex dependent. Accelerated aging occurred in frontal cortex (t = -3.019, P < .02) and precentral (t = -2.691, P < .05) and superior gyri (t = -2.763, P < .05) and could not be attributed to the amount of alcohol consumed, which was greater in younger-onset than older-onset participants with alcoholism (t = 6.1191, P < .001). Given the high drug-dependence incidence (54.5%) in the alcoholism group, analysis examined drug subgroups (cocaine, cannabis, amphetamines, opiates) compared with drug-dependence-free alcoholism and control groups. Although the alcohol plus cocaine (t = -2.310, P = .04) and alcohol plus opiate (t = -2.424, P = .04) groups had smaller frontal volumes than the drug-dependence-free alcoholism group, deficits in precentral (t = -2.575, P = .01), supplementary motor (t = -2.532, P = .01), and medial (t = -2.800, P = .01) volumes endured in drug-dependence-free participants with alcoholism compared with control participants. Those with HCV infection had greater deficits than those without HCV infection in frontal (t = 3.468, P = .01), precentral (t = 2.513, P = .03), superior (t = 2.533, P = .03), and orbital (t = 2.506, P = .03) volumes, yet total frontal (t = 2.660, P = .02), insular (t = 3.526, P = .003), parietal (t = 2.414, P = .03), temporal (t = 3.221, P = .005), and precentral (t = 3.180, P = .01) volume deficits persisted in the uninfected participants with alcoholism compared with control participants with known HCV status.Drug dependence and HCV infection compounded deleterious effects of alcohol dependence on frontal cortical volumes but could not account for the frontally distributed volume deficits in the drug-free participants with alcoholism. We speculate that age-alcohol interactions notable in frontal cortex put older adults at heightened risk for age-associated neurocompromise even if alcohol misuse is initiated later in life.

    View details for PubMedID 29541774

    View details for PubMedCentralID PMC5875381

  • Altered Brain Developmental Trajectories in Adolescents After Initiating Drinking. The American journal of psychiatry Pfefferbaum, A., Kwon, D., Brumback, T., Thompson, W. K., Cummins, K., Tapert, S. F., Brown, S. A., Colrain, I. M., Baker, F. C., Prouty, D., De Bellis, M. D., Clark, D. B., Nagel, B. J., Chu, W., Park, S. H., Pohl, K. M., Sullivan, E. V. 2018; 175 (4): 370–80


    OBJECTIVE: The authors sought evidence for altered adolescent brain growth trajectory associated with moderate and heavy alcohol use in a large national, multisite, prospective study of adolescents before and after initiation of appreciable alcohol use.METHOD: This study examined 483 adolescents (ages 12-21) before initiation of drinking and 1 and 2 years later. At the 2-year assessment, 356 participants continued to meet the study's no/low alcohol consumption entry criteria, 65 had initiated moderate drinking, and 62 had initiated heavy drinking. MRI was used to quantify regional cortical and white matter volumes. Percent change per year (slopes) in adolescents who continued to meet no/low criteria served as developmental control trajectories against which to compare those who initiated moderate or heavy drinking.RESULTS: In no/low drinkers, gray matter volume declined throughout adolescence and slowed in many regions in later adolescence. Complementing gray matter declines, white matter regions grew at faster rates at younger ages and slowed toward young adulthood. Youths who initiated heavy drinking exhibited an accelerated frontal cortical gray matter trajectory, divergent from the norm. Although significant effects on trajectories were not observed in moderate drinkers, their intermediate position between no/low and heavy drinkers suggests a dose effect. Neither marijuana co-use nor baseline volumes contributed significantly to the alcohol effect.CONCLUSIONS: Initiation of drinking during adolescence, with or without marijuana co-use, disordered normal brain growth trajectories. Factors possibly contributing to abnormal cortical volume trajectories include peak consumption in the past year and family history of alcoholism.

    View details for PubMedID 29084454

  • Contributions to Understanding the Neuropsychology of Alcoholism: An INS Legacy JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Sullivan, E. V. 2017; 23 (9-10): 843–59
  • Deviant functional activation and connectivity of the right insula are associated with lack of awareness of episodic memory impairment in nonamnesic alcoholism CORTEX Le Berre, A., Mueller-Oehring, E. M., Schulte, T., Serventi, M. R., Pfefferbaum, A., Sullivan, E. V. 2017; 95: 15–28


    A disorder of metamemory, expressed as unawareness of mnemonic ability, is typically associated with the profound amnesia of Korsakoff's Syndrome (KS). A similar but less severe type of limited awareness can also occur in non-KS alcoholism and is observed as an impairment in generating Feeling-of-Knowing (FOK) predictions about future recognition performance. We previously found that FOK accuracy was selectively related to volumes of the insula in alcoholics involved in the present study. Unknown, however, are the neural substrates of unawareness of memory impairment in alcoholism. A task-activated fMRI paradigm served to identify neural nodes and networks implicated in inaccurate self-estimation of mnemonic ability in sober alcoholics while they made prospective FOK judgments in an episodic memory paradigm. Lower activation in the right insula correlated with greater overestimations of future memory abilities in alcoholics. Weaker connectivity of the right insula with the left dorsal anterior cingulate cortex, a node of the salience network, and stronger connectivity of the right insula with the right ventromedial prefrontal cortex (vmPFC), a node of the default mode network (DMN), co-occurred in alcoholics relative to the controls. Specifically, alcoholics, who failed to desynchronize insula-vmPFC activity, had greater overestimation of their memory predictions and poorer recognition performance. This study provides novel support that deviant functional activation and connectivity involving the right insula, a hub of the salience network, appears to participate in disrupting metamemory functioning in alcoholics. Compromised FOK performance might result from disturbance of the switching mechanism between brain networks serving self-referential processes (i.e., DMN network) and networks serving externally-driven activities like memory monitoring (i.e., fronto-parietal network). Thus, compromise in insular network coupling could be a neural mechanism underlying anosognosia for subtle mnemonic impairment in nonamnesic alcoholism.

    View details for PubMedID 28806707

    View details for PubMedCentralID PMC5626611

  • Perspectives on fronto-fugal circuitry from human imaging of alcohol use disorders. Neuropharmacology Zahr, N. M., Pfefferbaum, A., Sullivan, E. V. 2017


    Descriptions of the cognitive functions affected by alcohol use disorders (AUD) often highlight dysfunction of executive processes such attention, inhibitory control, working memory, and cognitive flexibility. Such complex cognitive functions have historically been ascribed to the prefrontal cortex. AUD, however, disrupts extensive areas of the brain. Structural and functional MRI studies suggest a central role for degradation of circuitry originating in the prefrontal cortex including nodes in widespread brain regions. This review features fronto-fugal circuits affected by AUD including frontocerebellar, frontolimbic, and frontostriatal networks and their relations to the salient, enduring, and debilitating cognitive and motor deficits reported in AUD.

    View details for DOI 10.1016/j.neuropharm.2017.01.018

    View details for PubMedID 28118989

  • CNS Correlates of "Objective" Neuropathy in Alcohol Use Disorder. Alcoholism, clinical and experimental research Zahr, N. M., Pohl, K. M., Pfefferbaum, A., Sullivan, E. V. 2019


    BACKGROUND: Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to HIV or diabetes-related neuropathies, neuropathy associated with Alcohol Use Disorders (AUD) is understudied. In both the diabetes and HIV literature, emerging evidence supports a CNS component to peripheral neuropathy.METHODS: In seeking a central substrate for AUD-related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, ages 21-74) and 99 healthy controls (41 women, ages 21-77) and explored subjective symptoms (self-report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2-point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD-related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., gamma-glutamyl-transferase) were evaluated.RESULTS: The AUD group described more subjective symptoms of neuropathy and were more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD-related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: of these, age and volume of frontal precentral cortex were the most robust predictors.CONCLUSIONS: This study supports CNS involvement in objective signs of neuropathy in AUD. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/acer.14162

    View details for PubMedID 31386216

  • Sleep spindle characteristics in adolescents CLINICAL NEUROPHYSIOLOGY Goldstone, A., Willoughby, A. R., de Zambotti, M., Clark, D. B., Sullivan, E., Hasler, B. P., Franzen, P. L., Prouty, D. E., Colrain, I. M., Baker, F. C. 2019; 130 (6): 893–902
  • Thalamic Substructures in HIV: Volume Deficits and Correlates Zahr, N., Saranathan, M., Pohl, K., Sullivan, E. SPRINGER. 2019: 364–65
  • CNS CORRELATES OF OBJECTIVE NEUROPATHY IN ALCOHOL USE DISORDER (AUD) Zahr, N. M., Pohl, K. M., Sullivan, E. V., Pfefferbaum, A. WILEY. 2019: 102A
  • Prospective Study of Adolescents Reveals Disturbed Trajectories of Frontal Cortical and Cerebellar Volumes Following Initiation of Drinking Pfefferbaum, A., Sullivan, E. ELSEVIER SCIENCE INC. 2019: S12
  • Cognitive and Motor Impairment Severity Related to Signs of Subclinical Wernicke's Encephalopathy in HIV Infection. Journal of acquired immune deficiency syndromes (1999) Le Berre, A., Fama, R., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V., Zahr, N. M. 2019


    BACKGROUND: Wernicke's encephalopathy (WE) is a neurological condition resulting from thiamine deficiency. Although commonly associated with alcoholism, non-alcoholic WE has been described in individuals with Human Immunodeficiency Virus (HIV) infection, but subclinical WE may be underdiagnosed. The current study questioned whether presence of subclinical WE signs underlies cognitive and motor deficits in HIV individuals as observed in alcoholism.SETTING: 56 HIV positive individuals (HIV+) and 53 HIV negative controls (HIV-) were assessed on 6 cognitive and motor domains: attention/working memory, production, immediate and delayed episodic memory, visuospatial abilities, and upper limb motor function.METHODS: Based on a rating scheme by Caine et al, HIV+ individuals were categorized by subclinical WE risk factors (dietary deficiency, oculomotor abnormality, cerebellar dysfunction, and altered mental state). Performance was expressed as age- and education-corrected Z-scores standardized on controls.RESULTS: Sorting by Caine criteria yielded 20 HIV+ as Caine 0 (i.e., meeting no criteria), 22 as Caine 1 (i.e., meeting one criterion), and 14 as Caine 2 (i.e., meeting two criteria). Comparison among HIV+ Caine subgroups revealed a graded effect: Caine 0 performed at control levels, Caine 1 showed mild to moderate deficits on some domains, and Caine 2 showed the most severe deficits on each domain.CONCLUSION: This graded severity pattern of performance among Caine subgroups suggests that signs of subclinical WE can partly explain the heterogeneity in HIV-related cognitive and motor impairment. This study highlights the utility of Caine criteria in identifying potential causes of HIV-related neurocognitive disorders and has implications for disease management.

    View details for PubMedID 30958387

  • Effects of age, sex, and puberty on neural efficiency of cognitive and motor control in adolescents. Brain imaging and behavior Schulte, T., Hong, J., Sullivan, E. V., Pfefferbaum, A., Baker, F. C., Chu, W., Prouty, D., Kwon, D., Meloy, M. J., Brumback, T., Tapert, S. F., Colrain, I. M., Muller-Oehring, E. M. 2019


    Critical changes in adolescence involve brain cognitive maturation of inhibitory control processes that are essential for a myriad of adult functions. Cognitive control advances into adulthood as there is more flexible integration of component processes, including inhibitory control of conflicting information, overwriting inappropriate response tendencies, and amplifying relevant responses for accurate execution. Using a modified Stroop task with fMRI, we investigated the effects of age, sex, and puberty on brain functional correlates of cognitive and motor control in 87 boys and 91 girls across the adolescent age range. Results revealed dissociable brain systems for cognitive and motor control processes, whereby adolescents flexibly adapted neural responses to control demands. Specifically, when response repetitions facilitated planning-based action selection, frontoparietal-insular regions associated with cognitive control operations were less activated, whereas cortical-pallidal-cerebellar motor regions associated with motor skill acquisition, were more activated. Attenuated middle cingulate cortex activation occurred with older adolescent age for both motor control and cognitive control with automaticity from repetition learning. Sexual dimorphism for control operations occurred in extrastriate cortices involved in visuo-attentional selection: While boys enhanced extrastriate selection processes for motor control, girls activated these regions more for cognitive control. These sex differences were attenuated with more advanced pubertal stage. Together, our findings show that brain cognitive and motor control processes are segregated, demand-specific, more efficient in older adolescents, and differ between sexes relative to pubertal development. Our findings advance our understanding of how distributed brain activity and the neurodevelopment of automaticity enhances cognitive and motor control ability in adolescence.

    View details for PubMedID 30903550

  • Sleep spindle characteristics in adolescents. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Goldstone, A., Willoughby, A. R., de Zambotti, M., Clark, D. B., Sullivan, E. V., Hasler, B. P., Franzen, P. L., Prouty, D. E., Colrain, I. M., Baker, F. C. 2019; 130 (6): 893–902


    OBJECTIVE: Sleep changes substantially during adolescence; however, our understanding of age-related differences in specific electroencephalographic waveforms during this developmental period is limited.METHOD: Sigma power, spindle characteristics and cognitive data were calculated for fast (13 Hz) central and slow (11 Hz) frontal sleep spindles for a large cross-sectional sample of adolescents (N = 134, aged 12-21 years, from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study).RESULTS: Older age (and advanced pubertal development) was associated with lower absolute sigma power and greater fast spindle density, with spindles having a shorter duration and smaller amplitude and occurring at a faster average frequency than at a younger age. Spindle characteristics were not directly associated with cognition. An indirect relationship (age * density) provided some evidence for an association between better episodic memory performance and greater spindle density only for younger adolescents.CONCLUSION: Spindle characteristics in adolescents differed according to age, possibly reflecting underlying differences in thalamo-cortical connectivity, and may play a role in episodic memory early in adolescence.SIGNIFICANCE: Sleep spindles may serve as a marker of adolescent development, likely reflecting brain maturational status. Investigating specific spindle characteristics, in addition to sigma power, is necessary to fully characterize spindles during adolescence.

    View details for PubMedID 30981174

  • Hippocampal subfield CA2+3 exhibits accelerated aging in Alcohol Use Disorder: A preliminary study. NeuroImage. Clinical Zahr, N. M., Pohl, K. M., Saranathan, M., Sullivan, E. V., Pfefferbaum, A. 2019; 22: 101764


    The profile of brain structural dysmorphology of individuals with Alcohol Use Disorders (AUD) involves disruption of the limbic system. In vivo imaging studies report hippocampal volume loss in AUD relative to controls, but only recently has it been possible to articulate different regions of this complex structure. Volumetric analysis of hippocampal regions rather than total hippocampal volume may augment differentiation of disease processes. For example, damage to hippocampal subfield cornu ammonis 1 (CA1) is often reported in Alzheimer's disease (AD), whereas deficits in CA4/dentate gyrus are described in response to stress and trauma. Two previous studies explored the effects of chronic alcohol use on hippocampal subfields: one reported smaller volume of the CA2+3 in alcohol-dependent subjects relative to controls, associated with years of alcohol consumption; the other, smaller volumes of presubiculum, subiculum, and fimbria in alcohol-dependent relative to control men. The current study, conducted in 24 adults with DSM5-diagnosed AUD (7 women, 53.7 ± 8.8) and 20 controls (7 women, 54.1 ± 9.3), is the first to use FreeSurfer 6.0, which provides state-of-the art hippocampal parcellation, to explore the sensitivity of hippocampal sufields to alcoholism. T1- and T2- images were collected on a GE MR750 system with a 32-channel Nova head coil. FreeSurfer 6.0 hippocampal subfield analysis produced 12 subfields: parasubiculum; presubiculum; subiculum; CA1; CA2+3; CA4; GC-ML-DG (Granule Cell (GC) and Molecular Layer (ML) of the Dentate Gyrus (DG)); molecular layer; hippocampus-amygdala-transition-area (HATA); fimbria; hippocampal tail; hippocampal fissure; and whole volume for left and right hippocampi. A comprehensive battery of neuropsychological tests comprising attention, memory and learning, visuospatial abilities, and executive functions was administered. Multiple regression analyses of raw volumetric data for each subfields by group, age, sex, hemisphere, and supratentorial volume (svol) showed significant effects of svol (p < .04) on nearly all structures (excluding tail and fissure). Volumes corrected for svol showed effects of age (fimbria, fissure) and group (subiculum, CA1, CA4, GC-ML-DG, HATA, fimbria); CA2+3 showed a diagnosis-by-age interaction indicating older AUD individuals had a smaller volume than would be expected for their age. There were no selective relations between hippocampal subfields and performance on neuropsychological tests, likely due to lack of statistical power. The current results concur with the previous study identifying CA2+3 as sensitive to alcoholism, extend them by identifying an alcoholism-age interaction, and suggest an imaging phenotype distinguishing AUD from AD and stress/trauma.

    View details for PubMedID 30904825

  • Novel Machine Learning Identifies Brain Patterns Distinguishing Diagnostic Membership of Human Immunodeficiency Virus, Alcoholism, and Their Comorbidity of Individuals. Biological psychiatry. Cognitive neuroscience and neuroimaging Adeli, E., Zahr, N. M., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M. 2019


    The incidence of alcohol use disorder (AUD) in human immunodeficiency virus (HIV) infection is twice that of the rest of the population. This study documents complex radiologically identified, neuroanatomical effects of AUD+HIV comorbidity by identifying structural brain systems that predicted diagnosis on an individual basis. Applying novel machine learning analysis to 549 participants (199 control subjects, 222 with AUD, 68 with HIV, 60 with AUD+HIV), 298 magnetic resonance imaging brain measurements were automatically reduced to small subsets per group. Significance of each diagnostic pattern was inferred from its accuracy in predicting diagnosis and performance on six cognitive measures. While all three diagnostic patterns predicted the learning and memory score, the AUD+HIV pattern was the largest and had the highest predication accuracy (78.1%). Providing a roadmap for analyzing large, multimodal datasets, the machine learning analysis revealed imaging phenotypes that predicted diagnostic membership of magnetic resonance imaging scans of individuals with AUD, HIV, and their comorbidity.

    View details for DOI 10.1016/j.bpsc.2019.02.003

    View details for PubMedID 30982583

  • Longitudinally consistent estimates of intrinsic functional networks Human Brain Mapping Zhao, Q., Kwon, D., Müller-Oehring, E. M., Le Berre, A., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M. 2019

    View details for DOI 10.1002/hbm.24541

  • Longitudinally consistent estimates of intrinsic functional networks. Human brain mapping Zhao, Q., Kwon, D., Müller-Oehring, E. M., Le Berre, A. P., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M. 2019


    Increasing numbers of neuroimaging studies are acquiring data to examine changes in brain architecture by investigating intrinsic functional networks (IFN) from longitudinal resting-state functional MRI (rs-fMRI). At the subject level, these IFNs are determined by cross-sectional procedures, which neglect intra-subject dependencies and result in suboptimal estimates of the networks. Here, a novel longitudinal approach simultaneously extracts subject-specific IFNs across multiple visits by explicitly modeling functional brain development as an essential context for seeking change. On data generated by an innovative simulation based on real rs-fMRI, the method was more accurate in estimating subject-specific IFNs than cross-sectional approaches. Furthermore, only group-analysis based on longitudinally consistent estimates identified significant developmental effects within IFNs of 246 adolescents from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. The findings were confirmed by the cross-sectional estimates when the corresponding group analysis was confined to the developmental effects. Those effects also converged with current concepts of neurodevelopment.

    View details for PubMedID 30806009

  • Hippocampal subfield CA2+3 exhibits accelerated aging in Alcohol Use Disorder: A preliminary study NEUROIMAGE-CLINICAL Zahr, N. M., Pohl, K. M., Saranathan, M., Sullivan, E., Pfefferbaum, A. 2019; 22
  • Jacobian Maps Reveal Under-reported Brain Regions Sensitive to Extreme Binge Ethanol Intoxication in the Rat FRONTIERS IN NEUROANATOMY Zhao, Q., Fritz, M., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M., Zahr, N. M. 2018; 12
  • Ting-Kai Li: In Memoriam. Alcoholism, clinical and experimental research Hesselbrock, V., Hesselbrock, M., Pfefferbaum, A., Sullivan, E., Edenberg, H. 2018


    Ting-Kai (T-K) Li, MD died on November 18, 2018, just five days after his 84th birthday. T-K had a wonderful and distinguished academic and public service career, spanning almost five decades. Born in Nanjing, China, T-K fled with his family to South Africa during World War II, while a young boy. He initially enrolled in the University of the Witwatersrand but eventually made his way to Chicago where he obtained his undergraduate degree at Northwestern University prior to attending Harvard Medical School. T-K completed his residency in internal medicine at Peter Bent Brigham Hospital in Boston, where he was named chief medical resident in 1965. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/acer.13937

    View details for PubMedID 30536930

  • Chained regularization for identifying brain patterns specific to HIV infection NEUROIMAGE Adeli, E., Kwon, D., Zhao, Q., Pfefferbaum, A., Zahr, N. M., Sullivan, E. V., Pohl, K. M. 2018; 183: 425–37
  • Distribution of brain iron accrual in adolescence: Evidence from cross-sectional and longitudinal analysis. Human brain mapping Peterson, E. T., Kwon, D., Luna, B., Larsen, B., Prouty, D., De Bellis, M. D., Voyvodic, J., Liu, C., Li, W., Pohl, K. M., Sullivan, E. V., Pfefferbaum, A. 2018


    To track iron accumulation and location in the brain across adolescence, we repurposed diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data acquired in 513 adolescents and validated iron estimates with quantitative susceptibility mapping (QSM) in 104 of these subjects. DTI and fMRI data were acquired longitudinally over 1year in 245 male and 268 female, no-to-low alcohol-consuming adolescents (12-21 years at baseline) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Brain region average signal values were calculated for susceptibility to nonheme iron deposition: pallidum, putamen, dentate nucleus, red nucleus, and substantia nigra. To estimate nonheme iron, the corpus callosum signal (robust to iron effects) was divided by regional signals to generate estimated R2 (edwR2 for DTI) and R2 * (eR2 * for fMRI). Longitudinal iron deposition was measured using the normalized signal change across time for each subject. Validation using baseline QSM, derived from susceptibility-weighted imaging, was performed on 46 male and 58 female participants. Normalized iron deposition estimates from DTI and fMRI correlated with age in most regions; both estimates indicated less iron in boys than girls. QSM results correlated highly with DTI and fMRI results (adjusted R2 = 0.643 for DTI, 0.578 for fMRI). Cross-sectional and longitudinal analyses indicated an initial rapid increase in iron, notably in the putamen and red nucleus, that slowed with age. DTI and fMRI data can be repurposed for identifying regional brain iron deposition in developing adolescents as validated with high correspondence with QSM.

    View details for PubMedID 30496644

  • Regional growth trajectories of cortical myelination in adolescents and young adults: longitudinal validation and functional correlates. Brain imaging and behavior Kwon, D., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M. 2018


    Adolescence is a time of continued cognitive and emotional evolution occurring with continuing brain development involving synaptic pruning and cortical myelination. The hypothesis of this study is that heavy myelination occurs in cortical regions with relatively direct, predetermined circuitry supporting unimodal sensory or motor functions and shows a steep developmental slope during adolescence (12-21years) until young adulthood (22-35years) when further myelination decelerates. By contrast, light myelination occurs in regions with highly plastic circuitry supporting complex functions and follows a delayed developmental trajectory. In support of this hypothesis, cortical myelin content was estimated and harmonized across publicly available datasets provided by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) and the Human Connectome Project (HCP). The cross-sectional analysis of 226 no-to-low alcohol drinking NCANDA adolescents revealed relatively steeper age-dependent trajectories of myelin growth in unimodal primary motor cortex and flatter age-dependent trajectories in multimodal mid/posterior cingulate cortices. This pattern of continued myelination showed smaller gains when the same analyses were performed on 686 young adults of the HCP cohort free of neuropsychiatric diagnoses. Critically, a predicted correlation between a motor task and myelin content in motor or cingulate cortices was found in the NCANDA adolescents, supporting the functional relevance of this imaging neurometric. Furthermore, the regional trajectory slopes were confirmed by performing longitudinally consistent analysis of cortical myelin. In conclusion, coordination of myelin content and circuit complexity continues to develop throughout adolescence, contributes to performance maturation, and may represent active cortical development climaxing in young adulthood.

    View details for PubMedID 30406353

  • Chained regularization for identifying brain patterns specific to HIV infection. NeuroImage Adeli, E., Kwon, D., Zhao, Q., Pfefferbaum, A., Zahr, N. M., Sullivan, E. V., Pohl, K. M. 2018


    Human Immunodeficiency Virus (HIV) infection continues to have major adverse public health and clinical consequences despite the effectiveness of combination Antiretroviral Therapy (cART) in reducing HIV viral load and improving immune function. As successfully treated individuals with HIV infection age, their cognition declines faster than reported for normal aging. This phenomenon underlines the importance of improving long-term care, which requires better understanding of the impact of HIV on the brain. In this paper, automated identification of patients and brain regions affected by HIV infection are modeled as a classification problem, whose solution is determined in two steps within our proposed Chained-Regularization framework. The first step focuses on selecting the HIV pattern (i.e., the most informative constellation of brain region measurements for distinguishing HIV infected subjects from healthy controls) by constraining the search for the optimal parameter setting of the classifier via group sparsity (ℓ2,1-norm). The second step improves classification accuracy by constraining the parameterization with respect to the selected measurements and the Euclidean regularization (ℓ2-norm). When applied to the cortical and subcortical structural Magnetic Resonance Images (MRI) measurements of 65 controls and 65 HIV infected individuals, this approach is more accurate in distinguishing the two cohorts than more common models. Finally, the brain regions of the identified HIV pattern concur with the HIV literature that uses traditional group analysis models.

    View details for PubMedID 30138676

  • Alcohol use effects on adolescent brain development revealed by simultaneously removing confounding factors, identifying morphometric patterns, and classifying individuals SCIENTIFIC REPORTS Park, S., Zhang, Y., Kwon, D., Zhao, Q., Zahr, N. M., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M. 2018; 8: 8297


    Group analysis of brain magnetic resonance imaging (MRI) metrics frequently employs generalized additive models (GAM) to remove contributions of confounding factors before identifying cohort specific characteristics. For example, the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) used such an approach to identify effects of alcohol misuse on the developing brain. Here, we hypothesized that considering confounding factors before group analysis removes information relevant for distinguishing adolescents with drinking history from those without. To test this hypothesis, we introduce a machine-learning model that identifies cohort-specific, neuromorphometric patterns by simultaneously training a GAM and generic classifier on macrostructural MRI and microstructural diffusion tensor imaging (DTI) metrics and compare it to more traditional group analysis and machine-learning approaches. Using a baseline NCANDA MR dataset (N = 705), the proposed machine learning approach identified a pattern of eight brain regions unique to adolescents who misuse alcohol. Classifying high-drinking adolescents was more accurate with that pattern than using regions identified with alternative approaches. The findings of the joint model approach thus were (1) impartial to confounding factors; (2) relevant to drinking behaviors; and (3) in concurrence with the alcohol literature.

    View details for PubMedID 29844507

  • AGE-RELATED DIFFERENCES IN SLEEP SPINDLES AND THEIR ASSOCIATION WITH EPISODIC MEMORY IN ADOLESCENTS. Goldstone, A., Willoughby, A. R., de Zambotti, M., Franzen, P. L., Sullivan, E., Kardos, L. M., Claudatos, S. A., Rosas, L., Alschuler, V. R., Lim, Y., Gil, M., Hasler, B. P., Clark, D. B., Colrain, I. M., Baker, F. C. OXFORD UNIV PRESS INC. 2018: A99–A100
  • The mediating role of cortical thickness and gray matter volume on sleep slow-wave activity during adolescence BRAIN STRUCTURE & FUNCTION Goldstone, A., Willoughby, A. R., de Zambotti, M., Franzen, P. L., Kwon, D., Pohl, K. M., Pfefferbaum, A., Sullivan, E. V., Muller-Oehring, E. M., Prouty, D. E., Hasler, B. P., Clark, D. B., Colrain, I. M., Baker, F. C. 2018; 223 (2): 669–85


    During the course of adolescence, reductions occur in cortical thickness and gray matter (GM) volume, along with a 65% reduction in slow-wave (delta) activity during sleep (SWA) but empirical data linking these structural brain and functional sleep differences, is lacking. Here, we investigated specifically whether age-related differences in cortical thickness and GM volume and cortical thickness accounted for the typical age-related difference in slow-wave (delta) activity (SWA) during sleep. 132 healthy participants (age 12-21 years) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study were included in this cross-sectional analysis of baseline polysomnographic, electroencephalographic, and magnetic resonance imaging data. By applying mediation models, we identified a large, direct effect of age on SWA in adolescents, which explained 45% of the variance in ultra-SWA (0.3-1 Hz) and 52% of the variance in delta-SWA (1 to <4 Hz), where SWA was lower in older adolescents, as has been reported previously. In addition, we provide evidence that the structure of several, predominantly frontal, and parietal brain regions, partially mediated this direct age effect, models including measures of brain structure explained an additional 3-9% of the variance in ultra-SWA and 4-5% of the variance in delta-SWA, with no differences between sexes. Replacing age with pubertal status in models produced similar results. As reductions in GM volume and cortical thickness likely indicate synaptic pruning and myelination, these results suggest that diminished SWA in older, more mature adolescents may largely be driven by such processes within a number of frontal and parietal brain regions.

    View details for PubMedID 28913599

    View details for PubMedCentralID PMC5828920

  • Aberrant blood-oxygen-level-dependent signal oscillations across frequency bands characterize the alcoholic brain ADDICTION BIOLOGY Hong, J., Mueller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V., Kwon, D., Schulte, T. 2018; 23 (2): 824–35


    Chronic alcoholism is associated with widespread regional differences from controls in brain activity and connectivity dynamics measured by blood-oxygen-level-dependent (BOLD) signals. Identification of alcoholism-related neurofunctional power dynamics using functional magnetic resonance imaging (fMRI) that relate to cognition and behavior may serve as biomarkers of alcoholism. Previously, resting-state fMRI studies examined BOLD signals at a single low-frequency (LF) bandwidth. BOLD signals, however, oscillate systematically at different frequencies and are organized in a resting brain where LF oscillation facilitates long-distance communication between regions across cortical regions, whereas high-frequency (HF) oscillation occurs in closely localized, subcortical areas. Using a frequency power quantification approach, we investigated whether the organization of BOLD signal oscillations across all measured frequency bandwidths is altered in alcoholism and relates to cognitive performance. Frequency-dependent oscillation power differences between 56 sober alcoholics and 56 healthy controls occurred for all frequency bands. Alcoholics exhibited greater frequency oscillation power in the orbitofrontal cortex and less power in the posterior insula within the HF bandwidth than controls. Aberrant orbitofrontal HF power was associated with poorer memory performance and slower psychomotor speed in alcoholics. Middle-frequency and LF power proved sensitive in detecting altered frequency oscillation dynamics in parietal and postcentral cortical regions of alcoholics. This study is novel in identifying alcohol-related differences in BOLD oscillation power of the full fMRI frequency bandwidth. Specifically, HF power aberrations were associated with poorer cognitive functioning in alcoholism and may serve as a biomarker for identifying neural targets for repair.

    View details for PubMedID 28699704

  • Jacobian Maps Reveal Under-reported Brain Regions Sensitive to Extreme Binge Ethanol Intoxication in the Rat. Frontiers in neuroanatomy Zhao, Q., Fritz, M., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M., Zahr, N. M. 2018; 12: 108


    Individuals aged 12-20 years drink 11% of all alcohol consumed in the United States with more than 90% consumed in the form of binge drinking. Early onset alcohol use is a strong predictor of future alcohol dependence. The study of the effects of excessive alcohol use on the human brain is hampered by limited information regarding the quantity and frequency of exposure to alcohol. Animal models can control for age at alcohol exposure onset and enable isolation of neural substrates of exposure to different patterns and quantities of ethanol (EtOH). As with humans, a frequently used binge exposure model is thought to produce dependence and affect predominantly corticolimbic brain regions. in vivo neuroimaging enables animals models to be examined longitudinally, allowing for each animal to serve as its own control. Accordingly, we conducted 3 magnetic resonance imaging (MRI) sessions (baseline, binge, recovery) to track structure throughout the brains of wild type Wistar rats to test the hypothesis that binge EtOH exposure affects specific brain regions in addition to corticolimbic circuitry. Voxel-based comparisons of 13 EtOH- vs. 12 water- exposed animals identified significant thalamic shrinkage and lateral ventricular enlargement as occurring with EtOH exposure, but recovering with a week of abstinence. By contrast, pretectal nuclei and superior and inferior colliculi shrank in response to binge EtOH treatment but did not recover with abstinence. These results identify brainstem structures that have been relatively underreported but are relevant for localizing neurocircuitry relevant to the dynamic course of alcoholism.

    View details for PubMedID 30618652

  • Neurological, nutritional and alcohol consumption factors underlie cognitive and motor deficits in chronic alcoholism. Addiction biology Fama, R., Le Berre, A., Hardcastle, C., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V., Zahr, N. M. 2017


    Variations in pattern and extent of cognitive and motor impairment occur in alcoholism (ALC). Causes of such heterogeneity are elusive and inconsistently accounted for by demographic or alcohol consumption differences. We examined neurological and nutritional factors as possible contributors to heterogeneity in impairment. Participants with ALC (n=96) and a normal comparison group (n=41) were examined on six cognitive and motor domains. Signs of historically determined subclinical Wernicke's encephalopathy were detected using the Caine et al. criteria, which were based on postmortem examination and chart review of antemortem data of alcoholic cases with postmortem evidence for Wernicke's encephalopathy. Herein, four Caine criteria provided quantification of dietary deficiency, cerebellar dysfunction, low general cognitive functioning and oculomotor abnormalities in 86 of the 96 ALC participants. Subgroups based on Caine criteria yielded a graded effect, where those meeting more criteria exhibited greater impairment than those meeting no to fewer criteria. These results could not be accounted for by history of drug dependence. Multiple regression indicated that compromised performance on ataxia, indicative of cerebellar dysfunction, predicted non-mnemonic and upper motor deficits, whereas low whole blood thiamine level, consistent with limbic circuit dysfunction, predicted mnemonic deficits. This double dissociation indicates biological markers that contribute to heterogeneity in expression of functional impairment in ALC. That non-mnemonic and mnemonic deficits are subserved by the dissociable neural systems of frontocerebellar and limbic circuitry, both commonly disrupted in ALC, suggests neural mechanisms that can differentially affect selective functions, thereby contributing to heterogeneity in pattern and extent of dysfunction in ALC.

    View details for PubMedID 29243370

  • ASSOCIATION BETWEEN SLEEP SLOW WAVE ACTIVITY AND BRAIN STRUCTURE DURING ADOLESCENCE Goldstone, A., Mueller-Oehring, E., Willoughby, A., de Zambotti, M., Franzen, P., Pohl, K., Pfefferbaum, A., Sullivan, E., Prouty, D., Kwon, D., Hasler, B., Clads, D., Colrain, I., Baker, F. ELSEVIER SCIENCE BV. 2017: E113–E114
  • Peripheral TNF alpha Levels Correlate With Hippocampal Volume in Alcoholism but not in HIV Infection Zahr, N., Kwon, D., Pohl, K., Sullivan, E., Pfefferbaum, A. NATURE PUBLISHING GROUP. 2017: S277–S278
  • Eveningness and Later Sleep Timing Are Associated with Greater Risk for Alcohol and Marijuana Use in Adolescence: Initial Findings from the National Consortium on Alcohol and Neurodevelopment in Adolescence Study. Alcoholism, clinical and experimental research Hasler, B. P., Franzen, P. L., de Zambotti, M., Prouty, D., Brown, S. A., Tapert, S. F., Pfefferbaum, A., Pohl, K. M., Sullivan, E. V., De Bellis, M. D., Nagel, B. J., Baker, F. C., Colrain, I. M., Clark, D. B. 2017; 41 (6): 1154-1165


    Abundant cross-sectional evidence links eveningness (a preference for later sleep-wake timing) and increased alcohol and drug use among adolescents and young adults. However, longitudinal studies are needed to examine whether eveningness is a risk factor for subsequent alcohol and drug use, particularly during adolescence, which is marked by parallel peaks in eveningness and risk for the onset of alcohol use disorders. This study examined whether eveningness and other sleep characteristics were associated with concurrent or subsequent substance involvement in a longitudinal study of adolescents.Participants were 729 adolescents (368 females; age 12 to 21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence study. Associations between the sleep variables (circadian preference, sleep quality, daytime sleepiness, sleep timing, and sleep duration) and 3 categorical substance variables (at-risk alcohol use, alcohol bingeing, and past-year marijuana use [y/n]) were examined using ordinal and logistic regression with baseline age, sex, race, ethnicity, socioeconomic status, and psychiatric problems as covariates.At baseline, greater eveningness was associated with greater at-risk alcohol use, greater bingeing, and past-year use of marijuana. Later weekday and weekend bedtimes, but not weekday or weekend sleep duration, showed similar associations across the 3 substance outcomes at baseline. Greater baseline eveningness was also prospectively associated with greater bingeing and past-year use of marijuana at the 1-year follow-up, after covarying for baseline bingeing and marijuana use. Later baseline weekday and weekend bedtimes, and shorter baseline weekday sleep duration, were similarly associated with greater bingeing and past-year use of marijuana at the 1-year follow-up after covarying for baseline values.Findings suggest that eveningness and sleep timing may be under recognized risk factors and future areas of intervention for adolescent involvement in alcohol and marijuana that should be considered along with other previously identified sleep factors such as insomnia and insufficient sleep.

    View details for DOI 10.1111/acer.13401

    View details for PubMedID 28421617

  • Limited impact of alcoholism comorbidity in HIV on peripheral cytokine levels Zahr, N. M., Asok, P., Sullivan, E., Pfefferbaum, A. SPRINGER. 2017: S77
  • Influences of Age, Sex, and Moderate Alcohol Drinking on the Intrinsic Functional Architecture of Adolescent Brains. Cerebral cortex Müller-Oehring, E. M., Kwon, D., Nagel, B. J., Sullivan, E. V., Chu, W., Rohlfing, T., Prouty, D., Nichols, B. N., Poline, J., Tapert, S. F., Brown, S. A., Cummins, K., Brumback, T., Colrain, I. M., Baker, F. C., De Bellis, M. D., Voyvodic, J. T., Clark, D. B., Pfefferbaum, A., Pohl, K. M. 2017: 1-15

    View details for DOI 10.1093/cercor/bhx014

    View details for PubMedID 28168274

  • Effects of prior testing lasting a full year in NCANDA adolescents: Contributions from age, sex, socioeconomic status, ethnicity, site, family history of alcohol or drug abuse, and baseline performance. Developmental cognitive neuroscience Sullivan, E. V., Brumback, T., Tapert, S. F., Prouty, D., Fama, R., Thompson, W. K., Brown, S. A., Cummins, K., Colrain, I. M., Baker, F. C., Clark, D. B., Chung, T., De Bellis, M. D., Hooper, S. R., Nagel, B. J., Nichols, B. N., Chu, W., Kwon, D., Pohl, K. M., Pfefferbaum, A. 2017; 24: 72-83


    Longitudinal study provides a robust method for tracking developmental trajectories. Yet inherent problems of retesting pose challenges in distinguishing biological developmental change from prior testing experience. We examined factors potentially influencing change scores on 16 neuropsychological test composites over 1year in 568 adolescents in the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) project. The twice-minus-once-tested method revealed that performance gain was mainly attributable to testing experience (practice) with little contribution from predicted developmental effects. Group mean practice slopes for 13 composites indicated that 60% to ∼100% variance was attributable to test experience; General Ability accuracy showed the least practice effect (29%). Lower baseline performance, especially in younger participants, was a strong predictor of greater gain. Contributions from age, sex, ethnicity, examination site, socioeconomic status, or family history of alcohol/substance abuse were nil to small, even where statistically significant. Recognizing that a substantial proportion of change in longitudinal testing, even over 1-year, is attributable to testing experience indicates caution against assuming that performance gain observed during periods of maturation necessarily reflects development. Estimates of testing experience, a form of learning, may be a relevant metric for detecting interim influences, such as alcohol use or traumatic episodes, on behavior.

    View details for DOI 10.1016/j.dcn.2017.01.003

    View details for PubMedID 28214667

  • Contributions to Understanding the Neuropsychology of Alcoholism: An INS Legacy. Journal of the International Neuropsychological Society : JINS Sullivan, E. V. 2017; 23 (9-10): 843–59


    Alcohol use disorder (AUD) has been a major cause of family, social, and personal strife for centuries, with current prevalence estimates of 14% for 12-month and 29% lifetime AUD. Neuropsychological testing of selective cognitive, sensory, and motor functions complemented with in vivo brain imaging has enabled tracking the consequences of AUD, which follows a dynamic course of development, maintenance, and recovery or relapse. Controlled studies of alcoholism reviewed herein provide evidence for disruption of selective functions involving executive, visuospatial, mnemonic, emotional, and attentional processes, response inhibition, prosody, and postural stability and brain systems supporting these functions. On a hopeful front, longitudinal study provides convincing evidence for improvement in brain structure and function following sustained sobriety. These discoveries have a strong legacy in the International Neuropsychological Society (INS), starting from its early days when assumptions regarding which brain regions were disrupted relied solely on patterns of functional sparing and impairment deduced from testing. This review is based on the symposium presentation delivered at the 2017 annual North American meeting of the INS in celebration of the 50th anniversary since its institution in 1967. In the spirit of the meeting's theme, "Binding the Past and Present," the lecture and this review recognized the past by focusing on early, rigorous neuropsychological studies of alcoholism and their influence on research currently conducted using imaging methods enabling hypothesis testing of brain substrates of observed functional deficits. (JINS, 2017, 23, 843-859).

    View details for PubMedID 29198270

  • Executive Functions, Memory, and Social Cognitive Deficits and Recovery in Chronic Alcoholism: A Critical Review to Inform Future Research. Alcoholism, clinical and experimental research Le Berre, A. P., Fama, R., Sullivan, E. V. 2017; 41 (8): 1432–43


    Alcoholism is a complex and dynamic disease, punctuated by periods of abstinence and relapse, and influenced by a multitude of vulnerability factors. Chronic excessive alcohol consumption is associated with cognitive deficits, ranging from mild to severe, in executive functions, memory, and metacognitive abilities, with associated impairment in emotional processes and social cognition. These deficits can compromise efforts in initiating and sustaining abstinence by hampering efficacy of clinical treatment and can obstruct efforts in enabling good decision making success in interpersonal/social interactions, and awareness of cognitive and behavioral dysfunctions. Despite evidence for differences in recovery levels of selective cognitive processes, certain deficits can persist even with prolonged sobriety. Herein is presented a review of alcohol-related cognitive impairments affecting component processes of executive functioning, memory, and the recently investigated cognitive domains of metamemory, social cognition, and emotional processing; also considered are trajectories of cognitive recovery with abstinence. Finally, in the spirit of critical review, limitations of current knowledge are noted and avenues for new research efforts are proposed that focus on (i) the interaction among emotion-cognition processes and identification of vulnerability factors contributing to the development of emotional and social processing deficits and (ii) the time line of cognitive recovery by tracking alcoholism's dynamic course of sobriety and relapse. Knowledge about the heterochronicity of cognitive recovery in alcoholism has the potential of indicating at which points during recovery intervention may be most beneficial.

    View details for PubMedID 28618018

  • Adolescent Executive Dysfunction in Daily Life: Relationships to Risks, Brain Structure and Substance Use. Frontiers in behavioral neuroscience Clark, D. B., Chung, T., Martin, C. S., Hasler, B. P., Fitzgerald, D. H., Luna, B., Brown, S. A., Tapert, S. F., Brumback, T., Cummins, K., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M., Colrain, I. M., Baker, F. C., De Bellis, M. D., Nooner, K. B., Nagel, B. J. 2017; 11: 223


    During adolescence, problems reflecting cognitive, behavioral and affective dysregulation, such as inattention and emotional dyscontrol, have been observed to be associated with substance use disorder (SUD) risks and outcomes. Prior studies have typically been with small samples, and have typically not included comprehensive measurement of executive dysfunction domains. The relationships of executive dysfunction in daily life with performance based testing of cognitive skills and structural brain characteristics, thought to be the basis for executive functioning, have not been definitively determined. The aims of this study were to determine the relationships between executive dysfunction in daily life, measured by the Behavior Rating Inventory of Executive Function (BRIEF), cognitive skills and structural brain characteristics, and SUD risks, including a global SUD risk indicator, sleep quality, and risky alcohol and cannabis use. In addition to bivariate relationships, multivariate models were tested. The subjects (n = 817; ages 12 through 21) were participants in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. The results indicated that executive dysfunction was significantly related to SUD risks, poor sleep quality, risky alcohol use and cannabis use, and was not significantly related to cognitive skills or structural brain characteristics. In multivariate models, the relationship between poor sleep quality and risky substance use was mediated by executive dysfunction. While these cross-sectional relationships need to be further examined in longitudinal analyses, the results suggest that poor sleep quality and executive dysfunction may be viable preventive intervention targets to reduce adolescent substance use.

    View details for PubMedID 29180956

  • The neural correlates of priming emotion and reward systems for conflict processing in alcoholics. Brain imaging and behavior Schulte, T., Jung, Y., SULLIVAN, E. V., Pfefferbaum, A., SERVENTI, M., Müller-Oehring, E. M. 2016: -?


    Emotional dysregulation in alcoholism (ALC) may result from disturbed inhibitory mechanisms. We therefore tested emotion and alcohol cue reactivity and inhibitory processes using negative priming. To test the neural correlates of cue reactivity and negative priming, 26 ALC and 26 age-matched controls underwent functional MRI performing a Stroop color match-to-sample task. In cue reactivity trials, task-irrelevant emotion and alcohol-related pictures were interspersed between color samples and color words. In negative priming trials, pictures primed the semantic content of an alcohol or emotion Stroop word. Behaviorally, both groups showed response facilitation to picture cue trials and response inhibition to primed trials. For cue reactivity to emotion and alcohol pictures, ALC showed midbrain-limbic activation. By contrast, controls activated frontoparietal executive control regions. Greater midbrain-hippocampal activation in ALC correlated with higher amounts of lifetime alcohol consumption and higher anxiety. With negative priming, ALC exhibited frontal cortical but not midbrain-hippocampal activation, similar to the pattern observed in controls. Higher frontal activation to alcohol-priming correlated with less craving and to emotion-priming with fewer depressive symptoms. The findings suggest that neurofunctional systems in ALC can be primed to deal with upcoming emotion- and alcohol-related conflict and can overcome the prepotent midbrain-limbic cue reactivity response.

    View details for PubMedID 27815773

  • Transient CNS responses to repeated binge ethanol treatment. Addiction biology Zahr, N. M., Rohlfing, T., Mayer, D., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2016; 21 (6): 1199-1216


    The effects of ethanol (EtOH) on in vivo magnetic resonance (MR)-detectable brain measures across repeated exposures have not previously been reported. Of 28 rats weighing 340.66 ± 21.93 g at baseline, 15 were assigned to an EtOH group and 13 to a control group. Animals were exposed to five cycles of 4 days of intragastric (EtOH or dextrose) treatment and 10 days of recovery. Rats in both groups had structural MR imaging and whole-brain MR spectroscopy (MRS) scans at baseline, immediately following each binge period and after each recovery period (total = 11 scans per rat). Blood alcohol level at each of the five binge periods was ~300 mg/dl. Blood drawn at the end of the experiment did not show group differences for thiamine or its phosphate derivatives. Postmortem liver histopathology provided no evidence for hepatic steatosis, alcoholic hepatitis or alcoholic cirrhosis. Cerebrospinal fluid volumes of the lateral ventricles and cisterns showed enlargement with each binge EtOH exposure but recovery with each abstinence period. Similarly, changes in MRS metabolite levels were transient: levels of N-acetylaspartate and total creatine decreased, while those of choline-containing compounds and the combined resonance from glutamate and glutamine increased with each binge EtOH exposure cycle and then recovered during each abstinence period. Changes in response to EtOH were in expected directions based on previous single-binge EtOH exposure experiments, but the current MR findings do not provide support for accruing changes with repeated binge EtOH exposure.

    View details for DOI 10.1111/adb.12290

    View details for PubMedID 26283309

    View details for PubMedCentralID PMC4801670

  • Impairments in Component Processes of Executive Function and Episodic Memory in Alcoholism, HIV Infection, and HIV Infection with Alcoholism Comorbidity. Alcoholism, clinical and experimental research Fama, R., Sullivan, E. V., Sassoon, S. A., Pfefferbaum, A., Zahr, N. M. 2016


    Executive functioning and episodic memory impairment occur in HIV infection (HIV) and chronic alcoholism (ALC). Comorbidity of these conditions (HIV + ALC) is prevalent and heightens risk of vulnerability to separate and compounded deficits. Age and disease-related variables can also serve as mediators of cognitive impairment and should be considered, given the extended longevity of HIV-infected individuals in this era of improved pharmacological therapy.HIV, ALC, HIV + ALC, and normal controls (NC) were administered traditional and computerized tests of executive function and episodic memory. Test scores were expressed as age- and education-corrected Z-scores; selective tests were averaged to compute Executive Function and Episodic Memory Composite scores. Efficiency scores were calculated for tests with accuracy and response times.HIV, ALC, and HIV + ALC had lower scores than NC on Executive Function and Episodic Memory Composites, with HIV + ALC even lower than ALC and HIV on the Episodic Memory Composite. Impairments in planning and free recall of visuospatial material were observed in ALC, whereas impairments in psychomotor speed, sequencing, narrative free recall, and pattern recognition were observed in HIV. Lower decision-making efficiency scores than NC occurred in all 3 clinical groups. In ALC, age and lifetime alcohol consumption were each unique predictors of Executive Function and Episodic Memory Composite scores. In HIV + ALC, age was a unique predictor of Episodic Memory Composite score.Disease-specific and disease-overlapping patterns of impairment in HIV, ALC, and HIV + ALC have implications regarding brain systems disrupted by each disease and clinical ramifications regarding the complexities and compounded damping of cognitive functioning associated with dual diagnosis that may be exacerbated with aging.

    View details for DOI 10.1111/acer.13250

    View details for PubMedID 27759882

    View details for PubMedCentralID PMC5133188

  • Structural brain anomalies in healthy adolescents in the NCANDA cohort: relation to neuropsychological test performance, sex, and ethnicity. Brain imaging and behavior Sullivan, E. V., Lane, B., Kwon, D., Meloy, M. J., Tapert, S. F., Brown, S. A., Colrain, I. M., Baker, F. C., De Bellis, M. D., Clark, D. B., Nagel, B. J., Pohl, K. M., Pfefferbaum, A. 2016: -?


    Structural MRI of volunteers deemed "normal" following clinical interview provides a window into normal brain developmental morphology but also reveals unexpected dysmorphology, commonly known as "incidental findings." Although unanticipated, these anatomical findings raise questions regarding possible treatment that could even ultimately require neurosurgical intervention, which itself carries significant risk but may not be indicated if the anomaly is nonprogressive or of no functional consequence. Neuroradiological readings of 833 structural MRI from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) cohort found an 11.8 % incidence of brain structural anomalies, represented proportionately across the five collection sites and ethnic groups. Anomalies included 26 mega cisterna magna, 15 subarachnoid cysts, 12 pineal cysts, 12 white matter dysmorphologies, 5 tonsillar ectopias, 5 prominent perivascular spaces, 5 gray matter heterotopias, 4 pituitary masses, 4 excessively large or asymmetrical ventricles, 4 cavum septum pellucidum, 3 developmental venous anomalies, 1 exceptionally large midsagittal vein, and single cases requiring clinical followup: cranio-cervical junction stenosis, parietal cortical mass, and Chiari I malformation. A case of possible demyelinating disorder (e.g., neuromyelitis optica or multiple sclerosis) newly emerged at the 1-year NCANDA followup, requiring clinical referral. Comparing test performance of the 98 anomalous cases with 619 anomaly-free no-to-low alcohol consuming adolescents revealed significantly lower scores on speed measures of attention and motor functions; these differences were not attributed to any one anomaly subgroup. Further, we devised an automated approach for quantifying posterior fossa CSF volumes for detection of mega cisterna magna, which represented 26.5 % of clinically identified anomalies. Automated quantification fit a Gaussian distribution with a rightward skew. Using a 3SD cut-off, quantification identified 22 of the 26 clinically-identified cases, indicating that cases with percent of CSF in the posterior-inferior-middle aspect of the posterior fossa ≥3SD merit further review, and support complementing clinical readings with objective quantitative analysis. Discovery of asymptomatic brain structural anomalies, even when no clinical action is indicated, can be disconcerting to the individual and responsible family members, raising a disclosure dilemma: refrain from relating the incidental findings to avoid unnecessary alarm or anxiety; or alternatively, relate the neuroradiological findings as "normal variants" to the study volunteers and family, thereby equipping them with knowledge for the future should they have the occasion for a brain scan following an illness or accident that the incidental findings predated the later event.

    View details for PubMedID 27722828

  • Adolescent Development of Cortical and White Matter Structure in the NCANDA Sample: Role of Sex, Ethnicity, Puberty, and Alcohol Drinking. Cerebral cortex Pfefferbaum, A., Rohlfing, T., Pohl, K. M., Lane, B., Chu, W., Kwon, D., Nolan Nichols, B., Brown, S. A., Tapert, S. F., Cummins, K., Thompson, W. K., Brumback, T., Meloy, M. J., Jernigan, T. L., Dale, A., Colrain, I. M., Baker, F. C., Prouty, D., De Bellis, M. D., Voyvodic, J. T., Clark, D. B., Luna, B., Chung, T., Nagel, B. J., Sullivan, E. V. 2016; 26 (10): 4101-4121


    Brain structural development continues throughout adolescence, when experimentation with alcohol is often initiated. To parse contributions from biological and environmental factors on neurodevelopment, this study used baseline National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) magnetic resonance imaging (MRI) data, acquired in 674 adolescents meeting no/low alcohol or drug use criteria and 134 adolescents exceeding criteria. Spatial integrity of images across the 5 recruitment sites was assured by morphological scaling using Alzheimer's disease neuroimaging initiative phantom-derived volume scalar metrics. Clinical MRI readings identified structural anomalies in 11.4%. Cortical volume and thickness were smaller and white matter volumes were larger in older than in younger adolescents. Effects of sex (male > female) and ethnicity (majority > minority) were significant for volume and surface but minimal for cortical thickness. Adjusting volume and area for supratentorial volume attenuated or removed sex and ethnicity effects. That cortical thickness showed age-related decline and was unrelated to supratentorial volume is consistent with the radial unit hypothesis, suggesting a universal neural development characteristic robust to sex and ethnicity. Comparison of NCANDA with PING data revealed similar but flatter, age-related declines in cortical volumes and thickness. Smaller, thinner frontal, and temporal cortices in the exceeds-criteria than no/low-drinking group suggested untoward effects of excessive alcohol consumption on brain structural development.

    View details for DOI 10.1093/cercor/bhv205

    View details for PubMedID 26408800

  • Extracting patterns of morphometry distinguishing HIV associated neurodegeneration from mild cognitive impairment via group cardinality constrained classification. Human brain mapping Zhang, Y., Kwon, D., Esmaeili-Firidouni, P., Pfefferbaum, A., Sullivan, E. V., Javitz, H., Valcour, V., Pohl, K. M. 2016


    HIV-Associated Neurocognitive Disorder (HAND) is the most common constellation of cognitive dysfunctions in chronic HIV infected patients age 60 or older in the U.S. Only few published methods assist in distinguishing HAND from other forms of age-associated cognitive decline, such as Mild Cognitive Impairment (MCI). In this report, a data-driven, nonparameteric model to identify morphometric patterns separating HAND from MCI due to non-HIV conditions in this older age group was proposed. This model enhanced the potential for group separation by combining a smaller, longitudinal data set containing HAND samples with a larger, public data set including MCI cases. Using cross-validation, a linear model on healthy controls to harmonize the volumetric scores extracted from MRIs for demographic and acquisition differences between the two independent, disease-specific data sets was trained. Next, patterns distinguishing HAND from MCI via a group sparsity constrained logistic classifier were identified. Unlike existing approaches, our classifier directly solved the underlying minimization problem by decoupling the minimization of the logistic regression function from enforcing the group sparsity constraint. The extracted patterns consisted of eight regions that distinguished HAND from MCI on a significant level while being indifferent to differences in demographics and acquisition between the two sets. Individually selecting regions through conventional morphometric group analysis resulted in a larger number of regions that were less accurate. In conclusion, simultaneously analyzing all brain regions and time points for disease specific patterns contributed to distinguishing with high accuracy HAND-related impairment from cognitive impairment found in the HIV uninfected, MCI cohort. Hum Brain Mapp 37:4523-4538, 2016. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.23326

    View details for PubMedID 27489003

  • Differential compromise of prospective and retrospective metamemory monitoring and their dissociable structural brain correlates CORTEX Le Berre, A., Mueller-Oehring, E. M., Kwon, D., Serventi, M. R., Pfefferbaum, A., Sullivan, E. V. 2016; 81: 192-202
  • Differential compromise of prospective and retrospective metamemory monitoring and their dissociable structural brain correlates. Cortex; a journal devoted to the study of the nervous system and behavior Le Berre, A., Müller-Oehring, E. M., Kwon, D., Serventi, M. R., Pfefferbaum, A., Sullivan, E. V. 2016; 81: 192-202


    Metamemory refers to personal knowledge about one's own memory ability that invokes cognitive processes relevant to monitoring and controlling memory. An impaired monitoring system can potentially result in unawareness of symptoms as can occur in addiction denial. Monitoring processes can be assessed with prospective measures such as Feeling-Of-Knowing (FOK) judgments on prediction of future recognition performance, or retrospective confidence judgments (RCJ) made on previous memory performance. Alcoholic patients with amnesia showed poor FOK but intact RCJ. The neuropsychological continuum from mild to moderate deficits in nonamnesic to amnesic alcoholism raised the possibility that alcoholics uncomplicated by clinically-detectable amnesia may suffer anosognosia for their mild memory deficits. Herein 24 abstinent alcoholics and 26 age-matched controls completed an episodic memory paradigm including prospective FOK and retrospective RCJ monitoring measures and underwent 3T structural magnetic resonance imaging. Alcoholics were less accurate than controls in recognition and in assessing their future recognition performance, which was marked by overestimation, but were as accurate as controls on confidence ratings of actual recognition performance. Examination of brain structure-function relations revealed a double dissociation where FOK accuracy was selectively related to insular volume, and retrospective confidence accuracy was selectively related to frontolimbic structural volumes. Impaired FOK with intact RCJ was consistent with mild anosognosia and suggested evidence for neuropsychological and neural mechanisms of unawareness in addiction.

    View details for DOI 10.1016/j.cortex.2016.05.002

    View details for PubMedID 27244277

    View details for PubMedCentralID PMC4958575

  • Anosognosia for Memory Impairment in Addiction: Insights from Neuroimaging and Neuropsychological Assessment of Metamemory. Neuropsychology review Le Berre, A., Sullivan, E. V. 2016: -?


    In addiction, notably Alcohol Use Disorder (AUD), patients often have a tendency to fail to acknowledge the reality of the disease and to minimize the physical, psychological, and social difficulties attendant to chronic alcohol consumption. This lack of awareness can reduce the chances of initiating and maintaining sobriety. Presented here is a model focusing on compromised awareness in individuals with AUD of mild to moderate cognitive deficits, in particular, for episodic memory impairment-the ability to learn new information, such as recent personal experiences. Early in abstinence, alcoholics can be unaware of their memory deficits and overestimate their mnemonic capacities, which can be investigated with metamemory paradigms. Relevant neuropsychological and neuroimaging results considered suggest that the alcoholics' impairment of awareness of their attenuated memory function can be a clinical manifestation explained mechanistically by neurobiological factors, including compromise of brain systems that result in a mild form of mnemonic anosognosia. Specifically, unawareness of memory impairment in AUD may result from a lack of personal knowledge updating attributable to damage in brain regions or connections supporting conscious recollection in episodic memory. Likely candidates are posterior parietal and medial frontal regions known to be integral part of the Default Mode Network (DMN) and the insula leading to an impaired switching mechanism between the DMN and the Central-Executive Control (i.e., Lateral Prefronto-Parietal) Network. The cognitive concepts and neural substrates noted for addictive disorders may also be relevant for problems in self-identification of functional impairment resulting from injury following war-related blast, sport-related concussion, and insidiously occurring dementia.

    View details for PubMedID 27447979

  • Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo PSYCHOPHARMACOLOGY Zahr, N. M., Sullivan, E. V., Rohlfing, T., Mayer, D., Collins, A. M., Luong, R., Pfefferbaum, A. 2016; 233 (14): 2675-2686


    Serious neurological concomitants of alcoholism include Wernicke's encephalopathy (WE), Korsakoff's syndrome (KS), and hepatic encephalopathy (HE).This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation.Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment.Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls.These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.

    View details for DOI 10.1007/s00213-016-4313-y

    View details for Web of Science ID 000378874600004

    View details for PubMedID 27129864

    View details for PubMedCentralID PMC4919142

  • Cognitive, Emotion Control, and Motor Performance of Adolescents in the NCANDA Study: Contributions From Alcohol Consumption, Age, Sex, Ethnicity, and Family History of Addiction NEUROPSYCHOLOGY Sullivan, E. V., Brumback, T., Tapert, S. F., Fama, R., Prouty, D., Brown, S. A., Cummins, K., Thompson, W. K., Colrain, I. M., Baker, F. C., De Bellis, M. D., Hooper, S. R., Clark, D. B., Chung, T., Nagel, B. J., Nichols, B. N., Rohlfing, T., Chu, W., Pohl, K. M., Pfefferbaum, A. 2016; 30 (4): 449-473


    To investigate development of cognitive and motor functions in healthy adolescents and to explore whether hazardous drinking affects the normal developmental course of those functions.Participants were 831 adolescents recruited across 5 United States sites of the National Consortium on Alcohol and NeuroDevelopment in Adolescence 692 met criteria for no/low alcohol exposure, and 139 exceeded drinking thresholds. Cross-sectional, baseline data were collected with computerized and traditional neuropsychological tests assessing 8 functional domains expressed as composite scores. General additive modeling evaluated factors potentially modulating performance (age, sex, ethnicity, socioeconomic status, and pubertal developmental stage).Older no/low-drinking participants achieved better scores than younger ones on 5 accuracy composites (general ability, abstraction, attention, emotion, and balance). Speeded responses for attention, motor speed, and general ability were sensitive to age and pubertal development. The exceeds-threshold group (accounting for age, sex, and other demographic factors) performed significantly below the no/low-drinking group on balance accuracy and on general ability, attention, episodic memory, emotion, and motor speed scores and showed evidence for faster speed at the expense of accuracy. Delay Discounting performance was consistent with poor impulse control in the younger no/low drinkers and in exceeds-threshold drinkers regardless of age.Higher achievement with older age and pubertal stage in general ability, abstraction, attention, emotion, and balance suggests continued functional development through adolescence, possibly supported by concurrently maturing frontal, limbic, and cerebellar brain systems. Determination of whether low scores by the exceeds-threshold group resulted from drinking or from other preexisting factors requires longitudinal study. (PsycINFO Database Record

    View details for DOI 10.1037/neu0000259

    View details for PubMedID 26752122

  • Brain metabolite levels in recently sober individuals with alcohol use disorder: Relation to drinking variables and relapse PSYCHIATRY RESEARCH-NEUROIMAGING Zahr, N. M., Carr, R. A., Rohlfing, T., Mayer, D., Sullivan, E. V., Colrain, I. M., Pfefferbaum, A. 2016; 250: 42-49


    Magnetic resonance spectroscopy (MRS) studies in alcohol use disorder (AUD) typically report lower levels of N-acetylaspartate (NAA) and choline-containing compounds (Cho) in several brain regions. Metabolite levels, however, are labile and can be affected by several competing factors, some related to drinking variables.. This in vivo MRS study included 20 recently sober (19.6±12.6 days) individuals with AUD and 15 controls. MRS was performed in single voxels placed in frontal white matter and thalamic regions using Constant-Time Point Resolved Spectroscopy (CT-PRESS) for absolute quantification of NAA, Cho, total creatine (tCr), and glutamate (Glu). A trend toward a thalamic NAA deficit in the total AUD group compared with controls was attributable to the subgroup of alcoholics who relapsed 3 or so months after scanning. In the total AUD group, frontal and thalamic NAA and Cho levels were lower with more recent drinking; frontal and thalamic Cho levels were also lower in AUD individuals with past stimulant abuse. Thalamic Cho levels were higher in binge-drinking AUD individuals and in those with longer length of alcohol dependence. MRS-visible metabolite peaks appear to be modulated by variables related to drinking behaviors, suggesting a sensitivity of MRS in tracking and predicting the dynamic course of alcoholism.

    View details for DOI 10.1016/j.pscychresns.2016.01.015

    View details for Web of Science ID 000375160200007

    View details for PubMedID 27035062

  • Harmonizing DTI measurements across scanners to examine the development of white matter microstructure in 803 adolescents of the NCANDA study. NeuroImage Pohl, K. M., Sullivan, E. V., Rohlfing, T., Chu, W., Kwon, D., Nichols, B. N., Zhang, Y., Brown, S. A., Tapert, S. F., Cummins, K., Thompson, W. K., Brumback, T., Colrain, I. M., Baker, F. C., Prouty, D., De Bellis, M. D., Voyvodic, J. T., Clark, D. B., Schirda, C., Nagel, B. J., Pfefferbaum, A. 2016; 130: 194-213


    Neurodevelopment continues through adolescence, with notable maturation of white matter tracts comprising regional fiber systems progressing at different rates. To identify factors that could contribute to regional differences in white matter microstructure development, large samples of youth spanning adolescence to young adulthood are essential to parse these factors. Recruitment of adequate samples generally relies on multi-site consortia but comes with the challenge of merging data acquired on different platforms. In the current study, diffusion tensor imaging (DTI) data were acquired on GE and Siemens systems through the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a multi-site study designed to track the trajectories of regional brain development during a time of high risk for initiating alcohol consumption. This cross-sectional analysis reports baseline Tract-Based Spatial Statistic (TBSS) of regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), and radial diffusivity (LT) from the five consortium sites on 671 adolescents who met no/low alcohol or drug consumption criteria and 132 adolescents with a history of exceeding consumption criteria. Harmonization of DTI metrics across manufacturers entailed the use of human-phantom data, acquired multiple times on each of three non-NCANDA participants at each site's MR system, to determine a manufacturer-specific correction factor. Application of the correction factor derived from human phantom data measured on MR systems from different manufacturers reduced the standard deviation of the DTI metrics for FA by almost a half, enabling harmonization of data that would have otherwise carried systematic error. Permutation testing supported the hypothesis of higher FA and lower diffusivity measures in older adolescents and indicated that, overall, the FA, MD, and L1 of the boys were higher than those of the girls, suggesting continued microstructural development notable in the boys. The contribution of demographic and clinical differences to DTI metrics was assessed with General Additive Models (GAM) testing for age, sex, and ethnicity differences in regional skeleton mean values. The results supported the primary study hypothesis that FA skeleton mean values in the no/low-drinking group were highest at different ages. When differences in intracranial volume were covaried, FA skeleton mean reached a maximum at younger ages in girls than boys and varied in magnitude with ethnicity. Our results, however, did not support the hypothesis that youth who exceeded exposure criteria would have lower FA or higher diffusivity measures than the no/low-drinking group; detecting the effects of excessive alcohol consumption during adolescence on DTI metrics may require longitudinal study.

    View details for DOI 10.1016/j.neuroimage.2016.01.061

    View details for PubMedID 26872408

  • Brain responses to emotional salience and reward in alcohol use disorder. Brain imaging and behavior Alba-Ferrara, L., Müller-Oehring, E. M., SULLIVAN, E. V., Pfefferbaum, A., Schulte, T. 2016; 10 (1): 136-146


    Heightened neural responsiveness of alcoholics to alcohol cues and social emotion may impede sobriety. To test mesocorticolimbic network responsivity, 10 (8 men) alcohol use disorder (AUD) patients sober for 3 weeks to 10 months and 11 (8 men) controls underwent fMRI whilst viewing pictures of alcohol and non-alcohol beverages and of emotional faces (happy, sad, angry). AUD and controls showed similarities in mesocorticolimbic activity: both groups activated fusiform for emotional faces and hippocampal and pallidum regions during alcohol picture processing. In AUD, less fusiform activity to emotional faces and more pallidum activity to alcohol pictures were associated with longer sobriety. Using graph theory-based network efficiency measures to specify the role of the mesocorticolimbic network nodes for emotion and reward in sober AUD revealed that the left hippocampus was less efficiently connected with the other task-activated network regions in AUD than controls when viewing emotional faces, while the pallidum was more efficiently connected when viewing alcohol beverages. Together our findings identified lower occipito-temporal sensitivity to emotional faces and enhanced striatal sensitivity to alcohol stimuli in AUD than controls. Considering the role of the striatum in encoding reward, its activation enhancement with longer sobriety may reflect adaptive neural changes in the first year of drinking cessation and mesocorticolimbic system vulnerability for encoding emotional salience and reward potentially affecting executive control ability and relapse propensity during abstinence.

    View details for DOI 10.1007/s11682-015-9374-8

    View details for PubMedID 25875013

  • The Resting Brain of Alcoholics CEREBRAL CORTEX Mueller-Oehring, E. M., Jung, Y., Pfefferbaum, A., Sullivan, E. V., Schulte, T. 2015; 25 (11): 4155-4168


    Chronic alcohol consumption affects multiple cognitive processes supported by far-reaching cerebral networks. To identify neurofunctional mechanisms underlying selective deficits, 27 sober alcoholics and 26 age-matched controls underwent resting-state functional magnetic resonance imaging and neuropsychological testing. Functional connectivity analysis assessed the default mode network (DMN); integrative executive control (EC), salience (SA), and attention (AT) networks; primary somatosensory, auditory, and visual (VI) input networks; and subcortical reward (RW) and emotion (EM) networks. The groups showed an extensive overlap of intrinsic connectivity in all brain networks examined, suggesting overall integrity of large-scale functional networks. Despite these similar patterns, connectivity analyses identified network-specific differences of weaker within-network connectivity and expanded connectivity to regions outside the main networks in alcoholics compared with controls. For AT and VI networks, better task performance was related to expanded connectivity in alcoholism, supporting the concept of network expansion as a neural mechanism for functional compensation. For default mode, SA, RW, and EC networks, both weaker within-network and expanded outside-network connectivity correlated with poorer performance and mood. Current smoking contributed to some of these abnormalities in connectivity. The observed pattern of resting-state connectivity might reflect neural vulnerability of intrinsic networking in alcoholics and suggests a mechanism to explain signature impairments in EM, RW evaluation, and EC ability.

    View details for DOI 10.1093/cercor/bhu134

    View details for Web of Science ID 000366463300012

    View details for PubMedID 24935777

  • The National Consortium on Alcohol and Neuro-Development in Adolescence (NCANDA): A Multisite Study of Adolescent Development and Substance Use JOURNAL OF STUDIES ON ALCOHOL AND DRUGS Brown, S. A., Brumback, T. Y., Tomlinson, K., Cummins, K., Thompson, W. K., Nagel, B. J., De Bellis, M. D., Hooper, S. R., Clark, D. B., Chung, T., Hasler, B. P., Colrain, I. M., Baker, F. C., Prouty, D., Pfefferbaum, A., Sullivan, E. V., Pohl, K. M., Rohlfing, T., Nichols, B. N., Chu, W., Tapert, S. F. 2015; 76 (6): 895-908


    During adolescence, neurobiological maturation occurs concurrently with social and interpersonal changes, including the initiation of alcohol and other substance use. The National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) is designed to disentangle the complex relationships between onset, escalation, and desistance of alcohol use and changes in neurocognitive functioning and neuromaturation.A sample of 831 youth, ages 12-21 years, was recruited at five sites across the United States, oversampling those at risk for alcohol use problems. Most (83%) had limited or no history of alcohol or other drug use, and a smaller portion (17%) exceeded drinking thresholds. A comprehensive assessment of biological development, family background, psychiatric symptomatology, and neuropsychological functioning-in addition to anatomical, diffusion, and functional brain magnetic resonance imaging-was completed at baseline.The NCANDA sample of youth is nationally representative of sex and racial/ethnic groups. More than 50% have at least one risk characteristic for subsequent heavy drinking (e.g., family history, internalizing or externalizing symptoms). As expected, those who exceeded drinking thresholds (n = 139) differ from those who did not (n = 692) on identified factors associated with early alcohol use and problems.NCANDA successfully recruited a large sample of adolescents and comprehensively assessed psychosocial functioning across multiple domains. Based on the sample's risk profile, NCANDA is well positioned to capture the transition into drinking and alcohol problems in a large portion of the cohort, as well as to help disentangle the associations between alcohol use, neurobiological maturation, and neurocognitive development and functioning.

    View details for PubMedID 26562597

  • Cross-sectional versus longitudinal estimates of age-related changes in the adult brain: overlaps and discrepancies. Neurobiology of aging Pfefferbaum, A., Sullivan, E. V. 2015; 36 (9): 2563-2567


    The healthy adult brain undergoes tissue volume decline with age, but contradictory findings abound regarding rate of change. To identify a source of this discrepancy, we present contrasting statistical approaches to estimate hippocampal volume change with age based on 200 longitudinally-acquired magnetic resonance imaging in 70 healthy adults, age 20-70 years, who had 2-5 magnetic resonance imaging collected over 6 months to 8 years. Linear mixed-effects modeling using volume trajectories over age for each subject revealed significantly negative slopes with aging after a linear decline with a suggestion of acceleration in older individuals. By contrast, general linear modeling using either the first observation only of each subject or all observations treated independently (thereby disregarding trajectories) indicated no significant correlation between volume and age. Entering a quadratic term into the linear model yielded a biologically plausible function that was not supported by longitudinal analysis. The results underscore the importance of analyses that incorporate the trajectory of individuals in the study of brain aging.

    View details for DOI 10.1016/j.neurobiolaging.2015.05.005

    View details for PubMedID 26059713

    View details for PubMedCentralID PMC4523414

  • Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease BRAIN IMAGING AND BEHAVIOR Mueller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A., Huang, N. C., Poston, K. L., Bronte-Stewart, H. M., Schulte, T. 2015; 9 (3): 619-638


    Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

    View details for DOI 10.1007/s11682-014-9317-9

    View details for Web of Science ID 000361604300021

    View details for PubMedCentralID PMC4385510

  • Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease. Brain imaging and behavior Müller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A., Huang, N. C., Poston, K. L., Bronte-Stewart, H. M., Schulte, T. 2015; 9 (3): 619-638


    Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

    View details for DOI 10.1007/s11682-014-9317-9

    View details for PubMedID 25280970

    View details for PubMedCentralID PMC4385510

  • Brain pathways to recovery from alcohol dependence ALCOHOL Cui, C., Noronha, A., Warren, K. R., Koob, G. F., Sinha, R., Thakkar, M., Matochik, J., Crews, F. T., Chandler, L. J., Pfefferbaum, A., Becker, H. C., Lovinger, D., Everitt, B. J., Egli, M., Mandyam, C. D., Fein, G., Potenza, M. N., Harris, R. A., Grant, K. A., Roberto, M., Meyerhoff, D. J., Sullivan, E. V. 2015; 49 (5): 435-452


    This article highlights the research presentations at the satellite symposium on "Brain Pathways to Recovery from Alcohol Dependence" held at the 2013 Society for Neuroscience Annual Meeting. The purpose of this symposium was to provide an up to date overview of research efforts focusing on understanding brain mechanisms that contribute to recovery from alcohol dependence. A panel of scientists from the alcohol and addiction research field presented their insights and perspectives on brain mechanisms that may underlie both recovery and lack of recovery from alcohol dependence. The four sessions of the symposium encompassed multilevel studies exploring mechanisms underlying relapse and craving associated with sustained alcohol abstinence, cognitive function deficit and recovery, and translational studies on preventing relapse and promoting recovery. Gaps in our knowledge and research opportunities were also discussed.

    View details for DOI 10.1016/j.alcohol.2015.04.006

    View details for PubMedID 26074423

  • Thalamic structures and associated cognitive functions: Relations with age and aging NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Fama, R., Sullivan, E. V. 2015; 54: 29-37
  • Thalamic structures and associated cognitive functions: Relations with age and aging. Neuroscience and biobehavioral reviews Fama, R., Sullivan, E. V. 2015; 54: 29-37


    The thalamus, with its cortical, subcortical, and cerebellar connections, is a critical node in networks supporting cognitive functions known to decline in normal aging, including component processes of memory and executive functions of attention and information processing. The macrostructure, microstructure, and neural connectivity of the thalamus changes across the adult lifespan. Structural and functional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) have demonstrated, regional thalamic volume shrinkage and microstructural degradation, with anterior regions generally more compromised than posterior regions. The integrity of selective thalamic nuclei and projections decline with advancing age, particularly those in thalamofrontal, thalamoparietal, and thalamolimbic networks. This review presents studies that assess the relations between age and aging and the structure, function, and connectivity of the thalamus and associated neural networks and focuses on their relations with processes of attention, speed of information processing, and working and episodic memory.

    View details for DOI 10.1016/j.neubiorev.2015.03.008

    View details for PubMedID 25862940

    View details for PubMedCentralID PMC4457546

  • Brain Development in Heavy-Drinking Adolescents AMERICAN JOURNAL OF PSYCHIATRY Squeglia, L. M., Tapert, S. F., Sullivan, E. V., Jacobus, J., Meloy, M. J., Rohlfing, T., Pfefferbaum, A. 2015; 172 (6): 531-542


    Heavy alcohol use during adolescence may alter the trajectory of normal brain development. The authors measured within-subject changes in regional brain morphometry over longer intervals and in larger samples of adolescents than previously reported and assessed differences between adolescents who remained nondrinkers and those who drank heavily during adolescence as well as differences between the sexes.The authors examined gray and white matter volume trajectories in 134 adolescents, of whom 75 transitioned to heavy drinking and 59 remained light drinkers or nondrinkers over roughly 3.5 years. Each underwent MRI scanning two to six times between ages 12 and 24 and was followed for up to 8 years. The volumes of the neocortex, allocortex, and white matter structures were measured using atlas-based parcellation with longitudinal registration. Linear mixed-effects models described differences in trajectories of heavy drinkers and nondrinkers over age; secondary analyses considered the contribution of other drug use to identified alcohol use effects.Heavy-drinking adolescents showed accelerated gray matter reduction in cortical lateral frontal and temporal volumes and attenuated white matter growth of the corpus callosum and pons relative to nondrinkers. These results were largely unchanged when use of marijuana and other drugs was examined. Male and female drinkers showed similar patterns of development trajectory abnormalities.Longitudinal analysis enabled detection of accelerated typical volume decline in frontal and temporal cortical volumes and attenuated growth in principal white matter structures in adolescents who started to drink heavily. These results provide a call for caution regarding heavy alcohol use during adolescence, whether heavy drinking is the sole cause or one of several in these alterations in brain development.

    View details for DOI 10.1176/appi.ajp.2015.14101249

    View details for Web of Science ID 000355642800009

    View details for PubMedID 25982660

    View details for PubMedCentralID PMC4451385

  • Cognitive demands during quiet standing elicit truncal tremor in two frequency bands: differential relations to tissue integrity of corticospinal tracts and cortical targets FRONTIERS IN HUMAN NEUROSCIENCE Sullivan, E. V., Zahr, N. M., Rohlfing, T., Pfefferbaum, A. 2015; 9

    View details for DOI 10.3389/fnhum.2015.00175

    View details for Web of Science ID 000352655400001

    View details for PubMedID 25904858

  • Neuroimaging's Role in Neuropsychology: Introduction to the Special Issue of Neuropsychology Review on Neuroimaging in Neuropsychology. Neuropsychology review Sullivan, E. V., Bigler, E. D. 2015; 25 (3): 221–23

    View details for PubMedID 26275433

  • Sensitive biomarkers of alcoholism's effect on brain macrostructure: similarities and differences between France and the United States. Frontiers in human neuroscience Le Berre, A., Pitel, A., Chanraud, S., Beaunieux, H., Eustache, F., Martinot, J., Reynaud, M., Martelli, C., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2015; 9: 354-?


    Alcohol consumption patterns and recognition of health outcomes related to hazardous drinking vary widely internationally, raising the question whether these national differences are reflected in brain damage observed in alcoholism. This retrospective analysis assessed variability of alcoholism's effects on brain cerebrospinal fluid (CSF) and white matter volumes between France and the United States (U.S.). MRI data from two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) were acquired on 1.5T imaging systems in 287 controls, 165 uncomplicated alcoholics (ALC), and 26 alcoholics with Korsakoff's Syndrome (KS). All data were analyzed at the U.S. site using atlas-based parcellation. Results revealed graded CSF volume enlargement from ALC to KS and white matter volume deficits in KS only. In ALC from France but not the U.S., CSF and white matter volumes correlated with lifetime alcohol consumption, alcoholism duration, and length of sobriety. MRI highlighted CSF volume enlargement in both ALC and KS, serving as a basis for an ex vacuo process to explain correlated gray matter shrinkage. By contrast, MRI provided a sensitive in vivo biomarker of white matter volume shrinkage in KS only, suggesting a specific process sensitive to mechanisms contributing to Wernicke's encephalopathy, the precursor of KS. Identified structural brain abnormalities may provide biomarkers underlying alcoholism's heterogeneity in and among nations and suggest a substrate of gray matter tissue shrinkage. Proposed are hypotheses for national differences in interpreting whether the severity of sequelae observe a graded phenomenon or a continuum from uncomplicated alcoholism to alcoholism complicated by KS.

    View details for DOI 10.3389/fnhum.2015.00354

    View details for PubMedID 26157376

    View details for PubMedCentralID PMC4477159

  • Sensitive biomarkers of alcoholism's effect on brain macrostructure: similarities and differences between France and the United States. Frontiers in human neuroscience Le Berre, A., Pitel, A., Chanraud, S., Beaunieux, H., Eustache, F., Martinot, J., Reynaud, M., Martelli, C., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2015; 9: 354-?

    View details for DOI 10.3389/fnhum.2015.00354

    View details for PubMedID 26157376

  • Dynamic responses of selective brain white matter fiber tracts to binge alcohol and recovery in the rat. PloS one Pfefferbaum, A., Zahr, N. M., Mayer, D., Rohlfing, T., Sullivan, E. V. 2015; 10 (4)


    To determine the dynamics of white matter vulnerability to excessive alcohol consumption, diffusion tensor imaging (DTI) was used in an animal model of alcohol exposure. Quantitative, in vivo fiber tracking results are presented from rats with DTI conducted at 3 time points: baseline; after 4 days of intragastric alcohol to blood alcohol levels of ~250 mg/dL; and after one week of recovery. Binge alcohol followed by a week of sobriety resulted in rapidly reversible decreases in fractional anisotropy (FA), a measure of the coherence of fiber tracts, in callosal genu and fimbria-fornix but not splenium; and increases in mean diffusivity (MD), an index of freely diffusing water in tissue, selective to the fimbria-fornix. These effects were confirmed with tract-based spatial statistics (TBSS). The directionality of changes in DTI metrics reproduce those observed in human alcoholism. That a single exposure to binge alcohol can cause substantial transient changes detectable in DTI metrics demonstrates the potential for rapid neuroplasticity.

    View details for DOI 10.1371/journal.pone.0124885

    View details for PubMedID 25894968

    View details for PubMedCentralID PMC4403879

  • Quantitative Susceptibility Mapping by Inversion of a Perturbation Field Model: Correlation With Brain Iron in Normal Aging IEEE TRANSACTIONS ON MEDICAL IMAGING Poynton, C. B., Jenkinson, M., Adalsteinsson, E., Sullivan, E. V., Pfefferbaum, A., Wells, W. 2015; 34 (1): 339-353


    There is increasing evidence that iron deposition occurs in specific regions of the brain in normal aging and neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. Iron deposition changes the magnetic susceptibility of tissue, which alters the MR signal phase, and allows estimation of susceptibility differences using quantitative susceptibility mapping (QSM). We present a method for quantifying susceptibility by inversion of a perturbation model, or "QSIP." The perturbation model relates phase to susceptibility using a kernel calculated in the spatial domain, in contrast to previous Fourier-based techniques. A tissue/air susceptibility atlas is used to estimate B0 inhomogeneity. QSIP estimates in young and elderly subjects are compared to postmortem iron estimates, maps of the Field-Dependent Relaxation Rate Increase, and the L1-QSM method. Results for both groups showed excellent agreement with published postmortem data and in vivo FDRI: statistically significant Spearman correlations ranging from Rho=0.905 to Rho=1.00 were obtained. QSIP also showed improvement over FDRI and L1-QSM: reduced variance in susceptibility estimates and statistically significant group differences were detected in striatal and brainstem nuclei, consistent with age-dependent iron accumulation in these regions.

    View details for DOI 10.1109/TMI.2014.2358552

    View details for Web of Science ID 000346975900031

    View details for PubMedID 25248179

  • Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics PSYCHOPHARMACOLOGY Jung, Y., Schulte, T., Mueller-Oehring, E. M., Namkoong, K., Pfefferbaum, A., Sullivan, E. V. 2014; 231 (23): 4443-4453
  • Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics. Psychopharmacology Jung, Y., Schulte, T., Müller-Oehring, E. M., Namkoong, K., Pfefferbaum, A., Sullivan, E. V. 2014; 231 (23): 4443-4453


    Degradation of frontocerebellar circuitry is a principal neural mechanism of alcoholism-related executive dysfunctions affecting impulse control and cognitive planning.We tested the hypothesis that alcoholic patients would demonstrate compromised dorsal anterior cingulate cortex (dACC) -cerebellar functional connectivity when adjusting their strategies to accommodate uncertain conditions and would recruit compensatory brain regions to overcome ineffective response patterns.Twenty-six alcoholics and 26 healthy participants underwent functional MRI in two sequential runs while performing a decision-making task. The first run required a response regardless of level of ambiguity of the stimuli; the second run allowed a PASS option (i.e., no response choice), which was useful on ambiguous trials.Healthy controls demonstrated strong synchronous activity between the dACC and cerebellum while planning and executing a behavioral strategy. By contrast, alcoholics showed synchronous activity between the dACC and the premotor cortex, perhaps enabling successful compensation for accuracy and reaction time in certain conditions; however, a negative outcome of this strategy was rigidity in modifying response strategy to accommodate uncertain conditions. Compared with the alcoholic group, the control group had lower nonplanning impulsiveness, which correlated with using the option PASS to respond in uncertain conditions.These findings suggest that compromised dACC-cerebellar functional circuitry contributes to recruitment of an alternative network-dACC-premotor cortex- to perform well under low-risk, unambiguous conditions. This compensatory network, however, was inadequate to enable the alcoholics to avert making poor choices in planning and executing an effective behavioral strategy in high-risk, uncertain conditions.

    View details for DOI 10.1007/s00213-014-3594-2

    View details for PubMedID 24781521

  • One Perspective on the Value of Journal Editorship ACADEMIC PSYCHIATRY Sullivan, E. V. 2014; 38 (6): 728-730

    View details for DOI 10.1007/s40596-014-0194-8

    View details for Web of Science ID 000346794100016

    View details for PubMedID 25026952

  • Thalamic volume deficit contributes to procedural and explicit memory impairment in HIV infection with primary alcoholism comorbidity. Brain imaging and behavior Fama, R., Rosenbloom, M. J., Sassoon, S. A., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2014; 8 (4): 611-620


    Component cognitive and motor processes contributing to diminished visuomotor procedural learning in HIV infection with comorbid chronic alcoholism (HIV+ALC) include problems with attention and explicit memory processes. The neural correlates associated with this constellation of cognitive and motor processes in HIV infection and alcoholism have yet to be delineated. Frontostriatal regions are affected in HIV infection, frontothalamocerebellar regions are affected in chronic alcoholism, and frontolimbic regions are likely affected in both; all three of these systems have the potential of contributing to both visuomotor procedural learning and explicit memory processes. Here, we examined the neural correlates of implicit memory, explicit memory, attention, and motor tests in 26 HIV+ALC (5 with comorbidity for nonalcohol drug abuse/dependence) and 19 age-range matched healthy control men. Parcellated brain volumes, including cortical, subcortical, and allocortical regions, as well as cortical sulci and ventricles, were derived using the SRI24 brain atlas. Results indicated that smaller thalamic volumes were associated with poorer performance on tests of explicit (immediate and delayed) and implicit (visuomotor procedural) memory in HIV+ALC. By contrast, smaller hippocampal volumes were associated with lower scores on explicit, but not implicit memory. Multiple regression analyses revealed that volumes of both the thalamus and the hippocampus were each unique independent predictors of explicit memory scores. This study provides evidence of a dissociation between implicit and explicit memory tasks in HIV+ALC, with selective relationships observed between hippocampal volume and explicit but not implicit memory, and highlights the relevance of the thalamus to mnemonic processes.

    View details for DOI 10.1007/s11682-013-9286-4

    View details for PubMedID 24421067

    View details for PubMedCentralID PMC4097992

  • Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke's encephalopathy EXPERIMENTAL NEUROLOGY Zahr, N. M., Alt, C., Mayer, D., Rohlfing, T., Manning-Bog, A., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2014; 261: 109-119
  • Imaging neuroinflammation? A perspective from MR spectroscopy. Brain pathology Zahr, N. M., Mayer, D., Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. 2014; 24 (6): 654-664


    Neuroinflammatory mechanisms contribute to the brain pathology resulting from human immunodeficiency virus (HIV) infection. Magnetic resonance spectroscopy (MRS) has been touted as a suitable method for discriminating in vivo markers of neuroinflammation. The present MRS study was conducted in four groups: alcohol dependent (A, n = 37), HIV-infected (H, n = 33), alcohol dependent + HIV infected (HA, n = 38) and healthy control (C, n = 62) individuals to determine whether metabolites would change in a pattern reflecting neuroinflammation. Significant four-group comparisons were evident only for striatal choline-containing compounds (Cho) and myo-inositol (mI), which follow-up analysis demonstrated were due to higher levels in HA compared with C individuals. To explore the potential relevance of elevated Cho and mI, correlations between blood markers, medication status and alcohol consumption were evaluated in H + HA subjects. Having an acquired immune deficiency syndrome (AIDS)-defining event or hepatitis C was associated with higher Cho; lower Cho levels, however, were associated with low thiamine levels and with highly active antiretroviral HIV treatment (HAART). Higher levels of mI were related to greater lifetime alcohol consumed, whereas HAART was associated with lower mI levels. The current results suggest that competing mechanisms can influence in vivo Cho and mI levels, and that elevations in these metabolites cannot necessarily be interpreted as reflecting a single underlying mechanism, including neuroinflammation.

    View details for DOI 10.1111/bpa.12197

    View details for PubMedID 25345895

    View details for PubMedCentralID PMC4493672

  • Chronic alcohol consumption and its effect on nodes of frontocerebellar and limbic circuitry: Comparison of effects in France and the United States. Human brain mapping Le Berre, A., Pitel, A., Chanraud, S., Beaunieux, H., Eustache, F., Martinot, J., Reynaud, M., Martelli, C., Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. 2014; 35 (9): 4635-4653


    Alcohol use disorders present a significant public health problem in France and the United States (U.S.), but whether the untoward effect of alcohol on the brain results in similar damage in both countries remains unknown. Accordingly, we conducted a retrospective collaborative investigation between two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) with T1-weighted, structural MRI data collected on a common imaging platform (1.5T, General Electric) on 288 normal controls (NC), 165 uncomplicated alcoholics (ALC), and 26 patients with alcoholic Korsakoff's syndrome (KS) diagnosed at all sites with a common interview instrument. Data from the two countries were pooled, then preprocessed and analyzed together at the U.S. site using atlas-based parcellation. National differences indicated that thalamic volumes were smaller in ALC in France than the U.S. despite similar alcohol consumption levels in both countries. By contrast, volumes of the hippocampus, amygdala, and cerebellar vermis were smaller in KS in the U.S. than France. Estimated amount of alcohol consumed over a lifetime, duration of alcoholism, and length of sobriety were significant predictors of selective regional brain volumes in France and in the U.S. The common analysis of MRI data enabled identification of discrepancies in brain volume deficits in France and the U.S. that may reflect fundamental differences in the consequences of alcoholism on brain structure between the two countries, possibly related to genetic or environmental differences. Hum Brain Mapp 35:4635-4653, 2014. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.22500

    View details for PubMedID 24639416

  • White matter microstructural recovery with abstinence and decline with relapse in alcohol dependence interacts with normal ageing: a controlled longitudinal DTI study LANCET PSYCHIATRY Pfefferbaum, A., Rosenbloom, M. J., Chu, W., Sassoon, S. A., Rohlfing, T., Pohl, K. M., Zahr, N. M., Sullivan, E. V. 2014; 1 (3): 202-212


    Alcohol dependence exacts a toll on brain white matter microstructure, which has the potential of repair with prolonged sobriety. Diffusion tensor imaging (DTI) enables in-vivo quantification of tissue constituents and localisation of tracts potentially affected in alcohol dependence and its recovery. We did an extended longitudinal study of alcoholism's trajectory of effect on selective fibre bundles with sustained sobriety or decline with relapse.Participants were drawn from a longitudinal, 1·5T DTI database of 841 scans of individuals with various medical or neuropsychiatric conditions and normal ageing. Participants diagnosed with alcohol dependence had to meet the criteria from DSM-IV for alcohol dependence. Controls were screened and free of any DSM-IV axis I diagnosis, including being without history of alcohol or drug abuse or dependence. Tract-based spatial statistics (TBSS) quantified white matter integrity throughout the brain in 47 alcohol-dependent individuals and 56 controls examined 2-5 times over 1-8 year intervals. We identified regions showing group differences with a white matter atlas. For macrostructural comparison, we measured corpus callosum and centrum semiovale volumes on MRI.This study took place in the USA, between June 23, 2000, and Sept 6, 2011. TBSS identified a large cluster (threshold p<0·001), where controls showed significant fractional anisotropy (FA) decrease with ageing and alcohol-dependent individuals had significantly lower FA than controls regardless of age. Over the examination interval, 27 (57%) alcohol-dependent individuals abstained, ten (21%) relapsed into light drinking, and ten (21%) relapsed into heavy drinking (>5 kg of alcohol/year). Despite abnormally low FA, age trajectories of the abstainers were positive and progressing toward normality, whereas those of the relapsers and controls were negative. Axial diffusivity (lower values indexing myelin integrity) was abnormally high in the total alcohol-dependent group; however, the abstainers' slopes paralleled those of controls, whereas the heavy-drinking relapsers' slopes showed accelerated ageing. Callosal genu and body microstructure but not macrostructure showed untoward alcohol-related effects. Affected projection and association tracts had an anterior and superior neuroanatomical distribution.Return to heavy drinking resulted in accelerating microstructural white matter damage. Despite evidence for damage, alcohol-dependent individuals maintaining sobriety over extended periods showed improvement in brain fibre tract integrity reflective of fibre reorganisation and myelin restoration, indicative of a neural mechanism explaining recovery.US National Institute on Alcohol Abuse and Alcoholism (AA012388, AA017168, AA005965, AA013521-INIA).

    View details for Web of Science ID 000343703500022

  • Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study. Neurobiology of aging Pfefferbaum, A., Rogosa, D. A., Rosenbloom, M. J., Chu, W., Sassoon, S. A., Kemper, C. A., Deresinski, S., Rohlfing, T., Zahr, N. M., Sullivan, E. V. 2014; 35 (7): 1755-1768


    Advances in treatment have transformed human immunodeficiency virus (HIV) infection from an inexorable march to severe morbidity and premature death to a manageable chronic condition, often marked by good health. Thus, infected individuals are living long enough that there is a potential for interaction with normal senescence effects on various organ systems, including the brain. To examine this interaction, the brains of 51 individuals with HIV infection and 65 uninfected controls were studied using 351 magnetic resonance imaging and a battery of neuropsychological tests collected 2 or more times over follow-up periods ranging from 6 months to 8 years. Brain tissue regions of interest showed expected age-related decrease in volume; cerebrospinal fluid-filled spaces showed increase in volume for both groups. Although HIV-infected individuals were in good general health, and free of clinically-detectable dementia, several brain regions supporting higher-order cognition and integration of functions showed acceleration of the normal aging trajectory, including neocortex, which extended from the frontal and temporal poles to the parietal lobe, and the thalamus. Beyond an anticipated increase in lateral ventricle and Sylvian fissure volumes and decrease in tissue volumes (specifically, the frontal and sensorimotor neocortices, thalamus, and hippocampus) with longer duration of illness, most regions also showed accelerated disease progression. This accelerated loss of cortical tissue may represent a risk factor for premature cognitive and motor compromise if not dementia. On a more promising note, HIV-infected patients with increasing CD4 counts exhibited slower expansion of Sylvian fissure volume and slower declines of frontal and temporoparietal cortices, insula, and hippocampus tissue volumes. Thus, attenuated shrinkage of these brain regions, likely with adequate pharmacologic treatment and control of further infection, has the potential of abating decline in associated higher-order functions, notably, explicit memory, executive functions, self-regulation, and visuospatial abilities.

    View details for DOI 10.1016/j.neurobiolaging.2014.01.008

    View details for PubMedID 24508219

    View details for PubMedCentralID PMC3980003

  • Dissociation of preparatory attention and response monitoring maturation during adolescence. Clinical neurophysiology Padilla, M. L., Pfefferbaum, A., SULLIVAN, E. V., Baker, F. C., Colrain, I. M. 2014; 125 (5): 962-970


    Substantial brain development occurs during adolescence providing the foundation for functional advancement from stimulus-bound "bottom-up" to more mature executive-driven "top-down" processing strategies. The objective was to assess development of EEG markers of these strategies and their role in both preparatory attention (contingent negative variation, CNV) and response monitoring (Error Related Negativity, ERN, and Correct Related Negativity, CRN).CNV, ERN and CRN were assessed in 38 adolescents (18 girls), age 11-18 years, using a variation of a letter discrimination task.Accuracy increased with age and developmental stage. Younger adolescents used a posterior attention network involved in inhibiting irrelevant information. Activity in this juvenile network, as indexed by a posteriorly-biased CNV and CRN decreased with age and advancing pubertal development. Although enhanced frontal CNV, known to be predictive of accuracy in adults, was not detected even in the older adolescents, top-down medial frontal response monitoring processes (ERN) showed evidence of development within the age-range studied.The data revealed a dissociation of developmental progress, marked by relatively delayed onset of frontal preparatory attention relative to error monitoring.This dissociation may render adolescents vulnerable to excessive risk-taking and disinhibited behavior imposed by asynchronous development of component cognitive control processes.

    View details for DOI 10.1016/j.clinph.2013.10.012

    View details for PubMedID 24211003

    View details for PubMedCentralID PMC3981931

  • Synchrony of anterior cingulate cortex and insular-striatal activation predicts ambiguity aversion in individuals with low impulsivity. Cerebral cortex Jung, Y., Schulte, T., Müller-Oehring, E. M., Hawkes, W., Namkoong, K., Pfefferbaum, A., Sullivan, E. V. 2014; 24 (5): 1397-1408


    Personal attitude toward ambiguity contributes to individual differences in decision making in uncertain situations. Operationally, these attitudes reflect the various coping strategies elected to overcome the limited information. A key brain region involved in cognitive control for performance adjustments is the dorsal anterior cingulate cortex (dACC). To test how dACC functional network connectivity would be modulated by uncertainty and differ between individuals, 24 healthy participants underwent functional MRI in 3 sequential runs: 1 resting-state and 2 decision-making task runs. Individuals with lower nonplanning impulsiveness made greater use of a Pass option and avoided uncertain ambiguous situations. Seed-based functional connectivity analysis during the task runs revealed that stronger activation synchrony between the left dACC and the right anterior insula correlated with greater use of a Pass response option. During the resting-state, stronger resting-state functional connectivity between the left dACC and the ventral striatum predicted the adoption of Pass as a behavioral strategy and correlated with stronger task-activated synchrony between the dACC and the right anterior insula. Our findings indicate that that the synchrony between the dACC and insula-striatal circuitry was greater in individuals with low compared with high nonplanning impulsiveness and contributed to adopting Pass as a useful behavioral strategy.

    View details for DOI 10.1093/cercor/bht008

    View details for PubMedID 23355606

  • Monkeys that Voluntarily and Chronically Drink Alcohol Damage their Brains: a Longitudinal MRI Study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Kroenke, C. D., Rohlfing, T., Park, B., Sullivan, E. V., Pfefferbaum, A., Grant, K. A. 2014; 39 (4): 823-830


    Neuroimaging has consistently documented reductions in the brain tissue of alcoholics. Inability to control comorbidity, environmental insult, and nutritional deficiency, however, confound the ability to assess whether ethanol itself is neurotoxic. Here we report monkey oral ethanol self-administration combined with MR imaging to characterize brain changes over 15 months in 18 well-nourished rhesus macaques. Significant brain volume shrinkage occurred in the cerebral cortices of monkeys drinking3 g/kg ethanol/day (12 alcoholic drinks) at 6 months, and this persisted throughout the period of continuous access to ethanol. Correlation analyses revealed a cerebral cortical volumetric loss of ∼0.11% of the intracranial vault for each daily drink (0.25 g/kg), and selective vulnerability of cortical and non-cortical brain regions. These results demonstrate for the first time a direct relation between oral ethanol intake and measures of decreased brain gray matter volume in vivo in primates. Notably, greater volume shrinkage occurred in monkeys with younger drinking onset that ultimately became heavier drinkers than monkeys with older drinking onset. The pattern of volumetric changes observed in nonhuman primates following 15 months of drinking suggests that cerebral cortical gray matter changes are the first macroscopic manifestation of chronic ethanol exposure in the brain.

    View details for DOI 10.1038/npp.2013.259

    View details for PubMedID 24077067

  • Rat strain differences in brain structure and neurochemistry in response to binge alcohol PSYCHOPHARMACOLOGY Zahr, N. M., Mayer, D., Rohlfing, T., Hsu, O., Vinco, S., Orduna, J., Luong, R., Bell, R. L., Sullivan, E. V., Pfefferbaum, A. 2014; 231 (2): 429-445


    Ventricular enlargement is a robust phenotype of the chronically dependent alcoholic human brain, yet the mechanism of ventriculomegaly is unestablished. Heterogeneous stock Wistar rats administered binge EtOH (3 g/kg intragastrically every 8 h for 4 days to average blood alcohol levels (BALs) of 250 mg/dL) demonstrate profound but reversible ventricular enlargement and changes in brain metabolites (e.g., N-acetylaspartate (NAA) and choline-containing compounds (Cho)).Here, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats systematically bred from heterogeneous stock Wistar rats for differential alcohol drinking behavior were compared with Wistar rats to determine whether genetic divergence and consequent morphological and neurochemical variation affect the brain's response to binge EtOH treatment.The three rat lines were dosed equivalently and approached similar BALs. Magnetic resonance imaging and spectroscopy evaluated the effects of binge EtOH on brain.As observed in Wistar rats, P and NP rats showed decreases in NAA. Neither P nor NP rats, however, responded to EtOH intoxication with ventricular expansion or increases in Cho levels as previously noted in Wistar rats. Increases in ventricular volume correlated with increases in Cho in Wistar rats.The latter finding suggests that ventricular volume expansion is related to adaptive changes in brain cell membranes in response to binge EtOH. That P and NP rats responded differently to EtOH argues for intrinsic differences in their brain cell membrane composition. Further, differential metabolite responses to EtOH administration by rat strain implicate selective genetic variation as underlying heterogeneous effects of chronic alcoholism in the human condition.

    View details for DOI 10.1007/s00213-013-3253-z

    View details for Web of Science ID 000329321700013

    View details for PubMedID 24030467

    View details for PubMedCentralID PMC3904647

  • Methods of association and dissociation for establishing selective brain-behavior relations. Handbook of clinical neurology Fama, R., Sullivan, E. V. 2014; 125: 175-181


    Methods for identifying and understanding brain structure-function relations have evolved over the past century, from astute observations of selective impairments associated with focal brain damage to dissociations measured by combining quantitative neuropsychologic assessment and brain imaging. Enhanced spatial and temporal resolution in brain imaging modalities has led to refined visualization and quantification of the brain's substructures, microstructural integrity, and functional connectivity of neural networks. The double dissociation model has been a gold standard used to demonstrate that a particular cognitive, emotional, sensory, or motor process is selectively related to a particular brain region or neural network and not to others. This model has provided a fruitful means for testing hypotheses of functional localization and enabled examination and establishment of component processes contributing to complex cognitive and motor functions, parsing multifactorial behaviors and identifying brain regions, and networks subserving these complex abilities. In this chapter we discuss the evolution of the dissociation model and highlight how the modifications of this model are used presently to establish selective brain-behavior relationships in disorders such as chronic alcoholism with a neuropathologic signature but no localizable, space-occupying lesion.

    View details for DOI 10.1016/B978-0-444-62619-6.00011-2

    View details for PubMedID 25307575

  • The impact of consumer affordability on access to assisted reproductive technologies and embryo transfer practices: an international analysis. Fertility and sterility Chambers, G. M., Hoang, V. P., Sullivan, E. A., Chapman, M. G., Ishihara, O., Zegers-Hochschild, F., Nygren, K. G., Adamson, G. D. 2014; 101 (1): 191-198 e4


    To systematically quantify the impact of consumer cost on assisted reproduction technology (ART) utilization and numbers of embryos transferred.Ordinary least squared (OLS) regression models were constructed to measure the independent impact of ART affordability-measured as consumer cost relative to average disposable income-on ART utilization and embryo transfer practices.Not applicable.Women undergoing ART treatment.None.OLS regression coefficient for ART affordability, which estimates the independent effect of consumer cost relative to income on utilization and number of embryos transferred.ART affordability was independently and positively associated with ART utilization with a mean OLS coefficient of 0.032. This indicates that, on average, a decrease in the cost of a cycle of 1 percentage point of disposable income predicts a 3.2% increase in utilization. ART affordability was independently and negatively associated with the number of embryos transferred, indicating that a decrease in the cost of a cycle of 10 percentage points of disposable income predicts a 5.1% increase in single-embryo transfer cycles.The relative cost that consumers pay for ART treatment predicts the level of access and number of embryos transferred. Policies that affect ART funding should be informed by these findings to ensure equitable access to treatment and clinically responsible embryo transfer practices.

    View details for DOI 10.1016/j.fertnstert.2013.09.005

    View details for PubMedID 24156958

  • Compensatory recruitment of neural resources in chronic alcoholism. Handbook of clinical neurology Chanraud, S., Sullivan, E. V. 2014; 125: 369-380


    Functional recovery occurs with sustained sobriety, but the neural mechanisms enabling recovery are only now emerging. Theories about promising mechanisms involve concepts of neuroadaptation, where excessive alcohol consumption results in untoward structural and functional brain changes which are subsequently candidates for reversal with sobriety. Views on functional adaptation in chronic alcoholism have expanded with results from neuroimaging studies. Here, we first describe and define the concept of neuroadaptation according to emerging theories based on the growing literature in aging-related cognitive functioning. Then we describe findings as they apply to chronic alcoholism and factors that could influence compensation, such as functional brain reserve and the integrity of brain structure. Finally, we review brain plasticity based on physiologic mechanisms that could underlie mechanisms of neural compensation. Where possible, we provide operational criteria to define functional and neural compensation.

    View details for DOI 10.1016/B978-0-444-62619-6.00022-7

    View details for PubMedID 25307586

  • A Selective Insular Perfusion Deficit Contributes to Compromised Salience Network Connectivity in Recovering Alcoholic Men BIOLOGICAL PSYCHIATRY Sullivan, E. V., Mueller-Oehring, E., Pitel, A., Chanraud, S., Shankaranarayanan, A., Alsop, D. C., Rohlfing, T., Pfefferbaum, A. 2013; 74 (7): 547-555
  • Midbrain-driven emotion and reward processing in alcoholism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Müller-Oehring, E. M., Jung, Y., SULLIVAN, E. V., Hawkes, W. C., Pfefferbaum, A., Schulte, T. 2013; 38 (10): 1844-1853


    Alcohol dependence is associated with impaired control over emotionally motivated actions, possibly associated with abnormalities in the frontoparietal executive control network and midbrain nodes of the reward network associated with automatic attention. To identify differences in the neural response to alcohol-related word stimuli, 26 chronic alcoholics (ALC) and 26 healthy controls (CTL) performed an alcohol-emotion Stroop Match-to-Sample task during functional MR imaging. Stroop contrasts were modeled for color-word incongruency (eg, word RED printed in green) and for alcohol (eg, BEER), positive (eg, HAPPY) and negative (eg, MAD) emotional word content relative to congruent word conditions (eg, word RED printed in red). During color-Stroop processing, ALC and CTL showed similar left dorsolateral prefrontal activation, and CTL, but not ALC, deactivated posterior cingulate cortex/cuneus. An interaction revealed a dissociation between alcohol-word and color-word Stroop processing: ALC activated midbrain and parahippocampal regions more than CTL when processing alcohol-word relative to color-word conditions. In ALC, the midbrain region was also invoked by negative emotional Stroop words thereby showing significant overlap of this midbrain activation for alcohol-related and negative emotional processing. Enhanced midbrain activation to alcohol-related words suggests neuroadaptation of dopaminergic midbrain systems. We speculate that such tuning is normally associated with behavioral conditioning to optimize responses but here contributed to automatic bias to alcohol-related stimuli.Neuropsychopharmacology advance online publication, 29 May 2013; doi:10.1038/npp.2013.102.

    View details for DOI 10.1038/npp.2013.102

    View details for PubMedID 23615665

  • Fiber tract-driven topographical mapping (FTTM) reveals microstructural relevance for interhemispheric visuomotor function in the aging brain. NeuroImage Schulte, T., Maddah, M., Müller-Oehring, E. M., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2013; 77: 195-206


    We present a novel approach - DTI-based fiber tract-driven topographical mapping (FTTM) - to map and measure the influence of age on the integrity of interhemispheric fibers and challenge their selective functions with measures of interhemispheric integration of lateralized information. This approach enabled identification of spatially specific topographical maps of scalar diffusion measures and their relation to measures of visuomotor performance. Relative to younger adults, older adults showed lower fiber integrity indices in anterior than posterior callosal fibers. FTTM analysis identified a dissociation in the microstructural-function associates between age groups: in younger adults, genu fiber integrity correlated with interhemispheric transfer time, whereas in older adults, body fiber integrity was correlated with interhemispheric transfer time with topographical specificity along left-lateralized callosal fiber trajectories. Neural co-activation from redundant targets was evidenced by fMRI-derived bilateral extrastriate cortex activation in both groups, and a group difference emerged for a pontine activation cluster that was differently modulated by response hand in older than younger adults. Bilateral processing advantages in older but not younger adults further correlated with fiber integrity in transverse pontine fibers that branch into the right cerebellar cortex, thereby supporting a role for the pons in interhemispheric facilitation. In conclusion, in the face of compromised anterior callosal fibers, older adults appear to use alternative pathways to accomplish visuomotor interhemispheric information transfer and integration for lateralized processing. This shift from youthful associations may indicate recruitment of compensatory mechanisms involving medial corpus callosum fibers and subcortical pathways.

    View details for DOI 10.1016/j.neuroimage.2013.03.056

    View details for PubMedID 23567886

  • A mechanism of rapidly reversible cerebral ventricular enlargement independent of tissue atrophy. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Zahr, N. M., Mayer, D., Rohlfing, T., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2013; 38 (6): 1121-1129


    Ventricular enlargement, a common in vivo marker of aging, disease, and insult, is presumed to reflect atrophy of surrounding brain regions. Pathological mechanisms underlying ventricular enlargement, however, are likely specific to the condition under investigation. Here, multimodal imaging, incorporating structural magnetic resonance imaging (MRI), MR spectroscopy (MRS), and diffusion weighted imaging (DWI), was used in rats exposed to binge ethanol (EtOH) to provide insight into a mechanism of reversible ventricular enlargement. During intoxication, MRI revealed expansion of ventricles, but volume changes in dorsal or ventral hippocampi, caudate-putamen, or thalamus were not detectible. MRS of whole-brain parenchyma showed decreases in N-acetylasparate (NAA) and tissue water T2, and increases in choline-containing compounds (Cho). DWI showed decreased diffusivity selective to the thalamus. All MR parameters returned to baseline with 7 days of recovery. Rapid recovery of ventricular volume and the absence of detectable tissue volume reductions in brain regions adjacent to ventricles argue against atrophy as a mechanism of ventricular expansion. Decreased tissue water T2 and decreased thalamic diffusivity suggest lower tissue water content and a role for both NAA and Cho, as osmolytes is proposed. Together, these data support a model of fluid redistribution during acute EtOH intoxication and recovery to account for rapid ventricular volume changes.

    View details for DOI 10.1038/npp.2013.11

    View details for PubMedID 23306181

    View details for PubMedCentralID PMC3629396

  • Modulation of limbic-cerebellar functional connectivity enables alcoholics to recognize who is who BRAIN STRUCTURE & FUNCTION Pitel, A., Chanraud, S., Mueller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2013; 218 (3): 683-695
  • A Mechanism of Rapidly Reversible Cerebral Ventricular Enlargement Independent of Tissue Atrophy NEUROPSYCHOPHARMACOLOGY Zahr, N. M., Mayer, D., Rohlfing, T., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2013; 38 (6): 1121-1129

    View details for DOI 10.1038/npp.2013.11

    View details for Web of Science ID 000317584600023

    View details for PubMedID 23306181

  • Modulation of limbic-cerebellar functional connectivity enables alcoholics to recognize who is who. Brain structure & function Pitel, A., Chanraud, S., Müller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2013; 218 (3): 683-695


    Chronic alcoholism is known to disrupt functions served by distributed brain systems, including limbic and frontocerebellar circuits involved in resting-state and task-activated networks subserving component processes of memory often affected in alcoholics. Using an fMRI paradigm, we investigated whether memory performance by alcoholics on a face-name association test previously observed to be problematic for alcoholics could be explained by desynchronous activity between nodes of these specific networks. While in the scanner, 18 alcoholics and 15 controls performed a face-name associative learning task with different levels of processing at encoding. This task was designed to activate the hippocampus, cerebellum, and frontal cortex. Alcoholics and controls were also scanned at rest. Twelve alcoholics and 12 controls were selected to be matched on face-name recognition performance. Task-related fMRI analysis indicated that alcoholics had preserved limbic activation but lower cerebellar activation (Crus II) than the controls in the face-name learning task. Crus II was, therefore, chosen as a seed for functional connectivity MRI analysis. At rest, the left hippocampus and left Crus II had positively synchronized activity in controls, while hippocampal and cerebellar activities were negatively synchronized in alcoholics. Task engagement resulted in hippocampal-cerebellar desynchronization in both groups. We speculate that atypical cerebello-hippocampal activity synchronization during rest in alcoholics was reset to the normal pattern of asynchrony by task engagement. Aberrations from the normal pattern of resting-state default mode synchrony could be interpreted as enabling preserved face-name associative memory in alcoholism.

    View details for DOI 10.1007/s00429-012-0421-6

    View details for PubMedID 22585315

  • In vivo glutamate measured with magnetic resonance spectroscopy: behavioral correlates in aging NEUROBIOLOGY OF AGING Zahr, N. M., Mayer, D., Rohlfing, T., Chanraud, S., Gu, M., Sullivan, E. V., Pfefferbaum, A. 2013; 34 (4): 1265-1276


    Altered availability of the brain biochemical glutamate might contribute to the neural mechanisms underlying age-related changes in cognitive and motor functions. To investigate the contribution of regional glutamate levels to behavior in the aging brain, we used an in vivo magnetic resonance spectroscopy protocol optimized for glutamate detection in 3 brain regions targeted by cortical glutamatergic efferents-striatum, cerebellum, and pons. Data from 61 healthy men and women ranging in age from 20 to 86 years were used. Older age was associated with lower glutamate levels in the striatum, but not cerebellum or pons. Older age was also predictive of poorer performance on tests of visuomotor skills and balance. Low striatal glutamate levels were associated with high systolic blood pressure and worse performance on a complex visuomotor task, the Grooved Pegboard. These findings suggest that low brain glutamate levels are related to high blood pressure and that changes in brain glutamate levels might mediate the behavioral changes noted in normal aging.

    View details for DOI 10.1016/j.neurobiolaging.2012.09.014

    View details for Web of Science ID 000314708000027

    View details for PubMedID 23116877

    View details for PubMedCentralID PMC3545108

  • Introduction to the Special Issue of Neuropsychology Review on Cognitive Enhancement and Rehabilitation NEUROPSYCHOLOGY REVIEW Sullivan, E. V., Tapert, S. F. 2013; 23 (1): 10-12

    View details for DOI 10.1007/s11065-013-9231-8

    View details for Web of Science ID 000316222200001

    View details for PubMedID 23443579

  • Quantification of glutamate and glutamine using constant-time point-resolved spectroscopy at 3 T NMR IN BIOMEDICINE Gu, M., Zahr, N. M., Spielman, D. M., Sullivan, E. V., Pfefferbaum, A., Mayer, D. 2013; 26 (2): 164-172


    Separate quantification of glutamate (Glu) and glutamine (Gln) using conventional MRS on clinical scanners is challenging. In previous work, constant-time point-resolved spectroscopy (CT-PRESS) was optimized at 3 T to detect Glu, but did not resolve Gln. To quantify Glu and Gln, a time-domain basis set was constructed taking into account metabolite T(2) relaxation times and dephasing from B(0) inhomogeneity. Metabolite concentrations were estimated by fitting the basis one-dimensional CT-PRESS diagonal magnitude spectra to the measured spectrum. This method was first validated using seven custom-built phantoms containing variable metabolite concentrations, and then applied to in vivo data acquired in rats exposed to vaporized ethanol and controls. Separate metabolite quantification revealed increased Gln after 16 weeks and increased Glu after 24 weeks of vaporized ethanol exposure in ethanol-treated compared with control rats. Without separate quantification, the signal from the combined resonances of Glu and Gln (Glx) showed an increase at both 16 and 24 weeks in ethanol-exposed rats, precluding the determination of the independent and differential contribution of each metabolite at each time.

    View details for DOI 10.1002/nbm.2831

    View details for Web of Science ID 000313886500007

    View details for PubMedID 22761057

  • Variation in longitudinal trajectories of regional brain volumes of healthy men and women (ages 10 to 85 years) measured with atlas-based parcellation of MRI NEUROIMAGE Pfefferbaum, A., Rohlfing, T., Rosenbloom, M. J., Chu, W., Colrain, I. M., Sullivan, E. V. 2013; 65: 176-193


    Numerous cross-sectional MRI studies have characterized age-related differences in regional brain volumes that differ with structure and tissue type. The extent to which cross-sectional assumptions about change are accurate depictions of actual longitudinal measurement remains controversial. Even longitudinal studies can be limited by the age range of participants, sex distribution of the samples, and scan intervals. To address these issues, we calculated trajectories of regional brain volume changes from T1-weighted (SPGR) MRI data, quantified with our automated, unsupervised SRI24 atlas-based registration and parcellation method. Longitudinal MRIs were acquired at 3T in 17 boys and 12 girls, age 10 to 14 years, and 41 men and 41 women, age 20 to 85 years at first scan. Application of a regression-based correction function permitted merging of data acquired at 3T field strength with data acquired at 1.5T from additional subjects, thereby expanding the sample to a total of 55 men and 67 women, age 20 to 85 years at first scan. Adjustment for individual supratentorial volume removed regional volume differences between men and women due to sex-related differences in head size. Individual trajectories were computed from data collected on 2 to 6 MRIs at a single field strength over a ~1 to 8 year interval. Using linear mixed-effects models, the pattern of trajectories over age indicated: rises in ventricular and Sylvian fissure volumes, with older individuals showing faster increases than younger ones; declines in selective cortical volumes with faster tissue shrinkage in older than younger individuals; little effect of aging on volume of the corpus callosum; more rapid expansion of CSF-filled spaces in men than women after age 60 years; and evidence for continued growth in central white matter through early adulthood with accelerated decline in senescence greater in men than women.

    View details for DOI 10.1016/j.neuroimage.2012.10.008

    View details for Web of Science ID 000312283900016

    View details for PubMedID 23063452

  • Remapping the brain to compensate for impairment in recovering alcoholics. Cerebral cortex Chanraud, S., Pitel, A., Müller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2013; 23 (1): 97-104


    Abnormal brain activity may reflect compensation when observed in patients who perform normally on tests requiring functions usually observed as impaired. Operational criteria defining compensation have been described and aid in distinguishing compensatory from chance events. Here, we tested whether previously published functional magnetic resonance imaging data acquired in 15 recovering alcoholics and 15 controls at rest and while performing a spatial working memory task would fulfill criteria defining functional compensation. Multivariate analysis tested how well abnormal activation in the affected group predicted normal performance, despite low or no activation in brain regions invoked by controls to accomplish the same task. By identifying networks that uniquely and positively correlated with good performance, we provide evidence for compensatory recruitment of cerebellar-based functional networks by alcoholics. Whereas controls recruited prefrontal-cerebellar regions VI/Crus I known to subserve working memory, alcoholics recruited 2 other parallel frontocerebellar loops: dorsolateral prefrontal cortex (DLPFC)-cerebellar VIII system during rest and DLPFC-cerebellar VI system while task engaged. Greater synchronous activity between cerebellar lobule VIII and DLPFC at rest and greater activation within cerebellar lobule VI and DLPFC during task predicted better working memory performance. Thus, higher intrinsic cerebellar activity in alcoholics was an adequate condition for triggering task-relevant activity in the frontal cortex required for normal working memory performance.

    View details for DOI 10.1093/cercor/bhr381

    View details for PubMedID 22275479

    View details for PubMedCentralID PMC3513953

  • Remapping the Brain to Compensate for Impairment in Recovering Alcoholics CEREBRAL CORTEX Chanraud, S., Pitel, A., Mueller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2013; 23 (1): 97-104
  • Visual Search and the Aging Brain: Discerning the Effects of Age-Related Brain Volume Shrinkage on Alertness, Feature Binding, and Attentional Control NEUROPSYCHOLOGY Mueller-Oehring, E. M., Schulte, T., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2013; 27 (1): 48-59

    View details for DOI 10.1037/a0030921

    View details for Web of Science ID 000313757200006

    View details for PubMedID 23356596

  • Visual search and the aging brain: discerning the effects of age-related brain volume shrinkage on alertness, feature binding, and attentional control. Neuropsychology Müller-Oehring, E. M., Schulte, T., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2013; 27 (1): 48-59


    Decline in visuospatial abilities with advancing age has been attributed to a demise of bottom-up and top-down functions involving sensory processing, selective attention, and executive control. These functions may be differentially affected by age-related volume shrinkage of subcortical and cortical nodes subserving the dorsal and ventral processing streams and the corpus callosum mediating interhemispheric information exchange.Fifty-five healthy adults (25-84 years) underwent structural MRI and performed a visual search task to test perceptual and attentional demands by combining feature-conjunction searches with "gestalt" grouping and attentional cueing paradigms.Poorer conjunction, but not feature, search performance was related to older age and volume shrinkage of nodes in the dorsolateral processing stream. When displays allowed perceptual grouping through distractor homogeneity, poorer conjunction-search performance correlated with smaller ventrolateral prefrontal cortical and callosal volumes. An alerting cue attenuated age effects on conjunction search, and the alertness benefit was associated with thalamic, callosal, and temporal cortex volumes.Our results indicate that older adults can capitalize on early parallel stages of visual information processing, whereas age-related limitations arise at later serial processing stages requiring self-guided selective attention and executive control. These limitations are explained in part by age-related brain volume shrinkage and can be mitigated by external cues.

    View details for DOI 10.1037/a0030921

    View details for PubMedID 23356596

    View details for PubMedCentralID PMC3718286

  • Differential Effect of Alcoholism and HIV Infection on Visuomotor Procedural Learning and Retention ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Rosenbloom, M. J., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2012; 36 (10): 1738-1747


    Selective declarative memory processes are differentially compromised in chronic alcoholism (ALC) and HIV infection (HIV) and likely reflect neuropathology associated with each condition: frontocerebellar dysfunction in ALC and frontostriatal dysfunction in HIV infection. Evidence for disease overlap derives from observed exacerbated impairments in these declarative memory processes in ALC-HIV comorbidity. Less is known about nondeclarative memory processes in these disease conditions. Examination of visuomotor learning in chronic ALC and HIV infection could provide insight into the differential and combined contribution of selective disease-related injury to visuomotor procedural memory processes.We examined component processes of visuomotor learning and retention on the rotary pursuit task in 29 ALC, 23 HIV, 28 ALC + HIV, and 20 control subjects. Participants were given 4 rotary pursuit learning sessions over 2 testing days, typically separated by 1 week, to assess visuomotor learning and retention patterns. Ancillary measures of simple motor, psychomotor, explicit memory, and balance abilities were administered to test which component processes independently predicted visuomotor learning.All clinical groups showed visuomotor learning across rotary pursuit testing sessions, despite impairment in visuomotor speed in the HIV groups and impairment in explicit memory and psychomotor speed in the alcohol groups. The 2 alcoholic groups showed retention and consolidation over time (i.e., improved performance without further training), whereas the HIV-infected group showed learning and retention but no consolidation effect. The comorbid group shared impairments associated with the ALC-only group (explicit memory and psychomotor speed) and the HIV-only group (visuomotor speed), although there was no clear compounded effect of alcohol and HIV infection on visuomotor learning performance.This study supports the hypothesis that ALC and HIV infection exert differential effects on components of visuomotor procedural learning. Further, the results provide behavioral evidence for dissociable influences of frontocerebellar and frontostriatal disruption to visuomotor procedural learning and retention.

    View details for DOI 10.1111/j.1530-0277.2012.01790.x

    View details for Web of Science ID 000309390800009

    View details for PubMedID 22823125

    View details for PubMedCentralID PMC3463647

  • White matter fiber compromise contributes differentially to attention and emotion processing impairment in alcoholism, HIV-infection, and their comorbidity NEUROPSYCHOLOGIA Schulte, T., Mueller-Oehring, E. M., SULLIVAN, E. V., Pfefferbaum, A. 2012; 50 (12): 2812-2822


    Alcoholism (ALC) and HIV-1 infection (HIV) each affects emotional and attentional processes and integrity of brain white matter fibers likely contributing to functional compromise. The highly prevalent ALC+HIV comorbidity may exacerbate compromise. We used diffusion tensor imaging (DTI) and an emotional Stroop Match-to-Sample task in 19 ALC, 16 HIV, 15 ALC+HIV, and 15 control participants to investigate whether disruption of fiber system integrity accounts for compromised attentional and emotional processing. The task required matching a cue color to that of an emotional word with faces appearing between the color cue and the Stroop word in half of the trials. Nonmatched cue-word color pairs assessed selective attention, and face-word pairs assessed emotion. Relative to controls, DTI-based fiber tracking revealed lower inferior longitudinal fasciculus (ilf) integrity in HIV and ALC+HIV and lower uncinate fasciculus (uf) integrity in all three patient groups. Controls exhibited Stroop effects to positive face-word emotion, and greater interference was related to greater callosal, cingulum and ilf integrity. By contrast, HIV showed greater interference from negative Stroop words during color-nonmatch trials, correlating with greater uf compromise. For face trials, ALC and ALC+HIV showed greater Stroop-word interference, correlating with lower cingulate and callosal integrity. Thus, in HIV, conflict resolution was diminished when challenging conditions usurped resources needed to manage interference from negative emotion and to disengage attention from wrongly cued colors (nonmatch). In ALC and ALC+HIV, poorer callosal integrity was related to enhanced emotional interference suggesting curtailed interhemispheric exchange needed between preferentially right-hemispheric emotion and left-hemispheric Stroop-word functions.

    View details for DOI 10.1016/j.neuropsychologia.2012.07.042

    View details for Web of Science ID 000310945900012

    View details for PubMedID 22960416

    View details for PubMedCentralID PMC3473169

  • Selective neurocognitive deficits and poor life functioning are associated with significant depressive symptoms in alcoholism-HIV infection comorbidity PSYCHIATRY RESEARCH Sassoon, S. A., Rosenbloom, M. J., Fama, R., Sullivan, E. V., Pfefferbaum, A. 2012; 199 (2): 102-110


    Alcoholism, HIV, and depressive symptoms frequently co-occur and are associated with impairment in cognition and life function. We administered the Beck Depression Inventory-II (BDI-II), measures of life function, and neurocognitive tests to 67 alcoholics, 56 HIV+ patients, 63 HIV+ alcoholics, and 64 controls to examine whether current depressive symptom level (significant, BDI-II>14 vs. minimal, BDI-II<14) was associated with poorer cognitive or psychosocial function in alcoholism-HIV comorbidity. Participants with significant depressive symptoms demonstrated slower manual motor speed and poorer visuospatial memory than those with minimal depressive symptoms. HIV patients with depressive symptoms showed impaired manual motor speed. Alcoholics with depressive symptoms showed impaired visuospatial memory. HIV+ alcoholics with depressive symptoms reported the poorest quality of life; alcoholics with depressive symptoms, irrespective of HIV status, had poorest life functioning. Thus, significant depressive symptoms were associated with poorer selective cognitive and life functioning in alcoholism and in HIV infection, even though depressive symptoms had neither synergistic nor additive effects on cognition in alcoholism-HIV comorbidity. The results suggest the relevance of assessing and treating current depressive symptoms to reduce cognitive compromise and functional disability in HIV infection, alcoholism, and their comorbidity.

    View details for DOI 10.1016/j.psychres.2012.05.009

    View details for Web of Science ID 000312510700005

    View details for PubMedID 22648011

  • Regional Brain Structural Dysmorphology in Human Immunodeficiency Virus Infection: Effects of Acquired Immune Deficiency Syndrome, Alcoholism, and Age BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Rosenbloom, M. J., Sassoon, S. A., Kemper, C. A., Deresinski, S., Rohlfing, T., Sullivan, E. V. 2012; 72 (5): 361-370


    Human immunodeficiency virus (HIV) infection and alcoholism each carries liability for disruption of brain structure and function integrity. Despite considerable prevalence of HIV-alcoholism comorbidity, few studies examined the potentially heightened burden of disease comorbidity.Participants were 342 men and women: 110 alcoholics, 59 with HIV infection, 65 with HIV infection and alcoholism, and 108 healthy control subjects. This design enabled examination of independent and combined effects of HIV infection and alcoholism along with other factors (acquired immune deficiency syndrome [AIDS]-defining events, hepatitis C infection, age) on regional brain volumes derived from T1-weighted magnetic resonance images.Brain volumes, expressed as Z scores corrected for intracranial volume and age, were measured in 20 tissue and 5 ventricular and sulcal regions. The most profound and consistent volume deficits occurred with alcohol use disorders, notable in the cortical mantle, insular and anterior cingulate cortices, thalamus, corpus callosum, and frontal sulci. The HIV-only group had smaller thalamic and larger frontal sulcal volumes than control subjects. HIV disease-related factors associated with greater volume abnormalities included CD4 cell count nadir, clinical staging, history of AIDS-defining events, infection age, and current age. Longer sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities in both alcohol groups.Having HIV infection with alcoholism and AIDS had an especially poor outcome on brain structures. That longer periods of sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities encourages the inclusion of alcohol recovery efforts in HIV/AIDS therapeutic settings.

    View details for DOI 10.1016/j.biopsych.2012.02.018

    View details for Web of Science ID 000307308100006

    View details for PubMedID 22458948

    View details for PubMedCentralID PMC3393798

  • Face-Name Association Learning and Brain Structural Substrates in Alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pitel, A., Chanraud, S., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2012; 36 (7): 1171-1179


    Associative learning is required for face-name association and is impaired in alcoholism, but the cognitive processes and brain structural components underlying this deficit remain unclear. It is also unknown whether prompting alcoholics to implement a deep level of processing during face-name encoding would enhance performance.Abstinent alcoholics and controls performed a levels-of-processing face-name learning task. Participants indicated whether the face was that of an honest person (deep encoding) or that of a man (shallow encoding). Retrieval was examined using an associative (face-name) recognition task and a single-item (face or name only) recognition task. Participants also underwent 3T structural MRI.Compared with controls, alcoholics had poorer associative and single-item learning and performed at similar levels. Level of processing at encoding had little effect on recognition performance but affected reaction time (RT). Correlations with brain volumes were generally modest and based primarily on RT in alcoholics, where the deeper the processing at encoding, the more restricted the correlations with brain volumes. In alcoholics, longer control task RTs correlated modestly with smaller tissue volumes across several anterior to posterior brain regions; shallow encoding correlated with calcarine and striatal volumes; deep encoding correlated with precuneus and parietal volumes; and associative recognition RT correlated with cerebellar volumes. In controls, poorer associative recognition with deep encoding correlated significantly with smaller volumes of frontal and striatal structures.Despite prompting, alcoholics did not take advantage of encoding memoranda at a deep level to enhance face-name recognition accuracy. Nonetheless, conditions of deeper encoding resulted in faster RTs and more specific relations with regional brain volumes than did shallow encoding. The normal relation between associative recognition and corticostriatal volumes was not present in alcoholics. Rather, their speeded RTs occurred at the expense of accuracy and were related most robustly to cerebellar volumes.

    View details for DOI 10.1111/j.1530-0277.2011.01731.x

    View details for Web of Science ID 000306219400009

    View details for PubMedID 22509954

    View details for PubMedCentralID PMC3394892

  • Wernicke's Encephalopathy and Korsakoff's Syndrome Revisited NEUROPSYCHOLOGY REVIEW Sullivan, E. V., Fama, R. 2012; 22 (2): 69-71

    View details for DOI 10.1007/s11065-012-9205-2

    View details for Web of Science ID 000305248800001

    View details for PubMedID 22588370

  • Neuroimaging of Wernicke's Encephalopathy and Korsakoff's Syndrome NEUROPSYCHOLOGY REVIEW Jung, Y., Chanraud, S., Sullivan, E. V. 2012; 22 (2): 170-180


    There is considerable evidence that neuroimaging findings can improve the early diagnosis of Wernicke's encephalopathy (WE) in clinical settings. The most distinctive neuroimaging finding of acute WE are cytotoxic edema and vasogenic edema, which are represented by bilateral symmetric hyperintensity alterations on T2-weighted MR images in the periphery of the third ventricle, periaqueductal area, mammillary bodies and midbrain tectal plate. An initial bout of WE can result in Korsakoff's syndrome (KS), but repeated bouts in conjunction with its typical comorbidity, chronic alcoholism, can result in signs of tissue degeneration in vulnerable brain regions. Chronic abnormalities identified with neuroimaging enable examination of brain damage in living patients with KS and have expanded the understanding of the neuropsychological deficits resulting from thiamine deficiency, alcohol neurotoxicity, and their comorbidity. Brain structure and functional studies indicate that the interactions involving the thalamus, mammillary bodies, hippocampus, frontal lobes, and cerebellum are crucial for memory formation and executive functions, and the interruption of these circuits by WE and chronic alcoholism can contribute substantially to the neuropsychological deficits in KS.

    View details for DOI 10.1007/s11065-012-9203-4

    View details for Web of Science ID 000305248800009

    View details for PubMedID 22577003

  • Anterograde Episodic Memory in Korsakoff Syndrome NEUROPSYCHOLOGY REVIEW Fama, R., Pitel, A., Sullivan, E. V. 2012; 22 (2): 93-104


    A profound anterograde memory deficit for information, regardless of the nature of the material, is the hallmark of Korsakoff syndrome, an amnesic condition resulting from severe thiamine (vitamin B1) deficiency. Since the late nineteenth century when the Russian physician, S. S. Korsakoff, initially described this syndrome associated with "polyneuropathy," the observed global amnesia has been a primary focus of neuroscience and neuropsychology. In this review we highlight the historical studies that examined anterograde episodic memory processes in KS, present a timeline and evidence supporting the myriad theories proffered to account for this memory dysfunction, and summarize what is known about the neuroanatomical correlates and neural systems presumed affected in KS. Rigorous study of KS amnesia and associated memory disorders of other etiologies provide evidence for distinct mnemonic component processes and neural networks imperative for normal declarative and nondeclarative memory abilities and for mnemonic processes spared in KS, from whence emerged the appreciation that memory is not a unitary function. Debate continues regarding the qualitative and quantitative differences between KS and other amnesias and what brain regions and neural pathways are necessary and sufficient to produce KS amnesia.

    View details for DOI 10.1007/s11065-012-9207-0

    View details for Web of Science ID 000305248800004

    View details for PubMedID 22644546

  • Combining atlas-based parcellation of regional brain data acquired across scanners at 1.5 T and 3.0 T field strengths NEUROIMAGE Pfefferbaum, A., Rohlfing, T., Rosenbloom, M. J., Sullivan, E. V. 2012; 60 (2): 940-951


    Longitudinal brain morphometric studies designed for data acquisition at a single MRI field strength can be seriously limited by system replacements from lower to higher field strength. Merging data across field strengths has not been endorsed for a variety of reasons, yet the ability to combine such data would broaden longitudinal investigations. To determine whether structural T1-weighted MRI data acquired across MR field strengths could be merged, parcellations of archival SPGR data acquired in 114 individuals at 1.5 T and at 3.0 T within 3 weeks of each other were compared. The first set of analyses examined 1) the correspondence between regional tissue volumes derived from data collected at 1.5 T and 3.0 T and 2) whether there were systematic differences for which a correction factor could be determined and applied to improve measurement agreement. Comparability of regional volume determination at 1.5 T and 3.0 T was assessed with intraclass correlation (ICC) computed on volumes derived from the automated and unsupervised SRI24 atlas registration and parcellation method. A second set of analyses measured the reliability of the registration and quantification using the same approach on longitudinal data acquired in 69 healthy adults at a single field strength, 1.5 T, at an interval < 2 years. The mainstay of the analyses was based on the SRI24 method; to examine the potential of merging data across field strengths and across image analysis packages, a secondary set of analyses used FreeSurfer instead of the SRI24 method. For both methods, a regression-based linear correction function significantly improved correspondence. The results indicated high correspondence between most selected cortical, subcortical, and CSF-filled spaces; correspondence was lowest in the globus pallidus, a region rich in iron, which in turn has a considerable field-dependent effect on signal intensity. Thus, the application of a regression-based correction function that improved the correspondence in regional volume estimations argues well for the proposition that selected T1-weighted regional anatomical brain data can be reliably combined across 1.5 T and 3.0 T field strengths with the application of an appropriate correction procedure.

    View details for DOI 10.1016/j.neuroimage.2012.01.092

    View details for Web of Science ID 000303272300012

    View details for PubMedID 22297204

  • War-Related PTSD, Blast Injury, and Anosognosia NEUROPSYCHOLOGY REVIEW Sullivan, E. V. 2012; 22 (1): 1-2

    View details for DOI 10.1007/s11065-012-9188-z

    View details for Web of Science ID 000300892100001

    View details for PubMedID 22322795

  • MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping NEUROIMAGE Bilgic, B., Pfefferbaum, A., Rohlfing, T., Sullivan, E. V., Adalsteinsson, E. 2012; 59 (3): 2625-2635


    Quantifying tissue iron concentration in vivo is instrumental for understanding the role of iron in physiology and in neurological diseases associated with abnormal iron distribution. Herein, we use recently-developed Quantitative Susceptibility Mapping (QSM) methodology to estimate the tissue magnetic susceptibility based on MRI signal phase. To investigate the effect of different regularization choices, we implement and compare ℓ1 and ℓ2 norm regularized QSM algorithms. These regularized approaches solve for the underlying magnetic susceptibility distribution, a sensitive measure of the tissue iron concentration, that gives rise to the observed signal phase. Regularized QSM methodology also involves a pre-processing step that removes, by dipole fitting, unwanted background phase effects due to bulk susceptibility variations between air and tissue and requires data acquisition only at a single field strength. For validation, performances of the two QSM methods were measured against published estimates of regional brain iron from postmortem and in vivo data. The in vivo comparison was based on data previously acquired using Field-Dependent Relaxation Rate Increase (FDRI), an estimate of MRI relaxivity enhancement due to increased main magnetic field strength, requiring data acquired at two different field strengths. The QSM analysis was based on susceptibility-weighted images acquired at 1.5 T, whereas FDRI analysis used Multi-Shot Echo-Planar Spin Echo images collected at 1.5 T and 3.0 T. Both datasets were collected in the same healthy young and elderly adults. The in vivo estimates of regional iron concentration comported well with published postmortem measurements; both QSM approaches yielded the same rank ordering of iron concentration by brain structure, with the lowest in white matter and the highest in globus pallidus. Further validation was provided by comparison of the in vivo measurements, ℓ1-regularized QSM versus FDRI and ℓ2-regularized QSM versus FDRI, which again yielded perfect rank ordering of iron by brain structure. The final means of validation was to assess how well each in vivo method detected known age-related differences in regional iron concentrations measured in the same young and elderly healthy adults. Both QSM methods and FDRI were consistent in identifying higher iron concentrations in striatal and brain stem ROIs (i.e., caudate nucleus, putamen, globus pallidus, red nucleus, and substantia nigra) in the older than in the young group. The two QSM methods appeared more sensitive in detecting age differences in brain stem structures as they revealed differences of much higher statistical significance between the young and elderly groups than did FDRI. However, QSM values are influenced by factors such as the myelin content, whereas FDRI is a more specific indicator of iron content. Hence, FDRI demonstrated higher specificity to iron yet yielded noisier data despite longer scan times and lower spatial resolution than QSM. The robustness, practicality, and demonstrated ability of predicting the change in iron deposition in adult aging suggest that regularized QSM algorithms using single-field-strength data are possible alternatives to tissue iron estimation requiring two field strengths.

    View details for DOI 10.1016/j.neuroimage.2011.08.077

    View details for Web of Science ID 000299494000062

    View details for PubMedID 21925274

  • Synchrony of corticostriatal-midbrain activation enables normal inhibitory control and conflict processing in recovering alcoholic men. Biological psychiatry Schulte, T., Müller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A. 2012; 71 (3): 269-278


    Alcohol dependence is associated with inhibitory control deficits, possibly related to abnormalities in frontoparietal cortical and midbrain function and connectivity.We examined functional connectivity and microstructural fiber integrity between frontoparietal and midbrain structures using a Stroop Match-to-Sample task with functional magnetic resonance imaging and diffusion tensor imaging in 18 alcoholic and 17 control subjects. Manipulation of color cues and response repetition sequences modulated cognitive demands during Stroop conflict.Despite similar lateral frontoparietal activity and functional connectivity in alcoholic and control subjects when processing conflict, control subjects deactivated the posterior cingulate cortex (PCC), whereas alcoholic subjects did not. Posterior cingulum fiber integrity predicted the degree of PCC deactivation in control but not alcoholic subjects. Also, PCC activity was modulated by executive control demands: activated during response switching and deactivated during response repetition. Alcoholics showed the opposite pattern: activation during repetition and deactivation during switching. Here, in alcoholic subjects, greater deviations from the normal PCC activity correlated with higher amounts of lifetime alcohol consumption. A functional dissociation of brain network connectivity between the groups further showed that control subjects exhibited greater corticocortical connectivity among middle cingulate, posterior cingulate, and medial prefrontal cortices than alcoholic subjects. In contrast, alcoholic subjects exhibited greater midbrain-orbitofrontal cortical network connectivity than control subjects. Degree of microstructural fiber integrity predicted robustness of functional connectivity.Thus, even subtle compromise of microstructural connectivity in alcoholism can influence modulation of functional connectivity and underlie alcohol-related cognitive impairment.

    View details for DOI 10.1016/j.biopsych.2011.10.022

    View details for PubMedID 22137506

    View details for PubMedCentralID PMC3253929

  • Synchrony of Corticostriatal-Midbrain Activation Enables Normal Inhibitory Control and Conflict Processing in Recovering Alcoholic Men BIOLOGICAL PSYCHIATRY Schulte, T., Mueller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A. 2012; 71 (3): 269-278
  • The INIA19 Template and NeuroMaps Atlas for Primate Brain Image Parcellation and Spatial Normalization. Frontiers in neuroinformatics Rohlfing, T., Kroenke, C. D., Sullivan, E. V., Dubach, M. F., Bowden, D. M., Grant, K. A., Pfefferbaum, A. 2012; 6: 27-?


    The INIA19 is a new, high-quality template for imaging-based studies of non-human primate brains, created from high-resolution, T(1)-weighted magnetic resonance (MR) images of 19 rhesus macaque (Macaca mulatta) animals. Combined with the comprehensive cortical and sub-cortical label map of the NeuroMaps atlas, the INIA19 is equally suitable for studies requiring both spatial normalization and atlas label propagation. Population-averaged template images are provided for both the brain and the whole head, to allow alignment of the atlas with both skull-stripped and unstripped data, and thus to facilitate its use for skull stripping of new images. This article describes the construction of the template using freely available software tools, as well as the template itself, which is being made available to the scientific community (

    View details for DOI 10.3389/fninf.2012.00027

    View details for PubMedID 23230398

  • The INIA19 template and NeuroMaps atlas for primate brain image parcellation and spatial normalization FRONTIERS IN NEUROINFORMATICS Rohlfing, T., Kroenke, C. D., Sullivan, E. V., Dubach, M. F., Bowden, D. M., Grant, K. A., Pfefferbaum, A. 2012; 6
  • Age-related reorganization of functional networks for successful conflict resolution: A combined functional and structural MRI study NEUROBIOLOGY OF AGING Schulte, T., Mueller-Oehring, E. M., Chanraud, S., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2011; 32 (11): 2075-2090
  • Age-related reorganization of functional networks for successful conflict resolution: a combined functional and structural MRI study. Neurobiology of aging Schulte, T., Müller-Oehring, E. M., Chanraud, S., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2011; 32 (11): 2075-2090


    Aging has readily observable effects on the ability to resolve conflict between competing stimulus attributes that are likely related to selective structural and functional brain changes. To identify age-related differences in neural circuits subserving conflict processing, we combined structural and functional MRI and a Stroop Match-to-Sample task involving perceptual cueing and repetition to modulate resources in healthy young and older adults. In our Stroop Match-to-Sample task, older adults handled conflict by activating a frontoparietal attention system more than young adults and engaged a visuomotor network more than young adults when processing repetitive conflict and when processing conflict following valid perceptual cueing. By contrast, young adults activated frontal regions more than older adults when processing conflict with perceptual cueing. These differential activation patterns were not correlated with regional gray matter volume despite smaller volumes in older than young adults. Given comparable performance in speed and accuracy of responding between both groups, these data suggest that successful aging is associated with functional reorganization of neural systems to accommodate functionally increasing task demands on perceptual and attentional operations.

    View details for DOI 10.1016/j.neurobiolaging.2009.12.002

    View details for PubMedID 20022675

    View details for PubMedCentralID PMC2888896

  • Disruption of Functional Connectivity of the Default-Mode Network in Alcoholism CEREBRAL CORTEX Chanraud, S., Pitel, A., Pfefferbaum, A., Sullivan, E. V. 2011; 21 (10): 2272-2281


    The default mode network (DMN) comprises brain structures maximally active at rest. Disturbance of network nodes or their connections occurs with some neuropsychiatric conditions and may underlie associated dysfunction. DMN connectivity has not been examined in alcoholism, which is marked by compromised DMN nodes and impaired spatial working memory. To test whether performance would be related to DMN integrity, we examined DMN functional connectivity using functional magnetic resonance imaging (fMRI) data and graph theory analysis. We assumed that disruption of short paths between network nodes would attenuate processing efficiency. Alcoholics and controls were scanned at rest and during a spatial working memory task. At rest, the spontaneous slow fluctuations of fMRI signals in the posterior cingulate and cerebellar regions in alcoholics were less synchronized than in controls, indicative of compromised functional connectivity. Graph theory analysis indicated that during rest, alcoholics had significantly lower efficiency indices than controls between the posterior cingulate seed and multiple cerebellar sites. Greater efficiency in several connections correlated with longer sobriety in alcoholics. During the task, on which alcoholics performed on par with controls, connectivity between the left posterior cingulate seed and left cerebellar regions was more robust in alcoholics than controls and suggests compensatory networking to achieve normal performance.

    View details for DOI 10.1093/cercor/bhq297

    View details for Web of Science ID 000294808800007

    View details for PubMedID 21368086

    View details for PubMedCentralID PMC3169657

  • Ethanol-induced changes in the expression of proteins related to neurotransmission and metabolism in different regions of the rat brain PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR Zahr, N. M., Bell, R. L., Ringham, H. N., Sullivan, E. V., Witzmann, F. A., Pfefferbaum, A. 2011; 99 (3): 428-436


    Despite extensive description of the damaging effects of chronic alcohol exposure on brain structure, mechanistic explanations for the observed changes are just emerging. To investigate regional brain changes in protein expression levels following chronic ethanol treatment, one rat per sibling pair of male Wistar rats was exposed to intermittent (14 h/day) vaporized ethanol, the other to air for 26 weeks. At the end of 24 weeks of vapor exposure, the ethanol group had blood ethanol levels averaging 450 mg%, had not experienced a protracted (> 16 h) withdrawal from ethanol, and revealed only mild evidence of hepatic steatosis. Extracted brains were micro-dissected to isolate the prefrontal cortex (PFC), dorsal striatum (STR), corpus callosum genu (CCg), CC body (CCb), anterior vermis (AV), and anterior dorsal lateral cerebellum (ADLC) for protein analysis with two-dimensional gel electrophoresis. Expression levels for 54 protein spots were significantly different between the ethanol- and air-treated groups. Of these 54 proteins, tandem mass spectroscopy successfully identified 39 unique proteins, the levels of which were modified by ethanol treatment: 13 in the PFC, 7 in the STR, 2 in the CCg, 7 in the CCb, 7 in the AV, and 5 in the ADLC. The functions of the proteins altered by chronic ethanol exposure were predominantly associated with neurotransmitter systems in the PFC and cell metabolism in the STR. Stress response proteins were elevated only in the PFC, AV, and ADLC perhaps supporting a role for frontocerebellar circuitry disruption in alcoholism. Of the remaining proteins, some had functions associated with cytoskeletal physiology (e.g., in the CCb) and others with transcription/translation (e.g., in the ADLC). Considered collectively, all but 4 of the 39 proteins identified in the present study have been previously identified in ethanol gene- and/or protein-expression studies lending support for their role in ethanol-related brain alterations.

    View details for DOI 10.1016/j.pbb.2011.03.002

    View details for Web of Science ID 000293371100020

    View details for PubMedID 21397625

    View details for PubMedCentralID PMC3129429

  • Developmental change in regional brain structure over 7 months in early adolescence: Comparison of approaches for longitudinal atlas-based parcellation NEUROIMAGE Sullivan, E. V., Pfefferbaum, A., Rohlfing, T., Baker, F. C., Padilla, M. L., Colrain, I. M. 2011; 57 (1): 214-224


    Early adolescence is a time of rapid change in neuroanatomy and sexual development. Precision in tracking changes in brain morphology with structural MRI requires image segmentation with minimal error. Here, we compared two approaches to achieve segmentation by image registration with an atlas to quantify regional brain structural development over a 7-month interval in normal, early adolescent boys and girls. Adolescents were scanned twice (average interval=7.3 months), yielding adequate data for analysis in 16 boys (baseline age 10.9 to 13.9 years; Tanner Stage=1 to 4) and 12 girls (baseline age=11.2 to 13.7 years; Tanner Stage=3 to 4). Brain volumes were derived from T1-weighted (SPGR) images and dual-echo Fast Spin-Echo (FSE) images collected on a GE 3T scanner with an 8-channel phased-array head coil and analyzed by registration-based parcellation using the SRI24 atlas. The "independent" method required two inter-subject registrations: both baseline (MRI 1) to atlas and follow-up (MRI 2) to the atlas. The "sequential" method required one inter-subject registration, which was MRI 1 to the atlas, and one intra-subject registration, which was MRI 2 to MRI 1. Gray matter/white matter/CSF were segmented in both MRI-1 and MRI-2 using FSL FAST with tissue priors also based on the SRI24 atlas. Gray matter volumes were derived for 10 cortical regions, gray+white matter volumes for 5 subcortical structures, and CSF volumes for 4 ventricular regions and the cortical sulci. Across the 15 tissue regions, the coefficient of variation (CV) of change scores across individuals was significantly lower for the sequential method (CV=3.02), requiring only one inter-subject registration, than for the independent method (CV=9.43), requiring two inter-subject registrations. Volume change based on the sequential method revealed that total supratentorial and CSF volumes increased, while cortical gray matter volumes declined significantly (p<0.01) in anterior (lateral and medial frontal, anterior cingulate, precuneus, and parietal) but not posterior (occipital, calcarine) cortical regions. These volume changes occurred in all boys and girls who advanced a step in Tanner staging. Subcortical structures did not show consistent changes. Thus, longitudinal MRI assessment using robust registration methods is sufficiently sensitive to identify significant regional brain changes over a 7-month interval in boys and girls in early adolescence. Increasing the temporal resolution of the retest interval in longitudinal developmental studies could increase accuracy in timing of peak growth of regional brain tissue and refine our understanding of the neural mechanisms underlying the dynamic changes in brain structure throughout adolescence.

    View details for DOI 10.1016/j.neuroimage.2011.04.003

    View details for Web of Science ID 000291624100025

    View details for PubMedID 21511039

    View details for PubMedCentralID PMC3101309

  • Independent Contributions of Cortical Gray Matter, Aging, Sex and Alcoholism to K-Complex Amplitude Evoked During Sleep SLEEP Colrain, I. M., Sullivan, E. V., Rohlfing, T., Baker, F. C., Nicholas, C. L., Padilla, M. L., Chanraud, S., Pitel, A., Pfefferbaum, A. 2011; 34 (6): 787-795


    The amplitude of the N550 component derived from the averaged evoked K-complex decreases with normal aging and with alcoholism. The study was designed to determine whether these declines are related to the extent of cortical or subcortical shrinkage.Research sleep laboratory and MR imaging facility26 abstinent long-term alcoholic men, 14 abstinent long-term alcoholic women, 18 control men, and 22 control women.MRI data collected at 3T were analyzed from alcoholic and control men and women previously reported to have significantly different evoked delta activity during sleep. Segmented and parcellated MRI data collected at 3T were compared between these groups and evaluated for correlation with evoked K-complex amplitude measured at FP1, Fz, FCz, Cz, CPz, and Pz. Cortical gray matter and regional subcortical tissue volumes entered as predictors into stepwise multiple regression identified cortical gray matter as a unique significant predictor of evoked K-complex at all sites. Age added independent variance at 5 of the 6 sites, while alcoholism and sex added independent variance at frontal sites only.These data support recent intracranial studies showing cortical generation of K-complexes by indicating that cortical, but not subcortical volume contributes to K-complex amplitude. Establishing the extent of the relation between cortical volume and K-complex amplitude provides a mechanistic understanding of sleep compromise clinically relevant to normal aging, alcoholism, and likely other conditions affecting cortical volume and integrity.

    View details for DOI 10.5665/SLEEP.1050

    View details for Web of Science ID 000291158000015

    View details for PubMedID 21629367

    View details for PubMedCentralID PMC3099499

  • Disruption of Emotion and Conflict Processing in HIV Infection with and without Alcoholism Comorbidity JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Schulte, T., Mueller-Oehring, E. M., Sullivan, E. V., Pfefferbaum, A. 2011; 17 (3): 537-550
  • Pontocerebellar contribution to postural instability and psychomotor slowing in HIV infection without dementia BRAIN IMAGING AND BEHAVIOR Sullivan, E. V., Rosenbloom, M. J., Rohlfing, T., Kemper, C. A., Deresinski, S., Pfefferbaum, A. 2011; 5 (1): 12-24


    Postural instability occurs in HIV infection, but quantitative balance tests in conjunction with neuroimaging are lacking. We examined whether infratentorial brain tissue volume would be deficient in nondemented HIV-infected individuals and whether selective tissue deficits would be related to postural stability and psychomotor speed performance. The 123 participants included 28 men and 12 women with HIV infection without dementia or alcohol use disorders, and 40 men and 43 women without medical or psychiatric conditions. Participants completed quantitative balance testing, Digit Symbol test, and a test of finger movement speed and dexterity. An infratentorial brain region, supratentorial ventricular system, and corpus callosum were quantified with MRI-derived atlas-based parcellation, and together with archival DTI-derived fiber tracking of pontocerebellar and internal and external capsule fiber systems, brain measures were correlated with test performance. The tissue ratio of the infratentorium was ~3% smaller in the HIV than control group. The HIV group exhibited performance deficits in balancing on one foot, walking toe-to-heel, Digit Symbol substitution task, and time to complete all Digit Symbol grid boxes. Total infratentorial tissue ratio was a significant predictor of balance and Digit Symbol scores. Balance scores did not correlate significantly with ventricular volumes, callosal size, or internal or external capsule fiber integrity but did so with indices of pontocerebellar tract integrity. HIV-infected individuals specifically recruited to be without complications from alcohol use disorders had pontocerebellar tissue volume deficits with functional ramifications. Postural stability and psychomotor speed were impaired and attributable, at least in part, to compromised infratentorial brain systems.

    View details for DOI 10.1007/s11682-010-9107-y

    View details for Web of Science ID 000286464700002

    View details for PubMedID 20872291

    View details for PubMedCentralID PMC3292800

  • Remote Semantic Memory for Public Figures in HIV Infection, Alcoholism, and Their Comorbidity ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Rosenbloom, M. J., Sassoon, S. A., Thompson, M. A., Pfefferbaum, A., Sullivan, E. V. 2011; 35 (2): 265-276


    Impairments in component processes of working and episodic memory mark both HIV infection and chronic alcoholism, with compounded deficits often observed in individuals comorbid for these conditions. Remote semantic memory processes, however, have only seldom been studied in these diagnostic groups. Examination of remote semantic memory could provide insight into the underlying processes associated with storage and retrieval of learned information over extended time periods while elucidating spared and impaired cognitive functions in these clinical groups.We examined component processes of remote semantic memory in HIV infection and chronic alcoholism in 4 subject groups (HIV, ALC, HIV + ALC, and age-matched healthy adults) using a modified version of the Presidents Test. Free recall, recognition, and sequencing of presidential candidates and election dates were assessed. In addition, component processes of working, episodic, and semantic memory were assessed with ancillary cognitive tests.The comorbid group (HIV + ALC) was significantly impaired on sequencing of remote semantic information compared with age-matched healthy adults. Free recall of remote semantic information was also modestly impaired in the HIV + ALC group, but normal performance for recognition of this information was observed. Few differences were observed between the single diagnosis groups (HIV, ALC) and healthy adults, although examination of the component processes underlying remote semantic memory scores elicited differences between the HIV and ALC groups. Selective remote memory processes were related to lifetime alcohol consumption in the ALC group and to viral load and depression level in the HIV group. Hepatitis C diagnosis was associated with lower remote semantic memory scores in all 3 clinical groups. Education level did not account for group differences reported.This study provides behavioral support for the existence of adverse effects associated with the comorbidity of HIV infection and chronic alcoholism on selective component processes of memory function, with untoward effects exacerbated by Hepatitis C infection. The pattern of remote semantic memory function in HIV + ALC is consistent with those observed in neurological conditions primarily affecting frontostriatal pathways and suggests that remote memory dysfunction in HIV + ALC may be a result of impaired retrieval processes rather than loss of remote semantic information per se.

    View details for DOI 10.1111/j.1530-0277.2010.01342.x

    View details for Web of Science ID 000286510000010

    View details for PubMedID 21121935

    View details for PubMedCentralID PMC3058901

  • Signs of Preclinical Wernicke's Encephalopathy and Thiamine Levels as Predictors of Neuropsychological Deficits in Alcoholism without Korsakoff's Syndrome NEUROPSYCHOPHARMACOLOGY Pitel, A., Zahr, N. M., Jackson, K., Sassoon, S. A., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2011; 36 (3): 580-588


    The purpose of this study was to determine whether meeting historical criteria for unsuspected Wernicke's encephalopathy (WE), largely under-diagnosed in vivo, explains why some alcoholics have severe neuropsychological deficits, whereas others, with a similar drinking history, exhibit preserved performance. Demographic, clinical, alcohol related, and neuropsychological measures were collected in 56 abstinent alcoholics and 38 non-alcohol-dependent volunteers. Alcoholics were classified using the clinical criteria established by Caine et al (1997) and validated in their neuropathological study of alcoholic cases. Our alcoholics who met a single criterion were considered 'at risk for WE' and those with two or more criteria with 'signs of WE'. Whole blood thiamine was also measured in 22 of the comparison group and 28 alcoholics. Of the alcoholics examined, 27% met no criteria, 57% were at risk for WE, and 16% had signs of WE. Neuropsychological performance of the alcoholic subgroups was graded, with those meeting zero criteria not differing from controls, those meeting one criterion presenting mild-to-moderate deficits on some of the functional domains, and those meeting two or more criteria having the most severe deficits on each of the domains examined. Thiamine levels were selectively related to memory performance in the alcoholics. Preclinical signs of WE can be diagnosed in vivo, enabling the identification of ostensibly 'uncomplicated' alcoholics who are at risk for neuropsychological complications. The graded effects in neuropsychological performance suggest that the presence of signs of WE explains, at least partially, the heterogeneity of alcoholism-related cognitive and motor deficits.

    View details for DOI 10.1038/npp.2010.189

    View details for Web of Science ID 000286176700004

    View details for PubMedID 20962766

    View details for PubMedCentralID PMC3055684

  • Frontally mediated inhibitory processing and white matter microstructure: age and alcoholism effects PSYCHOPHARMACOLOGY Colrain, I. M., Sullivan, E. V., Ford, J. M., Mathalon, D. H., McPherson, S., Roach, B. J., Crowley, K. E., Pfefferbaum, A. 2011; 213 (4): 669-679


    The NOGO P3 event-related potential is a sensitive marker of alcoholism, relates to EEG oscillation in the δ and θ frequency ranges, and reflects activation of an inhibitory processing network. Degradation of white matter tracts related to age or alcoholism should negatively affect the oscillatory activity within the network.This study aims to evaluate the effect of alcoholism and age on δ and θ oscillations and the relationship between these oscillations and measures of white matter microstructural integrity.Data from ten long-term alcoholics to 25 nonalcoholic controls were used to derive P3 from Fz, Cz, and Pz using a visual GO/NOGO protocol. Total power and across trial phase synchrony measures were calculated for δ and θ frequencies. DTI, 1.5 T, data formed the basis of quantitative fiber tracking in the left and right cingulate bundles and the genu and splenium of the corpus callosum. Fractional anisotropy and diffusivity (λL and λT) measures were calculated from each tract.NOGO P3 amplitude and δ power at Cz were smaller in alcoholics than controls. Lower δ total power was related to higher λT in the left and right cingulate bundles. GO P3 amplitude was lower and GO P3 latency was longer with advancing age, but none of the time-frequency analysis measures displayed significant age or diagnosis effects.The relation of δ total power at CZ with λT in the cingulate bundles provides correlational evidence for a functional role of fronto-parietal white matter tracts in inhibitory processing.

    View details for DOI 10.1007/s00213-010-2073-7

    View details for Web of Science ID 000287764500002

    View details for PubMedID 21161189

    View details for PubMedCentralID PMC3033525

  • Electrophysiological evidence of enhanced performance monitoring in recently abstinent alcoholic men PSYCHOPHARMACOLOGY Padilla, M. L., Colrain, I. M., Sullivan, E. V., Mayer, B. Z., Turlington, S. R., Hoffman, L. R., Wagstaff, A. E., Pfefferbaum, A. 2011; 213 (1): 81-91


    Chronic alcoholism is associated with mild to moderate cognitive impairment. Under certain conditions, impairment can be ameliorated by invoking compensatory processes.To identify electrophysiological mechanisms of such compensation that would be required to resolve response conflict.14 abstinent alcoholic men and 14 similarly aged control men performed a variation of the Eriksen flanker task during an electroencephalography (EEG) recording to examine whether alcoholics could achieve and maintain control-level performance and whether EEG markers could identify evidence for the action of compensatory processes in the alcoholics. Monitoring processes engaged following a response were indexed by the correct related negativity (CRN) and error related negativity (ERN), two medial-frontal negative event-related potentials.The alcoholics were able to perform at control levels on accuracy and reaction time (RT). Alcoholics generated larger ERN amplitudes following incorrect responses and larger CRNs following correct responses than controls. Both groups showed evidence of post-error slowing. Larger CRN amplitudes in the alcoholics were related to longer RTs. Also observed in the alcoholics was an association between smaller CRN amplitudes and length of sobriety, suggesting a normalization of monitoring activity with extended abstinence.To the extent that greater amplitude of these electrophysiological markers of performance monitoring indexes greater resource allocation and performance compensation, the larger amplitudes observed in the alcoholic than control group support the view that elevated performance monitoring enables abstinent alcoholics to overcome response conflict, as was evident in their control-level performance.

    View details for DOI 10.1007/s00213-010-2018-1

    View details for Web of Science ID 000285781800009

    View details for PubMedID 20941595

    View details for PubMedCentralID PMC3015191

  • Cerebral Blood Flow in Posterior Cortical Nodes of the Default Mode Network Decreases with Task Engagement but Remains Higher than in Most Brain Regions CEREBRAL CORTEX Pfefferbaum, A., Chanraud, S., Pitel, A., Mueller-Oehring, E., Shankaranarayanan, A., Alsop, D. C., Rohlfing, T., Sullivan, E. V. 2011; 21 (1): 233-244
  • Cerebral blood flow in posterior cortical nodes of the default mode network decreases with task engagement but remains higher than in most brain regions. Cerebral cortex Pfefferbaum, A., Chanraud, S., Pitel, A., Müller-Oehring, E., Shankaranarayanan, A., Alsop, D. C., Rohlfing, T., Sullivan, E. V. 2011; 21 (1): 233-244


    Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic "default mode network" and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion.

    View details for DOI 10.1093/cercor/bhq090

    View details for PubMedID 20484322

  • Sheet-like white matter fiber tracts: representation, clustering, and quantitative analysis. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Maddah, M., Miller, J. V., Sullivan, E. V., Pfefferbaum, A., Rohlfing, T. 2011; 14: 191-199


    We introduce an automated and probabilistic method for subject-specific segmentation of sheet-like fiber tracts. In addition to clustering of trajectories into anatomically meaningful bundles, the method provides statistics of diffusion measures by establishing point correspondences on the estimated medial representation of each bundle. We also introduce a new approach for medial surface generation of sheet-like fiber bundles in order too initialize the proposed clustering algorithm. Applying the new method to a population study of brain aging on 24 subjects demonstrates the capabilities and strengths of the algorithm in identifying and visualizing spatial patterns of group differences.

    View details for PubMedID 21995029

  • Fiber tracking functionally distinct components of the internal capsule NEUROPSYCHOLOGIA Sullivan, E. V., Zahr, N. M., Rohlfing, T., Pfefferbaum, A. 2010; 48 (14): 4155-4163


    The internal capsule conveys information from primary and supplementary motor areas, frontopontine and thalamic peduncles to brain stem and cerebellar regions, and from thalamus to prefrontal cortex. Neurological accidents involving the internal capsule indicate differential functional correlates with its sectors. To examine the microstructural condition of this fiber system and to test functional correlates of its sectors in health and aging, 12 younger and 12 older adults were examined with diffusion tensor imaging (DTI) fiber tracking and neuropsychological tests. Greater age-related degradation was evident in the anterior than posterior limb and in the superior than inferior division of the internal capsule. The superior division age effect was especially notable in axial and radial diffusivity. Fractional anisotropy (FA) across the three (anterior, genu, posterior) fiber bundles of the inferior division accounted for 27-73% of the variance for each neuropsychological domain. Identification of a triple dissociation indicated selective correlations between anterior FA and set shifting, genu FA and motor skills, and posterior FA and fluency. Quantitative fiber tracking combined with assessment of cognitive and motor functions enabled the identification of selective brain structure-function relations in healthy adults without lesions that were previously observed only in patients with lesions of the internal capsule.

    View details for DOI 10.1016/j.neuropsychologia.2010.10.023

    View details for Web of Science ID 000285668200019

    View details for PubMedID 20974161

    View details for PubMedCentralID PMC2993875

  • Development of Brain Structures, Connections, and Functions NEUROPSYCHOLOGY REVIEW Sullivan, E. V. 2010; 20 (4): 325-326

    View details for DOI 10.1007/s11065-010-9149-3

    View details for Web of Science ID 000284425000001

    View details for PubMedID 20953989

  • Measurement of Serum, Liver, and Brain Cytokine Induction, Thiamine Levels, and Hepatopathology in Rats Exposed to a 4-Day Alcohol Binge Protocol ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Zahr, N. M., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2010; 34 (11): 1858-1870


     In rodent and human studies, ethanol (EtOH) exposure is associated with elevated brain levels of the magnetic resonance spectroscopy (MRS) signal representing choline-containing compounds (Cho). One interpretation of elevated brain Cho is that it is a marker of neuroinflammation, and some evidence suggests that EtOH exposure promotes neuroinflammation. This study aimed to determine whether binge EtOH exposure (intragastric 3 g/kg 25% EtOH every 8 hours for 4 days) would induce the expression of certain cytokines in blood, liver, or brain, thereby supporting the neuroinflammation hypothesis of elevated Cho.Ten of 18 wild-type male Wistar rats (~322 g at baseline) were exposed to EtOH and attained average blood alcohol levels of ~315 mg/dl across 4 days. Blood for cytokine immunoassays was collected at baseline, after 5 doses of EtOH (binge), and immediately preceding euthanasia either 4 or 24 hours after the last dose of EtOH. Blood was additionally assayed for the levels of thiamine and liver enzymes; liver histopathology was performed postmortem; and tissue from liver and 6 brain regions was assayed for the potential induction of 7 cytokines.There were no group effects on the levels of thiamine or its phosphate derivatives, thiamine monophosphate or thiamine diphosphate. ANOVAs of liver enzyme levels indicated that only alkaline phosphatase (ALP) levels were higher in the EtOH group than in control group at binge; ALP elevations, however, are difficult to explain in the absence of changes in the levels of additional liver enzymes. Postmortem liver pathology provided evidence for minimal microvesicular lipidosis and portocentric fibrosis in the EtOH group. Group effects on the levels of the measured cytokines in the blood (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-13, and GRO/CXCL1) were not significant. Similarly, postmortem evaluation of liver cytokines did not reveal group effects. Postmortem evaluation of the 7 cytokines in 6 brain regions (anterior cerebellar vermis, cingulate cortex, frontal cortex, hippocampus, hypothalamus, striatum) also failed to identify group effects.A single 4-day bout of binge EtOH exposure alone was insufficient to induce the expression of 7 cytokines in blood, liver, or 6 brain regions of wild-type Wistar rats. Alternative interpretations for elevations in brain Cho in response to a 4-day binge EtOH treatment are therefore necessary and may include induction of cytokines not measured herein or other noninflammatory mechanisms.

    View details for DOI 10.1111/j.1530-0277.2010.01274.x

    View details for Web of Science ID 000283594000005

    View details for PubMedID 20662804

  • Callosal microstructural abnormalities in Alzheimer's disease and alcoholism: same phenotype, different mechanisms PSYCHIATRY RESEARCH-NEUROIMAGING Pitel, A., Chanraud, S., Sullivan, E. V., Pfefferbaum, A. 2010; 184 (1): 49-56


    Magnetic resonance (MRI) and diffusion tensor imaging (DTI) data were acquired in 13 Alzheimer's disease (AD) patients, 15 elderly alcoholics, and 32 elderly controls. Midsagittal area, length, dorsoventral height, fractional anisotropy (FA), and mean diffusivity (MD) of the total corpus callosum and volume of the lateral ventricles were measured; area, FA, and MD were also determined for the callosal genu, body, and splenium. On DTI, both patient groups had lower FA and higher MD than controls in all callosal regions. On MRI, both patient groups had smaller genu than controls; additional size deficits were present in the alcoholism group's callosal body and the AD group's splenium. The callosal arch was higher in the AD but not the alcoholic group compared with controls. The two patient groups had larger ventricles than controls, and the AD group had larger ventricles than the alcoholic group. Callosal area correlated with its height, and callosal FA and MD correlated with ventricular volume in AD, whereas callosal area correlated only with FA in alcoholics. In AD, the disruption of the callosal integrity, which was associated with distorted callosal shape, was related to ventricular dilation, which has been shown in twin studies to be under a multitude of genetic, polygenetic, and environmental influences. Conversely, in alcoholism, disruption of callosal microstructural integrity was related to shrinkage of the corpus callosum itself.

    View details for DOI 10.1016/j.pscychresns.2010.07.006

    View details for Web of Science ID 000283406100007

    View details for PubMedID 20832253

    View details for PubMedCentralID PMC2949287

  • White Matter Fiber Degradation Attenuates Hemispheric Asymmetry When Integrating Visuomotor Information JOURNAL OF NEUROSCIENCE Schulte, T., Mueller-Oehring, E. M., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2010; 30 (36): 12168-12178


    Degradation of white matter fibers can affect the transmission of signals in brain circuits that normally enable integration of highly lateralized visual and motor processes. Here, we used diffusion tensor imaging tractography in combination with functional magnetic resonance imaging to examine the specific contributions of interhemispheric and intrahemispheric white matter fibers to functional measures of hemispheric transfer and parallel information processing using bilateral and unilateral left and right visual field stimulation in normal and compromised systems. In healthy adults, a greater degree of bilateral processing advantage with the left (nondominant) hand correlated with higher integrity of callosal fibers connecting occipital cortices, whereas less unilateral processing advantage with the right hand correlated with higher integrity of left-hemispheric posterior cingulate fibers. In contrast, alcoholics who have compromised callosal integrity showed less bilateral processing advantage than controls when responding with the left hand and greater unilateral processing advantage when responding with the right hand. We also found degraded left posterior cingulate and posterior callosal fibers in chronic alcoholics, which is consistent with functional imaging results of less left posterior cingulate and extrastriate cortex activation in alcoholics than controls when processing bilateral compared with unilateral visual field stimulation. Together, our results demonstrated that interhemispheric and intrahemispheric white matter fiber pathways mediate visuomotor integration asymmetrically and that subtle white matter fiber degradation in alcoholism attenuated the normal pattern of hemispheric asymmetry, which may have ramifications for the efficiency of visual information processing and fast response execution.

    View details for DOI 10.1523/JNEUROSCI.2160-10.2010

    View details for Web of Science ID 000281768000028

    View details for PubMedID 20826679

    View details for PubMedCentralID PMC2952637

  • Cognitive Functions of the Cerebellum NEUROPSYCHOLOGY REVIEW Sullivan, E. V. 2010; 20 (3): 227-228

    View details for DOI 10.1007/s11065-010-9144-8

    View details for Web of Science ID 000281792300001

    View details for PubMedID 20811946

  • Contributions of Studies on Alcohol Use Disorders to Understanding Cerebellar Function NEUROPSYCHOLOGY REVIEW Zahr, N. M., Pitel, A., Chanraud, S., Sullivan, E. V. 2010; 20 (3): 280-289


    Neuropathological, neuropsychological, and neuroimaging studies of human alcoholism provide evidence for degradation of frontal, pontine, thalamic, and cerebellar brain sites and disturbed associated functions. Current studies using neuroimaging combined with examination of executive functions, traditionally considered the sole purview of the frontal lobes, have identified a role for the cerebellum serving as a compensatory processing adjunct to enable normal performance on challenging tasks tapping executive functions. This overview proposes that disruption of an executive frontocerebellar network is a major contributor to characteristic behaviors of alcoholism that, on the one hand, enable alcohol use disorders, and on the other hand, lead to compensation for dysfunctions in alcoholism traditionally considered frontally-based.

    View details for DOI 10.1007/s11065-010-9141-y

    View details for Web of Science ID 000281792300006

    View details for PubMedID 20809198

    View details for PubMedCentralID PMC2998898

  • Dual Tasking and Working Memory in Alcoholism: Relation to Frontocerebellar Circuitry NEUROPSYCHOPHARMACOLOGY Chanraud, S., Pitel, A., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2010; 35 (9): 1868-1878


    Controversy exists regarding the role of cerebellar systems in cognition and whether working memory compromise commonly marking alcoholism can be explained by compromise of nodes of corticocerebellar circuitry. We tested 17 alcoholics and 31 age-matched controls with dual-task, working memory paradigms. Interference tasks competed with verbal and spatial working memory tasks using low (three item) or high (six item) memory loads. Participants also underwent structural MRI to obtain volumes of nodes of the frontocerebellar system. On the verbal working memory task, both groups performed equally. On the spatial working memory with the high-load task, the alcoholic group was disproportionately more affected by the arithmetic distractor than were controls. In alcoholics, volumes of the left thalamus and left cerebellar Crus I volumes were more robust predictors of performance in the spatial working memory task with the arithmetic distractor than the left frontal superior cortex. In controls, volumes of the right middle frontal gyrus and right cerebellar Crus I were independent predictors over the left cerebellar Crus I, left thalamus, right superior parietal cortex, or left middle frontal gyrus of spatial working memory performance with tracking interference. The brain-behavior correlations suggest that alcoholics and controls relied on the integrity of certain nodes of corticocerebellar systems to perform these verbal and spatial working memory tasks, but that the specific pattern of relationships differed by group. The resulting brain structure-function patterns provide correlational support that components of this corticocerebellar system not typically related to normal performance in dual-task conditions may be available to augment otherwise dampened performance by alcoholics.

    View details for DOI 10.1038/npp.2010.56

    View details for Web of Science ID 000279924400005

    View details for PubMedID 20410871

    View details for PubMedCentralID PMC2919220

  • Transcallosal White Matter Degradation Detected With Quantitative Fiber Tracking in Alcoholic Men and Women: Selective Relations to Dissociable Functions ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Rosenbloom, M. J., Fama, R., Sassoon, S. A., Sullivan, E. V. 2010; 34 (7): 1201-1211


    Excessive alcohol consumption can adversely affect white matter fibers and disrupt transmission of neuronal signals. Here, we examined six anatomically defined transcallosal white matter fiber bundles and asked whether any bundle was specifically vulnerable to alcohol, what aspect of white matter integrity was most affected, whether women were more vulnerable than men, and whether evidence of compromise in specific bundles was associated with deficits in balance, sustained attention, associative learning, and psychomotor function, commonly affected in alcoholics.Diffusion tensor imaging quantitative fiber tracking assessed integrity of six transcallosal white matter bundles in 87 alcoholics (59 men, 28 women) and 88 healthy controls (42 men, 46 women). Measures included orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, quantified separately for axial (longitudinal; lambdaL) and radial (transverse; lambdaT) diffusivity. The Digit Symbol Test and a test of ataxia were also administered.Alcoholism negatively affected callosal FA and lambdaT of all but the sensory-motor bundle. Women showed no evidence for greater vulnerability to alcohol than men. Multiple regression analyses confirmed a double dissociation: higher diffusivity in sensory-motor and parietal bundles was associated with poorer balance but not psychomotor speed, whereas higher diffusivity in prefrontal and temporal bundles was associated with slower psychomotor speed but not balance.This study revealed stronger alcohol effects for FA and radial diffusivity than axial diffusivity, suggesting myelin degradation, but no evidence for greater vulnerability to alcohol in women than men. The presence of brain-behavior relationships provides support for the role of alcoholism-related commissural white matter degradation as a substrate of cognitive and motor impairment. Identification of a double dissociation provides further support for the role of selective white matter integrity in specific domains of performance.

    View details for DOI 10.1111/j.1530-0277.2010.01197.x

    View details for Web of Science ID 000279122600009

    View details for PubMedID 20477772

    View details for PubMedCentralID PMC2910526

  • Volumetric cerebral perfusion imaging in healthy adults: Regional distribution, laterality, and repeatability of pulsed continuous arterial spin labeling (PCASL) PSYCHIATRY RESEARCH-NEUROIMAGING Pfefferbaum, A., Chanraud, S., Pitel, A., Shankaranarayanan, A., Alsop, D. C., Rohlfing, T., Sullivan, E. V. 2010; 182 (3): 266-273


    The regional distribution, laterality, and reliability of volumetric pulsed continuous arterial spin labeling (PCASL) measurements of cerebral blood flow (CBF) in cortical, subcortical, and cerebellar regions were determined in 10 normal volunteers studied on two occasions separated by 3 to 7 days. Regional CBF, normalized for global perfusion, was highly reliable when measured on separate days. Several regions showed significant lateral asymmetry; notably, in frontal regions CBF was greater in the right than left hemisphere, whereas left was greater than right in posterior regions. There was considerable regional variability across the brain, whereby the posterior cingulate and central and posterior precuneus cortices had the highest perfusion and the globus pallidus the lowest gray matter perfusion. The latter may be due to iron-induced T1 shortening affecting labeled spins and computed CBF signal. High CBF in the posterior cingulate and posterior and central precuneus cortices in this task-free acquisition suggests high activity in these principal nodes of the "default mode network."

    View details for DOI 10.1016/j.pscychresns.2010.02.010

    View details for Web of Science ID 000279521300012

    View details for PubMedID 20488671

  • Neural Connectivity and Neuropsychological Function NEUROPSYCHOLOGY REVIEW Sullivan, E. V. 2010; 20 (2): 121-122

    View details for DOI 10.1007/s11065-010-9136-8

    View details for Web of Science ID 000278470400001

    View details for PubMedID 20495960

  • MR Diffusion Tensor Imaging: A Window into White Matter Integrity of the Working Brain NEUROPSYCHOLOGY REVIEW Chanraud, S., Zahr, N., Sullivan, E. V., Pfefferbaum, A. 2010; 20 (2): 209-225


    As Norman Geschwind asserted in 1965, syndromes resulting from white matter lesions could produce deficits in higher-order functions and "disconnexion" or the interruption of connection between gray matter regions could be as disruptive as trauma to those regions per se. The advent of in vivo diffusion tensor imaging, which allows quantitative characterization of white matter fiber integrity in health and disease, has served to strengthen Geschwind's proposal. Here we present an overview of the principles of diffusion tensor imaging (DTI) and its contribution to progress in our current understanding of normal and pathological brain function.

    View details for DOI 10.1007/s11065-010-9129-7

    View details for Web of Science ID 000278470400008

    View details for PubMedID 20422451

    View details for PubMedCentralID PMC2910550

  • The SRI24 Multichannel Atlas of Normal Adult Human Brain Structure HUMAN BRAIN MAPPING Rohlfing, T., Zahr, N. M., Sullivan, E. V., Pfefferbaum, A. 2010; 31 (5): 798-819


    This article describes the SRI24 atlas, a new standard reference system of normal human brain anatomy, that was created using template-free population registration of high-resolution magnetic resonance images acquired at 3T in a group of 24 normal control subjects. The atlas comprises anatomical channels (T1, T2, and proton density weighted), diffusion-related channels (fractional anisotropy, mean diffusivity, longitudinal diffusivity, mean diffusion-weighted image), tissue channels (CSF probability, gray matter probability, white matter probability, tissue labels), and two cortical parcellation maps. The SRI24 atlas enables multichannel atlas-to-subject image registration. It is uniquely versatile in that it is equally suited for the two fundamentally different atlas applications: label propagation and spatial normalization. Label propagation, herein demonstrated using diffusion tensor image fiber tracking, is enabled by the increased sharpness of the SRI24 atlas compared with other available atlases. Spatial normalization, herein demonstrated using data from a young-old group comparison study, is enabled by its unbiased average population shape property. For both propagation and normalization, we also report the results of quantitative comparisons with seven other published atlases: Colin27, MNI152, ICBM452 (warp5 and air12), and LPBA40 (SPM5, FLIRT, AIR). Our results suggest that the SRI24 atlas, although based on 3T MR data, allows equally accurate spatial normalization of data acquired at 1.5T as the comparison atlases, all of which are based on 1.5T data. Furthermore, the SRI24 atlas is as suitable for label propagation as the comparison atlases and detailed enough to allow delineation of anatomical structures for this purpose directly in the atlas.

    View details for DOI 10.1002/hbm.20906

    View details for Web of Science ID 000277498800011

    View details for PubMedID 20017133

  • Brain Injury and Recovery Following Binge Ethanol: Evidence from In Vivo Magnetic Resonance Spectroscopy BIOLOGICAL PSYCHIATRY Zahr, N. M., Mayer, D., Rohlfing, T., Hasak, M. P., Hsu, O., Vinco, S., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2010; 67 (9): 846-854


    The binge-drinking model in rodents using intragastric injections of ethanol (EtOH) for 4 days results in argyrophilic corticolimbic tissue classically interpreted as indicating irreversible neuronal degeneration. However, recent findings suggest that acquired argyrophilia can also identify injured neurons that have the potential to recover. The current in vivo magnetic resonance (MR) imaging and spectroscopy study was conducted to test the hypothesis that binge EtOH exposure would injure but not cause the death of neurons as previously ascertained postmortem.After baseline MR scanning, 11 of 19 rats received a loading dose of 5 g/kg EtOH via oral gavage, then a maximum of 3 g/kg every 8 hours for 4 days, for a total average cumulative EtOH dose of 43 +/- 1.2 g/kg and average blood alcohol levels of 258 +/- 12 mg/dL. All animals were scanned after 4 days of gavage (post-gavage scan) with EtOH (EtOH group) or dextrose (control [Con] group) and again after 7 days of abstinence from EtOH (recovery scan).Tissue shrinkage at the post-gavage scan was reflected by significantly increased lateral ventricular volume in the EtOH group compared with the Con group. At the post-gavage scan, the EtOH group had lower dorsal hippocampal N-acetylaspartate and total creatine and higher choline-containing compounds than the Con group. At the recovery scan, neither ventricular volume nor metabolite levels differentiated the groups.Rapid recovery of ventricular volume and metabolite levels with removal of the causative agent argues for transient rather than permanent effects of a single EtOH binge episode in rats.

    View details for DOI 10.1016/j.biopsych.2009.10.028

    View details for Web of Science ID 000277064100008

    View details for PubMedID 20044076

    View details for PubMedCentralID PMC2854208

  • Mechanisms of Postural Control in Alcoholic Men and Women: Biomechanical Analysis of Musculoskeletal Coordination During Quiet Standing ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Rose, J., Pfefferbaum, A. 2010; 34 (3): 528-537


    Excessive sway during quiet standing is a common sequela of chronic alcoholism even with prolonged sobriety. Whether alcoholic men and women who have remained abstinent from alcohol for weeks to months differ from each other in the degree of residual postural instability and biomechanical control mechanisms has not been directly tested.We used a force platform to characterize center-of-pressure biomechanical features of postural sway, with and without stabilizing conditions from touch, vision, and stance, in 34 alcoholic men, 15 alcoholic women, 22 control men, and 29 control women. Groups were matched in age (49.4 years), general intelligence, socioeconomic status, and handedness. Each alcoholic group was sober for an average of 75 days.Analysis of postural sway when using all 3 stabilizing conditions versus none revealed diagnosis and sex differences in ability to balance. Alcoholics had significantly longer sway paths, especially in the anterior-posterior direction, than controls when maintaining erect posture without balance aids. With stabilizing conditions the sway paths of all groups shortened significantly, especially those of alcoholic men, who demonstrated a 3.1-fold improvement in sway path difference between the easiest and most challenging conditions; the remaining 3 groups, each showed a approximately 2.4-fold improvement. Application of a mechanical model to partition sway paths into open-loop and closed-loop postural control systems revealed that the sway paths of the alcoholic men but not alcoholic women were characterized by greater short-term (open-loop) diffusion coefficients without aids, often associated with muscle stiffening response. With stabilizing factors, all 4 groups showed similar long-term (closed loop) postural control. Correlations between cognitive abilities and closed-loop sway indices were more robust in alcoholic men than alcoholic women.Reduction in sway and closed-loop activity during quiet standing with stabilizing factors shows some differential expression in men and women with histories of alcohol dependence. Nonetheless, enduring deficits in postural instability of both alcoholic men and alcoholic women suggest persisting liability for falling.

    View details for DOI 10.1111/j.1530-0277.2009.01118.x

    View details for Web of Science ID 000275142100017

    View details for PubMedID 20028360

    View details for PubMedCentralID PMC2858249

  • Diffusion tensor imaging of deep gray matter brain structures: Effects of age and iron concentration NEUROBIOLOGY OF AGING Pfefferbaum, A., Adalsteinsson, E., Rohlfing, T., Sullivan, E. V. 2010; 31 (3): 482-493


    Diffusion tensor imaging (DTI) of the brain has become a mainstay in the study of normal aging of white matter, and only recently has attention turned to the use of DTI to examine aging effects in gray matter structures. Of the many changes in the brain that occur with advancing age is increased presence of iron, notable in selective deep gray matter structures. In vivo detection and measurement of iron deposition is possible with magnetic resonance imaging (MRI) because of iron's effect on signal intensity. In the process of a DTI study, a series of diffusion-weighted images (DWI) is collected, and while not normally considered as a major dependent variable in research studies, they are used clinically and they reveal striking conspicuity of the globus pallidus and putamen caused by signal loss in these structures, presumably due to iron accumulation with age. These iron deposits may in turn influence DTI metrics, especially of deep gray matter structures. The combined imaging modality approach has not been previously used in the study of normal aging. The present study used legacy DTI data collected in 10 younger (22-37 years) and 10 older (65-79 years) men and women at 3.0T and fast spin-echo (FSE) data collected at 1.5T and 3.0T to derive an estimate of the field-dependent relaxation rate increase (the "FDRI estimate") in the putamen, caudate nucleus, globus pallidus, thalamus, and a frontal white matter sample comparison region. The effect of age on the diffusion measures in the deep gray matter structures was distinctly different from that reported in white matter. In contrast to lower anisotropy and higher diffusivity typical in white matter of older relative to younger adults observed with DTI, both anisotropy and diffusivity were higher in the older than younger group in the caudate nucleus and putamen; the thalamus showed little effect of age on anisotropy or diffusivity. Signal intensity measured with DWI was lower in the putamen of elderly than young adults, whereas the opposite was observed for the white matter region and thalamus. As a retrospective study based on legacy data, the FDRI estimates were based on FSE sequences, which underestimated the classical FDRI index of brain iron. Nonetheless, the differential effects of age on DTI metrics in subcortical gray matter structures compared with white matter tracts appears to be related, at least in part, to local iron content, which in the elderly of the present study was prominent in the FDRI estimate of the putamen and visibly striking in the diffusion-weighted image of the basal ganglia structures.

    View details for DOI 10.1016/j.neurobiolaging.2008.04.013

    View details for Web of Science ID 000276759600012

    View details for PubMedID 18513834

  • Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: Relations to timed performance NEUROBIOLOGY OF AGING Sullivan, E. V., Rohlfing, T., Pfefferbaum, A. 2010; 31 (3): 464-481


    The integrity of white matter, as measured in vivo with diffusion tensor imaging (DTI), is disrupted in normal aging. A current consensus is that in adults advancing age affects anterior brain regions disproportionately more than posterior regions; however, the mainstay of studies supporting this anterior-posterior gradient is based primarily on measures of the corpus callosum. Using our quantitative fiber tracking approach, we assessed fiber tract integrity of samples of major white matter cortical, subcortical, interhemispheric, and cerebellar systems (11 bilateral and 2 callosal) on DTI data collected at 1.5T magnet strength. Participants were 55 men (age 20-78 years) and 65 women (age 28-81 years), deemed healthy and cognitively intact following interview and behavioral testing. Fiber integrity was measured as orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, which was quantified separately for longitudinal diffusivity (lambdaL), an index of axonal length or number, and transverse diffusivity (lambdaT), an index of myelin integrity. Aging effects were more evident in diffusivity than FA measures. Men and women, examined separately, showed similar age-related increases in longitudinal and transverse diffusivity in fibers of the internal and external capsules bilaterally and the fornix. FA was lower and diffusivity higher in anterior than posterior fibers of regional paired comparisons (genu versus splenium and frontal versus occipital forceps). Diffusivity with older age was generally greater or FA lower in the superior than inferior fiber systems (longitudinal fasciculi, cingulate bundles), with little to no evidence for age-related degradation in pontine or cerebellar systems. The most striking sex difference emerged for the corpus callosum, for which men showed significant decline in FA and increase in longitudinal and transverse diffusivity in the genu but not splenium. By contrast, in women the age effect was present in both callosal regions, albeit modestly more so in the genu than splenium. Functional meaningfulness of these age-related differences was supported by significant correlations between DTI signs of white matter degradation and poorer performance on cognitive or motor tests. This survey of multiple fiber systems throughout the brain revealed a differential pattern of age's effect on regional FA and diffusivity and suggests mechanisms of functional degradation, attributed at least in part to compromised fiber microstructure affecting myelin and axonal morphology.

    View details for DOI 10.1016/j.neurobiolaging.2008.04.007

    View details for Web of Science ID 000276759600011

    View details for PubMedID 18495300

    View details for PubMedCentralID PMC2815144

  • Callosal degradation in HIV-1 infection predicts hierarchical perception: A DTI study NEUROPSYCHOLOGIA Mueller-Oehring, E. M., Schulte, T., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2010; 48 (4): 1133-1143


    HIV-1 infection affects white matter circuits linking frontal, parietal, and subcortical regions that subserve visuospatial attention processes. Normal perception requires the integration of details, preferentially processed in the left hemisphere, and the global composition of an object or scene, preferentially processed in the right hemisphere. We tested whether HIV-related callosal white matter degradation contributes to disruption of selective lateralized visuospatial and attention processes. A hierarchical letter target detection paradigm was devised, where large (global) letters were composed of small (local) letters. Participants were required to identify target letters among distractors presented at global, local, both or neither level. Attention was directed to one (global or local) or both levels. Participants were 21 HIV-1 infected and 19 healthy control men and women who also underwent Diffusion Tensor Imaging (DTI). HIV-1 participants showed impaired hierarchical perception owing to abnormally enhanced global facilitation effects but no impairment in attentional control on local-global feature selection. DTI metrics revealed poorer fiber integrity of the corpus callosum in HIV-1 than controls that was more pronounced in posterior than anterior regions. Analysis revealed a double dissociation of anterior and posterior callosal compromise in HIV-1 infection: compromise in anterior but not posterior callosal fiber integrity predicted response conflict elicited by global targets, whereas compromise in posterior but not anterior callosal fiber integrity predicted response facilitation elicited by global targets. We conclude that component processes of visuospatial perception are compromised in HIV-1 infection attributable, at least in part, to degraded callosal microstructural integrity relevant for local-global feature integration.

    View details for DOI 10.1016/j.neuropsychologia.2009.12.015

    View details for Web of Science ID 000275933500033

    View details for PubMedID 20018201

    View details for PubMedCentralID PMC2828526

  • Pontocerebellar volume deficits and ataxia in alcoholic men and women: no evidence for "telescoping" PSYCHOPHARMACOLOGY Sullivan, E. V., Rohlfing, T., Pfefferbaum, A. 2010; 208 (2): 279-290


    Brain volume shrinkage is common in treatment-seeking patients with alcohol use disorders. Whether women are more vulnerable to brain dysmorphology than men despite lower alcohol consumption levels or shorter dependency ("telescoping effect") remains controversial and has not been considered with respect to infratentorial structures or their potential contribution to ataxia.The 200 participants included 64 men and 31 women with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence and 105 controls. An infratentorial region (pons, cerebellar hemispheres, vermis (anterior, posterior, and inferior sectors), fissures, cisterns, fourth ventricle) was quantified with atlas-based parcellation. To enable comparison of men and women, regional tissue volumes were expressed as ratios of tissue in the volume. Participants also completed quantitative ataxia testing.Total infratentorial and vermian tissue ratios were significantly smaller in alcoholics than controls; alcoholic women did not show disproportionately greater volume deficits than alcoholic men. A re-analysis including alcoholic men and women matched in alcohol consumption, onset age, abstinence duration, and age revealed again that alcoholic women did not have disproportionately greater regional vermian volume deficits than alcoholic men. Alcoholic men and women were impaired in all measures of ataxia, which correlated with low infratentorial tissue ratios in men.Alcoholic men showed deficits of pontocerebellar volume ratios, yet alcoholic women did not display signs of "telescoping". Further, alcoholic men and women both showed signs of ataxia of gait and balance, related to affected pontocerebellar systems in the men but not the women, suggesting the need to consider other neural substrates for ataxia in women.

    View details for DOI 10.1007/s00213-009-1729-7

    View details for Web of Science ID 000273097300011

    View details for PubMedID 19943036

    View details for PubMedCentralID PMC2819225

  • Alcohol's Effects on Brain and Behavior ALCOHOL RESEARCH & HEALTH Sullivan, E. V., Harris, A., Pfefferbaum, A. 2010; 33 (1-2): 127-143
  • Neurocircuitry of emotion and cognition in alcoholism: contributions from white matter fiber tractography. Dialogues in clinical neuroscience Schulte, T., Muller-Oehring, E. M., Pfefferbaum, A., Sullivan, E. V. 2010; 12 (4): 554-560


    Chronic alcoholism is characterized by impaired control over emotionally motivated actions towards alcohol use. Neuropathologically, it is associated with widespread brain structural compromise marked by gray matter shrinkage, ventricular enlargement, and white matter degradation. The extent to which cortical damage itself or cortical disconnection by white matter fiber pathway disruption contribute to deficits in emotion, cognition, and behavior can be investigated with in vivo structural neuroimaging and diffusion tensor imaging (DTI)-based quantitative fiber tracking. Tractography in alcoholism has revealed abnormalities in selective white matter fiber bundles involving limbic fiber tracts (fornix and cingulum) that connect cortico-limbic-striatal nodes of emotion and reward circuits. Studies documenting brain-behavior relationships support the role of alcoholism-related white matter fiber degradation as a substrate of clinical impairment. An understanding of the role of cortico-limbic fiber degradation in emotional dysregulation in alcoholism is now emerging.

    View details for PubMedID 21319499

  • Focus on the Brain: HIV Infection and Alcoholism. Alcohol research & health Rosenbloom, M. J., Sullivan, E. V., Pfefferbaum, A. 2010; 33 (3): 247-257


    Both HIV infection and alcohol abuse have negative effects on the brain, with some unique to each condition and others shared by both conditions. Investigators have used magnetic resonance imaging to study the size and integrity of various brain structures in participants with alcoholism, HIV infection, or both conditions and in healthy control subjects. In these studies, alcoholics exhibited enlarged, cerebrospinal fluid-filled spaces (i.e., ventricles) as well as tissue shrinkage in various brain regions (e.g., the corpus callosum and frontal cortex), whereas study participants with asymptomatic HIV infection showed few abnormalities. Those with both HIV infection and alcoholism also had these volume abnormalities, particularly if they had experienced an AIDS-defining event. Diffusion tensor imaging, which measures the integrity of white matter fibers, has identified abnormalities of constituents of these fibers in both diseases. Again, people with HIV infection plus alcoholism show the greatest abnormalities, particularly those with a history of an AIDS-defining event. Magnetic resonance spectroscopy, which assesses the levels of brain metabolites and selective neurotransmitters, has revealed different patterns of deficits in biochemical markers of brain integrity in individuals singly affected and a compounding of effects in individuals with both HIV infection and alcoholism. Finally, neuropsychological studies have revealed impairment in selective functions involving working memory, visuospatial abilities, and movement speed that are especially likely to occur in people with comorbid HIV infection and alcoholism. Thus, alcoholism is a major risk factor for development of neuropathology and its functional sequelae in HIV-infected people.

    View details for PubMedID 23584066

  • Longitudinal Study of Callosal Microstructure in the Normal Adult Aging Brain Using Quantitative DTI Fiber Tracking DEVELOPMENTAL NEUROPSYCHOLOGY Sullivan, E. V., Rohlfing, T., Pfefferbaum, A. 2010; 35 (3): 233-256


    We present a review of neuroimaging studies of normal adult aging conducted with diffusion tensor imaging (DTI) and data from one of the first longitudinal studies using DTI to study normal aging. To date, virtually all DTI studies of normal adult aging have been cross-sectional and have identified several patterns of white matter microstructural sparing and compromise that differentiate regional effects, fiber type, and diffusivity characteristics: (1) fractional anisotropy (FA) is lower and mean diffusivity is higher in older than younger adults, (2) aging is characterized by an anterior-to-posterior gradient of greater-to-lesser compromise also seen in superior-to-inferior fiber systems, and (3) association fibers connecting cortical sites appear to be more vulnerable to aging than projection fibers. The results of this longitudinal study of the macrostructure and microstructure of the corpus callosum yielded a consistent pattern of differences between healthy, young (20s to 30s) and elderly (60s to 70s) men and women without change over 2 years. We then divided the fibers of the corpus callosum into the midsagittal strip and the lateral distal fibers in an attempt to identify the locus of the age-related differences. The results indicated that, on average, mean values of FA and longitudinal diffusivity (lambdaL) were lower in the distal than midsagittal fibers in both groups, but the age effects and the anterior-to-posterior gradients were more pronounced for the distal than midsagittal fibers and extended more posteriorly in the distal than midsagittal fibers. Despite lack of evidence for callosal aging over 2 years, ventricular enlargement occurred and was disproportionately greater in the elderly relative to the young group, being 8.2% in the elderly but only 1.2% in the young group. Thus, different brain regions can express different rates of change with aging. Our longitudinal DTI data indicate that normal aging is associated with declining FA and increasing diffusivity in both lambdaL (longitudinal diffusivity) and lambdaT (transverse diffusivity), perhaps defining the normal ontological condition rather than a pathological one, which can be marked by low FA and low diffusivity.

    View details for DOI 10.1080/87565641003689556

    View details for Web of Science ID 000277518100002

    View details for PubMedID 20446131

    View details for PubMedCentralID PMC2867078

  • Alcohol's Effects on Brain and Behavior. Alcohol research & health Sullivan, E. V., Harris, R. A., Pfefferbaum, A. 2010; 33 (1): 127-143


    Over the past 40 years, rigorous examination of brain function, structure, and attending factors through multidisciplinary research has helped identify the substrates of alcohol-related damage in the brain. One main area of this research has focused on the neuropsychological sequelae of alcoholism, which has resulted in the description of a pattern of sparing and impairment that provided an essential understanding of the functional deficits as well as of spared capabilities that could be useful in recovery. These studies have elucidated the component processes of memory, problem solving, and cognitive control, as well as visuospatial, and motor processes and their interactions with cognitive control processes. Another large area of research has focused on observable brain pathology, using increasingly sophisticated imaging technologies-progressing from pneumoencephalography to computed tomography, magnetic resonance imaging (MRI), diffusion tensor imaging, and functional MRI-that have enabled ever more detailed insight into brain structure and function. These advancements also have allowed analysis of the course of brain structural changes through periods of drinking, abstinence, and relapse.

    View details for PubMedID 23579943

  • Physiological and Focal Cerebellar Substrates of Abnormal Postural Sway and Tremor in Alcoholic Women BIOLOGICAL PSYCHIATRY Sullivan, E. V., Rose, J., Pfefferbaum, A. 2010; 67 (1): 44-51


    Posturography analysis of static balance reveals marked sway and tremor in sober alcoholic men related to anterior vermis volume but can be attenuated by simple visual or tactile cues or alterations in stance. Whether alcoholic women, whose ataxia can persist with prolonged sobriety, exhibit the same physiological signature of balance instability and relation to cerebellar vermian volume as alcoholic men or can benefit from stabilizing factors is unknown.Groups comprised 15 alcohol-dependent women, alcohol-free (median 3 months) and 29 control women. Groups were matched in age, demographic features, and finger movement speed and underwent balance platform testing and magnetic resonance imaging scanning.Alcoholic women exhibited excessive sway path length (.6 SD), more dramatic in the anterior-posterior than medial-lateral direction. Truncal tremor, measured as peak sway velocity frequency, was disproportionately great in the 5 Hz to 7 Hz band of alcoholics. Control subjects and alcoholics exhibited sway and tremor reduction with visual, tactile, or stance-stabilizing conditions, which aided both groups equally well; thus, alcoholic women never achieved normal stability. Smaller anterior vermian volumes selectively correlated with longer sway path and higher 5 Hz to 7 Hz peak sway velocity.Sway and tremor abnormalities and the selective relations between greater sway and 5 Hz to 7 Hz tremor and smaller volumes of the anterior vermis had not heretofore been described in abstinent alcoholic women. Reduction in sway and tremor with stabilizing factors indicate that adaptive mechanisms involving sensorimotor integration can be invoked to compensate for vermian-related dysfunction.

    View details for DOI 10.1016/j.biopsych.2009.08.008

    View details for Web of Science ID 000272858600006

    View details for PubMedID 19782966

    View details for PubMedCentralID PMC2794976

  • Contribution of Regional White Matter Integrity to Visuospatial Construction Accuracy, Organizational Strategy, and Memory for a Complex Figure in Abstinent Alcoholics BRAIN IMAGING AND BEHAVIOR Rosenbloom, M. J., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2009; 3 (4): 379-390
  • In vivo glutamate decline associated with kainic acid-induced status epilepticus BRAIN RESEARCH Zahr, N. M., Crawford, E. L., Hsu, O., Vinco, S., Mayer, D., Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. 2009; 1300: 65-78


    Neurophysiological, biochemical, and anatomical evidence implicates glutamatergic mechanisms in epileptic seizures. Until recently, however, longitudinal characterization of in vivo glutamate dynamics was not possible. Here, we present data using in vivo magnetic resonance spectroscopy (MRS) optimized for the detection of glutamate to identify changes that evolve following kainic acid (KA)-induced status epilepticus. Wild-type male Wistar rats underwent whole-brain MR imaging and single-voxel MRS on a clinical 3 T scanner equipped with a high-strength insert gradient coil. Scanning took place before and then 3 days, 28-32 days, and 42-50 days after induction of status epilepticus. Analyses compared 5 seizure (Sz), 5 no-seizure (NoSz; received KA but did not exhibit seizures), and 6 control (Con) animals. This longitudinal study demonstrated reduced glutamate levels in vivo in the dorsal hippocampus 3 days and 1 month following status epilepticus in Sz animals compared with Con animals. Additionally, previous results were replicated: in the Sz group, computed T2 was higher in the ventral hippocampus and limbic cortex 3 days after seizure activity compared with baseline but resolved in both regions at the 1 month scan, suggesting a transient edema. Three days following seizure activity, N-acetylaspartate (NAA) declined and lactate increased in the dorsal hippocampus of the Sz group compared with the Con and NoSz group; both metabolites approached baseline levels by the third scan. Taken together, these results support the conclusion that seizure activity following KA infusion causes loss of glutamatergic neurons.

    View details for DOI 10.1016/j.brainres.2009.08.060

    View details for Web of Science ID 000271819200008

    View details for PubMedID 19715683

    View details for PubMedCentralID PMC2783661

  • Double dissociation between action-driven and perception-driven conflict resolution invoking anterior versus posterior brain systems NEUROIMAGE Schulte, T., Mueller-Oehring, E. M., Vinco, S., Hoeft, F., Pfefferbaum, A., Sullivan, E. V. 2009; 48 (2): 381-390


    The ability to select and integrate relevant information in the presence of competing irrelevant information can be enhanced by advance information to direct attention and guide response selection. Attentional preparation can reduce perceptual and response conflict, yet little is known about the neural source of conflict resolution, whether it is resolved by modulating neural responses for perceptual selection to emphasize task-relevant information or for action selection to inhibit pre-potent responses to interfering information. We manipulated perceptual information that either matched or did not match the relevant color feature of an upcoming Stroop stimulus and recorded hemodynamic brain responses to these events. Longer reaction times to incongruent than congruent color-word Stroop stimuli indicated conflict; however, conflict was even greater when a color cue correctly predicted the Stroop target's color (match) than when it did not (nonmatch). A predominantly anterior network was activated for Stroop-match and a predominantly posterior network was activated for Stroop-nonmatch. Thus, when a stimulus feature did not match the expected feature, a perceptually-driven posterior attention system was engaged, whereas when interfering, automatically-processed semantic information required inhibition of pre-potent responses, an action-driven anterior control system was engaged. These findings show a double dissociation of anterior and posterior cortical systems engaging in different types of control for perceptually-driven and action-driven conflict resolution.

    View details for DOI 10.1016/j.neuroimage.2009.06.058

    View details for Web of Science ID 000274723900008

    View details for PubMedID 19573610

  • Working and Episodic Memory in HIV Infection, Alcoholism, and Their Comorbidity: Baseline and 1-Year Follow-Up Examinations ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Rosenbloom, M. J., Nichols, B. N., Pfefferbaum, A., Sullivan, E. V. 2009; 33 (10): 1815-1824


    Selective memory deficits occur in individuals with human immunodeficiency virus (HIV) infection and those with chronic alcoholism, but the potential compounded effect of these conditions is seldom considered, despite the high prevalence of alcohol use disorders in HIV infection.Here, we examined component processes of working and episodic memory in HIV infection and chronic alcoholism (ALC) in 4 subject groups (HIV, ALC, HIV + ALC, and normal controls) at baseline and 1-year follow-up. Accuracy scores, response times, and rate of information processing were assessed with subtests of the computerized neuropsychological test battery, the MicroCog.Although individuals with either HIV infection or alcoholism generally performed at normal levels, individuals comorbid with HIV infection and alcoholism were impaired relative to controls and to the single diagnosis groups on selective memory processes. Immediate episodic memory was impaired, whereas working memory remained intact. Ability to retain information over time was not impaired in the clinical groups. Little performance change between groups was detected over 1 year. Results could not be explained by amount of alcohol consumed over a lifetime, CD4 cell count, AIDS diagnosis, or HAART medication.This study provides behavioral support for adverse synergism of HIV infection and chronic alcoholism on brain function and is consistent with neuroimaging reports of compromised hippocampal and associated memory structures related to episodic memory processes in these 2 conditions.

    View details for DOI 10.1111/j.1530-0277.2009.01020.x

    View details for Web of Science ID 000270068400018

    View details for PubMedID 19656122

  • Frontostriatal fiber bundle compromise in HIV infection without dementia AIDS Pfefferbaum, A., Rosenbloom, M. J., Rohlfing, T., Kemper, C. A., Deresinski, S., Sullivan, E. V. 2009; 23 (15): 1977-1985


    Quantitative fiber tracking derived from diffusion tensor imaging (DTI) was used to determine whether white matter association, projection, or commissural tracts are affected in nondemented individuals with HIV infection and to identify the regional distribution of sparing and impairment of fiber systems.DTI measured fractional anisotropy and diffusivity, quantified separately for longitudinal (lambdaL) diffusivity (index of axonal injury) and transverse (lambdaT) diffusivity (index of myelin injury), in 11 association and projection white matter tracts and six commissural tracts in 29 men and 13 women with HIV infection and 88 healthy, age-matched controls (42 men and 46 women).The total group of HIV-infected individuals had higher diffusivity (principally longitudinal) than controls in the posterior sectors of the corpus callosum, internal and external capsules, and superior cingulate bundles. High longitudinal diffusivity, indicative of axonal compromise, was especially prominent in posterior callosal sectors, fornix, and superior cingulate bundle in HIV with AIDS. Unmedicated patients had notably high transverse diffusivity, indicative of myelin compromise, in the occipital forceps, inferior cingulate bundle, and superior longitudinal fasciculus. Pontocerebellar projection fibers were resistant to HIV effects as were commissural fibers coursing through premotor and sensorimotor callosal sectors.This quantitative survey of brain fiber tract integrity indicates that even nondemented HIV patients can have neuroradiological evidence for damage to association and commissural tracts. These abnormalities were vulnerable to exacerbation with AIDS and possibly mitigated by HAART.

    View details for DOI 10.1097/QAD.0b013e32832e77fe

    View details for Web of Science ID 000270475400006

    View details for PubMedID 19730350

    View details for PubMedCentralID PMC2864007

  • MRI estimates of brain iron concentration in normal aging: Comparison of field-dependent (FDRI) and phase (SWI) methods NEUROIMAGE Pfefferbaum, A., Adalsteinsson, E., Rohlfing, T., Sullivan, E. V. 2009; 47 (2): 493-500


    Different brain structures accumulate iron at different rates throughout the adult life span. Typically, striatal and brain stem structures are higher in iron concentrations in older than younger adults, whereas cortical white matter and thalamus have lower concentrations in the elderly than young adults. Brain iron can be measured in vivo with MRI by estimating the relaxivity increase across magnetic field strengths, which yields the Field-Dependent Relaxation Rate Increase (FDRI) metric. The influence of local iron deposition on susceptibility, manifests as MR phase effects, forms the basis for another approach for iron measurement, Susceptibility-Weighted Imaging (SWI), for which imaging at only one field strength is sufficient. Here, we compared the ability of these two methods to detect and quantify brain iron in 11 young (5 men, 6 women; 21 to 29 years) and 12 elderly (6 men, 6 women; 64 to 86 years) healthy adults. FDRI was acquired at 1.5 T and 3.0 T, and SWI was acquired at 1.5 T. The results showed that both methods detected high globus pallidus iron concentration regardless of age and significantly greater iron in putamen with advancing age. The SWI measures were more sensitive when the phase signal intensities themselves were used to define regions of interest, whereas FDRI measures were robust to the method of region of interest selection. Further, FDRI measures were more highly correlated than SWI iron estimates with published postmortem values and were more sensitive than SWI to iron concentration differences across basal ganglia structures. Whereas FDRI requires more imaging time than SWI, two field strengths, and across-study image registration for iron concentration calculation, FDRI appears more specific to age-dependent accumulation of non-heme brain iron than SWI, which is affected by heme iron and non-iron source effects on phase.

    View details for DOI 10.1016/j.neuroimage.2009.05.006

    View details for Web of Science ID 000267756900009

    View details for PubMedID 19442747

  • Special Section of Neuropsychology Review on HIV/NeuroAIDS NEUROPSYCHOLOGY REVIEW Sullivan, E. V. 2009; 19 (2): 143-143

    View details for DOI 10.1007/s11065-009-9104-3

    View details for Web of Science ID 000266665400001

    View details for PubMedID 19466594

  • Relevance of Iron Deposition in Deep Gray Matter Brain Structures to Cognitive and Motor Performance in Healthy Elderly Men and Women: Exploratory Findings BRAIN IMAGING AND BEHAVIOR Sullivan, E. V., Adalsteinsson, E., Rohlfing, T., Pfefferbaum, A. 2009; 3 (2): 167-175
  • In Vivo Evidence for Alcohol-Induced Neurochemical Changes in Rat Brain Without Protracted Withdrawal, Pronounced Thiamine Deficiency, or Severe Liver Damage NEUROPSYCHOPHARMACOLOGY Zahr, N. M., Mayer, D., Vinco, S., Orduna, J., Luong, R., Sullivan, E. V., Pfefferbaum, A. 2009; 34 (6): 1427-1442


    Magnetic resonance spectroscopy (MRS) studies in human alcoholics report decreases in N-acetylaspartate (NAA) and choline-containing (Cho) compounds. Whether alterations in brain metabolite levels are attributable to alcohol per se or to physiological effects of protracted withdrawal or impaired nutritional or liver status remains unclear. Longitudinal effects of alcohol on brain metabolites measured in basal ganglia with single-voxel MRS were investigated in sibling pairs of wild-type Wistar rats, with one rat per pair exposed to escalating doses of vaporized alcohol, the other to vapor chamber air. MRS was conducted before alcohol exposure and twice during exposure. After 16 weeks of alcohol exposure, rats achieved average blood alcohol levels (BALs) of approximately 293 mg per 100 ml and had higher Cho and a trend for higher glutamine+glutamate (Glx) than controls. After 24 weeks of alcohol exposure, BALs rose to approximately 445 mg per 100 ml, and alcohol-exposed rats had higher Cho, Glx, and glutamate than controls. Thiamine and thiamine monophosphate levels were significantly lower in the alcohol than the control group but did not reach levels low enough to be considered clinically relevant. Histologically, livers of alcohol-exposed rats exhibited greater steatosis and lower glycogenosis than controls, but were not cirrhotic. This study demonstrates a specific pattern of neurobiochemical changes suggesting excessive membrane turnover or inflammation, indicated by high Cho, and alterations to glutamate homeostasis in the rat brain in response to extended vaporized alcohol exposure. Thus, we provide novel in vivo evidence for alcohol exposure as causing changes in brain chemistry in the absence of protracted withdrawal, pronounced thiamine deficiency, or severe liver damage.

    View details for DOI 10.1038/npp.2008.119

    View details for Web of Science ID 000265221000007

    View details for PubMedID 18704091

    View details for PubMedCentralID PMC2669706

  • Postural sway reduction in aging men and women: Relation to brain structure, cognitive status, and stabilizing factors NEUROBIOLOGY OF AGING Sullivan, E. V., Rose, J., Rohlfing, T., Pfefferbaum, A. 2009; 30 (5): 793-807


    Postural stability becomes compromised with advancing age, but the neural mechanisms contributing to instability have not been fully explicated. Accordingly, this quantitative physiological and MRI study of sex differences across the adult age range examined the association between components of postural control and the integrity of brain structure and function under different conditions of sensory input and stance stabilization manipulation. The groups comprised 28 healthy men (age 30-73 years) and 38 healthy women (age 34-74 years), who completed balance platform testing, cognitive assessment, and structural MRI. The results supported the hypothesis that excessive postural sway would be greater in older than younger healthy individuals when standing without sensory or stance aids, and that introduction of such aids would reduce sway in both principal directions (anterior-posterior and medial-lateral) and in both the open-loop and closed-loop components of postural control even in older individuals. Sway reduction with stance stabilization, that is, standing with feet apart, was greater in men than women, probably because older men were less stable than women when standing with their feet together. Greater sway was related to evidence for greater brain structural involutional changes, indexed as ventricular and sulcal enlargement and white matter hyperintensity burden. In women, poorer cognitive test performance related to less sway reduction with the use of sensory aids. Thus, aging men and women were shown to have diminished postural control, associated with cognitive and brain structural involution, in unstable stance conditions and with diminished sensory input.

    View details for DOI 10.1016/j.neurobiolaging.2007.08.021

    View details for Web of Science ID 000265018700012

    View details for PubMedID 17920729

    View details for PubMedCentralID PMC2684797

  • Degradation of Association and Projection White Matter Systems in Alcoholism Detected with Quantitative Fiber Tracking BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Rosenbloom, M., Rohlfing, T., Sullivan, E. V. 2009; 65 (8): 680-690


    Excessive alcohol use can cause macrostructural tissue shrinkage with regional preference for frontal systems. The extent and locus of alcoholism's effect on white matter microstructure is less known.Quantitative fiber tracking derived from diffusion tensor imaging (DTI) assessed the integrity of samples of 11 major white matter bundles in 87 alcoholics (59 men, 28 women) and 88 healthy control subjects (42 men, 46 women). Fiber integrity was expressed as fractional anisotropy (FA) and apparent diffusion coefficient (ADC), quantified separately for longitudinal diffusivity (lambdaL), a putative index of axonal integrity, and transverse diffusivity (lambdaT), a putative index of myelin integrity.Alcoholism affected FA and diffusivity, particularly lambdaT, of several fiber bundles. Frontal and superior sites (frontal forceps, internal and external capsules, fornix, and superior cingulate and longitudinal fasciculi) showed greatest abnormalities in alcoholics relative to control subjects. More posterior and inferior bundles were relatively spared. Lifetime alcohol consumption correlated with regional DTI measures in alcoholic men but not women. When matched for alcohol exposure, alcoholic women showed more DTI signs of white matter degradation than alcoholic men in several fiber bundles. Among all alcoholics, poorer performance on speeded tests correlated with DTI signs of regional white matter degradation.This survey of multiple brain fiber systems revealed a differential pattern of alcoholism's effect on regional FA and diffusivity with functional consequences attributable in part to compromised fiber microstructure with prominence in signs of myelin degradation. Sex-based differences suggest that women are at enhanced risk for alcoholism-related degradation in selective white matter systems.

    View details for DOI 10.1016/j.biopsych.2008.10.039

    View details for Web of Science ID 000264857400007

    View details for PubMedID 19103436

  • Global-Local Interference is Related to Callosal Compromise in Alcoholism: A Behavior-DTI Association Study ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Mueller-Oehring, E. M., Schulte, T., Fama, R., Pfefferbaum, A., Sullivan, E. V. 2009; 33 (3): 477-489


    Visuospatial ability is a multifactorial process commonly impaired in chronic alcoholism. Identification of which features of visuospatial processing are affected and which are spared in alcoholism, however, has not been clearly determined. We used a global-local paradigm to assess component processes of visuospatial ability and MR diffusion tensor imaging (DTI) to examine whether alcoholism-related microstructural degradation of the corpus callosum contributes to disruption of selective lateralized visuospatial and attention processes.A hierarchical letter paradigm was devised, where large global letters were composed of small local letters. The task required identification of target letters among distractors presented at global, local, both, or neither level. Attention was either selectively directed to global or local levels or divided between levels. Participants were 18 detoxified chronic alcoholics and 22 age-matched healthy controls. DTI provided quantitative assessment of the integrity of corpus callosal white matter microstructure.Alcoholics generally had longer reaction times than controls but obtained similar accuracy scores. Both groups processed local targets faster than global targets and showed interference from targets at the unattended level. Alcoholics exhibited moderate compromise in selectively attending to the global level when the global stimuli were composed of local targets. Such local interference was less with longer abstinence. Callosal microstructural integrity compromise predicted degree of interference from stimulus incongruency in the alcoholic group. This relationship was not observed for lateral or third ventricular volumes, which are measures of nonspecific cortical volume deficits.Global-local feature perception was generally spared in abstinent chronic alcoholics, but impairments were observed when directing attention to global features and when global and local information interfered at stimulus or response levels. Furthermore, the interference-callosal integrity relationship in alcoholics indicates that compromised visuospatial functions include those requiring bilateral integration of information.

    View details for DOI 10.1111/j.1530-0277.2008.00858.x

    View details for Web of Science ID 000263518400011

    View details for PubMedID 19120053

    View details for PubMedCentralID PMC2651990

  • Neuroimaging of the Wernicke-Korsakoff Syndrome ALCOHOL AND ALCOHOLISM Sullivan, E. V., Pfefferbaum, A. 2009; 44 (2): 155-165


    Presented is the neuroradiological signature of acute Wernicke's encephalopathy (WE), derived from different types of magnetic resonance imaging (MRI) sequences. WE results from thiamine depletion, and its most typical antecedent is chronic alcohol dependence. Brain regions observed with in vivo MRI affected in acute WE include the mammillary bodies, periaqueductal and periventricular gray matter, collicular bodies and thalamus. These affected areas are usually edematous and are best visualized and quantified with MRI sequences that highlight such tissue. Following the acute WE phase and resolution of edema and inflammation of affected brain tissue, WE, if not adequately treated with thiamine repletion, can herald Korsakoff's syndrome (KS), with its symptomatic hallmark of global amnesia, that is, the inability to commit newly encountered (episodic) information to memory for later recall or recognition.Neuropathology of KS detectable with MRI has a different neuroradiological signature from the acute stage and can be observed as tissue shrinkage or atrophy of selective brain structures, including the mammillary bodies and thalamus and ventricular expansion, probably indicative of atrophy of surrounding gray matter nuclei. Quantification of these and additional gray matter structures known to underlie global amnesia reveal substantial bilateral volume deficits in the hippocampus, in addition to the mammillary bodies and thalamus, and modest deficits in the medial septum/diagonal band of Broca. The infratentorium is also affected, exhibiting volume deficits in cerebellar hemispheres, anterior superior vermis and pons, contributing to ataxia of gait and stance.Consideration of WKS structural brain changes in the context of the neuropathology of non-WKS alcoholism revealed a graded pattern of volume deficits, from mild in non-WKS alcoholics to moderate or severe in WKS, in the mammillary bodies, hippocampus, thalamus, cerebellum and pons. The development and resolution of brain structures affected in acute, chronic and treated WE was verified in longitudinal MRI study of rats that modeled of the interaction of extensive alcohol consumption and thiamine depletion and repletion.Thus, neuroradiological examination with MRI is valuable in the diagnosis of acute WE and enables in vivo tracking of the progression of the brain pathology of WE from the acute pathological phase to resolution with thiamine treatment or to progression to KS without treatment. Further, in vivo MRI facilitates translational studies to model antecedent conditions contributing to the development, sequelae and treatment of WE.

    View details for DOI 10.1093/alcalc/agn103

    View details for Web of Science ID 000263603100009

    View details for PubMedID 19066199

    View details for PubMedCentralID PMC2724861

  • Problem solving, working memory, and motor correlates of association and commissural fiber bundles in normal aging: A quantitative fiber tracking study NEUROIMAGE Zahr, N. M., Rohlfing, T., Pfefferbaum, A., Sullivan, E. V. 2009; 44 (3): 1050-1062


    Normal aging is accompanied by decline in selective cognitive and motor functions. A concurrent decline in regional white matter integrity, detectable with diffusion tensor imaging (DTI), potentially contributes to waning function. DTI analysis of white matter loci indicates an anterior-to-posterior gradient distribution of declining fractional anisotropy (FA) and increasing diffusivity with age. Quantitative fiber tracking can be used to determine regional patterns of normal aging of fiber systems and test the functional ramifications of the DTI metrics. Here, we used quantitative fiber tracking to examine age effects on commissural (genu and splenium), bilateral association (cingulate, inferior longitudinal fasciculus and uncinate), and fornix fibers in 12 young and 12 elderly healthy men and women and tested functional correlates with concurrent assessment of a wide range of neuropsychological abilities. Principal component analysis of cognitive and motor tests on which the elderly achieved significantly lower scores than the young group was used for data reduction and yielded three factors: Problem Solving, Working Memory, and Motor. Age effects--lower FA or higher diffusivity--in the elderly were prominent in anterior tracts, specifically, genu, fornix, and uncinate fibers. Differential correlations between FA or diffusivity in fiber tracts and scores on Problem Solving, Working Memory, or Motor factors provide convergent validity to the biological meaningfulness of the integrity of the fibers tracked. The observed pattern of relations supports the possibility that regional degradation of white matter fiber integrity is a biological source of age-related functional compromise and may have the potential to limit accessibility to alternative neural systems to compensate for compromised function.

    View details for DOI 10.1016/j.neuroimage.2008.09.046

    View details for Web of Science ID 000262301500044

    View details for PubMedID 18977450

    View details for PubMedCentralID PMC2632960

  • Contribution of Regional White Matter Integrity to Visuospatial Construction Accuracy, Organizational Strategy, and Memory for a Complex Figure in Abstinent Alcoholics. Brain imaging and behavior Rosenbloom, M. J., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2009; 3 (4): 379–90


    Visuospatial construction ability as used in drawing complex figures is commonly impaired in chronic alcoholics, but memory for such information can be enhanced by use of a holistic drawing strategy during encoding. We administered the Rey-Osterrieth Complex Figure Test (ROCFT) to 41 alcoholic and 38 control men and women and assessed the contribution of diffusion tensor imaging (DTI) measures of integrity of selected white matter tracts to ROCFT copy accuracy, copy strategy, and recall accuracy. Although alcoholics copied the figure less accurately than controls, a more holistic strategy at copy was associated with better recall in both groups. Greater radial diffusivity, reflecting compromised myelin integrity, in occipital forceps and external capsule was associated with poorer copy accuracy in both groups. Lower FA, reflecting compromised fiber microstructure in the inferior cingulate bundle, which links frontal and medial temporal episodic memory systems, was associated with piecemeal copy strategy and poorer immediate recall in the alcoholics. The correlations were generally modest and should be considered exploratory. To the extent that the inferior cingulate was relatively spared in alcoholics, it may have provided an alternative pathway to the compromised frontal system for successful copy strategy and, by extension, aided recall.

    View details for PubMedID 20161607

    View details for PubMedCentralID PMC2811340

  • Regression Models of Atlas Appearance 21st International Conference on Information Processing in Medical Imaging Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. SPRINGER-VERLAG BERLIN. 2009: 151–162
  • Subject-Matched Templates for Spatial Normalization 12th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI2009) Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. SPRINGER-VERLAG BERLIN. 2009: 224–231
  • Subject-matched templates for spatial normalization. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. 2009; 12: 224-231


    Spatial normalization of images from multiple subjects is a common problem in group comparison studies, such as voxel-based and deformation-based morphometric analyses. Use of a study-specific template for normalization may improve normalization accuracy over a study-independent standard template (Good et al., NeuroImage, 14(1):21-36, 2001). Here, we develop this approach further by introducing the concept of subject-matched templates. Rather than using a single template for the entire population, a different template is used for every subject, with the template matched to the subject in terms of age, sex, and potentially other parameters (e.g., disease). All subject-matched templates are created from a single generative regression model of atlas appearance, thus providing a priori template-to-template correspondence without registration. We demonstrate that such an approach is technically feasible and significantly improves spatial normalization accuracy over using a single template.

    View details for PubMedID 20426116

  • Relevance of Iron Deposition in Deep Gray Matter Brain Structures to Cognitive and Motor Performance in Healthy Elderly Men and Women: Exploratory Findings. Brain imaging and behavior Sullivan, E. V., Adalsteinsson, E., Rohlfing, T., Pfefferbaum, A. 2009; 3 (2): 167–75


    Iron deposition increases in normal aging, has its greatest presence in structures of the extrapyramidal system, and may contribute to functional decline. MR imaging provides a method for indexing iron deposition in brain structures because of iron's ferromagnetic properties, which interact with the MRI environment to cause signal intensity attenuation that is quantifiable by comparing images collected at 1.5 and 3.0 T. We tested functional correlates of an MR-based iron index in 10 healthy, elderly individuals previously reported to have a higher iron burden in the putamen and lower in the thalamus than young individuals. Lower scores on the Dementia Rating Scale and longer reaction times on a two-choice attention test correlated with higher iron estimates in the caudate nucleus and putamen; poorer Mini-Mental State Examination and Digit Symbol scores correlated with lower iron estimates in the thalamus. Further analyses based on multiple regression, which considered regional FDRI estimates and volume measures as predictors of performance, identified iron but not the sampled volume as the unique predictor in each case. These exploratory correlations suggest a substrate of performance degradation in aging and have implications for regional signal darkening in an array of MR-based imaging protocols.

    View details for PubMedID 20161183

    View details for PubMedCentralID PMC2727611

  • Low striatal glutamate levels underlie cognitive decline in the elderly: Evidence from in vivo molecular spectroscopy CEREBRAL CORTEX Zahr, N. M., Mayer, D., Pfefferbaum, A., Sullivan, E. V. 2008; 18 (10): 2241-2250


    Glutamate (Glu), the principal excitatory neurotransmitter of prefrontal cortical efferents, potentially mediates higher order cognitive processes, and its altered availability may underlie mechanisms of age-related decline in frontally based functions. Although animal studies support a role for Glu in age-related cognitive deterioration, human studies, which require magnetic resonance spectroscopy for in vivo measurement of this neurotransmitter, have been impeded because of the similarity of Glu's spectroscopic signature to those of neighboring spectral brain metabolites. Here, we used a spectroscopic protocol, optimized for Glu detection, to examine the effect of age in 3 brain regions targeted by cortical efferents--the striatum, cerebellum, and pons--and to test whether performance on frontally based cognitive tests would be predicted by regional Glu levels. Healthy elderly men and women had lower Glu in the striatum but not pons or cerebellum than young adults. In the combined age groups, levels of striatal Glu (but no other proton metabolite also measured) correlated selectively with performance on cognitive tests showing age-related decline. The selective relations between performance and striatal Glu provide initial and novel, human in vivo support for age-related modification of Glu levels as contributing to cognitive decline in normal aging.

    View details for DOI 10.1093/cercor/bhm250

    View details for Web of Science ID 000259326700002

    View details for PubMedID 18234683

    View details for PubMedCentralID PMC2733311

  • Reproducibility study of whole-brain H-1 spectroscopic imaging with automated quantification MAGNETIC RESONANCE IN MEDICINE Gu, M., Kim, D., Mayer, D., Sullivan, E. V., Pfefferbaum, A., Spielman, D. M. 2008; 60 (3): 542-547


    A reproducibility study of proton MR spectroscopic imaging ((1)H-MRSI) of the human brain was conducted to evaluate the reliability of an automated 3D in vivo spectroscopic imaging acquisition and associated quantification algorithm. A PRESS-based pulse sequence was implemented using dualband spectral-spatial RF pulses designed to fully excite the singlet resonances of choline (Cho), creatine (Cre), and N-acetyl aspartate (NAA) while simultaneously suppressing water and lipids; 1% of the water signal was left to be used as a reference signal for robust data processing, and additional lipid suppression was obtained using adiabatic inversion recovery. Spiral k-space trajectories were used for fast spectral and spatial encoding yielding high-quality spectra from 1 cc voxels throughout the brain with a 13-min acquisition time. Data were acquired with an 8-channel phased-array coil and optimal signal-to-noise ratio (SNR) for the combined signals was achieved using a weighting based on the residual water signal. Automated quantification of the spectrum of each voxel was performed using LCModel. The complete study consisted of eight healthy adult subjects to assess intersubject variations and two subjects scanned six times each to assess intrasubject variations. The results demonstrate that reproducible whole-brain (1)H-MRSI data can be robustly obtained with the proposed methods.

    View details for DOI 10.1002/mrm.21713

    View details for Web of Science ID 000259053900006

    View details for PubMedID 18727040

  • Neuroinflammation as a neurotoxic mechanism in alcoholism: Commentary on "Increased MCP-1 and microglia in various regions of human alcoholic brain" EXPERIMENTAL NEUROLOGY Sullivan, E. V., Zahr, N. M. 2008; 213 (1): 10-17
  • Ventricular expansion in wild-type Wistar rats after alcohol exposure by vapor chamber ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Zahr, N. M., Mayer, D., Vinco, S., Orduna, J., Rohlfing, T., Sullivan, E. V. 2008; 32 (8): 1459-1467


    Structural magnetic resonance imaging (MRI) reveals widespread brain damage manifest as tissue shrinkage and complementary ventriculomegaly in human alcoholism. For an animal model to parallel the human condition, high alcohol exposure should produce similar radiologically detectable neuropathology. Our previous structural MRI study demonstrated only modest brain dysmorphology of the alcohol-preferring (P) rat with average blood alcohol levels(BALs) of 125 mg/dl achieved with voluntary consumption. Here, we tested the hypothesis that wild-type Wistar rats, exposed to vaporized alcohol ensuring higher BALs than typically achieved with voluntary consumption in rodents, would model MRI findings in the brains of humans with chronic alcoholism.The longitudinal effects of vaporized alcohol exposure on the brains of 10 wild-type Wistar rats compared with 10 sibling controls were investigated with structural MRI, conducted before (MRI 1) and after (MRI 2) 16 of alcohol exposure and after an additional 8 weeks at a higher concentration of alcohol (MRI 3).Two rats in the alcohol group died prior to MRI 2. The remaining vapor-exposed rats(n = 8) achieved BALs of 293 mg/dl by MRI 2 and 445 mg/dl by MRI 3. Whereas the controls gained 17% of their body weight from MRI 1 to MRI 3, the alcohol-exposed group lost 6%.MRI, quantified with atlas-based parcellation, revealed a profile of significant ventricular expansion,after alcohol vapor exposure, in 9 contiguous slices, extending from the dorsolateral to ventrolateral ventricles. In particular, from MRI 1 to MRI 2, this ventricular volume expanded by an average of 6.5% in the controls and by 27.1% in the alcohol-exposed rats but only an additional 1.5% in controls and 2.4% in alcohol-exposed rats from MRI 2 to MRI 3. The midsagittal volume of the full anterior-to-posterior extent of the corpus callosum grew between the first 2 MRIs in both groups followed by regression in the alcohol group by MRI 3. Although group differences were statistically significant, among animals there was substantial variability of the effects of alcohol exposure on brain morphology; some animals showed profound effects, whereas others were essentially unaffected.The ventricular dilatation and callosal shrinkage produced in wild-type rats following involuntary alcohol exposure yielded a modestly successful model of neurodysmorphology phenotypes of human alcoholism. As is the case for the human condition, however, in which some individuals express greater alcoholism-related neuropathology than others, some rats maybe more susceptible than others to extreme alcohol exposure.

    View details for DOI 10.1111/j.1530-0277.2008.00721.x

    View details for Web of Science ID 000258331500014

    View details for PubMedID 18798357

  • Frontal Callosal Fiber Integrity Selectively Predicts Coordinated Psychomotor Performance in Chronic Alcoholism BRAIN IMAGING AND BEHAVIOR Rosenbloom, M. J., Sassoon, S. A., Fama, R., Sullivan, E. V., Pfefferbaum, A. 2008; 2 (2): 74-83
  • Callosal Compromise Differentially Affects Conflict Processing and Attentional Allocation in Alcoholism, HIV, and Their Comorbidity BRAIN IMAGING AND BEHAVIOR Schulte, T., Mueller-Oehring, E. M., Javitz, H., Pfefferbaum, A., Sullivan, E. V. 2008; 2 (1): 27-38
  • Translational Studies of Alcoholism Bridging the Gap ALCOHOL RESEARCH & HEALTH Zahr, N. M., Sullivan, E. V. 2008; 31 (3): 215-230


    Human studies are necessary to identify and classify the brain systems predisposing individuals to develop alcohol use disorders and those modified by alcohol, while animal models of alcoholism are essential for a mechanistic understanding of how chronic voluntary alcohol consumption becomes compulsive, how brain systems become damaged, and how damage resolves. Our current knowledge of the neuroscience of alcohol dependence has evolved from the interchange of information gathered from both human alcoholics and animal models of alcoholism. Together, studies in humans and animal models have provided support for the involvement of specific brain structures over the course of alcohol addiction, including the prefrontal cortex, basal ganglia, cerebellum, amygdala, hippocampus, and the hypothalamic-pituitary-adrenal axis.

    View details for Web of Science ID 000261066500003

    View details for PubMedID 20041042

  • The SRI24 multi-channel brain atlas: Construction and applications Medical Imaging 2008 Conference Rohlfing, T., Zahr, N. M., Sullivan, E. V., Pfefferbaum, A. SPIE-INT SOC OPTICAL ENGINEERING. 2008

    View details for DOI 10.1117/12.770441

    View details for Web of Science ID 000256058600008

  • Interaction of thiamine deficiency and voluntary alcohol consumption disrupts rat corpus callosum ultrastructure NEUROPSYCHOPHARMACOLOGY He, X., Sullivan, E. V., Stankovic, R. K., Harper, C. G., Pfefferbaum, A. 2007; 32 (10): 2207-2216


    The relative roles of alcohol and thiamine deficiency in causing brain damage remain controversial in alcoholics without the Wernicke-Korsakoff syndrome. Experimental control over alcohol consumption and diet are impossible in humans but can be accomplished in animal models. This experiment was designed to differentiate the separate and combined effects on the macro- and ultrastructure of the corpus callosum of thiamine deficiency and voluntary alcohol consumption. Adult male alcohol-preferring (P) rats (9 chronically alcohol-exposed and 9 water controls) received a thiamine-deficient diet for 2 weeks. There were four groups: five rats previously exposed to alcohol were treated with pyrithiamine (a thiamine phosphorylation inhibitor); five rats never exposed to alcohol were treated with pyrithiamine; four alcohol-exposed rats were treated with thiamine; and four rats never exposed to alcohol were treated with thiamine. On day 14, thiamine was restored in all 18 rats; 2 weeks later the 10 pyrithiamine-treated rats received intraperitoneal thiamine. The rats were perfused 61 days post-pyrithiamine treatment at age 598 days. Brains were dissected and weight and volumes were calculated. Sagittal sections were stained to measure white matter structures. The corpus callosum was examined using transmission electron microscopy to determine density of myelinated fibers, fiber diameter, and myelin thickness. The corpus callosum in the alcohol/pyrithiamine group was significantly thinner, had greater fiber density, higher percentage of small fibers, and myelin thinning than in the alcohol/thiamine and water/thiamine groups. Several measures showed a graded effect, where the alcohol/pyrithiamine group had greater pathology than the water/pyrithiamine group, which had greater pathology than the two thiamine-replete groups. Across all 16 rats, thinner myelin sheaths correlated with higher percentage of small fibers. Myelin thickness and axon diameter together accounted for 71% of the variance associated with percentage of small fibers. Significant abnormalities in the alcohol/pyrithiamine group and lack of abnormality in the alcohol-exposed/thiamine-replete group indicate that thiamine deficiency caused white matter damage. The graded abnormalities across the dually to singly treated animals support a compounding effect of alcohol exposure and thiamine depletion, and indicate the potential for interaction between alcohol and thiamine deficiency in human alcohol-related brain damage.

    View details for DOI 10.1038/sj.npp.1301332

    View details for Web of Science ID 000249506000017

    View details for PubMedID 17299515

  • Alcohol and drug dependence: Brain mechanisms and behavioral impact NEUROPSYCHOLOGY REVIEW Sullivan, E. V. 2007; 17 (3): 235-238

    View details for DOI 10.1007/s11065-007-9039-5

    View details for Web of Science ID 000250142100004

    View details for PubMedID 17680366

  • Component cognitive and motor processes of the digit symbol test: Differential deficits in alcoholism, HIV infection, and their comorbidity ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sassoon, S. A., Fama, R., Rosenbloom, M. J., O'Reilly, A., Pfefferbaum, A., Sullivan, E. V. 2007; 31 (8): 1315-1324


    Alcoholism (ALC) is highly prevalent in patients with human immunodeficiency virus (HIV) infection (HIV), and those with comorbidity (ALC+HIV) may suffer compounded deficits in cognitive and motor functions affected by both conditions. Given that each disease can adversely affect motor, visuospatial, and executive functions, we used an expanded version of the Digit Symbol (DS) test to assess the separate and combined effects of ALC and HIV infection on these cognitive and motor components.Participants were 44 ALC, 43 HIV, 55 ALC+HIV, and 49 normal controls (NC). We modified DS test administration to assess sustained attention (grid completion speed), associative learning (number of boxes completed in 15-second epochs), and incidental learning (total number-symbol pairs correctly recalled) and also used ancillary tests of fine motor, visuospatial, and executive functions to assess their relationship with the different components of DS performance. All scores were corrected for age and education based on NC performance.Neither single diagnosis group-ALC nor HIV-was impaired on DS score or grid completion speed compared with the NC group, but the dual-diagnosis ALC+HIV group was impaired. Greater lifetime alcohol consumption was associated with longer grid completion time in both ALC and ALC+HIV. The HIV group demonstrated associative learning on DS but ALC+HIV and ALC did not. All groups performed similarly on incidental learning. Multiple regression analyses demonstrated that executive functions, assessed by Color Trails 2, predicted traditional DS performance in all groups. Fine Finger Movement additionally predicted traditional DS performance and grid completion speed in HIV. Visuospatial function, assessed by ability to copy the Rey-Osterrieth complex figure, did not contribute independently to DS performance in either alcohol group.Alcoholism combined with HIV infection resulted in deficits in visuospatial psychomotor function, as assessed by the DS test, although deficits were not observed in either disease condition alone. Neither alcohol group showed associative learning, and both had compromised sustained attention. Combined cognitive and motor adverse effects of alcoholism and HIV infection were manifest in psychomotor speed, sustained attention, and associative learning of visuospatial material and are testimony to the dangers of alcohol abuse even in relatively healthy patients with HIV infection.

    View details for DOI 10.1111/j.1530-0277.2007.00426.x

    View details for Web of Science ID 000248044300006

    View details for PubMedID 17550370

  • Improvement in memory and static balance with abstinence in alcoholic men and women: Selective relations with change in brain structure PSYCHIATRY RESEARCH-NEUROIMAGING Rosenbloom, M. J., Rohlfing, T., O'Reilly, A. W., Sassoon, S. A., Pfefferbaum, A., Sullivan, E. V. 2007; 155 (2): 91-102


    We investigated whether changes in memory or static balance in chronic alcoholics, occurring with abstinence or relapse, are associated with changes in lateral and fourth ventricular volume. Alcoholics meeting DSM-IV criteria for Alcohol Dependence (n=15) and non-alcoholic controls (n=26) were examined twice at a mean interval of 2 years with standard Wechsler Abbreviated Scale of Intelligence (WASI), Wechsler Memory Scale-Revised (WMS-R) tests, an ataxia battery, and structural MRI. At study entry, alcoholics had been abstinent on average for over 4 months and achieved lower scores than controls on WASI General IQ Index, WMS-R General Memory Index, and the ataxia battery. The 10 alcoholics who maintained sobriety at retest did not differ at study entry in socio-demographic measures, alcohol use, or WASI and WMS-R summary scores from the five relapsers. At follow-up, abstainers improved more than controls on the WMS-R General Memory Index. Ataxia tended to improve in abstainers relative to controls. Associations were observed between memory and lateral ventricular volume change and between ataxia and fourth ventricular volume change in alcoholics but not in the controls. Both memory and ataxia can improve with sustained sobriety, and brain-behavior associations suggest selective brain structural substrates for the changes observed.

    View details for DOI 10.1016/j.pscychresns.2006.12.019

    View details for Web of Science ID 000248061000002

    View details for PubMedID 17407808

    View details for PubMedCentralID PMC1949491

  • Upper and lower limb motor impairments in alcoholism, HIV infection, and their comorbidity 34th Annual Meeting of the International-Neuropsychological-Society Fama, R., Eisen, J. C., Rosenbloom, M. J., Sassoon, S. A., Kemper, C. A., Deresinski, S., Pfefferbaum, A., Sullivan, E. V. WILEY-BLACKWELL. 2007: 1038–44


    Both HIV infection and alcoholism can impair motor abilities involving manual dexterity and postural stability. Given the high prevalence of HIV and alcoholism comorbidity, we examined whether each disease selectively disrupts different components of upper and lower limb motor control and whether these impairments are compounded by disease comorbidity.Simple and complex upper (speed and finger dexterity) and lower (static posture) limb functions were tested in 31 men with HIV infection, 27 with alcoholism, 43 comorbid for HIV infection and alcoholism, and 22 normal healthy controls to assess whether comorbid patients would demonstrate greater motor impairment relative to those with a single diagnosis.Individuals with HIV infection and those with alcoholism had impaired upper and lower limb motor function. Disease comorbidity compounded deficits in speeded finger movement. Neither Beck Depression Inventory scores, self-reported peripheral neuropathy, nor HIV medication accounted for group differences. Lower limb motor composite scores with eyes open were correlated with upper limb motor scores in the alcoholism group.Overall, the observed impairment patterns indicate the presence of upper and lower limb motor impairment in both HIV infection and alcoholism and the relevance of alcoholism in exacerbating impairment in speeded fine finger movement, when it occurs in HIV infection.

    View details for DOI 10.1111/j.1530-0277.2007.00385.x

    View details for Web of Science ID 000246576500015

    View details for PubMedID 17403062

  • Development and resolution of brain lesions caused by pyrithiamine- and dietary-induced thiamine deficiency and alcohol exposure in the alcohol-preferring rat: A longitudinal magnetic resonance imaging and spectroscopy study NEUROPSYCHOPHARMACOLOGY Pfefferbaum, A., Adalsteinsson, E., Bell, R. L., Sullivan, E. V. 2007; 32 (5): 1159-1177


    Wernicke's encephalopathy (WE) is characterized by lesions in thalamus, hypothalamus (including mammillary nuclei), and inferior colliculi, results in serious disabilities, has an etiology of thiamine deficiency, is treatable with thiamine, and occurs most commonly with alcoholism. Despite decades of study, whether alcohol exposure exacerbates the neuropathology or retards its resolution remains controversial. To examine patterns of brain damage and recovery resulting from thiamine deprivation with and without alcohol exposure, we conducted in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3 T in alcohol-preferring (P) rats, which had voluntarily consumed large amounts of alcohol before thiamine manipulation. A total of 18 adult male P rats (nine alcohol-exposed) received a thiamine-deficient diet for 2 weeks: 10 (five alcohol-exposed) received intraperitoneal (i.p.) pyrithiamine (PT) and eight (four alcohol-exposed) received i.p. thiamine supplementation. Neurological signs developed by day 14. Rats were scanned before thiamine depletion and 18 and 35 days after thiamine repletion. Two-dimensional J-resolved MRS single-voxel spectra with water reference were collected in a voxel subtending the thalamus; metabolite quantification was corrected for voxel tissue content. MRI identified significant enlargement of dorsal ventricles and increase in signal intensities in thalamus, inferior colliculi, and mammillary nuclei of PT compared with thiamine-treated (TT) groups from MRI 1-2, followed by significant normalization from MRI 2-3 in thalamus and colliculi, but not mammillary nuclei and lateral ventricles. Voxel-by-voxel analysis revealed additional hyperintense signal clusters in the dorsal and ventral hippocampus and enlargement of the fourth ventricle. MRS showed a significant decline and then partial recovery in thalamic N-acetylaspartate, a marker of neuronal integrity, in PT compared with TT rats, with no change detected in creatine, choline, or glutamate. PT rats with prior alcohol exposure exhibited attenuated recovery in the thalamus and arrested growth of the corpus callosum; further, two of the five alcohol-exposed PT rats died prematurely. Parenchymal and ventricular changes with thiamine manipulation concur with human radiological signs of WE. The enduring macrostructural and neurochemical abnormalities involving critical nodes of Papez circuit carry liabilities for development of amnesia and incomplete recovery from other cognitive and motor functions subserved by the affected neural systems.

    View details for DOI 10.1038/sj.npp.1301107

    View details for Web of Science ID 000245758800016

    View details for PubMedID 16723995

  • Local-global interference is modulated by age, sex and anterior corpus callosum size BRAIN RESEARCH Mueller-Oehring, E. M., Schulte, T., Raassi, C., Pfefferbaum, A., Sullivan, E. V. 2007; 1142: 189-205


    To identify attentional and neural mechanisms affecting global and local feature extraction, we devised a global-local hierarchical letter paradigm to test the hypothesis that aging reduces functional cerebral lateralization through corpus callosum (CC) degradation. Participants (37 men and women, 26-79 years) performed a task requiring global, local, or global+local attention and underwent structural MRI for CC measurement. Although reaction time (RT) slowed with age, all participants had faster RTs to local than global targets. This local precedence effect together with greater interference from incongruent local information and greater response conflict from local targets each correlated with older age and smaller callosal genu (anterior) areas. These findings support the hypothesis that the CC mediates lateralized local-global processes by inhibition of task-irrelevant information under selective attention conditions. Further, with advancing age smaller genu size leads to less robust inhibition, thereby reducing cerebral lateralization and permitting interference to influence processing. Sex was an additional modifier of interference, in that callosum-interference relationships were evident in women but not in men. Regardless of age, smaller splenium (posterior) areas correlated with less response facilitation from repetition priming of global targets in men, but with greater response facilitation from repetition priming of local targets in women. Our data indicate the following dissociation: anterior callosal structure was associated with inhibitory processes (i.e., interference from incongruency and response conflict), which are vulnerable to the effects of age and sex, whereas posterior callosal structure was associated with facilitation processes from repetition priming dependent on sex and independent of age.

    View details for DOI 10.1016/j.brainres.2007.01.062

    View details for Web of Science ID 000245785000021

    View details for PubMedID 17335783

    View details for PubMedCentralID PMC1876662

  • In vivo metabolite differences between the basal ganglia and cerebellum of the rat brain detected with proton MRS at 3T PSYCHIATRY RESEARCH-NEUROIMAGING Mayer, D., Zahr, N. M., Sullivan, E. V., Pfefferbaum, A. 2007; 154 (3): 267-273


    In vivo magnetic resonance spectroscopy (MRS) enables non-invasive longitudinal tracking of brain chemistry changes that can accompany aging, neurodegenerative disease, drug addiction and experimental manipulations in animals modeling such conditions. J-coupled resonances, such as glutamate, which are highly relevant to neuropsychiatric conditions are difficult to resolve on a clinical 3T MR scanner using conventional one-dimensional MRS sequences. We, therefore, implemented Constant Time PRESS (CT-PRESS) to quantify major metabolite and neurotransmitter biochemical signals, including glutamate, in two brain regions of the rat, basal ganglia and cerebellum. We acquired spectra at two distinct time points in two independent groups of six rats and analyzed metabolite levels using either creatine or water as a reference. Our results provide evidence that CT-PRESS at 3T is adequate and reliable for in vivo detection and quantification of glutamate in the rat brain and that regional differences occur in the signal intensities of the major metabolites. That the directionality of the differences depends on whether creatine or water is used as a reference for metabolite levels emphasizes the benefit to in vivo MRS of incorporating methods to establish absolute baseline metabolite concentrations.

    View details for DOI 10.1016/j.pscychresns.2006.11.005

    View details for Web of Science ID 000246132000008

    View details for PubMedID 17346948

    View details for PubMedCentralID PMC1892789

  • In vivo riber tracking in the rat brain on a clinical 3T MRI system using a high strength insert gradient coil NEUROIMAGE Mayer, D., Zahr, N. M., Adalsteinsson, E., Rutt, B., Sullivan, E. V., Pfefferbaum, A. 2007; 35 (3): 1077-1085


    In vivo neuroimaging methods permit longitudinal quantitative examination of the dynamic course of neurodegenerative conditions in humans and animal models and enable assessment of therapeutic efforts in mitigating disease effects on brain systems. The study of conditions affecting white matter, such as multiple sclerosis, demyelinating conditions, and drug and alcohol dependence, can be accomplished with diffusion tensor imaging (DTI), a technique uniquely capable of probing the microstructural integrity of white matter fibers in the living brain. We used a 3T clinical MR scanner equipped with an insert gradient coil that yields an order of magnitude increase in performance over the whole-body hardware to acquire in vivo DTI images of rat brain. The resolution allowed for fiber tracking evaluation of fractional anisotropy (FA) and apparent diffusion coefficients in the genu and splenium of the corpus callosum. A comparison of short (46 min) and long (92 min) acquisition time DTI protocols indicated low but adequate signal-to-noise ratio (SNR=6.2) of the shorter protocol to conduct quantitative fiber tracking enhanced by multiple acquisitions. As observed in human studies, FA in the rat splenium was higher than in the genu. Advantages of this technology include the use of similar user interface, pulse sequences, and field strength for preclinical animal and clinical human research, enhancing translational capabilities. An additional benefit of scanning at lower field strength, such as 3 T, is the reduction of artifacts due to main field inhomogeneity relative to higher field animal systems.

    View details for DOI 10.1016/j.neuroimage.2007.01.006

    View details for Web of Science ID 000245956100009

    View details for PubMedID 17331742

    View details for PubMedCentralID PMC1868575

  • Neuroradiological characterization of normal adult ageing BRITISH JOURNAL OF RADIOLOGY Sullivan, E. V., Pfefferbaum, A. 2007; 80: S99-S108


    This paper provides a review of MRI and diffusion tensor imaging (DTI) findings in normal ageing as an essential context for evaluating imaging in dementia, and adding to the ever-growing number of such overviews. An additional extensive literature details the physics, MR acquisition, image reconstruction and mathematical computation approaches to both imaging modalities. The aim of this review is to illustrate how MR imaging modalities, spanning structural and diffusion tensor imaging, are suitable for visualizing and quantifying the macrostructural and microstructural disruptions sustained by the brain in normal ageing and to recognize the importance of normative data for identifying abnormalities characterizing neurodegenerative diseases and other conditions affecting brain tissue integrity.

    View details for DOI 10.1259/bjr/22893432

    View details for Web of Science ID 000256312300005

    View details for PubMedID 18445750

  • Divergence-based framework for diffusion tensor clustering, interpolation, and regularization 20th International Conference on Information Processing in Medical Imaging Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. SPRINGER-VERLAG BERLIN. 2007: 507–518
  • Divergence-based framework for diffusion tensor clustering, interpolation, and regularization. Information processing in medical imaging : proceedings of the ... conference Rohlfing, T., Sullivan, E. V., Pfefferbaum, A. 2007; 20: 507-518


    This paper introduces a novel framework for diffusion tensor combination, which can be used for tensor averaging, clustering, interpolation, and regularization. The framework is based on the physical interpretation of the tensors as the covariance matrices of Gaussian probability distributions. The symmetric Kullback-Leibler divergence provides a natural distance measure on these distributions, which leads to a closed-form expression for the distance between any two diffusion tensors, as well as for the weighted average of an arbitrary number of tensors. We illustrate the application of our technique in four different scenarios: (a) to combine tensor data from multiple subjects and generate population atlases from ten young and ten older subjects, (b) to perform k-means clustering and generate a compact Gaussian mixture of multiple tensors, (c) to interpolate between tensors, and (d) to regularize (i.e., smooth) noisy tensor data. For boundary-preserving regularization, we also propose a non-linear two-stage smoothing algorithm that can be considered remotely similar to a median filter.

    View details for PubMedID 17633725

  • Diffusion tensor imaging with quantitative fibre tracking in HIV infection and alcoholism comorbidity: synergistic white matter damage BRAIN Pfefferbaum, A., Rosenbloom, M. J., Adalsteinsson, E., Sullivan, E. V. 2007; 130: 48-64


    A substantial proportion of individuals infected with human immunodeficiency virus (HIV) also abuse alcohol. Given that each condition can disrupt brain structural integrity, with a predilection for white matter, we used MR diffusion tensor imaging (DTI) and quantitative fibre tracking to examine the separate and combined effects on the microstructure of the corpus callosum. Subjects were men and women with alcoholism alone (n = 87), HIV infection alone (n = 42), alcoholism and HIV infection comorbidity (n = 52) and non-affected controls (n = 88). The two alcoholism groups had similar lifetime alcohol consumption histories; the two HIV-infected groups had similar CD4+ counts and viral loads; all groups were matched in body mass index, and no participant was demented. Compared with controls, all patient groups had lower fractional anisotropy (FA) and higher mean diffusivity (MD) in callosal regions and fibre bundles coursing through the genu and splenium, but these effects were only significant in the two groups with alcoholism, which exhibited 0.65-1.2 SD abnormalities in FA and MD. The callosal regions were differentially affected by alcoholism, with the genu more affected than the splenium, a pattern even more pronounced in the fibre tracks. When the HIV-infected groups were divided by disease severity defined as an acquired immunodeficiency syndrome (AIDS)-defining event or low CD4+ counts (<200) and alcoholism comorbidity, the HIV-infected subgroup with AIDS and alcoholism exhibited approximately 2 SD FA and MD abnormalities in the callosal sectors and fibres, abnormalities that were more than twice the effect sizes observed in the other three HIV-infected subgroups. Degradation of the callosal microstructure was consistently associated with alcoholism, with evidence for compounded alcoholism-HIV effects. Functional relevance of the microstructural abnormalities was supported by associations between motor deficits and low FA or high MD within the diagnostic groups. The high prevalence of alcoholism in HIV-infected individuals and the interfering effect of alcohol on HIV pharmacological response and therapy compliance underscore the need to recognize the independent and synergistic contributions of each condition to brain structure and function.

    View details for DOI 10.1093/brain/awl242

    View details for Web of Science ID 000243061500005

    View details for PubMedID 16959813

  • Alcoholism, HIV infection, and their comorbidity: Factors affecting self-rated health-related quality of life JOURNAL OF STUDIES ON ALCOHOL AND DRUGS Rosenbloom, M. J., Sullivan, E. V., Sassoon, S. A., O'Reilly, A., Fama, R., Kemper, C. A., Deresinski, S., Pfefferbaum, A. 2007; 68 (1): 115-125


    Both alcoholism and HIV infection reduce health-related quality of life (HRQOL), and their co-occurrence is highly prevalent. We sought to determine whether comorbidity for both disorders further reduced HRQOL and what factors exacerbated or mitigated their effect.HRQOL, CD4 T-cell counts, lifetime alcohol consumption and length of sobriety, depressive symptoms (Beck Depression Inventory [BDI]-II), general cognitive status (Peabody Picture Vocabulary Test II), and other psychiatric comorbidities were assessed in patients with alcohol dependence or abuse (n = 44), HIV infection (n = 44), alcohol + HIV (n = 55), and healthy controls (n = 41).Alcohol + HIV patients had lower HRQOL and more psychiatric comorbidities compared with patients with only HIV or those with only alcohol dependence or abuse; however, they matched HIV patients with regard to CD4 counts and matched alcohol patients on lifetime alcohol consumption. Across patient groups, higher HRQOL was associated with lower BDI scores but was not associated with age, gender, lifetime alcohol use, or viral load. HRQOL was higher for alcoholics in remission than for those currently meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. In stepwise regression, BDI total score predicted 34% of HRQOL variance in alcohol, 52% in alcohol + HIV, and 55% in HIV groups. General cognitive status contributed an additional 4% to the prediction of HRQOL but only in the alcohol + HIV group.The superimposition of HIV infection onto alcoholism has a negative impact on HRQOL independent of the severity of either disease. Depression strongly predicts HRQOL, and general cognitive status plays a small role in enhancing quality of life for those at greatest clinical disadvantage.

    View details for Web of Science ID 000248712600015

    View details for PubMedID 17149525

  • In vivo quantification of ethanol kinetics in rat brain NEUROPSYCHOPHARMACOLOGY Adalsteinsson, E., Sullivan, E. V., Mayer, D., Pfefferbaum, A. 2006; 31 (12): 2683-2691


    Proton magnetic resonance spectroscopy was used at 3T to measure the uptake and clearance of brain ethanol in rats after bolus intraperitoneal (i.p.) or intragastric (i.g.) alcohol injection, and to estimate the effects of acute alcohol on brain metabolites. The observation duration was 1-1.5 h with temporal resolution of alcohol sampling ranging from 4 s-4 min. The observed time course of alcohol brain concentration followed a consistent pattern characterized by a rapid absorption, an intermediate distribution, and a slower clearance that approached a linear decay. In a sample of eight healthy Wistar rats, the intercept of the linear clearance term, extrapolated back to the time of injection, correlated well with the administered dose per unit of lean body mass. Alcohol concentration estimation based on spectroscopically measured clearance was compared with blood alcohol levels from blood samples at the end of observation, and were in good agreement with the administered dose. Serial proton spectroscopy measurements provide a valid in vivo method for quantifying brain alcohol uptake and elimination kinetics in real time.

    View details for DOI 10.1038/sj.npp.1301023

    View details for Web of Science ID 000242046800013

    View details for PubMedID 16407891

  • Callosal involvement in a lateralized Stroop task in alcoholic and healthy subjects NEUROPSYCHOLOGY Schulte, T., Muller-Oehring, E. M., Salo, R., Pfefferbaum, A., Sullivan, E. V. 2006; 20 (6): 727-736


    To investigate the role of interhemispheric attentional processes, 25 alcoholic and 28 control subjects were tested with a Stroop match-to-sample task and callosal areas were measured with magnetic resonance imaging. Stroop color-word stimuli were presented to the left or right visual field (VF) and were preceded by a color cue that did or did not match the word's color. For matching colors, both groups showed a right VF advantage; for nonmatching colors, controls showed a left VF advantage, whereas alcoholic subjects showed no VF advantage. For nonmatch trials, VF advantage correlated with callosal splenium area in controls but not alcoholic subjects, supporting the position that information presented to the nonpreferred hemisphere is transmitted via the splenium to the hemisphere specialized for efficient processing. The authors speculate that alcoholism-associated callosal thinning disrupts this processing route.

    View details for DOI 10.1037/0894-4105.20.6.727

    View details for Web of Science ID 000241761000011

    View details for PubMedID 17100517

  • Contribution of alcoholism to brain dysmorphology in HIV infection: Effects on the ventricles and corpus callosum NEUROIMAGE Pfefferbaum, A., Rosenbloom, M. J., Rohlfing, T., Adalsteinsson, E., Kemper, C. A., Deresinski, S., Sullivan, E. V. 2006; 33 (1): 239-251


    Nonrigid registration and atlas-based parcellation methods were used to compare the volume of the ventricular system and the cross-sectional area of the midsagittal corpus callosum on brain MRIs from 272 subjects in four groups: patients with HIV infection, with and without alcoholism comorbidity, alcoholics, and controls. Prior to testing group differences in regional brain metrics, each measure was corrected by regression analysis for significant correlations with supratentorial cranial volume and age, observed in 121 normal control men and women, whose age spanned six decades. Disregarding HIV disease severity, we observed a graded pattern of modest enlargement of the total ventricular system (0.28 SD for uncomplicated HIV, 0.65 SD for HIV comorbid with alcoholism, and 0.72 SD for the alcoholism group). The pattern of callosal thinning showed a similar but small ( approximately 0.5 SD) graded effect. A different pattern emerged, however, when HIV severity in the context of alcoholism comorbidity was factored into the analysis. Substantially greater volume abnormalities were present in individuals with a history of an AIDS-defining event or low CD4+ T cell counts (

    View details for DOI 10.1016/j.neuroimage.2006.05.052

    View details for Web of Science ID 000241209800025

    View details for PubMedID 16877010

  • Effect of vision, touch and stance on cerebellar vermian-related sway and tremor: A quantitative physiological and MRI study CEREBRAL CORTEX Sullivan, E. V., Rose, J., Pfefferbaum, A. 2006; 16 (8): 1077-1086


    Postural balance is impaired in individuals with pathology of the anterior superior vermis of the cerebellum. Chronic alcoholism, with its known vermian pathology, provides a viable model for studying the relationship between cerebellar pathology and postural stability. Decades of separate study of recovering alcoholics and post-mortem neuroanatomical analysis have demonstrated vermian pathology but few studies have used quantitative posturography, acquired concurrently with quantitative neuroimaging, to establish whether this brain structure-function relationship is selective in vivo. Here, 30 healthy men and 39 chronic alcoholic men, abstinent from alcohol for several months, underwent MRI for volumetric quantitation of the cerebellar vermis and three comparison brain regions, the cerebellar hemispheres, supratentorial cortex and corpus callosum. All subjects also participated in an experiment involving a force platform that measured sway path length and tremor during static standing balance under four sensory conditions and two stance conditions. Three novel findings emerged: (i) sway path length, a physiological index of postural control, was selectively related to volume of the cerebellar vermis and not to any comparison brain region in the alcoholics; (ii) spectral analysis revealed sway prominence in the 2-5 Hz band, another physiological sign of vermian lesions and also selectively related to vermian volume in the alcoholics; and (iii) despite substantial postural sway in the patients, they successfully used vision, touch and stance to normalize sway and reduce tremor. The selective relationship of sway path to vermian but not lateral cerebellar volume provides correlational evidence for functional differentiation of these cerebellar regions. Improvement to virtual normal levels in balance and reduction in sway and tremor with changes in vision, touch and stance provide evidence that adaptive mechanisms recruiting sensorimotor integration can be invoked to compensate for underlying cerebellar vermian-related dysfunction.

    View details for DOI 10.1093/cercor/bhj048

    View details for Web of Science ID 000238906300003

    View details for PubMedID 16221930

  • Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part II: Effects of voluntary chronic alcohol consumption ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Adalsteinsson, E., Sood, R., Mayer, D., Bell, R., McBride, W., Li, T., Sullivan, E. V. 2006; 30 (7): 1248-1261


    Tracking the dynamic course of human alcoholism brain pathology can be accomplished only through naturalistic study and without opportunity for experimental manipulation. Development of an animal model of alcohol-induced brain damage, in which animals consume large amounts of alcohol following cycles of alcohol access and deprivation and are examined regularly with neuroimaging methods, would enable hypothesis testing focused on the degree, nature, and factors resulting in alcohol-induced brain damage and the prospects for recovery or relapse.We report the results of longitudinal magnetic resonance imaging (MRI) studies of the effects of free-choice chronic alcohol intake on the brains of 2 cohorts of selectively bred alcohol-preferring (P) rats. In the companion paper, we described the MRI acquisition and analysis methods, delineation of brain regions, and growth patterns in total brain and selective structures of the control rats in the present study. Both cohorts were studied as adults for about 1 year and consumed high doses of alcohol for most of the study duration. The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark.Brain structures of the adult P rats in both the alcohol-exposed and the water control conditions showed significant growth, which was attenuated in a few measures in the alcohol-exposed groups. The region with the greatest demonstrable effect was the corpus callosum, measured on midsagittal images.The P rats showed an age-alcohol interaction different from humans, in that normal growth in selective brain regions that continues in adult rats was retarded.

    View details for DOI 10.1111/j.1530-0277.2006.00146.x

    View details for Web of Science ID 000238253100019

    View details for PubMedID 16792573

  • Dysmorphology and microstruotural degradation of the corpus callosum: Interaction of age and alcoholism NEUROBIOLOGY OF AGING Pfefferbaum, A., Adalsteinsson, E., Sullivan, E. V. 2006; 27 (7): 994-1009


    Chronic alcohol abuse is a ubiquitous health and societal problem, with a growing prevalence in the older population. Alcoholism is a source of substantial deterioration in brain tissue and has been consistently observed in vivo and postmortem in white matter. To quantify the potential compounded effect of age and alcoholism, we used conventional structural MRI and diffusion tensor imaging (DTI) to examine the macrostructural and microstructural integrity of the corpus callosum, one of the most prominent white matter structures of the brain, in 131 adults, age 27-75 years. Compared with the 74 controls, the 40 alcoholic men and 17 alcoholic women, who were abstinent from alcohol for an average of 3 months, showed similar patterns and extents of callosal shrinkage, which was greatest in the genu and body and less prominent in the splenium. Microstructural integrity was measured with DTI as fractional anisotropy, an index of intravoxel orientational coherence of white matter fibers, and bulk mean diffusivity, an index of the amount of intravoxel water motility. The macrostructural shrinkage was accompanied by abnormalities in anisotropy and diffusivity of the microstructural environment of these callosal regions, indicative of disruption of structural constituents of local brain white matter. Correlational analyses revealed an age-alcohol interaction, where older alcoholics had smaller genu and splenium and higher diffusivity in these regions than younger alcoholics. Significant correlations between regional MRI and DTI measures and performance on working memory, visuospatial ability, and gait and balance provided evidence for the functional ramifications of the callosal abnormalities in the alcoholics. Thus, despite abstinence from alcohol, the interaction of age and recent alcoholism history exerted a compounded untoward effect on callosal macrostructure and microstructure.

    View details for DOI 10.1016/j.neurobiolaging.2005.05.007

    View details for Web of Science ID 000238012700011

    View details for PubMedID 15964101

  • Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part I: Adult brain growth ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Adalsteinsson, E., Sood, R., Mayer, D., Bell, R., McBride, W., Li, T., Pfefferbaum, A. 2006; 30 (7): 1234-1247


    The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat.We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions.Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain structures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error.Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter-dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease.

    View details for DOI 10.1111/j.1530-0277.2006.00145.x

    View details for Web of Science ID 000238253100018

    View details for PubMedID 16792572

  • Selective age-related degradation of anterior callosal fiber bundles quantified in vivo with fiber tracking CEREBRAL CORTEX Sullivan, E. V., Adalsteinsson, E., Pfefferbaum, A. 2006; 16 (7): 1030-1039


    The corpus callosum, the principal white matter structure enabling interhemispheric information transfer, is heterogeneous in its microstructural composition, heterotopic in its anteroposterior cortical connectivity, and differentially susceptible to aging. In vivo characterization of callosal features is possible with diffusion tensor imaging (DTI), a magnetic resonance imaging method sensitive to the detection of white matter's linear structure. We implemented a quantitative fiber tracking approach to examine age-related variation in regional microstructural characteristics [fractional anisotropy (FA) and apparent diffusion coefficient (ADC)] of callosal fibers in 10 younger (29 +/- 5 years) and 10 older (72 +/- 5 years) healthy adults. Fiber tracking was performed on 2.5 mm isotropic voxels collected at 3 T. Fiber targets comprised the midsagittal corpus callosum, divided into six regions based on known callosal anatomical projections. FA and ADC for each voxel of each fiber identified were determined; lower FA and higher ADC reflect degraded microstructural tissue integrity. Older subjects had lower FA (P < 0.002), higher ADC (P < 0.006), and fewer (P < 0.005) fibers than younger subjects. Group x region interactions indicated disproportionately lower FA (P = 0.0001) and higher ADC (P < 0.006) in the older than younger group in frontal fiber bundles relative to posterior bundles. As a test of the functional significance of the fiber bundle metrics, the older subjects were administered the Stroop Task, which showed significant correlations between regional fiber bundle integrity and performance. These results validate this quantitative fiber tracking approach and confirm the selective vulnerability of frontal white matter systems to normal aging, likely substrates of age-related declines in cognitive processes dependent on prefrontal circuitry integrity.

    View details for DOI 10.1093/cercor/bhj045

    View details for Web of Science ID 000238391200012

    View details for PubMedID 16207932

  • FMRI evidence for individual differences in premotor modulation of extrastriatal visual-perceptual processing of redundant targets NEUROIMAGE Schulte, T., CHEN, S. H., Muller-Oehring, E. M., Adalsteinsson, E., Pfefferbaum, A., Sullivan, E. V. 2006; 30 (3): 973-982


    To perceive the vast array of stimuli in the world around us, the visual system employs parallel processing mechanisms that ensure efficiency in perceiving multiple objects in a scene. A way to test this efficiency is to measure reaction time (RT) to pairs of identical stimuli, presented singly or as doublets; typically, the resulting phenomenon is the redundant targets effect (RTE), which manifests as faster RTs to paired than singly presented stimuli. It is controversial, however, whether the neural locus of the parallel processing mechanisms invoked to produce the RTE is perceptual or motor and why some studies observe a substantial RTE and others do not. To resolve these two issues, we measured the RTE in young adults while undergoing functional MRI. Regarding the question of a perceptual or motor basis for the RTE, we observed that bilateral activation of extrastriate cortex was prominent in paired vs. the sum of the two single stimulus conditions, indicating that the RTE invoked perceptual mechanisms; by contrast, the motor cortex was not disproportionately activated in this comparison. Regarding the magnitude of the RTE, we compared activation patterns in individuals with small vs. large RTEs and observed that frontal and premotor areas were activated with small RTEs. These data indicate that the primary processing level of response facilitation, observed as the RTE, is perceptual, but the modulation of the RTE magnitude is premotor and associated with basic aspects of response selection and preparation.

    View details for DOI 10.1016/j.neuroimage.2005.10.023

    View details for Web of Science ID 000236894800030

    View details for PubMedID 16356737

  • Visuoperceptual learning in alcoholic Korsakoff syndrome ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Fama, R., Pfefferbaum, A., Sullivan, E. V. 2006; 30 (4): 680-687


    Relative to the characteristically profound deficits of explicit memory, components of implicit memory remain largely intact in patients with alcohol-induced Korsakoff syndrome (KS). Perceptual priming occurs in KS and transfer of learning has been consistently observed on mirror reading, a perceptual reversal task. Although priming also occurs with fragmented pictures, a perceptual closure task, it is unclear whether transfer of learning can occur. This study examined visuoperceptual learning in 4 men with alcoholic KS, 9 recently detoxified alcoholic men (ALC), 21 healthy age-matched normal control men (NC), and 6 young normal control men (YNC). Subjects were tested with the Gollin Incomplete Pictures Test at initial and 1-hour and 1-day retest sessions. Both alcoholic groups (KS, ALC) were impaired in visuoperceptual ability. All subject groups showed visuoperceptual learning. The KS group showed additional learning after continued exposure to the stimuli, despite their nonmnemonic visuospatial deficits and profound explicit memory impairment for the test stimuli. Transfer of learning to similar but new stimuli was not evident in either the KS or young healthy control subjects; learning occurred only for the specific items presented. The persistence of learning beyond the life of the percept, which was independent of declarative features (such as item recall), suggests that perceptual learning and memory reflects an intact cognitive memory process in KS. This process is likely mediated by posterior cortical networks relatively unaffected in KS and that are independent of the hippocampal-diencephalic declarative memory system.

    View details for DOI 10.1111/j.1530-0277.2006.00085.x

    View details for Web of Science ID 000236756300013

    View details for PubMedID 16573587

  • Deformation-based brain morphometry to track the course of alcoholism: Differences between intra-subject and inter-subject analysis PSYCHIATRY RESEARCH-NEUROIMAGING Rohlfing, T., SULLIVAN, E. V., Pfefferbaum, A. 2006; 146 (2): 157-170


    Substantial changes in brain morphology mark the course of alcoholism from development through dependence, recovery, and relapse. These changes can be characterized with deformation-based morphometry, which quantifies shape differences between anatomical structures, either in different subjects (cross-sectional) or in the same subject over time (longitudinal). Here we present analyses of data from a longitudinal magnetic resonance imaging (MRI) study on the effects of alcoholism on brain structure. Images were acquired from alcoholic women (n=7, mean age 47.8+/-8.3 years) and age-matched control women (n=16, mean age 51.2+/-7.5 years). From each subject, we acquired two structural MR brain images, separated by approximately 2 years (mean 21.6+/-7 months). We performed two types of morphometry using log-Jacobian maps of inter-subject and intra-subject nonrigid coordinate transformations, justified by the invariance of relevant statistics (mean, standard deviation, z-score, and t-test) under changes of the spatial and temporal reference coordinate system. With all images from one time point, a cross-sectional inter-subject morphometry determined group differences between alcoholics and normal controls. We compared these results with longitudinal intra-subject morphometry based on two images per subject acquired at different times (approximately 2 years apart). Inter- and intra-subject analysis produced partially conflicting results. Whereas the intra-subject analysis indicated faster ventricular volume increases in the alcoholics (+11% per year) than in the controls (+2% per year), the inter-subject analysis showed, on average, smaller absolute ventricle volumes in the alcoholics than in the controls (-33% relative volume). These differences were confirmed by manual planimetry and were statistically significant whether tested based on difference or change, integrated over the volume of the ventricles. Other changes and group differences were consistent between the two analyses, e.g., reduction of white matter (including corpus callosum) and increase in CSF volume, and these are in agreement with established effects of alcoholism on brain structure. We conclude that intra-subject morphometry of longitudinal data is preferable to inter-subject morphometry for detecting dynamic changes due to a disease, especially when only small samples are available. Our analysis demonstrates that the distinction between group differences observed at a point in time vs. over time is not merely academic but can substantially reduce the validity of the outcomes of actual morphometric studies. This discrepancy in results underscores the importance of distinguishing between volume differences and volume changes in morphometric analyses.

    View details for DOI 10.1016/j.pscychresns.2005.12.002

    View details for Web of Science ID 000237123700006

    View details for PubMedID 16500088

  • Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women BIOLOGICAL PSYCHIATRY Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2006; 59 (4): 364-372


    Postmortem and in vivo studies consistently report degeneration of brain white matter in alcohol-dependent men and women. The full extent of the white matter involvement in uncomplicated alcoholism, however, is unknown, yet knowledge of the distribution of white matter degradation might provide clues to mechanisms underlying the pathology.To examine whether the white matter involvement is widespread or, alternatively, is regionally restricted in uncomplicated alcoholism, we used in vivo magnetic resonance diffusion tensor imaging (DTI) to quantify the microstructure of brain tissue. Accordingly, we acquired DTI data in 57 alcoholics (40 men, 17 women) who had been sober, on average, for 3 months and 74 demographically-matched control subjects (32 men, 42 women). Alcoholic men had consumed about twice as much alcohol in their lifetimes as the alcoholic women. Supratentorial white matter fractional anisotropy (FA), a DTI measure of intravoxel orientational coherence of tissue, was calculated across the full anterior-posterior extent of the brain in coronal sections, and a slice profile of the mean white matter FA was created for each subject. Group differences between alcoholics and control subjects were tested for each slice in three regions: the left and right hemispheres and a midsagittal sample; men and women were tested separately.Alcoholic men and women each showed widespread FA deficits in all three regions relative to their gender-matched control subjects that were evident on a slice-by-slice basis. Furthermore, the number of slices showing FA deficits was significantly greater in the alcoholic men than women.The widespread distribution of white matter deficits is in contrast to the highly regional-specific deficits seen in nutritional deficiency syndromes that can accompany alcoholism.

    View details for DOI 10.1016/j.biopsych.2005.06.025

    View details for Web of Science ID 000235670800010

    View details for PubMedID 16125148

  • Diffusion tensor imaging and aging NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Sullivan, E. V., Pfefferbaum, A. 2006; 30 (6): 749-761


    Magnetic resonance diffusion tensor imaging (DTI) is a non-invasive in vivo method for characterizing the integrity of anatomical connections and white matter circuitry and provides a quantitative assessment of the brain's white matter microstructure. DTI studies reveal age-related declines in white matter fractional ansiotropy (FA) in normal healthy adults in whom volume declines are not necessarily detectable. The decline is equivalent in men and women, is linear from about age 20 years onwards, and has a frontal distribution. Studies combining regional DTI metrics and tests of specific cognitive and motor functions have shown that age-related declines in white matter integrity are associated with similar declines in interhemispheric transfer, especially dependent on frontal systems. Emerging from recent DTI findings and conceptualizations of neural causes of cognitive decline in aging, we propose three white matter-mediated neural system hypotheses of aging brain structure and function: (1) the anteroposterior gradient, (2) bilateral recruitment of brain systems via the corpus callosum for frontally based task execution, and (3) frontocerebellar synergism. These hypotheses are not mutually exclusive but establish a basis for posing testable questions about brain systems recruited when those used in youth are altered by aging.

    View details for DOI 10.1016/j.neubiorev.2006.06.002

    View details for Web of Science ID 000241208800004

    View details for PubMedID 16887187

  • Regional striatal volume abnormalities in schizophrenia: Effects of comorbidity for alcoholism, recency of alcoholic drinking, and antipsychotic medication type 59th Annual Meeting of the Society-of-Biological-Psychiatry Deshmukh, A., Rosenbloom, M. J., De Rosa, E., Sullivan, E. V., Pfefferbaum, A. ELSEVIER SCIENCE BV. 2005: 189–200


    Striatal structures form critical nodes of multiple circuits that are implicated in the pathophysiology of schizophrenia and alcoholism. Here, we examined the separate and combined effects of schizophrenia and alcoholism and effects of medication type and drinking recency on striatal volumes. Accordingly, we measured caudate nucleus, putamen, and nucleus accumbens in 27 schizophrenic, 25 alcohol-dependent, 19 comorbid (schizophrenia and alcohol dependence or abuse), and 51 age-matched control men. Schizophrenics were classified by antipsychotic medication (typical or atypical), and alcoholics were classified by recency of sobriety. All measured structures were smaller in the patient groups than the control group. The caudate deficit was comparable across groups, whereas putamen and nucleus accumbens deficits were greater in schizophrenia than alcoholism; comorbids fell between these groups. Schizophrenic patients treated with atypical medication showed greater volume deficits in the putamen than those treated with typical medication. Recently sober (<3 weeks) alcoholics had greater deficits in nucleus accumbens than longer sober drinkers. In conclusion, caudate, putamen, and nucleus accumbens exhibited different patterns of volume deficit in patients with alcoholism and schizophrenia alone, with no evidence for compounded deficits in comorbid patients. Further, these cross-sectional data provide indirect support for at least partial recovery of nucleus accumbens volume with sobriety in alcoholics, regardless of schizophrenia comorbidity.

    View details for DOI 10.1016/j.schres.2005.04.025

    View details for Web of Science ID 000233074600005

    View details for PubMedID 15963693

  • Corpus callosal microstructural integrity influences interhemispheric processing: A diffusion tensor imaging study CEREBRAL CORTEX Schulte, T., Sullivan, E. V., Muller-Oehring, E. M., Adalsteinsson, E., Pfefferbaum, A. 2005; 15 (9): 1384-1392


    Normal aging and chronic alcoholism result in disruption of brain white matter microstructure that does not typically cause complete lesions but may underlie degradation of functions requiring interhemispheric information transfer. We examined whether the microstructural integrity of the corpus callosum assessed with diffusion tensor imaging (DTI) would relate to interhemispheric processing speed. DTI yields estimates of fractional anisotropy (FA), a measure of orientation and intravoxel coherence of water diffusion usually in white matter fibers, and diffusivity (), a measure of the amount of intracellular and extracellular fluid diffusion. We tested the hypothesis that FA and would be correlated with (i) the crossed-uncrossed difference (CUD), testing visuomotor interhemispheric transfer; and (ii) the redundant targets effect (RTE), testing parallel processing of visual information presented to each cerebral hemisphere. FA was lower and higher in alcoholics than in controls. In controls but not alcoholics, large CUDs correlated with low FA and high in total corpus callosum and regionally in the genu and splenium. In alcoholics but not controls, small RTEs, elicited with equiluminant stimuli, correlated with low FA in genu and splenium and high in the callosal body. The results provide in vivo evidence for disruption of corpus callosum microstructure in normal aging and alcoholism that has functional ramifications for efficiency in interhemispheric processing.

    View details for DOI 10.1093/cercor/bhi020

    View details for Web of Science ID 000231296900010

    View details for PubMedID 15635059

  • Neurocircuitry in alcoholism: a substrate of disruption and repair PSYCHOPHARMACOLOGY Sullivan, E. V., Pfefferbaum, A. 2005; 180 (4): 583-594


    The chronic, excessive consumption of alcohol results in significant modification of selective neural systems of the brain structure, physiology, and function. Quantitative MR structural imaging, diffusion tensor imaging (DTI), and functional MRI (fMRI), together with neuropsychological challenges, have enabled rigorous in vivo characterization of the results of alcoholism on the brain in the human condition. Neuroimaging has also enabled longitudinal study for the examination of alcoholism's dynamic course through periods of drinking and sobriety. Controlled studies have revealed compelling evidence for alcohol-related brain structural and functional modification--some longstanding, some transient, and some compensatory. Patterns of circuitry disruption identified through structural and functional MRI studies suggest a central role for degradation of frontocerebellar neuronal nodes and connecting circuitry affecting widespread brain regions and contributing to alcoholism's salient, enduring, and debilitating cognitive and motor deficits--executive dysfunction, visuospatial impairment, and ataxia.

    View details for DOI 10.1007/s00213-005-2267-6

    View details for Web of Science ID 000231731800002

    View details for PubMedID 15834536

  • Alcoholic neurobiology: Changes in dependence and recovery 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism Crews, F. T., Buckley, T., Dodd, P. R., Ende, G., Foley, N., Harper, C., He, J., Innes, D., Loh, E. W., Pfefferbaum, A., Zou, J., SULLIVAN, E. V. WILEY-BLACKWELL. 2005: 1504–13


    This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October, 2004. Chronic alcoholism follows a fluctuating course, which provides a naturalistic experiment in vulnerability, resilience, and recovery of human neural systems in response to presence, absence, and history of the neurotoxic effects of alcoholism. Alcohol dependence is a progressive chronic disease that is associated with changes in neuroanatomy, neurophysiology, neural gene expression, psychology, and behavior. Specifically, alcohol dependence is characterized by a neuropsychological profile of mild to moderate impairment in executive functions, visuospatial abilities, and postural stability, together with relative sparing of declarative memory, language skills, and primary motor and perceptual abilities. Recovery from alcoholism is associated with a partial reversal of CNS deficits that occur in alcoholism. The reversal of deficits during recovery from alcoholism indicates that brain structure is capable of repair and restructuring in response to insult in adulthood. Indirect support of this repair model derives from studies of selective neuropsychological processes, structural and functional neuroimaging studies, and preclinical studies on degeneration and regeneration during the development of alcohol dependence and recovery form dependence. Genetics and brain regional specificity contribute to unique changes in neuropsychology and neuroanatomy in alcoholism and recovery. This symposium includes state-of-the-art presentations on changes that occur during active alcoholism as well as those that may occur during recovery-abstinence from alcohol dependence. Included are human neuroimaging and neuropsychological assessments, changes in human brain gene expression, allelic combinations of genes associated with alcohol dependence and preclinical studies investigating mechanisms of alcohol induced neurotoxicity, and neuroprogenetor cell expansion during recovery from alcohol dependence.

    View details for DOI 10.1097/01.alc.0000175013.50644.61

    View details for Web of Science ID 000231767900018

    View details for PubMedID 16156047

  • Preservation of hippocampal volume throughout adulthood in healthy men and women NEUROBIOLOGY OF AGING Sullivan, E. V., Marsh, L., Pfefferbaum, A. 2005; 26 (7): 1093-1098


    To address controversies regarding the effect of age on the hippocampus, volumes of hippocampus and a comparison structure, temporal cortex, were measured on magnetic resonance imaging (MRI) in 84 healthy men and 44 healthy women (20-85 years). Neither men nor women showed significant correlations between hippocampal volumes and age, despite significant age-related decline in temporal volumes. Absence of hippocampus age relationships endured when restricting analyses to older individuals (> or =50 years) and considering menopause and hormone replacement therapy.

    View details for DOI 10.1016/j.neurobiolaging.2004.09.015

    View details for Web of Science ID 000227821000014

    View details for PubMedID 15748789

  • Frontal circuitry degradation marks healthy adult aging: Evidence from diffusion tensor imaging NEUROIMAGE Pfefferbaum, A., Adalsteinsson, E., Sullivan, E. V. 2005; 26 (3): 891-899


    In vivo study of white matter microstructural integrity through magnetic resonance diffusion tensor imaging (DTI) permits examination of degradation of axonal circuitry that may underlie functional decline of frontally-based processes in normal adult aging. Determination of the pattern of age-related degradation of white matter microstructure requires quantitative comparison of the rostral-caudal and superior-inferior extents of the brain's white matter. To date, this has not been accomplished, probably because of significant artifacts from spatial distortion and poor signal resolution that precludes accurate analysis in prefrontal and inferior brain regions. Here, we report a profile analysis of the integrity of white matter microstructure across the supratentorium and in selected focal regions using DTI data collected at high-field strength (3 T), with isotropic voxel acquisition, and an analysis based on a concurrently-acquired field map to permit accurate quantification of artifact-prone, anterior and inferior brain regions. The groups comprised 10 younger and 10 older individuals; all were high functioning, highly educated, and in excellent health. The DTI profile analysis revealed a robust frontal distribution of low white matter anisotropy and high bulk mean diffusivity in healthy older compared with younger adults. In contrast to frontal fiber systems, posterior systems were largely preserved with age. A second analysis, based on focal samples of FA, confirmed that the age-related FA decline was restricted to frontal regions, leaving posterior and inferior brain regions relatively intact. The selective decline of anterior anisotropy with advancing age provides evidence for the potential of a microstructural white matter mechanism for the commonly observed decline in frontally-based functions.

    View details for DOI 10.1016/j.neuroimage.2005.02.034

    View details for Web of Science ID 000230211100025

    View details for PubMedID 15955499

  • Cortical NAA deficits in HIV infection without dementia: Influence of alcoholism comorbidity NEUROPSYCHOPHARMACOLOGY Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2005; 30 (7): 1392-1399


    Alcoholism comorbidity is highly prevalent in individuals infected with human immunodeficiency virus (HIV). Each condition is known to affect brain structure, function, and metabolism, but the combined effects on the brain have only recently been considered. Single-voxel, proton MR spectroscopy (MRS) has yielded sensitive measures of early brain deterioration in the progression of HIV, but has limited coverage of neocortex, whereas MRS imaging (MRSI) can simultaneously interrogate large regions of cortex. Included were 15 men with HIV+alcoholism, nine men with HIV alone, eight men with alcoholism alone (abstinent for 3-17 months), and 23 controls. The two HIV groups were matched in T-cell count and were not demented; the two alcoholism groups were relatively matched in lifetime alcohol consumption. We used MRSI with a variable-density spiral sequence to quantify major proton metabolites--N-acetylaspartate (NAA), creatine (Cr), and choline (Cho)-in the superior parietal-occipital cortex. Metabolites were expressed in absolute units and as the NAA/Cr ratio. Significant group effects were present for NAA and Cr. Only the HIV+alcoholism group was significantly affected, exhibiting a 0.8 SD deficit in NAA and a 1.0 SD deficit in Cr. The deficits were not related to highly active antiretroviral therapy (HAART) status. Neither HIV infection nor alcoholism independently resulted in parietal-occipital cortical metabolite abnormalities, yet each disease carried a liability that put affected individuals at a heightened risk of neuronal compromise when the diseases were compounded. Further, the use of absolute measures revealed deficits in NAA and Cr that would have gone undetected if these metabolites were expressed as a ratio.

    View details for DOI 10.1038/sj.npp.1300723

    View details for Web of Science ID 000229881800017

    View details for PubMedID 15812566

  • Differentiating pathologic delta from healthy physiologic delta in patients with Alzheimer disease SLEEP Crowley, K., SULLIVAN, E. V., Adalsteinsson, E., Pfefferbaum, A., Colrain, I. M. 2005; 28 (7): 865-870


    In patients with Alzheimer disease, the electroencephalogram during wakefulness shows pathologic signs of abundant, diffuse, large-amplitude delta activity. The carryover of this abnormal delta activity into non-rapid eye movement sleep raises the question of whether the observed delta electroencephalographic activity during sleep in Alzheimer disease in any way reflects normal physiologic delta activity slow-wave sleep. The objective of the study was to compare patients with Alzheimer disease with age-matched controls using an experimentally controlled procedure that can test the capacity of the nervous system to generate physiologic delta-frequency responses during sleep.Research sleep laboratory.Seven ambulatory patients with Alzheimer disease (mean age = 70.0 +/- 5.77 years) meeting the National Institute of Neurological and Communicative Diseases and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease and 8 controls (mean age = 69.25 +/- 4.95 years), underwent at least 1 night of evoked-potential recordings.Data were collected during stage 2 sleep. Responses to stimuli were classified based on whether they produced a K-complex. Averages of K-complex responses were calculated, latencies and amplitudes of components evaluated, and K-complex incidence was determined. Relative to controls, subjects with Alzheimer disease produced significantly fewer evoked K-complexes (P < .001) and had substantially smaller N550 amplitudes than controls (P < .05). A lower probability of eliciting a K-complex correlated with greater dementia severity, as measured by the Mini Mental State Examination and Dementia Rating Scale.Despite observed increases in pathologic delta-frequency electroencephalographic activity, patients with Alzheimer disease have an impaired capacity to generate normal physiologic delta responses during non-rapid eye movement sleep.

    View details for Web of Science ID 000230501700016

    View details for PubMedID 16124667

  • The pathophysiology of 'brain shrinkage' in alcoholics - Structural and molecular changes and clinical implications ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Harper, C., Matsumoto, L., Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V., Lewohl, J., Dodd, P., Taylor, M., Fein, G., Landman, B. 2005; 29 (6): 1106-1115
  • Striatal and forebrain nuclei volumes: Contribution to motor function and working memory deficits in alcoholism BIOLOGICAL PSYCHIATRY Sullivan, E. V., Deshmukh, A., De Rosa, E., Rosenbloom, M. J., Pfefferbaum, A. 2005; 57 (7): 768-776


    Striatal structures are involved in dopaminergic alcohol reward mechanisms and aspects of motor control. Basal forebrain structures hold cholinergic mechanisms influencing memory formation, vulnerable to chronic alcoholism; however, alcoholism's effect on volumes of these structures has seldom been considered with in vivo measurement.We measured bilateral volumes of caudate nucleus, putamen, nucleus accumbens, and medial septal/diagonal band (MS/DB) in 25 men with alcohol dependence and 51 age-matched control men. Six alcoholic subjects had been drinking recently, and 19 had been sober.Volumes of caudate and putamen were smaller in the alcoholics than in the control subjects, regardless of length of sobriety. Recent drinkers showed greater deficits in nucleus accumbens than sober alcoholics. Putamen volume was positively correlated with grip strength; MS/DB volume was positively correlated with verbal working memory independently of the negative association between age-standardized MS/DB and age in alcoholics.Caudate and putamen volume deficits occur and endure in chronic alcoholism. Nucleus accumbens might be especially sensitive to recent alcohol exposure. Striatal volumes should be considered in functional imaging studies of alcohol craving that target striatal brain regions. The age-alcohol interaction for MS/DB volumes is consistent with a cholinergic mechanism for the working memory impairment observed in the alcoholics.

    View details for DOI 10.1016/j.biopsych.2004.12.012

    View details for Web of Science ID 000228125000011

    View details for PubMedID 15820234

  • Persistent cognitive deficits in community-treated alcoholic men and women volunteering for research: Limited contribution from psychiatric comorbidity JOURNAL OF STUDIES ON ALCOHOL Rosenbloom, M. J., O'Reilly, A., Sassoon, S. A., SULLIVAN, E. V., Pfefferbaum, A. 2005; 66 (2): 254-265


    The contribution of psychiatric comorbidity to cognitive status was assessed in a sample of treatment-seeking alcoholics who met criteria to participate in studies of effects of chronic alcohol misuse on brain structure and cognition.Alcoholic men (n = 43) and women (n = 21) who responded to notices about a research study were screened, clinically assessed and administered Wechsler Memory and Intelligence tests after 3 months of sobriety, on average. Cognitive performance was compared with that of an age-matched sample of healthy controls (n = 51).As a group, the alcoholics achieved significantly lower scores than controls on summary indices of the Wechsler Memory and Adult Intelligence Scales and showed greater decline from estimated premorbid intelligence levels than controls. Almost 60% of the alcoholics had at least one additional psychiatric (mood or anxiety) or past substance-dependence comorbidity. There were no marked sex differences in patterns of comorbidity. Comorbid alcoholics were younger, had consumed less alcohol over their lifetime and performed between noncomorbid alcoholics and controls on all tests.Mood and anxiety comorbidity did not necessarily compound poor cognitive test performance associated with chronic alcohol misuse. While unexpected, this finding suggests that, in this sample, poorer cognitive performance was more a function of alcoholism per se than nonalcoholic comorbidity.

    View details for Web of Science ID 000229028100012

    View details for PubMedID 15957677

  • Neuroimaging of rodent and primate models of alcoholism: Initial reports from the integrative neuroscience initiative on alcoholism 27th Annual Meeting of the Research-Society-on-Alcoholism Sullivan, E. V., Sable, H. J., Strother, W. N., Friedman, D. P., Davenport, A., Tillman-Smith, H., Kraft, R. A., Wyatt, C., Szeliga, K. T., Buchheimer, N. C., Daunais, J. B., Adalsteinsson, E., Pfefferbaum, A., Grant, K. A. BLACKWELL PUBLISHING. 2005: 287–94


    Neuroimaging of animal models of alcoholism offers a unique path for translational research to the human condition. Animal models permit manipulation of variables that are uncontrollable in clinical, human investigation. This symposium, which took place at the annual meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, on June 29th, 2004, presented initial findings based on neuroimaging studies from the two centers of the Integrative Neuroscience Initiative on Alcoholism funded by the National Institute on Alcohol Abuse and Alcoholism. Effects of alcohol exposure were assessed with in vitro glucose metabolic imaging of rat brain, in vitro receptor imaging of monkey brain, in vivo magnetic resonance imaging of monkey brain, and in vivo magnetic resonance spectroscopic quantification of alcohol metabolism kinetics in rat brain.

    View details for DOI 10.1097/01.ALC.0000153546.39946.EC

    View details for Web of Science ID 000227221700013

    View details for PubMedID 15714052

  • A dissociation in attentional control: Evidence from methamphetamine dependence BIOLOGICAL PSYCHIATRY Salo, R., Nordahl, T. E., Moore, C., WATERS, C., Natsuaki, Y., Galloway, G. P., Kile, S., SULLIVAN, E. V. 2005; 57 (3): 310-313


    Selective attention comprises multiple, dissociable component processes, including task shifting and selective inhibition. The goal of this study was to test whether task-shifting, selective inhibition, or both processes were impaired in long-term but currently abstinent methamphetamine-dependent individuals.Participants were 34 methamphetamine-dependent subjects and 20 nonsubstance abusing controls who were tested on an alternating-runs switch task with conflict sequences that required subjects to switch tasks on every second trial (AABBAABB).Methamphetamine-dependent individuals committed more errors on trials that required inhibition of distracting information compared with controls (methamphetamine = 17%; controls = 13%; p = .02). By contrast, error rates did not differ between the groups on switch trials (methamphetamine = 7%; controls = 6%; p = .68).These results indicate that selective inhibition, but not task switching, is selectively compromised by methamphetamine.

    View details for DOI 10.1016/j.biopysch.2004.10.035

    View details for Web of Science ID 000226886400014

    View details for PubMedID 15691533

  • Disruption of brain white matter microstructure by excessive intracellular and extracellular fluid in alcoholism: Evidence from diffusion tensor imaging NEUROPSYCHOPHARMACOLOGY Pfefferbaum, A., SULLIVAN, E. V. 2005; 30 (2): 423-432


    Magnetic resonance diffusion tensor imaging (DTI) has revealed the disruption of brain white matter microstructure in normal aging and alcoholism undetectable with conventional structural MR imaging. The metrics of DTI can be useful in establishing the nature of the observed microstructural aberrations. Abnormally low fractional anisotropy (FA), a measure of diffusion orientation and coherence, may result from increased intracellular or extracellular fluid, which would be reflected in complementary high apparent diffusion coefficients (bulk mean diffusivity) and low FA, or from disorganization of fiber structure, which would be reflected in low FA but with a lack of the inverse FA and diffusivity relationship. To test these competing possibilities, we examined 15 alcoholic men and 31 control men with DTI to quantify diffusivity in the genu and splenium of the corpus callosum and centrum semiovale. In addition to the previously observed FA deficits in all the three brain regions, the alcoholics had abnormally high white matter diffusivity values in the genu and centrum. Further, inverse correlations between FA and diffusivity were significant in the genu (r=-0.52, p<0.05) and centrum (r=-0.92, p=0.0001). Multiple regression analyses examining diffusivity and age as predictors of FA identified diffusivity as a significant unique contributor to FA in both regions. These results suggest that decreased orientational coherence of brain white matter in alcoholism is attributable, at least in part, to the accumulation of intracellular and extracellular fluid in excess of that occurring in aging, and that the differential influence of these fluid compartments can vary across brain regions.

    View details for DOI 10.1038/sj.npp.1300623

    View details for Web of Science ID 000226569900022

    View details for PubMedID 15562292

  • Differential effect of HIV infection and alcoholism on conflict processing, attentional allocation, and perceptual load: Evidence from a Stroop Match-to-Sample task BIOLOGICAL PSYCHIATRY Schulte, T., Mueller-Oehring, E. M., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2005; 57 (1): 67-75


    Alcoholism and human immunodeficiency virus (HIV) infection each can impair components of selective attention, probably through disruption of the integrity of the frontoparietal neural systems that underlie conflict processing, attentional allocation, and perceptual load.We studied 18 patients with alcoholism (ALC) alone, 19 with HIV infection alone (HIV), 20 with both disorders (H+A), and 19 healthy control subjects (CTL). We used a novel paradigm (Stroop Match-to-Sample tasks), in which subjects saw either a valid or invalid color cue before a target word, printed in a color that was either congruent or incongruent with the word's meaning.All groups showed a significant Stroop effect, cue-target color Match effect, and interaction between Match and Stroop, with an exaggerated Stroop effect for the Match condition. The HIV patients were comparable to CTL, whereas ALC showed mild delays, with further delays associated with comorbidity with HIV. Although H+A profited from a valid match to Stroop stimuli, they were compromised in disengaging attention from the invalidly cued color.Impairment in conflict processing and attentional allocation in alcoholism suggests disruption of frontal-parietal attentional systems. Although HIV alone did not demonstrate detectable impairment in performance, HIV conferred liability on attentional processes when combined with alcohol abuse.

    View details for DOI 10.1016/j.biopsych.2004.09.025

    View details for Web of Science ID 000226421800010

    View details for PubMedID 15607302

  • Information fusion in biomedical image analysis: Combination of data vs. combination of interpretations 19th International Conference on Information Processing in Medical Imaging Rohlfing, T., Pfefferbaum, A., Sullivan, E. V., Maurer, C. R. SPRINGER-VERLAG BERLIN. 2005: 150–161
  • Cortical grey matter volume and sleep ERP amplitude in normal aging and alcoholism Nicholas, C. L., SULLIVAN, E. V., Pfefferbaum, A., Trinder, J., Colrain, I. M. WILEY-BLACKWELL. 2005: 32–32
  • In vivo structural imaging of the rat brain with a 3-T clinical human scanner JOURNAL OF MAGNETIC RESONANCE IMAGING Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2004; 20 (5): 779-785


    To examine the feasibility of using product acquisition software on a 3-T human MRI system to acquire high-resolution structural brain images in the rat.Three sets of dual spin-echo, high-resolution (0.234 x 0.234 mm in-plane, 0.5 mm thick) images covering the entire rat brain were collected and averaged in 66 min. The images had sufficient signal-to-noise ratio (SNR) and resolution for visual identification and manual outlining of exemplary structures, including the lateral ventricles and dorsal and ventral portions of the hippocampus. Further, the data were adequate for unsupervised, automated segmentation, permitting quantification of the dorsolateral ventricles. The images compared favorably with those collected on a 7-T system.Interrater reliabilities (intraclass correlations) of manual ventricular scoring were greater than 0.97, and manual vs. automated correlations were 0.97. The variability of lateral ventricular size across animals was substantially higher than that of the hippocampus.The large variability of some brain structures that can exist across even a highly selected strain of rats can readily be detected with the use of human 3-T systems for the study of small animals.

    View details for DOI 10.1002/jmri.20181

    View details for Web of Science ID 000224762700006

    View details for PubMedID 15503335

  • Perceptual learning in detoxified alcoholic men: Contributions from explicit memory, executive function, and age 32nd Annual Meeting of the International-Neuropsychological-Society Fama, R., Pfefferbaum, A., Sullivan, E. V. WILEY-BLACKWELL PUBLISHING, INC. 2004: 1657–65


    Visuospatial and visuoperceptual deficits have consistently been observed in detoxified alcoholics; however, the severity of impairment varies with test and task type. Identifying the component processes and factors that underlie a particular deficit may reveal why some visuospatial and visuoperceptual tasks are more compromised than others and may lead to the specification of neural systems that are particularly vulnerable in alcoholism.We examined visuoperception and perceptual learning with a picture fragment identification task in 51 recently detoxified nonamnesic alcoholic men (aged 29-66 years) compared with 63 normal control men (aged 21-70 years). Executive function and explicit declarative memory were also assessed.Despite deficits in the primary components of visuoperception and explicit memory for visuospatial stimuli, the alcoholics showed normal perceptual learning. Although the alcoholics and controls performed at comparable levels on the perceptual learning task, multiple regression analyses indicated that the factors accounting for perceptual learning variance differed between and within groups. Visuoperceptual abilities consistently predicted perceptual learning in the control subjects but not the alcoholic subjects. Explicit memory contributed to perceptual learning performance in both the alcoholic and control groups. Frontal executive ability consistently predicted perceptual learning in the alcoholic subjects, but it had predictive ability only in the control subjects as time elapsed. Age was significantly correlated with perceptual learning performance in both groups. Lifetime alcohol consumption, but not alcoholism duration, was an independent predictor of 1-hr perceptual learning.These correlational analyses suggest that controls invoke basic visuospatial processes to perform a perceptual learning task, whereas alcoholics invoke higher-order cognitive processes (i.e., frontal executive systems) to perform the same task at normal levels. Use of more demanding cognitive systems by the alcoholics may be less efficient and more costly to processing capacity than those invoked by controls.

    View details for DOI 10.1097/01.ALC.0000145690.48510.DA

    View details for Web of Science ID 000225201900009

    View details for PubMedID 15547452

  • Recovery of short-term memory and psychomotor speed but not postural stability with long-term sobriety in alcoholic women 25th Annual Meeting of the Research-Society-on-Alcoholism Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. AMER PSYCHOLOGICAL ASSOC. 2004: 589–97


    The authors assessed effects of extended abstinence on cognitive and motor function deficits previously observed in a group of alcoholic women (n = 43) initially tested after 15 weeks of sobriety. Alcoholic women were retested 1 and 4 years later, and control women were retested 3 years later. At Year 1, 14 of 23 returners had maintained sobriety, but they did not perform significantly better than relapsers; the group as a whole continued to show deficits relative to age norms. By Year 4, 13 of 14 returners had maintained sobriety for more than 30 months; as a group, these women had returned to normal levels on tests of memory and psychomotor speed but remained impaired in standing balance.

    View details for DOI 10.1037/0894-4105.18.3.589

    View details for Web of Science ID 000222706700020

    View details for PubMedID 15291737

  • Brain volumes, RBC status, and hepatic function in alcoholics after 1 and 4 weeks of sobriety: Predictors of outcome AMERICAN JOURNAL OF PSYCHIATRY Pfefferbaum, A., Rosenbloom, M. J., Serventi, K. L., SULLIVAN, E. V. 2004; 161 (7): 1190-1196


    The authors asked if hematological indices of RBC status and hepatic function in newly sober alcoholic men are related to abnormalities in brain morphology, change with normalization of brain function during short-term sobriety, and predict prolonged sobriety.Alcoholic men received brain magnetic resonance imaging and laboratory assessments on admission and before discharge from an inpatient treatment program. Healthy comparison men were similarly tested.On admission, RBC count, hemoglobin level, and hematocrit were significantly lower in alcoholic subjects than comparison subjects; mean corpuscular volume, SGOT, SGPT, and gamma-glutamyl transpeptidase were significantly higher. By discharge, all measures had improved, although RBC count, mean corpuscular volume, and gamma-glutamyl transpeptidase levels remained significantly different from those of comparison subjects. Upon admission, alcoholic men had smaller cortical white and gray matter and larger lateral and third ventricle volumes, with reduced lateral ventricle and increased anterior cortical gray matter volumes by discharge. Lower RBC count, hemoglobin level, and hematocrit were associated with lower white matter and higher ventricular volumes at admission. Change in these measures was related to reduction in ventricular volume with treatment. By discharge, associations among RBC count, hemoglobin level, and hematocrit and white matter and ventricular volumes were less marked than at admission. Discharge hemoglobin value and hematocrit discriminated patients who maintained sobriety from those who relapsed. Hepatic function showed limited association with brain measures at admission and discharge.Hemograms reflect alcohol-related abnormalities in brain morphology, improvement over short-term sobriety, and liability to relapse after treatment.

    View details for Web of Science ID 000222462700008

    View details for PubMedID 15229050

  • Dissociation of remote and anterograde memory impairment and neural correlates in alcoholic Korsakoff syndrome JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Fama, R., Marsh, L., Sullivan, E. V. 2004; 10 (3): 427-441


    Alcoholic Korsakoff's syndrome (KS) is marked by remote memory impairment together with characteristic profound anterograde memory deficits. Despite previous studies of memory processes in KS, questions remain regarding the nature and severity of these impairments and identification of brain systems that underlie these different memory impairments. This study examined remote and anterograde memory function in 5 KS patients in comparison with 8 patients with Alzheimer's disease (AD) and 24 normal control subjects (NC). In addition, relationships between memory performance and regional brain volumes were examined in the KS group. Overall, the KS group showed severe impairment on both remote and anterograde memory measures, performing at the level of the AD group on most measures. Differences were observed on the pattern of temporal gradient for verbal recognition, with KS exhibiting a more steeply graded rate of decline over the most recent period examined. Severity of the remote memory deficit in KS was not associated with severity of anterograde memory deficit. Examination of brain structure-function relationships in the KS subjects revealed that photo naming of remote historical information was related to posterior cortical white matter volumes but not hippocampal volumes; sequencing was related to prefrontal but not hippocampal volumes. By contrast, a measure of anterograde memory for nonverbal visual material showed a relationship to hippocampal but not regional cortical white matter volumes. This set of dissociations, which parallels that observed in our earlier study of AD, is now documented in KS and provides further evidence that these separate cortical and limbic brain systems are principal neural substrates of the remote and anterograde memory and sequencing deficits in KS.

    View details for DOI 10.1017/S135561770410310X

    View details for Web of Science ID 000221180500012

    View details for PubMedID 15147600

  • In vivo 2D J-resolved magnetic resonance spectroscopy of rat brain with a 3-T clinical human scanner NEUROIMAGE Adalsteinsson, E., Hurd, R. E., Mayer, D., Sailasuta, N., SULLIVAN, E. V., Pfefferbaum, A. 2004; 22 (1): 381-386


    A clinical 3-T scanner equipped with a custom-made transmit/receive birdcage coil was used to collect 2D J-resolved single-voxel spectroscopy in vivo of rat brain. Four adult Wistar rats were scanned twice each, with a 2-week interval. Voxel size was approximately 5 x 10 x 5 mm(3). Total spectroscopic acquisition time was 14 min for collection of two 4:20 min water-suppressed acquisitions and one 4:20 min acquisition acquired in the absence of water suppression. The unsuppressed water data were used in post-processing to reduce residual water side bands, as well as for metabolite signal normalization to account for variations in coil loading and voxel size. Peak areas were estimated for resonances from N-acetyl aspartate (NAA), creatine, choline, taurine, glutamate, and combined glutamate and glutamine. T(2)-relaxation times were estimated for NAA and creatine. The average deviation from the mean of repeated measures for glutamate, combined glutamate and glutamine, and taurine ranged from 7.6% to 18.3%, while for NAA, creatine, and choline, the deviation was less than 3%. The estimated T(2) values for NAA (mean +/- SD = 330 +/- 57 ms) and creatine (174 +/- 27 ms) were similar to those reported previously for rat brain and for human gray and white matter. These results indicate that reliable, small animal brain MR spectroscopy can be performed on a human clinical 3-T scanner.

    View details for DOI 10.1016/j.neuroimage.2003.12.046

    View details for Web of Science ID 000221190200039

    View details for PubMedID 15110030

  • Postmortem MR imaging of formalin-fixed human brain 41st Annual Meeting of the American-College-of-Neuropsychopharmacology Pfefferbaum, A., SULLIVAN, E. V., Adalsteinsson, E., Garrick, T., Harper, C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2004: 1585–95


    High-resolution postmortem neuroimaging of the brain can play a role in research programs by providing archival and reslicable images of brain specimens before permanent sectioning. These images can supplement evidence attained from both traditional neuropathological observations and in vivo neuroimaging. Differential brain tissue conspicuity, detectable with MRI, is determined by the density and mobility of water protons. Water content is about 70% in white matter, 80% in gray matter, and 99% in cerebrospinal fluid (CSF). To the extent that brain tissue contrast is determined by the number and microenvironment of water protons, timing parameters of MR image acquisition can interrogate this environment. Because the chemical environment of protons is different in living from dead tissue, optimal temporal imaging parameters, for example, for spin-echo imaging, commonly used for in vivo clinical and research study are different from those best for postmortem imaging. Here, we present a series of observations to identify relaxation times and optimal parameters for high-resolution structural imaging of formalin-fixed postmortem brain tissue using commercially available clinical scanners and protocols. Examples of high-resolution images and results from attempts at diffusion imaging are presented.

    View details for DOI 10.1016/j.neuroimage.2003.11.024

    View details for Web of Science ID 000220723900036

    View details for PubMedID 15050582

  • Balance and gait deficits in schizophrenia compounded by the comorbidity of alcoholism 41st Annual Meeting of the American-College-of-Neuropsychopharmacology Sullivan, E. V., Rosenbloom, M. J., Pfefferbaum, A. AMER PSYCHIATRIC PUBLISHING, INC. 2004: 751–55


    Alcoholism carries a liability of balance and gait instability that persists with sobriety. Such deficits are less well documented in schizophrenia and may be compounded by comorbidity with alcoholism, which is prevalent in schizophrenia.The authors administered quantitative ataxia tests to 10 patients comorbid for schizophrenia and alcohol dependence/abuse, 10 nonalcoholic patients with schizophrenia, 24 nonschizophrenic patients with alcohol dependence, and 27 age-matched comparison men.All three patient groups were impaired relative to the comparison subjects. The comorbid group was significantly more impaired than the alcoholic group on most tests and was more impaired than the schizophrenia patients, especially when tested with eyes open.Rigorous quantitative testing revealed gait and balance deficits in schizophrenia, even without alcohol dependence, and exacerbated deficits in schizophrenia comorbid with alcoholism. The enhancement of postural stability expected with visual information was dampened in comorbid patients, implicating compromised sensorimotor integrative abilities.

    View details for Web of Science ID 000221276200026

    View details for PubMedID 15056526

  • The human basal forebrain integrates the old and the new NEURON De Rosa, E., Desmond, J. E., Anderson, A. K., Pfefferbaum, A., SULLIVAN, E. V. 2004; 41 (5): 825-837


    Acquisition of new learning is challenged by the phenomenon of proactive interference (PI), which occurs when previous learning disrupts later learning. Whereas human neuroimaging studies have focused on the cortical contributions to interference resolution, animal studies demonstrate that efficient resolution of PI depends on cholinergic modulation from basal forebrain (BF). Whether the BF promotes PI resolution in humans is unknown. Here, we adapted a PI paradigm from animal studies for use in a functional MRI experiment. During PI resolution, neurologically intact subjects recruited a BF network that included afferent anterior and posterior cortical sites associated with efficient memory acquisition and perceptual processing. Despite normal performance, nonamnesic patients with alcoholism, which is known to disrupt BF function, did not activate a BF network but instead invoked anterior cortical sites traditionally associated with executive function. These results provide evidence for parallel neural systems, each with the potential to resolve interference in the face of competing information.

    View details for Web of Science ID 000221458200016

    View details for PubMedID 15003180

  • Morphological changes in aging brain structures are differentially affected by time-linked environmental influences despite strong genetic stability NEUROBIOLOGY OF AGING Pfefferbaum, A., SULLIVAN, E. V., Carmelli, D. 2004; 25 (2): 175-183


    This longitudinal study used the full twin model to estimate change and stability of genetic contributions to morphology of two brain structures, the corpus callosum and lateral ventricles. The 142 subjects were 34 monozygotic (MZ) and 37 dizygotic (DZ) elderly male twin pairs from the National Heart, Lung, and Blood Institute (NHLBI) Twin Study who underwent brain magnetic resonance imaging twice, separated by a 4-year interval. Genetic factors accounted for a substantial portion of individual differences in the size of the corpus callosum and its substructures and of lateral ventricular size. Longitudinal genetic analyses revealed no significant change in the heritability of these structures and no evidence for new genetic variance at Time 2 not present at Time 1. However, both the callosal and ventricular measures showed evidence for new environmental variance at Time 2 not present at Time 1. Confirming a previously posed hypothesis, the phenotypic correlation between absolute change in height of the corpus callosum and absolute change in ventricular volume was significant. Bivariate genetic analysis estimated a significant genetic correlation between the changes in these two structures and the genetic variance in the change of callosal height was entirely due to genes involved in the expansion of ventricles. Genetic stability was present even in old age when brain and other morphological changes can be rapid and highly variable across individuals, inconsistent with an hypothesis that random DNA damage is the cause of aging.

    View details for DOI 10.1016/S0197-4580(03)00045-9

    View details for Web of Science ID 000188844200005

    View details for PubMedID 14749135

  • Effects of age and sex on volumes of the thalamus, pons, and cortex NEUROBIOLOGY OF AGING Sullivan, E. V., Rosenbloom, M., Serventi, K. L., Pfefferbaum, A. 2004; 25 (2): 185-192


    Volumes of thalamus, pons, cortical gray matter, and white matter were derived from MR brain images of healthy men and women spanning the adult age range in order to delineate patterns of aging and to compare age and sex effects in thalamus and pons with such effects in cortical gray and white matter volumes. Men had larger intracranial volume (ICV) than women, but ICV did not correlate with age in either sex. Thalamic, pontine, and cortical white matter volumes did not differ between men and women once ICV differences were taken into account, but men had more cortical gray matter than women even after accounting for ICV. Volumes of pons and thalamus were associated, independent of ICV, in women but not in men. Thalamic volume declined linearly with age at a similar rate in both men and women, whereas cortical gray matter volume declined more steeply with age in men than women. Both pontine and cortical white matter volumes remained stable across the age span in both men and women.

    View details for DOI 10.1016/S0197-4580(03)00044-7

    View details for Web of Science ID 000188844200006

    View details for PubMedID 14749136

  • Parallel interhemispheric processing in aging and alcoholism: relation to corpus callosum size NEUROPSYCHOLOGIA Schulte, T., Pfefferbaum, A., Sullivan, E. V. 2004; 42 (2): 257-271


    We tested parallel processing of visual information using the redundant targets effect (RTE) in 12 alcoholics and 13 matched controls. The paradigm was a simple reaction time (RT) task with targets presented in the same (uncrossed), opposite (crossed), or both (redundant) visual-fields. In older alcoholics (>50 years) the RT gain invoked by redundant targets did not exceed probability measures, suggesting compromised interhemispheric processing of parallel information in this subgroup compared with controls or younger alcoholics. The difference between crossed and uncrossed reaction times (CUD), an index of interhemispheric transfer time (ITT), was greater in older than younger subjects. Moreover, the CUD was negatively correlated with the corpus callosum (CC) total area and body in controls, supporting the concept of a structure-function relationship of interhemispheric transfer. This relationship was not found in alcoholics, although the midsagittal area of the CC, genu, and body but not intracranial volume (ICV), was significantly smaller in alcoholics than controls. These results suggest that chronic alcohol abuse together with advancing age exert subtle disruption on parallel interhemispheric processing reliant on callosal connections.

    View details for DOI 10.1016/S0028-3932(03)00155-6

    View details for Web of Science ID 000187220600012

    View details for PubMedID 14644111

  • Hippocampal volume deficits in alcoholic Korsakoff's syndrome NEUROLOGY Sullivan, E. V., Marsh, L. 2003; 61 (12): 1716-1719


    To examine whether the amnesic syndrome of alcoholic Korsakoff's syndrome (KS) originates from pathology of the hippocampus and not solely the diencephalon.The authors studied 5 patients with KS and two comparison groups: 20 patients with Alzheimer's disease (AD) with known bilateral hippocampal volume loss and 36 healthy control subjects. The authors used quantitative MRI to characterize the hippocampus and comparison brain structures (temporal cortex, lateral ventricles, temporal horns, and third ventricle).Relative to healthy control subjects, the KS and AD groups had comparable, significant bilateral hippocampal volume deficits. Although both patient groups also had extensive volume abnormalities in temporal lobe cortical gray matter, temporal horns, and lateral and third ventricles, declarative memory test performance was selectively related to hippocampal volumes in KS and not to any of the comparison volumes.The characteristic memory deficit of Korsakoff's syndrome involves hippocampal and diencephalic pathology.

    View details for Web of Science ID 000187514900018

    View details for PubMedID 14694035

  • Gray matter-N-acetyl aspartate deficits in secondary progressive but not relapsing-remitting multiple sclerosis 11th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine Adalsteinsson, E., Langer-Gould, A., Homer, R. J., Rao, A., SULLIVAN, E. V., Lima, C. A., Pfefferbaum, A., Atlas, S. W. AMER SOC NEURORADIOLOGY. 2003: 1941–45


    Spectroscopic examination of multiple sclerosis (MS) patients has revealed abnormally low N-acetyl-aspartate (NAA) signal intensity, even in brain tissue that appears normal on high-resolution structural MR images but has yielded inconclusive evidence to distinguish the well-documented clinical differences between MS subtypes. This study used proton MR spectroscopic imaging (MRSI) and high-resolution MR imaging to characterize metabolite profiles in normal-appearing brain tissue of relapsing-remitting multiple sclerosis (RRMS) and secondary progressive (SP) MS.Volumetric spiral MRSI was used together with high-resolution MR imaging to derive absolute measures of metabolite concentrations separately in normal-appearing supratentorial cerebral gray matter and white matter in five RRMS patients, five SPMS patients, and nine age-matched controls. Structural MR images were segmented into compartments of gray matter, white matter, CSF, and lesions, and metabolite signals per unit of tissue volume were calculated for gray matter and white matter separately.Only the SPMS group had significantly lower NAA concentrations in normal-appearing gray matter compared with concentrations in controls. NAA in normal-appearing white matter was equally reduced in RRMS and SPMS patients. The functional relevance of this brain metabolite measure was suggested by the observed but statistically nonsignificant correlation between higher disability scores on the Expanded Disability Status Scale and lower gray matter NAA concentrations.The otherwise occult abnormality in supratentorial gray matter in SPMS but not RRMS may explain the more severe physical and cognitive impairments afflicting patients with SPMS that do not correlate well with visible lesion burden.

    View details for Web of Science ID 000186744800006

    View details for PubMedID 14625214

  • Replicability of diffusion tensor imaging measurements of fractional anisotropy and trace in brain JOURNAL OF MAGNETIC RESONANCE IMAGING Pfefferbaum, A., Adalsteinsson, E., SULLIVAN, E. V. 2003; 18 (4): 427-433


    To evaluate within-scanner and between-scanner reliability of fractional anisotropy (FA) and trace (sum of the diagonal elements of the diffusion tensor) as measured by diffusion tensor imaging (DTI).Ten young healthy adults were scanned on three separate days, on two different systems made by the same manufacturer. One scan was acquired at one site, and two scans were acquired on two different occasions on another scanner at another site. Three levels of analysis were used to compare the DTI metrics: 1) a voxel-by-voxel analysis of all supratentorial brain (gray matter + white matter + cerebrospinal fluid) and of supratentorial white matter; 2) a slice-by-slice analysis of supratentorial white matter; and 3) a single-region analysis of the corpus callosum.The voxel-by-voxel analysis of all supratentorial brain found that FA and trace measures and correlations were equivalently and significantly higher within than across scanners. For supratentorial white matter, FA was similar within and across scanners, whereas trace demonstrated across-scanner bias. A similar pattern was observed for the slice-by-slice comparison. For the single-region analysis of the corpus callosum, within-scanner FA and trace measures were highly reproducible for FA (CV = 1.9%) and trace (CV = 2.6%), but both DTI measures showed a systematic mean bias across scanners (CV = 4.5% for FA and CV = 7.5% for trace).These estimates of measurement variation and scanner bias can be used to predict effect sizes for longitudinal and multisite studies using diffusion tensor imaging.

    View details for DOI 10.1002/jmri.10377

    View details for Web of Science ID 000185630100005

    View details for PubMedID 14508779

  • Compromised pontocerebellar and cerebellothalamocortical systems: Speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V. 2003; 27 (9): 1409-1419


    Corticopontocerebellar and cerebellothalamocortical circuits underlie a wide range of neuropsychological processes compromised by alcoholism. The analyses herein tested whether abnormalities of volumes of brain structures forming nodes of these separate feed-forward and feedback systems are selectively related to each other and whether any of these noncortical regions can account for cognitive and motor deficits occurring as sequelae of chronic alcoholism.Regional brain measures originated from our prior neuroimaging studies, showing in alcoholics significant volume deficits in the principal structures of interest: cerebellar hemispheres, vermis, pons, and thalamus as well as prefrontal, frontal, and parietal cortex. Neuropsychological functions targeted for analysis-problem solving, visuospatial ability, and static postural stability-showed 0.6 to 1.6 SD deficits in these alcoholic men.In alcoholics, the patterns of correlations were consistent with dissociation of thalamic and pontine circuitry. Pontine and thalamic volumes were not correlated with each other. Pontine volumes correlated with white matter volumes of anterior superior vermis and gray and white matter volumes of the cerebellar hemispheres but not with cortical regional volumes. Thalamic volumes correlated with gray matter volumes of the cerebellar hemispheres, parietal cortex, and inferior posterior vermian lobule, which itself correlated with parietal, prefrontal, and frontal cortical volumes. Controls did not show these correlational patterns. Brain structure-function relationships in alcoholics examined with multiple regression identified anterior vermian but not prefrontal or parietal volume as a unique predictor of balance scores; vermian and thalamic but not prefrontal cortical volumes as predictors of card sorting scores; and cerebellar hemispheric white matter but not parietal cortical volume as a predictor of visuospatial ability.Each major node of frontocerebellar circuitry shows volume deficits in alcoholics but can be independently compromised. Disruption of these circuits may underlie alcoholism-related neuropsychological deficits, either by abnormalities present in individual nodes or by disconnection via interruption of selective circuitry.

    View details for DOI 10.1097/01.ALC.0000085586.91726.46

    View details for Web of Science ID 000185541600004

    View details for PubMedID 14506401

  • Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study NEUROIMAGE Desmond, J. E., CHEN, S. H., DeRosa, E., Pryor, M. R., Pfefferbaum, A., SULLIVAN, E. V. 2003; 19 (4): 1510-1520


    Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.

    View details for DOI 10.1016/S1053-8119(03)00102-2

    View details for Web of Science ID 000185079000022

    View details for PubMedID 12948707

  • Enhanced release from proactive interference in nonamnesic alcoholic individuals: Implications for impaired associative binding NEUROPSYCHOLOGY De Rosa, E., SULLIVAN, E. V. 2003; 17 (3): 469-481


    Proactive interference (PI) occurs when previously learned information reduces the ability to acquire new, related information. Given that PI is modulated by the cholinergic system in rats (E. De Rosa & M. E. Hasselmo, 2000) and that chronic alcohol dependence disrupts cholinergic function in rats and humans, associative properties of PI in patients with alcoholism were examined. It was hypothesized that normal PI contingencies would be disrupted in alcoholic participants. When tested with a paired-associate simultaneous discrimination paradigm, analogous to that used in the rat model, alcoholic participants showed significantly less PI than controls yet performed comparably on a control response reversal task. The absence of PI in alcoholic participants may reflect impaired configural binding of paired-associate stimuli while sparing the elemental ability to process each stimulus component.

    View details for DOI 10.1037/0894-4105.17.3.469

    View details for Web of Science ID 000184836600014

    View details for PubMedID 12959513

  • Effects of alcohol dependence comorbidity and antipsychotic medication on volumes of the thalamus and pons in schizophrenia 8th International Congress on Schizophrenia Research Sullivan, E. V., Rosenbloom, M. J., Serventi, K. L., Deshmukh, A., Pfefferbaum, A. AMER PSYCHIATRIC PUBLISHING, INC. 2003: 1110–16


    Postmortem and in vivo brain imaging studies have identified abnormalities in the thalamus and the pons in both schizophrenia and alcoholism. The authors sought to determine whether patients with both schizophrenia and alcohol dependence would manifest exaggerated volume deficits in either structure.Volumetric measures of the left and right thalamus and the pons were derived from magnetic resonance imaging scans obtained from 27 patients with schizophrenia, 19 patients with schizophrenia and comorbid alcohol dependence, 25 patients with alcohol dependence without comorbid axis I disorders, and 51 healthy comparison subjects.The alcohol-dependent patients had significant volume deficits in both the thalamus and the pons. Among patients with schizophrenia, there were no differences in thalamus volumes between those with and without comorbid alcohol dependence. However, patients with schizophrenia who were taking atypical antipsychotic medications had bilateral thalamic deficits, whereas those taking typical neuroleptics did not. Patients with schizophrenia and comorbid alcohol dependence had deficits in the pons.Patients with schizophrenia and comorbid alcohol dependence are at risk for alcohol-related reduction of pontine structures that are not necessarily affected by schizophrenia per se. The effect of alcohol dependence on the thalamus in schizophrenic patients may be mitigated by the type of neuroleptic medication they receive.

    View details for Web of Science ID 000183240800014

    View details for PubMedID 12777269

  • Alcoholic men endorse more DSM-IV withdrawal symptoms than alcoholic women matched in drinking history JOURNAL OF STUDIES ON ALCOHOL Deshmukh, A., Rosenbloom, M. J., Sassoon, S., O'Reilly, A., Pfefferbaum, A., SULLIVAN, E. V. 2003; 64 (3): 375-379


    Given gender differences in alcohol metabolism, drinking patterns and alcohol-related problems, we asked whether men and women recruited for research protocols from treatment programs would meet different subsets of alcohol dependence or withdrawal criteria or differ in current level of functioning.The subjects were 66 men and 62 women meeting DSM-III-R or DSM-IV criteria for alcohol dependence. Gender differences were tested infrequency counts of criteria endorsed and Global Assessment of Functioning (GAF) scores.All seven alcohol dependence criteria were endorsed by 50% of the sample. There were no significant gender differences in frequency of individual criteria endorsed. However, more men than women tended to endorse the withdrawal criterion for alcohol dependence and the tremor criterion for alcohol withdrawal, whereas women had higher GAF scores. When subgroups of men and women were matched on alcohol consumption variables, significantly more men than women endorsed the withdrawal criterion for alcohol dependence and the anxiety criterion for alcohol withdrawal, and women still had significantly higher GAF scores than men.DSM criteria provide a similar characterization of alcohol dependence in male and female research volunteers. Despite this similarity, the DSM criteria were sensitive to gender differences, which can now be challenged with rigorous testing.

    View details for Web of Science ID 000183221500009

    View details for PubMedID 12817826

  • Increased brain white matter diffusivity in normal adult aging: Relationship to anisotropy and partial voluming MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., SULLIVAN, E. V. 2003; 49 (5): 953-961


    Diffusion tensor imaging (DTI) was used to examine 1) age-related changes in genu, splenium, and centrum semiovale white matter diffusivity in 64 healthy men and women (age 23-85 years); 2) the relationship between diffusivity (trace) and fractional anisotropy (FA) across and within individuals; and 3) the role of macrostructural and microstructural partial voluming effects on the DTI metrics. Regional differences were greater in FA (approximately 43%) than in trace (approximately 16%). Depending on the region of interest, trace increased with age (r = 0.24 to 0.58) and FA decreased with age (r = -0.29 to -0.79). FA was inversely correlated with trace, even when controlling for age. Histogram analysis of trace and FA following systematic expansion and dilation of the white matter regions demonstrated greater susceptibility of FA than trace to error arising from macrostructural partial voluming, i.e., erroneous inclusion of primarily nonwhite-matter voxels. Three-phase ellipsoid shape analysis revealed that after morphometric erosion the spherical component remained greater in older than younger subjects in the splenium and centrum, suggesting that age-related reduction in FA arises from intravoxel increased interstitial fluid. Reducing the size of the white matter samples to control for macrostructural partial voluming attenuated but did not negate effects, indicating that observed changes in white matter with aging can reflect real microstructural alterations rather than sampling artifact. Morphological dilation of white matter regions of interest resulting in purposeful inclusion of non-white matter pixels significantly reduced mean FA, suggesting that reports of FA values below 0.25 in healthy adults may reflect partial voluming rather than actual changes in white matter coherence.

    View details for DOI 10.1002/mrm.10452

    View details for Web of Science ID 000182642400022

    View details for PubMedID 12704779

  • Compounded brain volume deficits in schizophrenia-alcoholism comorbidity 38th Annual Meeting of the American-College-of-Neuropsychopharmacology Mathalon, D. H., Pfefferbaum, A., Lim, K. O., Rosenbloom, M. J., SULLIVAN, E. V. AMER MEDICAL ASSOC. 2003: 245–52


    Schizophrenia and alcoholism are characterized by brain volume abnormalities. Despite the frequent comorbidity of these conditions, the potentially compounded effects of comorbidity on brain structure have seldom been rigorously assessed.To determine the compounding effect of schizophrenia and alcoholism on regional brain volumes, we performed retrospective quantitative analysis of magnetic resonance images from men who participated in research protocols at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif. Participants were selected on the basis of diagnostic criteria, yielding 4 comparison groups: 35 men comorbid for DSM-III-R schizophrenia or schizoaffective disorder and lifetime alcohol abuse or dependence; 64 men with DSM-III-R schizophrenia or schizoaffective disorder; 62 men with Research Diagnostic Criteria alcoholism; and 62 healthy men screened to exclude any Axis I diagnosis or heavy alcohol use. The comorbid group matched the schizophrenia group on age and illness severity but was younger and drank 5 times less alcohol in their lifetimes than the alcoholism group. Gray and white matter volumes from 6 cortical regions were expressed as age- and head size-corrected z scores and were subjected to multivariate profile analyses.Gray matter volume deficits were present in all 3 patient groups but were greatest in the comorbid group. In the comorbid group, the most prominent volume deficits were in the prefrontal and anterior superior temporal regions.Despite lower alcohol exposure than in pure alcoholism, the comorbidity of schizophrenia with alcoholism has a particularly profound effect on prefrontal gray matter volume, compounding the prominent prefrontal deficits present independently in schizophrenia and alcoholism.

    View details for Web of Science ID 000181572200004

    View details for PubMedID 12622657

  • Diffusion tensor imaging in normal aging and neuropsychiatric disorders EUROPEAN JOURNAL OF RADIOLOGY SULLIVAN, E. V., Pfefferbaum, A. 2003; 45 (3): 244-255


    The application of diffusion imaging to the quantitative study of the effects of normal aging and neuropsychiatric diseases on brain tissue microstructure has witnessed its greatest development just over the last few years. Measures derived from diffusion imaging have already been shown to have great utility in identifying age- and disease-related degradation of regional microstructure, particularly of white matter. Investigations comparing diagnoses hold promise for contribution to differential diagnosis. Correlations with cognitive and motor performance provide evidence for functional ramifications of these diffusion measures.

    View details for Web of Science ID 000181482500010

    View details for PubMedID 12595109

  • Disruption of frontocerebellar circuitry and function in alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V., Harding, A. J., Pentney, R., Dlugos, C., Martin, P. R., Parks, M. H., Desmond, J. E., CHEN, S. H., Pryor, M. R., De Rosa, E., Pfefferbaum, A. 2003; 27 (2): 301-309


    This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol-related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and Functional reorganization of the brain in alcoholism: neuroimaging evidence, by John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf Pfefferbaum, and Edith V. Sullivan.

    View details for DOI 10.1097/01.ALC.0000052584.05305.98

    View details for Web of Science ID 000181172400017

    View details for PubMedID 12605080

  • How important are brain banks for alcohol research? ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Harper, C., Garrick, T., Matsumoto, I., Pfefferbaum, A., Adalsteinsson, E., Sullivan, E., Dodd, P., Lewohl, J., Butterworth, R. 2003; 27 (2): 310-323


    This article contains the proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, organized and chaired by Clive Harper and co-chaired by Izuru Matsumoto. The presentations were (1) Introduction, by Clive Harper; (2) The quality of tissue-a critical issue, by Therese Garrick; (3) The first systematic brain tissue donor program in Japan, by Izuru Matsumoto; (4) Brain scans after death-really! by Adolf Pfefferbaum, Elfar Adalsteinsson, and Edith Sullivan; (5) Capture that (genial) expression, by Joanne Lewohl and Peter Dodd; and (6) Neurochemical/pharmacological studies: experimental design and limitations, by Roger Butterworth.

    View details for DOI 10.1097/01.ALC.0000052585.81056.CA

    View details for Web of Science ID 000181172400018

    View details for PubMedID 12605081

  • Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics ALCOHOL RESEARCH & HEALTH Rosenbloom, M., SULLIVAN, E. V., Pfefferbaum, A. 2003; 27 (2): 146-152


    Brain imaging using conventional magnetic resonance imaging (MRI) has revealed that several brain structures in people with a history of chronic alcohol dependence are smaller in volume than the same brain structures in nonalcoholic control subjects. Areas that are particularly affected are the frontal lobes, which are involved in reasoning, judgment, and problem solving. Older people are especially vulnerable to the damaging effects of alcohol. It is unclear whether women show consistently more vulnerability to these changes in the brain than men do. In general, alcoholics evaluated before and after a period of abstinence show some recovery of tissue volume, whereas alcoholics evaluated again after continued drinking show further reductions in brain tissue volume. A new MR technique called diffusion tensor imaging (DTI) can aid in detecting the degradation of fibers (i.e., white matter) that carry information between brain cells (i.e., gray matter). With DTI, researchers studying alcoholics have been able to detect abnormalities in white matter not visible with conventional MRI. Ultimately DTI may be useful in elucidating the mechanisms that underlie macrostructural and functional brain changes seen with abstinence and relapse.

    View details for Web of Science ID 000223800500004

    View details for PubMedID 15303625

  • Hippocampal volume deficits contribute to the amnesia of Alcoholic Korsakoff?s Syndrome. Neurology Sullivan EV, Marsh L 2003: 1716-1719
  • Motor sequencing in Parkinson's disease: Relationship to executive function and motor rigidity 20th European Workshop on Cognitive Neuropsychology Fama, R., Sullivan, E. V. ELSEVIER MASSON. 2002: 753–67


    Parkinson's disease (PD) is a movement disorder that also affects central cognitive processing; however, the extent to which high-order cognitive processes disrupted by PD affect complex motor function is incompletely explicated. The present analysis provides an examination of the relative contributions of simple motor versus complex cognitive functions involving sequencing, problem solving, and overall cognitive status to complex motor movements involving sequencing and temporal ordering in PD. Motor sequencing performance was videotaped for quantitative scoring. Compared with an age-matched control group, the PD group was impaired on motor agility and motor sequencing tasks in addition to cognitive sequencing and set shifting tasks. Neither current cognitive functioning, age, disease duration, nor overall intellectual abilities accounted for the relationships between motor sequencing and cognitive sequencing abilities in PD. By contrast, both sequencing and nonsequencing executive functions predicted motor sequencing performance as well as or better than motor rigidity or overall cognitive status. These relationships were strongest for the most challenging motor sequencing task, fist-edge-palm, and did not apply to the least challenging task, which required simple alternations of hand movements. Unlike PD, controls showed correlations between motor sequencing tests and executive functioning only tapping nonsequencing abilities. Thus, despite the predominant motor feature of PD, executive functions, as assessed by sequencing and set formation, predicted motor sequencing performance as well as or better than simple motor performance. The results further suggest that the more complex the motor sequencing task, the more susceptible it is to influence from generalized cognitive sequencing ability.

    View details for Web of Science ID 000180579100006

    View details for PubMedID 12507044

  • Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study. Magnetic resonance spectroscopy. Psychiatry research Nordahl, T. E., Salo, R., Possin, K., Gibson, D. R., Flynn, N., Leamon, M., Galloway, G. P., Pfefferbaum, A., Spielman, D. M., Adalsteinsson, E., Sullivan, E. V. 2002; 116 (1-2): 43-52


    Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/-6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03; MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.: control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.

    View details for PubMedID 12426033

  • Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: a preliminary proton MRS study PSYCHIATRY RESEARCH-NEUROIMAGING Nordahl, T. E., Salo, R., Possin, K., Gibson, D. R., Flynn, N., Leamon, M., Galloway, G. P., Pfefferbaum, A., Spielman, D. M., Adalsteinsson, E., SULLIVAN, E. V. 2002; 116 (1-2): 43-52
  • Assessment of low-flow CSF drainage as a treatment for AD - Results of a randomized pilot study NEUROLOGY Silverberg, G. D., Levinthal, E., SULLIVAN, E. V., Bloch, D. A., Chang, S. D., Leverenz, J., Flitman, S., Winn, R., Marciano, F., Saul, T., Huhn, S., Mayo, M., McGuire, D. 2002; 59 (8): 1139-1145


    This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD.Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals.There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)).The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

    View details for Web of Science ID 000178726700007

    View details for PubMedID 12391340

  • Clinical signs of cerebellar dysfunction in schizophrenia, alcoholism, and their comorbidity SCHIZOPHRENIA RESEARCH Deshmukh, A., Rosenbloom, M. J., Pfefferbaum, A., Sullivan, E. V. 2002; 57 (2-3): 281-291


    Abnormalities of cerebellar structure and function, long recognized as a hallmark of chronic alcohol abuse, have also occasionally been noted in patients with schizophrenia. We used a four-point rating scale to assess clinical signs of cerebellar dysfunction in men meeting DSM-IV criteria for schizophrenia (N=34) and alcohol dependence (N=15) as well as normal control subjects (N=28). Compared to controls, alcoholics had impaired ratings of gait ataxia and instability of stance with eyes closed, and schizophrenics had impaired ratings of stance with eyes closed. The incidence of dysdiadochokinesia was greater in schizophrenics, but not alcoholics, than controls. The incidence of gait and stance abnormalities was higher in both patient groups relative to controls: within the schizophrenic group, 50-70% of those with positive signs for gait or stance impairment were comorbid for alcoholism, while only 25% of those with positive signs for dysdiadochokinesia were comorbid for alcoholism. The presence of dysdiadochokinesia in the schizophrenic group suggests cerebellar dysfunction that is independent of the effects of alcohol. By contrast, clinical signs of cerebellar dysfunction of gait and stance in patients with schizophrenia may be secondary to the effects of alcohol on the cerebellum.

    View details for Web of Science ID 000178358100018

    View details for PubMedID 12223260

  • The effects of alcoholism on auditory evoked potentials during sleep JOURNAL OF SLEEP RESEARCH Nicholas, C. L., SULLIVAN, E. V., Pfefferbaum, A., Trinder, J., Colrain, I. M. 2002; 11 (3): 247-253


    Normal aging is associated with a reduction in the probability that an auditory stimulus will evoke a K-complex during sleep. Additional concomitants of aging are a reduction in the amplitude of the K-complex-related N550, an augmentation of the P2 component and the appearance of a long-lasting positivity (LLP) in the auditory evoked potential. Normal aging is also associated with a dramatic reduction in slow wave sleep (SWS) and a reduction in the volume of cortical gray matter, particularly in the frontal and prefrontal regions of the brain. As in aging, alcoholism is associated with reductions in both cortical gray matter and SWS. It can, therefore, be hypothesized that alcoholics would show similar evoked potential changes to those seen in aging. To test this hypothesis, we studied seven middle-aged abstinent long-term alcoholics and eight age-matched normal controls. Each subject spent one night in the laboratory. Electroencephalogram (EEG) was recorded from six midline scalp sites and auditory stimuli were presented during stage 2 non-rapid eye movement sleep. N550 amplitude in the K-complex average was lower in the alcoholics as compared with controls as was the likelihood of K-complex production. No differences were noted in either amplitude or latency of the P2 or N350 components, and both groups displayed a prominent LLP potential. The pattern of reduced K-complex production and N550 amplitude in alcoholics as compared with age-matched controls is consistent with an hypothesized association between atrophy of the frontal lobes and reductions in SWS and K-complexes. The finding also suggests that the evoked K-complex may be a relatively simple measure of the effect of alcoholism on EEG during sleep.

    View details for Web of Science ID 000177852300009

    View details for PubMedID 12220321

  • Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals PSYCHIATRY RESEARCH Salo, R., Nordahl, T. E., Possin, K., Leamon, M., Gibson, D. R., Galloway, G. P., Flynn, N. M., Henik, A., Pfefferbaum, A., SULLIVAN, E. V. 2002; 111 (1): 65-74


    Chronic methamphetamine abuse is associated with disruption of frontostriatal function involving serotonin and dopamine circuitry. Clinically, methamphetamine-dependent (MD) individuals are highly distractible and have difficulty focussing. Here, we used a computerized single-trial version of the Stroop Test to examine selective attention and priming in MD. Subject groups comprised eight MD men (31.7+/-7.2 years of age), who had used methamphetamine for 15.75+/-8.4 years but were currently abstinent for 2-4 months, and 12 controls (35.7+9.7 years of age). Compared with the control group, the MD group exhibited significantly greater interference (P<0.05) despite intact priming. Error rates did not differ between the groups. This preliminary finding of reduced cognitive inhibition in MD individuals is consistent with the distractibility they show clinically. Furthermore, the dissociation between explicit attentional performance and priming effects suggests that some attentional functions are not as affected by long-term methamphetamine use as others.

    View details for Web of Science ID 000177511200008

    View details for PubMedID 12140121

  • Alcoholism and AIDS: Magnetic resonance imaging approaches for detecting interactive neuropathology ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Rosenbloom, M., SULLIVAN, E. V. 2002; 26 (7): 1031-1046


    Both alcohol abuse and human immunodeficiency virus (HIV) infection have deleterious effects on brain structure, metabolism and function. In individuals with both afflictions these effects are doubtless additive and may interact to produce synergistic adverse effects. Further, the normal processes of aging produce brain degeneration that leaves older people especially vulnerable to the untoward effects of alcohol abuse and HIV infection. Advances in in vivo brain imaging now make practical the clinical study of the interaction of alcoholism and HIV infection and the potential of increased vulnerability produced by advancing age. In addition to structural magnetic resonance imaging (MRI), which provides quantitative assessments of brain macrostructure, are diffusion tensor imaging (DTI), which assesses microstructural integrity, magnetic resonance spectroscopy (MRS), which provides assessment of brain chemical moieties related to neuronal viability, and functional magnetic resonance imaging (fMRI), which provides assessment of localized blood oxygenation state association with performance of specific cognitive or motor tasks. Here, we first review postmortem observations on patients with HIV infection and with alcoholism to identify the cell types and brain regions most affected by the end stage of the disease. We then review in vivo neuroimaging studies of brain changes associated with HIV infection, chronic alcohol use, their interaction, and the potentiating effects of age. While there are many studies of people with either HIV infection or chronic alcohol use alone currently little has been published on the interactive effects of these variables, despite the high prevalence of overlap. We conclude with a consideration of the methodological issues such studies must address.

    View details for DOI 10.1097/01.ALC.0000021146.01778.55

    View details for Web of Science ID 000176989100013

    View details for PubMedID 12170114

  • Influences of chorion type on measurements of the corpus callosum in adult monozygotic male twins? AMERICAN JOURNAL OF HUMAN BIOLOGY Reed, T., Pfefferbaum, A., SULLIVAN, E. V., Carmelli, D. 2002; 14 (3): 338-346


    MRI imaging was used to estimate volumes of corpus callosum structure in 45 pairs of identical (monozygotic, MZ) twins from the National Heart, Lung, and Blood Institute (NHLBI) twin study. Age range of the study subjects was from 68-78 years. Finger, palm, and footprint data (dermatoglyphics) collected at previous examinations of the NHLBI twin study were available for 39 pairs. The dermatoglyphics were scored for an index to retrospectively assess chorion type in MZ twin-pairs. The results indicated an association between variability in various structures of the corpus callosum with some of these dermatoglyphic traits, suggesting greater structural variation within pairs with dichorionic placentas. In contrast, total intracranial volume, which has similar heritability estimates as a result of shared genetic effects with the corpus callosum, was unrelated to the dermatoglyphic traits. The results provide indirect evidence that the intrauterine environment may influence twin-pair similarity of corpus callosum measures in adults.

    View details for DOI 10.1002/ajhb.10027

    View details for Web of Science ID 000175224400006

    View details for PubMedID 12001090

  • Speed and efficiency but not accuracy or timing deficits of limb movements in alcoholic men and women 37th Annual Meeting of the American-College-of-Neuropsychopharmacology Sullivan, E. V., Desmond, J. E., Lim, K. O., Pfefferbaum, A. BLACKWELL PUBLISHING. 2002: 705–13


    Lesions of the cerebellum, a concomitant of alcoholism, can disrupt quality and regularity of movement. Whether evidence for such dysfunction lingers in patients with uncomplicated alcoholism, which is known to affect cerebellar structural integrity, is controversial.We used quantitative measures to examine component processes of five classes of movement associated with regional cerebellar function: limb ataxia (alternated finger tapping and variants of the finger-to-nose and heel-to-shin tests), paced tapping, eye-hand coordinated tracing, timed response reflecting preparation and execution time, and postural stability. The subjects examined were 39 abstinent alcoholics (13 men and 26 women) and 21 age-matched controls (9 men and 12 women). For limb ataxia, the dependent measures were the trajectory deviation from the subject's own average movement path and the speed of travel from beginning points to endpoints.Repeated-measures analysis of variance comparing movement speed of finger to nose and heel to shin yielded significant interactions in all conditions (p < 0.007); this indicated that the alcoholics were relatively slower in the upper- than lower-limb tasks. Movements by the alcoholic men were significantly slower but less deviant from an ideal trajectory in all upper-limb conditions than those of the control men (p < 0.002). Although measures of lower-limb movement trajectory did not distinguish the groups, tests of ataxia of stance and gait did. The groups did not differ, however, on tests of timed tapping or sinusoid tracing.Alcohol-related postural instability in abstinent alcoholics is functional evidence supporting the postulated damage to the anterior superior vermis. Altered speed or accuracy trade-offs, with alcoholics moving slower to attain equivalent or even smaller trajectory deviations, are symptomatic of cerebellar hemisphere dysfunction that is characterized by deliberation of otherwise automatic movements.

    View details for Web of Science ID 000175643900016

    View details for PubMedID 12045480

  • Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men CEREBRAL CORTEX Sullivan, E. V., Pfefferbaum, A., Adalsteinsson, E., Swan, G. E., Carmelli, D. 2002; 12 (4): 438-445


    Brain structure changes in size with normal aging, but the rate at which different structures change is controversial. We used magnetic resonance imaging (MRI) performed twice, 4 years apart, to compare rates of age-related size change of the corpus callosum, which has been inconsistently observed to thin with age, with change in the lateral ventricles, which are well established to enlarge. Subjects were 215 community dwelling, elderly men (70-82 years old at initial MRI), who were participants in a longitudinal study of cardiovascular risk factors. Percent change in size was significant for both the callosal and ventricular measures, but annual rate of ventricular expansion (2.9%) was significantly greater than annual rate of callosal thinning (-0.9%). Callosal regions showed statistically equivalent rates of shrinkage; ventricular dilatation was symmetrical. Neither callosal and ventricular rates of change correlated with each other (r = 0.01), nor did genu and splenium rates of change correlate with each other (r = 0.05). Tests of speeded processing were administered contemporaneously with both MRIs to examine functional ramifications of observed brain changes. Decline in the Mini-Mental State Examination was related to thinning of the splenium, and decline in Stroop test word reading was selectively related to thinning of the callosal body. These longitudinal data support the contentions that differential rates of change occur in different brain regions in normal aging, age-related callosal thinning contributes to functional declines, and rate of change in one region can be independent of rate of change in another region, even within a brain structure.

    View details for Web of Science ID 000174370200010

    View details for PubMedID 11884358

  • Corpus callosum, pons, and cortical white matter in alcoholic women ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Rosenbloom, M., Serventi, K. L., SULLIVAN, E. V. 2002; 26 (3): 400-406


    To measure the effect of alcohol abuse on white matter brain macrostructure in women with alcoholism and to determine whether observed abnormalities interact with age.Quantitative measures of corpus callosum area, cortical white matter volume, and pons volume were derived from magnetic resonance imaging scans obtained from 34 women with DSM-III-R alcoholism (aged 28-64, mean 41 years) and 35 healthy women (aged 22-65, mean 42 years). Transverse relaxation time of the pons was also obtained.No significant group differences in any brain measures were observed. However, in alcoholics greater length of sobriety was associated with more cortical white matter, and higher lifetime levels of alcohol consumption were associated with smaller volumes and prolonged transverse relaxation time in the pons.Despite a lack of overall deficits in white matter macrostructural size in alcoholic women, certain white matter structures showed alcohol exposure vulnerability whereas others showed evidence of recovery with abstinence.

    View details for Web of Science ID 000174612800015

    View details for PubMedID 11923595

  • Microstructural but not macrostructural disruption of white matter in women with chronic alcoholism NEUROIMAGE Pfefferbaum, A., SULLIVAN, E. V. 2002; 15 (3): 708-718


    The results of in vivo neuroimaging studies assessing whether and where brain white matter damage occurs in alcoholic women is controversial. To address this controversy, we examined regional white matter macrostructure and microstructure, the latter of which may be more sensitive to the detection of subtle fiber disruption than gross measures of size. Accordingly, we used conventional magnetic resonance imaging (MRI) to quantify regional callosal size and diffusion tensor imaging (DTI) to examine intravoxel coherence (fractional anisotropy, FA) and intervoxel coherence (C) of white matter of the genu and splenium of the corpus callosum and of the centrum semiovale in 12 detoxified alcoholic women and 18 control women. Additional analyses examined sex differences in FA and C in alcoholic women compared with alcoholic men. Despite absence of group differences in regional areas of callosal macrostructure, the alcoholic women had lower FA and C in genu and centrum semiovale than the control group of women. These measures also correlated with total lifetime consumption of alcohol and performance on a test of visual search in the alcoholic women. Sex comparisons revealed similar extents of FA abnormality in the genu and centrum semiovale in alcoholic men and women and differential effects in other DTI measures, with abnormalities present in splenium FA and C in the men and abnormalities present in centrum C in the women. These results provide in vivo evidence for disruption of white matter microstructure in alcoholic women not necessarily detectable with coarser measures of white matter mass and perhaps antedating its appearance.

    View details for DOI 10.1006/nimg.2001.1018

    View details for Web of Science ID 000174163900025

    View details for PubMedID 11848714

  • A profile of neuropsychological deficits in alcoholic women 20th Annual Meeting of the Research-Society-on-Alcoholism Sullivan, E. V., Fama, R., Rosenbloom, M. J., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2002: 74–83


    Neuropsychological deficits, most notable in executive, visuospatial, and functions of gait and balance, are detectable in alcoholic men even after a month of sobriety. Less well established are the severity and profile of persisting deficits in alcoholic women. The authors used an extensive test battery to examine cognitive and motor functions in 43 alcoholic women who were sober, on average, for 3.6 months. Functions most severely affected in alcoholic women involved visuospatial and verbal and nonverbal working memory processes as well as gait and balance. Areas of relative sparing were executive functions, declarative memory, and upper-limb strength and speed. The authors found that lifetime alcohol consumption was related to impairment severity on Block Design (Wechsler Adult Intelligence Scale-Revised, D. Wechsler, 1981) and verbal and nonverbal working memory, suggesting a dose effect of alcohol abuse. The alcohol-related deficits in working memory, visuospatial, and balance implicate disruption of prefrontal, superior parietal, and cerebellar brain systems.

    View details for DOI 10.1037//0894-4105.16.1.74

    View details for Web of Science ID 000173794700009

    View details for PubMedID 11853359

  • N-acetylaspartate - A marker of neuronal integrity ANNALS OF NEUROLOGY SULLIVAN, E. V., Adalsteinsson, E., Spielman, D. M., Hurd, R. E., Pfefferbaum, A. 2001; 50 (6): 823-823

    View details for Web of Science ID 000172410900022

    View details for PubMedID 11761485

  • Structural brain abnormalities in patients with schizophrenia, epilepsy, and epilepsy with chronic interictal psychosis PSYCHIATRY RESEARCH-NEUROIMAGING Marsh, L., SULLIVAN, E. V., Morrell, M., Lim, K. O., Pfefferbaum, A. 2001; 108 (1): 1-15


    Chronic interictal psychotic syndromes, often resembling schizophrenia, develop in some patients with epilepsy. Although widespread brain abnormalities are recognized as characteristic of schizophrenia, prevailing but controversial hypotheses on the co-occurrence of epilepsy and psychosis implicate left temporal lobe pathology. In this study, quantitative MRI methods were used to address the regional specificity of structural brain abnormalities in patients with epilepsy plus chronic interictal psychosis (E+PSY, n=9) relative to three comparison groups: unilateral temporal lobe epilepsy without chronic psychosis (TLE, n=18), schizophrenia (SCZ, n=46), and healthy control subjects (HC, n=57). Brain measures, derived from a coronal spin-echo MRI sequence, were adjusted for age and cerebral volume. Relative to HC, all patient groups had ventricular enlargement and smaller temporal lobe, frontoparietal, and superior temporal gyrus gray matter volumes, with the extent of these abnormalities greatest in E+PSY. Only TLE had temporal lobe white matter deficits, as well as smaller hippocampi, which were ipsilateral to the seizure focus. Structural brain abnormalities in E+PSY are not restricted to the left temporal lobe. The confluence of cortical gray matter deficits in E+PSY and SCZ suggests salience to chronic psychosis.

    View details for Web of Science ID 000172053800001

    View details for PubMedID 11677063

  • Magnetic resonance relaxometry reveals central pontine abnormalities in clinically asymptomatic alcoholic men 39th Annual Meeting of the American-College-of-Neuropsychopharmacology Sullivan, E. V., Pfefferbaum, A. BLACKWELL PUBLISHING. 2001: 1206–12


    Central pontine myelinolysis (CPM) is a rare, debilitating, life-threatening condition, associated with chronic alcoholism, rapid correction of hyponatremia, and advanced age. It is unknown, however, whether older alcoholic patients who by age and diagnosis are at risk for CPM have objectively determined neuroimaging evidence of preclinical CPM that could be valuable in understanding its development and in initiating appropriate treatment. Accordingly, we examined central pontine magnetic resonance (MR) transverse relaxation time (T2), which reflects myelin and axonal integrity when measured in white matter and is prolonged with pathology that causes increased free water content in tissue.The subjects were 46 alcoholic men who were abstinent from alcohol for about 1 month and were asymptomatic for CPM, 9 men and 1 woman with alcoholic Korsakoff's syndrome (KS), and 74 healthy control men. All subjects received coronally acquired dual-echo MR imaging (MRI), from which T2 times were calculated in central pons. MRI films were read clinically and independently of relaxometry results. Hematological and neuropsychological data were also available for many subjects.Only the KS group showed prolonged T2 times; however, pontine T2 prolongation increased significantly with older age in the asymptomatic alcoholics but not controls. Clinical radiological readings detected pontine signal hyperintensity in five KS subjects (two without dementia and three with dementia), one control, and no alcoholic patient. Hematologic indexes of macrocytic anemia and nutritional deficiency and neuropsychological measures of verbal and nonverbal fluency correlated with prolonged T2 times in alcoholic men.This CPM-like condition, manifest as prolonged T2, may occur with higher incidence than previously thought in clinically asymptomatic alcoholism and may contribute to neuropsychological compromise of initiation and production. Preclinical detection of abnormal pontine signal properties with MR relaxometry may identify patients at high risk for developing CPM.

    View details for Web of Science ID 000170458200017

    View details for PubMedID 11505052

  • Reorganization of frontal systems used by alcoholics for spatial working memory: An fMRI study NEUROIMAGE Pfefferbaum, A., Desmond, J. E., Galloway, C., Menon, V., Glover, G. H., SULLIVAN, E. V. 2001; 14 (1): 7-20


    Chronic alcoholism is associated with impairment in sustained attention and visual working memory. Thus, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks, assumed to be subserved by regions of prefrontal cortex. To identify neural substrates associated with this impairment, we used functional MRI (fMRI) to determine whether alcoholics invoke the same or different brain systems as controls when engaged in working memory tasks that the two groups were able to perform at equivalent levels. The fMRI spatial working memory paradigm instructed subjects to respond with a button press when a target position was either in the center of the field (match to center) or matched the spatial position of one presented two items previously (match 2-back) or to rest. Using whole-brain fMRI, alcoholics showed diminished activation frontal cortical systems compared to controls (bilateral dorsolateral prefrontal cortex) when responding 2-back vs rest. In the center vs rest contrast, the control group compared with the alcoholic group activated a large expanse of prefrontal cortex (including Brodmann areas 9, 10, and 45), whereas there was significantly greater activation by the alcoholic group relative to the control group localized more posteriorly and inferiorly in the frontal cortex (area 47). Examination of within group activation patterns revealed two different patterns of activation: the control group exhibited activation of the dorsal ("Where?") stream for visual spatial working memory processing, whereas the alcoholic group exhibited activation of the ventral ("What?") stream and declarative memory systems to accomplish the spatial working memory task. The differences in the pattern of brain activations exhibited by the alcoholic and control groups, despite equivalence in behavioral performance, is consistent with a functional reorganization of the brain systems invoked by alcoholic individuals or invocation of an inappropriate brain system when engaged in a visual spatial task requiring working memory.

    View details for Web of Science ID 000169498000002

    View details for PubMedID 11525339

  • Sex differences in corpus callosum size: relationship to age and intracranial size 27th Annual Meeting of the International-Neuropsychological-Society SULLIVAN, E. V., Rosenbloom, M. J., Desmond, J. E., Pfefferbaum, A. ELSEVIER SCIENCE INC. 2001: 603–11


    This quantitative MRI study reports measurement of corpus callosum area taken from midsagittal brain images in 51 healthy men and 41 healthy women, spanning the adult age range (22 to 71 years). Men had larger brains and corpora callosa than women, but callosal size did not correlate with age in either sex. Intracranial (i.c.) volume (ICV) and midsagittal i.c. area (ICA) of brain were used in covariate, regression, and ratio analyses to determine whether sex differences in the corpus callosum endured with statistical adjustment for sex differences in maximally attained brain size. With the exception of one ratio measure, the different statistical adjustments for the contribution of sex differences in brain size to corpus callosum size all indicated that men had larger corpora callosa than women for their brain size. A subsample of men and women selected to be matched on i.c. volume and age confirmed this statistical observation. Sexual dimorphism in the corpus callosum is not a simple artifact of sex differences in brain size and may reflect differences in connectivity necessitated by differences in brain size.

    View details for Web of Science ID 000169912200011

    View details for PubMedID 11445261

  • Motor sequencing deficits in schizophrenia: A comparison with Parkinson's disease International Congress on Schizophrenia Sullivan, E. V., Fama, R., Shear, P. K., Cahn-Weiner, D. A., Stein, M., Zipursky, R. B., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2001: 342–50


    Motor abnormalities occur in schizophrenia (SZ) and may arise from striatal dysfunction. This study examined whether the pattern of performance on simple and complex motor abilities in SZ was similar to that of patients with Parkinson's disease (PD). Quantitative tests of speeded movement and motor and cognitive sequencing were used to assess 25 SZ, 16 PD, and 84 normal controls (NCs). Sequencing performance was also examined with motor rigidity taken into account. Compared with the NC group, the SZ and PD groups were impaired on measures of motor rigidity and motor sequencing. With rigidity accounted for, the SZ group was significantly more impaired than the PD group on motor sequencing; cognitive and motor processes contributed to the motor deficit. Cognitive sequencing performance predicted motor sequencing performance in PD but not SZ. Although both SZ and PD resulted in significant motor and cognitive sequencing deficits, the pattern and correlates of these deficits differ, suggesting that the affected neural systems underlying motor deficits in SZ are different from those involved in PD.

    View details for DOI 10.1037//0894-4105.15.3.342

    View details for Web of Science ID 000170947000003

    View details for PubMedID 11499989

  • Genetic regulation of regional microstructure of the corpus callosum in late life NEUROREPORT Pfefferbaum, A., SULLIVAN, E. V., Carmelli, D. 2001; 12 (8): 1677-1681


    In order to identify brain structural phenotypes that remain under significant genetic control in late adulthood, we examined the heritability of corpus callosum macrostructure (i.e. size) using MRI and microstructure (e.g. myelin) using diffusion tensor imaging in 15 monozygotic and 18 dizygotic twin pairs of elderly men. The relative proportion of genetic to environmental influences varied considerably by region and structural type and was 5:1 for callosal macrostructure, 3:1 for splenium microstructure, and 1:1 for genu microstructure. This is the first in vivo identification of quantifiable phenotypes of brain white matter microstructure and demonstrates significant and differential genetic regulation in old age, with anterior interhemispheric connecting pathways more susceptible than posterior pathways to environmental influences.

    View details for Web of Science ID 000169185400028

    View details for PubMedID 11409738

  • Neuroimaging in alcoholism: Ethanol and brain damage 35th Annual Meeting of the Japanese-Medical-Society-of-Alcohol-and-Drug-Studies/10th International-Society-for-Biomedical-Research-on-Alcoholism Mann, K., Agartz, I., Harper, C., Shoaf, S., RAWLINGS, R. R., Momenan, R., Hommer, D. W., Pfefferbaum, A., SULLIVAN, E. V., Anton, R. F., Drobes, D. J., George, M. S., Bares, R., Machulla, H. J., Mundle, G., Reimold, M., Heinz, A. WILEY-BLACKWELL. 2001: 104S–109S


    This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

    View details for Web of Science ID 000168846000019

    View details for PubMedID 11391058

  • An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sobel, N., Thomason, M. E., Stappen, I., Tanner, C. M., Tetrud, J. W., Bower, J. M., SULLIVAN, E. V., Gabrielli, J. D. 2001; 98 (7): 4154-4159


    Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.

    View details for Web of Science ID 000167833700098

    View details for PubMedID 11259673

  • Remote memory for public figures in Alzheimer's disease: Relationships to regional cortical and limbic brain volumes JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Fama, R., Shear, P. K., Marsh, L., Yesavage, J. A., Tinklenberg, J. R., Lim, K. O., Pfefferbaum, A., Sullivan, E. V. 2001; 7 (3): 384-390


    This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal-occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory.

    View details for Web of Science ID 000168425100012

    View details for PubMedID 11311039

  • Progressive brain volume changes and the clinical course of schizophrenia in men - A longitudinal magnetic resonance imaging study 55th Annual Meeting of the Society-of-Biological-Psychiatry Mathalon, D. H., SULLIVAN, E. V., Lim, K. O., Pfefferbaum, A. AMER MEDICAL ASSOC. 2001: 148–57


    We sought to determine whether the brain dysmorphology previously observed cross-sectionally in people with schizophrenia progresses over time and whether such progression is related to the severity of the illness course.Men with chronic schizophrenia (n = 24) and control men (n = 25) received 2 brain magnetic resonance imaging scans, on average 4 years apart. Changes in brain volume were adjusted for head-repositioning error and expressed as slopes (cubic centimeters per year). Clinical course severity for the schizophrenic patients was assessed using the mean of time 1 and time 2 Brief Psychiatric Rating Scale (BPRS) scores and the percentage of time the patient was hospitalized during the interscan interval.Schizophrenic patients exhibited faster volume decline than control subjects in right frontal gray matter and bilateral posterior superior temporal gray matter, as well as faster cerebrospinal fluid volume expansion in right frontal sulci, left lateral ventricle, and bilateral prefrontal and posterior superior temporal sulci. Faster rates of frontal sulcal expansion were related to greater BPRS total and positive symptom scores and longer time hospitalized. Prefrontal gray matter decline and sulcal expansion were associated with greater BPRS negative symptom scores and longer time hospitalized. Temporal lobe gray matter decline was associated with greater BPRS total and negative symptom scores.This controlled study revealed that patients with chronic schizophrenia exhibited accelerated frontotemporal cortical gray matter decline and cortical sulcal and lateral ventricular expansion. Further, greater clinical severity was associated with faster rates of frontotemporal brain volume changes. These observations are consistent with a progressive pathophysiological process but need to be replicated in a larger sample.

    View details for Web of Science ID 000166842600005

    View details for PubMedID 11177116

  • Sex differences in the effects of alcohol on brain structure Annual Meeting of the Research-Society-of-Alcoholism Pfefferbaum, A., Rosenbloom, M., Deshmukh, A., SULLIVAN, E. V. AMER PSYCHIATRIC PUBLISHING, INC. 2001: 188–97


    This study investigated whether alcoholic women manifest deficits in cortical gray and white matter volumes and ventricular enlargement similar to those seen in alcoholic men.Volumetric measures of intracranium, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of 42 women and 44 men with DSM-III-R alcoholism and age-matched healthy comparison groups (37 women and 48 men). Groups of alcoholic men and women were matched on age and length of sobriety, but men had a 2.5 times higher lifetime alcohol consumption than women.Women, regardless of diagnosis, had less cortical gray and white matter and smaller third ventricles than men, consistent with sex-related differences in intracranial volume. Alcoholics had larger volumes of cortical sulci and lateral and third ventricles than comparison subjects. Diagnosis-by-sex interactions for cortical white matter and sulcal volumes were due to abnormalities in alcoholic men but not alcoholic women, relative to same-sex comparison subjects. This interaction persisted for cortical sulci after covarying for lifetime alcohol consumption. Slopes relating cortical gray matter and sulcal volumes to age were steeper in alcoholic than in comparison men. Slopes relating lateral ventricle volume to age were steeper in alcoholic than in comparison women. In alcoholic women, longer sobriety was associated with larger white matter volumes.Alcoholic men and women show different brain morphological deficits, relative to same-sex comparison subjects. However, age and alcoholism interact in both sexes, which puts all older alcoholics at particular risk for the negative sequelae of alcoholism.

    View details for Web of Science ID 000166761400007

    View details for PubMedID 11156800

  • Equivalent disruption of regional white matter microstructure in ageing healthy men and women NEUROREPORT SULLIVAN, E. V., Adalsteinsson, E., Hedehus, M., Ju, C., Moseley, M., Lim, K. O., Pfefferbaum, A. 2001; 12 (1): 99-104


    Diffusion tensor imaging was used to measure regional differences in brain white matter microstructure (intravoxel coherence) and macrostructure (intervoxel coherence) and age-related differences between men and women. Neuropsychiatrically healthy men and women, spanning the adult age range, showed the same pattern of variation in regional white matter coherence. The greatest coherence measured was in corpus callosum, where commissural fibers have one primary orientation, lower in the centrum semiovale, where fibers cross from multiple axes, and lowest in pericallosal areas, where fibers weave and interstitial fluid commonly pools. Age-related declines in intravoxel coherence was equally strong and strikingly similar in men and women, with evidence for greater age-dependent deterioration in frontal than parietal regions. Degree of regional white matter coherence correlated with gait, balance, and interhemispheric transfer test scores.

    View details for Web of Science ID 000166411900022

    View details for PubMedID 11201100

  • Heritability of hippocampal size in elderly twin men: Equivalent influence from genes and environment HIPPOCAMPUS Sullivan, E. V., Pfefferbaum, A., Swan, G. E., Carmelli, D. 2001; 11 (6): 754-762


    Recent studies have established that environmental factors can modify hippocampal structure and enhance function in adult rodents, but the extent to which genes and the environment exert differential contributions to hippocampal structural integrity in humans is unknown. Here, we applied the twin model in a large sample of elderly twin men to examine in late life the balance of environmental and genetic effects on the size of the hippocampus in comparison with other brain structures. This study provides novel evidence that the volume of the hippocampus, as measured on MRI, is subject to substantially less genetic control than are comparison brain regions also measured: temporal horn volume, midsagittal area of the corpus callosum, and intracranial volume (ICV). In particular, about 60% of the temporal horn variance and 80% of the callosal and ICV variance was attributable to genetic influences, whereas only 40% of the hippocampal variance was attributable to genetic influences. These results suggest that environment, whether by itself or in interaction with genes, has the potential of exerting greater and possibly longer control in modifying hippocampal size than other brain regions that are under greater genetic control. Considering the potential of environmental modification of this structure suggested by lower heritability, the hippocampus appears well-suited to support the dynamic processes of encoding and consolidation of new, declarataive memories.

    View details for Web of Science ID 000172988800016

    View details for PubMedID 11811670

  • Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia ARCHIVES OF GENERAL PSYCHIATRY Sullivan, E. V., Deshmukh, A., Desmond, J. E., Mathalon, D. H., Rosenbloom, M. J., Lim, K. O., Pfefferbaum, A. 2000; 57 (9): 894-902


    It is controversial whether cerebellar tissue volume deficits occur in schizophrenia and, if so, what regions and tissue types are affected. Complicating such investigations is the high incidence of alcoholism comorbidity in patients with schizophrenia that itself can contribute to cerebellar abnormalities.We studied 61 healthy men (control subjects), 25 men with alcoholism, 27 men with schizophrenia, and 19 men comorbid for schizophrenia and alcoholism with the use of magnetic resonance imaging. Cerebellar structures were outlined manually, tissue classification was determined statistically, and regional volumes were corrected for normal variation in head size and age.Patients with schizophrenia alone had enlarged fourth ventricles (1.5 SD relative to controls) but showed no cerebellar tissue volume deficits. The alcoholic group had gray and white matter vermian deficits (-0.5 SD), most prominent in anterior superior lobules, and gray matter hemisphere deficits (-0.8 SD), but not fourth ventricle enlargement. The comorbid group had cerebellar hemisphere (-1.3 SD) and vermian gray matter volume deficits (-0.7 SD) and fourth ventricular enlargement (1.6 SD); these abnormalities were greater than in either single-diagnosis group, despite significantly lower levels of alcohol consumption compared with the alcoholic group. Gray matter volume in the anterior superior vermis correlated with lifetime alcohol consumption in the schizophrenic and comorbid groups when combined.Cerebellar tissue volume deficits were detected in schizophrenia only when accompanied by alcoholism. By contrast, fourth ventricular enlargement occurred in schizophrenia even without alcoholism, although it was exacerbated by alcoholism. These findings support a model of cerebellar supersensitivity to alcohol-related tissue volume deficits in schizophrenia.

    View details for Web of Science ID 000089179500011

    View details for PubMedID 10986553

  • In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., SULLIVAN, E. V., Hedehus, M., Adalsteinsson, E., Lim, K. O., Moseley, M. 2000; 24 (8): 1214-1221


    Postmortem studies report degradation of brain white matter microstructure in chronic alcoholism, but until recently, in vivo neuroimaging could provide measurement only at a macrostructural level. The development of magnetic resonance diffusion tensor imaging (DTI) for clinical use offers a method for depicting and quantifying the diffusion properties of white matter expressed as intravoxel and intervoxel coherence of tracts and fibers.This study used DTI to examine the intravoxel coherence measured as fractional anisotropy (FA) and intervoxel coherence (C) of white matter tracts of the genu and splenium of the corpus callosum and of the centrum semiovale in 15 detoxified alcoholic men and 31 nonalcoholic control subjects. Exploratory correlational analyses examined the relationships between regional DTI measures and tests of attention and working memory in the alcoholic patients.The alcoholic group had lower regional FA than the control group. C was lower in the alcoholics than controls in the splenium only. Working memory correlated positively with splenium FA, whereas attention correlated positively with genu C.These results provide in vivo evidence for disruption of white matter microstructure in alcoholism and suggest that interruption of white matter fiber coherence contributes to disturbance in attention and working memory in chronic alcoholism.

    View details for Web of Science ID 000088831600012

    View details for PubMedID 10968660

  • Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., SULLIVAN, E. V., Hedehus, M., Lim, K. O., Adalsteinsson, E., Moseley, M. 2000; 44 (2): 259-268


    Echo planar (EP) diffusion tensor imaging (DTI) permits in vivo identification of the orientation and coherence of brain white matter tracts but suffers from field inhomogeneity-induced geometric distortion. To reduce spatial distortion, polynomial warping corrections were applied and the effects tested on measures of fractional anisotropy (FA) in the genu and splenium of corpus callosum. Implementation entailed spatially warping EP images obtained without diffusion weighting (b = 0) to long-echo T(2)-weighted fast spin echo images, collected for anatomical delineation, tissue segmentation, and coregistration with the diffusion images. Using the optimal warping procedure (third-order polynomial), the effects of age on FA and a quantitative measure of intervoxel coherence (C) in the genu, splenium, centrum semiovale, and frontal and parietal pericallosal white matter were examined in 31 healthy men (23-76 years). FA declined significantly with age in all regions except the splenium, whereas intervoxel coherence positively correlated with age in the genu. Magn Reson Med 44:259-268, 2000.

    View details for Web of Science ID 000088545600013

    View details for PubMedID 10918325

  • Cerebellar volume decline in normal aging, alcoholism, and Korsakoff's syndrome: Relation to ataxia 6th International Congress on Schizophrenia Research SULLIVAN, E. V., Deshmukh, A., Desmond, J. E., Lim, K. O., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2000: 341–52


    The authors used magnetic resonance imaging to measure gray and white matter volumes in cerebellar hemispheres and 4 vermian regions in 61 normal control (NC) men aged 23-72 years, 25 men with uncomplicated alcoholism (ALC), and 8 men and 1 woman with alcoholic Korsakoff s syndrome (KS). NC and ALC took quantitative gait and balance tests. Gray but not white matter volume declined with normal age in both hemispheres and anterior-superior vermis. ALC had gray but not white matter cerebellar hemisphere volume deficits, whereas KS had deficits in both tissue types. ALC and KS had gray and white matter volume deficits in anterior superior but not posterior inferior vermis. ALC had a 1 SD ataxia deficit, significantly and selectively correlated with white matter volume in anterior superior vermis. Regional distribution but not severity of cerebellar volume deficits is similar in alcoholic individuals whether or not complicated by KS and relates to ataxia.

    View details for Web of Science ID 000088253400002

    View details for PubMedID 10928737

  • Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer's disease LANCET Adalsteinsson, E., SULLIVAN, E. V., Kleinhans, N., Spielman, D. M., Pfefferbaum, A. 2000; 355 (9216): 1696-1697


    In patients with Alzheimer's disease, but not in health controls, longitudinal magnetic resonance spectroscopy shows a striking decline in the neuronal marker, N-acetyl aspartate, despite little decline in underlying grey-matter volume.

    View details for Web of Science ID 000086983800017

    View details for PubMedID 10905250

  • Pattern of motor and cognitive deficits in detoxified alcoholic men ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Sullivan, E. V., Rosenbloom, M. J., Pfefferbaum, A. 2000; 24 (5): 611-621


    Chronic excessive consumption of alcohol produces marked deficits in cognitive and motor abilities, although not all functions are affected to the same extent. Furthermore, although the occurrence of neuropsychological deficits in recently detoxified alcoholics is firmly established, the relative severity of these deficits, the specific neural systems that underlie the deficits, and their relationship to age and alcohol consumption variables either are less established or have proven elusive altogether.We administered an extensive battery of neuropsychological tests, chosen for their known sensitivity to brain lesions in specific locations, to 71 recently (1 month) detoxified alcoholic men and 74 healthy controls who spanned the adult age range. Test scores were standardized to the controls for age and grouped a priori into composites that reflected performance in six functional domains: executive functions, short-term memory, upper limb motor ability, declarative memory, visuospatial abilities, and gait and balance. Analogous verbal and nonverbal materials and left- and right-hand upper limb motor tasks were used to test whether alcohol-related deficits were greater for left or right hemisphere.Compared with controls, the alcoholics were impaired on executive functions, visuospatial abilities, and gait and balance even after we accounted for group differences in estimated premorbid IQ and education. Within the alcoholic group, the most salient deficits were in gait and balance and visuospatial abilities. No consistent lateralized deficit was observed across the four domains tested. Unlike the cognitive composites, the upper limb motor ability and gait and balance composites both showed increasing vulnerability to age, with an independent contribution to the gait and balance dysfunction from the amount of alcohol consumed over a lifetime.The pattern of functional deficits implicates at least two principal neural systems: the cerebellar-frontal system and the corticocortical system between the prefrontal and parietal cortices. In addition, age and amount of alcohol consumption were better predictors of motor than cognitive impairments.

    View details for Web of Science ID 000087216000005

    View details for PubMedID 10832902

  • Extent, pattern, and correlates of remote memory impairment in Alzheimer's disease and Parkinson's disease Annual Meeting of the International-Neuropsychological-Society Fama, R., Sullivan, E. V., Shear, P. K., Stein, M., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2000: 265–76


    Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.

    View details for DOI 10.1037//0894-4105.14.2.265

    View details for Web of Science ID 000087480700010

    View details for PubMedID 10791866

  • Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: Relationships to changes in brain structure NEUROPSYCHOLOGY Sullivan, E. V., Rosenbloom, M. J., Lim, K. O., Pfefferbaum, A. 2000; 14 (2): 178-188


    Chronic alcoholism is associated with cognitive and motor deficits, and there is evidence for reversibility with sobriety. Alcoholic men were examined after 1 month of sobriety and 2 to 12 months later with cognitive and motor tests and magnetic resonance imaging. In this naturalistic study, 20 alcoholic participants had abstained and 22 had resumed drinking at retesting. Abstainers sustained greater improvement than relapsers on tests of delayed recall of drawings, visuospatial function, attention, gait, and balance. Shrinkage in 3rd ventricle volume across all participants significantly correlated with improvement in nonverbal short-term memory. Additional brain structure-function relationships, most involving short-term memory, were observed when analyses were restricted to alcoholic men who had maintained complete abstinence, were light relapsers for at least 3 months, or had consumed no more than 10 drinks prior to follow-up testing. Thus, alcoholic men who maintain abstinence can show substantial functional improvement that is related to improvement in brain structure condition.

    View details for DOI 10.1037//0894-4105.14.2.178

    View details for Web of Science ID 000087480700002

    View details for PubMedID 10791858

  • Sniffing longer rather than stronger to maintain olfactory detection threshold CHEMICAL SENSES Sobel, N., Khan, R. M., Hartley, C. A., SULLIVAN, E. V., Gabrieli, J. D. 2000; 25 (1): 1-8


    Air flow-rate is usually higher in one nostril in comparison to the other. Also, within bounds, higher nasal flow-rate improves odorant detection. It follows from the above that odorant detection should be better in the nostril with higher flow-rate in comparison to the nostril with lower flow-rate. Paradoxically, previous research has shown that odorant detection thresholds are equal for the high and low flow-rate nostrils. Here we resolve this apparent paradox by showing that when detecting through the nostril with lower air flow-rate, humans sniffed longer than when detecting through the nostril with higher air flow-rate, thus equalizing performance between the nostrils. When this compensatory mechanism was blocked, a pronounced advantage in odorant detection was seen for the nostril with higher air flow-rate over the nostril with lower air flow-rate. Finally, we show that normal birhinal sniff duration may enable only one nostril to reach optimal threshold. This finding implies that during each sniff, each nostril conveys to the brain a slightly different image of the olfactory world. It remains to be shown how the brain combines these images into a single olfactory percept.

    View details for Web of Science ID 000085401200001

    View details for PubMedID 10667988

  • alpha 2 macroglobulin and the risk of Alzheimer's disease NEUROLOGY Dodel, R. C., Du, Y., Bales, K. R., Gao, F., Eastwood, B., Glazier, B., Zimmer, R., Cordell, B., Hake, A., Evans, R., Gallagher-Thompson, D., Thompson, L. W., Tinklenberg, J. R., Pfefferbaum, A., SULLIVAN, E. V., Yesavage, J., Altstiel, L., Gasser, T., Farlow, M. R., Murphy, G. M., Paul, S. M. 2000; 54 (2): 438-442


    alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56).We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism.We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors.Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

    View details for Web of Science ID 000085043800030

    View details for PubMedID 10668709

  • Time course of odorant-induced activation in the human primary olfactory cortex JOURNAL OF NEUROPHYSIOLOGY Sobel, N., Prabhakaran, V., Zhao, Z., Desmond, J. E., Glover, G. H., SULLIVAN, E. V., Gabrieli, J. D. 2000; 83 (1): 537-551


    Paradoxically, attempts to visualize odorant-induced functional magnetic resonance imaging (fMRI) activation in the human have yielded activations in secondary olfactory regions but not in the primary olfactory cortex-piriform cortex. We show that odorant-induced activation in primary olfactory cortex was not previously made evident with fMRI because of the unique time course of activity in this region: in primary olfactory cortex, odorants induced a strong early transient increase in signal amplitude that then habituated within 30-40 s of odorant presence. This time course of activation seen here in the primary olfactory cortex of the human is almost identical to that recorded electrophysiologically in the piriform cortex of the rat. Mapping activation with analyses that are sensitive to both this transient increase in signal amplitude, and temporal-variance, enabled us to use fMRI to consistently visualize odorant-induced activation in the human primary olfactory cortex. The combination of continued accurate odorant detection at the behavioral level despite primary olfactory cortex habituation at the physiological level suggests that the functional neuroanatomy of the olfactory response may change throughout prolonged olfactory stimulation.

    View details for Web of Science ID 000084777800048

    View details for PubMedID 10634894

  • Structural brain correlates of verbal and nonverbal fluency measures in Alzheimer's disease 26th Annual Meeting of the International-Neuropsychological-Society Fama, R., Sullivan, E. V., Shear, P. K., Cahn-Weiner, D. A., Marsh, L., Lim, K. O., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. AMER PSYCHOLOGICAL ASSOC. 2000: 29–40


    This study examined the relationships between regional brain volumes and semantic, phonological, and nonverbal fluency in 32 participants with Alzheimer's disease (AD). Object but not animal semantic fluency correlated with frontal and temporal gray matter volumes. Phonological fluency was not significantly associated with any brain volume examined. Nonverbal fluency was selectively associated with bilateral frontal gray matter volumes. Hippocampal volumes, although markedly reduced in these patients, were not related to any of the fluency measures. Results lend evidence to the importance of the frontal lobes in the directed generation of nonverbal and verbal exemplars by AD patients. Furthermore, both left- and right-hemisphere regions contribute to the generation of verbal and nonverbal exemplars.

    View details for Web of Science ID 000085020000003

    View details for PubMedID 10674796

  • Brain structure in men remains highly heritable in the seventh and eighth decades of life NEUROBIOLOGY OF AGING Pfefferbaum, A., SULLIVAN, E. V., Swan, G. E., Carmelli, D. 2000; 21 (1): 63-74


    The midsagittal cross-sectional dimensions of the corpus callosum, the coronal cross-sectional area of the lateral ventricles at the level of the pons, and a three-dimensional estimate of intracranial volume were derived from magnetic resonance brain images obtained from 45 monozygotic and 40 dizygotic male twin pairs aged 68 to 78. Univariate genetic analyses indicated strong genetic influences contributing significantly to the variability of each brain structure. The estimated proportion of genetic variance (i.e. heritability) was 81% for intracranial volume, 79% for the midline cross-sectional area of the corpus callosum, and 79% for lateral ventricle size. There was no evidence that shared environmental influences contributed significantly to twin-pair similarities. We further used bivariate genetic modeling to estimate the genetic and environmental correlation between correlated brain structures. Intracranial volume and corpus callosum area was highly correlated, and this relationship was entirely due to shared genetic effects between these two brain structures. By contrast, the relationship between the height of the corpus callosum and the size of the lateral ventricles was due to both genetic and environmental influences in common. Corresponding genetic and environmental correlations were 0.68 and 0.58, respectively, indicating that more than half of the genetic and environmental influences on these two brain structures were shared. The manner in which the brain responds to the environment with advancing age is highly genetically determined, both for the lateral ventricles, which dilate with aging and disease, and for the corpus callosum, which is deformed in shape by age-related ventricular enlargement, whereas its midline cross-sectional area remains unchanged.

    View details for Web of Science ID 000086931500009

    View details for PubMedID 10794850

  • Cortical gray matter deficit in patients with bipolar disorder SCHIZOPHRENIA RESEARCH Lim, K. O., Rosenbloom, M. J., Faustman, W. O., SULLIVAN, E. V., Pfefferbaum, A. 1999; 40 (3): 219-227


    cortical gray matter volume deficit and ventricular enlargement are well documented in schizophrenia, but their presence in bipolar disorder is less well cortical gray matter, white matter and sulcal CSF, as well as lateral and third ventricular volume measures, were derived from axial MRI brain images obtained on age-matched bipolar (n=9), schizophrenic (n=9), and control (n=16) subjects. All subjects were free of history of alcohol or other substance dependence.relative to controls, bipolar patients had widespread volume deficits of cortical gray matter but not of cortical white matter. Schizophrenic patients had an even more severe cortical gray matter deficit and greater sulcal and lateral ventricular enlargement than the bipolar patients.this group of patients with bipolar disorder had a widespread deficit of cortical gray matter similar to, but less pronounced than, that observed in patients with schizophrenia.

    View details for Web of Science ID 000084023000006

    View details for PubMedID 10638860

  • Olfaction - The world smells different to each nostril NATURE Sobel, N., Khan, R. M., Saltman, A., SULLIVAN, E. V., Gabrieli, J. D. 1999; 402 (6757): 35-35

    View details for Web of Science ID 000083638600032

    View details for PubMedID 10573415

  • In vivo mammillary body volume deficits in amnesic and nonamnesic alcoholics ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V., Lane, B., Deshmukh, A., Rosenbloom, M. J., Desmond, J. E., Lim, K. O., Pfeferbaum, A. 1999; 23 (10): 1629-1636


    Neuropathological studies use the presence of mammillary body (MB) pathology as a cardinal, diagnostic feature of Wernicke's encephalopathy (WE) in neuropsychiatric diseases, most notably alcoholism. Although Korsakoffs Syndrome (KS), which is marked behaviorally by dense global amnesia, is a typical sequela of WE, it remains controversial whether these two conditions necessarily co-occur and whether MB pathology is therefore a diagnostic requisite for KS.We investigated these issues by examining, in vivo, 24 nonamnesic alcoholics (ALC), 5 amnesic alcoholics (KS), and 51 normal controls with three-dimensional MRI and memory testing. MB volume was determined from successive, 1 mm thick slices.The ALC group had significantly smaller MB volumes bilaterally (mean = 54.5 +/- 22.0 mm3) than controls (mean = 66.3 +/- 17.1 mm3), and the KS group had even smaller MB volumes than the ALC group (mean = 20.7 +/- 14.8 mm3). Only 2 ALC patients met historical clinical criteria for past WE, and their MB volumes were well within range of the remaining 22 ALC patients. Although all five KS patients met historical clinical criteria for WE, three KS did not have accompanying dementia and had the same degree of MB volume loss as the ALC; the remaining two KS had accompanying dementia and MB volumes half the volume of the ALC group and of KS patients without dementia.These findings provide volumetric in vivo evidence that: (1) MB volume deficits do occur in alcoholics without amnesia, although these deficits are not present in ail such alcoholics; (2) greater MB volume deficits are present in alcoholics with clinically detectable amnesia or dementia; (3) MB shrinkage is related to severity of cognitive and memory dysfunction, which suggests a continuum of MB pathology in chronic alcoholism to KS; and (4) the presence of WE in all of the KS patients and in the two ALC patients with the greatest long-term declarative memory deficit supports the possibility of an additional and unique pathology distinguishing nonamnesic and amnesic alcoholism.

    View details for Web of Science ID 000083279500011

    View details for PubMedID 10549995

  • Brain structural and cognitive correlates of clock drawing performance in Alzheimer's disease 26th Annual Meeting of the International-Neuropsychological-Society Cahn-Weiner, D. A., SULLIVAN, E. V., Shear, P. K., Fama, R., Lim, K. O., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. CAMBRIDGE UNIV PRESS. 1999: 502–9


    The Clock Drawing Test (CDT) is widely used in the assessment of dementia and is known to be sensitive to the detection of deficits in neurodegenerative disorders such as Alzheimer's disease (AD). CDT performance is dependent not only on visuospatial and constructional abilities, but also on conceptual and executive functioning; therefore, it is likely to be mediated by multiple brain regions. The purpose of the present study was to identify component cognitive processes and regional cortical volumes that contribute to CDT performance in AD. In 29 patients with probable AD, CDT performance was significantly related to right-, but not left-hemisphere, regional gray matter volume. Specifically, CDT score correlated significantly with the right anterior and posterior superior temporal lobe volumes. CDT scores showed significant relationships with tests of semantic knowledge, executive function, and visuoconstruction, and receptive language. These results suggest that in AD patients, CDT performance is attributable to impairment in multiple cognitive domains but is related specifically to regional volume loss of right temporal cortex.

    View details for Web of Science ID 000083339700003

    View details for PubMedID 10561930

  • Brain gray and white matter transverse relaxation time in schizophrenia 7th International Congress on Schizophrenia Research Pfefferbaum, A., SULLIVAN, E. V., Hedehus, M., Moseley, M., Lim, K. O. ELSEVIER IRELAND LTD. 1999: 93–100


    Recent in vivo diffusion brain imaging studies of schizophrenic patients have revealed microstructural abnormalities, with low diffusion anisotropy present throughout much of cortical white matter. Brain anisotropy is produced when proton movement reflects physically restricted water movement, for example, by myelin sheaths. Conditions that increase self-diffusion, such as edema, may also alter the longitudinal and transverse relaxation time of protons, and it is possible that such changes could explain the observed anisotropy diminution seen in schizophrenia. To test this possibility, we calculated pixel-by-pixel transverse relaxation time (T2) and proton density (PD) maps for gray matter and white matter across eight 5-mm-thick axial slices of fast spin echo MRI in 10 control men (age 30-57 years) and 10 men with schizophrenia (age 32-64 years). Schizophrenics had significantly longer mean white matter T2 (84.0 vs. 81.9 ms, P<0.03) and gray matter T2 (95.1 vs. 92.2, P = 0.003); their mean white and gray matter PD values were not significantly different from those of controls. Correlations were not significant between anisotropy and T2 in either grey or white matter but were significant between anisotropy and PD in white matter. T2 relaxation times are longer in schizophrenics than in controls in both gray and white matter whereas anisotropy reduction is restricted to white matter. Taken together, these results suggest that the process producing prolonged T2 does not fully account for the abnormally low anisotropy observed selectively in white matter in this group of schizophrenic patients.

    View details for Web of Science ID 000082888500003

    View details for PubMedID 10515464

  • Compromised white matter tract integrity in schizophrenia inferred from diffusion tensor imaging ARCHIVES OF GENERAL PSYCHIATRY Lim, K. O., Hedehus, M., Moseley, M., de Crespigny, A., SULLIVAN, E. V., Pfefferbaum, A. 1999; 56 (4): 367-374


    Current investigations suggest that brain white matter may be qualitatively altered in schizophrenia even in the face of normal white matter volume. Diffusion tensor imaging provides a new approach for quantifying the directional coherence and possibly connectivity of white matter fibers in vivo.Ten men who were veterans of the US Armed Forces and met the DSM-IV criteria for schizophrenia and 10 healthy, age-matched control men were scanned using magnetic resonance diffusion tensor imaging and magnetic resonance structural imaging.Relative to controls, the patients with schizophrenia exhibited lower anisotropy in white matter, despite absence of a white matter volume deficit. In contrast to the white matter pattern, gray matter anisotropy did not distinguish the groups, even though the patients with schizophrenia had a significant gray matter volume deficit. The abnormal white matter anisotropy in patients with schizophrenia was present in both hemispheres and was widespread, extending from the frontal to occipital brain regions.Despite the small sample size, diffusion tensor imaging was powerful enough to yield significant group differences, indicating widespread alteration in brain white matter integrity but not necessarily white matter volume in schizophrenia.

    View details for Web of Science ID 000079504400011

    View details for PubMedID 10197834

  • In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: Effects of normal aging MAGNETIC RESONANCE IN MEDICINE Pfefferbaum, A., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Lim, K. O. 1999; 41 (2): 276-284


    Volumetric proton magnetic resonance spectroscopic imaging (MRSI) was used to generate brain metabolite maps in 15 young and 19 elderly adult volunteers. All subjects also had structural MR scans, and a model, which took into account the underlying structural composition of the brain contributing to each metabolite voxel, was developed and used to estimate the concentration of the N-acetyl-moiety (NAc), creatine (Cr), and choline (Cho) in gray matter and white matter. NAc concentration (signal intensity per unit volume of brain) was higher in gray than white matter and did not differ between young and old subjects despite significant gray matter volume deficits in the older subjects. To the extent that NAc is an index of neuronal integrity, the available gray matter appears to be intact in these older healthy adults. Cr concentrations were much higher in gray than white matter and significantly higher in the old than young subjects. Cho concentration in gray matter was also significantly higher in old than young subjects. Independent determination of metabolite values rather than use of ratios is essential for characterizing age-related changes in brain MRS metabolites.

    View details for Web of Science ID 000078804500010

    View details for PubMedID 10080274

  • In vivo brain concentrations of N-acetyl compounds, creatine, and choline in Alzheimer disease ARCHIVES OF GENERAL PSYCHIATRY Pfefferbaum, A., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Lim, K. O. 1999; 56 (2): 185-192


    Alzheimer disease (AD) and normal aging result in cortical gray matter volume deficits. The extent to which the remaining cortex is functionally compromised can be estimated in vivo with magnetic resonance spectroscopic imaging.To assess the effects of age and dementia on gray matter and white matter concentrations of 3 metabolites visible in the proton spectrum: N-acetyl compounds, present only in living neurons; creatine plus phosphocreatine, reflecting high-energy phosphate metabolism; and choline, increasing with membrane synthesis and degradation.Fifteen healthy young individuals, 19 healthy elderly individuals, and 16 patients with AD underwent 3-dimensional magnetic resonance spectroscopic imaging and memory and language testing.Gray matter N-acetyl compound concentrations (signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal) was significantly reduced only in patients with AD, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young control group. Both the healthy elderly and AD groups had abnormally high gray matter creatine plus phosphocreatine concentrations. Gray matter choline concentrations were higher in the elderly than the younger controls, and even higher in the AD group than in the elderly control group. Functional significance of these findings was supported by correlations between poorer performance on recognition memory tests and lower gray matter N-acetyl compounds in elderly controls and higher gray matter creatine plus phosphocreatine and choline concentrations in patients with AD.Cortical gray matter volume deficits in patients with AD are accompanied by disease-related increases in gray matter choline concentrations suggestive of cellular degeneration and reduced N-acetyl compound concentrations, with possible effects on behavioral function.

    View details for Web of Science ID 000078553600010

    View details for PubMedID 10025444

  • Blind smell: brain activation induced by an undetected air-borne chemical BRAIN Sobel, N., Prabhakaran, V., Hartley, C. A., Desmond, J. E., Glover, G. H., SULLIVAN, E. V., Gabrieli, J. D. 1999; 122: 209-217


    EEG and behavioural evidence suggests that air-borne chemicals can affect the nervous system without being consciously detected. EEG and behaviour, however, do not specify which brain structures are involved in chemical sensing that occurs below a threshold of conscious detection. Here we used functional MRI to localize brain activation induced by high and low concentrations of the air-borne compound oestra-1,3,5(10),16-tetraen-3yl acetate. Following presentations of both concentrations, eight of eight subjects reported verbally that they could not detect any odour (P = 0.004). Forced choice detection performed during the presentations revealed above-chance detection of the high concentration, but no better than chance detection of the low concentration compound. Both concentrations induced significant brain activation, primarily in the anterior medial thalamus and inferior frontal gyrus. Activation in the inferior frontal gyrus during the high concentration condition was significantly greater in the right than in the left hemisphere (P = 0.03). A trend towards greater thalamic activation was observed for the high concentration than the low concentration compound (P = 0.08). These findings localize human brain activation that was induced by an undetectable air-borne chemical (the low concentration compound).

    View details for Web of Science ID 000078756900005

    View details for PubMedID 10071050

  • Severity of schizophrenia and magnetic resonance imaging abnormalities: A comparison of state and veterans hospital patients 6th International Congress on Schizophrenia Research Marsh, L., Lim, K. O., Hoff, A. L., Harris, D., Beal, M., Minn, K., Faustman, W. O., Csernansky, J. G., SULLIVAN, E. V., Pfefferbaum, A. ELSEVIER SCIENCE INC. 1999: 49–61


    The relationship between illness severity and neuroanatomical abnormalities in schizophrenia remains unclear. The purpose of this study was to test whether the pattern and extent of brain volume abnormalities differed between two patient groups, distinguished by their overall severity and clinical course of schizophrenia.Subjects were 56 severely ill, chronically hospitalized schizophrenic men from Napa State Hospital (SH-SZ), 44 moderately ill, acutely hospitalized schizophrenic men from the Palo Alto Veterans Administration Health Care System (VA-SZ), and 52 healthy male control subjects. Temporolimbic, ventricular, and frontoparietal volumes, quantified from 3-mm coronal spin-echo magnetic resonance images and adjusted for cerebral volume and age, were compared using analysis of variance.Compared to control subjects, both SZ groups had smaller (p < .05) temporal lobe and frontoparietal gray matter volumes and larger ventricles and temporal sulci. Whereas SH-SZ had more pronounced cerebrospinal fluid and frontoparietal abnormalities relative to VA-SZ; VA-SZ had greater temporal lobe gray matter deficits. Neither patients group had hippocampal or cerebral volume deficits relative to control subjects. There were no differences between diagnostic subtypes.The magnitude of volume abnormalities in schizophrenia varies with respect to disease severity and to brain region, but disease severity is not associated with anatomically distinct subgroups.

    View details for Web of Science ID 000077967900006

    View details for PubMedID 9894575

  • Fluency performance patterns in Alzheimer's disease and Parkinson's disease CLINICAL NEUROPSYCHOLOGIST Fama, R., Sullivan, E. V., Shear, P. K., Cahn-Weiner, D. A., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. 1998; 12 (4): 487-499
  • Odorant-induced and sniff-induced activation in the cerebellum of the human JOURNAL OF NEUROSCIENCE Sobel, N., Prabhakaran, V., Hartley, C. A., Desmond, J. E., Zhao, Z., Glover, G. H., Gabrieli, J. D., SULLIVAN, E. V. 1998; 18 (21): 8990-9001


    Functional magnetic resonance imaging was used to test whether odorants induce activation in the cerebellum of the human. The odorants vanillin and propionic acid both induced significant activation, primarily in the posterior lateral hemispheres. Activation was concentration-dependent, greater after stimulation with higher concentration odorants. By contrast, the action of sniffing nonodorized air induced significant activation in the anterior cerebellum, primarily in the central lobule. These findings demonstrate that the cerebellum plays a role in human olfaction. A hypothesis is proposed whereby the cerebellum maintains a feedback mechanism that regulates sniff volume in relation to odor concentration.

    View details for Web of Science ID 000076616600042

    View details for PubMedID 9787004

  • Differential contributions of cognitive and motor component processes to physical and instrumental activities of daily living in Parkinson's disease ARCHIVES OF CLINICAL NEUROPSYCHOLOGY Cahn, D. A., SULLIVAN, E. V., Shear, P. K., Pfefferbaum, A., Heit, G., Silverberg, G. 1998; 13 (7): 575-583


    Patients with Parkinson's disease (PD) become dependent upon caregivers because motor and cognitive disabilities interfere with their ability to carry out activities of daily living (ADLs). However, PD patients display diverse motor and cognitive symptoms, and it is not yet known which are most responsible for ADL dysfunction. The purpose of this study was to identify the contributions that specific cognitive and motor functions make to ADLs. Executive functioning, in particular sequencing, was a significant independent predictor of instrumental ADLs whereas simple motor functioning was not. By contrast, simple motor functioning, but not executive functioning, was a significant independent predictor of physical ADLs. Dementia severity, as measured by the Dementia Rating Scale, was significantly correlated with instrumental but not physical ADLs. The identification of selective relationships between motor and cognitive functioning and ADLs may ultimately provide a model for evaluating the benefits and limitations of different treatments for PD.

    View details for Web of Science ID 000075851200001

    View details for PubMedID 14590618

  • A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval Annual Meeting of the Research-Society-on-Alcoholism Pfefferbaum, A., SULLIVAN, E. V., Rosenbloom, M. J., Mathalon, H., Lim, K. O. AMER MEDICAL ASSOC. 1998: 905–12


    We report on structural brain changes during a 5-year period in healthy control and alcoholic men.Alcoholic patients (n = 16), from an initial group of 58 who underwent brain magnetic resonance imaging scanning while in treatment, were rescanned with the same acquisition sequence approximately 5 years later. Control subjects (n = 28) spanning the same age range also were scanned twice at a comparable interval. Changes in brain volume were corrected for error due to differences in head placement between scans and expressed as slopes (cubic centimeters per year), percentage of change over baseline for the control subjects, and standardized change for the alcoholic patients. The alcoholic patients varied considerably in the percentage of time that symptoms of alcohol dependence were present and in the amount of alcohol consumed during follow-up.The cortical gray matter diminished in volume over time in the control subjects, most prominently in the prefrontal cortex, while the lateral and third ventricles enlarged. The alcoholic patients showed similar age-related changes with a greater rate of gray matter volume loss than the control subjects in the anterior superior temporal lobe. The amount of alcohol consumed during follow-up predicted the rate of cortical gray matter volume loss, as well as sulcal expansion. The rate of ventricular enlargement in alcoholic patients who maintained virtual sobriety was comparable to that in the control subjects.During a 5-year period, brain volume shrinkage is exaggerated in the prefrontal cortex in normal aging with additional loss in the anterior superior temporal cortex in alcoholism. The association of cortical gray matter volume reduction with alcohol consumption over time suggests that continued alcohol abuse results in progressive brain tissue volume shrinkage.

    View details for Web of Science ID 000076415500008

    View details for PubMedID 9783561

  • Neuropsychological and motor functioning after unilateral anatomically guided posterior ventral pallidotomy - Preoperative performance and three-month follow-up NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY Cahn, D. A., SULLIVAN, E. V., Shear, P. K., Heit, G., Lim, K. O., Marsh, L., Lane, B., Wasserstein, P., Silverberg, G. D. 1998; 11 (3): 136-145


    This study presents baseline and 3-month follow-up motor and neuropsychological data for 22 patients with Parkinson's disease (PD) who underwent anatomically guided unilateral posterior ventral pallidotomy (PVP). Postsurgical improvements were seen in psychomotor speed, fine motor accuracy, and dyskinesia, whereas grip strength decreased on the side contralateral to the surgery. No change was detected in overall level of cognitive functioning, nor were changes demonstrated in memory, language, or working memory when the entire sample of patients was evaluated. When the group was divided on the basis of side of surgery, patients with left-sided pallidotomies showed a decline in verbal fluency. Patients and caregivers reported improvement in psychosocial functioning. These initial findings of improved motor performance and largely unaffected cognitive functions are consistent with results obtained with functional PVP and provide support for the use of anatomically guided posterior ventral pallidotomy in the treatment of motor symptoms of PD.

    View details for Web of Science ID 000078976500004

    View details for PubMedID 9742512

  • Association between regional brain volumes and clozapine response in schizophrenia BIOLOGICAL PSYCHIATRY Lauriello, J., Mathalon, D. H., Rosenbloom, M., SULLIVAN, E. V., Faustman, W. O., Ringo, D. L., Lim, K. O., Pfefferbaum, A. 1998; 43 (12): 879-886


    Clozapine has shown considerable therapeutic promise in the treatment of schizophrenia; however, the clinical risks and initial high treatment costs associated with its administration motivate the search to identify patients who will best respond. Neuroimaging studies have suggested that prefrontal sulcal prominence may be a predictor of nonresponsiveness.We used magnetic resonance imaging (MRI) to test whether volumes in any cortical regions of the brain were associated with symptom improvement with clozapine treatment. The 21 schizophrenic men studied were clinically evaluated during treatment with typical neuroleptics (baseline) and after a mean of 6.2 months treatment with clozapine (final dose 300-900, median = 562 mg/day). At least a 20% improvement on total Brief Psychiatric Rating Scale (BPRS) was seen in 47.6% of the schizophrenics. Clinical improvement was regressed on baseline differences in clinical severity, and the residual scores were related to MRI values.Patients with larger anterior superior temporal lobe cerebrospinal fluid volumes (primarily sylvian fissure) showed greater improvement on total BPRS and withdrawal/retardation symptoms.Even schizophrenics with significant brain dysmorphology can have a positive clinical response to clozapine.

    View details for Web of Science ID 000074039800005

    View details for PubMedID 9627742

  • Proton magnetic resonance spectroscopic imaging of cortical gray and white matter in schizophrenia 6th International Congress on Schizophrenia Research Lim, K. O., Adalsteinsson, E., Spielman, D., SULLIVAN, E. V., Rosenbloom, M. J., Pfefferbaum, A. AMER MEDICAL ASSOC. 1998: 346–52


    To apply in vivo proton magnetic resonance spectroscopy imaging estimates of N-acetylaspartate (NAA), a neuronal marker, to clarify the relative contribution of neuronal and glial changes to the widespread volume deficit of cortical gray matter seen in patients with schizophrenia with magnetic resonance images.Ten male veterans meeting criteria of the DSM-IV, for schizophrenia and 9 healthy age-matched men for comparison were scanned using spectroscopic, anatomical, and field-map sequences. Instrument and collection variables were standardized to allow an estimation of comparable values for NAA, choline, and creatine for all subjects. Metabolite values from each voxel on 3 upper cortical slices were regressed against the gray tissue proportion of that voxel to derive estimates of gray and white matter NAA, creatine, and choline concentrations.The volume of cortical gray matter was reduced in patients with schizophrenia, but NAA signal intensity from a comparable region was normal. In contrast, the volume of cortical white matter was normal in patients with schizophrenia, but NAA signal intensity from a comparable region was reduced.The lack of reduction in gray matter NAA signal intensity suggests that the cortical gray matter deficit in these patients involved both neuronal and glial compartments rather than a neurodegenerative process in which there is a decrease in the neuronal relative to the glial compartment. Reduced white matter NAA signal intensity without a white matter volume deficit may reflect abnormal axonal connections.

    View details for Web of Science ID 000072993300009

    View details for PubMedID 9554430

  • Working and strategic memory deficits in schizophrenia NEUROPSYCHOLOGY Stone, M., Gabrieli, J. D., Stebbins, G. T., SULLIVAN, E. V. 1998; 12 (2): 278-288


    Working memory and its contribution to performance on strategic memory tests in schizophrenia were studied. Patients (n = 18) and control participants (n = 15), all men, received tests of immediate memory (forward digit span), working memory (listening, computation, and backward digit span), and long-term strategic (free recall, temporal order, and self-ordered pointing) and nonstrategic (recognition) memory. Schizophrenia patients performed worse on all tests. Education, verbal intelligence, and immediate memory capacity did not account for deficits in working memory in schizophrenia patients. Reduced working memory capacity accounted for group differences in strategic memory but not in recognition memory. Working memory impairment may be central to the profile of impaired cognitive performance in schizophrenia and is consistent with hypothesized frontal lobe dysfunction associated with this disease. Additional medial-temporal dysfunction may account for the recognition memory deficit.

    View details for Web of Science ID 000072725200011

    View details for PubMedID 9556774

  • Sniffing and smelling: separate subsystems in the human olfactory cortex NATURE Sobel, N., Prabhakaran, V., Desmond, J. E., Glover, G. H., Goode, R. L., SULLIVAN, E. V., Gabrieli, J. D. 1998; 392 (6673): 282-286


    The sensation and perception of smell (olfaction) are largely dependent on sniffing, which is an active stage of stimulus transport and therefore an integral component of mammalian olfaction. Electrophysiological data obtained from study of the hedgehog, rat, rabbit, dog and monkey indicate that sniffing (whether or not an odorant is present) induces an oscillation of activity in the olfactory bulb, driving the piriform cortex in the temporal lobe, in other words, the piriform is driven by the olfactory bulb at the frequency of sniffing. Here we use functional magnetic resonance imaging (fMRI) that is dependent on the level of oxygen in the blood to determine whether sniffing can induce activation in the piriform of humans, and whether this activation can be differentiated from activation induced by an odorant. We find that sniffing, whether odorant is present or absent, induces activation primarily in the piriform cortex of the temporal lobe and in the medial and posterior orbito-frontal gyri of the frontal lobe. The source of the sniff-induced activation is the somatosensory stimulation that is induced by air flow through the nostrils. In contrast, a smell, regardless of sniffing, induces activation mainly in the lateral and anterior orbito-frontal gyri of the frontal lobe. The dissociation between regions activated by olfactory exploration (sniffing) and regions activated by olfactory content (smell) shows a distinction in brain organization in terms of human olfaction.

    View details for Web of Science ID 000072612300047

    View details for PubMedID 9521322

  • Profile of cortical gray matter volume deficits characteristic of schizophrenia 51st Annual Meeting of the Society-of-Biological-Psychiatry SULLIVAN, E. V., Lim, K. O., Mathalon, D., Marsh, L., Beal, D. M., Harris, D., Hoff, A. L., Faustman, W. O., Pfefferbaum, A. OXFORD UNIV PRESS INC. 1998: 117–24


    Quantitative magnetic resonance imaging (MRI) studies from our laboratory have reported that patients with schizophrenia show a widespread cortical gray matter volume deficit, which is especially pronounced in the prefrontal and anterior superior temporal cortices. The present study compared two separate samples of schizophrenic patients -- 71 men from a Veterans Administration (VA) hospital and a sample of 57 severely ill men from a state hospital (SH) -- in an effort to test whether the pattern of brain volume abnormalities previously observed in VA schizophrenic patients can be generalized to other groups of schizophrenic patients. MRI-derived brain volumes of gray matter, white matter and sulcal cerebrospinal fluid (CSF) in six cortical regions, and CSF in the lateral and third ventricles were computed. All MRI volumes were adjusted for normal variation in head size and age and were expressed as standardized Z-scores, which also permitted structures of different sizes to be compared directly. The two schizophrenic groups displayed similar patterns of volume abnormalities: cortical gray matter but not white matter volume deficits that were widespread but especially notable in the prefrontal and temporal regions. The regional gray matter deficits in the SH group were generally greater than those in the VA group, particularly in the prefrontal and posterior superior temporal regions. Both schizophrenic groups had abnormally large volumes of the cortical sulci and lateral and third ventricles; however, the SH group showed greater enlargements, the most prominent occurring in the ventricles and temporal sulci. The overlapping patterns of cortical gray matter deficits in the two groups provide evidence for generality of this pattern of regional brain volume abnormalities in schizophrenia.

    View details for Web of Science ID 000072118300003

    View details for PubMedID 9542891

  • Structural MRI correlates of recognition memory in Alzheimer's disease JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Cahn, D. A., SULLIVAN, E. V., Shear, P. K., Marsh, L., Fama, R., Lim, K. O., Yesavage, J. A., Tinklenberg, J. R., Pfefferbaum, A. 1998; 4 (2): 106-114


    Neuroimaging and lesion studies have demonstrated that hippocampal volume correlates with memory performance, but material-specific lateralization of this structure-function relationship has been inconsistent. This MRI study examined the relative contributions of left and right temporal lobe volumes to verbal and nonverbal recognition memory in a group of 20 Alzheimer's disease (AD) patients. There was a significant relationship between extent of right hippocampal and right temporal gray matter tissue volume deficit and performance on the face recognition subtest of the Warrington Recognition Memory Test. The face recognition test correlated with right hemisphere volume but not to left, indicating a material-specific relationship between brain structure and function in this patient group. Right temporal horn volume did not account for a significant proportion of variance in face recognition memory. Although word recognition was not significantly correlated with either left or right hippocampal volume in the total group, there was a strong correlation between left hippocampal volume and word recognition memory in the female AD patients. Thus, face recognition shows a material specific relationship with select lateralized hippocampal and temporal cortical volumes in AD patients, regardless of gender, whereas the verbal recognition-left-hippocampal volume relationship may be mediated by gender.

    View details for Web of Science ID 000075146200002

    View details for PubMedID 9529820

  • Patterns of regional cortical dysmorphology distinguishing schizophrenia and chronic alcoholism 5th International Congress on Schizophrenia Research SULLIVAN, E. V., Mathalon, D. H., Lim, K. O., Marsh, L., Pfefferbaum, A. ELSEVIER SCIENCE INC. 1998: 118–31


    This study used magnetic resonance imaging (MRI) to compare the extent and pattern of tissue volume deficit and cerebrospinal fluid volume enlargement in chronic alcoholics and schizophrenics.The subjects included 62 detoxified chronic alcoholics (26-63 years), 71 schizophrenics (23-63 years), and 73 controls spanning the adult age range (21-70 years). MRI volumes were adjusted for normal variation in head size and age established from the control group.Both patient groups showed widespread cortical gray matter volume deficits compared with controls, but only the alcoholics had white matter volume deficits. The schizophrenics had significantly greater volume deficits in the prefrontal and anterior superior temporal gray matter than in the more posterior cortical regions. By contrast, the deficits in the alcoholics were relatively homogeneous across the cortex. For white matter, the deficits in the alcoholics were greatest in the prefrontal and temporal-parietal regions. Although both patient groups had abnormally larger cortical sulci and lateral and third ventricles than the controls, the alcoholics had significantly larger sulcal volumes in the frontal, anterior, and posterior parietal-occipital regions than the schizophrenics.This quantitative MRI study revealed different patterns of regional cortical volume abnormalities in schizophrenics and alcoholics. The schizophrenic group exhibited cortical gray matter volume deficits of modestly greater magnitude than that observed in the alcoholic group, and the alcoholics but not the schizophrenics exhibited cortical white matter volume deficits.

    View details for Web of Science ID 000072093000005

    View details for PubMedID 9474444

  • A method for functional magnetic resonance imaging of olfaction JOURNAL OF NEUROSCIENCE METHODS Sobel, N., Prabhakaran, V., Desmond, J. E., Glover, G. H., SULLIVAN, E. V., Gabrieli, J. D. 1997; 78 (1-2): 115-123


    A method for generating olfactory stimuli for humans within a functional magnetic resonance imaging (fMRI) experimental design is described. The system incorporates a nasal-mask in which the change from odorant to no-odorant conditions occurs in less than 500 ms and is not accompanied by visual, auditory, tactile, or thermal cues. The mask provides an ordorant-free environment following prolonged ordorant presence. Specific imaging parameters that are conducive to the study of the human olfactory system are described. In a pilot study performed using these methods, the specific patterns of activation observed converged with published experimental and clinical findings.

    View details for Web of Science ID 000071852900012

    View details for PubMedID 9497007

  • Structural magnetic resonance imaging abnormalities in men with severe chronic schizophrenia and an early age at clinical onset ARCHIVES OF GENERAL PSYCHIATRY Marsh, L., Harris, D., Lim, K. O., Beal, M., Hoff, A. L., Minn, K., Csernansky, J. G., DEMENT, S., Faustman, W. O., SULLIVAN, E. V., Pfefferbaum, A. 1997; 54 (12): 1104-1112


    Early age at onset of schizophrenia often signifies a more severe form of the illness. However, the relationship between age at onset and brain abnormalities has not been established. We assessed temporal-limbic morphometry in severely ill men with chronic schizophrenia who had a relatively early onset of illness and examined the relationships among regional brain volumes, clinical symptoms, and age at illness onset.Temporal lobe, superior temporal gyrus, hippocampus, temporal horn, lateral ventricles, third ventricle, and frontoparietal volumes were measured on magnetic resonance imaging data from 56 schizophrenic men (mean [SD] age at illness onset, 16.6 [4.2] years) recruited from a state hospital and 52 age- and range-matched healthy control men.Patients had significantly smaller gray matter volumes in the temporal lobe, superior temporal gyrus, and frontoparietal regions; smaller temporal lobe white matter volumes; and larger cerebrospinal fluid volumes for temporal lobe sulci and the 3 ventricular measures. There were no group differences in hippocampal volumes. Psychotic symptom subscores from the Brief Psychiatric Rating Scale were selectively correlated with smaller left posterior superior temporal gyrus gray matter volumes. None of the brain measurements were significantly correlated with age at illness onset.Data from this unique sample of severely ill schizophrenic men emphasize a pattern of structural abnormalities involving the cortex, but not the hippocampus, in schizophrenia. Furthermore, these data support theories suggesting that superior temporal gyrus abnormalities contribute selectively to psychotic symptoms and that the extent of structural abnormalities is unrelated to age of clinical symptom onset.

    View details for Web of Science ID A1997YJ96900006

    View details for PubMedID 9400346

  • Quantification of cerebellar structures with MRI PSYCHIATRY RESEARCH-NEUROIMAGING Deshmukh, A. R., Desmond, J. E., SULLIVAN, E. V., Lane, B. F., Lane, B., Matsumoto, B., Marsh, L., Lim, K. O., Pfefferbaum, A. 1997; 75 (3): 159-171


    Methodological issues have limited neuroimaging studies of cerebellar structures. In this article we describe a method that addresses some of these limitations and phantom studies that examine the validity of the image manipulations. We compared volumes derived from 3D Spoiled Gradient Recalled Acquisition MR images sliced with respect to three different alignment methods: one based on cerebellar landmarks, another on cerebral landmarks and a third on the plane of acquisition. Examination of coefficients of variation, coefficients of error and convergent validity suggests that although regional cerebellar volumes based on cerebellar landmarks provide the best estimates of the true volumes, observed differences between volume measurements from alignments based on cerebellar or cerebral landmarks were generally not significant and were inconsequential. In this case, the measure was improved with alignment along local, relevant cerebellar landmarks. A set of phantom experiments showed that realignment, reslicing and interpolation in 3-dimensional image processing exerted, at most, trivial distortion on the estimates of actual object volumes.

    View details for Web of Science ID 000071115400003

    View details for PubMedID 9437773

  • Deficits in multiple systems of working memory in schizophrenia SCHIZOPHRENIA RESEARCH Spindler, K. A., SULLIVAN, E. V., Menon, V., Lim, K. O., Pfefferbaum, A. 1997; 27 (1): 1-10


    Working memory, the ability to hold and manipulate information 'on-line' in a temporary memory store, is impaired in schizophrenia. This impairment may be characterized within the framework of two opposing theoretical models: (1) central executive as coordinator of component processes of working memory or (2) multiple independent systems of spatial and object memory. In order to test which of these models better explains the working memory deficit of schizophrenia, 14 schizophrenic patients and 12 age- and gender-matched control subjects performed tests of spatial memory (dot location), object memory (shapes, color dots) and a dual paradigm (dot location + shapes). If schizophrenia impairs the central executive, a group-by-task interaction would demonstrate excessively worse performance on the dual than single tasks in schizophrenics relative to controls; however, the absence of an interaction would be consistent with deficits in the multiple working memory systems. The schizophrenic group was significantly impaired on all measures, and both the schizophrenic and control performance was worse on the dual than the single tasks. Despite the schizophrenic group performance deficits on the single tasks, the extent of such deficit did not appear additive and contributive to the dual tasks. The lack of a group-by-task interaction provided no support for the central executive model of dysfunction. Rather, the results uphold the model of working memory deficits arising from compromise of multiple (here spatial and object), relatively independent systems, both of which are affected in schizophrenia.

    View details for Web of Science ID A1997YD36900001

    View details for PubMedID 9373889

  • Similar extent of brain dysmorphology in severely ill women and men with schizophrenia 5th International Congress of Schizophrenia Research Lauriello, J., Hoff, A., Wieneke, M. H., Blankfeld, H., Faustman, W. O., Rosenbloom, M., DEMENT, S., SULLIVAN, E. V., Lim, K. O., Pfefferbaum, A. AMER PSYCHIATRIC PUBLISHING, INC. 1997: 819–25


    The purpose of this study was to determine whether women with chronic, severe schizophrenia manifest a widespread deficit in cortical gray matter and ventricular enlargement similar to that seen in men with schizophrenia and whether this deficit is related to age at onset of illness, length of illness, or current illness severity.Volumetric measures of head size, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of chronic inpatient schizophrenic women (N = 19) and men (N = 18) and healthy comparison women (N = 19) and men (N = 18). Sex and group differences were assessed by using a two-factor analysis of variance of brain measures. Age was entered as a covariate in assessments of associations between brain measures and age at onset and length of illness.The schizophrenic patients as a group had less cortical gray matter but comparable white matter and significantly more lateral and third ventricular CSF than the comparison group. Compared to the combined groups of men, women, regardless of diagnosis, had smaller heads, less cortical gray and white matter, and less sulcal, lateral, and third ventricular CSF. There were no group-by-sex interactions, suggesting that in schizophrenia these aspects of gross volumetric morphology in male and female brains are affected equally. There was no relationship between cortical gray matter deficit or ventricular enlargements and age at symptom onset or length of illness in either men or women with schizophrenia, when variance due to age was accounted for statistically.The process that contributes to cortical gray matter deficit in schizophrenia appears to affect men and women to a similar extent.

    View details for Web of Science ID A1997XA58700015

    View details for PubMedID 9167510

  • Selective cortical and hippocampal volume correlates of Mattis Dementia Rating Scale in Alzheimer disease Annual Meeting of the International-Neuropsychological-Society Fama, R., SULLIVAN, E. V., Shear, P. K., Marsh, L., Yesavage, J. A., Tinklenberg, J. R., Lim, K. O., Pfefferbaum, A. AMER MEDICAL ASSOC. 1997: 719–28


    To examine whether each of the 5 Mattis Dementia Rating Scale (DRS) scores related to magnetic resonance imaging-derived volumes of specific cortical or limbic brain regions in patients with Alzheimer disease (AD).Relations between DRS measures and regional brain volume measures were tested with bivariate and multivariate regression analyses.The Aging Clinical Research Center of the Stanford (Calif) University Department of Psychiatry and Behavioral Science and the Geriatric Psychiatry Rehabilitation Unit of the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif.Fifty patients with possible or probable AD. Magnetic resonance imaging data from 136 healthy control participants, age 20 to 84 years, were used to correct brain volumes for normal variation arising from intracranial volume and age.The DRS scores and volumes of regional cortical gray matter and of the hippocampus.Memory scores of the patients with AD were selectively related to hippocampal volumes. Attention and construction scores were related to several anterior brain volume measures, with attention showing a significantly greater association to right than left hemisphere measures. Initiation/perseveration scores were not significantly correlated with any measure of regional gray matter volume, but performance was related to prefrontal sulcal widening, with a greater association with the left than right sulcal volume.Certain DRS subtests are predictably correlated with selective regional brain volumes in AD. The specific relation between memory and hippocampal volumes and the nonsignificant relations between memory and regional cortical volumes suggest a dissociation between cortical and hippocampal contributions to explicit memory performance.

    View details for Web of Science ID A1997XE00100008

    View details for PubMedID 9193207

  • Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics Annual Meeting of the Research-Society-on-Alcoholism Pfefferbaum, A., SULLIVAN, E. V., Mathalon, D. H., Lim, K. O. WILEY-BLACKWELL. 1997: 521–29


    This study used magnetic resonance imaging to quantify the extent and pattern of tissue volume deficit and cerebrospinal fluid volume enlargement in younger versus older chronic alcoholics relative to normal controls. In the present analysis, we divided our previously reported group of 62 alcoholic men into a younger group (n = 33, age mean = 37.5 +/- 4.5, and range = 26 to 44 years) and an older group (n = 29, age mean = 52.7 +/- 6.0, and range = 45 to 63 years) to examine whether, in addition to extent, the two age groups differed in pattern of tissue type and regional brain volume abnormalities quantified with magnetic resonance imaging. Brain volumes were adjusted for normal variation in head size and age established from a group of healthy controls and were expressed as Z-scores. The younger group had significant cortical gray, but not white, matter volume deficits and sulcal and ventricular enlargement relative to age-matched controls. The older group had volume deficits in both cortical gray and white matter and sulcal and ventricular enlargement that significantly exceeded the younger alcoholic group. An analysis of six cortical regions revealed that, although both age groups had gray matter volume deficits throughout the cortex, the older alcoholic group had a selectively more severe deficit in prefrontal gray matter relative to the younger alcoholic group. Similarly, the cortical white matter volume deficit in the older alcoholics was especially severe in the prefrontal and frontal regions. The differences in brain dysmorphology between the two alcoholic groups cannot easily be attributed to potential alcohol history differences typically related to age because the two groups had similar disease durations and amounts of lifetime alcohol consumption. These results provide in vivo evidence that the frontal lobes are especially vulnerable to chronic alcoholism in older men.

    View details for Web of Science ID A1997WZ64500020

    View details for PubMedID 9161613

  • Cortical and hippocampal volume deficits in temporal lobe epilepsy EPILEPSIA Marsh, L., Morrell, M. J., Shear, P. K., SULLIVAN, E. V., Freeman, H., Marie, A., Lim, K. O., Pfefferbaum, A. 1997; 38 (5): 576-587


    To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE).Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA).As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe.Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.

    View details for Web of Science ID A1997WX71900011

    View details for PubMedID 9184604

  • No association between the alpha 1-antichymotrypsin A allele and Alzheimer's disease NEUROLOGY Murphy, G. M., SULLIVAN, E. V., GALLAGHERTHOMPSON, D., Thompson, L. W., vanDuijn, C. M., Forno, L. S., Ellis, W. G., Jagust, W. J., Yesavage, J., Tinklenberg, J. R. 1997; 48 (5): 1313-1316


    The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.

    View details for Web of Science ID A1997WZ77800030

    View details for PubMedID 9153464

  • Patterns of content, contextual, and working memory impairments in schizophrenia and nonamnesic alcoholism NEUROPSYCHOLOGY SULLIVAN, E. V., Shear, P. K., Zipursky, R. B., SAGAR, H. J., Pfefferbaum, A. 1997; 11 (2): 195-206


    This study used tests of content memory (item recognition of words and abstract designs), context memory (order recognition of verbal and nonverbal items), and working memory (recognition at a short retention interval) to examine patterns of performance in 27 schizophrenic patients, 52 chronic alcoholic patients, and 66 healthy control participants. When performance was age- and IQ-adjusted the schizophrenia group was significantly impaired in item and order recognition of verbal and nonverbal material; the alcoholic group was impaired only in order recognition for both material types. Item- and order-recognition deficits in the schizophrenia group were greatest at the shortest retention intervals, a pattern previously observed in patients with Parkinson's disease, suggesting a prominence of a working memory deficit in schizophrenia.

    View details for Web of Science ID A1997WT56900004

    View details for PubMedID 9110327

  • Proton magnetic resonance spectroscopy of a gray matter heterotopia NEUROLOGY Marsh, L., Lim, K. O., SULLIVAN, E. V., Lane, B., Spielman, D. 1996; 47 (6): 1571-1574


    We used proton magnetic resonance spectroscopy to examine resonances representing metabolites containing N-acetyl (NA) groups (predominantly N-acetyl aspartate), choline, and creatine within a large left-hemispheric gray matter heterotopia (GMH) in a 35-year-old man with corpus callosum agenesis. In contrast to normal brain tissue, including gray matter regions, heterotopic gray matter was characterized by relatively increased choline and creatine resonances and a normal NA signal. These data suggest increased cellular activity or persistent immature neuronal tissue in GMH relative to unaffected tissue.

    View details for Web of Science ID A1996VX50700040

    View details for PubMedID 8960748

  • Mammillary body and cerebellar shrinkage in chronic alcoholics with and without amnesia ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Shear, P. K., SULLIVAN, E. V., Lane, B., Pfefferbaum, A. 1996; 20 (8): 1489-1495


    Mammillary body and cerebellar atrophy have been described as postmorten neuropathologic markers of Korsakoff's syndrome. This study examined whether shrinkage in the mammillary bodies and cerebellum is present consistently in amnesic chronic alcoholics during life and whether the degree of abnormality in these patients differs from that in nonamnesic alcoholic and healthy controls. The severity of shrinkage in the mammillary bodies, cerebellar hemispheres, and cerebellar vermis visualizable on MRI scans was rated on a three-point scale in 33 chronic nonamnesic alcoholics, 9 amnesic alcoholics, and 20 healthy controls. Although both alcoholic groups showed significant mammillary body and cerebellar shrinkage relative to controls, the two patient groups did not differ from each other. Furthermore, four of eight amnesic patients in our sample did not demonstrate clinically significant mammillary body atrophy. These results suggest that alcoholism is associated with mammillary body and cerebellar tissue volume loss but do not provide evidence that these markers distinguish accurately between amnesic and nonamnesic patients. In addition, they suggest that visualizable mammillary body atrophy is not necessary for the development of amnesia in alcoholic patients.

    View details for Web of Science ID A1996VU64400025

    View details for PubMedID 8947329

  • N400 evidence of abnormal responses to speech in Alzheimer's disease ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY Ford, J. M., Woodward, S. H., SULLIVAN, E. V., Isaacks, B. G., Tinklenberg, J. R., Yesavage, J. A., Roth, W. T. 1996; 99 (3): 235-246


    The status of semantic priming in Alzheimer's disease (AD) was examined using the speech elicited N400 component of the event-related brain potential (ERP). Speech was naturally paced, with 1 s of silence before the final word. In the semantic task, subjects attended to the meaning of the sentences for a subsequent memory test. In the phonemic monitoring task, they counted the words beginning with the letter 'p'. The effects of age were assessed by comparing young and elderly, and the effects of disease by comparing elderly and AD subjects. In healthy young and elderly subjects, N400s were large to semantically unprimed words and small to semantically primed words. In AD subjects, N400s were large to primed words, reflecting a failure of the sentence stem to prime the final word, and probably an impairment in semantic knowledge. The N400 priming effect was not smaller during the phonemic than semantic task in any group, suggesting that the semantic qualities of speech are processed even when subjects are attending to phonemic qualities. N400 latency was delayed with age and further delayed with dementia.

    View details for Web of Science ID A1996VL66900004

    View details for PubMedID 8862113

  • Gray matter deficits in young onset schizophrenia are independent of age of onset BIOLOGICAL PSYCHIATRY Lim, K. O., Harris, D., Beal, M., Hoff, A. L., Minn, K., Csernansky, J. G., Faustman, W. O., Marsh, L., SULLIVAN, E. V., Pfefferbaum, A. 1996; 40 (1): 4-13


    This study examined whether the degree of brain dysmorphology observable in adulthood was related to onset age of schizophrenic symptoms. Brain magnetic resonance imaging (MRI) scans were acquired in 57 men with schizophrenia, whose age at MRI was 19-53 years, and whose symptom onset ranged from age 7 to 29 years; all were inpatients in a state hospital. Volumes of intracranial space, cortical gray matter (GM) and white matter (WM), and cerebrospinal fluid (CSF) in lateral and third ventricles and cortical sulci were derived from MRI scans and corrected by regression analysis for variations attributable to age and head size, quantified in a control sample of healthy community volunteers. The schizophrenic patients had larger volumes of cortical and ventricular CSF and smaller volumes of cortical GM but not WM than age-matched controls, whether or not volumes were adjusted for head size and age norms. Age of onset did not correlate with any of the five age-adjusted brain measures. Neither current age, length of illness, nor symptom severity correlated with age-normalized volumes of cortical GM, sulcal CSF, or ventricular CSF. These observations are consistent with the theory that brain structure deficits 1) first develop prior to symptom onset (perhaps during the prenatal and/or early childhood process of GM development); 2) probably establish a vulnerability to subsequent dysfunctionality; but 3) are nonprogressive.

    View details for Web of Science ID A1996UQ17800002

    View details for PubMedID 8780849

  • Thinning of the corpus callosum in older alcoholic men: A magnetic resonance imaging study ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Pfefferbaum, A., Lim, K. O., Desmond, J. E., SULLIVAN, E. V. 1996; 20 (4): 752-757


    A brain image averaging technique was applied to three-dimensional magnetic resonance images to identify visually detectable brain volume abnormalities in chronically alcoholic men, compared with healthy control men. This technique, which was based on pixel-by-pixel statistical probability mapping, revealed a dramatic reduction in the area of the corpus callosum in older alcoholics (age 45 years or older), relative to age-matched controls. Subsequent analysis used anatomical landmarks to outline the borders of midsagittal sections of the corpus callosum in a larger group of alcoholics and controls, who spanned the adult age range from 23 to 71 years. This analysis revealed significant reduction, most prominent in the genu and body, of total callosal area in the alcoholic group relative to the control group; the results were the same whether raw area measures or head size plus age adjusted measure were analyzed. Significant thinning of the callosal body in alcoholics is usually attributed to the relatively rare, nutritional-deficient condition, Marchiafava-Bignami disease. However, callosal thinning was present in vivo in chronic alcoholics without clinical symptoms of severe liver disease, amnesia, or alcoholic dementia. These data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic-related subsyndromes, such as Marchiafava-Bignami disease.

    View details for Web of Science ID A1996UT99900021

    View details for PubMedID 8800395

  • Cortical gray matter volume deficits in schizophrenia: A replication SCHIZOPHRENIA RESEARCH Lim, K. O., SULLIVAN, E. V., Zipursky, R. B., Pfefferbaum, A. 1996; 20 (1-2): 157-164


    We sought to replicate an earlier finding of widespread deficit in cortical gray matter in schizophrenia by testing new samples of 22 schizophrenic patients and 27 controls between the ages of 21-46 years. Brain values for both patients and controls were standardized against age and head size norms derived from a larger control group (n = 73) spanning a wider age range (21-70). Compared to the new age-matched controls, the new schizophrenic sample showed a deficit in gray matter volume affecting the cortex as a whole and enlargement of the lateral and third ventricles. Thus, widespread cortical gray matter deficit is a replicable feature of the brain dysmorphology of schizophrenia in young to middle-aged men.

    View details for Web of Science ID A1996UR72100017

    View details for PubMedID 8794504

  • Relationship between alcohol withdrawal seizures and temporal lobe white matter volume deficits ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH SULLIVAN, E. V., Marsh, L., Mathalon, D. H., Lim, K. O., Pfefferbaum, A. 1996; 20 (2): 348-354


    A previous magnetic resonance imaging study from our laboratory reported significant temporal lobe volume deficits in cortical gray matter, white matter, and anterior hippocampus in chronic alcoholic men relative to controls. In the present study, we reexamined these data and asked whether withdrawal seizure history was predictive of either the hippocampal or the extrahippocampal volume deficits. A review of the medical charts indicated that 11 alcoholics had experienced one or more alcohol-related seizures and 35 were seizure-free; no patient had a seizure disorder unrelated to alcohol. The two alcoholic groups did not differ significantly in age, education, alcohol consumption variables, premorbid intelligence, Memory Quotient, Trail Making, or detection of hidden figures. Although each alcoholic group showed significant bilateral volume deficits of the anterior hippocampus and frontal-parietal and temporal gray matter, relative to controls, the seizure group had significantly smaller temporal lobe white matter volumes than either the control or the seizure-free groups; the latter two groups did not differ from each other. Both alcoholic groups, however, had white matter volume deficits in the frontal-parietal region. Thus, the seizure group accounted for the white matter volume deficits in the temporal lobe previously reported in the full sample of alcoholics. It seems, then, that reduced white matter volume in the temporal lobes may be either a risk factor for or sequela of alcohol withdrawal seizures.

    View details for Web of Science ID A1996UE73700023

    View details for PubMedID 8730229

  • Slow wave sleep and computed tomographic measures of brain morphology in schizophrenia PSYCHIATRY RESEARCH Benson, K. L., SULLIVAN, E. V., Lim, K. O., Lauriello, J., Zarcone, V. P., Pfefferbaum, A. 1996; 60 (2-3): 125-134


    To test the hypothesis that slow wave sleep in schizophrenia is inversely correlated with ventricular system volume, polysomnography and computed tomographic (CT) brain imaging were carried out in 14 psychiatric patients who met Research Diagnostic Criteria for schizophrenia (h = 11) or schizoaffective disorder (n = 3). Three measures of ventricular system volume were analyzed: (1) raw ventricular volume expressed in cm3; (2) ventricle-to-brain ratio; and (3) ventricular volume corrected for normal variation in age and head size expressed as a standardized (z) score. All three quantifications of ventricular volume were significantly and inversely correlated with visually scored measures of stage 3 and stage 4 sleep. This finding suggests that the etiology of slow wave sleep deficits in schizophrenia is related either directly or indirectly to underlying brain dysmorphology.

    View details for Web of Science ID A1996UH31100005

    View details for PubMedID 8723303

  • Cognitive and motor impairments are related to gray matter volume deficits in schizophrenia BIOLOGICAL PSYCHIATRY SULLIVAN, E. V., Shear, P. K., Lim, K. O., Zipursky, R. B., Pfefferbaum, A. 1996; 39 (4): 234-240


    This study examined whether the neuropsychological deficits observed in patients with schizophrenia were related to cortical gray matter volume deficits in these patients. All subjects were men and included 34 patients with DSM-III-R Schizophrenia and 47 age-matched healthy controls. Subjects received a battery of 21 tests, assessing four different functional domains: executive functions, short-term memory and production, declarative memory, and motor ability. MRI volumes were corrected for normal variation in head size and age, and neuropsychological test scores were corrected for normal variation in age. The schizophrenic group had significantly smaller cortical gray matter volumes (p < .05) and lower test scores in all functional domain than the control group (p = .0001). Within the schizophrenic group, lower scores in each domain were significantly correlated with smaller total cortical gray matter volumes; however, no predictable relationships were observed between neuropsychological test performance and the volumes of specific cortical regions.

    View details for Web of Science ID A1996TW73000002

    View details for PubMedID 8645769

  • White matter MR hyperintensities in adult patients with congenital rubella AMERICAN JOURNAL OF NEURORADIOLOGY Lane, B., SULLIVAN, E. V., Lim, K. O., Beal, D. M., Harvey, R. L., Myers, T., Faustman, W. O., Pfefferbaum, A. 1996; 17 (1): 99-103


    To observe and quantify white matter hyperintensities on MR images in adults with schizophrenialike symptoms who had had congenital rubella, in order to elucidate the neuropathologic sequelae of this perinatal viral infection and to explore the potential relationship of these lesions to schizophrenia.Eleven deaf adult patients with documented prenatal rubella virus infection and schizophrenialike symptoms were compared with 19 age-matched patients with early-onset schizophrenia who did not have congenital rubella and with 18 age-matched control subjects. All MR images (obtained at 1.5 T) were evaluated by a neuroradiologist who was blinded to diagnosis and were rated for white matter lesions on a five-point scale: 0 = no lesions; 1 = 1 lesion less than 1 mm in diameter; 2 = 1 to 4 lesions 1 mm or greater; 3 = 5 to 10 lesions; 4 = more than 10 lesions or a single lesion more than 1 cm in diameter. In addition, the white matter hyperintensities were volumed objectively with a manual threshold technique.Ratings of white matter lesions were significantly higher in the rubella patients than in the control subjects: 6 of the 11 patients had ratings greater than 1 compared with 1 of the 18 control subjects and none of the 19 schizophrenic patients. Also, MR images in five rubella patients received ratings at the highest end of the scale of abnormality (3 or 4). The white matter hyperintensities were characterized as bilateral T2 signal hyperintensities in periventricular and subcortical regions, punctate or linear in shape; they were observed predominantly in parietal lobes.This quantitative MR study of adult rubella patients disclosed abnormal white matter lesions that may correspond to neurovascular lesions known neuropathologically. They do not appear to be directly related to schizophrenialike symptoms.

    View details for Web of Science ID A1996TP96800017

    View details for PubMedID 8770257

  • Effects of cortical gray matter, attention, and schizophrenia on P300 amplitude 11th International Conference on Event-Related Potentials (EPIC XI) Ford, J. M., Mathalon, D. H., SULLIVAN, E. V., Lim, K. O., Pfefferbaum, A. ELSEVIER SCIENCE BV. 1996: 916–921


    Chronic alcoholism is associated with smaller volumes of cortical gray matter and white matter and a complementary increase in brain cerebrospinal fluid (CSF) volumes, relative to age norms. This longitudinal study quantified the extent of brain volume changes associated with abstinence and drinking at three time points in chronic alcoholics. We obtained magnetic resonance imaging (MRI) on 58 alcoholic men after an average of 12 days (MRI-1) and 32 days (MRI-2) of sobriety. In addition, 58 healthy control subjects were scanned at a comparable interval. At MRI-3, 11 controls and 39 alcoholics were rescanned, 2-12 months after MRI-2; 19 alcoholics had abstained, and 20 had resumed drinking. Axial MRI slices were segmented into cortical gray matter, white matter, and CSF and summed over seven slices; lateral and third ventricular volumes were also estimated. MRI volume changes were corrected using an estimate of interscan measurement error caused by head positioning differences, and then divided by the interval to yield rates of change (slopes). From MRI-1 to MRI-2, the alcoholic group showed declines in CSF volumes of the lateral ventricles and posterior cortical sulci, and a trend toward an increase in anterior cortical gray matter volume relative to the control group. From MRI-2 to MRI-3, third ventricular volumes decreased in the abstainers relative to the relapsers and controls; cortical white matter volume decreased in the relapsers. In the relapsers, lifetime consumption of alcohol (as of MRI-1) predicted later vulnerability to white matter volume decline and third ventricular enlargement with resumption of drinking. These data suggest that improvement in cortical gray matter, sulcal, and lateral ventricular volumes occur early in the course of abstinence, and that improvement in third ventricular volume appears later with continued abstinence.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995TA73800014

    View details for PubMedID 8561288



    The effect of normal aging on the volume of the hippocampus and temporal cortex was assessed cross-sectionally with quantitative Magnetic Resonance Imaging (MRI) in 72 healthy men, spanning 5 decades of the adult age range (21 to 70 years). Neither the hippocampal nor cortical white matter volumes were significantly correlated with age. By contrast, left and right temporal lobe gray matter volumes, exclusive of the hippocampal measures, each decreased with age (p < 0.01). Volumes of temporal lobe sulcal CSF and the ventricular system (temporal horns and lateral and third ventricles) significantly increased with age. Measures of verbal and nonverbal working memory showed age-related declines and were related to enlargement of the three ventricular regions, which may be indicative of age-related atrophy of the adjacent cortex but not the hippocampus, at least up to age 70 years.

    View details for Web of Science ID A1995RL48800012

    View details for PubMedID 8544910



    Brain morphology was quantified with magnetic resonance imaging (MRI) in adult patients with congenital rubella who also had schizophrenialike symptoms. MRIs were compared with those of adult early-onset schizophrenic patients without congenital rubella and age-matched healthy control subjects. The rubella patients had significantly smaller intracranial volumes and shorter stature than the schizophrenic patients or the controls; however, both patient groups had smaller cortical gray matter, but not white matter, volumes than the control group, even when the MRI volumes were corrected for head size and age. In addition, both patient groups showed significant enlargement of the lateral ventricles but not cortical sulci when compared with expected values of normal adults of the same age and head size. Overall, the pattern of dysmorphology was identical in the rubella and the schizophrenic groups. The observations in the rubella group are consistent with a developmental lesion that limits full brain growth, with the small intracranial volume due at least in part to a severe cortical gray matter volume deficit. Thus, the brain dysmorphology of congenital rubella may provide an instance of prenatal viral infection that models the schizophrenic pattern and provides indirect support for a developmental hypothesis of the neuropathogenesis of schizophrenia.

    View details for Web of Science ID A1995RA24400002

    View details for PubMedID 7647161



    This study used a semiautomated image analysis technique to quantify the rate and regional pattern of cerebrospinal fluid (CSF) volume changes in the computed tomographic brain examinations of healthy adults and patients with Alzheimer's disease (AD).Longitudinal, within-subject design, with statistical correction for longitudinal method error (eg, head repositioning effects).Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 41 patients with AD were recruited from the Geriatric Psychiatry Research Unit and the National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 35 healthy control subjects were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans.Even after accounting for an estimate of method error (eg, head positioning effects) across computed tomographic examinations, the patients with AD showed greater annual CSF volume increases than did the control group. This CSF volume enlargement was not uniform across brain regions of interest; rather, the patients with AD showed disproportionate volume increases in the ventricular system and the sylvian fissures. Greater CSF volume changes in the patients with AD were significantly associated with greater cognitive decline on the Mini-Mental State Examination. Furthermore, younger patients with AD showed more rapid progression on computed tomographic scans than did older patients.The rate of CSF volume enlargement is region specific, with the most marked annual rate of change occurring in the ventricular system and the sylvian fissures. In addition, younger patients show more rapid progression in the ventricular and frontal sulcal brain regions of interest than do older patients.

    View details for Web of Science ID A1995QR98600014

    View details for PubMedID 7710375



    Magnetic resonance imaging was used to quantify the volume of the hippocampus in 47 men with chronic alcoholism and 72 healthy male control subjects. The subjects ranged in age from 21 to 70 years, thus permitting a test of whether older alcoholics suffer greater brain tissue volume reduction than do younger ones. Comparison brain regions included temporal lobe gray matter, white matter, and cerebrospinal fluid, as well as measures of the lateral ventricles, third ventricle, and temporal horns. The results of this cross-sectional study showed that the anterior, but not the posterior, portions of the hippocampus in both hemispheres were significantly smaller in the alcoholic than the healthy control group. Furthermore, the bilateral anterior hippocampal volume loss was greater in older than younger alcoholics. Despite the hippocampal volume deficit, these alcoholics did not demonstrate an explicit memory impairment; furthermore, memory test scores did not correlate significantly with hippocampal volumes. In the alcoholics, the age-related volume loss, which was over and above that expected in normal aging, was also evident in the temporal cortex and white matter. Likewise, alcoholic ventricular enlargement was age-related. Analysis of covariance revealed that the anterior hippocampal deficit persisted after accounting for the temporal lobe gray matter volume deficit. Multiple regression analysis revealed that the age-related brain volume abnormalities observed in the alcoholics could not be attributed to duration of alcoholism or total lifetime consumption of alcohol.

    View details for Web of Science ID A1995QG62500018

    View details for PubMedID 7771636

  • Structural brain alterations associated with alcoholism ALCOHOL HEALTH & RESEARCH WORLD Rosenbloom, M. J., Pfefferbaum, A., SULLIVAN, E. V. 1995; 19 (4): 266-272


    This study examined the neuropsychological deficits associated with schizophrenia and the interrelationships among multiple dissociable cognitive and motor functions. The tests were selected for their previously demonstrated sensitivity to circumscribed brain pathology and included four functional domains: executive functions, short-term memory and production, motor ability, and declarative memory. Each test composite was divided according to verbal versus nonverbal material or left- versus right-hand performance; this distinction permitted functions principally subserved by the left or right cerebral hemispheres to be tested separately. Data reduction was theoretically driven by the test selection and was achieved first by standardizing the scores of each test for age-related differences observed in the normal control group, and then by calculating test composite scores as an average of the age-corrected Z-scores of the tests comprising a functional composite. The schizophrenic group was impaired equivalently on all composites for both cerebral hemispheres; on average, the Z-scores of the patients were 1 standard deviation below those of the control group. The cognitive test composite scores were highly intercorrelated but showed only weak associations with motor ability. Multiple regression analyses suggested that symptom severity was a significant predictor of the Declarative Memory and Short-Term Memory/Production composite scores after accounting for disease duration, whereas disease duration uniquely contributed to the Executive Functions composite scores after controlling for symptom severity. Even though the schizophrenics as a group showed an equivalent level of deficit across all test composites, 1) the deficits were associated with different aspects of psychiatric symptomatology, 2) the motor deficit was independent of the cognitive deficits, and 3) each neuropsychological domain contributed independently to the deficit pattern. Thus, what appears to be a generalized functional deficit in schizophrenia may actually be, at least in part, combinations of multiple specific deficits.

    View details for Web of Science ID A1994PT24700001

    View details for PubMedID 7661935



    To model in vivo the dynamic interrelations of head size, gray matter, white matter, and cerebrospinal fluid (CSF) volumes from infancy to old age using magnetic resonance imaging (MRI).Cross-sectional, between-subjects using an age-regression model.A Veterans Affairs medical center and community hospitals.There were 88 male and female subjects aged 3 months to 30 years whose clinical MRI film had been read as normal and 73 healthy male volunteers aged 21 to 70 years who had an MRI performed specifically for this study.These MRI data were quantified using a semiautomated computer technique for segmenting images into gray matter, white matter, and CSF compartments. The cortex was defined geometrically as the outer 45% on each analyzed slice, and the volumes of cortical white matter, gray matter, and CSF were computed. Subcortical (ventricular) CSF volume was computed for the inner 55% of each analyzed slice.In the younger sample, intracranial volume increased by about 300 mL from 3 months to 10 years. The same patterns of change in volume of each compartment across the age range were seen in both sexes: cortical gray matter volume peaked around age 4 years and decreased thereafter; cortical white matter volume increased steadily until about age 20 years; cortical and ventricular CSF volumes remained constant. In the older sample, brain volumes were statistically adjusted for normal variation in head size through a regression procedure and revealed the following pattern: cortical gray matter volume decreased curvilin-early, showing an average volume loss of 0.7 mL/y, while cortical white matter volume remained constant during the five decades; complementary to the cortical gray matter decrease, cortical CSF volume increased by 0.6 mL/y and ventricular volumes increased by 0.3 mL/y.These patterns of growth and change seen in vivo with MRI are largely consistent with neuropathological studies, as well as animal models of development, and may reflect neuronal progressive and regressive processes, including cell growth, myelination, cell death, and atrophy.

    View details for Web of Science ID A1994PG22500008

    View details for PubMedID 8080387

  • VOLUMETRIC MRI ASSESSMENT OF TEMPORAL-LOBE STRUCTURES IN SCHIZOPHRENIA BIOLOGICAL PSYCHIATRY Zipursky, R. B., Marsh, L., Lim, K. O., DEMENT, S., Shear, P. K., SULLIVAN, E. V., Murphy, G. M., Csernansky, J. G., Pfefferbaum, A. 1994; 35 (8): 501-516


    This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

    View details for Web of Science ID A1994NJ34700001

    View details for PubMedID 8038294



    Event-related potentials (ERPs) and brain magnetic resonance images (MRIs) were acquired from 28 normal men, age 21-60 years. ERPs were recorded during 3 paradigms designed to elicit automatic or effortful attention, and a combination of both. MRI-derived measures of brain gray matter, white matter and cerebral spinal fluid (CSF) volumes were computed from frontal, parietal and temporal lobes. P300 amplitude correlated significantly with gray matter volumes but not with white matter or CSF volumes. Furthermore, the relationships between P300 amplitude and gray matter volumes reflected functional rather than direct topographical relationships: P300 recorded at Pz during automatically elicited attention correlated significantly with frontal but not parietal lobe gray matter volumes, P300 recorded during effortful attention correlated significantly with parietal but not frontal lobe gray matter volumes, and P300 recorded when both types of attention were invoked correlated significantly with both frontal and parietal gray matter volumes. Startle blinks, also elicited during automatic attention-engaging paradigms, were significantly correlated with frontal but not parietal lobe gray matter volumes. There was no evidence for a direct spatial relationship between P300 amplitude and the gray matter volumes underlying the recording electrode.

    View details for Web of Science ID A1994ND22100006

    View details for PubMedID 7511503



    This cross-sectional study used a semi-automated analysis technique to quantify regional brain cerebrospinal fluid (CSF) volumes derived from computed tomography (CT) in 84 healthy men ranging from 21 to 82 years of age and 28 patients meeting Research Diagnostic Criteria for alcohol dependence. The goals were to replicate an earlier CT study of an independent sample of alcoholic and control subjects (Pfefferbaum et al., 1988a; Zipursky et al., 1988) and to compare CT assessments of brain changes with magnetic resonance imaging (MRI) assessments made in the same alcoholic patients (Pfefferbaum et al., 1992). Regional brain changes associated with normal aging were derived by regression analysis, using CT data collected from the healthy control subjects. As in the earlier CT study and in the concurrent MRI study, ventricular and sulcal CSF volumes in alcoholic patients were greater than would be expected for their age. Furthermore, the present CT study replicated the previous CT and MRI findings of a positive relationship between age and CSF volume enlargement in alcoholic patients over and above the normal age-related increase in CSF volume, suggesting greater vulnerability of the aging brain to alcohol. Comparison of CT- and MRI-derived estimates of ventricular and cortical sulcal volume revealed high correlations (> 0.80). MRI and CT produced similar absolute ventricular volumes, while MRI produced larger sulcal volume estimates than did CT. The difference in sulcal volume estimate may be due to differences between CT and MRI in slice thickness and sensitivity to partial volume effects.

    View details for Web of Science ID A1993MT42000004

    View details for PubMedID 8177924



    Studies of Parkinson's disease (PD) have shown impaired temporal ordering but interpretation may be confounded by task requirements and the effects of medication. We examined item recognition and recency discrimination in PD in relation to treatment and performance on other tests. Patients showed increased response latency and impaired recency discrimination only at short retention intervals. The deficits were greater in chronically medicated patients but treatment with levodopa, bromocriptine or anticholinergic drugs did not affect performance of newly diagnosed cases. The short-term memory deficits correlated with scores on tests of working memory, attention and executive function. These results do not indicate a generalised temporal ordering deficit in PD but suggest that much of the cognitive impairment in the disorder arises from attentional deficits affecting short-term and working memory.

    View details for Web of Science ID A1993LZ62000005

    View details for PubMedID 8232850



    Structural brain-imaging measurements based on computed tomography (CT) or magnetic resonance imaging (MRI) are often corrected or adjusted for normal variation in head size. Some methods of head-size correction, such as the ventricle-brain ratio (VBR), are based on taking the brain structure size as a proportion of the estimated head size, while other methods have used a regression model to obtain head-size residualized structure measures. Recently, head-size correction was shown to result in less reliable volumetric measures of brain structures (Arndt et al., 1991). In the present study, MRI was used to examine the effects of head-size correction on the interrater reliability of volumetric measures of gray matter, white matter, and cerebrospinal fluid. Four raters independently scored MRI brain images from 26 subjects, generating separate estimates of head size and region of interest (ROI) size. Two methods were used to correct MRI values for differences in head size, one based on proportions and the other based on linear regression. Results confirmed that head-size correction did produce measures with lower reliability; however, further analysis based on classical measurement theory showed that the lower reliability was attributable not only to increased measurement error variance, but also to reduced true score variance. Subsequent analyses of criterion validity compared the raw (uncorrected) and head-size-corrected ROI measures in terms of their correlations with age in a sample of 43 normal control subjects, and in terms of their ability to differentiate schizophrenic patients (n = 22) from normal control subjects (n = 20). Results indicated that head-size correction often improved criterion validity, producing higher correlations with age and with diagnostic status than those produced by the raw measures. These findings suggest that head-size correction removes irrelevant true-score variance which reduces reliability yet improves the correlations with validity criteria such as age and diagnostic status.

    View details for Web of Science ID A1993LK62400006

    View details for PubMedID 8378488



    This study used a semiautomated analysis technique to quantify differences in regional brain cerebrospinal fluid volumes observed with computed tomography between healthy adults and patients with Alzheimer's disease (AD).Cross-sectional, between-subject design, using an age-regression model.Palo Alto (Calif) Department of Veterans Affairs Medical Center.The 117 patients with probable or definite AD were recruited from the Geriatric Psychiatry Research Unit and National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 114 healthy volunteers were recruited from the local community.Cerebrospinal fluid volumes estimated from computed tomographic scans and neuropsychological test scores.The computed tomographic estimates of ventricular and sulcal cerebrospinal fluid volumes increased significantly in all sampled brain regions in normal aging and were vastly larger in AD than in normal aging. Furthermore, younger patients with AD had significantly greater cerebrospinal fluid volume enlargement than did older patients with AD compared with healthy controls of their age. When the AD group was divided on the basis of reported age at symptom onset, patients in the early-onset group (onset before age 65 years) were quantitatively more abnormal than and showed a different pattern of abnormality from the patients in the late-onset group. This onset difference was also evident in neuropsychological test performance.This cross-sectional study revealed a number of converging findings that suggested greater abnormality in the early-onset than in the late-onset group of patients with AD. The possibility remains, however, that the two onset groups represent different stages along a continuum of pathologic changes.

    View details for Web of Science ID A1993KV70200007

    View details for PubMedID 8460957



    The purpose of this study was to examine the factor structure of the Wisconsin Card Sorting Test (WCST). The scores of 22 patients with schizophrenia, 20 patients with chronic alcoholism, and 16 normal control subjects were entered into a principal components analysis, which yielded three factors: Perseveration, Inefficient Sorting, and Nonperseverative Errors. WCST performance of seven patients with lesions invading the dorsolateral prefrontal cortex, available from another study, provided criterion validity for the Perseveration factor and, less strongly, for the Inefficient Sorting factor. Two patterns of performance characterized the three patient groups: the schizophrenic group and frontal lobe group had the highest Perseveration factor scores, whereas the alcoholic group had the highest Inefficient Sorting scores; the Nonperseverative Errors factor showed no significant group differences. Construct validity of these factors involved assessing, in all but the frontal group, the degree of overlap (convergent validity) and separation (discriminant validity) of each WCST factor with scores from tests of other cognitive functions. The convergent and discriminant validity of the Perseveration factor, but not the remaining two factors, received support only within the group of schizophrenic patients.

    View details for Web of Science ID A1993KU96900007

    View details for PubMedID 8483976



    The cognitive performance of a group of 82 newly diagnosed patients with Parkinson's disease who had never been treated was reassessed approximately 4 mths after randomization to one of three monotherapies (levodopa, bromocriptine or anticholinergic drugs). Dopaminergic and anticholinergic treatments both led to improvement in motor control but their effects upon cognitive performance dissociated. Anticholinergic drugs produced impairment in processes underlying the immediate registration of information whilst dopaminergic therapy produced improvement on a task dependent on working memory and cognitive sequencing. Other cognitive measures showed no change on treatment. The deficits that were affected by cholinergic and dopaminergic modulation are those that were most compromised in the early, untreated state in Parkinson's disease. The data support the notion that cognitive impairment in Parkinson's disease is multifactorial in origin: short-term memory processes are served by both dopaminergic and cholinergic subcortico-frontal systems but much of the cognitive impairment of Parkinson's disease is independent of this subcortical neurochemical pathology and may be due to early neuronal dysfunction within the cerebral cortex.

    View details for Web of Science ID A1992KJ44600006

    View details for PubMedID 1486457



    Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.

    View details for Web of Science ID A1992KD40900012

    View details for PubMedID 1471762



    The Rey-Osterrieth complex figure was used to assess the separate influences of the constructional accuracy and the organizational strategy employed while copying the figure on the later, incidental recall of the figure. We tested a model, which hypothesized that subjects who copied the main framework of the figure holistically would be more likely to achieve good copy accuracy scores and to reproduce the figure more accurately at recall than subjects who used a piecemeal approach during copy. Subjects included 68 detoxified, chronic alcoholics (ALC), 28 patients with schizophrenia (SZ), and 69 normal control subjects (NCS). The results showed that the ALC and the SZ groups, on average, had lower accuracy and strategy scores at copy than did the NCS group, and furthermore, that the combined contributions of copy accuracy and copy strategy accounted for group differences at recall. A path analysis revealed that, for all three groups, copy strategy had a significant direct effect on copy accuracy. Moreover, copy accuracy and copy strategy made independent contributions to recall accuracy within the ALC and NCS groups; by contrast, within the SZ group, copy strategy made an independent contribution to recall performance but copy accuracy did not. These results suggest that (1) organizational strategy can influence constructional accuracy at both copy and recall; (2) copy accuracy and strategy have the potential to influence recall independently; and (3) the recall deficit in ALC could be attributed to abnormalities in both accuracy and strategy at copy, whereas in SZ it could be attributed only to strategy abnormalities. The deficits observed on the complex figure test in the ALC and SZ were primarily nonmnemonic and were related to ability in figure construction and organizational strategy.

    View details for Web of Science ID A1992JW49300003

    View details for PubMedID 1420646



    Magnetic resonance imaging was used to investigate whether the structural brain differences commonly observed in patients with schizophrenia as compared with normal control subjects are specific to gray or white matter, and furthermore whether such abnormalities are localizable to circumscribed cortical regions. Accordingly, 22 patients meeting DSM-III-R criteria for schizophrenia and 20 healthy community volunteers, all 23 to 45 years old, received magnetic resonance imaging scans. Seven axial magnetic resonance imaging sections of 5-mm thickness were segmented into cerebrospinal fluid, gray matter, and white matter compartments and used for volumetric quantification. For the healthy control subjects, age correlated significantly with the percentage of all magnetic resonance imaging sections taken up by gray matter but not white matter. After correcting for the normal effect of age, the schizophrenic group was found to have significantly less gray matter than the control group but no difference in white matter; ventricular volume was 34% greater in the schizophrenic group. The schizophrenic group had less gray matter in all six cortical subregions analyzed; these differences attained statistical significance for all but the parietal measure. These findings have implications for studies of localized gray matter abnormalities and suggest that regional brain volume measurements need to be expressed in the context of possible widespread gray matter volume deficits in schizophrenia.

    View details for Web of Science ID A1992HG92500003

    View details for PubMedID 1567274



    Current knowledge of cognitive dysfunction in Parkinson's disease (PD) has largely been obtained from studies of chronically treated patients in whom effects of disease chronicity, treatment, depression and dementia are confounding factors. Studies of untreated patients have examined few cognitive domains and relationships between cognition, depression and motor disability have been incompletely explored. Accordingly, we studied 60 consecutive patients with newly diagnosed, untreated, idiopathic PD and 37 matched, healthy control subjects; no subject had clinical dementia or depression. All subjects received tests of specific processes of memory and cognition, including working memory, verbal and non-verbal short- and long-term memory, language, visuospatial capacity, set-formation and shifting and sequencing. Patients also received quantitative global clinical measures of severity of dementia, depression and motor disability. The PD group as a whole showed deficits in immediate recall of verbal material, language production and semantic fluency, set-formation, cognitive sequencing and working memory and visuomotor construction. However, this group was unimpaired in immediate memory span, long-term forgetting, naming, comprehension and visual perception. Language deficits and more severe frontal lobe impairments were confined to those PD patients scoring abnormally on a Mini Mental State examination. Motor disability correlated strongly with severity of depression but weakly with cognitive impairment. Cognitive sequencing, set-formation and set-shifting deficits tended to associate with depression, but otherwise there was no association between cognition and depression. The results indicate dissociation of cognition and motor control in early PD which suggests that cognitive dysfunction is largely independent of frontostriatal dopamine deficiency underlying motor disability. Some, but not all, of the frontal lobe deficits of chronic disease are detectable in early, untreated PD. The pathogenesis of the cognitive deficits shown here appears to involve extrastriatal dopamine systems or non-dopaminergic pathology. Longitudinal study is necessary to determine whether increasing disease duration exacerbates the early cognitive deficits and affects new cognitive domains, in addition to producing increasing motor disability.

    View details for Web of Science ID A1991GR31100006

    View details for PubMedID 1933236



    This study presents a structural and functional description of a case of striatonigral degeneration (SND) and emphasizes neuropsychological findings. The patient, a 55-year-old woman with progressive and relatively intractable rigidity and bradykinesia, particularly of the right side, was studied with brain MR scans and with a wide variety of sensory, motor, and cognitive tests known to be subserved by specific brain regions. T2-weighted MR images revealed curvilinear areas of high signal in the lateral putamen at low magnetic field strength (0.3T) and adjacent regions of marked low signal in the posterior-lateral putamen at high magnetic field (1.5T). High signal changes in the insular cortex were also noted on the high field images. Letter fluency and short-term memory as well as motor speed, strength, and sequencing were selectively impaired. Taken together, the data of this case suggest that structural involvement of the putamen resulted in dysfunctions usually associated with the primary motor cortex and orbitofrontal cortex, while sparing functions of other frontal regions as well as temporal and parietal cortices.

    View details for Web of Science ID A1991GK47600011

    View details for PubMedID 1955531



    The traditional concept of memory disorder is deficiency of the long-term (LTM) but not short-term (STM) component of memory. STM impairment with LTM sparing is seldom reported. The present study investigated STM and LTM for nonverbal material in three neurological conditions associated with memory impairment: bilateral medial temporal lobe lesions (patient H.M.), Parkinson's disease (PD) and Alzheimer's disease (AD). Subjects received 3 tests of nonverbal memory: forward block span, immediate and delayed recall of the Wechsler Memory Scale drawings, and immediate and delayed recognition of abstract designs. Compared with the normal control group, the patient groups displayed different patterns of sparing and loss of the two components of memory: in PD, only STM was impaired; in medial temporal lobe amnesia, only LTM was impaired; and in AD, STM and LTM were both impaired. The contrasting patterns of sparing and loss of STM and LTM in PD and global amnesia were present for both recognition and recall. These results provide evidence that STM and LTM are dissociable processes and are served by separate neurological systems: STM depends upon intact corticostriatal systems, whereas LTM depends upon intact medial temporal lobe systems.

    View details for Web of Science ID A1991FQ67500015

    View details for PubMedID 2043956



    The relationship of release from proactive interference (PI) to set-shifting, explicit free recall and language remains controversial. We tested 56 patients with Parkinson's disease (PD) who had never received medication and 37 matched normal control subjects on a test of PI release based on semantic category. The PD group showed normal PI release but impaired word recall. PI release was independent of impaired Wisconsin card-sorting test performance, language production, explicit memory, overall cognitive status and severity of depression. The results indicate dissociation between ability to benefit from semantic stimulus properties and processes of explicit memory, set-shifting and expressive language.

    View details for Web of Science ID A1991GT34300001

    View details for PubMedID 1775225

  • Long-term Perseveration in Alzheimer's Disease: A Case Report. Behavioural neurology Sullivan, E. V. 1991; 4 (4): 225–33


    The most common clinical sign of Alzheimer's disease (AD) is progressive memory loss. Presented here is a case of AD who, despite ultimate profound dementia with severe amnesia, showed retention of a perseverative response she developed during 26 encounters, over 4.5 years, with the Brown-Peterson distractor test. From Test 9 onwards, she responded from the first distractor-filled trial with one consonant trigram, appearing in none of the seven test forms given her. At Test 26, she could not repeat heard trigrams yet faithfully responded with her perseverative trigram. The trigram, ostensibly declarative information, apparently became part and parcel of the task's procedure. Although perseveration is a form of impairment probably resulting from Alzheimer pathology involving frontal and parietal cortex, it may also reflect a form of preserved memory, albeit distorted, supported by posterior cortical regions spared in AD.

    View details for PubMedID 24487577

  • Autobiographical memory in normal ageing and dementia. Behavioural neurology SAGAR, H. J., SULLIVAN, E. V., Corkin, S. 1991; 4 (4): 235-248


    Autobiographical memories in young and elderly normal subjects are drawn mostly from the recent past but elderly subjects relate a second peak of memories from early adulthood. Memory for remote past public events is relatively preserved in dementia, possibly reflecting integrity of semantic relative to episodic memory. We examined recall of specific, consistent autobiographical episodes in Alzheimer's disease (AD) in response to cue words. Patients and control subjects drew most memories from the recent 20 years: episode age related to anterograde memory function but not subject age or dementia. Subjects also related a secondary peak of memories from early adulthood; episode age related to subject age and severity of dementia. The results suggest that preferential recall of memories from early adulthood is based on the salience of retrieval cues, altered by age and dementia, superimposed on a temporal gradient of semantic memory. Further, AD shows behavioural similarity to normal ageing.

    View details for DOI 10.3233/BEN-1991-4403

    View details for PubMedID 24487578


    View details for Web of Science ID A1991HB51400033

    View details for PubMedID 1915027

  • A QUANTITATIVE-ANALYSIS OF CT AND COGNITIVE MEASURES IN NORMAL AGING AND ALZHEIMERS-DISEASE PSYCHIATRY RESEARCH-NEUROIMAGING Pfefferbaum, A., SULLIVAN, E. V., Jernigan, T. L., Zipursky, R. B., Rosenbloom, M. J., Yesavage, J. A., Tinklenberg, J. R. 1990; 35 (2): 115-136


    Patients with presumptive Alzheimer's disease (AD) and healthy community volunteers received computed tomographic (CT) brain scans and cognitive tests. The CT scans were quantitatively analyzed with a semiautomated thresholding technique to derive volumetric measures of cerebrospinal fluid (CSF)-to-tissue ratios in six regions of interest (ROIs): lateral ventricles; vertex sulci, frontal sulci, Sylvian fissures, parieto-occipital sulci, and third ventricle. Regression analysis was performed on CT data from 85 older volunteers (ages 51-82) to generate age norms for each ROI. Within this group, tissue loss, as measured by the % CSF in each ROI, was highly correlated with age, although each ROI showed different rates of change over age. For all ROIs, the AD group had significantly more tissue loss than expected in normal aging. In addition, AD patients with a presenescent onset (before age 65) tended to have greater vertex sulcal and frontal sulcal tissue reduction than AD patients with a senescent onset (age 65 or after). When regional tissue reduction, corrected for age, was correlated with cognitive test scores, two sets of double dissociations emerged within the AD group: large CT z scores (i.e., decreased tissue and increased CSF) of frontal sulci, but not of the third ventricle, correlated with low Comprehension and Boston Naming Test scores, whereas large CT z scores of the third ventricle, but not of the frontal sulci, correlated with low scores on Digit Symbol and Picture Arrangement. These results suggest that heterogeneity of structural and functional integrity exists among patients with AD.

    View details for Web of Science ID A1990EU28600003

    View details for PubMedID 2100804



    Temporal contextual memory and event memory were compared across retention intervals in the patient H.M. who is amnesic following bilateral medial temporal lobectomy. Memory for temporal context was assessed using verbal and nonverbal recency discrimination tasks and a frequency task in which subjects made discriminations between words repeated 1, 3 or 5 times. The tests evaluated event memory under parallel conditions by two-choice content recognition tasks. In both recency and frequency tests, H.M. showed above-chance and often normal temporal contextual memory under conditions of impaired and even chance-level content recognition. These results show that temporal contextual memory does not require intact content recognition and is independent of medial temporal lobe structures. Furthermore, the amnesia of bilateral medial temporal lobe resection does not manifest primary loss of temporal contextual memory.

    View details for Web of Science ID A1990DJ97800001

    View details for PubMedID 2364261



    Patients with Parkinson's disease (PD) displayed a different pattern of cognitive deficit from patients with dementia resulting from Alzheimer's disease (AD). Specifically, PD patients, whether or not impaired on a mental status examination, had deficient Picture Arrangement but normal Vocabulary test scores whereas AD patients were impaired on both measures. Furthermore, PD patients with impaired mental status examination scores showed a deficit in set formation on Picture Arrangement not seen in the AD patients. Finally, when recent memory performance, as measured by the Wechsler Memory Scale, was predicted from an estimated IQ, 71% of PD patients who had normal mental status examination scores were seen to have at least a mild memory impairment.

    View details for Web of Science ID A1989CC21500003

    View details for PubMedID 2592525



    In a study of verbal temporal ordering, patients with Parkinson's disease (PD) were impaired in making judgements of the relative recency of serially-presented words but were normal in word recognition; by contrast, patients with Alzheimer's disease (AD) were impaired on both verbal tasks (Sagar et al., 1985, 1988b). The present study used a nonverbal analogue of the verbal temporal ordering task to examine whether the deficit in recency discrimination of the PD patients transcended material-specific bounds or was specific to verbal material. The nonverbal task was administered to the patients with PD, patients with AD and normal control subjects studied with the verbal task. The results showed that the retention functions for the recognition of verbal and nonverbal material differed qualitatively from each other and this difference was present in all three subject groups. For verbal and nonverbal recency discrimination and verbal content recognition, performance declined with increasing retention intervals; for nonverbal content recognition, however, performance was essentially unchanging across retention intervals. As on the verbal test, recency discrimination on the nonverbal test was impaired in both patient groups. In contrast to the results with the verbal task, both groups were impaired on content recognition. The patterns of impairment, however, differed between the two patient groups in a parallel way to those of the verbal task: performance of the AD group was impaired at the longest retention intervals but not at the shortest intervals, whereas the performance of the PD group was impaired at the shortest but not at the longest intervals. This deficit in nonverbal short-term recognition memory was present even in PD patients who scored within the normal range on a quantitative test of dementia. These results show that deficits in recency discrimination and short-term memory processing in PD extend to nonverbal as well as verbal material and imply bilateral frontal lobe dysfunction in the genesis of these deficits.

    View details for Web of Science ID A1989CH26400007

    View details for PubMedID 2597993



    Few investigators have studied whether the behavioral effects of brain insult in adulthood are stable after the period of maximum recovery. We addressed this issue in a 30-year longitudinal study of 84 veterans of World War II, 57 with penetrating head injury (HI) and 27 with peripheral nerve injury (PNI), matched with respect to age, premorbid intelligence, and premorbid education. Each subject was examined during the 1950s and during the 1980s; each examination included the largely verbal Army General Classification Test (AGCT) (with Vocabulary, Arithmetic, and Block Counting subscales) and the Hidden Figures Test (which measures figure-ground discrimination). HI exacerbated decline in performance over time, irrespective of lesion site or cognitive test. HI and PNI subjects differed significantly (p less than 0.05) in AGCT Total and Arithmetic change scores, and means were in the same direction for all other measures. In analyses contrasting subjects in each of the eight lesion groups to PNI subjects, those with left parietal lobe injuries showed significantly greater decline from the 1950s to the 1980s on the Vocabulary and Arithmetic subscales of the AGCT, as did those with left temporal lobe injuries on the Arithmetic subscale, whereas subjects with right parietal lobe injuries showed significantly greater decline on the Hidden Figures Test. We hypothesize that the observed reduction of cognitive capacities late in life was due to some combination of HI in young adulthood, secondary effects of the injury occurring with time, effects of stress on remaining brain tissue caused by functioning for decades in a compromised state, and changes in the brain occurring with age. Although the HI subjects were not demented, follow-up studies must assess whether exacerbated decline is a harbinger of dementia.

    View details for Web of Science ID A1989CA47400018

    View details for PubMedID 2585058



    Asymmetries in tactile short-term memory related to differential specialization of the cerebral hemispheres were studied in normal human adults using the Brown-Peterson distractor task. When the distractor was an auditory arithmetic task, no difference emerged between the two hands for the retention of touches to the fingers; however, when the distractor was a tactual maze task executed by the right hand, asymmetry in favor of the left hand was observed. Specifically, when the right hand performed the tactual maze, there was greater interference with tactile memory than when the left hand performed the maze, independent of which hand received the memory material. The results support a characterization of short-term memory as embracing multiple, limited storage capacities divided along the lines of processing demands, arising from different classes of material, placed on the two cerebral hemispheres.

    View details for Web of Science ID A1989U075800007

    View details for PubMedID 2707007



    Previous studies of remote memory function have indicated a dissociability between memory for the content and date of past events and suggested selective deficits of dating capacity in Parkinson's disease (PD). The present study examined the hypothesis that poor dating in PD is linked to a specific deficit in temporal contextual memory which also affects new learning. Patients with PD and patients with Alzheimer's disease (AD) were compared in their ability to perform tasks of content recognition and recency discrimination of words presented sequentially. Compared with AD patients, PD patients were disproportionately impaired in recency discrimination relative to content recognition. When performance was analysed as a function of retention interval, AD patients showed impairment in both tasks at all intervals. PD patients, by contrast, showed deficits in content recognition at the short stimulus-test intervals only, possibly reflecting the clinical phenomenon of bradyphrenia. These results suggest that recency discrimination deficits and impaired short-term memory processing are specific cognitive deficits in PD that may be linked to subcortical deafferentation of the frontal lobes.

    View details for Web of Science ID A1988P166400004

    View details for PubMedID 3382911



    Remote memory for public and personal events was evaluated in Alzheimer's disease (AD) and Parkinson's disease (PD), using a series of recall and recognition tests. Information related to content and date of past events was assessed separately. In recall of the content of personal and public events, both groups showed a gradient of deficit in which remote events were affected less than recent ones; the magnitude and temporal extent of the retrograde loss was related to severity of dementia. By contrast, gradient effects were not evident in the recall of date and were less marked in the recognition of content or date. In public and personal events tests, patients with PD showed a relative impairment in dating capacity, compared with their memory for the content of events, which was independent of dementia. These results suggest that dementia affects the recall of distant events less than recall of recent ones. Furthermore, the selective gradient effects in recall of content suggest that memory for date is served by cognitive processes independent of memory for event content. In PD, dating capacity is a sensitive measure of remote memory function that may be disrupted independently of dementia.

    View details for Web of Science ID A1988N438100010

    View details for PubMedID 3365547

  • Verbal and Nonverbal Short-Term Memory in Patients With Alzheimer's Disease and in Healthy Elderly Subjects DEVELOPMENTAL NEUROPSYCHOLOGY Sullivan, E. V., Corkin, S., Growdon, J. H. 1986; 2 (4): 387-400

    View details for Web of Science ID A1985AML0500002

    View details for PubMedID 3860084



    Survival curves were made for 190 World War II veterans with penetrating head injuries, and for 106 WW II veterans with peripheral nerve injuries who matched the subjects with head injuries with respect to age at injury, years of formal education, and preinjury intelligence-test score. The results indicated that penetrating head injury coupled with posttraumatic epilepsy shortened life expectancy in subjects who survived the early postinjury period, but that head injury alone did not. Educational level was also a significant variable independent of seizures: subjects with more education survived longer than those with less education. Age at injury and the difference between preinjury and postinjury intelligence-test scores did not predict survival status.

    View details for Web of Science ID A1984TG03000016

    View details for PubMedID 6433861



    Recent longitudinal studies of aging have suggested that intellectually inferior subjects selectively drop out during the course of the investigation. This issue of subject attrition was addressed in a neuropsychological study of 314 veterans who had sustained head or peripheral nerve injuries in World War II. These men were examined originally by Teuber and his colleagues at New York University in the 1940s and 1950s, and the veterans' participation was sought for a 40-year follow-up study at the Massachusetts Institute of Technology. In the current follow-up study, the veterans were subdivided according to their response to recent recruitment letters: those who agreed to be retested, those with whom recent contact was established but who declined to participate, those who did not reply to our correspondence, and those who were deceased. Those who agreed to be retested in the 1980s had significantly more education and achieved significantly higher Army General Classification Test scores both before and after injury than did the untested cohort. Even with the selective subject attrition, however, the remaining sample represented a broad range of intellectual competence.

    View details for Web of Science ID A1984TS26800013

    View details for PubMedID 6491184

  • On the short-term retention of serial, tactile stimuli. Memory & cognition SULLIVAN, E. V., Turvey, M. T. 1974; 2 (4): 601-606


    In three experiments using the short-term memory distractor paradigm, Ss attempted to remember which three or four phalanges of the left hand had been stimulated and in what order. The experiments showed that forgetting increased as a function of trials, that such proactive effects could be eliminated by separating the successive trials by several minutes, that both verbal and nonverbal distractor tasks impaired retention, and that forgetting reached a maximum in approximately 6 sec. All of these results concur with those generally obtained for the short-term retention of verbal material. In addition, it was shown that the tactile recall was significantly poorer after an arithmetic distractor task presented visually than after the same task presented aurally. This result suggests an overlap between the mechanisms of tactile retention and the mechanisms of vision.

    View details for DOI 10.3758/BF03198127

    View details for PubMedID 24203726

  • Short-term retention of tactile stimulation. Quarterly journal of experimental psychology SULLIVAN, E. V., Turvey, M. T. 1972; 24 (3): 253-261

    View details for PubMedID 5049927