Antonio Hardan, M.D.

All Publications

• Interrelationship Between Cognitive Control, Anxiety, and Restricted and Repetitive Behaviors in Children with 22q11.2 Deletion Syndrome. Autism research : official journal of the International Society for Autism Research Uljarevic, M., McCabe, K. L., Angkustsiri, K., Simon, T. J., Hardan, A. Y. 2019

  Abstract

  Restricted and repetitive behaviors (RRB) are common in individuals with 22q11.2 microdeletion syndrome (22q11.2DS), yet the underlying mechanisms of these behaviors remain poorly characterized. In the present pilot investigation, we aimed to further our understanding of RRB in 22q11.2DS by exploring their relationship with cognitive control and anxiety as well as with sex, chronological age, and full-scale IQ. Parents of 38 children with 22q11.2DS (17 females; Mage = 11.15years, SD = 2.46) completed the Social Communication Questionnaire as a measure of RRB and social and communication (SC) problems and the Behavioral Assessment System for Children-2 as a measure of anxiety and cognitive control. Higher RRB scores were significantly associated with higher anxiety levels (r = 0.44, P = 0.006), more impairments in cognitive control (r = 0.56, P<0.001), and higher SC scores (r = 0.43, P = 0.011). In the first step of the hierarchical regression model, anxiety accounted for 24.5% of variance (F = 10.05, P = 0.003); cognitive control accounted for an additional 18.1% of variance (Fchange = 11.15, P<0.001) in the second step; SC score accounted for only 0.8% of additional variance in the third step (Fchange = 0.40, P = 0.53). The final model explained 43.4% of variance (F = 7.42, P = 0.001), with cognitive control as a unique independent predictor of RRB score (t = 2.52, P = 0.01). The current study provides the first exploration of the cognitive control-anxiety-RRB link in individuals with 22q11.2DS and points to cognitive control as a potentially viable target for treatments aimed at reducing RRB. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with 22q11.2 deletion syndrome show high levels of repetitive behaviors, however, the previous research has not explored why people with this syndrome exhibit high rates of repetitive behaviors. Understanding the reasons for the high levels of repetitive behaviors is important given that these behaviors can be highly impairing. Our study found that repetitive behaviors were associated with impaired ability to self-regulate and high levels of anxiety. These findings need to be further replicated; however, they are important as they suggest potentially promising ways of reducing these behaviors.

  View details for DOI 10.1002/aur.2194

  View details for PubMedID 31433576

• A Pivotal Response Treatment Package for Children With Autism Spectrum Disorder: An RCT. Pediatrics Gengoux, G. W., Abrams, D. A., Schuck, R., Millan, M. E., Libove, R., Ardel, C. M., Phillips, J. M., Fox, M., Frazier, T. W., Hardan, A. Y. 2019

  Abstract

  OBJECTIVES: Our aim was to conduct a randomized controlled trial to evaluate a pivotal response treatment package (PRT-P) consisting of parent training and clinician-delivered in-home intervention on the communication skills of children with autism spectrum disorder.METHODS: Forty-eight children with autism spectrum disorder and significant language delay between 2 and 5 years old were randomly assigned to PRT-P (n = 24) or the delayed treatment group (n = 24) for 24 weeks. The effect of treatment on child communication skills was assessed via behavioral coding of parent-child interactions, standardized parent-report measures, and blinded clinician ratings.RESULTS: Analysis of child utterances during the structured laboratory observation revealed that, compared with the delayed treatment group, children in PRT-P demonstrated greater improvement in frequency of functional utterances (F1,41 = 6.07; P = .026; d = 0.61). The majority of parents in the PRT-P group (91%) were able to implement pivotal response treatment (PRT) with fidelity within 24 weeks. Children receiving PRT-P also demonstrated greater improvement on the Brief Observation of Social Communication Change, on the Clinical Global Impressions Improvement subscale, and in number of words used on a parent-report questionnaire.CONCLUSIONS: This is the first 24-week randomized controlled trial in which community treatment is compared with the combination of parent training and clinician-delivered PRT. PRT-P was effective for improving child social communication skills and for teaching parents to implement PRT. Additional research will be needed to understand the optimal combination of treatment settings, intensity, and duration, and to identify child and parent characteristics associated with treatment response.

  View details for DOI 10.1542/peds.2019-0178

  View details for PubMedID 31387868

• A non randomized mentalization intervention for parents of children with autism AUTISM RESEARCH Enav, Y., Erhard-Weiss, D., Kopelman, M., Samson, A. C., Mehta, S., Gross, J. J., Hardan, A. Y. 2019; 12 (7): 1077?86

  View details for DOI 10.1002/aur.2108

  View details for Web of Science ID 000474485800008

• Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research Mariscal, M. G., Oztan, O., Rose, S. M., Libove, R. A., Jackson, L. P., Sumiyoshi, R. D., Trujillo, T. H., Carson, D. S., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2019

  Abstract

  Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.

  View details for DOI 10.1002/aur.2135

  View details for PubMedID 31132232

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)

  View details for DOI 10.1126/scitranslmed.aau7356

  View details for Web of Science ID 000467273900004

• A non randomized mentalization intervention for parents of children with autism. Autism research : official journal of the International Society for Autism Research Enav, Y., Erhard-Weiss, D., Kopelman, M., Samson, A. C., Mehta, S., Gross, J. J., Hardan, A. Y. 2019

  Abstract

  Parents of children diagnosed with autism spectrum disorder (ASD) report higher levels of stress and other negative affective states than parents of typically developing children. One important resource in managing these heightened levels of negative affect is emotion regulation, which in turn depends upon the ability to recognize and understand one's own and others' mental states (referred to as mentalization or reflective functioning). In this study, parents of children with ASD either participated in a mentalization-based group intervention (N=36) or a delayed treatment (N=28). Compared to delayed treatment participants, parents in the mentalization-based group had increases in reflective functioning and in the belief that emotions can change. Moreover, they reported decreased behavioral and emotional symptoms in their children, and greater parental self-efficacy. These preliminary findings support previous studies, which have shown that mentalization-based interventions for parents lead to positive outcomes, and suggest that these findings may apply to a diverse population of parents such as those of children with broader autism phenotype or children with different neurological disorders. Further studies to evaluate the effects of the intervention are recommended. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, parents of children with ASD participated in a group intervention designed to increase their awareness of mental states (their own and their children's) and to enhance their emotion regulation. Compared to delayed treatment parents, those in the intervention group showed increased awareness of developmental states, and reported increased belief that emotions can change and decreased levels of behavioral and emotional symptoms in their children.

  View details for PubMedID 31002483

• Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder AUTISM Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2019; 23 (3): 713?25

  View details for DOI 10.1177/1362361318775538

  View details for Web of Science ID 000464503900017

• A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism JOURNAL OF PSYCHIATRIC RESEARCH Hegarty, J. P., Gengoux, G. W., Berquist, K. L., Milian, M., Tamura, S. M., Karve, S., Rosenthal, M. D., Phillips, J. M., Hardan, A. Y. 2019; 111: 140?44

  View details for DOI 10.1016/j.jpsychires.2019.02.001

  View details for Web of Science ID 000466252700020

• A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism. Journal of psychiatric research Hegarty, J. P., Gengoux, G. W., Berquist, K. L., Millan, M. E., Tamura, S. M., Karve, S., Rosenthal, M. D., Phillips, J. M., Hardan, A. Y. 2019; 111: 140?44

  Abstract

  Children with autism spectrum disorder (ASD) frequently exhibit language delays and functional communication deficits. Pivotal response treatment (PRT) is an effective intervention for targeting these skills; however, similar to other behavioral interventions, response to PRT is variable across individuals. Thus, objective markers capable of predicting treatment response are critically-needed to identify which children are most likely to benefit from this intervention. In this pilot study, we investigated whether structural neuroimaging measures from language regions in the brain are associated with response to PRT. Children with ASD (n?=?18) who were receiving PRT to target their language deficits were assessed with MRI at baseline. T1-weighted images were segmented with FreeSurfer and morphometric measures of the primary language regions (inferior frontal (IFG) and superior temporal (STG) gyri) were evaluated. Children with ASD and language deficits did not exhibit the anticipated relationships between baseline structural measures of language regions and baseline language abilities, as assessed by the number of utterances displayed during a structured laboratory observation (SLO). Interestingly, the level of improvement on the SLO was correlated with baseline asymmetry of the IFG, and the size of the left STG at baseline was correlated with the level of improvement on standardized parental questionnaires. Although very preliminary, the observed associations between baseline structural properties of language regions and improvement in language abilities following PRT suggest that neuroimaging measures may be able to help identify which children are most likely to benefit from specific language treatments, which could help improve precision medicine for children with ASD.

  View details for PubMedID 30771619

• Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder. Molecular psychiatry Hegarty, J. P., Pegoraro, L. F., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  Abstract

  Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n=164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

  View details for PubMedID 30659287

• Challenges to the social motivation theory of autism: The dangers of counteracting an imprecise theory with even more imprecision BEHAVIORAL AND BRAIN SCIENCES Uljarevic, M., Vivanti, G., Leekam, S. R., Hardan, A. Y. 2019; 42

  View details for DOI 10.1017/S0140525X18002339

  View details for Web of Science ID 000477605900031

• Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies. Autism : the international journal of research and practice Hardan, A. Y., Hendren, R. L., Aman, M. G., Robb, A., Melmed, R. D., Andersen, K. A., Luchini, R., Rahman, R., Ali, S., Jia, X. D., Mallick, M., Lateiner, J. E., Palmer, R. H., Graham, S. M. 2019: 1362361318824103

  Abstract

  Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ?48?weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ?10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

  View details for PubMedID 31027422

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Science translational medicine Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019

  Abstract

  The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F1,20 = 9.853; P = 0.0052; ?p2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

  View details for PubMedID 31043522

• Development and Validation of Objective and Quantitative Eye Tracking-Based Measures of Autism Risk and Symptom Levels. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Klingemier, E. W., Parikh, S., Speer, L., Strauss, M. S., Eng, C., Hardan, A. Y., Youngstrom, E. A. 2018; 57 (11): 858?66

  Abstract

  OBJECTIVE: The primary aim of this study was to develop and validate eye tracking-based measures for estimating autism spectrum disorder (ASD) risk and quantifying autism symptom levels.METHOD: Eye tracking data were collected from youth during an initial evaluation visit, with administrators blinded to all clinical information. Consensus diagnoses were given by the multidisciplinary team. Participants viewed a 5-minute video that included 44 dynamic stimuli from 7 distinct paradigms while gaze was recorded. Gaze metrics were computed for temporally defined regions of interest. Autism risk and symptom indices aggregated gaze measures showing significant bivariate relationships with ASD diagnosis and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) symptom severity levels in a training sample (75%, n= 150). Receiver operating characteristic curve analysis and nonparametric correlations were used to cross-validate findings in a test sample (25%; n= 51).RESULTS: Most children (n= 201, 92%) completed a valid eye tracking assessment (ages 1.6?17.6; 80% male; ASD n= 91, non-ASD n= 110). In the test subsample, the autism risk index had high accuracy for ASD diagnosis (area under the curve [AUC]= 0.86, 95% CI=0.75-0.95), whereas the autism symptom index was strongly associated with ADOS-2 total severity scores (r= 0.41, p< .001). Validity was not substantively attenuated after adjustment for language, nonverbal cognitive ability, or other psychopathology symptoms (r= 0.40-0.67, p > .001).CONCLUSION: Eye tracking measures appear to be useful quantitative, objective measures of ASD risk and autism symptom levels. If independently replicated and scaled for clinical use, eye tracking-based measures could be used to inform clinical judgment regarding ASD identification and to track autism symptom levels.

  View details for PubMedID 30392627

• Cerebrospinal fluid vasopressin and symptom severity in children with autism. Annals of neurology Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., Parker, K. J. 2018

  Abstract

  Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30152888

• Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Garner, J. P., Oztan, O., Tarara, E. R., Li, J., Sclafani, V., Del Rosso, L. A., Chun, K., Berquist, S. W., Chez, M. G., Partap, S., Hardan, A. Y., Sherr, E. H., Capitanio, J. P. 2018; 10 (439)

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.

  View details for PubMedID 29720452

• Effects of a parent-implemented Developmental Reciprocity Treatment Program for children with autism spectrum disorder. Autism : the international journal of research and practice Gengoux, G. W., Schapp, S., Burton, S., Ardel, C. M., Libove, R. A., Baldi, G., Berquist, K. L., Phillips, J. M., Hardan, A. Y. 2018: 1362361318775538

  Abstract

  Developmental approaches to autism treatment aim to establish strong interpersonal relationships through joint play. These approaches have emerging empirical support; however, there is a need for further research documenting the procedures and demonstrating their effectiveness. This pilot study evaluated changes in parent behavior and child autism symptoms following a 12-week Developmental Reciprocity Treatment parent-training program. A total of 22 children with autism spectrum disorder between 2 and 6years (mean age=44.6months, standard deviation=12.7) and a primary caregiver participated in 12 weekly sessions of Developmental Reciprocity Treatment parent training, covering topics including introduction to developmental approaches, supporting attention and motivation, sensory regulation and sensory-social routines, imitation/building nonverbal communication, functional language development, and turn taking. Results indicated improvement in aspects of parent empowerment and social quality of life. Improvement in core autism symptoms was observed on the Social Responsiveness Scale total score (F(1,19): 5.550, p=0.029), MacArthur-Bates Communicative Development Inventories number of words produced out of 680 (F(1,18): 18.104, p=0.000), and two subscales of the Repetitive Behavior Scale, Revised (compulsive, p=0.046 and restricted, p=0.025). No differences in sensory sensitivity were observed on the Short Sensory Profile. Findings from this pilot study indicate that Developmental Reciprocity Treatment shows promise and suggest the need for future controlled trials of this developmentally based intervention.

  View details for PubMedID 29775078

• Plasma anandamide concentrations are lower in children with autism spectrum disorder MOLECULAR AUTISM Karhson, D. S., Krasinska, K. M., Dallaire, J., Libove, R. A., Phillips, J. M., Chien, A. S., Garner, J. P., Hardan, A. Y., Parker, K. J. 2018; 9: 18

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N?=?112).Anandamide concentrations significantly differentiated ASD cases (N?=?59) from controls (N?=?53), such that children with lower anandamide concentrations were more likely to have ASD (p?=?0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p?=?0.034).These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

  View details for PubMedID 29564080

• Comprehensive Examination of the GABAergic System in Adults With Autism by Simultaneous [18F] Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy Fung, L., Flores, R., Liu, K., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2017: S206?S207

  View details for Web of Science ID 000416846301148

• Biomarker Discovery for Social Impairments: Translation From a Novel Monkey Model to Patients With Autism Parker, K., Garner, J., Oztan, O., Tarara, E., Li, J., Sclafani, V., Del Rosso, L., Chun, K., Berquist, S., Chez, M., Partap, S., Hardan, A., Sherr, E., Capitanio, J. NATURE PUBLISHING GROUP. 2017: S501?S502

  View details for Web of Science ID 000416846303041

• A Meta-Analysis of Gaze Differences to Social and Nonsocial Information Between Individuals With and Without Autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Strauss, M., Klingemier, E. W., Zetzer, E. E., Hardan, A. Y., Eng, C., Youngstrom, E. A. 2017; 56 (7): 546?55

  Abstract

  Numerous studies have identified abnormal gaze in individuals with autism. However, only some findings have been replicated, the magnitude of effects is unclear, and the pattern of gaze differences across stimuli remains poorly understood. To address these gaps, a comprehensive meta-analysis of autism eye-tracking studies was conducted.PubMed and a manual search of 1,132 publications were used to identify studies comparing looking behavior to social and/or nonsocial stimuli between individuals with autism and controls. Sample characteristics, eye-tracking methods, stimulus features, and regions of interest (ROIs) were coded for each comparison within each study. Multivariate mixed-effects meta-regression analyses examined the impact of study methodology, stimulus features, and ROI on effect sizes derived from comparisons using gaze-fixation metrics.The search yielded 122 independent studies with 1,155 comparisons. Estimated effect sizes tended to be small to medium but varied substantially across stimuli and ROIs. Overall, nonsocial ROIs yielded larger effect sizes than social ROIs; however, eye and whole-face regions from stimuli with human interaction produced the largest effects (Hedges g = 0.47 and 0.50, respectively). Studies with weaker study designs or reporting yielded larger effects, but key effects remained significant and medium in size, even for high-rigor designs.Individuals with autism show a reliable pattern of gaze abnormalities that suggests a basic problem with selecting socially relevant versus irrelevant information for attention and that persists across ages and worsens during perception of human interactions. Aggregation of gaze abnormalities across stimuli and ROIs could yield clinically useful risk assessment and quantitative, objective outcome measurements.

  View details for PubMedID 28647006

  View details for PubMedCentralID PMC5578719

• The measurement properties of the spence children's anxiety scale-parent version in a large international pooled sample of young people with autism spectrum disorder. Autism research Magiati, I., Lerh, J. W., Hollocks, M. J., Uljarevic, M., Rodgers, J., McConachie, H., Ozsivadjian, A., South, M., Van Hecke, A., Hardan, A., Libove, R., Leekam, S., Simonoff, E. 2017

  Abstract

  Anxiety-related difficulties are common in ASD, but measuring anxiety reliably and validly is challenging. Despite an increasing number of studies, there is no clear agreement on which existing anxiety measure is more psychometrically sound and what is the factor structure of anxiety in ASD. The present study examined the internal consistency, convergent, divergent, and discriminant validity, as well as the factor structure of the Spence Children's Anxiety Scale-Parent Version (SCAS-P), in a large international pooled sample of 870 caregivers of youth with ASD from 12 studies in the United Kingdom, United States, and Singapore who completed the SCAS-P. Most were community recruited, while the majority had at least one measure of ASD symptomatology and either cognitive or adaptive functioning measures completed. Existing SCAS-P total scale and subscales had excellent internal consistency and good convergent, divergent and discriminant validity similar to or better than SCAS-P properties reported in typically developing children, except for the poorer internal consistency of the physical injury subscale. Confirmatory Factor Analysis (CFA) of the existing SCAS-P six-correlated factor structure was a poor fit for this pooled database. Principal component analysis using half of the pooled sample identified a 30-item five correlated factor structure, but a CFA of this PCA-derived structure in the second half of this pooled sample revealed a poor fit, although the PCA-derived SCAS-P scale and subscales had stronger validity and better internal consistency than the original SCAS-P. The study's limitations, the use of the SCAS-P to screen for DSM-derived anxiety problems in ASD and future research directions are discussed. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1809

  View details for PubMedID 28574646

• Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Aman, M. G., Findling, R. L., Hardan, A. Y., Hendren, R. L., Melmed, R. D., Kehinde-Nelson, O., Hsu, H., Trugman, J. M., Palmer, R. H., Graham, S. M., Gage, A. T., Perhach, J. L., Katz, E. 2017; 27 (5): 403?12

  Abstract

  Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15?mg/day.There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p?=?0.02) after 12 weeks.This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

  View details for PubMedID 26978327

  View details for PubMedCentralID PMC5510039

• Simultaneous [18F]Flumazenil-Positron Emission Tomography and GABA-Magnetic Resonance Spectroscopy in Adults with Autism and Healthy Volunteers Fung, L., Flores, R., Gu, M., Hjoernevik, T., Hardan, A., Spielman, D., Chin, F. ELSEVIER SCIENCE INC. 2017: S127?S128

  View details for DOI 10.1016/j.biopsych.2017.02.325

  View details for Web of Science ID 000400348700311

• Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking? WORLD NEUROSURGERY Sivanesan, S., Tan, A., Jeyaraj, R., Lam, J., Gole, M., Hardan, A., Ashkan, K., Rajadas, J. 2017; 98: 659-672

  Abstract

  Autism Spectrum Disorders (ASDs) are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention, and impaired social and communication skills. ASDs are also associated with a number of functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. Although the exact causes of ASDs are currently unknown, it is suggested that genetic, epigenetic and environmental factors play critical roles. Recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive. In this review, we seek to provide a contemporary account of the key pathological events pertaining to autism: the theory of oxidative stress and inflammatory causes; ideas of immune dysfunction; the probable biomarkers that can be used for diagnostics - and the use of pharmaceuticals and stem cells as possible candidates for the treatment of ASDs.

  View details for DOI 10.1016/j.wneu.2016.09.100

  View details for Web of Science ID 000397028300082

• Incidental brain MRI findings in an autism twin study. Autism research Monterrey, J. C., Philips, J., Cleveland, S., Tanaka, S., Barnes, P., Hallmayer, J. F., Reiss, A. L., Lazzeroni, L. C., Hardan, A. Y. 2017; 10 (1): 113-120

  Abstract

  Brain magnetic resonance imaging (MRI) studies suggest the prevalence of asymptomatic "incidental" findings (IF) in autism spectrum disorder (ASD) is similar to that of neurotypically developing (NT) controls. However, given the causes of IF may include both genetic and environmental factors, a twin study would facilitate comparing brain IF between ASD and NT subjects. MRI scans were examined to assess the prevalence of brain IF in twin "case pairs" (at least one twin with diagnosis of ASD) and twin "control pairs" (NT). Fifty case pairs and thirty-two control pairs were analyzed. IF were found in 68% of subjects with ASD, 71% of unaffected ASD siblings, and in 58% of control subjects (P?=?0.4). IF requiring clinical follow-up occurred more frequently in subjects with ASD compared to NT controls (17% vs. 5%, respectively; P?=?0.02). The concordance rate of IF in twins was 83%. A mixed effects model found younger age, male sex, and "family environment" to be significantly associated with IF. There was no difference in the prevalence rate of IF between ASD subjects and NT controls. More IF required clinical follow-up in ASD subjects compared to NT controls. The prevalence rate of IF observed in this twin study was higher than rates previously reported in singleton studies. Our results suggest the shared environment of twins - perhaps in utero - increases the risk of brain IF. Brain MRI in the initial work-up of ASD may be indicated in twins, especially in males. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1720

  View details for PubMedID 27874265

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedCentralID PMC5544319

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119?24

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for PubMedID 28696286

• Biomarker discovery for disease status and symptom severity in children with autism. Psychoneuroendocrinology Oztan, O., Jackson, L. P., Libove, R. A., Sumiyoshi, R. D., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2017; 89: 39?45

  Abstract

  Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

  View details for PubMedID 29309996

• A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry Hegarty, J. P., Gu, M., Spielman, D. M., Cleveland, S. C., Hallmayer, J. F., Lazzeroni, L. C., Raman, M. M., Frazier, T. W., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2017

  Abstract

  Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with (1)H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

  View details for PubMedID 28941767

• Intranasal Vasopressin Treatment Improves Social Abilities in Children With Autism Parker, K., Oztan, O., Libove, R., Sumiyoshi, R., Summers, J., Hinman, K., Fung, L., Motonaga, K., Carson, D., Phillips, J., Garner, J., Hardan, A. NATURE PUBLISHING GROUP. 2016: S341

  View details for Web of Science ID 000440365600575

• Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking? World neurosurgery Sivanesan, S., Tan, A., Jeyaraj, R., Lam, J., Gole, M., Hardan, A., Ashkan, K., Rajadas, J. 2016

  Abstract

  Autism Spectrum Disorders (ASDs) are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention, and impaired social and communication skills. ASDs are also associated with a number of functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. Although the exact causes of ASDs are currently unknown, it is suggested that genetic, epigenetic and environmental factors play critical roles. Recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive. In this review, we seek to provide a contemporary account of the key pathological events pertaining to autism: the theory of oxidative stress and inflammatory causes; ideas of immune dysfunction; the probable biomarkers that can be used for diagnostics - and the use of pharmaceuticals and stem cells as possible candidates for the treatment of ASDs.

  View details for DOI 10.1016/j.wneu.2016.09.100

  View details for PubMedID 27725300

• White matter structure in the uncinate fasciculus: Implications for socio-affective deficits in Autism Spectrum Disorder. Psychiatry research Samson, A. C., Dougherty, R. F., Lee, I. A., Phillips, J. M., Gross, J. J., Hardan, A. Y. 2016; 255: 66-74

  Abstract

  Individuals with Autism Spectrum Disorder (ASD) have social and communication deficits and difficulties regulating emotions. The brain bases of these socio-affective deficits are not yet clear, but one candidate is structural connectivity in the left uncinate fasciculus, which connects limbic temporal and frontal areas thought to be involved in socio-affective processing. In this study, we assessed white matter structure in the left and right uncinate fasciculus in 18 high-functioning individuals with ASD and 18 group-matched typically developing (TD) controls using Diffusion Tensor Imaging. To test specificity of the associations, we also examined the association between both uncinate fasciculi and restricted and repetitive behaviors. Compared to TD individuals, individuals with ASD had significantly lower fractional anisotropy (FA) in the left and right uncinate. Group status significantly moderated the association between left uncinate and socio-affective deficits, indicating that within the ASD group, FA was associated with socio-affective deficits: Individuals with ASD with lower FA in the left uncinate had significantly more social and emotion regulation deficits. There was no association with restricted and repetitive behaviors. This study provides evidence that the left uncinate may play a critical role in socio-affective skills in individuals with ASD.

  View details for DOI 10.1016/j.pscychresns.2016.08.004

  View details for PubMedID 27552717

• Endocannabinoid signaling in social functioning: an RDoC perspective. Translational psychiatry Karhson, D. S., Hardan, A. Y., Parker, K. J. 2016; 6 (9)

  Abstract

  Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning. This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors-?9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.

  View details for DOI 10.1038/tp.2016.169

  View details for PubMedID 27676446

  View details for PubMedCentralID PMC5048207

• Equivalence of symptom dimensions in females and males with autism. Autism Frazier, T. W., Hardan, A. Y. 2016

  Abstract

  This study investigated equivalence of autism symptom domains in males and females with autism. Symptom data were obtained from 2643 children and adolescents with autism spectrum disorder (352 females, 2291 males; age range?=?4-17?years) included in the Simons Simplex Collection. Items from the Social Responsiveness Scale and Autism Diagnostic Interview-Revised were mapped to nine a priori symptom dimensions. Multi-group confirmatory factor models, including measurement equivalence and item response theory analyses, examined whether males and females showed measurement or structural differences in autism symptom constructs. Results indicated mean differences in restricted interests that were not due to measurement bias. No other symptom dimension showed evidence of measurement bias and autism symptom structure was highly similar between males and females. Future studies are needed to carefully estimate any sex differences in the content, frequency, or intensity/severity of restricted interests in females and males.

  View details for PubMedID 27503465

• The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Schill, L., Schoyer, L., Andresen, B. S., Bakker, A., Bayrak-Toydemir, P., Burkitt-Wright, E., Chatfield, K., Elefteriou, F., Elgersma, Y., Fisher, M. J., Franz, D., Gelb, B. D., Goriely, A., Gripp, K. W., Hardan, A. Y., Keppler-Noreuil, K. M., Kerr, B., Korf, B., Leoni, C., McCormick, F., Plotkin, S. R., Rauen, K. A., Reilly, K., Roberts, A., Sandler, A., Siegel, D., Walsh, K., Widemann, B. C. 2016; 170 (8): 1959-1966

  Abstract

  The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37723

  View details for PubMedID 27155140

• A proton spectroscopy study of white matter in children with autism. Progress in neuro-psychopharmacology & biological psychiatry Hardan, A. Y., Fung, L. K., Frazier, T., Berquist, S. W., Minshew, N. J., Keshavan, M. S., Stanley, J. A. 2016; 66: 48-53

  Abstract

  White matter abnormalities have been described in autism spectrum disorder (ASD) with mounting evidence implicating these alterations in the pathophysiology of the aberrant connectivity reported in this disorder. The goal of this investigation is to further examine white matter structure in ASD using proton magnetic resonance spectroscopy ((1)H MRS). Multi-voxel, short echo-time in vivo(1)H MRS data were collected from 17 male children with ASD and 17 healthy age- and gender-matched controls. Key (1)H MRS metabolite ratios relative to phosphocreatine plus creatine were obtained from four different right and left white matter regions. Significantly lower N-acetylaspartate/creatine ratios were found in the anterior white matter regions of the ASD group when compared to controls. These findings reflect impairment in neuroaxonal white matter tissue and shed light on the neurobiologic underpinnings of white matter abnormalities in ASD by implicating an alteration in myelin and/or axonal development in this disorder.

  View details for DOI 10.1016/j.pnpbp.2015.11.005

  View details for PubMedID 26593330

• Development of an Objective Autism Risk Index Using Remote Eye Tracking. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Klingemier, E. W., Beukemann, M., Speer, L., Markowitz, L., Parikh, S., Wexberg, S., Giuliano, K., Schulte, E., Delahunty, C., Ahuja, V., Eng, C., Manos, M. J., Hardan, A. Y., Youngstrom, E. A., Strauss, M. S. 2016; 55 (4): 301-309

  Abstract

  Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD), and numerous studies have identified abnormal attention patterns in ASD. The primary aim of the present study was to create an objective, eye tracking-based autism risk index.In initial and replication studies, children were recruited after referral for comprehensive multidisciplinary evaluation of ASD and subsequently grouped by clinical consensus diagnosis (ASD n = 25/15, non-ASD n = 20/19 for initial/replication samples). Remote eye tracking was blinded to diagnosis and included multiple stimuli. Dwell times were recorded to each a priori-defined region of interest (ROI) and averaged across ROIs to create an autism risk index. Receiver operating characteristic curve analyses examined classification accuracy. Correlations with clinical measures evaluated whether the autism risk index was associated with autism symptom severity independent of language ability.In both samples, the autism risk index had high diagnostic accuracy (area under the curve [AUC] = 0.91 and 0.85, 95% CIs = 0.81-0.98 and 0.71-0.96), was strongly associated with Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) severity scores (r = 0.58 and 0.59, p < .001), and not significantly correlated with language ability (r ?| -0.28|, p > .095).The autism risk index may be a useful quantitative and objective measure of risk for autism in at-risk settings. Future research in larger samples is needed to cross-validate these findings. If validated and scaled for clinical use, this measure could inform clinical judgment regarding ASD diagnosis and track symptom improvements.

  View details for DOI 10.1016/j.jaac.2016.01.011

  View details for PubMedID 27015721

  View details for PubMedCentralID PMC4808563

• Development of an Objective Autism Risk Index Using Remote Eye Tracking JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Klingemier, E. W., Beukemann, M., Speer, L., Markowitz, L., Parikh, S., Wexberg, S., Giuliano, K., Schulte, E., Delahunty, C., Ahuja, V., Eng, C., Manos, M. J., Hardan, A. Y., Youngstrom, E. A., Strauss, M. S. 2016; 55 (4): 301-309

  Abstract

  Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD), and numerous studies have identified abnormal attention patterns in ASD. The primary aim of the present study was to create an objective, eye tracking-based autism risk index.In initial and replication studies, children were recruited after referral for comprehensive multidisciplinary evaluation of ASD and subsequently grouped by clinical consensus diagnosis (ASD n = 25/15, non-ASD n = 20/19 for initial/replication samples). Remote eye tracking was blinded to diagnosis and included multiple stimuli. Dwell times were recorded to each a priori-defined region of interest (ROI) and averaged across ROIs to create an autism risk index. Receiver operating characteristic curve analyses examined classification accuracy. Correlations with clinical measures evaluated whether the autism risk index was associated with autism symptom severity independent of language ability.In both samples, the autism risk index had high diagnostic accuracy (area under the curve [AUC] = 0.91 and 0.85, 95% CIs = 0.81-0.98 and 0.71-0.96), was strongly associated with Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) severity scores (r = 0.58 and 0.59, p < .001), and not significantly correlated with language ability (r ?| -0.28|, p > .095).The autism risk index may be a useful quantitative and objective measure of risk for autism in at-risk settings. Future research in larger samples is needed to cross-validate these findings. If validated and scaled for clinical use, this measure could inform clinical judgment regarding ASD diagnosis and track symptom improvements.

  View details for DOI 10.1016/j.jaac.2016.01.011

  View details for Web of Science ID 000373315400009

  View details for PubMedCentralID PMC4808563

• Irritability and Problem Behavior in Autism Spectrum Disorder: A Practice Pathway for Pediatric Primary Care PEDIATRICS McGuire, K., Fung, L. K., Hagopian, L., Vasa, R. A., Mahajan, R., Bernal, P., Silberman, A. E., Wolfe, A., Coury, D. L., Hardan, A. Y., Veenstra-VanderWeele, J., Whitaker, A. H. 2016; 137: S136-S148

  Abstract

  Pediatric primary care providers (PCPs) caring for patients with autism spectrum disorder (ASD) often encounter irritability (vocal or motoric outbursts expressive of anger, frustration, or distress) and problem behavior (directed acts of aggression toward other people, self, or property). The Autism Intervention Research Network on Physical Health and Autism Speaks Autism Treatment Network charged a multidisciplinary workgroup with developing a practice pathway to assist PCPs in the evaluation and treatment of irritability and problem behavior (I/PB).The workgroup reviewed the literature on the evaluation and treatment of contributory factors for I/PB in ASD. The workgroup then achieved consensus on the content and sequence of each step in the pathway.The practice pathway is designed to help the PCP generate individualized treatment plans based on contributing factors identified in each patient. These factors may include medical conditions, which the PCP is in a key position to address; functional communication challenges that can be addressed at school or at home; psychosocial stressors that may be ameliorated; inadvertent reinforcement of I/PB; and co-occurring psychiatric conditions that can be treated. The pathway provides guidance on psychotropic medication use, when indicated, within an individualized treatment plan. In addition to guidance on assessment, referral, and initial treatment, the pathway includes monitoring of treatment response and periodic reassessment.The pediatric PCP caring for the patient with ASD is in a unique position to help generate an individualized treatment plan that targets factors contributing to I/PB and to implement this plan in collaboration with parents, schools, and other providers.

  View details for DOI 10.1542/peds.2015-2851L

  View details for Web of Science ID 000371393700011

  View details for PubMedID 26908469

• Pharmacologic Treatment of Severe Irritability and Problem Behaviors in Autism: A Systematic Review and Meta-analysis. Pediatrics Fung, L. K., Mahajan, R., Nozzolillo, A., Bernal, P., Krasner, A., Jo, B., Coury, D., Whitaker, A., Veenstra-VanderWeele, J., Hardan, A. Y. 2016; 137: S124-35

  Abstract

  Autism spectrum disorder (ASD) is increasingly recognized as a public health issue. Irritability and aggression (IA) often negatively affect the lives of people with ASD and their families. Although many medications have been tested for IA in ASDs in randomized controlled trials (RCTs), critical quantitative analyses of these trials are lacking in the literature.To systematically review and quantitatively analyze the efficacy and safety of pharmacologic treatments for IA in youth with ASD.Studies were identified from Medline, PsycINFO, Embase, and review articles.Original articles on placebo-controlled RCTs of pharmacologic treatments of IA in youth age 2 to 17 years with ASD were included. Data items included study design, study goals, details of study participants, details of intervention, study results, statistical methods, side effects, and risks of bias. The primary study outcome measure was the effect size of reduction in the Aberrant Behavioral Checklist-Irritability (ABC-I) scores in the medication group, as compared with placebo, in RCTs using parallel groups design.Forty-six RCTs were identified. Compared with placebo, 3 compounds resulted in significant improvement in ABC-I at the end of treatment. Risperidone and aripiprazole were found to be the most effective, with the largest effect sizes. Sedation, extrapyramidal sides effects, and weight gain were assessed quantitatively.Although risperidone and aripiprazole have the strongest evidence in reducing ABC-I in youth with ASD, a few other compounds also showed significant efficacy with fewer potential side effects and adverse reactions in single studies.

  View details for DOI 10.1542/peds.2015-2851K

  View details for PubMedID 26908468

• Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography JOURNAL OF CLINICAL SLEEP MEDICINE Primeau, M., Gershon, A., Talbot, L., Cotto, I., Lotspeich, L., Hardan, A., Hallmayer, J., O'Hara, R. 2016; 12 (3): 357-362

  Abstract

  Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

  View details for DOI 10.5664/jcsm.5584

  View details for Web of Science ID 000374139600013

  View details for PubMedCentralID PMC4773615

• Pregnenolone in the Treatment of Irritability in Autism Spectrum Disorder: A Post-Hoc Metabolomic Analysis Fung, L., Sun, W., Libove, R., Tanaka, S., Kwa, L., Philips, J., Haddad, F., Rajadas, J., Hardan, A. NATURE PUBLISHING GROUP. 2015: S188

  View details for Web of Science ID 000366597700336

• Maladaptive Behavior in Autism Spectrum Disorder: The Role of Emotion Experience and Emotion Regulation. Journal of autism and developmental disorders Samson, A. C., Hardan, A. Y., Lee, I. A., Phillips, J. M., Gross, J. J. 2015; 45 (11): 3424-3432

  Abstract

  Maladaptive behavior is common in Autism Spectrum Disorder (ASD). However, the factors that give rise to maladaptive behavior in this context are not well understood. The present study examined the role of emotion experience and emotion regulation in maladaptive behavior in individuals with ASD and typically developing (TD) participants. Thirty-one individuals with ASD and 28 TD participants and their parents completed questionnaires assessing emotion experience, regulation, and maladaptive behavior. Compared to TD participants, individuals with ASD used cognitive reappraisal less frequently, which was associated with increased negative emotion experience, which in turn was related to greater levels of maladaptive behavior. By decreasing negative emotions, treatments targeting adaptive emotion regulation may therefore reduce maladaptive behaviors in individuals with ASD.

  View details for DOI 10.1007/s10803-015-2388-7

  View details for PubMedID 25711546

• Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families MOLECULAR AUTISM Frazier, T. W., Youngstrom, E. A., Hardan, A. Y., Georgiades, S., Constantino, J. N., Eng, C. 2015; 6

  Abstract

  Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation.Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels.Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families-this effect was accentuated for male children in female ASD-containing families-or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families.Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis.

  View details for DOI 10.1186/s13229-015-0050-z

  View details for Web of Science ID 000363636200001

  View details for PubMedID 26512313

  View details for PubMedCentralID PMC4623917

• Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation. Journal of autism and developmental disorders Gengoux, G. W., Berquist, K. L., Salzman, E., Schapp, S., Phillips, J. M., Frazier, T. W., Minjarez, M. B., Hardan, A. Y. 2015; 45 (9): 2889-2898

  Abstract

  This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p = .009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p = .001] and the Mullen Scales of Early Learning Composite score [F(1, 20) = 5.43, p = .03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12 weeks post treatment.

  View details for DOI 10.1007/s10803-015-2452-3

  View details for PubMedID 25911977

• Pivotal Response Treatment Parent Training for Autism: Findings from a 3-Month Follow-Up Evaluation JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Gengoux, G. W., Berquist, K. L., Salzman, E., Schapp, S., Phillips, J. M., Frazier, T. W., Minjarez, M. B., Hardan, A. Y. 2015; 45 (9): 2889-2898

  Abstract

  This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p = .009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p = .001] and the Mullen Scales of Early Learning Composite score [F(1, 20) = 5.43, p = .03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12 weeks post treatment.

  View details for DOI 10.1007/s10803-015-2452-3

  View details for Web of Science ID 000360545800018

• Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children MOLECULAR PSYCHIATRY Carson, D. S., Berquist, S. W., Trujillo, T. H., Garner, J. P., Hannah, S. L., Hyde, S. A., Sumiyoshi, R. D., Jackson, L. P., MOSS, J. K., Strehlow, M. C., Cheshier, S. H., Partap, S., Hardan, A. Y., Parker, K. J. 2015; 20 (9): 1085-1090

  Abstract

  The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.

  View details for DOI 10.1038/mp.2014.132

  View details for Web of Science ID 000360175500009

• Emotion regulation in autism spectrum disorder: evidence from parent interviews and children's daily diaries. Journal of child psychology and psychiatry, and allied disciplines Samson, A. C., Wells, W. M., Phillips, J. M., Hardan, A. Y., Gross, J. J. 2015; 56 (8): 903-913

  Abstract

  Although emotion dysregulation is not a defining feature of Autism Spectrum Disorder (ASD), there is a growing consensus that emotional problems play a prominent role in this disorder.The present study examined a wide range of emotion regulation (ER) strategies in 32 individuals with ASD compared to 31 group-matched typically developing (TD) participants in three emotional domains (anger, anxiety, and amusement). Parents of individuals with ASD and TD individuals were interviewed about their child's emotional experience and the use and efficacy of 10 ER strategies. In addition, participants filled out daily diaries on experience and regulation in the same emotional domains.Compared to TD individuals, parents reported that individuals with ASD experienced more anger and anxiety and less amusement, made less frequent use of a variety of adaptive ER strategies (e.g. problem solving, cognitive reappraisal), and made more frequent use of maladaptive strategies (e.g. repetitive behavior). Moreover, individuals with ASD were less effective at utilizing adaptive ER strategies. Self-reports showed differences in experience of amusement and in ER strategies for anger and anxiety, but not in experience of anger and anxiety.This study provides evidence that individuals with ASD less frequently use adaptive - but more frequently use maladaptive - ER strategies. Implications for ASD treatments that focus on increasing the use of adaptive strategies are discussed.

  View details for DOI 10.1111/jcpp.12370

  View details for PubMedID 25442191

• A randomized controlled trial of Pivotal Response Treatment Group for parents of children with autism. Journal of child psychology and psychiatry, and allied disciplines Hardan, A. Y., Gengoux, G. W., Berquist, K. L., Libove, R. A., Ardel, C. M., Phillips, J., Frazier, T. W., Minjarez, M. B. 2015; 56 (8): 884-892

  Abstract

  With rates of autism diagnosis continuing to rise, there is an urgent need for effective and efficient service delivery models. Pivotal Response Treatment (PRT) is considered an established treatment for autism spectrum disorder (ASD); however, there have been few well-controlled studies with adequate sample size. The aim of this study was to conduct a randomized controlled trial to evaluate PRT parent training group (PRTG) for targeting language deficits in young children with ASD.Fifty-three children with autism and significant language delay between 2 and 6 years old were randomized to PRTG (N = 27) or psychoeducation group (PEG; N = 26) for 12 weeks. The PRTG taught parents behavioral techniques to facilitate language development. The PEG taught general information about ASD (clinical trial NCT01881750; http://www.clinicaltrials.gov).Analysis of child utterances during the structured laboratory observation (primary outcome) indicated that, compared with children in the PEG, children in the PRTG demonstrated greater improvement in frequency of utterances (F(2, 43) = 3.53, p = .038, d = 0.42). Results indicated that parents were able to learn PRT in a group format, as the majority of parents in the PRTG (84%) met fidelity of implementation criteria after 12 weeks. Children also demonstrated greater improvement in adaptive communication skills (Vineland-II) following PRTG and baseline Mullen visual reception scores predicted treatment response to PRTG.This is the first randomized controlled trial of group-delivered PRT and one of the largest experimental investigations of the PRT model to date. The findings suggest that specific instruction in PRT results in greater skill acquisition for both parents and children, especially in functional and adaptive communication skills. Further research in PRT is warranted to replicate the observed results and address other core ASD symptoms.

  View details for DOI 10.1111/jcpp.12354

  View details for PubMedID 25346345

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for Web of Science ID 000358597100030

  View details for PubMedCentralID PMC4511760

• Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date CNS DRUGS Fung, L. K., Hardan, A. Y. 2015; 29 (6): 453-463

  Abstract

  Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

  View details for DOI 10.1007/s40263-015-0252-0

  View details for Web of Science ID 000358443400003

• Emotion regulation in children and adolescents with autism spectrum disorder. Autism research Samson, A. C., Hardan, A. Y., Podell, R. W., Phillips, J. M., Gross, J. J. 2015; 8 (1): 9-18

  Abstract

  Emotion dysregulation is not a formal criterion for the diagnosis of autism spectrum disorder (ASD). However, parents and clinicians have long noted the importance of emotional problems in individuals with ASD (e.g. tantrums and "meltdowns"). In this study, 21 high-functioning children and adolescents with ASD and 22 age and gender group-matched typically developing (TD) controls completed a Reactivity and Regulation Situation Task. This task assesses emotional reactivity and spontaneous use of emotion regulation strategies (problem solving, cognitive reappraisal, avoidance, distraction, venting, suppression, and relaxation) in the context of age-appropriate ambiguous and potentially threatening negative scenarios. After the concept of cognitive reappraisal was explained, the scenarios were presented again to participants, and they were prompted to use this strategy. Results indicated that individuals with ASD exhibited the same level of reactivity to negative stimuli as TD participants. Furthermore, youth with ASD had a different emotion regulation profile than TD individuals, characterized by a less frequent use of cognitive reappraisal and more frequent use of suppression. When prompted to use cognitive reappraisal, participants with ASD were less able to implement reappraisal, but benefitted from this strategy when they were able to generate a reappraisal. Findings from this study suggest that cognitive reappraisal strategies may be useful to children and adolescents with ASD. Therefore, the development of treatment programs that focus on enhancing the use of adaptive forms of emotion regulation might decrease emotional problems and optimize long-term outcomes in youth with ASD. Autism Res 2014, ??: ??-??. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1387

  View details for PubMedID 24863869

• Emotion Regulation in Children and Adolescents With Autism Spectrum Disorder AUTISM RESEARCH Samson, A. C., Hardan, A. Y., Podell, R. W., Phillips, J. M., Gross, J. J. 2015; 8 (1): 9-18

  Abstract

  Emotion dysregulation is not a formal criterion for the diagnosis of autism spectrum disorder (ASD). However, parents and clinicians have long noted the importance of emotional problems in individuals with ASD (e.g. tantrums and "meltdowns"). In this study, 21 high-functioning children and adolescents with ASD and 22 age and gender group-matched typically developing (TD) controls completed a Reactivity and Regulation Situation Task. This task assesses emotional reactivity and spontaneous use of emotion regulation strategies (problem solving, cognitive reappraisal, avoidance, distraction, venting, suppression, and relaxation) in the context of age-appropriate ambiguous and potentially threatening negative scenarios. After the concept of cognitive reappraisal was explained, the scenarios were presented again to participants, and they were prompted to use this strategy. Results indicated that individuals with ASD exhibited the same level of reactivity to negative stimuli as TD participants. Furthermore, youth with ASD had a different emotion regulation profile than TD individuals, characterized by a less frequent use of cognitive reappraisal and more frequent use of suppression. When prompted to use cognitive reappraisal, participants with ASD were less able to implement reappraisal, but benefitted from this strategy when they were able to generate a reappraisal. Findings from this study suggest that cognitive reappraisal strategies may be useful to children and adolescents with ASD. Therefore, the development of treatment programs that focus on enhancing the use of adaptive forms of emotion regulation might decrease emotional problems and optimize long-term outcomes in youth with ASD. Autism Res 2014, ??: ??-??. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1387

  View details for Web of Science ID 000350458000002

  View details for PubMedID 24863869

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism. PloS one Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for PubMedID 26200852

• Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date. CNS drugs Fung, L. K., Hardan, A. Y. 2015

  Abstract

  Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

  View details for PubMedID 26104862

• Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography. Journal of clinical sleep medicine Primeau, M., Gershon, A., Talbot, L., Cotto, I., Lotspeich, L., Hardan, A., Hallmayer, J., O'Hara, R. 2015; 12 (3): 357-362

  Abstract

  Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

  View details for DOI 10.5664/jcsm.5584

  View details for PubMedID 26564388

  View details for PubMedCentralID PMC4773615

• Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates. Peptides Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16

  Abstract

  Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

  View details for DOI 10.1016/j.peptides.2014.08.003

  View details for PubMedID 25148831

• Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates PEPTIDES Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16

  Abstract

  Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

  View details for DOI 10.1016/j.peptides.2014.08.003

  View details for Web of Science ID 000344232700003

• Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977

  Abstract

  The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

  View details for DOI 10.1007/s10803-014-2144-4

  View details for Web of Science ID 000343724000027

• Autism in DSM-5 under the microscope: Implications to patients, families, clinicians, and researchers. Asian journal of psychiatry Fung, L. K., Hardan, A. Y. 2014; 11: 93-97

  Abstract

  The changes in the diagnostic classification of the pervasive developmental disorders from the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) to DSM-5 are expected to affect patients with autism, their families, as well as clinicians and researchers in the field of autism. This article reviews the new DSM-5 diagnostic criteria for Autism Spectrum Disorder (ASD) and Social Communication Disorder (SCD), and discusses potential consequences in the perspectives of major stakeholders.

  View details for DOI 10.1016/j.ajp.2014.08.010

  View details for PubMedID 25219947

• Basal ganglia and restricted and repetitive behaviours in Autism Spectrum Disorders: current status and future perspectives EPIDEMIOLOGY AND PSYCHIATRIC SCIENCES Calderoni, S., Bellani, M., Hardan, A. Y., Muratori, F., Brambilla, P. 2014; 23 (3): 235-238

  Abstract

  This editorial offers a concise overview of the recent structural magnetic resonance imaging studies that evaluate the basal ganglia (BG) volumes in autism spectrum disorders (ASD). The putative relationship between the repetitive or stereotyped behaviours of ASD and BG volumes is also explored, with a focus on possible translational approaches.

  View details for DOI 10.1017/S2045796014000171

  View details for Web of Science ID 000340400000006

  View details for PubMedID 24816251

• Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C., Phillips, J. M., Hallmayer, J. F., Hardan, A. Y. 2014; 111 (33): 12258-12263

  Abstract

  The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

  View details for DOI 10.1073/pnas.1402236111

  View details for Web of Science ID 000340438800080

  View details for PubMedID 25092315

• A twin study of heritable and shared environmental contributions to autism. Journal of autism and developmental disorders Frazier, T. W., Thompson, L., Youngstrom, E. A., Law, P., Hardan, A. Y., Eng, C., Morris, N. 2014; 44 (8): 2013-2025

  Abstract

  The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined autism spectrum disorders (ASD). Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels ([Formula: see text]). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95 % CI 0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements.

  View details for DOI 10.1007/s10803-014-2081-2

  View details for PubMedID 24604525

• Emotion dysregulation and the core features of autism spectrum disorder. Journal of autism and developmental disorders Samson, A. C., Phillips, J. M., Parker, K. J., Shah, S., Gross, J. J., Hardan, A. Y. 2014; 44 (7): 1766-1772

  Abstract

  The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child Behavior Checklist. Compared to typically developing controls, children and adolescents with ASD showed more emotion dysregulation and had significantly greater symptom severity on all scales. Within ASD participants, emotion dysregulation was related to all core features of the disorder, but the strongest association was with repetitive behaviors. These findings may facilitate the development of more effective therapeutic strategies targeting emotion dysregulation in order to optimize long-term outcomes for individuals with ASD.

  View details for DOI 10.1007/s10803-013-2022-5

  View details for PubMedID 24362795

• Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis. Autism Frazier, T. W., Youngstrom, E. A., Embacher, R., Hardan, A. Y., Constantino, J. N., Law, P., Findling, R. L., Eng, C. 2014; 18 (5): 571-582

  Abstract

  Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder.

  View details for DOI 10.1177/1362361313481506

  View details for PubMedID 24104512

• Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis AUTISM Frazier, T. W., Youngstrom, E. A., Embacher, R., Hardan, A. Y., Constantino, J. N., Law, P., Findling, R. L., Eng, C. 2014; 18 (5): 571-582

  Abstract

  Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder.

  View details for DOI 10.1177/1362361313481506

  View details for Web of Science ID 000337562700012

  View details for PubMedCentralID PMC4269571

• Dr. Frazier et al. reply. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Georgiades, S., Bishop, S. L., Hardan, A. Y. 2014; 53 (6): 700-701

  View details for DOI 10.1016/j.jaac.2014.04.002

  View details for PubMedID 24839891

• Plasma Vasopressin Levels Positively Predict Social Cognition in Children with Autism Spectrum Disorder but not in Siblings of Probands or Healthy Controls Carson, D. S., Howerton, C. L., Garner, J. P., Libove, R. A., Hyde, S. A., Phillips, J. M., Hardan, A. Y., Parker, K. J. ELSEVIER SCIENCE INC. 2014: 255S?256S

  View details for Web of Science ID 000334101801368

• Behavioral and cognitive characteristics of females and males with autism in the simons simplex collection. Journal of the American Academy of Child and Adolescent Psychiatry Frazier, T. W., Georgiades, S., Bishop, S. L., Hardan, A. Y. 2014; 53 (3): 329-340 e3

  Abstract

  To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD).We analyzed data from 2,418 probands with autism (304 females and 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure that sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or were driven by cognitive ability.Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability.A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high-functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high-functioning cases are reduced if female-specific indicators of restricted interests are included.

  View details for DOI 10.1016/j.jaac.2013.12.004

  View details for PubMedID 24565360

  View details for PubMedCentralID PMC3935179

• A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism FRONTIERS IN GENETICS Carayol, J., Schellenberg, G. D., Dombroski, B., Amiet, C., Genin, B., Fontaine, K., Rousseau, F., Vazart, C., Cohen, D., Frazier, T. W., Hardan, A. Y., Dawson, G., Frio, T. R. 2014; 5

  Abstract

  Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.

  View details for DOI 10.3389/fgene.2014.00033

  View details for Web of Science ID 000346986900001

  View details for PubMedCentralID PMC3927086

• A preliminary longitudinal volumetric MRI study of amygdala and hippocampal volumes in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Frazier, T. W., Piacenza, L., Minshew, N. J., Keshavan, M. S., Reiss, A. L., Hardan, A. Y. 2014; 48: 124-128

  Abstract

  Previous studies suggest that amygdala volume, when compared with healthy controls, is increased in young children with autism, is unchanged in cohorts of older youth, and is smaller in adults. Hippocampal volume, however, does not appear to have age-related changes, and it is unclear whether individuals with autism have volumetric differences in this structure. The goal of this pilot investigation is to characterize the developmental trajectories of the amygdala and hippocampus in children with autism between the ages of 8 and 14years and to examine clinical correlates of volume change.Twenty-three children with autism and 23 controls between the ages of 8 and 12 underwent a magnetic resonance imaging procedure of the brain (T1-weighted) at two time points. Nine children with autism and 14 controls had good quality scans from both time points; however, all usable scans from all subjects (15 children with autism and 22 controls) were included in a mixed effect analysis. Regression models were used to estimate group differences in amygdala and hippocampal volumes. Changes in amygdala and hippocampal volumes (Time 2-Time 1) were correlated with clinical severity measures.Amygdala volume changes with time were similar between the two groups. Within the autism group, right amygdala volume change was correlated with the ability to establish appropriate eye contact. Right hippocampal volume was significantly increased in the autism group when compared with controls. Differences in right hippocampal volume change with time between the two groups approached significance.This study provides preliminary evidence of normalization of amygdala volumes in late childhood and adolescence. It also suggests that hippocampal volumetric differences may exist in autism in late childhood and adolescence.

  View details for DOI 10.1016/j.pnpbp.2013.09.010

  View details for Web of Science ID 000328074200018

  View details for PubMedID 24075822

• Cortisol, cytokines, and hippocampal volume interactions in the elderly. Frontiers in aging neuroscience Sudheimer, K. D., O'Hara, R., Spiegel, D., Powers, B., Kraemer, H. C., Neri, E., Weiner, M., Hardan, A., Hallmayer, J., Dhabhar, F. S. 2014; 6: 153-?

  Abstract

  Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  View details for DOI 10.3389/fnagi.2014.00153

  View details for PubMedID 25071562

  View details for PubMedCentralID PMC4079951

• A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism. Frontiers in genetics Carayol, J., Schellenberg, G. D., Dombroski, B., Amiet, C., Génin, B., Fontaine, K., Rousseau, F., Vazart, C., Cohen, D., Frazier, T. W., Hardan, A. Y., Dawson, G., Rio Frio, T. 2014; 5: 33-?

  Abstract

  Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.

  View details for DOI 10.3389/fgene.2014.00033

  View details for PubMedID 24600472

• Cortisol, cytokines, and hippocampal volume interactions in the elderly. Frontiers in aging neuroscience Sudheimer, K. D., O'Hara, R., Spiegel, D., Powers, B., Kraemer, H. C., Neri, E., Weiner, M., Hardan, A., Hallmayer, J., Dhabhar, F. S. 2014; 6: 153-?

  Abstract

  Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  View details for DOI 10.3389/fnagi.2014.00153

  View details for PubMedID 25071562

  View details for PubMedCentralID PMC4079951

• A two-year longitudinal pilot MRI study of the brainstem in autism. Behavioural brain research Jou, R. J., Frazier, T. W., Keshavan, M. S., Minshew, N. J., Hardan, A. Y. 2013; 251: 163-167

  Abstract

  Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range=8-17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns.

  View details for DOI 10.1016/j.bbr.2013.04.021

  View details for PubMedID 23619132

• Structural MRI Investigations in Twins with Autism 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Hardan, A. Y., Hallmayer, J., Lazzeroni, L., Berquist, S., Raman, M. R., Patnaik, S., Phillips, J., Reiss, A. L., Cleveland, S. ELSEVIER SCIENCE INC. 2013: 88S?88S

  View details for Web of Science ID 000318671800269

• Impact of Pivotal Response Training Group Therapy on Stress and Empowerment in Parents of Children With Autism JOURNAL OF POSITIVE BEHAVIOR INTERVENTIONS Minjarez, M. B., Mercier, E. M., Williams, S. E., Hardan, A. Y. 2013; 15 (2): 71-78

  View details for DOI 10.1177/1098300712449055

  View details for Web of Science ID 000319527300002

• Parental Interest in a Genetic Risk Assessment Test for Autism Spectrum Disorders CLINICAL PEDIATRICS Narcisa, V., Discenza, M., Vaccari, E., Rosen-Sheidley, B., Hardan, A. Y., Couchon, E. 2013; 52 (2): 139-146

  Abstract

  To better understand parental opinions regarding the diagnostic process and use of genetic testing to assess risk for autism spectrum disorders (ASDs) in the younger siblings of affected children in the Unites States, we conducted a survey of parents who had at least one child with ASD. A total of 162 surveys were completed anonymously using an Internet-based survey tool. The mean reported time to ASD diagnosis and age at diagnosis were 35.2 months and 56.6 months, respectively. Seventy-two percent of parents felt there was a delay in diagnosis. Most parents indicated they would want to pursue genetic testing if a test were available that could identify risk in a younger sibling (80%). Earlier evaluation/intervention, closer monitoring, and lessened anxiety were reasons cited for testing. Our survey indicates most parents would pursue genetic risk assessment testing in children at high risk for ASD.

  View details for DOI 10.1177/0009922812466583

  View details for Web of Science ID 000314475300005

  View details for PubMedID 23193169

• Priapism Associated with Risperidone in a 21-Year-Old Male with Autism. Journal of child and adolescent psychopharmacology Pradhan, T., Hardan, A. 2013

  View details for PubMedID 23738870

• Underutilization of Genetics Services for Autism: The Importance of Parental Awareness and Provider Recommendation JOURNAL OF GENETIC COUNSELING Vande Wydeven, K., Kwan, A., Hardan, A. Y., Bernstein, J. A. 2012; 21 (6): 803-813

  Abstract

  Reasons for the underutilization of genetics services by families of children with autism spectrum disorders (ASD) are not well understood. We report the identification of factors associated with this underuse. Survey-based study of parents and/or guardians of children with ASD. One hundred fifty-five families completed the questionnaire. Thirty-one of 155 (20%) children had seen a genetics professional. Forty-nine of 154 (32%) children had undergone genetic testing. Parents whose child saw a genetics professional were more likely to 1) Have a primary provider refer for or suggest a genetics evaluation 2) Have asked for a referral, and/or 3) Know another person with a genetic cause of ASD. amilies of children with ASD who have not received genetics services are less aware of their availability and utility. They are also less likely to have their provider recommend a clinical genetics evaluation. Efforts should be taken to increase awareness of both health providers and parents regarding the usefulness of genetics services for ASD.

  View details for DOI 10.1007/s10897-012-9494-x

  View details for PubMedID 22415587

• A Two-Year Longitudinal MRI Study of the Corpus Callosum in Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Frazier, T. W., Keshavan, M. S., Minshew, N. J., Hardan, A. Y. 2012; 42 (11): 2312-2322

  Abstract

  A growing body of literature has identified size reductions of the corpus callosum (CC) in autism. However, to our knowledge, no published studies have reported on the growth of CC volumes in youth with autism. Volumes of the total CC and its sub-divisions were obtained from 23 male children with autism and 23 age- and gender-matched controls at baseline and 2-year follow-up. Persistent reductions in total CC volume were observed in participants with autism relative to controls. Only the rostral body subdivision showed a normalization of size over time. Persistent reductions are consistent with the diagnostic stability and life-long impairment observed in many individuals with autism. Multi-modal imaging studies are needed to identify specific fiber tracks contributing to CC reductions.

  View details for DOI 10.1007/s10803-012-1478-z

  View details for Web of Science ID 000310088600004

  View details for PubMedID 22350341

• Clinical Practice Pathways for Evaluation and Medication Choice for Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Disorders PEDIATRICS Mahajan, R., Bernal, M. P., Panzer, R., Whitaker, A., Roberts, W., Handen, B., Hardan, A., Anagnostou, E., Veenstra-VanderWeele, J. 2012; 130: S125-S138

  Abstract

  Hyperactivity, impulsivity, and inattention (referred to as "ADHD [attention-deficit/hyperactivity disorder] symptoms") occur in 41% to 78% of children with autism spectrum disorders (ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms.Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee.The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations.These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future.

  View details for DOI 10.1542/peds.2012-0900J

  View details for Web of Science ID 000209485500010

• Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics Mahajan, R., Bernal, M. P., Panzer, R., Whitaker, A., Roberts, W., Handen, B., Hardan, A., Anagnostou, E., Veenstra-VanderWeele, J. 2012; 130: S125-38

  Abstract

  Hyperactivity, impulsivity, and inattention (referred to as "ADHD [attention-deficit/hyperactivity disorder] symptoms") occur in 41% to 78% of children with autism spectrum disorders (ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms.Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee.The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations.These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future.

  View details for DOI 10.1542/peds.2012-0900J

  View details for PubMedID 23118243

• A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Fung, L. K., Libove, R. A., Obukhanych, T. V., Nair, S., Herzenberg, L. A., Frazier, T. W., Tirouvanziam, R. 2012; 71 (11): 956-961

  Abstract

  An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

  View details for DOI 10.1016/j.biopsych.2012.01.014

  View details for Web of Science ID 000303814800007

  View details for PubMedID 22342106

• A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Fung, L. K., Chahal, L., Libove, R. A., Bivas, R., Hardan, A. Y. 2012; 22 (3): 245-248

  Abstract

  Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism.

  View details for DOI 10.1089/cap.2010.0103

  View details for Web of Science ID 000305337300009

  View details for PubMedID 22537360

• Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Tirouvanziam, R., Obukhanych, T. V., Laval, J., Aronov, P. A., Libove, R., Banerjee, A. G., Parker, K. J., O'Hara, R., Herzenberg, L. A., Herzenberg, L. A., Hardan, A. Y. 2012; 42 (5): 827-836

  Abstract

  The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

  View details for DOI 10.1007/s10803-011-1314-x

  View details for Web of Science ID 000302771500017

  View details for PubMedID 21713591

• Validation of Proposed DSM-5 Criteria for Autism Spectrum Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Frazier, T. W., Youngstrom, E. A., Speer, L., Embacher, R., Law, P., Constantino, J., Findling, R. L., Hardan, A. Y., Eng, C. 2012; 51 (1): 28-40

  Abstract

  The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for autism spectrum disorder (ASD).We analyzed symptoms from 14,744 siblings (8,911 ASD and 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth 2 through 18 years of age were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and subdimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD.A hybrid model that included both a category (ASD versus non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and subsamples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (0.97 versus 0.86); however sensitivity was lower (0.81 versus 0.95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (0.93 versus 0.81), with minimal reduction in specificity (0.95 versus 0.97).Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I Field Trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.

  View details for DOI 10.1016/j.jaac.2011.09.021

  View details for Web of Science ID 000298530300005

  View details for PubMedID 22176937

  View details for PubMedCentralID PMC3244681

• Multivariate Searchlight Classification of Structural Magnetic Resonance Imaging in Children and Adolescents with Autism BIOLOGICAL PSYCHIATRY Uddin, L. Q., Menon, V., Young, C. B., Ryali, S., Chen, T., Khouzam, A., Minshew, N. J., Hardan, A. Y. 2011; 70 (9): 833-841

  Abstract

  Autism spectrum disorders (ASD) are neurodevelopmental disorders with a prevalence of nearly 1:100. Structural imaging studies point to disruptions in multiple brain areas, yet the precise neuroanatomical nature of these disruptions remains unclear. Characterization of brain structural differences in children with ASD is critical for development of biomarkers that may eventually be used to improve diagnosis and monitor response to treatment.We use voxel-based morphometry along with a novel multivariate pattern analysis approach and searchlight algorithm to classify structural magnetic resonance imaging data acquired from 24 children and adolescents with autism and 24 age-, gender-, and IQ-matched neurotypical participants.Despite modest voxel-based morphometry differences, multivariate pattern analysis revealed that the groups could be distinguished with accuracies of approximately 90% based on gray matter in the posterior cingulate cortex, medial prefrontal cortex, and bilateral medial temporal lobes-regions within the default mode network. Abnormalities in the posterior cingulate cortex were associated with impaired Autism Diagnostic Interview communication scores. Gray matter in additional prefrontal, lateral temporal, and subcortical structures also discriminated between groups with accuracies between 81% and 90%. White matter in the inferior fronto-occipital and superior longitudinal fasciculi, and the genu and splenium of the corpus callosum, achieved up to 85% classification accuracy.Multiple brain regions, including those belonging to the default mode network, exhibit aberrant structural organization in children with autism. Brain-based biomarkers derived from structural magnetic resonance imaging data may contribute to identification of the neuroanatomical basis of symptom heterogeneity and to the development of targeted early interventions.

  View details for DOI 10.1016/j.biopsych.2011.07.014

  View details for Web of Science ID 000296228000010

  View details for PubMedID 21890111

  View details for PubMedCentralID PMC3191298

• Advances in clinical neuroimaging: implications for autism spectrum disorders. Expert opinion on medical diagnostics Barnea-Goraly, N., Hardan, A. 2011; 5 (6): 475-482

  Abstract

  Introduction: Neuroimaging research has been labeled 'modern phrenology', suggesting that this line of research does not advance our knowledge of neuropsychiatric disorders beyond spatial localization of brain abnormalities. In this paper, we argue against this claim and discuss the application of neuroimaging techniques in neuropsychiatric disorders in general and in autism spectrum disorders (ASDs) in particular. Areas covered: Recent neuroimaging literature, and its role in increasing our understanding of the neurobiologic underpinnings of several disorders, is reviewed. Neuroimaging is discussed, with respect to the identification of at-risk individuals, prediction of treatment response and development of new treatment approaches. Furthermore, the authors discuss the clinical relevance of such methodologies in the context of autism. Specifically, the article shows how recent advances in the understanding of psychiatric and neurologic disorders, through the use of neuroimaging techniques, can be beneficially applied to the unique needs of ASD diagnosis and treatment. Expert opinion: This is an exciting time for neuroimaging research. Studies have already shown the potential of neuroimaging to better inform clinicians about disorders such as depression, anxiety and psychosis. The application of neuroimaging to ASD may provide new insight into the disorder and help deliver better care for affected individuals.

  View details for DOI 10.1517/17530059.2011.595785

  View details for PubMedID 23484746

• Safety and Efficacy of Donepezil in Children and Adolescents with Autism: Neuropsychological Measures JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Handen, B. L., Johnson, C. R., McAuliffe-Bellin, S., Murray, P. J., Hardan, A. Y. 2011; 21 (1): 43-50

  Abstract

  There has been recent interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for executive functioning (EF) deficits in autism spectrum disorder (ASD). The goal of this study was to assess the tolerability, safety, and efficacy of donepezil on EF in a sample of children and adolescents with ASD.Thirty-four children and adolescents with ASD (age range 8-17 years; IQ >75) were enrolled in a 10-week, double-blind, placebo-controlled trial of donepezil (doses of 5 and 10?mg), followed by a 10-week open label trial for placebo nonresponders.The effect of donepezil treatment on EF was examined. Despite improvement on a number of EF measures, no statistically significant between-group differences were found (with gains observed for both the placebo and donepezil groups).The results suggest that short-term treatment with donepezil may have limited impact on cognitive functioning in ASD. Future controlled trials may need to consider a longer treatment period to detect significant gains on EF measures.

  View details for DOI 10.1089/cap.2010.0024

  View details for Web of Science ID 000287230000004

  View details for PubMedID 21309696

  View details for PubMedCentralID PMC3037196

• Pivotal Response Group Treatment Program for Parents of Children with Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Minjarez, M. B., Williams, S. E., Mercier, E. M., Hardan, A. Y. 2011; 41 (1): 92-101

  Abstract

  The number of children diagnosed with autism spectrum disorders is increasing, necessitating the development of efficient treatment models. Research has demonstrated that parent-delivered behavioral interventions are a viable treatment model; however, little research has focused on teaching parents in groups. The aim of this study was to demonstrate that parents can learn Pivotal Response Training (PRT) in group therapy, resulting in correlated gains in children's language. Baseline and post-treatment data were obtained and examined for changes in (a) parent fidelity of PRT implementation, and (b) child functional verbal utterances. Significant differences were observed for both variables. These findings suggest that parents can learn PRT in a group format, resulting in correlated child language gains, thus future controlled studies are warranted.

  View details for DOI 10.1007/s10803-010-1027-6

  View details for Web of Science ID 000285928200010

  View details for PubMedID 20440638

• Reduced central white matter volume in autism: Implications for long-range connectivity PSYCHIATRY AND CLINICAL NEUROSCIENCES Jou, R. J., Mateljevic, N., Minshew, N. J., Keshavan, M. S., Hardan, A. Y. 2011; 65 (1): 98-101

  Abstract

  Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5 T were analyzed using BRAINS2 software (University of Iowa, Iowa City, IA, USA). Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity.

  View details for DOI 10.1111/j.1440-1819.2010.02164.x

  View details for Web of Science ID 000286620700014

  View details for PubMedID 21265943

  View details for PubMedCentralID PMC3114568

• Cortical Gyrification in Autistic and Asperger Disorders: A Preliminary Magnetic Resonance Imaging Study JOURNAL OF CHILD NEUROLOGY Jou, R. J., Minshew, N. J., Keshavan, M. S., Hardan, A. Y. 2010; 25 (12): 1462-1467

  Abstract

  The validity of Asperger disorder as a distinct syndrome from autism is unclear partly because of the paucity of differentiating neurobiological evidence. Frontal lobe cortical folding between these disorders was compared using the gyrification index. Twenty-three boys underwent structural magnetic resonance imaging: 6 with high-functioning autism, 9 with Asperger disorder, and 8 controls. Using the first coronal slice anterior to the corpus callosum, total and outer cortical contours were traced to calculate the gyrification index. This index was also calculated for superior and inferior regions to examine dorsolateral prefrontal and orbitofrontal cortices, respectively. Analysis of variance revealed differences in the left inferior gyrification index, which was higher in the autism group compared with Asperger and control groups. There were no differences in age, intelligence quotient, and brain volume. These preliminary findings suggest that cortical folding may be abnormally high in the frontal lobe in autism but not Asperger disorder, suggesting distinct frontal lobe neuropathology.

  View details for DOI 10.1177/0883073810368311

  View details for Web of Science ID 000285147100002

  View details for PubMedID 20413799

  View details for PubMedCentralID PMC3115701

• Enlarged right superior temporal gyrus in children and adolescents with autism BRAIN RESEARCH Jou, R. J., Minshew, N. J., Keshavan, M. S., Vitale, M. P., Hardan, A. Y. 2010; 1360: 205-212

  Abstract

  The superior temporal gyrus has been implicated in language processing and social perception. Therefore, anatomical abnormalities of this structure may underlie some of the deficits observed in autism, a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. In this study, volumes of the left and right superior temporal gyri were measured using magnetic resonance imaging obtained from 18 boys with high-functioning autism (mean age=13.5±3.4years; full-scale IQ=103.6±13.4) and 19 healthy controls (mean age=13.7±3.0years; full-scale IQ=103.9±10.5), group-matched on age, gender, and handedness. When compared to the control group, right superior temporal gyral volumes was significantly increased in the autism group after controlling for age and total brain volume. There was no significant difference in the volume of the left superior temporal gyrus. Post-hoc analysis revealed a significant increase of the right posterior superior temporal gyral volume in the autism group, before and after controlling for age and total brain volume. Examination of the symmetry index for the superior temporal gyral volumes did not yield statistically significant between-group differences. Findings from this preliminary investigation suggest the existence of volumetric alterations in the right superior temporal gyrus in children and adolescents with autism, providing support for a neuroanatomical basis of the social perceptual deficits characterizing this severe neurodevelopmental disorder.

  View details for DOI 10.1016/j.brainres.2010.09.005

  View details for Web of Science ID 000284252600020

  View details for PubMedID 20833154

  View details for PubMedCentralID PMC2990401

• Risperidone: Switching from Brand Name to Generic JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Fung, L. K., Amin, H. 2010; 20 (5): 457-458

  View details for DOI 10.1089/cap.2010.0013

  View details for Web of Science ID 000283436700013

  View details for PubMedID 20973719

• Dorsolateral Prefrontal Cortex Magnetic Resonance Imaging Measurements and Cognitive Performance in Autism JOURNAL OF CHILD NEUROLOGY Griebling, J., Minshew, N. J., Bodner, K., Libove, R., Bansal, R., Konasale, P., Keshavan, M. S., Hardan, A. 2010; 25 (7): 856-863

  Abstract

  This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. Magnetic resonance imaging (MRI) scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the 2 groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.

  View details for DOI 10.1177/0883073809351313

  View details for Web of Science ID 000279409100008

  View details for PubMedID 20097663

  View details for PubMedCentralID PMC3428128

• Evidence for Anatomical Alterations in the Corpus Callosum in Autism Spectrum Disorders European Psychiatric Review Frazier T, Barnea-Goraly N, Hardan A 2010; 3: 29-33
• A Meta-Analysis of the Corpus Callosum in Autism BIOLOGICAL PSYCHIATRY Frazier, T. W., Hardan, A. Y. 2009; 66 (10): 935-941

  Abstract

  Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism.PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements.Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons.Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.

  View details for DOI 10.1016/j.biopsych.2009.07.022

  View details for Web of Science ID 000271497400006

  View details for PubMedID 19748080

  View details for PubMedCentralID PMC2783565

• Corpus callosum volume in children with autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Pabalan, M., Gupta, N., Bansal, R., Melhem, N. M., Fedorov, S., Keshavan, M. S., Minshew, N. J. 2009; 174 (1): 57-61

  Abstract

  The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications.

  View details for DOI 10.1016/j.pscychresns.2009.03.005

  View details for Web of Science ID 000271686900008

  View details for PubMedID 19781917

  View details for PubMedCentralID PMC2761427

• A Preliminary Longitudinal Magnetic Resonance Imaging Study of Brain Volume and Cortical Thickness in Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Libove, R. A., Keshavan, M. S., Melhem, N. M., Minshew, N. J. 2009; 66 (4): 320-326

  Abstract

  Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism.MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline.No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology.Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.

  View details for DOI 10.1016/j.biopsych.2009.04.024

  View details for Web of Science ID 000268840200005

  View details for PubMedID 19520362

  View details for PubMedCentralID PMC2905654

• Brainstem volumetric alterations in children with autism PSYCHOLOGICAL MEDICINE Jou, R. J., Minshew, N. J., Melhem, N. M., Keshavan, M. S., Hardan, A. Y. 2009; 39 (8): 1347-1354

  Abstract

  Although several studies have examined brainstem volume in autism, results have been mixed and no investigation has specifically measured gray- and white-matter structures. The aim of this investigation was to assess gray- and white-matter volumes in children with autism.Subjects included 22 right-handed, non-mentally retarded boys with autism and 22 gender- and age-matched controls. Magnetic resonance imaging (MRI) scans were obtained using a 1.5-T scanner and volumetric measurements were performed using the BRAINS2 software package. Gray- and white-matter volumes were measured using a semi-automated segmentation process.There were no significant differences in age and total brain volume (TBV) between the two groups but full-scale IQ was higher in controls. A decrease in brainstem gray-matter volume was observed in the autism group before and after controlling for TBV. No significant differences were observed in white-matter volume. A significant relationship was observed between brainstem gray-matter volume and oral sensory sensitivity as measured by the Sensory Profile Questionnaire (SPQ).Findings from this study are suggestive of brainstem abnormalities in autism involving gray-matter structures with evidence supporting the existence of a relationship between these alterations and sensory deficits. These results are consistent with previous investigations and support the existence of disturbances in brainstem circuitry thought to be implicated in the sensory dysfunction observed in autism.

  View details for DOI 10.1017/S0033291708004376

  View details for Web of Science ID 000268165300013

  View details for PubMedID 18812009

• Corpus Callosum Volume and Neurocognition in Autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Keary, C. J., Minshew, N. J., Bansal, R., Goradia, D., Fedorov, S., Keshavan, M. S., Hardan, A. Y. 2009; 39 (6): 834-841

  Abstract

  The corpus callosum has recently been considered as an index of interhemispheric connectivity. This study applied a novel volumetric method to examine the size of the corpus callosum in 32 individuals with autism and 34 age-, gender- and IQ-matched controls and to investigate the relationship between this structure and cognitive measures linked to interhemispheric functioning. Participants with autism displayed reductions in total corpus callosum volume and in several of its subdivisions. Relationships were also observed between volumetric alterations and performance on several cognitive tests including the Tower of Hanoi test. These findings provide further evidence for anatomical alterations in the corpus callosum in autism, but warrant additional studies examining the relationship of this structure and specific measures of interhemispheric connectivity.

  View details for DOI 10.1007/s10803-009-0689-4

  View details for Web of Science ID 000266089900002

  View details for PubMedID 19165587

  View details for PubMedCentralID PMC3229274

• Reduced Central White Matter Volume in Autism: Implications for Long-Range Connectivity Jou, R. J., Hardan, A. Y. ELSEVIER SCIENCE INC. 2009: 87S?88S

  View details for Web of Science ID 000265144200280

• Guanfacine in children with autism and/or intellectual disabilities JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Handen, B. L., Sahl, R., Hardan, A. Y. 2008; 29 (4): 303-308

  Abstract

  Attention-deficit/hyperactivity disorder (ADHD) affects 3%-5% of typical school-age children. However, considerably higher rates of ADHD (15%-25%) are observed in children with intellectual disability and autism. Studies of psychostimulants in the latter two populations have found poorer response rates compared to typically developing children. In addition, evidence suggests that children with developmental disabilities experience higher rates of adverse events. Guanfacine, an alpha2-adrenergic receptor agonist, has shown some promise as an alternative to psychostimulants.The present study involved a double-blind, placebo-controlled, crossover trial of guanfacine in 11 children (ages 5-9 years) with developmental disabilities and symptoms of inattention/overactivity. The 6-week trial involved a maximum dose of 3 mg/day of guanfacine.Significant benefits were observed on the Hyperactivity subscale of the parent and teacher Aberrant Behavior Checklist (ABC) and Global Improvement Ratings. No gains were noted on other ABC subscales. Five of the 11 subjects (45%) were judged to be responders based on a 50% decrease in the ABC Hyperactivity subscale score between the placebo and guanfacine conditions. Several side effects were reported, including drowsiness and irritability.While guanfacine appears to be an alternative to psychostimulants among children with developmental disabilities, clinicians need to remain vigilant to the possibility of side effects.

  View details for Web of Science ID 000258411900012

  View details for PubMedID 18552703

• An MRI and proton spectroscopy study of the thalamus in children with autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Minshew, N. J., Melhem, N. M., Srihari, S., Jo, B., Bansal, R., Keshavan, M. S., Stanley, J. A. 2008; 163 (2): 97-105

  Abstract

  Thalamic alterations have been reported in autism, but the relationships between these abnormalities and clinical symptoms, specifically sensory features, have not been elucidated. The goal of this investigation is to combine two neuroimaging methods to examine further the pathophysiology of thalamic anomalies in autism and to identify any association with sensory deficits. Structural MRI and multi-voxel, short echo-time proton magnetic resonance spectroscopy ((1)H MRS) measurements were collected from 18 male children with autism and 16 healthy children. Anatomical measurements of thalamic nuclei and absolute concentration levels of key (1)H MRS metabolites were obtained. Sensory abnormalities were assessed using a sensory profile questionnaire. Lower levels of N-acetylaspartate (NAA), phosphocreatine and creatine, and choline-containing metabolites were observed on the left side in the autism group compared with controls. No differences in thalamic volumes were observed between the two groups. Relationships, although limited, were observed between measures of sensory abnormalities and (1)H MRS metabolites. Findings from this study support the role of the thalamus in the pathophysiology of autism and more specifically in the sensory abnormalities observed in this disorder. Further investigations of this structure are warranted, since it plays an important role in information processing as part of the cortico-thalamo-cortical pathways.

  View details for DOI 10.1016/j.pscychresns.2007.12.002

  View details for Web of Science ID 000257581200001

  View details for PubMedID 18508243

  View details for PubMedCentralID PMC2467447

• Longitudinal study of the corpus callosum in autism Hardan, A. Y., Keshavan, M. S., Bansal, R., Fedorov, S., Minshew, N. J. ELSEVIER SCIENCE INC. 2008: 30S

  View details for Web of Science ID 000254163700095

• Brief report: Abnormal association between the thalamus and brain size in Asperger's disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., GirgiS, R. R., Adams, J., Gilbert, A. R., Melhem, N. M., Keshavan, M. S., Minshew, N. J. 2008; 38 (2): 390-394

  Abstract

  The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation was found between total brain volume and thalamic size in controls, but not in ASP subjects. This occurred in the absence of differences in mean thalamic volumes between the study groups. Findings from this investigation point to an abnormal relationship between the thalamus and its projection areas in ASP and are consistent with similar studies in autism, supporting that these disorders are qualitatively similar and possibly quantitatively different.

  View details for DOI 10.1007/s10803-007-0385-1

  View details for Web of Science ID 000252673600017

  View details for PubMedID 17641963

• Morphology of the orbitofrontal cortex in first-episode schizophrenia: Relationship with negative symptomatology PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Lacerda, A. L., Hardan, A. Y., Yorbik, O., Vemulapalli, M., Prasad, K. M., Keshavan, M. S. 2007; 31 (2): 510-516

  Abstract

  Different studies have documented OFC abnormalities in schizophrenia, but it is unclear if they are present at disease onset or are a consequence of disease process and/or drug exposure. The evaluation of first-episode, drug-naïve subjects allows us to clarify this issue. Magnetic resonance imaging was performed on 43 first-episode, antipsychotic-naïve schizophrenia patients and 53 healthy comparison subjects matched for age, gender, race, and handedness. Gray matter OFC volumes were measured blind to the diagnoses. As compared to controls, patients had greater volumes in left total OFC (p=0.048) and left lateral OFC (p=0.037). Severity of negative symptoms (anhedonia, flattened affect, and alogia) positively correlated with both the left lateral (Spearman's, rho=0.37, p=0.019; rho=0.317, p=0.041; r=0.307, p=0.048, respectively) and the left total OFC (Spearman's, rho=0.384, p=0.014; rho=0.349, p=0.023; rho=0.309, p=0.047, respectively). The present results suggest that first-episode, antipsychotic-naïve schizophrenia subjects exhibit increased OFC volumes that correlate with negative symptoms severity. The OFC, through extensive and complex interconnections with several brain structures with putative role in pathophysiology of schizophrenia including amygdala, hippocampus, thalamus, DLPFC, and superior temporal lobe, may mediate schizophrenia symptoms such as blunting of emotional affect and impaired social functioning. Although the specific neuropathological mechanisms underlying structural abnormalities of the OFC remain unclear, increased OFC volumes might be related to deviations in neuronal migration and/or pruning. Future follow-up studies examining high-risk individuals who subsequently develop schizophrenia at different stages of disease could be especially instructive.

  View details for DOI 10.1016/j.pnpbp.2006.11.022

  View details for Web of Science ID 000244808800031

  View details for PubMedID 17239513

• Volumetric alterations of the orbitofrontal cortex in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY GirgiS, R. R., Minshew, N. J., Melhern, N. M., Nutche, J. J., Keshavan, M. S., Hardan, A. Y. 2007; 31 (1): 41-45

  Abstract

  Recent evidence has implicated the orbitofrontal cortex (OFC) in the pathophysiology of social deficits in autism. An MRI-based morphometric study of the OFC was conducted involving 11 children with autism (age range 8.1-12.7 years) and 18 healthy, age-matched controls (age range 8.9-12.8 years). Decreased grey matter volume in the right lateral OFC in the patient group was found, and correlations were observed between social deficits and white, but not grey, matter structures of the OFC. These findings support the role of OFC in autism and warrant further investigations of this structure using structural and functional methodologies.

  View details for DOI 10.1016/j.pnpbp.2006.06.007

  View details for Web of Science ID 000243738000005

  View details for PubMedID 16863674

  View details for PubMedCentralID PMC2888006

• Abnormal brain size effect on the thalamus in autism PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., GirgiS, R. R., Adams, J., Gilbert, A. R., Keshavan, M. S., Minshew, N. J. 2006; 147 (2-3): 145-151

  Abstract

  This study was conducted to examine the volume of the thalamus in autism and to investigate the effect of brain size on this structure in an attempt to replicate, in a larger sample, findings from a previous study reporting the existence of a relationship between brain volume and thalamus in healthy controls but not in individuals with autism. Additionally, the relationships between thalamic volumes and clinical features were examined. Volumetric measurements of the right and left thalamic nuclei were performed on MRI scans obtained from 40 high-functioning individuals with autism (age range: 8-45 years) and 41 healthy controls (age range: 9-43 years). No differences were observed between the two groups for unadjusted thalamic volumes. However, the expected linear relationship between TBV and thalamic volume was not observed in individuals with autism. Furthermore, no correlations were observed between thalamic volumes and clinical features. Findings from this larger study are consistent with the previous report of an abnormal brain size effect on the thalamus in autism and support the possibility of abnormal connections between cortical and subcortical structures in this disorder.

  View details for DOI 10.1016/j.pscychresns.2005.12.009

  View details for Web of Science ID 000241326800006

  View details for PubMedID 16945509

• Magnetic resonance imaging study of the orbitofrontal cortex in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., GirgiS, R. R., Lacerda, A. L., Yorbik, O., Kilpatiick, M., Keshavan, M. S., Minshew, N. J. 2006; 21 (10): 866-871

  Abstract

  The orbitofrontal cortex is involved in multiple psychologic functions, such as emotional and cognitive processing, learning, and social behavior. These functions are variably impaired in individuals with autism. The present study examined the size of the orbitofrontal cortex, and its medial and lateral subdivisions, using magnetic resonance imaging (MRI) scans obtained from 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any of the orbitofrontal cortex measurements. However, when compared with controls, a smaller right lateral orbitofrontal cortex was observed in children and adolescents with autism, whereas a larger right lateral orbitofrontal cortex was found in adult patients. Interestingly, a positive relationship was found in the patient group between circumscribed interests and all orbitofrontal cortex structures. The present study suggests the absence of global volumetric abnormalities in the orbitofrontal cortex in autism and indicates that the functional disturbances in this structure might not be related to anatomic alterations.

  View details for DOI 10.2310/7010.2006.00199

  View details for Web of Science ID 000243206700007

  View details for PubMedID 17005103

• Open-label, prospective trial of olanzapine in adolescents with subaverage intelligence and disruptive behavior disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Handen, B. L., Hardan, A. Y. 2006; 45 (8): 928-935

  Abstract

  Olanzapine, an atypical antipsychotic, has been shown to be efficacious for treatment of psychotic and mood disorders in adults. This prospective, open-label study was conducted to examine the safety and usefulness of olanzapine in treating disruptive behavior disorders in adolescents with subaverage intelligence.Sixteen adolescents (ages 13-17 years) with borderline to moderate mental retardation and disruptive behavior were enrolled in an 8-week olanzapine trial (5-20 mg/day). Dependent measures included the Aberrant Behavior Checklist, Conners Parent Rating Scale, Clinical Global Impressions, and two side effects scales.Statistically significant improvement (p <.002) was found on the Irritability and Hyperactivity subscales of the Aberrant Behavior Checklist and the Conners Parent Rating Scale Hyperactivity Index. No subjects developed extrapyramidal side effects. However, four were terminated prematurely from the trial because of either worsening of symptoms (requiring psychiatric inpatient hospitalization in two subjects) or side effects. The most common side effect for the sample was weight gain (averaging 12.7 lb), with 67% of subjects gaining > or =10 lb. Although there was also a statistically significant increase in prolactin levels, no subjects reported prolactin-related side effects (e.g., gynecomastia, galactorhea, amenorrhea).Olanzapine may be useful in treating disruptive behavior in adolescents with subaverage intelligence. However, side effects, especially weight gain, are a significant issue. Future double-blind, placebo-controlled studies need to confirm these findings and assess long-term safety and outcome of olanzapine treatment.

  View details for DOI 10.1097/01.chi.0000223312.48406.6e

  View details for Web of Science ID 000239290500006

  View details for PubMedID 16865035

• An MRI study of increased cortical thickness in autism AMERICAN JOURNAL OF PSYCHIATRY Hardan, A. Y., Muddasani, S., Vemulapalli, M., Keshavan, M. S., Minshew, N. J. 2006; 163 (7): 1290-1292

  Abstract

  The purpose of this study was to examine cortical thickness in autism in light of the postmortem evidence of cortical abnormalities of the disorder.Magnetic resonance imaging (MRI) scans were acquired from 17 children with autism and 14 healthy comparison subjects, and sulcal and gyral thickness were measured for the total brain and for all lobes.Increases in total cerebral sulcal and gyral thickness were observed in children with autism relative to comparison subjects. Similar findings were noted in the temporal and parietal lobes but not in the frontal and occipital lobes.These preliminary findings indicate that increased cortical thickness may contribute to the increased gray matter volume and total brain size that have been observed in autism and may also be related to anomalies in cortical connectivity.

  View details for PubMedID 16816240

• An MRI study of minor physical anomalies in autism JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., Keshavan, M. S., Sreedhar, S., Vemulapalli, M., Minshew, N. J. 2006; 36 (5): 607-611

  Abstract

  The objective of this investigation was to examine the existence of minor physical anomalies (MPA) in autism. The interorbital and interlens distances were measured on MRI scans obtained from a sample of 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any measurements. However, when the analysis was conducted using a split median procedure, individuals with autism and either low FSIQ, PIQ, or VIQ had shorter interorbital distances when compared to controls. Hypotelorism is a MPA that may be present in a subgroup of individuals with autism. Additional research is warranted using large sample sizes with a wide range of intellectual functioning.

  View details for DOI 10.1007/s10803-006-0103-4

  View details for Web of Science ID 000239927900004

  View details for PubMedID 16609827

• Volumetric alterations of the corpus callosum in children with autism Hardan, A. Y., Bansal, R., Pabalan, M., Nutche, J., Fedorov, S., Minshew, N. J., Keshavan, M. S. ELSEVIER SCIENCE INC. 2006: 168S

  View details for Web of Science ID 000236767301123

• Brainstern volumetric alterations in children with pervasive developmental disorders Jou, R., Keshavan, M., Minshew, N. J., Hardan, A. Y. ELSEVIER SCIENCE INC. 2006: 49S?50S

  View details for Web of Science ID 000236767300162

• Preliminary findings from a double-blind placebo-controlled study of donepezil in pervasive developmental disorders Hardan, A. Y., Johnson, C., Handen, B. L. ELSEVIER SCIENCE INC. 2006: 50S

  View details for Web of Science ID 000236767300163

• Risperidone in first-episode psychosis: A longitudinal, exploratory voxel-based morphometric study SCHIZOPHRENIA RESEARCH Girgis, R. R., Diwadkar, V. A., Nutche, J. J., Sweeney, J. A., Keshavan, M. S., Hardan, A. Y. 2006; 82 (1): 89-94

  Abstract

  Previous studies have provided evidence supporting a neuroplastic effect of atypical antipsychotics. The present investigation explores the short-term effects of risperidone on brain parenchyma by performing voxel-based morphometry on baseline and 6-week follow-up MRI scans obtained from 15 neuroleptic-naïve individuals with first-episode psychosis treated with risperidone and 15 healthy controls. The risperidone-treated subjects demonstrated changes in grey matter and white matter in several brain regions, including superior temporal gyrus. No areas of change were found in controls. The results of this exploratory investigation support the possibility that risperidone has short-term effects on brain parenchyma in individuals with first-episode psychosis.

  View details for DOI 10.1016/j.schres.2005.10.019

  View details for Web of Science ID 000235664100009

  View details for PubMedID 16413757

• Reduced cortical folding in individuals at high risk for schizophrenia: a pilot study SCHIZOPHRENIA RESEARCH Jou, R. J., Hardan, A. Y., Keshavan, M. S. 2005; 75 (2-3): 309-313

  Abstract

  While cortical gyrification anomalies have been reported in schizophrenia, it is unknown if individuals at high risk for schizophrenia (HR) might also exhibit abnormal cortical folding. Using MRI scans, the gyrification index (GI) was calculated for 9 adolescent HR males and 12 healthy male controls. Using the first coronal slice anterior to the corpus callosum, cortical contours were manually traced to calculate the GI. The left GI was lower in HR when compared to controls, but no difference in the right GI was observed. These results are consistent with studies of affected individuals, supporting genetic and neurodevelopmental models of schizophrenia.

  View details for DOI 10.1016/j.schres.2004.11.008

  View details for Web of Science ID 000229665100017

  View details for PubMedID 15885522

• Retrospective study of quetiapine in children and adolescents with pervasive developmental disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hardan, A. Y., Jou, R. J., Handen, B. L. 2005; 35 (3): 387-391

  Abstract

  A retrospective study was conducted in a clinic specialized in treating individuals with developmental disabilities to examine the effectiveness and tolerability of quetiapine in children and adolescents with pervasive developmental disorders. Ten consecutive outpatients (age = 12.0 +/- 5.1 years) treated with quetiapine (dose = 477 +/- 212 mg, duration = 22.0 +/- 10.1 weeks) were identified and six were judged to be responders based on impressions from chart review and Conners Parent Scale (CPS). Improvements were observed in the conduct, inattention, and hyperactivity subscales of the CPS. Adverse events were mild with sedation being the most common, and no patient required treatment termination. Quetiapine may be beneficial in children and adolescents with pervasive developmental disorders, however open-label and double-blind, placebo-controlled studies are warranted.

  View details for DOI 10.1007/s10803-005-3306-1

  View details for Web of Science ID 000230559200013

  View details for PubMedID 16119479

• Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Jou, R. J., Handen, B. L., Hardan, A. Y. 2005; 15 (2): 325-330

  Abstract

  A retrospective study was conducted to assess the effectiveness and tolerability of atomoxetine in children and adolescents with pervasive developmental disorders (PDD). An outpatient clinic registry of individuals with PDD was used to identify all children and adolescents who received atomoxetine over a period of 12 months. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI) based on the Conners Parent Rating Scale (CPRS) routinely completed by primary caretakers and other clinical information available in the registry. Twenty patients were identified, including 16 males and 4 females (age, 11.5 years; standard deviation, 3.5). Most patients (80%) were taking at least 1 concomitant medication. Treatment dose was 43.3 mg (standard deviation, 18.1) and duration was 19.5 weeks (standard deviation, 10.5). Twelve patients were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Differences between baseline and the end of the trial period were observed in the following CPRS subscales: Conduct, hyperactivity, inattention, and learning. No differences were noted in the anxiety and psychosomatic subscales. One patient discontinued atomoxetine because of severe mood swings. Atomoxetine may be beneficial for treating secondary symptoms of PDD, and prospective open-label or double-blind, placebo-controlled studies are needed to assess its efficacy and safety.

  View details for Web of Science ID 000229787000021

  View details for PubMedID 15910217

• Quetiapine in children and adolescents with subaverage IQ Journal of Pediatric Neurology Jou R, Handen BL, Hardan AY 2005; 3: 35-39
• Psychostimulant treatment of adults with mental retardation and attention-deficit hyperactivity disorder. Australasian psychiatry Jou, R., Handen, B., Hardan, A. 2004; 12 (4): 376-379

  Abstract

  To examine the potential effectiveness and tolerability of psychostimulants in adults with mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD).A retrospective chart review was conducted in a clinic specialized in treating individuals with developmental disabilities. Improvement was assessed using the Aberrant Behaviour Checklist-Community Version (ABC-C) and the global improvement item of the Clinical Global Impression scale.Ten consecutive adult outpatients were identified. Five were judged to be responders, based on impressions from chart review and the ABC-C. Significant improvements were observed in the hyperactivity and irritability subscales of the ABC-C. Adverse events were minimal and no patients required treatment termination.Psychostimulants might be effective and well-tolerated in the treatment of ADHD in adults with MR. However, larger prospective open-label studies, and, eventually, double-blind placebo-controlled studies are needed to confirm these findings.

  View details for PubMedID 15715811

• A retrospective assessment of topiramate in children and adolescents with pervasive developmental disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Jou, R. J., Handen, B. L. 2004; 14 (3): 426-432

  Abstract

  An open-label retrospective study was conducted to assess the effectiveness and tolerability of topiramate in children and adolescents with pervasive developmental disorders (PDD). Topiramate is a novel antiepileptic drug approved as an adjunctive treatment for seizure disorders. A retrospective chart review was conducted in an outpatient clinic specialized in treating individuals with developmental disabilities, to identify all children and adolescents with PDD who received topiramate. Patients were included if concomitant medications remained unchanged. Treatment response was assessed using the Global Improvement item of the Clinical Global Impressions scale (CGI-GI), based on a review of medical records and the Conners Parent Scale (CPS), as completed by parents. Fifteen patients were identified (12 male, 3 female; age = 14.7 +/- 3.3 years), including 11 patients with autistic disorder, 2 patients with Asperger's disorder, and 2 patients with PDD not otherwise specified (PDD, NOS). Eight patients (4 patients with autistic disorder, 2 patients with Asperger's disorder, and 2 patients with PDD, NOS) were judged to be responders, as defined by a score of 1 or 2 on the CGI-GI. Treatment duration was 25 +/- 16 weeks, and the mean dose was 235 +/- 88 mg. Differences between baseline and the end-of-trial period were observed in the following CPS subscales: conduct, hyperactivity, and inattention. No differences were noted in the psychosomatic, learning, and anxiety subscales. Three patients discontinued topiramate because of side effects, with 2 patients experiencing cognitive difficulties and 1 patient a skin rash. Topiramate may be beneficial for treating secondary symptoms of PDD, and prospective openlabel studies and double-blind, placebo-controlled studies to assess its efficacy and safety are needed.

  View details for Web of Science ID 000224838500017

  View details for PubMedID 15650499

• Increased frontal cortical folding in autism: a preliminary MRI study PSYCHIATRY RESEARCH-NEUROIMAGING Hardan, A. Y., Jou, R. J., Keshavan, M. S., Varma, R., Minshew, N. J. 2004; 131 (3): 263-268

  Abstract

  The gyrification index (GI), the ratio of total to outer cortical contour, was applied to measure the cerebral folding patterns in autism. GI was examined on a frontal coronal slice obtained from MRI scans of 30 nonmentally retarded individuals with autism and 32 matched healthy controls. In the autistic group, left frontal GI was higher in children and adolescents but not in adults. Cortical folding was decreased bilaterally with age in the total autistic sample but not in controls. These preliminary findings suggest that the gyrification patterns in autism may be abnormal, which could be related to the various cortical anomalies observed in this disorder.

  View details for DOI 10.1016/j.pscychresns.2004.06.001

  View details for Web of Science ID 000224608800008

  View details for PubMedID 15465295

• Neuropsychiatric problems in tuberous sclerosis complex JOURNAL OF CHILD NEUROLOGY Asato, M. R., Hardan, A. Y. 2004; 19 (4): 241-249

  Abstract

  Tuberous sclerosis complex is an autosomal dominant disorder characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. It is a disease affecting multiple organ systems and typically has brain involvement, causing severe disabilities. This article reviews the literature of the commonly associated neuropsychiatric complications, including mental retardation, autism-like features, and other behavior problems, which are discussed in the context of the neuropathology and epilepsy observed in tuberous sclerosis complex. The potential pathogenesis of neuropsychiatric problems is explored, including links to the genetics, neuropathology, neurotrophins, and epilepsy factors associated with tuberous sclerosis complex. Treatment of neuropsychiatric symptoms, including autism-like features, attention deficits, and sleep disorders, is also discussed.

  View details for Web of Science ID 000221419000001

  View details for PubMedID 15163088

• Anatomic evaluation of the orbitofrontal cortex in major depressive disorder BIOLOGICAL PSYCHIATRY Lacerda, A. L., Keshavan, M. S., Hardan, A. Y., Yorbik, O., Brambilla, P., Sassi, R. B., NICOLETTI, M., Mallinger, A. G., Frank, E., Kupfer, D. J., Soares, J. C. 2004; 55 (4): 353-358

  Abstract

  The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation. This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects.Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly.The MDD patients had smaller gray matter volumes in right medial [two-way analysis of covariance F(1,60) = 4.285; p =.043] and left lateral OFC [F(1,60) = 4.252; p =.044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender.These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative.

  View details for DOI 10.1016/j.biopsych.2003.08.021

  View details for Web of Science ID 000188964700004

  View details for PubMedID 14960287

• The functional neuroanatomy of autism FUNCTIONAL NEUROLOGY Brambilla, P., Hardan, A. Y., di Nemi, S. U., Caverzasi, E., Soares, J. C., Perez, J., Barale, F. 2004; 19 (1): 9-17

  Abstract

  Autism is a neurodevelopmental syndrome characterized by impaired social and executive functions. Functional magnetic resonance imaging (fMRI) is a non-invasive technique that allows investigation of the neural networks underlying cognitive impairments in autism. In this article, brain imaging studies investigating the functional brain anatomy of autism are reviewed. Face recognition, theory of mind and executive functions have all been explored in functional neuroimaging studies involving autistic patients. The available literature suggests an involvement of abnormal functional mechanisms in face recognition, mentalization and executive functions in adults with high-functioning autism or Asperger's syndrome, possibly due to brain maturation abnormalities, and resulting in dysfunctional reciprocal cortico-subcortical connections. Future functional neuroimaging research should investigate subgroups of autistic children and adolescents longitudinally and attempt to integrate genetic, cognitive and empirical approaches. Such studies will be instrumental in furthering understanding of the pathophysiology of autism and in exploring the importance of dimensional measures of the broader phenotype currently defined as autism.

  View details for Web of Science ID 000222004200002

  View details for PubMedID 15212111

• Brain anatomy and development in autism: review of structural MRI studies BRAIN RESEARCH BULLETIN Brambilla, P., Hardan, A., di Nemi, S. U., Perez, J., Soares, J. C., Barale, F. 2003; 61 (6): 557-569

  Abstract

  Autism is a neurodevelopmental disorder that severely disrupts social and cognitive functions. MRI is the method of choice for in vivo and non-invasively investigating human brain morphology in children and adolescents. The authors reviewed structural MRI studies that investigated structural brain anatomy and development in autistic patients. All original MRI research papers involving autistic patients, published from 1966 to May 2003, were reviewed in order to elucidate brain anatomy and development of autism and rated for completeness using a 12-item check-list. Increased total brain, parieto-temporal lobe, and cerebellar hemisphere volumes were the most replicated abnormalities in autism. Interestingly, recent findings suggested that the size of amygdala, hippocampus, and corpus callosum may also be abnormal. It is conceivable that abnormalities in neural network involving fronto-temporo-parietal cortex, limbic system, and cerebellum may underlie the pathophysiology of autism, and that such changes could result from abnormal brain development during early life. Nonetheless, available MRI studies were often conflicting and could have been limited by methodological issues. Future MRI investigations should include well-characterized groups of autistic and matched healthy individuals, while taking into consideration confounding factors such as IQ, and socioeconomic status.

  View details for DOI 10.1016/j.brainresbull.2003.06.001

  View details for Web of Science ID 000189133800001

  View details for PubMedID 14519452

• Measurement of the orbitofrontal cortex: a validation study of a new method NEUROIMAGE Lacerda, A. L., Hardan, A. Y., Yorbik, O., Keshavan, M. S. 2003; 19 (3): 665-673

  Abstract

  The orbital frontal cortex (OFC) plays a critical role in the pathophysiology of several neuropsychiatric disorders. Few morphometric neuroimaging studies have examined the OFC using different methodologies and have reported discrepant values. Substantial variability in gyri and sulci across individuals as well as unclear landmarks underline the difficulties in obtaining accurate and reliable measurements. We propose a new geometrical method for measuring the OFC taking into account individual brain variability. The OFC was defined by using the intercommissural line and the inferior edge of the frontal lobe as the main landmarks. The medial and lateral subdivisions of OFC were also separately measured using the olfactory sulcus as the boundary to distinguish between them. After resampling and refitting, 10 scans were independently traced by two trained researchers using BRAINS software. Talairach coordinates were identified on each scan from the OFC and surrounding adjacent brain regions to assess the validity of this method. Brain regions were assigned using Talairach Daemon system. OFC volumes were comparable with those previously reported. Sensitivity and specificity for OFC gray matter were 87.6 and 84.8%, respectively. Intraclass coefficients (ICCs) for gray, white, and total OFC were 0.995, 0.994, and 0.997, respectively. ICCs for OFC medial and lateral subdivisions ranged between 0.996 and 0.998. This method appears to be a valid method for measuring the OFC with excellent reliability. This uncomplicated approach is easy to apply and has the potential to be a valuable alternative to the previously published methods.

  View details for DOI 10.1016/S1053(03)00137-X

  View details for Web of Science ID 000184485400017

  View details for PubMedID 12880797

• Motor performance and anatomic magnetic resonance imaging (MRI) of the basal ganglia in autism 57th Annual Meeting of the Society-of-Biological-Psychiatry Hardan, A. Y., Kilpatrick, M., Keshavan, M. S., Minshew, N. J. SAGE PUBLICATIONS INC. 2003: 317?24

  Abstract

  This study was conducted to examine the volume of the basal ganglia in individuals with autism and to evaluate whether performance on specific motor tasks correlated with the volume of these structures. Volumetric measurements of the caudate nucleus and putamen were obtained from magnetic resonance images (MRI) of 40 non-mentally retarded individuals with autism and 41 healthy controls. Motor performance was assessed in these subjects by using the Finger Tapping Test, the Grooved Pegboard Test, and the measurement of Grip Strength. No volumetric differences of the basal ganglia were found between the two groups after adjusting for brain volume. The autistic subjects' performance was slower on the Grooved Pegboard Test and weaker on Grip Strength. Our findings suggest that the motor deficits observed in autism may not be related to structural abnormalities of the basal ganglia, and other brain regions, such as the cerebellum and the frontal lobe, may be involved in the pathophysiology of motor disturbances in autism.

  View details for Web of Science ID 000183405600002

  View details for PubMedID 12822815

• A retrospective open trial of adjunctive donepezil in children and adolescents with autistic disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Handen, B. L. 2002; 12 (3): 237-241

  Abstract

  In light of the recently reported neuropathologic and neurochemical abnormalities of the cholinergic pathways in autism, donepezil, a cholinesterase inhibitor, is a potentially useful agent in the treatment of cognitive and behavioral symptoms observed in this disorder. A retrospective pilot study was conducted to determine whether donepezil is effective in the treatment of children and adolescents with autism. Eight patients (mean age = 11.0 +/- 4.1 years; range 7-19 years) who met Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria for autistic disorder were openly treated with donepezil. All patients were on concomitant psychoactive medications. Four of these patients (50%) demonstrated significant improvement as assessed by the Aberrant Behavior Checklist and the Clinical Global Impression Scale. Decreases in the Irritability and Hyperactivity subscales were observed, but no changes in the Inappropriate Speech, Lethargy, and Stereotypies subscales were noted. Limited and transient side effects were reported, with one patient experiencing gastrointestinal disturbances and another reporting mild irritability. Double-blind, placebo-controlled investigations are needed to provide further evidence of the potential benefits of donepezil to patients with autistic disorder.

  View details for Web of Science ID 000178736200007

  View details for PubMedID 12427297

• Posterior fossa magnetic resonance imaging in autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hardan, A. Y., Minshew, N. J., Harenski, K., Keshavan, M. S. 2001; 40 (6): 666-672

  Abstract

  To determine whether the sizes and volumes of the posterior fossa structures are abnormal in non-mentally retarded autistic adolescents and adults.Volume measurements of the cerebellum, vermis, and brainstem were obtained from coronal magnetic resonance imaging scans in 16 autistic subjects and 19 group-matched healthy controls. For the purpose of comparison with previous studies, area measurements of the midbrain, pons, medulla, total cerebellar vermis, and its three subregions were also obtained from a larger sample of 22 autistic males (mean age: 22.4 years; range: 12.2-51.8 years) and 22 individually matched controls (mean age 22.4 years; range: 12.9-52.2 years).The total volume of the cerebellum and the cerebellar hemispheres were significantly larger in the autistic subjects with and without correcting for total brain volume. Volumes of the vermis and the brainstem and all area measurements did not differ significantly between groups.There is an increase in the volume of the cerebellum in people with autism consistent with the increase in regional and total brain size reported in this developmental disorder. This finding is also concordant with evidence of cerebellar abnormalities from neuropathological and neuropsychological studies that point to the role of this structure, as part of a complex neural system, in the pathophysiology of autism.

  View details for Web of Science ID 000168786400011

  View details for PubMedID 11392344

• Brain volume in autism JOURNAL OF CHILD NEUROLOGY Hardan, A. Y., Minshew, N. J., Mallikarjuhn, M., Keshavan, M. S. 2001; 16 (6): 421-424

  Abstract

  Increased brain size has been observed in individuals with autism with a wide range of cognitive functioning. The purpose of this investigation was to obtain measurements of the brain volume in a sample of nonmentally retarded autistic individuals. Magnetic resonance imaging scans from 16 nonmentally retarded individuals with autism and 19 male volunteer comparison subjects were obtained and the following structures were measured: third, fourth, and lateral ventricles and intracranial and cerebral volumes. Mean cerebral and third ventricle volumes in the autistic subjects were significantly greater than in the controls when adjusted for intracranial volume. No other significant results were found. Our finding of increased brain volume in autism is consistent with previous reports in the literature. Additional longitudinal neuroimaging and, more importantly, neuropathologic studies are warranted to provide a better understanding of the complexities underlying increased brain size in autism.

  View details for Web of Science ID 000171025800007

  View details for PubMedID 11417608

• Corpus callosum size in autism NEUROLOGY Hardan, A. Y., Minshew, N. J., Keshavan, M. S. 2000; 55 (7): 1033-1036

  Abstract

  The size of the seven subregions of the corpus callosum was measured on MRI scans from 22 non-mentally retarded autistic subjects and 22 individually matched controls. Areas of the anterior subregions were smaller in the autistic group. In a subsample, measurements were adjusted for intracranial, total brain, and white matter volumes and the differences between groups remained significant. No differences were found in the other subregions. This observation is consistent with the frontal lobe dysfunction reported in autism.

  View details for Web of Science ID 000089696500025

  View details for PubMedID 11061265

• Inositol as an add-on treatment for bipolar depression BIPOLAR DISORDERS Chengappa, K. N., Levine, J., Gershon, S., Mallinger, A. G., Hardan, A., Vagnucci, A., Pollock, B., Luther, J., Buttenfield, J., Verfaille, S., Kupfer, D. J. 2000; 2 (1): 47-55

  Abstract

  Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood-brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression.Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) were randomly assigned to receive either 12 g of inositol or D-glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged.Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of 'much' or 'very much' improved, as compared to three (30%) subjects assigned to placebo, a statistically nonsignificant difference. On the Montgomery-Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p = 0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered.These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the 'natural substance' aspect of inositol may be particularly appealing to subjects with bipolar depression.

  View details for Web of Science ID 000089479600007

  View details for PubMedID 11254020

• Prolactin secretion in depressed children BIOLOGICAL PSYCHIATRY Hardan, A., Birmaher, B., Williamson, D. E., Dahl, R. E., Ambrosini, P., Rabinovich, H., Ryan, N. D. 1999; 46 (4): 506-511

  Abstract

  Few studies have examined the involvement of the central dopaminergic system in the pathophysiology of mood disorders. The study of prolactin (PRL) secretion may be an informative indirect method for the assessment of the dopaminergic system in children with major depressive disorder (MDD).Plasma PRL concentrations were measured at 20-min intervals over a 24-hr period in 40 pre-pubertal children with MDD, 18 with non-affective psychiatric disorders (PC), and 6 normal controls (NC). A subgroup of depressed children (n = 21) was restudied after recovery.There was no significant differences in either the amount or the pattern of PRL secretion between the MDD, PC, and NC groups. Children who recovered from their depression secreted less PRL during sleep and more while awake compared to when they were acutely depressed.Overall, there were no differences in baseline PRL secretion between children with MDD, NC and psychiatric control. These results suggest that the dopaminergic system as measured by baseline PRL blood levels is not compromised in children with MDD.

  View details for Web of Science ID 000082036700008

  View details for PubMedID 10459400

• Suicidal behavior in children and adolescents with developmental disorders RESEARCH IN DEVELOPMENTAL DISABILITIES Hardan, A., SAHL, R. 1999; 20 (4): 287-296

  Abstract

  Children and adolescents with developmental disorders exhibit a wide range of self-destructive behaviors. Interestingly, suicidal ideation and gestures have been underreported in this population. This study was designed to examine suicidality in a clinically referred sample. The medical records of all individuals assessed in a specialized program during a 1-year period were reviewed looking at the incidence, the type and the clinical characteristics of any suicidal behavior. Forty-seven patients (20%) experienced either suicidal ideation, threats, or attempts with hanging being the most frequent method considered. Suicidality was more often encountered in individuals diagnosed with oppositional defiant disorder, depressive disorders, and post traumatic stress disorder, and less often in the autistic and the severely/profoundly mentally retarded groups. Suicidal behaviors were frequently encountered in children and adolescents with developmental disabilities. Prospective studies should be conducted to examine rigorously the variables associated with suicidality in this population.

  View details for Web of Science ID 000081321200004

  View details for PubMedID 10425656

• Psychopathology in children and adolescents with developmental disorders RESEARCH IN DEVELOPMENTAL DISABILITIES Hardan, A., SAHL, R. 1997; 18 (5): 369-382

  Abstract

  Children and adolescents with developmental disorders suffer from a wide range of psychopathology. However, there are no published studies examining this subject exclusively in this population using recent diagnostic criteria. The primary purpose of this paper is to report on the diagnosis encountered in a clinical setting using DSM-III-R. The medical records of all individuals assessed in a specialized program during a 1-year period were reviewed looking at their demographic features, diagnoses, and target behaviors. Our sample consisted of 233 subjects and contained significantly more boys than girls. The most common psychiatric diagnoses were oppositional defiant disorder and attention deficit hyperactivity disorder. Pica, organic mental disorder NOS, and Autistic Disorder were more often encountered in individuals with low intellectual functioning. Depressive disorders, posttraumatic stress disorder, and developmental speech/language disorders were diagnosed more in high functioning subjects. The most common symptom was impulsivity. This retrospective study highlights the need for more rigorous examination of current diagnostic concepts and criteria in children and adolescents with developmental disorders. Prospective studies should be conducted with standardized instruments in clinics and community samples to provide more information on psychiatric disorders in this population.

  View details for Web of Science ID A1997XV51300005

  View details for PubMedID 9292930

• Risperidone treatment of children and adolescents with developmental disorders JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hardan, A., Johnson, K., Johnson, C., HRECZNYJ, B. 1996; 35 (11): 1551-1556

  Abstract

  In a clinical trial, 20 children and adolescents with developmental disorders (age range 8 through 17 years) refractory to previous psychotropic treatments were administered the atypical neuroleptic risperidone (dose range 1.5 to 10 mg/day). In a follow-up period ranging from 8 to 15 months, risperidone demonstrated clinical efficacy in 13 children. Twelve patients were free of side effects and two had minor ones. Three patients had marked weight increase, and galactorrhea developed in two adolescent girls. In this open study, risperidone was associated with clinical improvement. However, controlled studies are needed to determine its relative efficacy and safety in this special population.

  View details for Web of Science ID A1996VN95400025

  View details for PubMedID 8936923