Dr. Williams is the founding Director of the PanLab for Precision Psychiatry and Translational Neuroscience. She has developed a radical new way to understand and treat mental disorders, anchored in a neuroscience-informed model for precision mental health.

In 2018, Dr. Williams launched as founding Director Stanford's Center for Precision Mental Health and Wellness. The Center connects researchers across the campus to advance high definition imaging biotypes for mental health, sensor technology, machine learning approaches, targeted therapeutics and the world's first biotype-guided trials. Dr. Williams also leads department-wide initiatives in precision mental health as Associate Chair of Translational Neuroscience. She has a joint position at the Palo Alto VA Mental Illness Research, Education and Clinical Center where she is Director of education and dissemination.

After first graduating Dr. Williams worked with patients experiencing serious mental disorders and who had been hospitalized for many years. This experience transformed the trajectory of her career. She went on to complete her PhD in 1996 with a British Council scholarship for study at Oxford University. She joined the Stanford faculty as a Professor of Psychiatry and Behavioral Sciences in 2013. Prior to this time, she was foundation Professor of Cognitive Neuropsychiatry at the Sydney Medical School and Director of the interdisciplinary Sydney Brain Dynamics Center for 12 years.

Her translational programs integrate advanced neuroimaging, technology and digital innovation to transform the way we detect mental disorders, predict mental states, tailor interventions and promote wellness. Data-driven computational approaches are used to refine this transformative approach. Her experience is that a neuroscience-informed model empowers each person with an understanding of their own brain function and can reduce stigma. Her research forms the foundation of the first patented taxonomy for depression and anxiety that quantifies brain circuits for diagnostic precision and prediction. She has contributed over 270 scientific papers to the field.

Academic Appointments

Administrative Appointments

  • Director, Stanford Center for Precision Mental Health and Wellness (2018 - Present)
  • Associate Chair, Translational Neuroscience, Psychiatry and Behavioral Sciences, Stanford University (2018 - Present)
  • Associate Chair, Research Strategy, Psychiatry and Behavioral Sciences, Stanford University (2016 - 2018)
  • Chair, Steering Committee, Major Laboratories and Clinical Translational Neurosciences Incubator, Psychiatry and Behavioral Sciences, Stanford University (2015 - 2018)
  • Director of PTSD Education and Disssemination, VA Palo Alto Sierra-Pacific MIRECC (2013 - Present)

Honors & Awards

  • Fellow, American College of Neuropsychopharmacology (2017)
  • Chairman's Award for Advancing Science, Stanford University (2016)
  • Ernst Strüngmann Award: “Schizophrenia evolution and synthesis”, Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Institute (2012)
  • Presidential Award, American Psychosomatic Society (2008)
  • Senior Biomedical Research Fellowship, Pfizer Foundation (2004)
  • Young Investigator Award, International Schizophrenia Congress (2001)
  • Senior Scientist Award, 10th Biennial Winter Workshop on Schizophrenia (2000)
  • Research Award for advanced study at the Institute of Psychiatry London, Wellcome Trust-Ramaciotti Foundation (1998)
  • Outstanding Postgraduate Lecturer of the Year, University of Sydney (1997)
  • Postgraduate scholarship for Oxford University, British Council (1991)
  • Australian Postgraduate Research Award, Australian federal government (1990)
  • Prize for Top Honors Research Thesis, Australian Psychological Society (1990)

Boards, Advisory Committees, Professional Organizations

  • Member, Society for Biological Psychiatry (2009 - Present)
  • Member, Society for Biological Psychiatry Women's Leadership Group (2016 - Present)
  • Editorial Board, Depression and Anxiety (Wiley-Blackwell) (2018 - Present)
  • Editorial Board, Network Neuroscience (MIT Press) (2017 - Present)
  • Editorial Board, Personalized Medicine for Psychiatry (Elsevier) (2016 - Present)
  • Scientific Advisory Board, Psyberguide, A project of the One Mind Institute (2015 - Present)
  • Faculty member, Stanford Precision Health and Integrated Diagnostics Center (PHIND) (2018 - Present)
  • Faculty member, Stanford Neurosciences Institute (2016 - Present)

Community and International Work

  • Brain Research and Integrative Neuroscience Network: BRAINnet,


    collaborative human clinical neuroscience

    Partnering Organization(s)

    BRAINnet Foundation

    Populations Served

    research and community



    Ongoing Project


    Opportunities for Student Involvement


Research & Scholarship

Current Research and Scholarly Interests

A revolution is under way in psychiatry.
We can now understand mental illness as an expression of underlying brain circuit disruptions, shaped by experience and genetics.

Our challenge is to now accelerate the translation of these insights into new models of mental disorder, and improve lives. Right now, mental disorders are our number one cause of ruined lives. At least 1 in 10 of us is affected by these disorders but only a fraction get access to treatment. Fewer still get better after the first treatment they try.

My lab is finding solutions to these problems.

We are defining precision brain circuit types for mood, anxiety and attention disorders. We apply computational models to large amounts of brain imaging, behavior and other data. These precision brain types inform our translational intervention studies. To close the loop, field ready insights are applied in practice.

We are advancing a neuroscience-informed approach to Precision Mental Health for Psychiatry.

1. Neural circuit taxonomy
We have developed a novel brain-based taxonomy for understanding mental disorders. Each person's experience of mental disorder is characterized as an expression of the way in which underlying circuits are disrupted. Our model accounts for how circuit disruptions are shaped by early life experience, by daily function, and by genetic contributions.

2. Advanced computational models
To continually refine our taxonomy, and to discover new types, we use advanced machine-learning approaches. By choosing to use common data elements, we have amassed the largest available databank of integrated imaging, physiological, behavioral and genetic data on a spectrum of mood, anxiety and attention disorders, people at risk of these disorders and healthy people. With these large amounts of data, we are accelerating the discovery of new types, and the detailed mapping between brain circuits, behavior and experience.

3. Mapping human connectomes
In a new human connectome study, we are adding higher resolution imaging of brain connectivity to our brain circuit model. With these connectome data, we extend our taxonomy to the precise mapping of how each person's brain circuits connect and communicate, and how "short circuits" in these connections cause particular types of symptom experiences.

4. Biomarkers to predict treatment
Our lab led the first multi-site international studies to identify imaging and genetic biomarkers that predict the right treatment for the right person at the right time. With these advances, we can double the number of people who recover from depression.

5. Accelerating translation into practice
There is a giant chasm between neuroscience insights and their application in practice to improve lives for people experiencing mental disorders. To close this loop, we lead first-in-nation studies to accelerate the translation of field-ready insights into clinical practice and education.

Because our focus is on changing the way we understand mental disorder, our lab embraces the heterogeneity of these disorders. We focus on the commonly co-occurring experiences of mood, anxiety and attentional disruption in adults and in young people. We also investigate other commonly associated experiences such as substance use.

For more about what motivates us see:

Clinical Trials

  • International Study to Predict Optimised Treatment - in Depression Recruiting

    The aim of this study is to identify genetic, physical (brain) and psychological (cognitive) markers (or combinations of them) that predict specific response to a range of antidepressants treatment (Escitalopram, Venlafaxine, Sertraline) in patients diagnosed with major depressive disorder. This study is focused on outcomes which may impact on how "personalised medicine" is implemented in depression.

    View full details

  • Research Aimed at Improving Both Mood and Weight Recruiting

    The RAINBOW study is an NIH R01-funded randomized controlled trial to evaluate the clinical and cost effectiveness and implementation potential of a primary care integrated multicondition intervention program to help improve mood and weight for obese adults with clinically significant depressive symptoms. The ENGAGE study is a mechanistic investigation added to the main trial with funding through the NIH common fund for the Science of Behavior Change roadmap initiative. Beginning Jan 11, 2016, at least 100 of newly enrolled trial participants will be consented to undergo additional assays evaluating neurobiological mechanisms of self-regulation.

    View full details

  • Stanford RAD-AT Study (Research on Anxiety and Depression - Anhedonia Treatment) Recruiting

    This research study is aimed at understanding behaviors and brain circuits that relate to anxiety and depression. Our goal is to learn which circuits of the brain are involved in anxiety and how these circuits might affect daily functioning. This study has recently added an additional treatment component: participants undergo a 12 week course of either Pramipexole medication or rTMS therapy (explained below). The ultimate goal of the study is to offer participants experiencing anxiety and depression a treatment that is alternative to ones that have failed them in the past, and to apply the knowledge we gain from investigating the brain circuits involved in anxiety and depression to help personalize treatments. We invite anyone who has recently experienced any symptoms of anxiety and/or depression to participate (no diagnosis is required to participate).

    View full details


  • Precision Health for Depression

    The goal of this research is to revolutionize our approach to treating depression by identifying underlying brain circuitry disruptions and malfunctions in each patients and guiding personalized treatments that correct them. We are personalizing treatment by targeting brain circuitry with advanced imaging technology. This is a Clinical Translational Biomedical Innovation project within the School of Medicine.




    For More Information:

  • Precision Psychiatry Continuity Clinic Project: Translating neuroscience into mental health care, Stanford (7/25/2017)

    In the last several years there have been incredible advances in human neuroscience, many of them due to groundbreaking research done right here at Stanford. Now, a unique collaboration between researchers, educators, and clinicians in the Stanford Psychiatry Department is beginning to bring these advances into clinical care. This study, the first of its kind in the nation, is a joint initiative of Dr. Leanne Williams, Director of the PanLab for Precision Psychiatry and Translational Neuroscience, and Dr. Chris Hayward, Chief of Adult Psychiatry and Director of Residency Training. The initiative’s implementation is led by Dr. Tali Ball, PanLab Fellow, in collaboration with Dr. Belinda Bandstra, Director of the Continuity Clinic. Patients entering the Continuity Clinic are offered a thorough assessment of symptoms, cognition, genetics, and brain circuit functioning. For half of participating patients, their doctor will receive information from the assessment to their first appointment. The remaining patients receive the information 12 weeks later, to allow the research team to test the impact of receiving information from neuroscience assessments relative to usual care. The research team also provides advanced training in neuroscience models and their applicability to clinical care to the PGY3 residents rotating in the clinic. This study establishes Stanford as a national leader in neuroscience-informed psychiatry in both training and practice.




    • Leanne Williams, Professor of Psychiatry and Behavioral Sciences (Major Laboratories and Clinical Translational Neurosciences Incubator), Stanford
    • Chris Hayward, Chief of the Division of Adult Psychiatry Director of Residency Training and Associate Chair, Stanford
    • Tali Ball, School of Medicine
    • Belinda Bandstra, Clinical Associate Professor, Psychiatry and Behavioral Sciences
    • Kristin Raj, Clinical Assistant Professor, Psychiatry and Behavioral Sciences
    • Mytilee Vemuri, Clinical Associate Professor, Psychiatry and Behavioral Sciences
    • Sarah Adler, Clinical Assistant Professor, Psychiatry and Behavioral Sciences
  • RAD-AT Project: Research on Anxiety and Depression – Anhedonia Treatment, Stanford University School of Medicine and VA Palo Alto

    The RAD-AT study is developing a precision psychiatry approach to testing new treatments for anhedonia. We focus on the reward circuits of the brain that underlie the experience of pleasure and motivated behavior. People with anhedonic depression have lost the ability to feel pleasure and have disrupted reward circuit function. Current treatments are not effective for them. We are assessing two novel treatments that target anhedonia and reward circuit dysfunction. One of these is Pramipexole, a drug that acts on the major neurotransmitter system involved in reward processing. The other is repetitive transcranial magnetic stimulation (rTMS), a direct neurostimulation treatment. Using a personalized, precision approach, we identify people experiencing anhedonia. We offer either pramipexole or rTMS for 8-12 weeks and examine anhedonia and reward-associated circuits before and after these treatments. The purpose of the study is to offer participants experiencing anhedonia a treatment that is alternative to ones that have failed them in the past, and to apply the knowledge we gain to help personalize mental health treatments in the future.
    This project extends on our RAD Project and NIH study # 11255773.


    Palo Alto


    • Zoe Samara, School of Medicine
    • Trisha Suppes, Professor, Stanford University and Palo Alto VA
    • Michael Ostacher, Associate Professor of Psychiatry and Behavioral Sciences (Public Mental Health and Population Sciences) at the Palo Alto Veterans Affairs Health Care System, Stanford University and Palo Alto VA
    • Nolan Williams, Assistant Professor of Psychiatry and Behavioral Sciences (General Psychiatry and Psychology) at the Stanford University Medical Center, Stanford
    • Jerome Yesavage, Stanford University and Palo Alto VA
  • RAD Project: Neural Dimensions of Threat Reactivity and Regulation for Understanding Anxiety, Stanford University and PAVIR (September 1, 2013 - Present)

    Short title "Research criteria for Anxiety and Depression; RAD Project". The RAD project is an R01 project funded under the NIMH Research Domain Criteria (RDoC) program. It is designed to use functional imaging to define dimensional constructs for reactivity and regulation of potential threat, within the Negative Valence system of RDoC. This is a novel study determining the cohesion with which these constructs relate to specific aspects of behavioral performance, features of anxious arousal and apprehensive expectations, and functional capacity.

    Grant Number: 1R01MH101496-01


    Palo Alto


    • Ruth O'hara, Professor of Psychiatry and Behavioral Sciences (Public Mental Health and Population Sciences), Stanford
    • Alan Schatzberg, Professor, Stanford
    • Jerome Yesavage, Stanford University and Palo Alto VA
    • Trisha Suppes, Professor, Stanford University and Palo Alto VA

    For More Information:

  • ENGAGE Project: Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes, Stanford University and University of Chicago Illinois (9/30/2015)

    Using brain scans, mobile technology, and virtual-reality experiments, we are investigating how the brain responds to two integrated behavioral therapies to help patients with co-existing obesity and depression to manage both conditions. We will then try to optimize the therapy and follow the further changes in the brain and improvements in mood and weight loss. The study is based on our understanding of the large-scale human brain circuits involved in self-regulation. Adopting and sticking to lifestyle changes is a reflection of a person’s ability to self-regulate, or manage their health issues on their own. By knowing more about how the brain changes or adapts in response to behavioral therapy, especially areas involved in self-regulation, then we can begin to tailor therapy to individual patients.
    The three-year study is first phase of a two-phase, five-year project funded through the NIH Common Fund’s Science of Behavior Change roadmap initiative.
    The project involves a collaboration between investigators at the University of Illinois Chicago, Stanford University School of Medicine, Palo Alto Medical Foundation Research Institute, and the University of Washington, Seattle,

    We will enroll 100 adults with co-occurring obesity and depression who are currently part of RAINBOW, a five-year randomized controlled trial led by PI Jun Ma (UIC) and Lisa Goldman Rosas, assistant scientist at the Palo Alto institute and an instructor of medicine at Stanford’s Prevention Research Center, and also funded by the NIH.
    Functional magnetic resonance imaging (fMRI) brain scans will be done before the start of behavioral therapy and after four weeks and six, 12 and 24 months of therapy to track changes in brain function. The participants’ brain activity will be compared to control subjects who didn’t receive the intervention. In collaboration with Stanford’s Virtual Human Interaction Lab, we will also assess emotional, cognitive, and self-reflective regulation by exposing participants to simulations of real-world situations in a virtual environment. We will also collect information on the subjects’ social engagement through an app on their smartphones. We aim to make real steps forward in the field of precision lifestyle medicine. The study will let us develop and validate the tools we need to be able to adjust and guide behavioral therapies based on neurobiological mechanisms — so that they are precise and personalized for the individual, and are scalable and sustainable for population health management.




    • Jun Ma , Professor , University of Chicago Illinois
    • Leanne Williams, Professor of Psychiatry and Behavioral Sciences (Major Laboratories and Clinical Translational Neurosciences Incubator), Stanford
    • Jeremy Bailenson, Professor of Communication , Stanford
    • Mark Snowden , Associate Professor, University of Washington
    • Philip Lavori, Stanford University
    • Olivier Gevaert, Assistant Professor of Medicine (Biomedical Informatics Research), Stanford University
    • Trisha Suppes, Professor, Stanford University and Palo Alto VA
    • Brian Wandell, Isaac and Madeline Stein Family Professor and Professor, by courtesy, of Electrical Engineering and of Ophthalmology, Stanford
    • Paul Dagum , CEO, Mindstrong
  • iSPOT-D: International Study to Predict Optimized Treatment - in Depression, Stanford University and collaborating sites

    Background: Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.
    Methods/Design: The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi- centre, international, randomized, prospective, open-label trial. It is enrolling MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; brain imaging; cognitive performance; electroencephalogram and event- related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self- reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.
    Discussion: First enrolment was in December 2008, and 1700 patients have been tested, including 204 with brain imaging (structural MRI, functional MRI and diffusion MRI).


    401 Quarry Road, Stanford Univ., Stanford University, Palo Alto, CA 94304, USA

    For More Information:

  • Family Study: Emotional and Cognitive Brain Function Biomarkers of Risk in First Degree Relatives of Depressed Probands, Stanford University and Sydney Medical School

    Data acquisition for 101 relatives and 101 non-relative matched controls is complete. Opportunities exist for graduate students and post-doctoral fellows to analyze the data in new ways, for publication.
    This study was funded by the Australian Research Council from 2007-13. The aims of the study were as follows:
    The aim of this project is to understand vulnerability for depression in individuals. By understanding how depression develops, we can develop prevention and early intervention strategies.

    While factors in the environment, such as a difficult family environment, or stressful life events, are major contributors to the likelihood of a person developing MDD, part of the risk for depression depends on an individual’s biological predisposition. Because MDD is a heritable disorder, the relatives of people with depression can give provide us with information about the biological predisposition for vulnerability and resilience.

    We have investigated a range of contributing factors including genetics, brain structure and function (using neuroimaging and EEG/ERPs), behavior, personality and experienced symptoms, as well as the impact of life events. We will follow participants up one year after the initial visit to see how the initial measures relate to wellbeing and symptom development overtime. Integration across these measures will contribute to a deeper understanding of the development of depression.


    401 Quarry Road

    For More Information:

  • GEM Study: General and Emotional Cognition in First Onset Psychosis, Stanford University and Sydney Medical School

    Data acquisition for this study is complete. There are opportunities for graduate student and post-doctoral involvement in new ways to analyze the data for publication. The study tested the following aims:

    Schizophrenia is a disorder of cognition. Cognitive impairment is the strongest contributor to burden of illness. Yet, there are currently no routine tests for diagnosing cognitive impairments in schizophrenia, nor treatments for ameliorating these impairments.
    The evidence base for developing new cognitive treatments requires cognitive measures that link to functional capacity on the one hand, and to brain changes involved in schizophrenia pathophysiology on the other.
    Specific aims are to identify:
    1. What cognitive impairments characterize schizophrenia patients at first onset.
    2. Whether functional capacities are predicted by these impairments at first onset.
    3. What brain systems are involved.
    4. How cognitive impairments, and their relationships with functional capacity and brain function, progress over 12 months.
    A longitudinal design, targeting a total of 50 first onset schizophrenia patients and matched healthy controls.
    Patient eligibility is a primary diagnosis of schizophrenia or schizophrenia spectrum disorder, according to DSM-IV criteria and confirmed by at least one psychiatrist independent of the study.
    First onset status is defined by; first contact with a mental health service with psychotic symptoms, and testing occurs within 3 months of this contact. It is not possible in these clinical services to test patients prior to medication. However, since patients are first onset, medication will be limited in duration. For consistency, testing will occur once patients are on a maintenance dose.
    Healthy controls will be screened for lack of psychiatric status, and matched to patients for age, sex, years of education, premorbid IQ and geographic region.
    Exclusion criteria for both groups are: (1) treatment with antidepressants during past month, (2) meeting diagnostic criteria for primary depressive disorder, (3) illicit substance dependence, (4) mental retardation, (5) medical condition or disease that might interfere with the assessments (e.g. hearing impairment); (6) did not provide sign informed consent to take part.
    Test-retest from Baseline to 6 months follow up testing:
    (a) Baseline: Clinic status will be assessed to confirm diagnosis in patients, and healthy status in controls. Cognition will be assessed in both groups with the computerized touchscreen battery, IntegNeuro, and functional capacity with performance-based measures. EEG (for Gamma synchrony) and fMRI will be recorded to test the brain basis of cognition.
    (b) 6 months follow up: Repeat testing of both groups with clinical status, cognitive performance, functional outcome using the same performance-based measures, and both EEG and fMRI recording.
    Clinical status.
    Diagnosis: The Structured Clinical Interview for DSM disorder (SCID) will be used to confirm diagnosis in patients and screen for absence of psychiatric symptoms in healthy controls.
    Symptoms: Symptoms will be rated using the Positive and Negative Syndrome Scales (PANSS), summed for positive and negative symptoms according to standard criteria.
    Medication: Medication dose will be quantified in chlorpromazine equivalent units. Patients at study sites are typically receiving risperidone or quetiapine, routine atypical antipsychotics.
    Functional capacity and outcome.


    401 Quarry Road, Stanford

  • ACTION Study: ADHD Controlled Trial Investigation Of a Non-stimulant, University of Sydney Medical School and Stanford University

    Background: The ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non- stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD) and associated anxiety. The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD.
    Methods: Children and adolescents aged 6 - 17 y with ADHD have been enrolled. Clinical interview and validated scales were used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions were conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, “IntegNeuroTM”, will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Data acquisition is now complete and analyses are underway.
    The goal of this study is to make a significant step towards a ‘personalized medicine’ (and therefore a more efficient) approach to treatment of ADHD and comorbid anxiety.


    Sydney, NSW; Stanford, CA

    For More Information:

  • TWIN-E Project: The Twin study in Wellbeing using Integrative Neuroscience of Emotion, Sydney Medical School, Flinders University, Neuroscience Australia and Stanford University

    Despite significant advances, we still have limited knowledge about endophenotype markers of which aspects of brain function cause risk for mental disorder and which aspects confers resilience. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to establish endophenotype markers of mental health across cognitive, brain imaging and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype- phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18–65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene–environment and endophenotype contributions to treatment response.
    Data acquisition is now complete and analyses are underway.


    401 Quarry Road, Stanford Univ., Stanford University, Palo Alto, CA 94304, USA

  • LIMCA Project: LImbic Maturational Changes in Adolescence and young adulthood

    LIMCA is a longitudinal imaging study to understand how the healthy brain changes and develops with age. Changes in the brain, especially the limbic regions, have been commonly linked to a number of psychiatric disorders. Most of these disorders emerge at an early age, mainly during childhood and adolescents. The aim of this study is to use a new brain imaging technique to understand how the healthy brain changes and develops during this critical period. Using this information we can then identify the differences in brain development that predict mental illness. These results will help us develop better early intervention strategies to maintain good mental health.


    Sydney Medical School and Stanford University

  • Brain Connectivity Imaging Markers to Confirm Diagnosis for Bipolar vs. Unipolar Depression, University of Sydney Medical School (3/1/2015)

    National Health and Medical Research Council Project Grant 1087560
    Chief Investigator A, Mayuresh Korgaonkar, PhD
    Chief Investigator B, Stuart Grieve, MD, PhD
    Chief Investigator C, Anthony Harris, MD, PhD
    Chief Investigator D, Philip Boyce, MD
    Chief Investigator E, Leanne Williams, PhD




2018-19 Courses

Stanford Advisees


All Publications

  • Transdiagnostic Symptom Clusters and Associations With Brain, Behavior, and Daily Function in Mood, Anxiety, and Trauma Disorders JAMA PSYCHIATRY Grisanzio, K. A., Goldstein-Piekarski, A. N., Wang, M., Ahmed, A. R., Samara, Z., Williams , L. M. 2018; 75 (2): 201-209
  • Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Goldstein-Piekarski, A. N., Korgaonkar, M. S., Green, E., Suppes, T., Schatzberg, A. F., Hastie, T., Nemeroff, C. B., Williams, L. M. 2016; 113 (42): 11955-11960


    Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.

    View details for DOI 10.1073/pnas.1606671113

    View details for PubMedID 27791054

  • Precision psychiatry: a neural circuit taxonomy for depression and anxiety LANCET PSYCHIATRY Williams, L. M. 2016; 3 (5): 472-480


    Although there have been tremendous advances in the understanding of human dysfunctions in the brain circuitry for self-reflection, emotion, and cognitive control, a brain-based taxonomy for mental disease is still lacking. As a result, these advances have not been translated into actionable clinical tools, and the language of brain circuits has not been incorporated into training programmes. To address this gap, I present this synthesis of published work, with a focus on functional imaging of circuit dysfunctions across the spectrum of mood and anxiety disorders. This synthesis provides the foundation for a taxonomy of putative types of dysfunction, which cuts across traditional diagnostic boundaries for depression and anxiety and includes instead distinct types of neural circuit dysfunction that together reflect the heterogeneity of depression and anxiety. This taxonomy is suited to specifying symptoms in terms of underlying neural dysfunction at the individual level and is intended as the foundation for building mechanistic research and ultimately guiding clinical practice.

    View details for DOI 10.1016/S2215-0366(15)00579-9

    View details for Web of Science ID 000376262300029

    View details for PubMedID 27150382

    View details for PubMedCentralID PMC4922884

  • Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial NEUROPSYCHOPHARMACOLOGY Williams, L. M., Korgaonkar, M. S., Song, Y. C., Paton, R., Eagles, S., Goldstein-Piekarski, A., Grieve, S. M., Harris, A. W., Usherwood, T., Etkin, A. 2015; 40 (10): 2398-2408


    Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.Neuropsychopharmacology advance online publication, 29 April 2015; doi:10.1038/npp.2015.89.

    View details for DOI 10.1038/npp.2015.89

    View details for Web of Science ID 000359493700012

    View details for PubMedID 25824424

  • ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial AMERICAN JOURNAL OF PSYCHIATRY Schatzberg, A. F., DeBattista, C., Lazzeroni, L. C., Etkin, A., Murphy, G. M., Williams, L. M. 2015; 172 (8): 751-759


    The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

    View details for DOI 10.1176/appi.ajp.2015.14050680

    View details for Web of Science ID 000359274700015

    View details for PubMedID 25815420

  • Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety MOLECULAR PSYCHIATRY Gatt, J. M., Nemeroff, C. B., Dobson-Stone, C., Paul, R. H., Bryant, R. A., Schofield, P. R., Gordon, E., Kemp, A. H., Williams, L. M. 2009; 14 (7): 681-695


    Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P<0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P=0.013), heart rate elevations (P=0.0002) and a decline in working memory (P=0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P<0.001), and associated lateral prefrontal cortex (P<0.001) and, in turn, higher depression (P=0.005). Higher depression was associated with poorer working memory (P=0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P<0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P=0.003) and associated medial prefrontal cortex (P<0.001), which in turn predicted startle-elicited heart rate variability (P=0.026) and higher anxiety (P=0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies.

    View details for DOI 10.1038/mp.2008.143

    View details for Web of Science ID 000267284800005

    View details for PubMedID 19153574

  • Misinterpreting emotional expressions in attention-deficit/hyperactivity disorder: Evidence for a neural marker and stimulant effects BIOLOGICAL PSYCHIATRY Williams, L. M., Hermens, D. F., Palmer, D., Kohn, M., Clarke, S., Keage, H., Clark, C. R., Gordon, E. 2008; 63 (10): 917-926


    In addition to cognitive impairment, there are disruptions to mood and emotion processing in attention-deficit/hyperactivity disorder (ADHD) but little is known about their neural basis. We examined ADHD disturbances in mood and emotion recognition and underlying neural systems before and after treatment with stimulant medication.Participants were 51 unmedicated ADHD adolescents and 51 matched healthy control subjects rated for depressed and anxious mood and accuracy for identifying facial expressions of basic emotion. Brain function was recorded using event-related potentials (ERPs) while subjects viewed these expressions. ADHD subjects were retested after 4 weeks, following treatment with methylphenidate (MPH).ADHD subjects showed a profile of emotion-related impairment: higher depression and anxiety, deficits in identifying threat-related emotional expressions in particular, and alterations in ERPs. There was a pronounced reduction in occipital activity during the early perceptual analysis of emotional expression (within 120 msec), followed by an exaggeration of activity associated with structural encoding (120-220 msec) and subsequent reduction and slowing of temporal brain activity subserving context processing (300-400 msec). Methylphenidate normalized neural activity and produced some improvement of emotion recognition but had no impact on negative mood. Improvements in neural activity with MPH were consistent predictors of improvement in clinical features of emotional lability and hyperactivity.Objective behavioral and brain function measures of emotion processing may provide a valuable addition to the clinical armamentarium for assessing emotional disturbances in ADHD and the efficacy of stimulants for treating these disturbances.

    View details for DOI 10.1016/j.biopsych.2007.11.022

    View details for Web of Science ID 000255604000003

    View details for PubMedID 18272140

  • Mode of functional connectivity in amygdala pathways dissociates level of awareness for signals of fear JOURNAL OF NEUROSCIENCE Williams, L. M., Das, P., Liddell, B. J., Kemp, A. H., Rennie, C. J., Gordon, E. 2006; 26 (36): 9264-9271


    Many of the same regions of the human brain are activated during conscious attention to signals of fear and in the absence of awareness for these signals. The neural mechanisms that dissociate level of awareness from activation in these regions remain unknown. Using functional magnetic resonance imaging with connectivity analysis in healthy human subjects, we demonstrate that level of awareness for signals of fear depends on mode of functional connectivity in amygdala pathways rather than discrete patterns of activation in these pathways. Awareness for fear relied on negative connectivity within both cortical and subcortical pathways to the amygdala, suggesting that reentrant feedback may be necessary to afford such awareness. In contrast, responses to fear in the absence of awareness were supported by positive connections in a direct subcortical pathway to the amygdala, consistent with the view that excitatory feedforward connections along this pathway may be sufficient for automatic responses to "unseen" fear.

    View details for DOI 10.1523/JNEUROSCI.1016-06.2006

    View details for Web of Science ID 000240324400022

    View details for PubMedID 16957082

  • "Gamma synchrony" in first-episode schizophrenia: A disorder of temporal connectivity? AMERICAN JOURNAL OF PSYCHIATRY Symond, M. B., Harris, A. W., Gordon, E., Williams, L. M. 2005; 162 (3): 459-465


    There has been a convergence of models describing schizophrenia as a disconnection syndrome, with a focus on the temporal connectivity of neural activity. Synchronous gamma-band (40-Hz) activity has been implicated as a candidate mechanism for the binding of distributed neural activity. To the authors' knowledge, this is the first study to investigate "gamma synchrony" in first-episode schizophrenia.Forty medicated first-episode schizophrenia patients and 40 age- and sex-matched healthy comparison subjects participated in a conventional auditory oddball paradigm. Gamma synchrony, time-locked to target stimuli, was extracted from an ongoing EEG. The magnitude and latency of both early (gamma 1: -150 msec to 150 msec poststimulus) and late (gamma 2: 200 to 550 msec poststimulus) synchrony were analyzed with multiple analysis of variance.First-episode schizophrenia patients showed a decreased magnitude and delayed latency for global gamma 1 synchrony in relation to healthy comparison subjects. By contrast, there were no group differences in gamma 2 synchrony.These findings suggest that first-episode schizophrenia patients have a global decrease and delay of temporal connectivity of neural activity in early sensory response to task-relevant stimuli. This is consistent with cognitive evidence of perceptual integration deficits in this disorder and raises the possibility that a breakdown in the early synchrony of distributed neural networks is a marker for the onset of schizophrenia.

    View details for Web of Science ID 000227523500008

    View details for PubMedID 15741462

  • Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Williams, L. M., Das, P., Harris, A. W., Liddell, B. B., Brammer, M. J., Olivieri, G., Skerrett, D., Phillips, M. L., David, A. S., Peduto, A., Gordon, E. 2004; 161 (3): 480-489


    The authors investigated impaired differentiation of limbic-prefrontal systems by autonomic arousal in schizophrenia. It was predicted that paranoid patients would be distinguished by a disjunction of hyperarousal but reduced amygdala and medial prefrontal activity relative to both healthy comparison subjects and patients with nonparanoid schizophrenia.Pictures depicting facial expressions of fear were presented to 27 schizophrenia patients (13 paranoid, 14 nonparanoid) and 22 matched healthy comparison subjects in an implicit perception task to evoke limbic activity. Simultaneous functional magnetic resonance imaging and skin conductance arousal recordings were acquired during presentation of faces expressing fear or neutral emotion. Responses to fear stimuli were further examined by contrasting those that were associated with a skin conductance response ("with arousal") and those that were not ("without arousal").In the comparison subjects, arousal dissociated amygdala/medial prefrontal ("visceral") networks and hippocampus/lateral prefrontal ("context") networks for fear perception. Excessive arousal responses were elicited in the schizophrenia subjects, but there was an associated reduction in amygdala/medial prefrontal activity. This disjunction was pronounced in paranoid patients relative to both healthy subjects and nonparanoid patients. Paranoid patients also showed a relatively greater prefrontal deficit for "without-arousal" responses.This is the first study to reveal a functional disconnection in autonomic and central systems for processing threat-related signals in patients with paranoid schizophrenia. Paranoid cognition may reflect an internally generated cycle of misattribution regarding incoming fear signals due to a breakdown in the regulation of these systems.

    View details for Web of Science ID 000221276000014

    View details for PubMedID 14992974

  • Characterising anxiety in major depressive disorder and its use in predicting antidepressant treatment outcome: An iSPOT-D report. The Australian and New Zealand journal of psychiatry Braund, T. A., Palmer, D. M., Williams, L. M., Harris, A. W. 2019: 4867419835933


    OBJECTIVE:: Major depressive disorder commonly co-occurs with one or more anxiety disorders or with clinically significant levels of anxiety symptoms. Although evidence suggests that anxious forms of depression are prognostic of poorer antidepressant outcomes, there is no clear definition of anxious depression, and inferences about clinical outcomes are thus limited. Our objective was to compare and evaluate definitions of anxious depression and anxiety-related scales according to clinical and antidepressant outcome criteria.METHOD:: A total of 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic, major depressive disorder were assessed at baseline on clinical features. Participants were then randomised to one of three antidepressants and reassessed at 8weeks regarding remission and response of the 17-item Hamilton Rating Scale Depression (HRSD17) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16). Anxious depression was defined as major depressive disorder with one or more anxiety disorders or major depressive disorder with a HRSD17 anxiety/somatisation factor score ⩾7. Anxiety-related scales included the HRSD17 anxiety/somatisation factor and the 42-item Depression Anxiety Stress Scales (DASS42) anxiety and stress subscales.RESULTS:: Anxious depression definitions showed poor agreement (kappa=0.15) and the HRSD17 anxiety/somatisation factor was weakly correlated with both DASS42 anxiety ( r=0.24) and stress subscales ( r=0.20). Anxious depression definitions were also associated with few impairments on clinical features and did not predict poorer antidepressant treatment outcome. However, higher DASS42 anxiety predicted poorer HRSD17 and QIDS-SR16 remission, and item-level analysis found higher scores on items 9 (situational anxiety) and 23 (somatic anxiety) of the DASS42 predicted poorer treatment outcome, even after adjusting for covariates and multiple comparisons.CONCLUSION:: Common definitions of anxious depression show poor agreement and do not predict poorer treatment outcome. Anxiety symptoms may be better characterised dimensionally using DASS42 when predicting treatment outcome.

    View details for PubMedID 30880405

  • Biomarkers to differentiate bipolar and unipolar depression disorder Chen, W., Breukelaar, I. A., Erlinger, M., Barreiros, A. R., Medway, M., Krishnan, V., Chakouch, C., Antees, C., Foster, S., Gomes, L., Grieve, S., Hazell, P., Boyce, P., Williams, L., Harris, A., Malhi, G. S., Korgaonkar, M. WILEY. 2019: 146–47
  • The Effects of Bullying in Depression on White Matter Integrity. Behavioural brain research Graziano, R. C., Bruce, S. E., Paul, R. H., Korgaonkar, M. S., Williams, L. M. 2019


    Individuals with elevated symptoms of depression exhibit alterations in white matter integrity, including lower fractional anisotropy (FA) evident on diffusion tensor imaging (DTI). Similarly, individuals with a history of early life stress (ELS) exhibit lower FA in the white matter independent of concurrent depression. Prior studies have not determined whether the neuroimaging signature of comorbid ELS and adult depression differs from the pattern of brain white matter changes associated with depression in the absence of self-reported ELS. The current study examined FA in multiple white matter tracts in 186 adults (93 males; 93 females) with a current diagnosis of major depressive disorder, including 88 who reported a history of bullying before the age of 18 (43 males; 45 females). All patients were antidepressant medication free at the time of testing. After adjusting for demographics and other ELS subtypes, participants with a history of bullying exhibited increased FA in the right medial lemniscus (p =.039) and left posterior corona radiata (p =.008) compared to participants with depression but no self-reported history of bullying. Both groups endorsed similar levels of depression. Group differences were most pronounced among individuals who endorsed bullying in late adolescence (14-17 years of age). Results suggest bullying in late adolescence is uniquely related to abnormal brain microstructure among individuals with current diagnoses of depression, possibly due to an overactive fear response. Further work is needed to differentiate why ELS within bullying is associated with higher FA.

    View details for PubMedID 30710613

  • Gender-specific structural abnormalities in major depressive disorder revealed by fixel-based analysis. NeuroImage. Clinical Lyon, M., Welton, T., Varda, A., Maller, J. J., Broadhouse, K., Korgaonkar, M. S., Koslow, S. H., Williams, L. M., Gordon, E., Rush, A. J., Grieve, S. M. 2019; 21: 101668


    BACKGROUND: Major depressive disorder (MDD) is a chronic disease with a large global impact. There are currently no clinically useful predictors of treatment outcome, and the development of biomarkers to inform clinical treatment decisions is highly desirable.METHODS: In this exploratory study we performed fixel-based analysis of diffusion MRI data from the International Study to Predict Optimized Treatment in Depression with the aim of identifying novel biomarkers at baseline that may relate to diagnosis and outcome to treatment with antidepressant medications. Analyses used MR data from individuals with MDD (n = 221) and healthy controls (n = 67).RESULTS: We show focal, gender-specific differences in the anterior limb of the internal capsule (males) and bilaterally in the genu of the corpus callosum (females) associated with diagnosis. Lower fibre cross-section in the tapetum, the conduit between the right and left hippocampi, were also associated with a decreased probability of remission. Analysis of conventional fractional anisotropy showed scattered abnormalities in the corona radiata, cerebral peduncles and mid-brain which were much lower in total volume compared to fixel-based analysis.CONCLUSIONS: Fixel-based analysis appeared to identify different underlying abnormalities than conventional tensor-based metrics, with almost no overlap between significant regions. We show that MDD is associated with gender specific abnormalities in the genu of the corpus callosum (females) and in the anterior limb of the internal capsule (males), as well as gender-independent differences in the tapetum that predict remission. Diffusion MRI may play a key role in future guidance of clinical decision-making for MDD.

    View details for PubMedID 30690418

  • Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent 11C-raclopride positron emission tomography and functional magnetic resonance imaging investigation. Translational psychiatry Hamilton, J. P., Sacchet, M. D., Hjornevik, T., Chin, F. T., Shen, B., Kampe, R., Park, J. H., Knutson, B. D., Williams, L. M., Borg, N., Zaharchuk, G., Camacho, M. C., Mackey, S., Heilig, M., Drevets, W. C., Glover, G. H., Gambhir, S. S., Gotlib, I. H. 2018; 8 (1): 264


    Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.

    View details for PubMedID 30504860

  • A negative association between brainstem pontine grey-matter volume, well-being and resilience in healthy twins Journal of psychiatry & neuroscience : JPN Gatt, J. M., Burton, K. L., Routledge, K. M., Grasby, K. L., Korgaonkar, M. S., Grieve, S. M., Schofield, P. R., Harris, A. W., Clark, C. R., Williams, L. M. 2018; 43 (6): 386–95


    Background: Associations between well-being, resilience to trauma and the volume of grey-matter regions involved in affective processing (e.g., threat/reward circuits) are largely unexplored, as are the roles of shared genetic and environmental factors derived from multivariate twin modelling.Methods: This study presents, to our knowledge, the first exploration of well-being and volumes of grey-matter regions involved in affective processing using a region-of-interest, voxel-based approach in 263 healthy adult twins (60% monozygoticpairs, 61% females, mean age 39.69 yr). To examine patterns for resilience (i.e., positive adaptation following adversity), we evaluated associations between the same brain regions and well-being in a trauma-exposed subgroup.Results: We found a correlated effect between increased well-being and reduced grey-matter volume of the pontine nuclei. This association was strongest for individuals with higher resilience to trauma. Multivariate twin modelling suggested that the common variance between the pons volume and well-being scores was due to environmental factors.Limitations: We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample.Conclusion: Associations with altered grey matter of the pontine nuclei suggest that basic sensory processes, such as arousal, startle, memory consolidation and/or emotional conditioning, may have a role in well-being and resilience.

    View details for PubMedID 30372012

  • Heart rate variability as a biomarker of anxious depression response to antidepressant medication. Depression and anxiety Kircanski, K., Williams, L. M., Gotlib, I. H. 2018


    BACKGROUND: There is a need to identify biomarkers of treatment outcomes for major depressive disorder (MDD) that can be disseminated. We investigated the predictive utility of pretreatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pretreatment anxious depression as a hypothesized moderator of HRV effects.METHODS: A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment in Depression) in patients with current nonpsychotic MDD (N=1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pretreatment, patients were defined as having anxious (N=309) versus nonanxious (N=413) depression and their resting high-frequency HRV (root mean square of successive differences) was assessed. Patients' usual treating clinicians managed medication. At 8weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission.RESULTS: Pretreatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates.CONCLUSIONS: These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach.

    View details for PubMedID 30311742

  • Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans A Randomized Clinical Trial JAMA PSYCHIATRY Yesavage, J. A., Fairchild, J., Mi, Z., Biswas, K., Davis-Karim, A., Phibbs, C. S., Forman, S. D., Thase, M., Williams, L. M., Etkin, A., O'Hara, R., Georgette, G., Beale, T., Huang, G. D., Noda, A., George, M. S., VA Cooperative Studies Program Stu 2018; 75 (9): 884–93


    Treatment-resistant major depression (TRMD) in veterans is a major clinical challenge given the high risk for suicidality in these patients. Repetitive transcranial magnetic stimulation (rTMS) offers the potential for a novel treatment modality for these veterans.To determine the efficacy of rTMS in the treatment of TRMD in veterans.A double-blind, sham-controlled randomized clinical trial was conducted from September 1, 2012, to December 31, 2016, in 9 Veterans Affairs medical centers. A total of 164 veterans with TRD participated.Participants were randomized to either left prefrontal rTMS treatment (10 Hz, 120% motor threshold, 4000 pulses/session) or to sham (control) rTMS treatment for up to 30 treatment sessions.The primary dependent measure of the intention-to-treat analysis was remission rate (Hamilton Rating Scale for Depression score ≤10, indicating that depression is in remission and not a clinically significant burden), and secondary analyses were conducted on other indices of posttraumatic stress disorder, depression, hopelessness, suicidality, and quality of life.The 164 participants had a mean (SD) age of 55.2 (12.4) years, 132 (80.5%) were men, and 126 (76.8%) were of white race. Of these, 81 were randomized to receive active rTMS and 83 to receive sham. For the primary analysis of remission, there was no significant effect of treatment (odds ratio, 1.16; 95% CI, 0.59-2.26; P = .67). At the end of the acute treatment phase, 33 of 81 (40.7%) of those in the active treatment group achieved remission of depressive symptoms compared with 31 of 83 (37.4%) of those in the sham treatment group. Overall, 64 of 164 (39.0%) of the participants achieved remission.A total of 39.0% of the veterans who participated in this trial experienced clinically significant improvement resulting in remission of depressive symptoms; however, there was no evidence of difference in remission rates between the active and sham treatments. These findings may reflect the importance of close clinical surveillance, rigorous monitoring of concomitant medication, and regular interaction with clinic staff in bringing about significant improvement in this treatment-resistant Identifier: NCT01191333.

    View details for PubMedID 29955803

  • Amygdala Activation and Connectivity to Emotional Processing Distinguishes Asymptomatic Patients With Bipolar Disordersand Unipolar Depression. Biological psychiatry. Cognitive neuroscience and neuroimaging Korgaonkar, M. S., Erlinger, M., Breukelaar, I. A., Boyce, P., Hazell, P., Antees, C., Foster, S., Grieve, S. M., Gomes, L., Williams, L. M., Harris, A. W., Malhi, G. S. 2018


    BACKGROUND: Mechanistically based neural markers, such as amygdala reactivity, offer one approach to addressing the challenges of differentiating bipolar and unipolar depressive disorders independently from mood state and acute symptoms. Although emotion-elicited amygdala reactivity has been found to distinguish patients with bipolar depression from patients with unipolar depression, it remains unknown whether this distinction is traitlike and present in the absence of an acutely depressed mood. We addressed this gap by investigating patients with bipolar disorder (BP) and unipolar major depressive disorder (MDD) in remission.METHODS: Supraliminal and subliminal processing of faces exhibiting threat, sad, happy, and neutral emotions during functional magnetic resonance imaging was completed by 73 participants (23 BP patients and 25 MDD patients matched for age and gender, number of depressive episodes and severity; 25 age- and gender-matched healthy control subjects). We compared groups for activation and connectivity for the amygdala.RESULTS: BP patients had lower left amygdala activation than MDD patients during supraliminal and subliminal threat, sad, and neutral emotion processing and for subliminal happy faces. BP patients also exhibited lower amygdala connectivity to the insula and hippocampus for threat and to medial orbitofrontal cortex for happy supraliminal and subliminal processing. BP patients also demonstrated greater amygdala-insula connectivity for sad supraliminal and subliminal face processing. Both patient groups were distinct from control subjects across several measures for activation and connectivity.CONCLUSIONS: Independent of valence or level of emotional awareness, amygdala activation and connectivity during facial emotion processing can distinguish BP patients and MDD patients. These findings provide evidence that this neural substrate could be a potential trait marker to differentiate these two disorders largely independent of illness state.

    View details for PubMedID 30343134

  • Cognitive ability is associated with changes in the functional organization of the cognitive control brain network. Human brain mapping A Breukelaar, I., Williams, L. M., Antees, C., Grieve, S. M., Foster, S. L., Gomes, L., Korgaonkar, M. S. 2018


    Cognitive control is one of the most important skills in day-to-day social and intellectual functioning but we are yet to understand the neural basis of the group of behaviors required to carry this out. Here, we probed changes over time in the brain network associated with cognitive control (the dorsolateral prefrontal cortex, the dorsal posterior parietal cortex, and the dorsal anterior cingulate cortex) using both behavioral assays and functional brain imaging during a selective working memory task in 69 healthy participants within the age range 18-38years (mean: 25, SD: ±6), assessed twice, 2years apart. We aimed to explore the relationship of changing network activation and connectivity with behavioral tasks associated with cognitive control in this otherwise neurodevelopmentally stable group. We found that increased connectivity between frontoparietal cognitive control network regions during the working memory task was associated with improved memory and executive functions over the 2-year period and that this association was not impacted by age, gender, or baseline performance. These results provide evidence that changes in the functional organization of the cognitive control brain network occur despite the absence of neurodevelopment, aging or targeted cognitive training effects, and could modulate cognitive performance in early to mid-adulthood. Understanding how and why this change is occurring could provide insights into the mechanisms through which cognitive control ability is cultivated over time. This could aid in the development of interventions in cases where cognitive control is impaired.

    View details for PubMedID 30136345

  • A negative association between brainstem pontine grey-matter volume, well-being and resilience in healthy twins. Journal of psychiatry & neuroscience : JPN Gatt, J. M., Burton, K. L., Routledge, K. M., Grasby, K. L., Korgaonkar, M. S., Grieve, S. M., Schofield, P. R., Harris, A. W., Clark, C. R., Williams, L. M. 2018; 43 (5): 170125


    BACKGROUND: Associations between well-being, resilience to trauma and the volume of grey-matter regions involved in affective processing (e.g., threat/reward circuits) are largely unexplored, as are the roles of shared genetic and environmental factors derived from multivariate twin modelling.METHODS: This study presents, to our knowledge, the first exploration of well-being and volumes of grey-matter regions involved in affective processing using a region-of-interest, voxel-based approach in 263 healthy adult twins (60% monozygotic pairs, 61% females, mean age 39.69 yr). To examine patterns for resilience (i.e., positive adaptation following adversity), we evaluated associations between the same brain regions and well-being in a trauma-exposed subgroup.RESULTS: We found a correlated effect between increased well-being and reduced grey-matter volume of the pontine nuclei. This association was strongest for individuals with higher resilience to trauma. Multivariate twin modelling suggested that the common variance between the pons volume and well-being scores was due to environmental factors.LIMITATIONS: We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample.CONCLUSION: Associations with altered grey matter of the pontine nuclei suggest that basic sensory processes, such as arousal, startle, memory consolidation and/or emotional conditioning, may have a role in well-being and resilience.

    View details for PubMedID 29924721

  • More Research Needed on the Association Between Genotype and Antidepressant Response: Response to Fabbri et al. The American journal of psychiatry Williams, L. M. 2018; 175 (6): 576–77

    View details for PubMedID 29869545

  • Genetic correlations between wellbeing, depression and anxiety symptoms and behavioral responses to the emotional faces task in healthy twins. Psychiatry research Routledge, K. M., Williams, L. M., Harris, A. W., Schofield, P. R., Clark, C. R., Gatt, J. M. 2018; 264: 385–93


    Currently there is a very limited understanding of how mental wellbeing versus anxiety and depression symptoms are associated with emotion processing behaviour. For the first time, we examined these associations using a behavioural emotion task of positive and negative facial expressions in 1668 healthy adult twins. Linear mixed model results suggested faster reaction times to happy facial expressions was associated with higher wellbeing scores, and slower reaction times with higher depression and anxiety scores. Multivariate twin modelling identified a significant genetic correlation between depression and anxiety symptoms and reaction time to happy facial expressions, in the absence of any significant correlations with wellbeing. We also found a significant negative phenotypic relationship between depression and anxiety symptoms and accuracy for identifying neutral emotions, although the genetic or environment correlations were not significant in the multivariate model. Overall, the phenotypic relationships between speed of identifying happy facial expressions and wellbeing on the one hand, versus depression and anxiety symptoms on the other, were in opposing directions. Twin modelling revealed a small common genetic correlation between response to happy faces and depression and anxiety symptoms alone, suggesting that wellbeing and depression and anxiety symptoms show largely independent relationships with emotion processing at the behavioral level.

    View details for PubMedID 29677622

  • Electrocortical reactivity to negative and positive facial expressions in individuals with a family history of major depression. Biological psychology Watters, A. J., Harris, A. W., Williams, L. M. 2018


    Facial expressions signaling threat and mood-congruent loss have been used to probe abnormal neural reactivity in major depressive disorder (MDD) and may be implicated in genetic vulnerability to MDD. This study investigated electro-cortical reactivity to facial expressions 101 unaffected, adult first degree relatives of probands with MDD and non-relative controls (n = 101). We investigated event-related potentials (ERPs) to five facial expressions of basic emotion: fear, anger, disgust, sadness and happiness under both subliminal (masked) and conscious (unmasked) presentation conditions, and the source localization of group differences. In the conscious condition, controls showed a distinctly positive-going shift in responsive to negative versus happy faces, reflected in a greater positivity for the VPP frontally and the P300 parietally, and less negativity for the N200. By contrast, relatives showed less differentiation of emotions, reflected in less VPP and P300 positivity, particularly for anger and disgust, and which produced an enhanced N200 for sadness. These group differences were consistently source localized to the anterior cingulate cortex. The findings contribute new evidence for neural disruptions underlying the differentiation of salient emotions in familial risk for depression. These disruptions occur in the appraisal (200 ms post-stimulus) through to the context evaluation (300 ms+ post-stimulus) phases of of emotion processing, consistent with theories that risk for depression involves biased or attenuated processing of emotion.

    View details for PubMedID 29792907

  • Feature-Based Selective Attention as a Biomarker of Impaired Cognition in Depression Keller, A., Korgaonkar, M., Williams, L. ELSEVIER SCIENCE INC. 2018: S281–S282
  • Cognitive and Emotional Biomarkers of Anxious Major Depressive Disorder: An iSPOT-D Report Braund, T., Palmer, D., Williams, L. M., Etkin, A., Harris, A. ELSEVIER SCIENCE INC. 2018: S126
  • Does White Matter Microstructural Integrity Differ in the Combined and Inattentive Subtypes of ADHD? A Diffusion Tensor Imaging Study Saad, J., Griffiths, K., Kohn, M., Clarke, S., Williams, L., Korgaonkar, M. S. ELSEVIER SCIENCE INC. 2018: S151
  • Developing a Standardized Taxonomy of Circuit Dysfunction Related to Phenotypes of Mood and Anxiety Disorder Samara, Z., Ball, T., Goldstein-Piekarski, A., Grisanzio, K., Correa, C., Williams, L. M. ELSEVIER SCIENCE INC. 2018: S377
  • Differences in Cognitive Control Brain Activation Between Euthymic Bipolar and Remitted Unipolar Depressed Individuals Breukelaar, I., Erlinger, M., Harris, A., Boyce, P., Malhi, G. S., Hazell, P., Grieve, S., Antes, C., Foster, S., Gomes, L., Williams, L. M., Korgaonkar, M. S. ELSEVIER SCIENCE INC. 2018: S395–S396
  • Neural Differences Between Euthymic Bipolar and Remitted Unipolar Depressed Individuals: An fMRI Study of Emotion Processing Korgaonkar, M., Erlinger, M., Breukelaar, I., Boyce, P., Hazell, P., Antes, C., Foster, S., Grieve, S., Gomes, L., Williams, L., Harris, A., Malhi, G. S. ELSEVIER SCIENCE INC. 2018: S399–S400
  • Integrating Brain-Behavior Data to Identify Clinically Meaningful Biotypes for Depression and Anxiety Williams, L. ELSEVIER SCIENCE INC. 2018: S88–S89
  • What can treatment research offer general practice? LANCET PSYCHIATRY Humphreys, K., Williams, L. M. 2018; 5 (4): 295–97

    View details for PubMedID 29248404

  • Sex, Sleep Deprivation, and the Anxious Brain JOURNAL OF COGNITIVE NEUROSCIENCE Goldstein-Piekarski, A. N., Greer, S. M., Saletin, J. M., Harvey, A. G., Williams, L. M., Walker, M. P. 2018; 30 (4): 565–78


    Insufficient sleep is a known trigger of anxiety. Nevertheless, not everyone experiences these effects to the same extent. One determining factor is sex, wherein women experience a greater anxiogenic impact in response to sleep loss than men. However, the underlying brain mechanism(s) governing this sleep-loss-induced anxiety increase, including the markedly different reaction in women and men, is unclear. Here, we tested the hypothesis that structural brain morphology in a discrete network of emotion-relevant regions represents one such explanatory factor. Healthy participants were assessed across sleep-rested and sleep-deprived conditions, with brain structure quantified using gray matter volume measures. Sleep loss triggered greater levels of anxiety in women compared with men. Reduced gray matter volume in the anterior insula and lateral orbitofrontal cortex predicted the anxiogenic impact of sleep loss in women, yet predicted resilience in men, and did so with high discrimination accuracy. In contrast, gray matter volume in ventromedial prefrontal cortex predicted the anxiogenic impact of sleep loss in both men and women. Structural human brain morphology therefore appears to represent one mechanistic pathway (and possible biomarker) determining anxiety vulnerability to sleep loss-a discovery that may help explain the higher prevalence of sleep disruption and anxiety in women.

    View details for PubMedID 29244642

  • Intrinsic, task-evoked and absolute gamma synchrony during cognitive processing in first onset schizophrenia JOURNAL OF PSYCHIATRIC RESEARCH Brennan, A. M., Williams, L. M., Harris, A. F. 2018; 99: 10–21


    Cognitive deficits present from the first onset of schizophrenia are thought to arise from a core problem in neural synchrony. This is the first study to characterize the profile of gamma (30-100 Hz) synchrony (rather than power) and behavioral performance during higher-order cognitive processing in schizophrenia. Gamma synchrony was acquired from the EEG, and elicited by a Continuous Performance Test (CPT). We quantitated synchrony for regions associated with the fronto-parietal attention and visual networks for 59 young people with First Onset Schizophrenia (FOS) and 59 matched controls, facilitated by the data sharing initiative. We compared groups on gamma synchrony for intrinsic (pre-stimulus), task-evoked change (relative to baseline) and absolute (not relative to baseline) measures. Relationships between synchrony and CPT accuracy, symptoms and functioning were also assessed. FOS showed a reduced ability to modulate task-evoked changes in gamma synchrony, in the context of generally higher intrinsic and absolute synchrony, particularly in frontal regions. These gamma synchrony abnormalities in FOS were associated with performance on the CPT, but not with symptoms or functioning. Task-relevant changes in synchrony may be constrained by an overall excess of intrinsic background synchrony that is unrelated to specific task demands and this relates to cognitive performance. Results are in line with theoretical accounts of gamma synchrony as a core abnormality in schizophrenia, affecting functional connectivity in central executive circuits and causing cognitive symptoms. This study is the first to demonstrate that these gamma synchrony abnormalities are not limited to perceptual or lower-order cognitive processing.

    View details for PubMedID 29407283

  • UNDERSTANDING TREATMENT RESPONSE TO INTEGRATED BEHAVIOR THERAPY FOR COMORBID OBESITY AND DEPRESSION IN PRIMARY CARE Ma, J., Lv, N., Rosas, L., Xiao, L., Lavori, P., Venditti, E., Lewis, M., Snowden, M., Ward, E., Smyth, J., Suppes, T., Goldstein-Piekarski, A., Williams, L. OXFORD UNIV PRESS INC. 2018: S129
  • Response inhibition and emotional cognition improved by atomoxetine in children and adolescents with ADHD: The ACTION randomized controlled trial. Journal of psychiatric research Griffiths, K. R., Leikauf, J. E., Tsang, T. W., Clarke, S., Hermens, D. F., Efron, D., Williams, L. M., Kohn, M. R. 2018; 102: 57–64


    Although the non-stimulant medication atomoxetine is effective for attention-deficit hyperactivity disorder (ADHD) in children and adolescents, there are still significant gaps in our knowledge about whether atomoxetine improves anxiety symptoms or cognition in children. Furthermore, while cognition has been proposed as an intermediate phenotype for ADHD dysfunction, the relationships between clinical and cognitive outcomes are not yet understood. We addressed these knowledge gaps in a controlled trial using objective assessments of both general and emotional cognitive functions implicated in ADHD and in anxiety, which commonly co-occurs with ADHD. A total of 136 children and adolescents with ADHD (ages 6-17years; 80% male; 31.6% with a comorbid anxiety disorder) were enrolled in a randomized double-blind, placebo-controlled, cross-over trial of 6-weeks treatment with atomoxetine. Of these, 109 completed the second cross-over phase. Selected cognitive domains associated with ADHD and anxiety disorders (Sustained attention, response inhibition and fearful face identification) were assessed using a normed, computerized test battery. Symptom outcomes were assessed by parent reports on the ADHD Rating Scale-IV and Conners' Anxious-Shy subscale. For completers, atomoxetine caused a greater improvement in the primary cognitive outcomes of response inhibition and fear identification compared to placebo, but not in sustained attention. Atomoxetine also improved ADHD and anxiety symptoms. Anxiety symptoms improved most for ADHD and anxiety disorder combined, but presence of an anxiety disorder did not moderate any other outcomes. Changes in cognitive and clinical outcomes were not correlated. These findings contribute to the foundations of measurement-based treatment planning and offer targets for probing the mechanisms of atomoxetine action.

    View details for PubMedID 29674270

  • Intrinsic functional connectivity predicts remission on antidepressants: a randomized controlled trial to identify clinically applicable imaging biomarkers TRANSLATIONAL PSYCHIATRY Goldstein-Piekarski, A. N., Staveland, B. R., Ball, T. M., Yesavage, J., Korgaonkar, M. S., Williams, L. M. 2018; 8: 57


    Default mode network (DMN) dysfunction (particularly within the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC)) has been implicated in major depressive disorder (MDD); however, its contribution to treatment outcome has not been clearly established. Here we tested the role of DMN functional connectivity as a general and differential biomarker for predicting treatment outcomes in a large, unmedicated adult sample with MDD. Seventy-five MDD outpatients completed fMRI scans before and 8 weeks after randomization to escitalopram, sertraline, or venlafaxine-XR. A whole-brain voxel-wise t-test identified profiles of pretreatment intrinsic functional connectivity that distinguished patients who were subsequently classified as remitters or non-remitters at follow-up. Connectivity was seeded in the PCC, an important node of the DMN. We further characterized differences between remitters, non-remitters, and 31 healthy controls and characterized changes pretreatment to posttreatment. Remitters were distinguished from non-remitters by relatively intact connectivity between the PCC and ACC/mPFC, not distinguishable from healthy controls, while non-remitters showed relative hypo-connectivity. In validation analyses, we demonstrate that PCC-ACC/mPFC connectivity predicts remission status with >80% cross-validated accuracy. In analyses testing whether intrinsic connectivity differentially relates to outcomes for a specific type of antidepressant, interaction models did not survive the corrected threshold. Our findings demonstrate that the overall capacity to remit on commonly used antidepressants may depend on intact organization of intrinsic functional connectivity between PCC and ACC/mPFC prior to treatment. The findings highlight the potential utility of functional scans for advancing a more precise approach to tailoring antidepressant treatment choices.

    View details for PubMedID 29507282

  • Profiling risk for depressive disorder by circuit, behavior and self-report measures of emotion function JOURNAL OF AFFECTIVE DISORDERS Watters, A. J., Korgaonkar, M. S., Carpenter, J. S., Harris, A. F., Gross, J. J., Williams, L. M. 2018; 227: 595–602


    Major depressive disorder (MDD) is characterized by maladaptions in affective brain circuitry and in emotion regulation. It remains unknown whether these maladaptions characterize first-degree relatives of probands who are unaffected yet have a higher risk of developing MDD.Participants were 72 unaffected first-degree relatives of probands with MDD and 66 matched non-relative controls. We investigated brain circuit function and self-reported emotion regulation strategies for reappraisal and suppression. During functional magnetic resonance imaging, we probed circuitry relevant to both negative and positive valence systems using facial expressions signaling potential threat, sadness and happiness, presented under both conscious and subliminal viewing conditions. We compared groups using a statistically controlled region of interest (ROI) approach including the amygdala, insula, anterior cingulate cortex (ACC), ventromedial prefrontal cortex and dorsolateral prefrontal cortex. We also used a data-driven cluster analytic approach for characterizing the relatives by their brain function profiles.As a group, relatives were distinguished by hyper-reactivity of the pregenual ACC during subliminal viewing of threat-related expressions but hypo-activation of the amygdala, insula and dorsal ACC during explicit viewing of the same threat-related expressions and sadness. When considered individually, this brain function profile characterized two-thirds of relatives, and these relatives were also less likely to use reappraisal to regulate negative emotion.The design was cross-sectional and therefore does not provide direct evidence as to the trait- (versus state-) like profile observed in relatives.Familial risk for MDD may involve a disruption to the normal recruitment of neural circuits for appraising salient emotions, both implicit and explicit. Interventions targeting reappraisal strategies for regulating negative emotion may serve to buffer this risk.

    View details for PubMedID 29172052

  • Transdiagnostic Symptom Clusters and Associations With Brain, Behavior, and Daily Function in Mood, Anxiety, and Trauma Disorders Grisanzio, K. A., Goldstein-Piekarski, A. N., Wang, M., Ahmed, A., Samara, Z., Williams, L. M. AMER MEDICAL ASSOC. 2018: 201–9


    The symptoms that define mood, anxiety, and trauma disorders are highly overlapping across disorders and heterogeneous within disorders. It is unknown whether coherent subtypes exist that span multiple diagnoses and are expressed functionally (in underlying cognition and brain function) and clinically (in daily function). The identification of cohesive subtypes would help disentangle the symptom overlap in our current diagnoses and serve as a tool for tailoring treatment choices.To propose and demonstrate 1 approach for identifying subtypes within a transdiagnostic sample.This cross-sectional study analyzed data from the Brain Research and Integrative Neuroscience Network Foundation Database that had been collected at the University of Sydney and University of Adelaide between 2006 and 2010 and replicated at Stanford University between 2013 and 2017. The study included 420 individuals with a primary diagnosis of major depressive disorder (n = 100), panic disorder (n = 53), posttraumatic stress disorder (n = 47), or no disorder (healthy control participants) (n = 220). Data were analyzed between October 2016 and October 2017.We followed a data-driven approach to achieve the primary study outcome of identifying transdiagnostic subtypes. First, machine learning with a hierarchical clustering algorithm was implemented to classify participants based on self-reported negative mood, anxiety, and stress symptoms. Second, the robustness and generalizability of the subtypes were tested in an independent sample. Third, we assessed whether symptom subtypes were expressed at behavioral and physiological levels of functioning. Fourth, we evaluated the clinically meaningful differences in functional capacity of the subtypes. Findings were interpreted relative to a complementary diagnostic frame of reference.Four hundred twenty participants with a mean (SD) age of 39.8 (14.1) years were included in the final analysis; 256 (61.0%) were female. We identified 6 distinct subtypes characterized by tension (n=81; 19%), anxious arousal (n=55; 13%), general anxiety (n=38; 9%), anhedonia (n=29; 7%), melancholia (n=37; 9%), and normative mood (n=180; 43%), and these subtypes were replicated in an independent sample. Subtypes were expressed through differences in cognitive control (F5,383 = 5.13, P < .001, ηp2 = 0.063), working memory (F5,401 = 3.29, P = .006, ηp2 = 0.039), electroencephalography-recorded β power in a resting paradigm (F5,357 = 3.84, P = .002, ηp2 = 0.051), electroencephalography-recorded β power in an emotional paradigm (F5,365 = 3.56, P = .004, ηp2 = 0.047), social functional capacity (F5,414 = 21.33, P < .001, ηp2 = 0.205), and emotional resilience (F5,376 = 15.10, P < .001, ηp2 = 0.171).These findings offer a data-driven framework for identifying robust subtypes that signify specific, coherent, meaningful associations between symptoms, behavior, brain function, and observable real-world function, and that cut across DSM-IV-defined diagnoses of major depressive disorder, panic disorder, and posttraumatic stress disorder.

    View details for PubMedID 29197929

    View details for PubMedCentralID PMC5838569

  • "Motoring in idle": The default mode and somatomotor networks are overactive in children and adolescents with functional neurological symptoms NEUROIMAGE-CLINICAL Kozlowska, K., Spooner, C. J., Palmer, D. M., Harris, A., Korgaonkar, M. S., Scher, S., Williams, L. M. 2018; 18: 730–43


    Children and adolescents with functional neurological symptom disorder (FND) present with diverse neurological symptoms not explained by a disease process. Functional neurological symptoms have been conceptualized as somatoform dissociation, a disruption of the brain's intrinsic organization and reversion to a more primitive level of function. We used EEG to investigate neural function and functional brain organization in children/adolescents with FND.EEG was recorded in the resting eyes-open condition in 57 patients (aged 8.5-18 years) and 57 age- and sex-matched healthy controls. Using a topographical map, EEG power data were quantified for regions of interest that define the default mode network (DMN), salience network, and somatomotor network. Source localization was examined using low-resolution brain electromagnetic tomography (LORETA). The contributions of chronic pain and arousal as moderators of differences in EEG power were also examined.Children/adolescents with FND had excessive theta and delta power in electrode clusters corresponding to the DMN-both anteriorly (dorsomedial prefrontal cortex [dmFPC]) and posteriorly (posterior cingulate cortex [PCC], precuneus, and lateral parietal cortex)-and in the premotor/supplementary motor area (SMA) region. There was a trend toward increased theta and delta power in the salience network. LORETA showed activation across all three networks in all power bands and localized neural sources to the dorsal anterior cingulate cortex/dmPFC, mid cingulate cortex, PCC/precuneus, and SMA. Pain and arousal contributed to slow wave power increases in all three networks.These findings suggest that children and adolescents with FND are characterized by overactivation of intrinsic resting brain networks involved in threat detection, energy regulation, and preparation for action.

    View details for PubMedID 29876262

  • An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Gignoux, C. R., Torgerson, D. G., Pino-Yanes, M., Uricchio, L. H., Galanter, J., et al 2018; in press
  • The ENGAGE study: Integrating neuroimaging, virtual reality and smartphone sensing to understand self-regulation for managing depression and obesity in a precision medicine model. Behaviour research and therapy Williams, L. M., Pines, A., Goldstein-Piekarski, A. N., Rosas, L. G., Kullar, M., Sacchet, M. D., Gevaert, O., Bailenson, J., Lavori, P. W., Dagum, P., Wandell, B., Correa, C., Greenleaf, W., Suppes, T., Perry, L. M., Smyth, J. M., Lewis, M. A., Venditti, E. M., Snowden, M., Simmons, J. M., Ma, J. 2018; 101: 58–70


    Precision medicine models for personalizing achieving sustained behavior change are largely outside of current clinical practice. Yet, changing self-regulatory behaviors is fundamental to the self-management of complex lifestyle-related chronic conditions such as depression and obesity - two top contributors to the global burden of disease and disability. To optimize treatments and address these burdens, behavior change and self-regulation must be better understood in relation to their neurobiological underpinnings. Here, we present the conceptual framework and protocol for a novel study, "Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes (ENGAGE)". The ENGAGE study integrates neuroscience with behavioral science to better understand the self-regulation related mechanisms of behavior change for improving mood and weight outcomes among adults with comorbid depression and obesity. We collect assays of three self-regulation targets (emotion, cognition, and self-reflection) in multiple settings: neuroimaging and behavioral lab-based measures, virtual reality, and passive smartphone sampling. By connecting human neuroscience and behavioral science in this manner within the ENGAGE study, we develop a prototype for elucidating the underlying self-regulation mechanisms of behavior change outcomes and their application in optimizing intervention strategies for multiple chronic diseases.

    View details for PubMedID 29074231

  • Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein. The American journal of psychiatry O'Connell, C. P., Goldstein-Piekarski, A. N., Nemeroff, C. B., Schatzberg, A. F., Debattista, C., Carrillo-Roa, T., Binder, E. B., Dunlop, B. W., Craighead, W. E., Mayberg, H. S., Williams, L. M. 2018; 175 (3): 251–61


    Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials.The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression.The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

    View details for PubMedID 29241359

    View details for PubMedCentralID PMC5832545

  • A Public Database of Immersive VR Videos with Corresponding Ratings of Arousal, Valence, and Correlations between Head Movements and Self Report Measures FRONTIERS IN PSYCHOLOGY Li, B. J., Bailenson, J. N., Pines, A., Greenleaf, W. J., Williams, L. M. 2017; 8: 2116


    Virtual reality (VR) has been proposed as a methodological tool to study the basic science of psychology and other fields. One key advantage of VR is that sharing of virtual content can lead to more robust replication and representative sampling. A database of standardized content will help fulfill this vision. There are two objectives to this study. First, we seek to establish and allow public access to a database of immersive VR video clips that can act as a potential resource for studies on emotion induction using virtual reality. Second, given the large sample size of participants needed to get reliable valence and arousal ratings for our video, we were able to explore the possible links between the head movements of the observer and the emotions he or she feels while viewing immersive VR. To accomplish our goals, we sourced for and tested 73 immersive VR clips which participants rated on valence and arousal dimensions using self-assessment manikins. We also tracked participants' rotational head movements as they watched the clips, allowing us to correlate head movements and affect. Based on past research, we predicted relationships between the standard deviation of head yaw and valence and arousal ratings. Results showed that the stimuli varied reasonably well along the dimensions of valence and arousal, with a slight underrepresentation of clips that are of negative valence and highly arousing. The standard deviation of yaw positively correlated with valence, while a significant positive relationship was found between head pitch and arousal. The immersive VR clips tested are available online as supplemental material.

    View details for PubMedID 29259571

  • Emotion Regulation, Brain Structural Connectivity, and Affective Behavior in Comorbid Major Depressive Disorder and Obesity Sacchet, M., Pines, A., Kullar, M., Ma, J., Williams, L. M. NATURE PUBLISHING GROUP. 2017: S312–S313
  • Clustering Identifies Symptom-Brain-Behavior Subtypes That cut Across Mood, Anxiety, and Trauma Disorders Grisanzio, K. A., Goldstein-Piekarski, A. N., Wang, M., Ahmed, A., Samara, Z., Williams, L. NATURE PUBLISHING GROUP. 2017: S371–S372
  • An Approach to Profiling Mood and Anxiety Disorders Based on Functional Brain Circuits, Behavior and Symptoms Samara, Z., Ball, T., Goldstein-Piekarshi, A. N., Grizansio, K. A., Correa, C., Williams, L. M. NATURE PUBLISHING GROUP. 2017: S368
  • Modulation of the Neural Circuitry Underlying Trait Hypnotizability With Spaced Continuous Theta-Burst Stimulation Williams, N., Sudheimer, K., Stimpson, K., Duvio, D., Chung, C., DeSouza, D., Jo, B., Williams, L., Yeomans, D., Spiegel, D. NATURE PUBLISHING GROUP. 2017: S508–S509
  • Quantifying person-level brain network functioning to facilitate clinical translation TRANSLATIONAL PSYCHIATRY Ball, T. M., Goldstein-Piekarski, A. N., Gatt, J. M., Williams, L. M. 2017; 7: e1248


    Although advances in neuroimaging have yielded insights into the intrinsic organization of human brain networks and their relevance to psychiatric and neurological disorders, there has been no translation of these insights into clinical practice. One necessary step toward clinical translation is identifying a summary metric of network function that is reproducible, reliable, and has known normative data, analogous to normed neuropsychological tests. Our aim was therefore to establish the proof of principle for such a metric, focusing on the default mode network (DMN). We compared three candidate summary metrics: global clustering coefficient, characteristic path length, and average connectivity. Across three samples totaling 322 healthy, mostly Caucasian adults, average connectivity performed best, with good internal consistency (Cronbach's α=0.69-0.70) and adequate eight-week test-retest reliability (intra-class coefficient=0.62 in a subsample N=65). We therefore present normative data for average connectivity of the DMN and its sub-networks. These proof of principle results are an important first step for the translation of neuroimaging to clinical practice. Ultimately, a normed summary metric will allow a single patient's DMN function to be quantified and interpreted relative to normative peers.

    View details for PubMedID 29039851

  • Genetic and Environmental Influences on Emotion Regulation: A Twin Study of Cognitive Reappraisal and Expressive Suppression EMOTION McRae, K., Rhee, S., Gatt, J. M., Godinez, D., Williams, L. M., Gross, J. J. 2017; 17 (5): 772–77


    Previous studies have established that personality traits related to emotionality are moderately heritable. However, the relative heritability of the strategies people use to regulate emotions is unknown. The present study compared the magnitude of additive genetic, shared environmental, and nonshared environmental influences on 2 commonly used emotion regulation strategies: cognitive reappraisal and expressive suppression. In 743 twin pairs (1,486 twins), we replicated previous estimates of heritability of neuroticism (a2 = .41). Furthermore, cognitive reappraisal was significantly less heritable and more influenced by nonshared environment (a2 = .20; e2 = .80) than either neuroticism or suppression (a2 = .35; e2 = .65), another emotion regulation strategy. Finally, Cholesky decomposition modeling suggested that while there were common genetic and environmental influences on neuroticism, reappraisal and suppression, there were also significant nonshared environmental influences common between reappraisal and adaptive emotional functioning after controlling for neuroticism and suppression. These findings highlight that different aspects of emotional processing, even the use of different emotion regulation strategies, are differentially heritable. The importance of the nonshared environmental influences specific to reappraisal and adaptive emotional functioning speaks to the potential impact of social context, social partners, and psychosocial interventions on reappraisal habits. (PsycINFO Database Record

    View details for PubMedID 28406678

  • Cognitive control network anatomy correlates with neurocognitive behavior: A longitudinal study HUMAN BRAIN MAPPING Breukelaar, I. A., Antees, C., Grieve, S. M., Foster, S. L., Gomes, L., Williams, L. M., Korgaonkar, M. S. 2017; 38 (2): 631-643


    Cognitive control is the process of employing executive functions, such as attention, planning or working memory, to guide appropriate behaviors in order to achieve a specific goal. Functional magnetic resonance imaging studies suggest a superordinate cognitive control network, comprising the dorsal regions of the lateral prefrontal cortex (DLPFC), anterior cingulate cortex (dACC) and parietal cortex (DPC). How gray matter structure changes across this network throughout neurodevelopment and how these changes impact cognitive control are not yet fully understood. Here we investigate changes in gray matter volume of the key nodes of the cognitive control network using structural MRI scans from 176 participants aged 8-38 years. One hundred and eleven of these also completed a longitudinal follow-up at two years. We compare these with performance on a cognitive battery also measured at these two time points. We found that volume decreases in the cognitive control network were associated with improved performance in executive function (in left DLPFC and bilateral DPC), information processing (in bilateral dACC and right DPC) and emotion identification tasks (left DLPFC). These results were significant after controlling for age. Furthermore, gray matter changes were coordinated across the network. These findings imply age-independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains. This study provides insight into the direct impact of structural changes on behavior within this network during neurodevelopment and provides a normative evidence base to better understand development of cognitive dysfunction in brain disorders. Hum Brain Mapp 38:631-643, 2017. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.23401

    View details for Web of Science ID 000393786500003

    View details for PubMedID 27623046

  • Altered Microstructural Caudate Integrity in Posttraumatic Stress Disorder but Not Traumatic Brain Injury. PloS one Waltzman, D., Soman, S., Hantke, N. C., Fairchild, J. K., Kinoshita, L. M., Wintermark, M., Ashford, J. W., Yesavage, J., Williams, L., Adamson, M. M., Furst, A. J. 2017; 12 (1)


    Given the high prevalence and comorbidity of combat-related PTSD and TBI in Veterans, it is often difficult to disentangle the contributions of each disorder. Examining these pathologies separately may help to understand the neurobiological basis of memory impairment in PTSD and TBI independently of each other. Thus, we investigated whether a) PTSD and TBI are characterized by subcortical structural abnormalities by examining diffusion tensor imaging (DTI) metrics and volume and b) if these abnormalities were specific to PTSD versus TBI.We investigated whether individuals with PTSD or TBI display subcortical structural abnormalities in memory regions by examining DTI metrics and volume of the hippocampus and caudate in three groups of Veterans: Veterans with PTSD, Veterans with TBI, and Veterans with neither PTSD nor TBI (Veteran controls).While our results demonstrated no macrostructural differences among the groups in these regions, there were significant alterations in microstructural DTI indices in the caudate for the PTSD group but not the TBI group compared to Veteran controls.The result of increased mean, radial, and axial diffusivity, and decreased fractional anisotropy in the caudate in absence of significant volume atrophy in the PTSD group suggests the presence of subtle abnormalities evident only at a microstructural level. The caudate is thought to play a role in the physiopathology of PTSD, and the habit-like behavioral features of the disorder could be due to striatal-dependent habit learning mechanisms. Thus, DTI appears to be a vital tool to investigate subcortical pathology, greatly enhancing the ability to detect subtle brain changes in complex disorders.

    View details for DOI 10.1371/journal.pone.0170564

    View details for PubMedID 28114393

    View details for PubMedCentralID PMC5256941

  • Defining biotypes for depression and anxiety based on large-scale circuit dysfunction: a theoretical review of the evidence and future directions for clinical translation DEPRESSION AND ANXIETY Williams, L. M. 2017; 34 (1): 9-24


    Complex emotional, cognitive and self-reflective functions rely on the activation and connectivity of large-scale neural circuits. These circuits offer a relevant scale of focus for conceptualizing a taxonomy for depression and anxiety based on specific profiles (or biotypes) of neural circuit dysfunction. Here, the theoretical review first outlines the current consensus as to what constitutes the organization of large-scale circuits in the human brain identified using parcellation and meta-analysis. The focus is on neural circuits implicated in resting reflection (default mode), detection of "salience," affective processing ("threat" and "reward"), "attention," and "cognitive control." Next, the current evidence regarding which type of dysfunctions in these circuits characterize depression and anxiety disorders is reviewed, with an emphasis on published meta-analyses and reviews of circuit dysfunctions that have been identified in at least two well-powered case:control studies. Grounded in the review of these topics, a conceptual framework is proposed for considering neural circuit-defined "biotypes." In this framework, biotypes are defined by profiles of extent of dysfunction on each large-scale circuit. The clinical implications of a biotype approach for guiding classification and treatment of depression and anxiety is considered. Future research directions will develop the validity and clinical utility of a neural circuit biotype model that spans diagnostic categories and helps to translate neuroscience into clinical practice in the real world.

    View details for DOI 10.1002/da.22556

    View details for Web of Science ID 000393774000002

    View details for PubMedCentralID PMC5702265

  • Sex Differences Modulating Serotonergic Polymorphisms Implicated in the Mechanistic Pathways of Risk for Depression and Related Disorders JOURNAL OF NEUROSCIENCE RESEARCH Perry, L. M., Goldstein-Piekarski, A. N., Williams, L. M. 2017; 95 (1-2): 737-762


    Despite consistent observations of sex differences in depression and related emotional disorders, we do not yet know how these sex differences modulate the effects of genetic polymorphisms implicated in risk for these disorders. This Mini-Review focuses on genetic polymorphisms of the serotonergic system to illustrate how sex differences might modulate the neurobiological pathways involved in the development of depression. We consider the interacting role of environmental factors such as early-life stress. Given limited current knowledge about this topic, we highlight methodological considerations, challenges, and guidelines for future research. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/jnr.23877

    View details for Web of Science ID 000388443900071

    View details for PubMedID 27870440

    View details for PubMedCentralID PMC5119468

  • The Utility (or Not) of Self-Report Instruments in Family Assessment for Child and Adolescent Conversion Disorders? AUSTRALIAN AND NEW ZEALAND JOURNAL OF FAMILY THERAPY Kozlowska, K., Cruz, C., Davies, F., Brown, K. J., Palmer, D. M., Mclean, L., Scher, S., Williams, L. M. 2016; 37 (4): 480-499

    View details for DOI 10.1002/anzf.1187

    View details for Web of Science ID 000392652000006

  • Altered gray matter organization in children and adolescents with ADHD: a structural covariance connectome study. Translational psychiatry Griffiths, K. R., Grieve, S. M., Kohn, M. R., Clarke, S., Williams, L. M., Korgaonkar, M. S. 2016; 6 (11)


    Although multiple studies have reported structural deficits in multiple brain regions in attention-deficit hyperactivity disorder (ADHD), we do not yet know if these deficits reflect a more systematic disruption to the anatomical organization of large-scale brain networks. Here we used a graph theoretical approach to quantify anatomical organization in children and adolescents with ADHD. We generated anatomical networks based on covariance of gray matter volumes from 92 regions across the brain in children and adolescents with ADHD (n=34) and age- and sex-matched healthy controls (n=28). Using graph theory, we computed metrics that characterize both the global organization of anatomical networks (interconnectivity (clustering), integration (path length) and balance of global integration and localized segregation (small-worldness)) and their local nodal measures (participation (degree) and interaction (betweenness) within a network). Relative to Controls, ADHD participants exhibited altered global organization reflected in more clustering or network segregation. Locally, nodal degree and betweenness were increased in the subcortical amygdalae in ADHD, but reduced in cortical nodes in the anterior cingulate, posterior cingulate, mid temporal pole and rolandic operculum. In ADHD, anatomical networks were disrupted and reflected an emphasis on subcortical local connections centered around the amygdala, at the expense of cortical organization. Brains of children and adolescents with ADHD may be anatomically configured to respond impulsively to the automatic significance of stimulus input without having the neural organization to regulate and inhibit these responses. These findings provide a novel addition to our current understanding of the ADHD connectome.

    View details for DOI 10.1038/tp.2016.219

    View details for PubMedID 27824356

  • Shared versus distinct genetic contributions of mental wellbeing with depression and anxiety symptoms in healthy twins PSYCHIATRY RESEARCH Routledge, K. M., Burton, K. L., Williams, L. M., Harris, A., Schofield, P. R., Clark, C. R., Gatt, J. M. 2016; 244: 65-70


    Mental wellbeing and mental illness symptoms are typically conceptualized as opposite ends of a continuum, despite only sharing about a quarter in common variance. We investigated the normative variation in measures of wellbeing and of depression and anxiety in 1486 twins who did not meet clinical criteria for an overt diagnosis. We quantified the shared versus distinct genetic and environmental variance between wellbeing and depression and anxiety symptoms. The majority of participants (93%) reported levels of depression and anxiety symptoms within the healthy range, yet only 23% reported a wellbeing score within the "flourishing" range: the remainder were within the ranges of "moderate" (67%) or "languishing" (10%). In twin models, measures of wellbeing and of depression and anxiety shared 50.09% of variance due to genetic factors and 18.27% due to environmental factors; the rest of the variance was due to unique variation impacting wellbeing or depression and anxiety symptoms. These findings suggest that an absence of clinically-significant symptoms of depression and anxiety does not necessarily indicate that an individual is flourishing. Both unique and shared genetic and environmental factors may determine why some individuals flourish in the absence of symptoms while others do not.

    View details for DOI 10.1016/j.psychres.2016.07.016

    View details for Web of Science ID 000384776700011

    View details for PubMedID 27472172

  • Is the Alzheimer's disease cortical thickness signature a biological marker for memory? BRAIN IMAGING AND BEHAVIOR Busovaca, E., Zimmerman, M. E., Meier, I. B., Griffith, E. Y., Grieve, S. M., Korgaonkar, M. S., Williams, L. M., Brickman, A. M. 2016; 10 (2): 517-523


    Recent work suggests that analysis of the cortical thickness in key brain regions can be used to identify individuals at greatest risk for development of Alzheimer's disease (AD). It is unclear to what extent this "signature" is a biological marker of normal memory function - the primary cognitive domain affected by AD. We examined the relationship between the AD signature biomarker and memory functioning in a group of neurologically healthy young and older adults. Cortical thickness measurements and neuropsychological evaluations were obtained in 110 adults (age range 21-78, mean = 46) drawn from the Brain Resource International Database. The cohort was divided into young adult (n = 64, age 21-50) and older adult (n = 46, age 51-78) groups. Cortical thickness analysis was performed with FreeSurfer, and the average cortical thickness extracted from the eight regions that comprise the AD signature. Mean AD-signature cortical thickness was positively associated with performance on the delayed free recall trial of a list learning task and this relationship did not differ between younger and older adults. Mean AD-signature cortical thickness was not associated with performance on a test of psychomotor speed, as a control task, in either group. The results suggest that the AD signature cortical thickness is a marker for memory functioning across the adult lifespan.

    View details for DOI 10.1007/s11682-015-9413-5

    View details for Web of Science ID 000382390000018

    View details for PubMedID 26040979

    View details for PubMedCentralID PMC4670278

  • Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression TRANSLATIONAL PSYCHIATRY Williams, L. M., Debattista, C., Duchemin, A., Schatzberg, A. F., Nemeroff, C. B. 2016; 6


    Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.

    View details for DOI 10.1038/tp.2016.61

    View details for Web of Science ID 000377305600005

    View details for PubMedID 27138798

  • Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study LANCET PSYCHIATRY Shilyansky, C., Williams, L. M., Gyurak, A., Harris, A., Usherwood, T., Etkin, A. 2016; 3 (5): 425-435


    Antidepressant treatment failure is a common problem worldwide. In this study, we assess whether or not an important aspect of depression, cognitive impairment, is untreated by antidepressants by studying the effect of acute antidepressant treatment on a range of cognitive domains.In this randomised longitudinal study, which is part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D) trial, we assessed the effects of acute antidepressant treatment in a large patient population, across clinical remission outcomes, on a range of cognitive domains: attention, response inhibition, executive function during visuospatial navigation, cognitive flexibility, verbal memory, working memory, decision speed, information processing speed, and psychomotor response speed. We enrolled patients from primary or specialty care clinics in a multicentre, international, open-label, randomised, prospective trial. Eligible patients (aged 18-65 years) were previously untreated or were willing to undergo a 1-week medication washout before the study start, and could not have had inadequate response to study medications in the past. We enrolled a large population of medication-free (ie, untreated) outpatients in a depressive episode and assessed them for cognitive function at enrolment (pre-treatment), and again after 8 weeks of treatment with one of three antidepressant drugs (escitalopram, sertraline, or venlafaxine extended-release). Patients were randomly assigned (1:1:1) to one of the three antidepressants using a blocked randomisation procedure (block size of 12). As a comparison group, we also simultaneously enrolled matched healthy participants. Healthy participants received no medication or intervention, but were assessed for change in cognitive and clinical measures during the same interval and testing protocol. Therefore, this group acts as a test-retest control for the primary outcome measure examined in this study, change in cognitive measures over 8 weeks of treatment in depressed patients. This study is registered with, number NCT00693849.Between Dec 8, 2008, and Sept 30, 2011, we enrolled 1008 eligible people into the study. Impairment in five domains-attention, response inhibition, verbal memory, decision speed, and information processing-showed no relative improvement with acute treatment (controlling for time or repeated testing), irrespective of antidepressant treatment group, even in patients whose depression remitted acutely according to clinical measures. Broader cognitive impairment was associated with greater illness chronicity (earlier illness onset) but not with symptom severity or previous antidepressant failures.Depression is associated with impairments in higher-order cognitive functions and information processing, which persist independently of clinical symptom change with treatment. We recorded no difference between the three antidepressants tested, with none showing efficacy for these impairments. Although the 8-week treatment period limits interpretation to acute treatment effects, it does highlight cognitive impairment as an untargeted contributor to incomplete treatment success.Brain Resource Company Operations Pty Ltd and NIH.

    View details for DOI 10.1016/S2215-0366(16)00012-2

    View details for Web of Science ID 000376262300024

    View details for PubMedID 26995298

    View details for PubMedCentralID PMC4860142

  • Prediction of Nonremission to Antidepressant Therapy Using Diffusion Tensor Imaging JOURNAL OF CLINICAL PSYCHIATRY Grieve, S. M., Korgaonkar, M. S., Gordon, E., Williams, L. M., Rush, A. J. 2016; 77 (4): E436-U44


    Over 50% of outpatients with nonpsychotic major depressive disorder (MDD) do not achieve remission with any single antidepressant medication (ADM). There are currently no clinically useful pretreatment measures that inform the decision to prescribe or select ADMs. This report examines whether a biomarker based on diffusion tensor imaging (DTI) measures of brain connectivity can identify a subset of nonremitting patients with a sufficiently high degree of specificity that use of a medication that is likely to fail could be avoided.MDD outpatients recruited from community and primary-care settings underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment in Depression (conducted December 2008-June 2014). DSM-IV criteria and a 17-item Hamilton Depression Rating Scale (HDRS17) score ≥ 16 confirmed the primary diagnosis of nonpsychotic MDD. Data from the first cohort of MDD patients (n = 74) were used to calculate fractional anisotropy measures of the stria terminalis and cingulate portion of the cingulate bundle (CgC). On the basis of our previous data, we hypothesized that nonremission might be predicted using a ratio of these 2 values. Remission was defined as an HDRS17 score of ≤ 7 following 8 weeks of open-label treatment with escitalopram, sertraline, or venlafaxine extended-release, randomized across participants. The second study cohort (n = 83) was used for replication.Thirty-four percent of all participants achieved remission. A value > 1.0 for the ratio of the fractional anisotropy of the stria terminalis over the CgC identified 38% of the nonremitting participants with an accuracy of 88% (test cohort; odds ratio [OR] = 9.6; 95% CI, 2.0-45.9); 24% with an accuracy of 83% (replication cohort; OR = 1.8; 95% CI, 0.5-6.9) and 29% with an accuracy of 86% (pooled data; OR = 4.0; 95% CI, 1.5-11.1). Treatment moderation analysis showed greater specificity for escitalopram and sertraline (χ(2) = 8.07; P = .003).To our knowledge, this simple DTI-derived metric represents the first brain biomarker to reliably identify nonremitting patients in MDD. The test identifies a meaningful proportion of nonremitters, has high specificity, and may assist in managing the antidepressant treatment of identifier: NCT00693849.

    View details for DOI 10.4088/JCP.14m09577

    View details for Web of Science ID 000379247700005

    View details for PubMedID 27137427

  • Frontoparietal Activation During Response Inhibition Predicts Remission to Antidepressants in Patients With Major Depression BIOLOGICAL PSYCHIATRY Gyurak, A., Patenaude, B., Korgaonkar, M. S., Grieve, S. M., Williams, L. M., Etkin, A. 2016; 79 (4): 274-281
  • Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project. BMC psychiatry Williams, L. M., Goldstein-Piekarski, A. N., Chowdhry, N., Grisanzio, K. A., Haug, N. A., Samara, Z., Etkin, A., O'Hara, R., Schatzberg, A. F., Suppes, T., Yesavage, J. 2016; 16 (1): 68-?


    Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time.Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing.This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 Identifier: NCT02220309 . Registered: August 13, 2014.

    View details for DOI 10.1186/s12888-016-0771-3

    View details for PubMedID 26980207

  • A trans-diagnostic review of anxiety disorder comorbidity and the impact of multiple exclusion criteria on studying clinical outcomes in anxiety disorders. Translational psychiatry Goldstein-Piekarski, A. N., Williams, L. M., Humphreys, K. 2016; 6 (6)


    Anxiety disorders are highly comorbid with each other and with other serious mental disorders. As our field progresses, we have the opportunity to pursue treatment study designs that consider these comorbidities. In this perspective review, we first characterized the prevalence of multiple anxiety disorder comorbidity by reanalyzing national survey data, then conducted an English-language PubMed search of studies analyzing the impact of exclusion criteria on treatment outcome data. In the prevalence data, 60% of people with an anxiety disorder had one or more additional anxiety or depression diagnosis. Because our commonly applied exclusion criteria focus on a single diagnosis and do not consider a multiple comorbidity profile, the impact of the criteria may be to exclude up to 92% of anxiety disorder treatment seekers. Moreover, the findings do not suggest a consistent relationship between the number of exclusion criteria and the effect size of treatment outcomes. Thus, future studies might consider a more trans-diagnostic rationale for determining exclusion criteria, one that is generalizable to real-world settings in which multiple diagnoses commonly co-occur. The findings also encourage a more systematic reporting of rationales for the choice of-and the implications of-each exclusion criterion.

    View details for DOI 10.1038/tp.2016.108

    View details for PubMedID 27351601

    View details for PubMedCentralID PMC4931606

  • Sex differences in the shared genetics of dimensions of self-reported depression and anxiety JOURNAL OF AFFECTIVE DISORDERS Burton, K. L., Williams, L. M., Clark, C. R., Harris, A., Schofield, P. R., Gatt, J. M. 2015; 188: 35-42

    View details for DOI 10.1016/j.jad.2015.08.053

    View details for PubMedID 26342886

  • Utility of event-related potentials in predicting antidepressant treatment response: An iSPOT-D report EUROPEAN NEUROPSYCHOPHARMACOLOGY van Dinteren, R., Arns, M., Kenemans, L., Jongsma, M. L., Kessels, R. P., Fitzgerald, P., Fallahpour, K., DeBattista, C., Gordon, E., Williams, L. M. 2015; 25 (11): 1981-1990


    It is essential to improve antidepressant treatment of major depressive disorder (MDD) and one way this could be achieved is by reducing the number of treatment steps by employing biomarkers that can predict treatment outcome. This study investigated differences between MDD patients and healthy controls in the P3 and N1 component from the event-related potential (ERP) generated in a standard two-tone oddball paradigm. Furthermore, the P3 and N1 are investigated as predictors for treatment outcome to three different antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D)--a multi-center, international, randomized, prospective practical trial--1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression. P3 and N1 latencies and amplitudes were analyzed using a peak-picking approach and further replicated by using exact low resolution tomography (eLORETA). A reduced P3 was found in MDD patients compared to controls by a peak-picking analysis. This was validated in a temporal global field power analysis. Source density analysis revealed that the difference in cortical activity originated from the posterior cingulate and parahippocampal gyrus. Male non-responders to venlafaxine-XR had significantly smaller N1 amplitudes than responders. This was demonstrated by both analytical methods. Male non-responders to venlafaxine-XR had less activity originating from the left insular cortex. The observed results are discussed from a neural network viewpoint.

    View details for DOI 10.1016/j.euroneuro.2015.07.022

    View details for Web of Science ID 000369152500014

    View details for PubMedID 26282359

  • Emotion circuits differentiate symptoms of psychosis versus mania in adolescents NEUROCASE Brennan, A. M., Hainsworth, C., Starling, J., Korgaonkar, M. S., Harris, A. W., Williams, L. M. 2015; 21 (5): 592-600


    The diagnostic boundary between schizophrenia and bipolar disorder can be unclear, particularly with early onset. We assessed if emotion brain circuits differentiate psychosis versus mania symptoms in a series of six early onset patients. Symptoms were dissociated by direction, awareness condition, and brain regions. Greater psychosis symptoms were correlated with greater prefrontal, anterior cingulate, amygdala, and fusiform face area activation during masked fear processing. By contrast, greater mania symptoms were correlated with less amygdala activation during unmasked fear and happy processing. This suggests emotion dysfunction in schizophrenia versus bipolar disorder may arise from partially distinct neural mechanisms of susceptibility.

    View details for DOI 10.1080/13554794.2014.960426

    View details for Web of Science ID 000356354500007

    View details for PubMedID 25265277

  • Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial AMERICAN JOURNAL OF PSYCHIATRY Arnow, B. A., Blasey, C., Williams, L. M., Palmer, D. M., Rekshan, W., Schatzberg, A. F., Etkin, A., Kulkarni, J., Luther, J. F., Rush, A. J. 2015; 172 (8): 743-750


    The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications.Participants 18-65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report).Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect.There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.

    View details for DOI 10.1176/appi.ajp.2015.14020181

    View details for Web of Science ID 000359274700014

    View details for PubMedID 25815419

  • Frontal and rostral anterior cingulate (rACC) theta EEG in depression: Implications for treatment outcome? EUROPEAN NEUROPSYCHOPHARMACOLOGY Arns, M., Etkin, A., Hegerl, U., Williams, L. M., DeBattista, C., Palmer, D. M., Fitzgerald, P. B., Harris, A., deBeuss, R., Gordon, E. 2015; 25 (8): 1190-1200


    In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram (EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.

    View details for DOI 10.1016/j.euroneuro.2015.03.007

    View details for Web of Science ID 000359875500014

    View details for PubMedID 25936227



    Childhood maltreatment (CM) history has been associated with poor treatment response in major depressive disorder (MDD), but the mechanisms underlying this relationship remain opaque. Dysfunction in the neural circuits for executive cognition is a putative neurobiological consequence of CM that may contribute importantly to adverse clinical outcomes. We used behavioral and neuroimaging measures of executive functioning to assess their contribution to the relationship between CM and antidepressant response in MDD patients.Ninety eight medication-free MDD outpatients participating in the International Study to Predict Optimized Treatment in Depression were assessed at baseline on behavioral neurocognitive measures and functional magnetic resonance imaging during tasks probing working memory (continuous performance task, CPT) and inhibition (Go/No-go). Seventy seven patients completed 8 weeks of antidepressant treatment. Baseline behavioral and neuroimaging measures were assessed in relation to CM (history of childhood physical, sexual, and/or emotional abuse) and posttreatment depression outcomes.Patients with maltreatment exhibited decreased modulation of right dorsolateral prefrontal cortex (DLPFC) activity during working memory updating on the CPT, and a corresponding impairment in CPT behavioral performance outside the scanner. No between-group differences were found for imaging or behavior on the Go/No-go test of inhibition. Greater DLPFC activity during CPT significantly predicted posttreatment symptom improvement in patients without maltreatment, whereas the relationship between DLPFC activity and symptom change was nonsignificant, and in the opposite direction, in patients with maltreatment.The effect of CM on prefrontal circuitry involved in executive function is a potential predictor of antidepressant outcomes.

    View details for DOI 10.1002/da.22368

    View details for Web of Science ID 000358621900006

  • Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report JOURNAL OF AFFECTIVE DISORDERS Day, C. V., Gatt, J. M., Etkin, A., DeBattista, C., Schatzberg, A. F., Williams, L. M. 2015; 176: 141-150


    Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception.MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score ≥16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history.Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity.Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task.Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic-cortical circuitry for motivationally-directed behavior.

    View details for DOI 10.1016/j.jad.2015.01.061

    View details for Web of Science ID 000350975500019

    View details for PubMedID 25710095

  • Reduction of Autonomic Regulation in Children and Adolescents With Conversion Disorders PSYCHOSOMATIC MEDICINE Kozlowska, K., Palmer, D. M., Brown, K. J., Mclean, L., Scher, S., Gevirtz, R., Chudleigh, C., Williams, L. M. 2015; 77 (4): 356-370


    Conversion symptoms--functional neurological disturbances of body function--occur in association with extreme arousal, often in the context of emotional distress. The mechanisms that determine how and why such symptoms occur remain unknown. In this study, we used cardiac measures to assess arousal and cardiac autonomic regulation in children and adolescents who presented with acute conversion symptoms.Heart rate was recorded in 57 children and adolescents (41 girls; 8.5-18 years old) with acute conversion symptoms and 57 age- and sex-matched healthy controls, during a resting condition and then during tasks involving cognitive and emotional activation. Arousal and autonomic regulation were assessed by measures of heart rate and heart rate variability. Psychological measures included attachment and emotional distress.Children and adolescents with conversion symptoms displayed higher autonomic arousal than did the controls, both at baseline and during task conditions (higher heart rate: baseline mean [standard deviation] = 82 [9.49] versus 74 [10.79] beats/min, p < .001; lower root mean squared successive differences-heart rate variability: 45.35 [27.97] versus 58.62 [25.69] ms(2), p = .012; and lower high-frequency heart rate variability: 6.50 [1.19] versus 7.01 [0.95] ln[ms(2)] p = .017), and decreased autonomic regulation (attenuation of heart rate increases across tasks). The baseline pattern of increased autonomic arousal was especially pronounced in children with coercive-preoccupied patterns of attachment. Autonomic measures were not correlated with measures of emotional distress.High autonomic arousal may be a precondition for generating conversion symptoms. Functional dysregulations of the cardiac, respiratory, and circulatory systems may mediate fainting episodes and nonepileptic seizures, and aberrant patterns of functional connectivity between motor areas and central arousal systems may be responsible for generating motor conversion symptoms.

    View details for DOI 10.1097/PSY.0000000000000184

    View details for Web of Science ID 000354553000002

    View details for PubMedID 25954919

  • A Cognitive-Emotional Biomarker for Predicting Remission with Antidepressant Medications: A Report from the iSPOT-D Trial NEUROPSYCHOPHARMACOLOGY Etkin, A., Patenaude, B., Song, Y. J., Usherwood, T., Rekshan, W., Schatzberg, A. F., Rush, A. J., Williams, L. M. 2015; 40 (6): 1332-1342


    Depression involves impairments in a range of cognitive and emotional capacities. It is unknown whether these functions can inform medication choice when considered as a composite predictive biomarker. We tested whether behavioral tests, grounded in the neurobiology of cognitive and emotional functions, predict outcome with common antidepressants. Medication-free outpatients with nonpsychotic major depressive disorder (N=1008; 665 completers) were assessed before treatment using 13 computerized tests of psychomotor, executive, memory-attention, processing speed, inhibitory, and emotional functions. Matched healthy controls (N=336) provided a normative reference sample for test performance. Depressed participants were then randomized to escitalopram, sertraline, or venlafaxine-extended release, and were assessed using the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) and the 17-item Hamilton Rating Scale for Depression. Given the heterogeneity of depression, analyses were furthermore stratified by pretreatment performance. We then used pattern classification with cross-validation to determine individual patient-level composite predictive biomarkers of antidepressant outcome based on test performance. A subgroup of depressed participants (approximately one-quarter of patients) were found to be impaired across most cognitive tests relative to the healthy norm, from which they could be discriminated with 91% accuracy. These patients with generally impaired cognitive task performance had poorer treatment outcomes. For this impaired subgroup, task performance furthermore predicted remission on the QIDS-SR16 at 72% accuracy specifically following treatment with escitalopram but not the other medications. Therefore, tests of cognitive and emotional functions can form a clinically meaningful composite biomarker that may help drive general treatment outcome prediction for optimal treatment selection in depression, particularly for escitalopram.

    View details for DOI 10.1038/npp.2014.333

    View details for Web of Science ID 000352968100004

    View details for PubMedID 25547711

    View details for PubMedCentralID PMC4397406

  • Conversion disorder in children and adolescents: A disorder of cognitive control JOURNAL OF NEUROPSYCHOLOGY Kozlowska, K., Palmer, D. M., Brown, K. J., Scher, S., Chudleigh, C., Davies, F., Williams, L. M. 2015; 9 (1): 87-108


    To assess cognitive function in children and adolescents presenting with acute conversion symptoms.Fifty-seven participants aged 8.5-18 years (41 girls and 16 boys) with conversion symptoms and 57 age- and gender-matched healthy controls completed the IntegNeuro neurocognitive battery, an estimate of intelligence, and self-report measures of subjective emotional distress.Participants with conversion symptoms showed poorer performance within attention, executive function, and memory domains. Poorer performance was reflected in more errors on specific tests: Switching of Attention (t(79) = 2.17, p = .03); Verbal Interference (t(72) = 2.64, p = .01); Go/No-Go (t(73) = 2.20, p = .03); Memory Recall and Verbal Learning (interference errors for memory recall; t(61) = 3.13, p < .01); and short-delay recall (t(75) = 2.05, p < .01) and long-delay recall (t(62) = 2.24, p = .03). Poorer performance was also reflected in a reduced span of working memory on the Digit Span Test for both forward recall span (t(103) = -3.64, p < .001) and backward recall span (t(100) = -3.22, p < .01). There was no difference between participants and controls on IQ estimate (t(94) = -589, p = .56), and there was no correlation between cognitive function and perceived distress.Children and adolescents with acute conversion symptoms have a reduced capacity to manipulate and retain information, to block interfering information, and to inhibit responses, all of which are required for effective attention, executive function, and memory.

    View details for DOI 10.1111/jnp.12037

    View details for Web of Science ID 000350478100008

    View details for PubMedID 24405496

  • The International Study to Predict Optimized Treatment in Depression (iSPOT-D): Outcomes from the acute phase of antidepressant treatment. Journal of psychiatric research Saveanu, R., Etkin, A., Duchemin, A., Goldstein-Piekarski, A., Gyurak, A., DeBattista, C., Schatzberg, A. F., Sood, S., Day, C. V., Palmer, D. M., Rekshan, W. R., Gordon, E., Rush, A. J., Williams, L. M. 2015; 61: 1-12


    We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients (18-65 years old) at 17 sites (five countries). At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the "none" to minimal/mild range for intensity and burden. Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.

    View details for DOI 10.1016/j.jpsychires.2014.12.018

    View details for PubMedID 25586212

  • Anxiety in Young People With ADHD: Clinical and Self-Report Outcomes. Journal of attention disorders Tsang, T. W., Kohn, M. R., Efron, D., Clarke, S. D., Clark, C. R., Lamb, C., Williams, L. M. 2015; 19 (1): 18-26


    Objective: (a) To determine the prevalence of comorbid anxiety disorder in ADHD, defined by diagnostic criteria and (b) to compare anxiety as reported by parents and participants with clinician assessment. Method: Children with ADHD were assessed for comorbid anxiety disorder using the Anxiety Disorder Interview Schedule for Children. Parent report (Conners' Parent Rating Scale-Revised: Long version) and self-report (State-Trait Anxiety Inventory and Brain Resource Inventory for Screening Cases-Child version) scales were used to assess anxiety. The ADHD-Rating Scale IV was used to measure ADHD symptoms. Results: Of 134 participants (11.0 ± 2.6 years), 31.3% had comorbid anxiety disorder. Comorbid anxiety disorder was associated with greater severity of ADHD. Anxiety symptoms from parent reports (p < .05) but not from child/self-report (p > .05) correlated with clinician assessment. Conclusion: Assessment for comorbid anxiety disorder and inclusion of parent rating in this assessment are important components of ADHD treatment in children and adolescents. (J. of Att. Dis. 2012; XX(X) 1-XX).

    View details for DOI 10.1177/1087054712446830

    View details for PubMedID 22713359

  • Specific and common genes implicated across major mental disorders: A review of meta-analysis studies JOURNAL OF PSYCHIATRIC RESEARCH Gatt, J. M., Burton, K. L., Williams, L. M., Schofield, P. R. 2015; 60: 1-13
  • Impairment and distress patterns distinguishing the melancholic depression subtype: An iSPOT-D report. Journal of affective disorders Day, C. V., John Rush, A., Harris, A. W., Boyce, P. M., Rekshan, W., Etkin, A., DeBattista, C., Schatzberg, A. F., Arnow, B. A., Williams, L. M. 2015; 174: 493-502


    This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress.Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress.Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants.Due to the cross-sectional nature of this study, causal pathways cannot be concluded.Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.

    View details for DOI 10.1016/j.jad.2014.10.046

    View details for PubMedID 25554994

  • Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress JOURNAL OF PSYCHIATRIC RESEARCH Myers, A. J., Williams, L., Gatt, J. M., McAuley-Clark, E. Z., Dobson-Stone, C., Schofield, P. R., Nemeroff, C. B. 2014; 59: 93-100
  • Facial emotion identification in early-onset psychosis SCHIZOPHRENIA RESEARCH Barkl, S. J., Lah, S., Starling, J., Hainsworth, C., Harris, A. W., Williams, L. M. 2014; 160 (1-3): 150-156


    Facial emotion identification (FEI) deficits are common in patients with chronic schizophrenia and are strongly related to impaired functioning. The objectives of this study were to determine whether FEI deficits are present and emotion specific in people experiencing early-onset psychosis (EOP), and related to current clinical symptoms and functioning. Patients with EOP (n=34, mean age=14.11, 53% female) and healthy controls (HC, n=42, mean age 13.80, 51% female) completed a task of FEI that measured accuracy, error pattern and response time. Relative to HC, patients with EOP (i) had lower accuracy for identifying facial expressions of emotions, especially fear, anger and disgust, (ii) were more likely to misattribute other emotional expressions as fear or disgust, and (iii) were slower at accurately identifying all facial expressions. FEI accuracy was not related to clinical symptoms or current functioning. Deficits in FEI (especially for fear, anger and disgust) are evident in EOP. Our findings suggest that while emotion identification deficits may reflect a trait susceptibility marker, functional deficits may represent a sequelae of illness.

    View details for DOI 10.1016/j.schres.2014.10.035

    View details for Web of Science ID 000345961300040

    View details for PubMedID 25464918

  • Neural processing of facial expressions of emotion in first onset psychosis PSYCHIATRY RESEARCH Brennan, A. M., Harris, A. W., Williams, L. M. 2014; 219 (3): 477-485


    Schizophrenia is characterized by deficits in face and facial emotion processing. This is the first study using event-related potentials (ERPs) to investigate the corresponding neural activation in first onset psychosis. ERPs for 108 first onset psychosis participants and 108 matched healthy controls were recorded while they viewed facial expressions. Group differences on general (neutral) face processing and emotional valence were examined under both unmasked (conscious) and backward-masked (nonconscious implicit) conditions over frontal and temporo-occipital regions. Clinical significance was assessed by comparing diagnoses and correlating ERPs with symptoms. During general face processing, patients showed reduced activation within 70ms and exaggerated later processing from 160ms over the frontal region, with a negative shift in voltage over left temporal and occipital regions across the time course. In addition, from 70ms onwards, patients showed a positive shift in voltage for disgust whereas controls showed a negative shift in voltage for fear and anger (both compared to happy) over temporo-occipital regions. Effects were related to disorganization and depression symptoms and (preliminarily) were apparent across psychotic diagnoses. These results suggest that first onset psychosis is characterized by general as well as emotion-specific face processing impairments from the earliest, automatic processing period.

    View details for DOI 10.1016/j.psychres.2014.06.017

    View details for Web of Science ID 000341901600012

    View details for PubMedID 25015712

  • Abnormal Structural Networks Characterize Major Depressive Disorder: A Connectome Analysis BIOLOGICAL PSYCHIATRY Korgaonkar, M. S., Fornito, A., Williams, L. M., Grieve, S. M. 2014; 76 (7): 567-574
  • Facial emotion identification in early-onset and first-episode psychosis: A systematic review with meta-analysis SCHIZOPHRENIA RESEARCH Barkl, S. J., Lah, S., Harris, A. W., Williams, L. M. 2014; 159 (1): 62-69


    Patients with chronic schizophrenia are characterized by deficits in identifying facial expressions of emotion, and these deficits relate to impaired social and occupational function. It is not yet known if these deficits are trait-like and present at the onset of psychosis, preceding a subsequent diagnosis of schizophrenia. Our objective was to systematically review and analyze the extant literature to assess if there is a consistent profile of emotion identification problems in early-onset and first-episode psychosis.We conducted a systematic review and meta-analysis of 12 peer-reviewed studies of facial emotion identification in early-onset and first-episode psychosis, published between 1980 and March 2013. We examined the average mean difference between patients and controls on measures of facial emotion identification.Findings suggest that patients with early-onset and first-episode psychosis have impairment in identifying facial expressions of biologically salient emotion. Across the 12 studies, the onset of psychosis was distinguished by a generalized effect of significantly poorer accuracy for identifying facial expressions of emotion than healthy controls, and this difference had a substantial effect size (d=-0.88, N=378, 95% CI=-1.42 to -0.32). Within this general effect some emotions were also harder for patients to identify than others, with the magnitude of impairment found to be (i) large for disgust, fear and surprise, and (ii) medium for sadness, and happiness. No between groups mean differences were found for anger or neutral facial expressions.Deficits in facial emotion identification are evident at first onset of a psychotic episode. The findings suggest that, over and above a generalized deficit in identifying facial emotion, patients may find some emotions harder to identifying than others. This reflects findings with chronic schizophrenia populations and suggests that emotion identification impairment represents a trait susceptibility marker, rather than a sequeale of illness. They signal the urgent need to treat emotion identification deficits at the onset of illness, which could improve functional outcomes.

    View details for DOI 10.1016/j.schres.2014.07.049

    View details for Web of Science ID 000343107400011

    View details for PubMedID 25178803

  • Diffusion tensor imaging predictors of treatment outcomes in major depressive disorder BRITISH JOURNAL OF PSYCHIATRY Korgaonkar, M. S., Williams, L. M., Song, Y. J., Usherwood, T., Grieve, S. M. 2014; 205 (4): 321-328
  • The heritability of mental health and wellbeing defined using COMPAS-W, a new composite measure of wellbeing. Psychiatry research Gatt, J. M., Burton, K. L., Schofield, P. R., Bryant, R. A., Williams, L. M. 2014; 219 (1): 204-213


    Mental health is not simply the absence of mental illness; rather it is a distinct entity representing wellness. Models of wellbeing have been proposed that emphasize components of subjective wellbeing, psychological wellbeing, or a combination of both. A new 26-item scale of wellbeing (COMPAS-W) was developed in a cohort of 1669 healthy adult twins (18-61 years). The scale was derived using factor analysis of multiple scales of complementary constructs and confirmed using tests of reliability and convergent validity. Bivariate genetic modeling confirmed its heritability. From an original 89 items we identified six independent subcomponents that contributed to wellbeing. The COMPAS-W scale and its subcomponents showed construct validity against psychological and physical health behaviors, high internal consistency (average r=0.71, Wellbeing r=0.84), and 12-month test-retest reliability (average r=0.62, Wellbeing r=0.82). There was a moderate contribution of genetics to total Wellbeing (heritability h(2)=48%) and its subcomponents: Composure (h(2)=24%), Own-worth (h(2)=42%), Mastery (h(2)=40%), Positivity (h(2)=42%), Achievement (h(2)=32%) and Satisfaction (h(2)=43%). Multivariate genetic modeling indicated genetic variance was correlated across the scales, suggesting common genetic factors contributed to Wellbeing and its subcomponents. The COMPAS-W scale provides a validated indicator of wellbeing and offers a new tool to quantify mental health.

    View details for DOI 10.1016/j.psychres.2014.04.033

    View details for PubMedID 24863866

  • Establishing the resting state default mode network derived from functional magnetic resonance imaging tasks as an endophenotype: A twins study. Human brain mapping Korgaonkar, M. S., Ram, K., Williams, L. M., Gatt, J. M., Grieve, S. M. 2014; 35 (8): 3893-3902


    The resting state default mode network (DMN) has been shown to characterize a number of neurological and psychiatric disorders. Evidence suggests an underlying genetic basis for this network and hence could serve as potential endophenotype for these disorders. Heritability is a defining criterion for endophenotypes. The DMN is measured either using a resting-state functional magnetic resonance imaging (fMRI) scan or by extracting resting state activity from task-based fMRI. The current study is the first to evaluate heritability of this task-derived resting activity. 250 healthy adult twins (79 monozygotic and 46 dizygotic same sex twin pairs) completed five cognitive and emotion processing fMRI tasks. Resting state DMN functional connectivity was derived from these five fMRI tasks. We validated this approach by comparing connectivity estimates from task-derived resting activity for all five fMRI tasks, with those obtained using a dedicated task-free resting state scan in an independent cohort of 27 healthy individuals. Structural equation modeling using the classic twin design was used to estimate the genetic and environmental contributions to variance for the resting-state DMN functional connectivity. About 9-41% of the variance in functional connectivity between the DMN nodes was attributed to genetic contribution with the greatest heritability found for functional connectivity between the posterior cingulate and right inferior parietal nodes (P < 0.001). Our data provide new evidence that functional connectivity measures from the intrinsic DMN derived from task-based fMRI datasets are under genetic control and have the potential to serve as endophenotypes for genetically predisposed psychiatric and neurological disorders. Hum Brain Mapp 35:3893-3902, 2014. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.22446

    View details for PubMedID 24453120

  • Effects of antidepressant medication on emotion regulation in depressed patients: An iSPOT-D report JOURNAL OF AFFECTIVE DISORDERS McRae, K., Rekshan, W., Williams, L. M., Cooper, N., Gross, J. J. 2014; 159: 127-132


    Antidepressant medication (ADM) is thought to reduce depressive symptoms by altering emotion-generative brain systems. However, it is unknown whether successful ADM treatment is associated with changes in psychobehavioral strategies used to regulate emotions. We examined depressive symptoms and emotion regulation strategies before and after ADM in the international Study to Predict Optimized Treatment in Depression (iSPOT-D).The study enrolled 1008 adult patients with MDD (18-65 years old) from 18 primary and psychiatric care sites worldwide. Patients were randomly assigned to an 8-week course of escitalopram, sertraline, or venlafaxine-extended-release. We examined whether ADM is associated with changes in suppression, usually associated with maladaptive outcomes, and reappraisal, usually associated with adaptive outcomes. We also tested whether changes in emotion regulation predict changes in depressive symptoms following ADM.We observed more adaptive emotion regulation (decreased use of suppression and increased use of reappraisal) following ADM. Furthermore, the largest improvements in emotion regulation were associated with the best treatment outcomes.Because we assessed acute outcomes, it is not yet known if the effects of ADM on emotion regulation would persist over time.ADMs are associated with acute, adaptive changes in the psychobehavioral strategies used to regulate emotions.

    View details for DOI 10.1016/j.jad.2014.12.037

    View details for Web of Science ID 000333398400019

    View details for PubMedID 24679400

  • Tractography of the Brainstem in Major Depressive Disorder Using Diffusion Tensor Imaging PLOS ONE Song, Y. J., Korgaonkar, M. S., Armstrong, L. V., Eagles, S., Williams, L. M., Grieve, S. M. 2014; 9 (1)


    The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem's role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls.MDD patients (n = 95) and age- and gender-matched controls (n = 34) were assessed using probabilistic tractography of DTI to delineate three distinct brainstem tracts: the nigrostriatal tract (connecting brainstem to striatum), solitary tract (connecting brainstem to amygdala) and corticospinal tract (connecting brainstem to precentral cortex). Fractional anisotropy (FA) was used to measure the white matter integrity of these tracts, and measures were compared between MDD and control participants.MDD participants were characterized by a significant and specific decrease in white matter integrity of the right solitary tract (p<0.009 using independent t-test), which is a "bottom up" afferent pathway that connects the brainstem to the amygdala. This decrease was not related to symptom severity.The results provide new evidence to suggest that structural connectivity between the brainstem and the amygdala is altered in MDD. These results are interesting in light of predominant theories regarding amygdala-mediated emotional reactivity observed in functional imaging studies of MDD. The characterization of altered white matter integrity in the solitary tract in MDD supports the possibility of dysfunctional brainstem-amygdala connectivity impacting vulnerable circuits in MDD.

    View details for DOI 10.1371/journal.pone.0084825

    View details for Web of Science ID 000330244500016

    View details for PubMedID 24465436

    View details for PubMedCentralID PMC3897382

  • Diffusion tensor imaging predictors of treatment outcomes in major depressive disorder. The British journal of psychiatry : the journal of mental science Korgaonkar, M. S., Williams, L. M., Song, Y. J., Usherwood, T., Grieve, S. M. 2014


    Functional neuroimaging studies implicate anterior cingulate and limbic dysfunction in major depressive disorder (MDD) and responsiveness to antidepressants. Diffusion tensor imaging (DTI) enables characterisation of white matter tracts that relate to these regions.To examine whether DTI measures of anterior cingulate and limbic white matter are useful prognostic biomarkers for MDD.Of the 102 MDD out-patients from the International Study to Predict Optimized Treatment for Depression (iSPOT-D) who provided baseline magnetic resonance imaging (MRI) data, 74 completed an 8-week course of antidepressant medication (randomised to escitalopram, sertraline or extended-release venlafaxine) and were included in the present analyses. Thirty-four matched controls also provided DTI data. Fractional anisotropy was measured for five anterior cingulate-limbic white matter tracts: cingulum cingulate and hippocampus bundle, fornix, stria terminalis and uncinate fasciculus. (Trial registered at NCT00693849.) RESULTS: A cross-validated logistic regression model demonstrated that altered connectivity for the cingulum part of the cingulate and stria terminalis tracts significantly predicted remission independent of demographic and clinical measures with 62% accuracy. Prediction improved to 74% when age was added to this model.Anterior cingulate-limbic white matter is a useful predictor of antidepressant treatment outcome in MDD.

    View details for PubMedID 24970773

  • Reduced Amygdala and Ventral Striatal Activity to Happy Faces in PTSD Is Associated with Emotional Numbing. PloS one Felmingham, K. L., Falconer, E. M., Williams, L., Kemp, A. H., Allen, A., Peduto, A., Bryant, R. A. 2014; 9 (9)


    There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1) individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2) that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral) faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing.

    View details for DOI 10.1371/journal.pone.0103653

    View details for PubMedID 25184336

    View details for PubMedCentralID PMC4153581

  • Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing PLOS ONE Felmingham, K. L., Falconer, E. M., Williams , L. M., Kemp, A. H., Allen, A., Peduto, A. S., Bryant, R. A. 2014; 9 (9)
  • Abnormal Structural Networks Characterize Major Depressive Disorder: A Connectome Analysis. Biological psychiatry Korgaonkar, M. S., Fornito, A., Williams, L. M., Grieve, S. M. 2014


    Major depressive disorder (MDD) has been shown to be associated with a disrupted topological organization of functional brain networks. However, little is known regarding whether these changes have a structural basis. Diffusion tensor imaging (DTI) enables comprehensive whole-brain mapping of the white matter tracts that link regions distributed throughout the entire brain, the so-called human connectome.We examined whole-brain structural networks in a cohort of 95 MDD outpatients and 102 matched control subjects. Structural networks were represented by an 84 × 84 connectivity matrix representing probabilistic white matter connections between 84 parcellated cortical and subcortical regions using DTI tractography. Network-based statistics were used to assess differences in the interregional connectivity matrix between the two groups, and graph theory was used to examine overall topological organization.Our network-based statistics analysis demonstrates lowered structural connectivity within two distinct brain networks that are present in depression: the first primarily involves the regions of the default mode network and the second comprises the frontal cortex, thalamus, and caudate regions that are central in emotional and cognitive processing. These two altered networks were observed in the context of an overall preservation of topology as reflected as no significant group differences for the graph-theory measures.This is the first report to use DTI to show the structural connectomic alterations present in MDD. Our findings highlight that altered structural connectivity between nodes of the default mode network and the frontal-thalamo-caudate regions are core neurobiological features associated with MDD.

    View details for PubMedID 24690111

  • Causal interactions between fronto-parietal central executive and default-mode networks in humans PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chen, A. C., Oathes, D. J., Chang, C., Bradley, T., Zhou, Z., Williams, L. M., Glover, G. H., Deisseroth, K., Etkin, A. 2013; 110 (49): 19944-19949


    Information processing during human cognitive and emotional operations is thought to involve the dynamic interplay of several large-scale neural networks, including the fronto-parietal central executive network (CEN), cingulo-opercular salience network (SN), and the medial prefrontal-medial parietal default mode networks (DMN). It has been theorized that there is a causal neural mechanism by which the CEN/SN negatively regulate the DMN. Support for this idea has come from correlational neuroimaging studies; however, direct evidence for this neural mechanism is lacking. Here we undertook a direct test of this mechanism by combining transcranial magnetic stimulation (TMS) with functional MRI to causally excite or inhibit TMS-accessible prefrontal nodes within the CEN or SN and determine consequent effects on the DMN. Single-pulse excitatory stimulations delivered to only the CEN node induced negative DMN connectivity with the CEN and SN, consistent with the CEN/SN's hypothesized negative regulation of the DMN. Conversely, low-frequency inhibitory repetitive TMS to the CEN node resulted in a shift of DMN signal from its normally low-frequency range to a higher frequency, suggesting disinhibition of DMN activity. Moreover, the CEN node exhibited this causal regulatory relationship primarily with the medial prefrontal portion of the DMN. These findings significantly advance our understanding of the causal mechanisms by which major brain networks normally coordinate information processing. Given that poorly regulated information processing is a hallmark of most neuropsychiatric disorders, these findings provide a foundation for ways to study network dysregulation and develop brain stimulation treatments for these disorders.

    View details for DOI 10.1073/pnas.1311772110

    View details for Web of Science ID 000327744900066

    View details for PubMedID 24248372

    View details for PubMedCentralID PMC3856839

  • Early Exposure to Traumatic Stressors Impairs Emotional Brain Circuitry PLOS ONE Korgaonkar, M. S., Antees, C., Williams, L. M., Gatt, J. M., Bryant, R. A., Cohen, R., Paul, R., O'Hara, R., Grieve, S. M. 2013; 8 (9)


    Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder.

    View details for DOI 10.1371/journal.pone.0075524

    View details for PubMedID 24073270

  • Using multiple methods to characterize the phenotype of individuals with a family history of major depressive disorder JOURNAL OF AFFECTIVE DISORDERS Watters, A. J., Gotlib, I. H., Harris, A. W., Boyce, P. M., Williams, L. M. 2013; 150 (2): 474-480


    Unaffected relatives (URs) of individuals with major depressive disorder (MDD) are biologically more vulnerable to depression. We compare healthy URs and controls at the level of phenotype (symptoms and functioning) and endophenotype (negative emotion bias), and further investigate the interrelation between these and the contribution of environmental early life stress.URs (n=101), identified using Family History Screen interview methods and matched controls completed written and interview questions assessing symptoms of depression and anxiety, negative cognitive style, life functioning and early life stress. Biases in emotion processing were measured using a facial expression of emotion identification paradigm.Compared to controls, URs reported higher levels of depression and anxiety, a stronger negative cognitive bias, and poorer functioning and lower satisfaction with life. URs were slower to correctly identify fear and sad facial expressions. A slower response time to identify sad faces was correlated with lower quality of life in the social domain. Early life stress (ELS) did not contribute significantly to any outcome.The methodology relies on accurate reporting of participants' own psychiatric history and that of their family members. The degree of vulnerability varies among URs.A family history of depression accounts for subtle differences in symptom levels and functioning without a necessary role of ELS. A negative emotion bias in processing emotion may be one vulnerability marker for MDD. Biological markers may affect functioning measures before symptoms at the level of experience.

    View details for DOI 10.1016/j.jad.2013.04.042

    View details for Web of Science ID 000323563300043

    View details for PubMedID 23764382

  • Inhibitory neural activity predicts response to cognitive-behavioral therapy for posttraumatic stress disorder. journal of clinical psychiatry Falconer, E., Allen, A., Felmingham, K. L., Williams, L. M., Bryant, R. A. 2013; 74 (9): 895-901


    Despite cognitive-behavioral therapy (CBT) being an effective treatment for posttraumatic stress disorder (PTSD), many patients do not respond to CBT. Understanding the neural bases of treatment response may inform treatment refinement, thereby improving treatment response rates. Adequate working memory function is proposed to enable engagement in CBT.This study employed a Go/No-Go task to examine inhibitory function and its functional brain correlates as predictors of response to CBT in PTSD. Participants were recruited between October 2003 and May 2005. Thirteen treatment-seeking patients who met DSM-IV criteria for PTSD completed the Go/No-Go task while undergoing functional magnetic resonance imaging (fMRI), after which they entered 8 once-weekly sessions of CBT. PTSD severity was measured before treatment and again at 6 months following treatment completion using the Clinician-Administered PTSD Scale (primary outcome measure).After controlling for initial PTSD severity and ongoing depressive symptoms, greater activity in left dorsal striatal (Z = 3.19, P = .001) and frontal (Z = 3.03, P = .001) networks during inhibitory control was associated with lower PTSD symptom severity after treatment, suggesting better treatment response.These results suggest that neural circuitry underpinning inhibitory control plays a role in the outcome of CBT for patients with Identifier: ACTRN12610000017022.

    View details for DOI 10.4088/JCP.12m08020

    View details for PubMedID 24107763

  • GSK3B and MAPT Polymorphisms Are Associated with Grey Matter and Intracranial Volume in Healthy Individuals PLOS ONE Dobson-Stone, C., Polly, P., Korgaonkar, M. S., Williams, L. M., Gordon, E., Schofield, P. R., Mather, K., Armstrong, N. J., Wen, W., Sachdev, P. S., Kwok, J. B. 2013; 8 (8)


    The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037-0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082-0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.

    View details for DOI 10.1371/journal.pone.0071750

    View details for Web of Science ID 000323097300153

    View details for PubMedID 23951236

  • Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial TRIALS Grieve, S. M., Korgaonkar, M. S., Etkin, A., Harris, A., Koslow, S. H., Wisniewski, S., Schatzberg, A. F., Nemeroff, C. B., Gordon, E., Williams, L. M. 2013; 14


    Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD.The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n = 102), test the findings in the second half, and then extend the analyses to the total sample.International Study to Predict Optimized Treatment - in Depression (iSPOT-D)., NCT00693849.

    View details for DOI 10.1186/1745-6215-14-224

    View details for Web of Science ID 000322542800001

    View details for PubMedCentralID PMC3729660

  • Functional dysconnectivity in schizophrenia and its relationship to neural synchrony EXPERT REVIEW OF NEUROTHERAPEUTICS Brennan, A. M., Harris, A. W., Williams, L. M. 2013; 13 (7): 755-765


    Schizophrenia is a debilitating disorder of unknown cause. There is increasing momentum to consider functional dysconnectivity as an endophenotype of schizophrenia, and in particular, how it relates to cognition as a core feature of the disorder. Here, the authors review the conceptual models of functional dysconnectivity in schizophrenia to date, the evidence they are based on and some of the limitations of these models. The authors then propose 'neural synchrony' as a potential mechanism for functional dysconnectivity and review the current state of evidence for a link between neural synchrony and cognition in schizophrenia across behavioral, physiological, brain imaging, neurochemical and neurogenetic units of enquiry. The authors conclude by outlining the unmet needs in this field and give an outlook on how to fill these gaps.

    View details for DOI 10.1586/14737175.2013.811899

    View details for Web of Science ID 000330536100011

    View details for PubMedID 23898848

  • Impact of early vs. late childhood early life stress on brain morphometrics. Brain imaging and behavior Baker, L. M., Williams, L. M., Korgaonkar, M. S., Cohen, R. A., Heaps, J. M., Paul, R. H. 2013; 7 (2): 196-203


    Previous studies of early life trauma suggest that in addition to its emotional impact, exposure to early life stress (ELS) is associated with alterations in brain structure. However, little attention has been devoted to the relationship between emotional processing and brain integrity as a function of age of ELS onset. In the present study we examined whether ELS onset in older ages of youth rather than younger ages is associated with smaller limbic and basal ganglia volumes as measured by magnetic resonance imaging (MRI). We hypothesized that later age of manifestation during youth is associated with smaller volumetric morphology in limbic and basal ganglia volumes in adulthood. A total of 173 individuals were divided into three groups based on the age of self-reported ELS. The three groups included individuals only experiencing early childhood ELS (1 month-7 years, n = 38), those only experiencing later childhood ELS (8 years -17 years, n = 59), and those who have not experienced ELS (n = 76). Anterior cingulate cortex (ACC), hippocampus, amygdala, insula and caudate volumes were measured using a T1-weighted MRI. Analyses confirmed that later childhood ELS was associated with volumetric reductions in the ACC and insula volumes, while ELS experienced between the ages of 1 month and 7 years was not associated with lower brain volumes in these regions. The results may reflect the influence of more fully developed emotional processing of ELS on the developing brain and reinforce a body of research implicating both the ACC and insula in neuropsychiatric disorders and emotional regulation.

    View details for DOI 10.1007/s11682-012-9215-y

    View details for PubMedID 23247614

  • Cognitive and Emotion Predictors of Response to Atomoxetine in Children and Adolescents with Attention Deficit Hyperactivity Disorder, with and without Comorbid Anxiety 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Tsang, T. W., Kohn, M. R., Clarke, S. D., Williams, L. M. ELSEVIER SCIENCE INC. 2013: 47S–47S
  • Using Standardized fMRI Protocols to Identify Patterns of Prefrontal Circuit Dysregulation that are Common and Specific to Cognitive and Emotional Tasks in Major Depressive Disorder: First Wave Results from the iSPOT-D Study NEUROPSYCHOPHARMACOLOGY Korgaonkar, M. S., Grieve, S. M., Etkin, A., Koslow, S. H., Williams, L. M. 2013; 38 (5): 863-871


    Functional neuroimaging studies have implicated dysregulation of prefrontal circuits in major depressive disorder (MDD), and these circuits are a viable target for predicting treatment outcomes. However, because of the heterogeneity of tasks and samples used in studies to date, it is unclear whether the central dysfunction is one of prefrontal hyperreactivity or hyporeactivity. We used a standardized battery of tasks and protocols for functional magnetic resonance imaging, to identify the common vs the specific prefrontal circuits engaged by these tasks in the same 30 outpatients with MDD compared with 30 matched, healthy control participants, recruited as part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Reflecting cognitive neuroscience theory and established evidence, the battery included cognitive tasks designed to assess functions of selective attention, sustained attention-working memory and response inhibition, and emotion tasks to assess explicit conscious and implicit nonconscious viewing of facial emotion. MDD participants were distinguished by a distinctive biosignature of: hypoactivation of the dorsolateral prefrontal cortex during working memory updating and during conscious negative emotion processing; hyperactivation of the dorsomedial prefrontal cortex during working memory and response inhibition cognitive tasks and hypoactivation of the dorsomedial prefrontal during conscious processing of positive emotion. These results show that the use of standardized tasks in the same participants provides a way to tease out prefrontal circuitry dysfunction related to cognitive and emotional functions, and not to methodological or sample variations. These findings provide the frame of reference for identifying prefrontal biomarker predictors of treatment outcomes in MDD.

    View details for DOI 10.1038/npp.2012.252

    View details for Web of Science ID 000316161300015

    View details for PubMedID 23303059

    View details for PubMedCentralID PMC3671994

  • The long-term impact of early adversity on late-life psychiatric disorders. Current psychiatry reports Gershon, A., Sudheimer, K., Tirouvanziam, R., Williams, L. M., O'Hara, R. 2013; 15 (4): 352-?

    View details for DOI 10.1007/s11920-013-0352-9

    View details for PubMedID 23443532

  • Specific biases for identifying facial expression of emotion in children and adolescents with conversion disorders. Psychosomatic medicine Kozlowska, K., Brown, K. J., Palmer, D. M., Williams, L. M. 2013; 75 (3): 272-280


    This study aimed to assess how children and adolescents with conversion disorders identify universal facial expressions of emotion and to determine whether identification of emotion in faces relates to subjective emotional distress.Fifty-seven participants (41 girls and 16 boys) aged 8.5 to 18 years with conversion disorders and 57 age- and sex-matched healthy controls completed a computerized task in which their accuracy and reaction times for identifying facial expressions were recorded. To isolate the effect of individual emotional expressions, participants' reaction times for each emotion (fear, anger, sadness, disgust, and happiness) were subtracted from their reaction times for the neutral control face. Participants also completed self-report measures of subjective emotional distress.Children/Adolescents with conversion disorders showed faster reaction times for identifying expressions of sadness (t(112) = -2.2, p = .03; 444 [609] versus 713 [695], p = .03) and slower reactions times for happy expressions (t(99.3) = 2.28, p ≤ .024; -33 [35] versus 174 [51], p = .024), compared with controls (F(33.75, 419.81) = 3.76, p < .001). There were no significant correlations (at the corrected p value of .01) between reaction times and subjective reports of perceived distress (r values ranged from 092 to 0.221; p > .018). There were also no differences in identification accuracy for any emotion (p > .82).The observation of faster reaction times to sad faces in children and adolescents with conversion disorders suggests increased vigilance and motor readiness to emotional signals that are potential threats to self or to close others. These effects may occur before conscious processing.

    View details for DOI 10.1097/PSY.0b013e318286be43

    View details for PubMedID 23440229

  • The presentation of early-onset psychotic disorders AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Starling, J., Williams, L. M., Hainsworth, C., Harris, A. W. 2013; 47 (1): 43-50


    This study aims to describe the clinical course of psychotic disorders, including the premorbid history, symptoms and level of functioning in a group of children and adolescents treated by paediatric mental health services, mainly as inpatients.A sample of 45 children and adolescents with a psychotic disorder (mean age 13.2 years) was assessed using questionnaires, semi-structured interviews, parent interviews and file audit. The symptoms of those with a schizophrenia spectrum disorder (SSD) were compared to those with a mood disorder (MD).This population showed a high level of premorbid impairment, including previous treatment for other psychiatric disorders. As well as hallucinations and delusions, high levels of self-harm, aggression, anxiety and depression were reported. The SSD and MD groups differed mainly in their levels of premorbid functioning.While it is well known that childhood-onset schizophrenia is a severe disorder with a poor outcome, this study found that young people diagnosed with other psychotic disorders also have significant impairment and are likely to require high levels of care to maximize their functional recovery.

    View details for DOI 10.1177/0004867412463615

    View details for Web of Science ID 000313056700009

    View details for PubMedID 23047960

  • Widespread reductions in gray matter volume in depression NEUROIMAGE-CLINICAL Grieve, S. M., Korgaonkar, M. S., Koslow, S. H., Gordon, E., Williams, L. M. 2013; 3: 332-339


    Abnormalities in functional limbic-anterior cingulate-prefrontal circuits associated with emotional reactivity, evaluation and regulation have been implicated in the pathophysiology of major depressive disorder (MDD). However, existing knowledge about structural alterations in depression is equivocal and based on cohorts of limited sample size. This study used voxel-based morphometry (VBM) and surface-based cortical thickness to investigate the structure of these circuits in a large and well-characterized patient cohort with MDD. Non-geriatric MDD outpatients (n = 102) and age- and gender-matched healthy control participants (n = 34) provided T1-weighted magnetic resonance imaging data during their baseline visit as part of the International Study to Predict Optimized Treatment for Depression. Whole-brain VBM volumetric and surface-based cortical thickness assessments were performed voxel-wise and compared (at p < 0.05 corrected for multiple comparisons) between the MDD and control groups. MDD participants had reduced gray matter volume in the anterior cingulate cortex, regions of the prefrontal circuits, including dorsolateral and dorsomedial prefrontal cortices, and lateral and medial orbitofrontal cortices, but not in limbic regions. Additional reductions were observed cortically in the posterior temporal and parieto-occipital cortices and, subcortically in the basal ganglia and cerebellum. Focal cortical thinning in the medial orbitofrontal cortex was also observed for the MDD group. These alterations in volume and cortical thickness were not associated with severity of depressive symptoms. The findings demonstrate that widespread gray matter structural abnormalities are present in a well-powered study of patients with depression. The patterns of gray matter loss correspond to the same brain functional network regions that were previously established to be abnormal in MDD, which may support an underlying structural abnormality for these circuits.

    View details for DOI 10.1016/j.nicl.2013.08.016

    View details for Web of Science ID 000209276900036

    View details for PubMedCentralID PMC3814952

  • Dysregulation in cortical reactivity to emotional faces in PTSD patients with high dissociation symptoms. European journal of psychotraumatology Klimova, A., Bryant, R. A., Williams, L. M., Felmingham, K. L. 2013; 4


    Predominant dissociation in posttraumatic stress disorder (PTSD) is characterized by restricted affective responses to positive stimuli. To date, no studies have examined neural responses to a range of emotional expressions in PTSD with high dissociative symptoms.This study tested the hypothesis that PTSD patients with high dissociative symptoms will display increased event-related potential (ERP) amplitudes in early components (N1, P1) to threatening faces (angry, fearful), and reduced later ERP amplitudes (Vertex Positive Potential (VPP), P3) to happy faces compared to PTSD patients with low dissociative symptoms.Thirty-nine civilians with PTSD were classified as high dissociative (n=16) or low dissociative (n=23) according to their responses on the Clinician Administered Dissociative States Scale. ERPs were recorded, whilst participants viewed emotional (happy, angry, fear) and neutral facial expressions in a passive viewing task.High dissociative PTSD patients displayed significantly increased N120 amplitude to the majority of facial expressions (neutral, happy, and angry) compared to low dissociative PTSD patients under conscious and preconscious conditions. The high dissociative PTSD group had significantly reduced VPP amplitude to happy faces in the conscious condition.High dissociative PTSD patients displayed increased early (preconscious) cortical responses to emotional stimuli, and specific reductions to happy facial expressions in later (conscious), face-specific components compared to low dissociative PTSD patients. Dissociation in PTSD may act to increase initial pre-attentive processing of affective stimuli, and specifically reduce cortical reactivity to happy faces when consciously processing these stimuli.

    View details for DOI 10.3402/ejpt.v4i0.20430

    View details for PubMedID 24020010

  • Early life trauma predicts self-reported levels of depressive and anxiety symptoms in nonclinical community adults: Relative contributions of early life stressor types and adult trauma exposure JOURNAL OF PSYCHIATRIC RESEARCH Chu, D. A., Williams, L. M., Harris, A. W., Bryant, R. A., Gatt, J. M. 2013; 47 (1): 23-32


    Exposure to early life trauma is a known risk factor for depression and anxiety disorders in adulthood. This study aimed to evaluate the relative contributions of early life versus adult trauma in predicting levels of depressive and anxiety symptoms in nonclinical community adults. 1209 nonclinical community adults (18-70 years; 45% male) were assessed for mental health status, early life stressors, lifetime trauma exposure, and self-reported levels of depressive and anxiety symptoms. A subset of the full sample subjected to group comparisons (n = 1088) indicated that early life stressor exposure primarily accounted for significantly higher depressive and anxiety symptom scores when compared against adults reporting to be free of childhood stressor or adult trauma exposure. Subsequent hierarchical multiple regression analyses of this subset using five distinct early life stressor types, namely 'Interpersonal violation', 'Family breakup', 'Disasters/war', 'Familial health trauma/death' and 'Personal health trauma' derived from principal component analysis of a wide range of self-reported early stressor events in the full sample, showed childhood 'Interpersonal violation' differentially predicted higher self-reported depressive and anxiety symptom scores in both males and females. Adult trauma exposure did not significantly predict these symptom scores. These findings underline the relative importance of exposure to 'interpersonal violation' relative to other types of early life stressors and adult trauma in the risk of depressive and anxiety symptoms in nonclinical community adults.

    View details for DOI 10.1016/j.jpsychires.2012.08.006

    View details for Web of Science ID 000312354400004

    View details for PubMedID 23020924

  • Hippocampal volume varies with educational attainment across the life-span FRONTIERS IN HUMAN NEUROSCIENCE Noble, K. G., Grieve, S. M., Korgaonkar, M. S., Engelhardt, L. E., Griffith, E. Y., Williams, L. M., Brickman, A. M. 2012; 6


    Socioeconomic disparities-and particularly differences in educational attainment-are associated with remarkable differences in cognition and behavior across the life-span. Decreased educational attainment has been linked to increased exposure to life stressors, which in turn have been associated with structural differences in the hippocampus and the amygdala. However, the degree to which educational attainment is directly associated with anatomical differences in these structures remains unclear. Recent studies in children have found socioeconomic differences in regional brain volume in the hippocampus and amygdala across childhood and adolescence. Here we expand on this work, by investigating whether disparities in hippocampal and amygdala volume persist across the life-span. In a sample of 275 individuals from the BRAINnet Foundation database ranging in age from 17 to 87, we found that socioeconomic status (SES), as operationalized by years of educational attainment, moderates the effect of age on hippocampal volume. Specifically, hippocampal volume tended to markedly decrease with age among less educated individuals, whereas age-related reductions in hippocampal volume were less pronounced among more highly educated individuals. No such effects were found for amygdala volume. Possible mechanisms by which education may buffer age-related effects on hippocampal volume are discussed.

    View details for DOI 10.3389/fnhum.2012.00307

    View details for Web of Science ID 000311228800001

    View details for PubMedID 23162453

  • Sensitivity, specificity, and predictive power of the "Brief Risk-resilience Index for SCreening," a brief pan-diagnostic web screen for emotional health BRAIN AND BEHAVIOR Williams, L. M., Cooper, N. J., Wisniewski, S. R., Gatt, J. M., Koslow, S. H., Kulkarni, J., Devarney, S., Gordon, E., Rush, A. J. 2012; 2 (5): 576-589


    Few standardized tools are available for time-efficient screening of emotional health status across diagnostic categories, especially in primary care. We evaluated the 45-question Brief Risk-resilience Index for SCreening (BRISC) and the 15-question mini-BRISC in identifying poor emotional health and coping capacity across a range of diagnostic groups - compared with a detailed clinical assessment - in a large sample of adult outpatients. Participants 18-60 years of age (n = 1079) recruited from 12 medical research and clinical sites completed the computerized assessments. Three index scores were derived from the full BRISC and the mini-BRISC: one for risk (negativity-positivity bias) and two for coping (resilience and social capacity). Summed answers were converted to standardized z-scores. BRISC scores were compared with detailed health assessment and diagnostic interview (for current psychiatric, psychological, and neurological conditions) by clinicians at each site according to diagnostic criteria. Clinicians were blinded to BRISC scores. Clinical assessment stratified participants as having "clinical" (n = 435) or "healthy" (n = 644) diagnostic status. Receiver operating characteristic analyses showed that a z-score threshold of -1.57 on the full BRISC index of emotional health provided an optimal classification of "clinical" versus "healthy" status (sensitivity: 81.2%, specificity: 92.7%, positive predictive power: 80.2%, and negative predictive power: 93.1%). Comparable findings were revealed for the mini-BRISC. Negativity-positivity bias index scores contributed the most to prediction. The negativity-positivity index of emotional health was most sensitive to classifying major depressive disorder (100%), posttraumatic stress disorder (95.8%), and panic disorder (88.7%). The BRISC and mini-BRISC both offer a brief, clinically useful screen to identify individuals at risk of disorders characterized by poor emotion regulation, from those with good emotional health and coping.

    View details for DOI 10.1002/brb3.76

    View details for Web of Science ID 000209174200006

    View details for PubMedCentralID PMC3489810

  • Testing the white matter retrogenesis hypothesis of cognitive aging NEUROBIOLOGY OF AGING Brickman, A. M., Meier, I. B., Korgaonkar, M. S., Provenzano, F. A., Grieve, S. M., Siedlecki, K. L., Wasserman, B. T., Williams, L. M., Zimmerman, M. E. 2012; 33 (8): 1699-1715


    The retrogenesis hypothesis postulates that late-myelinated white matter fibers are most vulnerable to age- and disease-related degeneration, which in turn mediate cognitive decline. While recent evidence supports this hypothesis in the context of Alzheimer's disease, it has not been tested systematically in normal cognitive aging. In the current study, we examined the retrogenesis hypothesis in a group (n = 282) of cognitively normal individuals, ranging in age from 7 to 87 years, from the Brain Resource International Database. Participants were evaluated with a comprehensive neuropsychological battery and were imaged with diffusion tensor imaging. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (DA), measures of white matter coherence, were computed in 2 prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and 2 prototypical late-myelinated fiber tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus) chosen to parallel previous studies; mean summary values were also computed for other early- and late-myelinated fiber tracts. We examined age-associated differences in FA, RD, and DA in the developmental trajectory (ages 7-30 years) and degenerative trajectory (ages 31-87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group. FA and DA values were greater for early-myelinated fibers than for late-myelinated fibers, and RD values were lower for early-myelinated than late-myelinated fibers. There were age-associated differences in FA, RD, and DA across early- and late-myelinated fiber tracts in the younger group, but the magnitude of differences did not vary as a function of early or late myelinating status. FA and RD in most fiber tracts showed reliable age-associated differences in the older age group, but the magnitudes were greatest for the late-myelinated tract summary measure, inferior longitudinal fasciculus (late fiber tract), and cerebral peduncles (early fiber tract). Finally, FA in the inferior longitudinal fasciculus and cerebral peduncles and RD in the cerebral peduncles mediated age-associated differences in an executive functioning factor. Taken together, the findings highlight the importance of white matter coherence in cognitive aging and provide some, but not complete, support for the white matter retrogenesis hypothesis in normal cognitive aging.

    View details for DOI 10.1016/j.neurobiolaging.2011.06.001

    View details for Web of Science ID 000306070800020

    View details for PubMedID 21783280

  • Finding a biosignature for melancholic depression EXPERT REVIEW OF NEUROTHERAPEUTICS Day, C. V., Williams, L. M. 2012; 12 (7): 835-847


    Melancholia is typified by features of psychomotor slowing, anxiety, appetite loss and sleep changes. It is usually observed in 20-30% of individuals meeting diagnostic criteria for major depressive disorder (MDD). There is currently no agreement on whether melancholic MDD represents a distinct entity defined by neurobiological as well as clinical features or, rather, a specifier for MDD. This situation is reflected in the revisions to DSM, including in the DSM-5 due for release in 2013. With this context in mind, the authors review the origins of the construct of melancholia in MDD, its theoretical grounding and the defining characteristics that arose from this research. The authors then outline the state of knowledge on the neurobiology of melancholia. This second aspect is illustrative of the National Institutes of Mental Health's research domain criteria initiative, which offers a framework for redefining constructs along neurobiological dimensions. The authors also consider the outlook for identifying a useful biosignature of melancholia.

    View details for DOI 10.1586/ERN.12.72

    View details for Web of Science ID 000308784200014

    View details for PubMedID 22853791

  • Mapping inter-regional connectivity of the entire cortex to characterize major depressive disorder: a whole-brain diffusion tensor imaging tractography study NEUROREPORT Korgaonkar, M. S., Cooper, N. J., Williams, L. M., Grieve, S. M. 2012; 23 (9): 566-571


    Diffusion tensor imaging (DTI) can be used to study the organization of brain white matter noninvasively. The aim of this study was to present a proof of concept for integrating DTI with high-resolution anatomical (T1) images to map and assess inter-regional connectivity across the entire cortex in a cohort of healthy participants and compared with patients with major depressive disorder. We used MRI data of 23 patients and 23 matched controls, assessed as part of baseline testing in the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Freesurfer was used to analyze the T1 images to automatically label 35 gyral-based areas for each hemisphere. DTI tractography was performed to parcellate intercortical tracts using each of these areas in seed-target combinations. We quantified fractional anisotropy, number-of-fiber connections, and fiber path length for each DTI connection, with the goal of identifying the best measure or combination of measures to characterize major depression. The best classification accuracy for the individual measures was achieved using the number-of-fibers data, whereas the combination model provided a slight improvement. The most discriminant features between the two groups were for white matter associated with the limbic, frontal, and thalamic projection fibers and as part of cortical connections between the left inferior temporal and the postcentral cortex; the left parstriangularis and the left superior frontal; the left cuneus and the corpus callosum; the left lingual and the right lateral occipital, the right superior parietal and the right superior temporal cortices; and the right inferior parietal and the right insula and postcentral cortices.

    View details for DOI 10.1097/WNR.0b013e3283546264

    View details for Web of Science ID 000304317200010

    View details for PubMedID 22562047

  • The TWIN-E Project in Emotional Wellbeing: Study Protocol and Preliminary Heritability Results Across Four MRI and DTI Measures TWIN RESEARCH AND HUMAN GENETICS Gatt, J. M., Korgaonkar, M. S., Schofield, P. R., Harris, A., Clark, C. R., Oakley, K. L., Ram, K., Michaelson, H., Yap, S., Stanners, M., Wise, V., Williams, L. M. 2012; 15 (3): 419-441


    Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18-65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene-environment and endophenotype contributions to treatment response. Preliminary heritability results are provided for the first 50% of the MRI subgroup (n = 142) for the grey matter volume, thickness, and surface area measures, and white matter diffuse tensor imaging fractional anisotropy.

    View details for DOI 10.1017/thg.2012.12

    View details for Web of Science ID 000306253200015

    View details for PubMedID 22856376

  • Magnetic Resonance Imaging of Major Depressive Disorder (MDD): First Planned Outcomes from the ISPOT-D Study 67th Annual Meeting of the Society-of-Biological-Psychiatry Korgaonkar, M. S., Grieve, S. M., Etkin, A., Foster, S., Gomes, L., Song, Y., Armstrong, L., Boyce, P., Usherwood, T., Harris, A. W., Koslow, S. H., Williams, L. M. ELSEVIER SCIENCE INC. 2012: 210S–210S
  • Neural Correlates of Emotion Processing in Psychosis Provide Evidence for Very Early Disruptions to Emotional Brain Circuitry 67th Annual Meeting of the Society-of-Biological-Psychiatry Brennan, A. M., Harris, A. W., Williams, L. M. ELSEVIER SCIENCE INC. 2012: 98S–98S
  • Prefrontal Dysfunction in Depression using Standardized fMRI Protocols: First Wave of Results from the iSPOT-D Study 67th Annual Meeting of the Society-of-Biological-Psychiatry Song, Y. J., Armstrong, L. V., Korgaonkar, M., Grieve, S., Etkin, A., Boyce, P., Harris, A. W., Williams, L. M. ELSEVIER SCIENCE INC. 2012: 196S–196S
  • Cognition and Emotion in Child and Adolescent ADHD 67th Annual Meeting of the Society-of-Biological-Psychiatry Tsang, T. W., Kohn, M. R., Clarke, S. D., Williams, L. M. ELSEVIER SCIENCE INC. 2012: 74S–74S
  • Identifying Risk and Resilience Gene-Brain Markers of Emotional Wellbeing: The TWIN-E Project 67th Annual Meeting of the Society-of-Biological-Psychiatry Gatt, J. M., Korgaonkar, M., Schofield, P. R., Harris, A., Clark, R., Williams, L. M. ELSEVIER SCIENCE INC. 2012: 14S–14S
  • Loss of White Matter Integrity in Major Depressive Disorder: Evidence Using Tract-Based Spatial Statistical Analysis of Diffusion Tensor Imaging HUMAN BRAIN MAPPING Korgaonkar, M. S., Grieve, S. M., Koslow, S. H., Gabrieli, J. D., Gordon, E., Williams, L. M. 2011; 32 (12): 2161-2171


    White matter (WM) has been shown to be affected in elderly patients with major depressive disorders (MDD). There is only limited evidence of WM structural abnormalities in nongeriatric MDD patients. This study investigates WM microstructural integrity in nongeriatric MDD patients recruited as part of the International Study to Predict Optimized Treatment in Depression clinical trial and establishes the validity of diffusion tensor imaging measures for the investigation of depression. Baseline diffusion tensor imaging data from 29 nongeriatric MDD participants (11 with melancholia) and 39 healthy control participants were used in this analysis. We performed tract-based spatial statistics analyses to evaluate WM microstructural integrity (1) between all healthy controls and all MDD participants, (2) between melancholic and nonmelancholic MDD participants, and (3) between each subgroup (melancholic and nonmelancholic) and controls. Significant WM integrity deficits were seen only for the melancholic MDD participants compared with controls. Compared with controls, melancholic participants showed an average reduction of 7.8% in fractional anisotropy over WM regions associated with the limbic system, dorsolateral prefrontal cortex, thalamic projection fibers, corpus callosum, and other association fibers. These fractional anisotropy deficits were also associated with decreased axial and increased radial diffusivity in these WM regions, suggesting a pattern of decreased myelination or other degeneration change. Our findings of WM structural abnormalities associated with the limbic system, the frontal cortex, and the thalamus support the prevailing theory of limbic-dorsolateral prefrontal cortex-thalamic dysfunction in depression. Our results also suggest that these deficits are most prominent in the melancholic subtype of MDD.

    View details for DOI 10.1002/hbm.21178

    View details for Web of Science ID 000297918500012

    View details for PubMedID 21170955

  • Patterns of Emotional-Cognitive Functioning in Pediatric Conversion Patients: Implications for the Conceptualization of Conversion Disorders PSYCHOSOMATIC MEDICINE Kozlowska, K., Scher, S., Williams, L. M. 2011; 73 (9): 775-788


    To examine patterns of emotion processing in children and adolescents with conversion disorders and to determine whether those patterns are associated with particular clusters of conversion symptoms. Autobiographical narratives were used to investigate the organization of information about distressing feelings and memories.Structured interviews about attachment relationships and autobiographical events were administered to 76 controls and 76 matched subjects aged 6 to 18 years. Age-appropriate assessments of attachment were used: the School-aged Assessment of Attachment for children and the Transition to Adulthood Attachment Interview for adolescents. Patterns of emotion processing were identified using dynamic-maturational model discourse analysis and categorized into four clusters: inhibitory, normative/balanced, coercive-preoccupied, and mixed inhibitory and coercive-preoccupied. These clusters were then cross-tabulated with the sensorimotor characteristics of children with conversion disorders.Emotion processing in children with conversion disorders was categorized as psychological inhibition (57%), psychological coercion-preoccupation (34%), and mixed (9%). Psychological inhibition was associated with negative conversion symptoms (discrete sensorimotor deficits, p = .003) and positive conversion symptoms (tremors and tics, p = .04). Psychological coercion-preoccupation was associated with all other disturbances of motor function: bizarre gaits and postures, whole-body floppiness, and refusals to move (p < .0001). Nonepileptic seizures occurred across both groups (56% versus 42%, p = .8).Contrary to the classic understanding of conversion disorder as a unified diagnostic entity with diverse symptoms, this study identified two distinct subtypes of conversion patients-those using psychological inhibition and those using psychological coercion-preoccupation-whose symptoms fell into discrete clusters. Further research is needed to determine the neural mechanisms underlying these processes.

    View details for DOI 10.1097/PSY.0b013e3182361e12

    View details for Web of Science ID 000297205700008

    View details for PubMedID 22048837



    Negativity biases and their impact on reactivity to negative emotion are implicated in the mechanisms of risk for depression. The aim of this study was to determine whether self-reported negativity bias is related to objective cognitive measures of emotional reactivity.A previously established Web self-report measure of negativity bias was used to assess 1,080 volunteers from the Brain Resource International Database (overseen by the nonprofit BRAINnet Foundation). We identified matched subgroups of "High Risk" (n = 216) and "Low Risk" (n = 216) participants using a psychometric high-risk method, which classified High Risk as the sample's top 30% of negativity bias scores and Low Risk as the bottom 30%. These subsamples also completed the WebNeuro cognitive tasks for assessing both conscious and nonconscious reactions to facial emotions. Task performance was quantified by accuracy, reaction time, and misidentification errors.The High Risk (high negativity bias) subgroup was distinguished by greater reactivity to negative emotion in both conscious and nonconscious processing. The High Risk profile was reflected in higher accuracy for sadness (nonconsciously) and disgust (consciously), and more frequent misidentification of neutral as anger (consciously).These results are consistent with seminal theories that a systematic cognitive negativity bias produces a hyper-reactivity to negative emotion, which can impact nonconscious as well as conscious processing. The results provide a step toward objective markers of risk for depression that would help the community act regarding preventative programs. Replication in patient samples is warranted.

    View details for DOI 10.1002/da.20854

    View details for Web of Science ID 000293808000011

    View details for PubMedID 21796742

  • Identifying Gene, Brain, Cognition and Emotion Markers for Response to Antidepressants: The iSPOT-D Trial 66th Annual Meeting of the Society-of-Biological-Psychiatry Williams, L. M., Rush, A. J., Koslow, S., Wisniewski, S., Cooper, N., Nemeroff, C., Schatzberg, A., Gordon, E. ELSEVIER SCIENCE INC. 2011: 135S–135S
  • Regional heterogeneity in limbic maturational changes: Evidence from integrating cortical thickness, volumetric and diffusion tensor imaging measures NEUROIMAGE Grieve, S. M., Korgaonkar, M. S., Clark, C. R., Williams, L. M. 2011; 55 (3): 868-879


    Magnetic resonance imaging (MRI) studies of structural brain development have suggested that the limbic system is relatively preserved in comparison to other brain regions with healthy aging. The goal of this study was to systematically investigate age-related changes of the limbic system using measures of cortical thickness, volumetric and diffusion characteristics. We also investigated if the "relative preservation" concept is consistent across the individual sub-regions of the limbic system. T1 weighted structural MRI and Diffusion Tensor Imaging data from 476 healthy participants from the Brain Resource International Database was used for this study. Age-related changes in grey matter (GM)/white matter (WM) volume, cortical thickness, diffusional characteristics for the pericortical WM and for the fiber tracts associated with the limbic regions were quantified. A regional variability in the aging patterns across the limbic system was present. Four important patterns of age-related changes were highlighted for the limbic sub-regions: 1. early maturation of GM with late loss in the hippocampus and amygdala; 2. an extreme pattern of GM preservation in the entorhinal cortex; 3. a flat pattern of reduced GM loss in the anterior cingulate and the parahippocampus and; 4. accelerated GM loss in the isthmus and posterior cingulate. The GM volumetric data and cortical thickness measures proved to be internally consistent, while the diffusional measures provided complementary data that seem consistent with the GM trends identified. This heterogeneity can be hypothesized to be associated with age-related changes of cognitive function specialized for that region and direct connections to the other brain regions sub-serving these functions.

    View details for DOI 10.1016/j.neuroimage.2010.12.087

    View details for Web of Science ID 000288313800003

    View details for PubMedID 21224000

  • A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): Rationale and design TRIALS Tsang, T. W., Kohn, M. R., Hermens, D. F., Clarke, S. D., Clark, C. R., Efron, D., Cranswick, N., Lamb, C., Williams, L. M. 2011; 12


    The ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study.Children and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo.The methodology for the ACTION study has been detailed.The ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment.Australian and New Zealand Clinical Trials Registry ANZCTRN12607000535471.

    View details for DOI 10.1186/1745-6215-12-77

    View details for Web of Science ID 000288969100001

    View details for PubMedID 21396130

    View details for PubMedCentralID PMC3068100

  • GAMMA SYNCHRONY IN FIRST EPISODE SCHIZOPHRENIA: ASSOCIATION WITH SYMPTOMATOLOGY AND NEUROCOGNITIVE DEFICITS 13th International Congress on Schizophrenia Research (ICSR) Harris, A. W., Starling, J., Galletley, C., HUBY, A., Williams, L. M. OXFORD UNIV PRESS. 2011: 35–35
  • Using Brain-Based Cognitive Measures to Support Clinical Decisions in ADHD Response PEDIATRIC NEUROLOGY Williams, L. M., Kohn, M. R., Clarke, S. D. 2011; 44 (2): 157-157
  • International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol TRIALS Williams, L. M., Rush, A. J., Koslow, S. H., Wisniewski, S. R., Cooper, N. J., Nemeroff, C. B., Schatzberg, A. F., Gordon, E. 2011; 12


    Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide.International Study to Predict Optimised Treatment - in Depression (iSPOT-D) Identifier: NCT00693849. URL:

    View details for DOI 10.1186/1745-6215-12-4

    View details for Web of Science ID 000287157700001

    View details for PubMedID 21208417

    View details for PubMedCentralID PMC3036635

  • EEG in Adolescent Anorexia Nervosa: Impact of Refeeding and Weight Gain INTERNATIONAL JOURNAL OF EATING DISORDERS Hatch, A., Madden, S., Kohn, M. R., Clarke, S., Touyz, S., Gordon, E., Williams, L. M. 2011; 44 (1): 65-75


    To examine resting awake EEG in adolescent AN participants before and after refeeding to determine if EEG abnormalities in Anorexia Nervosa (AN) are reversible.In 37 adolescent first admission AN patients and 45 healthy controls, EEG was recorded during short duration "eyes open" and "eyes closed" awake resting conditions. Repeat testing occurred in 28 AN participants after refeeding and subsequent weight gain.In "eyes open," underweight AN participants exhibit reduced relative alpha power and increased beta power in frontal brain regions. A significant increase in alpha, and decrease in beta and delta power was observed within participants after refeeding. In "eyes closed", underweight AN participants had elevated theta in parietal-occipital regions which remained after refeeding.EEG abnormalities (reduced alpha/increased beta power) in AN normalizes with refeeding, while increased theta power persists in parietal-occipital regions in an eyes closed context.

    View details for DOI 10.1002/eat.20777

    View details for Web of Science ID 000285308400009

    View details for PubMedID 20063377

  • COMT Val(108/158)Met polymorphism effects on emotional brain function and negativity bias NEUROIMAGE Williams, L. M., Gatt, J. M., Grieve, S. M., Dobson-Stone, C., Paul, R. H., Gordon, E., Schofield, P. R. 2010; 53 (3): 918-925


    Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders.

    View details for DOI 10.1016/j.neuroimage.2010.01.084

    View details for Web of Science ID 000282039300014

    View details for PubMedID 20139013

  • Early Life Stress Combined with Serotonin 3A Receptor and Brain-Derived Neurotrophic Factor Valine 66 to Methionine Genotypes Impacts Emotional Brain and Arousal Correlates of Risk for Depression BIOLOGICAL PSYCHIATRY Gatt, J. M., Nemeroff, C. B., Schofield, P. R., Paul, R. H., Clark, C. R., Gordon, E., Williams, L. M. 2010; 68 (9): 818-824


    Depression will be the second largest burden of disease by 2020. Developing new tools for identifying risk and ultimately prevention of depression relies on elucidating the integrative relationships between susceptibility markers from gene-stress interactions and how they impact emotional brain and arousal systems. They have largely been studied in isolation.We examined how genetic (brain-derived neurotrophic factor [BDNF] valine 66 to methionine [Val66Met] and serotonin receptor gene 3A [HTR3A]) and early life stress susceptibility factors interact in predicting electroencephalogram (EEG) asymmetry, emotion-elicited heart rate, and self-reported negativity bias, each correlates of risk for depression. Caucasian volunteers (n = 363) were derived from the Brain Resource International Database, via the Brain Research And Integrative Neuroscience Network.Individuals with both BDNF methionine and HTR3A CC risk genotypes and early life stressors demonstrated a profile of elevated emotion-elicited heart rate and right frontal hyper-activation with right parietotemporal hypoactivation in EEG asymmetry. Elevations in heart rate were a moderator of negativity bias.The findings provide new evidence that these gene-stress susceptibility factors contribute to a brain-arousal profile indicative of risk for depression. They are a step toward identifying biological markers for detecting risk before overt symptoms. It would be valuable for future studies to examine comorbidity and specificity issues; for instance, whether these gene-stress factors contribute in different ways to the partially distinct EEG asymmetry profiles found with anxiety.

    View details for DOI 10.1016/j.biopsych.2010.06.025

    View details for Web of Science ID 000283608600007

    View details for PubMedID 20728877

  • An 'integrative neuroscience' perspective on ADHD: linking cognition, emotion, brain and genetic measures with implications for clinical support EXPERT REVIEW OF NEUROTHERAPEUTICS Williams, L. M., Tsang, T. W., Clarke, S., Kohn, M. 2010; 10 (10): 1607-1621


    There remains a translational gap between research findings and their implementation in clinical practice that applies to attention-deficit/hyperactivity disorder (ADHD), as well as to other major disorders of brain health in childhood, adolescence and adulthood. Research studies have identified potential 'markers' to support diagnostic, functional assessment and treatment decisions, but there is little consensus about these markers. Of these potential markers, cognitive measures of thinking functions, such as sustaining attention and associated electrical brain activity, show promise in complementing the clinical management process. Emerging evidence highlights the relevance of emotional, as well as thinking, functions to ADHD. Here, we outline an integrative neuroscience framework for ADHD that offers one means to bring together cognitive measures of thinking functions with measures of emotion, and their brain and genetic correlates. Understanding these measures and the relationships between them is a first step towards the development of tools that will help to assess the heterogeneity of ADHD, and aid in tailoring treatment choices.

    View details for DOI 10.1586/ERN.10.140

    View details for Web of Science ID 000283454500018

    View details for PubMedID 20925475

  • IMPACT OF THE HTR3A GENE WITH EARLY LIFE TRAUMA ON EMOTIONAL BRAIN NETWORKS AND DEPRESSED MOOD DEPRESSION AND ANXIETY Gatt, J. M., Williams, L. M., Schofield, P. R., Dobson-Stone, C., Paul, R. H., Grieve, S. M., Clark, C. R., Gordon, E., Nemeroff, C. B. 2010; 27 (8): 752-759


    The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing.Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed.The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident.These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.

    View details for DOI 10.1002/da.20726

    View details for Web of Science ID 000280696000008

    View details for PubMedID 20694966

  • Emotion brain alterations in anorexia nervosa: a candidate biological marker and implications for treatment JOURNAL OF PSYCHIATRY & NEUROSCIENCE Hatch, A., Madden, S., Kohn, M. R., Clarke, S., Touyz, S., Gordon, E., Williams, L. M. 2010; 35 (4): 267-274


    Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain.In a retest design, 28 adolescent females with AN were tested at first ad not mission to hospital and again after they had gained weight. Matched healthy control participants were tested at the same times. We assessed emotion-elicited event-related potentials (ERPs) during overt and covert presentation of emotion expressions, scores on an emotion-identification behavioural task, and symptom measures. We performed between and within group analyses.Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP componotnents were significantly reduced in AN patients at baseline (when underweight) and on retest (after weight gain), especially in the temporo-occipital regions, suggesting a persistent disruption of the early automatic appraisal of salient emotional signals.This study could have been improved with a longer standardized retest interval.There is likely a core, generic disturbance in AN in the early "automatic" neural processing of emotion irrespective of weight or nutritional status. New innovative emotion-based psychologic or pharmacologic treatments targeting these nonconscious processes may prove beneficial.

    View details for DOI 10.1503/jpn.090073

    View details for Web of Science ID 000279240900008

    View details for PubMedID 20598239

    View details for PubMedCentralID PMC2895157

  • Impact of depression heterogeneity on attention: An auditory oddball event related potential study JOURNAL OF AFFECTIVE DISORDERS Kemp, A. H., Benito, L. P., Quintana, D. S., Clark, C. R., McFarlane, A., Mayur, P., Harris, A., Boyce, P., Williams, L. M. 2010; 123 (1-3): 202-207


    Major depressive disorder is associated with a reduced ability to attend and concentrate, however, the extent to which attentional impairment is dependent on subtype remains to be clarified.Event-related potentials (ERPs) associated with a well-validated auditory oddball, selective attention task, were recorded to determine the impact of melancholia (n=57) versus non-melancholia (n=48) relative to controls (n=116).The key findings were an exaggeration of the P200 to both non-target and target stimuli and a reduction in the P300 to targets in patients with melancholia, relative to patients with non-melancholia and controls. In addition, the N200/P300 complex was slowed in latency corresponding to the slowed behavioural responses to targets in melancholia. Stepwise regression analysis also revealed that depression severity, but not psychomotor slowing, contributed to increases in P200 amplitude.This study is cross-sectional and cannot determine whether the observed ERP changes are a state or trait marker, highlighting the need for a longitudinal study of ERP characteristics in different subgroups of depressed patients.Results point to a difficulty in differentiating significant stimuli in the environment in the depressed individual. The combined disruption of early sensory processing (P200) and subsequent context processing (N200/P300 complex) may provide a potential mechanism for the attentional impairment that is frequently observed in depression, particularly in more severe depression.

    View details for DOI 10.1016/j.jad.2009.08.010

    View details for Web of Science ID 000277894900027

    View details for PubMedID 19740547

  • Anorexia Nervosa: Towards An Integrative Neuroscience Model EUROPEAN EATING DISORDERS REVIEW Hatch, A., Madden, S., Kohn, M., Clarke, S., Touyz, S., Williams, L. M. 2010; 18 (3): 165-179


    We reviewed the evidence for emotion-related disturbances in anorexia nervosa (AN) from behavioural, cognitive, biological and genetic domains of study. These domains were brought together within the framework of an integrative neuroscience model that emphasizes the role of emotion and feeling and their regulation, in brain organization. PsychInfo and Medline searches were performed to identify published peer-reviewed papers on AN within each domain. This review revealed evidence for 'Emotion', 'Thinking and Feeling' and 'Self-regulation' disturbances in AN that span non-conscious to conscious processes. An integrative neuroscience framework was then applied to develop a model of AN, from which hypotheses for empirical investigation are generated. We propose that AN reflects a core disturbance in emotion at the earliest time stage of information processing with subsequent effects on the later stages of thinking, feeling and self-regulation.

    View details for DOI 10.1002/erv.974

    View details for Web of Science ID 000277333200002

    View details for PubMedID 20443202

  • In First Presentation Adolescent Anorexia Nervosa, Do Cognitive Markers of Underweight Status Change with Weight Gain Following a Refeeding Intervention? INTERNATIONAL JOURNAL OF EATING DISORDERS Hatch, A., Madden, S., Kohn, M. R., Clarke, S., Touyz, S., Gordon, E., Williams, L. M. 2010; 43 (4): 295-306


    To determine the nature and severity of cognitive functioning impairment in adolescent anorexia nervosa (AN) when underweight and following weight gain.In 37 first admission adolescent (12-18 years) AN patients and 45 matched controls, general cognitive functions were assessed at baseline and follow-up using the IntegNeuro-computerized battery. AN participants were tested between days 3 and 10 of their admission when underweight, with retesting conducted after weight restoration.When underweight, AN participants performed more poorly than controls on sensori-motor speed tasks and exhibited a susceptibility to interference, but had superior working memory. Once the weight is restored, individuals significantly improved relative to their own performance. Relative to controls, they were significantly faster on attention and executive function tasks, exhibited superior verbal fluency, working memory, and a significantly superior ability to inhibit well-learnt responses.Cognitive impairments in adolescent AN appear to normalize with refeeding and weight gain.

    View details for DOI 10.1002/eat.20695

    View details for Web of Science ID 000276741800002

    View details for PubMedID 19434607

  • Personalized medicine for the brain: a call for action MOLECULAR PSYCHIATRY Koslow, S. H., Williams, L. M., Gordon, E. 2010; 15 (3): 229-230

    View details for DOI 10.1038/mp.2009.147

    View details for Web of Science ID 000274726700002

    View details for PubMedID 20065956

  • Neural Responses to Masked Fear Faces: Sex Differences and Trauma Exposure in Posttraumatic Stress Disorder JOURNAL OF ABNORMAL PSYCHOLOGY Felmingham, K., Williams, L. M., Kemp, A. H., Liddell, B., Falconer, E., Peduto, A., Bryant, R. 2010; 119 (1): 241-247


    Although women have a greater propensity than men to develop posttraumatic stress disorder (PTSD) following trauma, sex differences in neural activations to threat have received little investigation. This study tested the prediction that trauma would heighten activity in automatic fear-processing networks to a greater extent in women than in men. Functional magnetic resonance imaging (fMRI) data were recorded in 23 participants with PTSD (13 women, 10 men), 21 trauma-exposed controls (9 women, 12 men), and 42 non-trauma-exposed controls (22 women, 20 men) while they viewed masked facial expressions of fear. Exposure to trauma was associated with enhanced brainstem activity to fear in women, regardless of the presence of PTSD, but in men, it was associated only with the development of PTSD. Men with PTSD displayed greater hippocampal activity to fear than did women. Both men and women with PTSD showed enhanced amygdala activity to fear relative to controls. The authors conclude that greater brainstem activation to threat stimuli may contribute to the greater prevalence of PTSD in women, and greater hippocampal activation in men may subserve an enhanced capacity for contextualizing fear-related stimuli.

    View details for DOI 10.1037/a0017551

    View details for Web of Science ID 000274445000024

    View details for PubMedID 20141261

  • Using Brain-Based Cognitive Measures to Support Clinical Decisions in ADHD PEDIATRIC NEUROLOGY Williams, L. M., Hermens, D. F., Thein, T., Clark, C. R., Cooper, N. J., Clarke, S. D., Lamb, C., Gordon, E., Kohn, M. R. 2010; 42 (2): 118-126


    Measures of cognition support diagnostic and treatment decisions in attention deficit hyperactivity disorder. We used an integrative neuroscience framework to assess cognition and associated brain-function correlates in large attention deficit hyperactivity disorder and healthy groups. Matched groups of 175 attention deficit hyperactivity disorder children/adolescents and 175 healthy control subjects were assessed clinically, with the touch screen-based cognitive assessment battery "IntegNeuro" (Brain Resource Ltd., Sydney, Australia) and the "LabNeuro" (Brain Resource Ltd., Sydney, Australia) platform for psychophysiologic recordings of brain function and body arousal. IntegNeuro continuous performance task measures of sustained attention classified 68% of attention deficit hyperactivity disorder patients with 76% specificity, consistent with previous reports. Our additional cognitive measures of impulsivity, intrusive errors, inhibition, and response variability improved sensitivity to 88%, and specificity to 91%. Positive predictive power was 96%, and negative predictive power, 88%. These metrics were stable across attention deficit hyperactivity disorder subtypes and age. Consistent with their brain-based validity, cognitive measures were correlated with corresponding brain-function and body-arousal measures. We propose a combination of candidate cognitive "markers" that define a signature for attention deficit hyperactivity disorder: "sustained attention," "impulsivity," "inhibition," "intrusions," and "response variability." These markers offer a frame of reference to support diagnostic and treatment decisions, and an objective benchmark for monitoring outcomes of interventions.

    View details for DOI 10.1016/j.pediatrneurol.2009.08.010

    View details for Web of Science ID 000276968800007

    View details for PubMedID 20117748

  • Heterogeneity of non-conscious fear perception in posttraumatic stress disorder as a function of physiological arousal: An fMRI study PSYCHIATRY RESEARCH-NEUROIMAGING Kemp, A. H., Felmingham, K. L., Falconer, E., Liddell, B. J., Bryant, R. A., Williams, L. M. 2009; 174 (2): 158-161


    While posttraumatic stress disorder (PTSD) is often characterised by an excessive fear response and hyperarousal, research has generally neglected other clinical characteristics including hypoarousal. Findings indicate that concurrent autonomic activity is associated with increased non-conscious processing of fear, highlighting that autonomic responsivity may be an important determinant in the degree of activation within the brainstem-amygdala-MPFC (medial prefrontal cortex) network.

    View details for DOI 10.1016/j.pscychresns.2009.04.012

    View details for Web of Science ID 000272072300012

    View details for PubMedID 19836929

  • Duration of posttraumatic stress disorder predicts hippocampal grey matter loss NEUROREPORT Felmingham, K., Williams, L. M., Whitford, T. J., Falconer, E., Kemp, A. H., Peduto, A., Bryant, R. A. 2009; 20 (16): 1402-1406


    To examine the impact of environmental stress on grey matter volume in posttraumatic stress disorder (PTSD), we investigated the relationship between duration of PTSD and grey matter volume of hippocampus and anterior cingulate cortex. Twenty-one participants with PTSD and 17 trauma-exposed controls, matched for age and sex and with no history of substance dependence, underwent a T1-weighted structural MRI scan and voxel-based morphometry was employed. After controlling for age, depression and whole-brain volume, analysis of covariance revealed significant reductions in hippocampus and rostral anterior cingulate cortex in PTSD, and there was a significant negative correlation between right hippocampal volume and PTSD duration. This pattern suggests that prolonged PTSD may have cumulative adverse effects on hippocampal volume, highlighting the potential role of genetic-environmental interactions.

    View details for DOI 10.1097/WNR.0b013e3283300fbc

    View details for Web of Science ID 000271292400002

    View details for PubMedID 19794316

  • Self-protective organization in children with conversion and somatoform disorders JOURNAL OF PSYCHOSOMATIC RESEARCH Kozlowska, K., Williams, L. M. 2009; 67 (3): 223-233


    Two centuries of clinical observations have suggested that conversion symptoms are associated with strong emotions or situations that threaten the individual's physical or psychological integrity. This study tested the hypothesis that childhood conversion reactions reflect the motor-sensory components of two distinct emotional responses (one inhibitory, one excitatory) that develop as adaptations to recurring threats within intimate relationships.Emotional responses to interpersonal threats were assessed in 28 children with conversion disorders using Dynamic-Maturational-Model (DMM) assessments of attachment. Attachment strategies (the inhibitory, Type A; the balanced, Type B; and the excitatory, Type C) provide information about (1) the child's behavioural (motor-sensory) organization in the face of interpersonal threats, and (2) the information processing that underpins this behavioural organization.Twelve children (43%) used an inhibitory attachment strategy. Twelve (43%) used an excitatory attachment strategy. A smaller group (14%) alternated between inhibitory and excitatory strategies, their conversion symptoms reflecting the latter.These data suggest that conversion reactions are not a single clinical entity and reflect the motor-sensory components of two distinct human emotional responses to threat. This distinction may help to account for the broad range of conversion symptoms seen in clinical practice, both those that involve loss of function and can be explained by a central inhibition hypothesis and those that involve positive symptoms and secondary gain.

    View details for DOI 10.1016/j.jpsychores.2009.03.016

    View details for Web of Science ID 000269423800006

    View details for PubMedID 19686878

  • 'Negativity bias' in risk for depression and anxiety: Brain-body fear circuitry correlates, 5-HTT-LPR and early life stress NEUROIMAGE Williams, L. M., Gatt, J. M., Schofield, P. R., Olivieri, G., Peduto, A., Gordon, E. 2009; 47 (3): 804-814


    The INTEGRATE Model draws on the framework of 'integrative neuroscience' to bring together brain-body and behavioral concepts of emotion, thinking and feeling and their regulation. The key organizing principle is the drive to 'minimize danger and maximize reward' that determines what is significant to us at each point in time. Traits of 'negativity bias' reflect the tendency to perceive danger rather than reward related information, and this bias influences emotion, thinking and feeling processes. Here, we examined a self-report measure of Negativity Bias in relation to its impact on brain and body correlates of emotion processing. The contributions of the serotonin transporter (5-HTT-LPR) allelic variants and early life stress to both negativity bias and these correlates were also examined. Data were accessed in collaboration with the Brain Resource International Database (BRID) which provides standardized data across these domains of measurement. From an initial sample of 303 nonclinical subjects from the BRID, subjects scoring one standard deviation below (n=55) and above (n=47) the mean on the measure of negativity bias were identified as 'Negativity Bias' and 'Positivity Bias' groups for analysis, respectively. These subjects had been genotyped for 5-HTT-LPR Short allele versus LL homozygote status, and completed the early life stress scale, and recording of startle responses and heart rate for conscious and nonconscious fear conditions. A matched subset (n=39) of BRID subjects completed functional MRI with the same facial emotion tasks. The Negativity Bias (compared to Positivity Bias) group was distinguished by both arousal and brain function correlates: higher startle amplitude, higher heart rate for conscious and nonconscious fear conditions, and heightened activation in neural circuitry for both fear conditions. Regions of heightened activation included brainstem and bilateral amygdala, anterior cingulate and ventral and dorsal medial prefrontal cortex (mPFC) for conscious fear, and brainstem and right-sided amygdala, anterior cingulate and ventral, mPFC for nonconscious fear. The 5-HTT-LPR Short allele (versus LL) conferred a similar pattern of arousal and neural activation. For those with the 5-HTT-LPR Short allele, the addition of early life stress contributed to enhanced negativity bias, and to further effects on heart rate and neural activation for nonconscious fear in particular. These findings suggest that traits of negativity bias impact brain-body arousal correlates of fear circuitry. Both genetic variation and life stressors contribute to the impact of negativity bias. Given that negativity bias is a feature of conditions such as depression and associated biological alterations, the findings have implications for translation into clinical decision support.

    View details for DOI 10.1016/j.neuroimage.2009.05.009

    View details for Web of Science ID 000268926200005

    View details for PubMedID 19446647

  • Anterior cingulate activity to salient stimuli is modulated by autonomic arousal in Posttraumatic Stress Disorder PSYCHIATRY RESEARCH-NEUROIMAGING Felmingham, K. L., Williams, L. M., Kemp, A. H., Rennie, C., Gordon, E., Bryant, R. A. 2009; 173 (1): 59-62


    Reduced ventral anterior cingulate (vACC) activity to threat is thought to reflect an impairment in regulating arousal networks in posttraumatic stress disorder (PTSD). Concurrent functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) recording were used to examine neural functioning when arousal networks are engaged. Eleven participants with PTSD and 11 age- and sex-matched non-traumatized controls performed an oddball task that required responding to salient, non-trauma-related auditory target tones embedded in lower frequency background tones. Averaged target-background analyses revealed significantly greater dorsal ACC, supramarginal gyrus, and hippocampal activity in PTSD relative to control participants.With-SCR target responses resulted in increased vACC activity in controls, and dorsal ACC activity in PTSD. PTSD participants had reduced vACC activity relative to controls to target tones when SCR responses were present. This reduction in vACC in PTSD relative to controls was not apparent in without-SCR responses. These findings suggest that a reduction in vACC in PTSD occurs specifically when arousal networks are engaged.

    View details for DOI 10.1016/j.pscychresns.2008.12.005

    View details for Web of Science ID 000267469400009

    View details for PubMedID 19446442

  • Emotion-elicited gamma synchrony in patients with first-episode schizophrenia: a neural correlate of social cognition outcomes JOURNAL OF PSYCHIATRY & NEUROSCIENCE Williams, L. M., Whitford, T. J., Nagy, M., Flynn, G., Harris, A. W., Silverstein, S. M., Gordon, E. 2009; 34 (4)


    Schizophrenia may be understood as a disorder of neural synchrony. There is also increasing evidence that emotional and social cognitive impairments are central to this disorder. In patients with first-episode schizophrenia, we examined whether emotion perception is associated with disruptions to high-frequency (40 Hz) gamma synchrony and whether these disruptions predict self-regulatory adaptive compensations reflected in social cognitive behaviours.We obtained electroencephalography recordings from 28 patients with first-episode schizophrenia and matched healthy controls during perception of facial emotion under both conscious and nonconscious conditions. We extracted gamma-band synchrony from the electroencephalogram. We also used behavioural measures of emotion identification, emotional intelligence, negativity bias and social function, along with ratings of first-episode schizophrenia symptoms. We analyzed group differences and predicted social cognition to assess the potential contribution of medication.Within 200 ms poststimulus, patients with first-episode schizophrenia showed alterations in gamma synchrony during both conscious and nonconscious emotion perception. Stimulus-locked synchrony was reduced in patients, particularly over the temporal cortex, whereas complementary enhancements in absolute gamma synchrony (independent of stimuli) were more distributed over temporal and left parieto-occipital regions. This pattern of altered synchrony predicted poor performance on each measure of social cognition among these patients. Medication dosage did not correlate significantly with either gamma synchrony or behavioural measures in this group.Limitations to our study include the lack of comparison between medicated and unmedicated patients or between types of medication.These findings suggest that disruptions in integrative processing of motivationally important stimuli show promise as a potential biological marker of social cognitive impairments, present from the first episode of schizophrenia, and their outcomes.

    View details for Web of Science ID 000267324500007

    View details for PubMedID 19568482

  • Delusions and dorso-medial frontal cortex volume in first-episode schizophrenia: A voxel-based morphometry study PSYCHIATRY RESEARCH-NEUROIMAGING Whitford, T. J., Farrow, T. F., Williams, L. M., Gomes, L., Brennan, J., Harris, A. W. 2009; 172 (3): 175-179


    Of the few studies that have directly investigated the neuroanatomical correlates of delusions in patients with recent-onset schizophrenia, a number have paradoxically reported a positive correlation between delusion severity and regional grey matter volume. In order to explore this relationship, 31 patients with first-episode schizophrenia (FES) underwent a clinical interview and a T1-weighted structural MRI scan. Patients' scores on the Delusions subscale of the Positive and Negative Syndrome Scale were correlated with the volume of every voxel in their grey matter images in SPM99. Patients' delusion scores were found to correlate with the volume of a cluster of voxels located in the dorso-medial frontal cortex, centred on the medial frontal gyrus. Post-hoc analysis revealed that this 'region-of-correlation' was volumetrically reduced in the FES patients relative to a group of 21 matched healthy controls. The results of this study support the hypothesis that while a certain level of structural brain atrophy is necessary for delusion formation in patients with FES, excessive structural atrophy may in fact preclude the formation of highly systematized delusions.

    View details for DOI 10.1016/j.pscychresns.2008.07.011

    View details for Web of Science ID 000266580800001

    View details for PubMedID 19395244

  • A Polymorphism of the MAOA Gene is Associated with Emotional Brain Markers and Personality Traits on an Antisocial Index NEUROPSYCHOPHARMACOLOGY Williams, L. M., Gatt, J. M., Kuan, S. A., Dobson-Stone, C., Palmer, D. M., Paul, R. H., Song, L., Costa, P. T., Schofield, P. R., Gordon, E. 2009; 34 (7): 1797-1809


    Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.

    View details for DOI 10.1038/npp.2009.1

    View details for Web of Science ID 000265980400016

    View details for PubMedID 19194374

  • Brain Derived Neurotrophic Factor Val66Met Polymorphism, the Five Factor Model of Personality and Hippocampal Volume: Implications for Depressive Illness HUMAN BRAIN MAPPING Joffe, R. T., Gatt, J. M., Kemp, A. H., Grieve, S., Dobson-Stone, C., Kuan, S. A., Schofield, P. R., Gordon, E., Williams, L. M. 2009; 30 (4): 1246-1256


    Altered hippocampal volume, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and neuroticism have each been implicated in the etiology of psychiatric disorders, especially depression. However, the relationship between these variables is not well understood. Here, we determined the effects of the BDNF Val66met polymorphism on the five-factor personality dimensions (assessed using the NEO-FFI), trait depression (assessed with the DASS-21) in a cross-sectional cohort of 467 healthy volunteers. A large matched subset of this cohort was also assessed for grey matter volume of the hippocampus and contiguous temporal cortical regions using magnetic resonance imaging. In Met carriers, elevations in neuroticism and trait depression and stress were associated with lower mean hippocampal volume, but there were no such associations in Val homozygotes. Trait depression, in particular, was found to moderate the effects of BDNF genotypes on hippocampal volume. Met carriers with high trait depression showed a reduction in grey matter volume of the mean hippocampus compared with Val homozygotes. These findings suggest that even in otherwise healthy subjects, trait depression may contribute to the susceptibility of Met carriers to hippocampal grey matter loss.

    View details for DOI 10.1002/hbm.20592

    View details for Web of Science ID 000264696300018

    View details for PubMedID 18548532

  • Computerized Neuropsychological Assessments: Pros and Cons CNS SPECTRUMS Kemp, A. H., Hatch, A., Williams, L. M. 2009; 14 (3): 118-119

    View details for Web of Science ID 000264967000002

    View details for PubMedID 19407707

  • Small-World Properties of Nonlinear Brain Activity in Schizophrenia HUMAN BRAIN MAPPING Rubinov, M., Knock, S. A., Stam, C. J., Micheloyannis, S., Harris, A. W., Williams, L. M., Breakspear, M. 2009; 30 (2): 403-416


    A disturbance in the interactions between distributed cortical regions may underlie the cognitive and perceptual dysfunction associated with schizophrenia. In this article, nonlinear measures of cortical interactions and graph-theoretical metrics of network topography are combined to investigate this schizophrenia "disconnection hypothesis." This is achieved by analyzing the spatiotemporal structure of resting state scalp EEG data previously acquired from 40 young subjects with a recent first episode of schizophrenia and 40 healthy matched controls. In each subject, a method of mapping the topography of nonlinear interactions between cortical regions was applied to a widely distributed array of these data. The resulting nonlinear correlation matrices were converted to weighted graphs. The path length (a measure of large-scale network integration), clustering coefficient (a measure of "cliquishness"), and hub structure of these graphs were used as metrics of the underlying brain network activity. The graphs of both groups exhibited high levels of local clustering combined with comparatively short path lengths--features consistent with a "small-world" topology--as well as the presence of strong, central hubs. The graphs in the schizophrenia group displayed lower clustering and shorter path lengths in comparison to the healthy group. Whilst still "small-world," these effects are consistent with a subtle randomization in the underlying network architecture--likely associated with a greater number of links connecting disparate clusters. This randomization may underlie the cognitive disturbances characteristic of schizophrenia.

    View details for DOI 10.1002/hbm.20517

    View details for Web of Science ID 000263232800006

    View details for PubMedID 18072237

  • Total red blood cell concentrations of omega-3 fatty acids are associated with emotion-elicited neural activity in adolescent boys with attention-deficit hyperactivity disorder PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS Gow, R. V., Matsudaira, T., Taylor, E., Rubia, K., Crawford, M., Ghebremeskel, K., Ibrahimovic, A., Vallee-Tourangeau, F., Williams, L. M., Sumich, A. 2009; 80 (2-3): 151-156


    Affective impairment is observed in children and adolescents with attention-deficit hyperactivity disorder (ADHD). Low levels of long-chain polyunsaturated fatty acids (LC-PUFA), specifically omega-3 (omega-3) fatty acids in blood measures have been linked to a range of behavioural and mood disorders including ADHD. However, nothing is known about the relationship between omega-3 and brain function in children with ADHD. In the current study, 20 adolescent boys with ADHD were assessed for total lipid fractions in red blood cells and their event-related potential (ERP) response to the presentation of facial expressions of happiness, sadness and fearfulness. The results supported the hypothesis of a positive association between eicosapentaenoic acid (EPA) and a cognitive bias in orientation to overt expressions of happiness over both sad and fearful faces as indexed by midline frontal P300 amplitude. Additional exploratory analyses revealed a positive association between levels of docosahexaenoic acid (DHA) and the right temporal N170 amplitude in response to covert expressions of fear. The arachidonic (AA)/DHA ratio was negatively associated with the right temporal N170 amplitude also to covert expressions of fear. These findings indicate that EPA and DHA may be involved in distinct aspects of affect processing in ADHD and have implications for understanding currently inconsistent findings in the literature on EFA supplementation in ADHD and depression.

    View details for DOI 10.1016/j.plefa.2008.12.007

    View details for Web of Science ID 000265128100010

    View details for PubMedID 19230637

  • Fronto-Temporal Alterations Within the First 200 ms During an Attentional Task Distinguish Major Depression, Non-Clinical Participants With Depressed Mood and Healthy Controls: A Potential Biomarker? HUMAN BRAIN MAPPING Kemp, A. H., Hopkinson, P. J., Hermens, D. F., Rowe, D. L., Sumich, A. L., Clark, C. R., Drinkenburg, W., Abdi, N., Penrose, R., McFarlane, A., Boyce, P., Gordon, E., Williams, L. M. 2009; 30 (2): 602-614


    Attentional impairment in depression is a cardinal feature of depression and has been proposed as a candidate endophenotype for major depressive disorder. Event-related potentials (ERPs) elicited by oddball signal detection tasks provide objective markers of selective stimulus processing, and are pertinent endophenotypic markers for depression. While previous studies have sought to determine objective markers for attentional impairment in depression, evidence is inconsistent and may involve heterogeneity in relatively small samples. Here, we brought together oddball ERP recording with source localization of neural correlates of selective attention in outpatients with major depressive disorder (MDD; n = 78) and participants with depressed mood (PDM; n = 127) relative to healthy controls (CTL; n = 116). The key finding was a dimensional exaggeration of the P200 (140-270 ms) to both target (signal) and non-target (noise) stimuli, most pronounced in MDD, followed by PDM, relative to CTL. This exaggeration was coupled with slower and more variable response times, suggesting that neural systems are attempting to compensate for a difficulty in discriminating signal from noise. P200 alterations were localised to limbic (hippocampal), temporal and ventral prefrontal regions, key components of the signal detection network. A subsequent reduction and delay in the P300 was also revealed for MDD indicating that the pronounced lack of discrimination in clinical depression may also lead to impaired stimulus evaluation. This P200 increase in depression could provide a potential mechanism for the attentional impairment frequently observed in depression and consequent alterations in the P300 may differentiate clinically significant depression.

    View details for DOI 10.1002/hbm.20528

    View details for Web of Science ID 000263232800021

    View details for PubMedID 18181154

  • Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: Evidence from cognition, the P300 and fronto-hippocampal systems BIOLOGICAL PSYCHOLOGY Schofield, P. R., Williams, L. M., Paul, R. H., Gatt, J. M., Brown, K., Luty, A., Cooper, N., Grieve, S., Dobson-Stone, C., Morris, C., Kuan, S. A., Gordon, E. 2009; 80 (2): 176-188


    In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.

    View details for DOI 10.1016/j.biopsycho.2008.09.001

    View details for Web of Science ID 000264044300004

    View details for PubMedID 18838100

  • Explicit identification and implicit recognition of facial emotions: II. Core domains and relationships with general cognition JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Mathersul, D., Palmer, D. M., Gur, R. C., Gur, R. E., Cooper, N., Gordon, E., Williams, L. M. 2009; 31 (3): 278-291


    Both general and social cognition are important in providing endophenotypic markers and predicting real-world functional outcomes of clinical psychiatric disorders. However, to date, focus has been on general cognition, rather than on core domains of social/emotional cognition. This study sought to determine core domains of emotion processing for both explicit identification and implicit recognition and their relationships with core domains of general cognition. Age effects and sex differences were also investigated. A sample of 1,000 healthy individuals (6 to 91 years, 53.5% female) undertook the WebNeuro tests of emotion identification and recognition and tests of general cognitive function. Factor analysis revealed seven core domains of emotion processing: speed of explicit emotion identification, speed of implicit emotion recognition, implicit emotion recognition accuracy, "threat" processing, sadness-disgust identification, "positive emotion" processing, and general "face perception." Seven corresponding core domains of general cognition were identified: information-processing speed, executive function, sustained attention/vigilance, verbal memory, working-memory capacity, inhibition/impulsivity, and sensorimotor function. Factors of emotion processing generally showed positive associations with those of general cognitive function, suggesting commonality in processing speed in particular. Moreover, age had a consistent nonlinear impact on both emotion processing and general cognitive factors, while sex differences were more specific. These findings contribute to a normative and standardized structure for assessment of emotional and general cognition in clinical groups.

    View details for DOI 10.1080/13803390802043619

    View details for Web of Science ID 000264510100002

    View details for PubMedID 18720178

  • Psychological and neural correlates of emotional intelligence in a large sample of adult males and females PERSONALITY AND INDIVIDUAL DIFFERENCES Craig, A., Tran, Y., Hermens, G., Williams, L. M., Kemp, A., Morris, C., Gordon, E. 2009; 46 (2): 111-115
  • Neural synchrony in patients with a first episode of schizophrenia: tracking relations with grey matter and symptom profile JOURNAL OF PSYCHIATRY & NEUROSCIENCE Williams, L. M., Whitford, T. J., Gordon, E., Gomes, L., Brown, K. J., Harris, A. W. 2009; 34 (1): 21-29


    Although schizophrenia has been characterized by disruptions to neural synchrony, it remains unknown whether these disturbances are related to symptoms and loss of grey matter. We examined relations between 40 Hz Gamma band synchrony and grey matter in patients with schizophrenia at first episode and after 2.5 years.From an initial recruitment of 35 medicated patients with a first episode of schizophrenia, 25 patients completed clinical and oddball task-elicited Gamma synchrony within 3 months of health service contact and again after 2.5 years, 23 completed magnetic resonance imaging (MRI) at these time points, and 13 completed all sessions. We compared patients with 35 matched healthy controls. We identified early (0-150 ms) and late (250-500 ms) peaks in Gamma synchrony locked to oddball targets, and we analyzed MRI data using voxel-based morphometry. We evaluated group and test-retest differences using repeated-measures analyses of variance.Compared with controls, at first contact, patients with a first episode of schizophrenia showed a disruption to the laterality of early Gamma synchrony and global reduction in late Gamma synchrony, with a corresponding loss of fronto-temporal-parietal grey matter. Gamma synchrony was increased at follow-up among patients with a first episode of schizophrenia. It related negatively to further loss of grey matter, but positively to improvement in reality distortion symptoms. These relations could not be explained by medication dose.Our study did not include unmedicated patients or normative follow-up testing.Gamma synchrony may track the progression of schizophrenia from first episode. An increase in Gamma synchrony over time might reflect an attempt to adapt to a progressive loss of cortical grey matter and associated changes in cognitive and emotional function.

    View details for Web of Science ID 000261898000003

    View details for PubMedID 19125210

  • Explicit identification and implicit recognition of facial emotions: I. Age effects in males and females across 10 decades JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Williams, L. M., Mathersul, D., Palmer, D. M., Gur, R. C., Gur, R. E., Gordon, E. 2009; 31 (3): 257-277


    A number of psychiatric and neurological disorders are characterized by impairments in facial emotion recognition. Recognition of individual emotions has implicated limbic, basal ganglionic, and frontal brain regions. Since these regions are also implicated in age-related decline and sex differences in emotion processing, an understanding of normative variation is important for assessing deficits in clinical groups. An internet-based test ("WebNeuro") was administered to 1,000 healthy participants (6 to 91 years, 53% female) to assess explicit identification of basic expressions of emotion (happiness, sadness, fear, anger, disgust, neutral). A subsequent implicit recognition condition was based on a priming protocol, in which explicit identification provided the "study" phase. Responses were most accurate for happiness and slowest for fear in the explicit condition, but least accurate for happiness and fastest for fear in the implicit condition. The effects of age, by contrast, showed a similar pattern for both explicit and implicit conditions, following a nonlinear distribution in which performance improved from childhood through adolescence and early adulthood and declined in later adulthood. Females were better than males at explicit identification of fear in particular. These findings are consistent with the priority of threat-related signals, but indicate opposing biases depending on whether emotion processing is conscious or nonconscious. The lifespan trends in emotion processing over 10 decades point to an interaction of brain-based (maturation, stability, and then atrophy of cortical and subcortical systems) and experiential contributing factors. These findings provide a robust normative platform for assessing clinical groups.

    View details for DOI 10.1080/13803390802255635

    View details for Web of Science ID 000264510100001

    View details for PubMedID 18720177

  • Improving the Prediction of Treatment Response in Depression: Integration of Clinical, Cognitive, Psychophysiological, Neuroimaging, and Genetic Measures CNS SPECTRUMS Kemp, A. H., Gordon, E., Rush, J., Williams, L. M. 2008; 13 (12): 1066-1086


    Antidepressants are important in the treatment of depression, and selective serotonin reuptake inhibitors are first-line pharmacologic options. However, only 50% to 70% of patients respond to first treatment and <40% remit. Since depression is associated with substantial morbidity, mortality, and family burden, it is unfortunate and demanding on health resources that patients must remain on their prescribed medications for at least 4 weeks without knowing whether the particular antidepressant will be effective. Studies have suggested a number of predictors of treatment response, including clinical, psychophysiological, neuroimaging, and genetics, each with varying degrees of success and nearly all with poor prognostic sensitivity and specificity. Studies are yet to be conducted that use multiple measures from these different domains to determine whether sensitivity and specificity can be improved to predict individual treatment response. It is proposed that a focus on standardized testing methodologies across multiple testing modalities and their integration will be crucial for translation of research findings into clinical practice.

    View details for Web of Science ID 000262250300012

    View details for PubMedID 19179943

  • Dissociative responses to conscious and non-conscious fear impact underlying brain function in post-traumatic stress disorder PSYCHOLOGICAL MEDICINE Felmingham, K., Kemp, A. H., Williams, L., FALCONER, E., Olivieri, G., Peduto, A., Bryant, R. 2008; 38 (12): 1771-1780


    Dissociative reactions in post-traumatic stress disorder (PTSD) have been regarded as strategic responses that limit arousal. Neuroimaging studies suggest distinct prefrontal responses in individuals displaying dissociative and hyperarousal responses to threat in PTSD. Increased prefrontal activity may reflect enhanced regulation of limbic arousal networks in dissociation. If dissociation is a higher-order regulatory response to threat, there may be differential responses to conscious and automatic processing of threat stimuli. This study addresses this question by examining the impact of dissociation on fear processing at different levels of awareness.Functional magnetic resonance imaging (fMRI) with a 1.5-T scanner was used to examine activation to fearful (versus neutral) facial expressions during consciously attended and non-conscious (using backward masking) conditions in 23 individuals with PTSD. Activation in 11 individuals displaying non-dissociative reactions was compared to activation in 12 displaying dissociative reactions to consciously and non-consciously perceived fear stimuli.Dissociative PTSD was associated with enhanced activation in the ventral prefrontal cortex for conscious fear, and in the bilateral amygdala, insula and left thalamus for non-conscious fear compared to non-dissociative PTSD. Comparatively reduced activation in the dissociative group was apparent in dorsomedial prefrontal regions for conscious fear faces.These findings confirm our hypotheses of enhanced prefrontal activity to conscious fear and enhanced activity in limbic networks to non-conscious fear in dissociative PTSD. This supports the theory that dissociation is a regulatory strategy invoked to cope with extreme arousal in PTSD, but this strategy appears to function only during conscious processing of threat.

    View details for DOI 10.1017/S0033291708002742

    View details for Web of Science ID 000261549000012

    View details for PubMedID 18294420

  • Association between BDNF Val66Met polymorphism and trait depression is mediated via resting EEG alpha band activity BIOLOGICAL PSYCHOLOGY Gatt, J. M., Kuan, S. A., Dobson-Stone, C., Paul, R. H., Joffe, R. T., Kemp, A. H., Gordon, E., Schofield, P. R., Williams, L. M. 2008; 79 (2): 275-284


    A functional polymorphism of the brain-derived neurotrophic factor, BDNF Val66Met, is associated with risk for major depression alongside impairments in memory and selective attention. This study aims to identify the mediating neural mechanisms in links between BDNF and depression using highly heritable electroencephalographic (EEG) recordings. In 305 healthy subjects, BDNF Val66Met genotypes were compared in terms of trait depression, neural function (EEG during a resting state) and cognitive performance. The mediating effects of the EEG brain imaging endophenotypes were also examined using structural equation (path) modeling. A genotype-endophenotype-phenotype path model showed that Met homozygosity predicted elevated working memory commission errors and altered EEG activity; that is elevated relative theta and delta power coupled with reduced alpha power. In turn, reduced EEG alpha activity mediated the relationship between the Met/Met genotype and trait depression. These findings demonstrate the utility of an integrative endophenotype approach. They suggest that the BDNF Met/Met homozygote has a direct impact on memory systems, but impacts trait depression via the secondary effects of neural changes.

    View details for DOI 10.1016/j.biopsycho.2008.07.004

    View details for Web of Science ID 000260283400020

    View details for PubMedID 18721847

  • Increased absolute magnitude of gamma synchrony in first-episode psychosis SCHIZOPHRENIA RESEARCH Flynn, G., Alexander, D., Harris, A., Whitford, T., Wong, W., Galletly, C., Silverstein, S., Gordon, E., Williams, L. M. 2008; 105 (1-3): 262-271


    Recent studies have explored a model of the disconnection hypothesis of schizophrenia through the demonstration of abnormal stimulus induced gamma phase synchrony (GPS). These studies have principally examined synchrony in the 40 Hz band elicited in post-stimulus time periods, relative to a pre-stimulus baseline. In this study we examined the absolute magnitude of GPS elicited by a selective attention task, in first-episode psychosis (FEP). We hypothesized that FEP would be associated with abnormalities in absolute GPS, particularly when required to selectively attend to task-relevant stimuli.Fifty-five first-episode psychosis (FEP) subjects and one hundred and ten matched healthy control subjects underwent an auditory oddball selective attention task during EEG recording. The absolute magnitude of GPS was extracted for the range 35-45 Hz, and time-locked to stimulus onset. GPS averaged were computed for oddball 'target' (task-relevant) and 'non-target' (task-irrelevant) stimuli, for each subject.FEP subjects showed a significant elevation in absolute GPS relative to controls, apparent across the 35-45 Hz range. This elevation was most marked in the left centro-temporal region, across the 800 ms post-stimulus period. In FEP subjects, the elevation in GPS was also greater for target compared to non-target stimuli, while healthy controls did not show a stimulus effect.These findings complement previous evidence for reductions in peak gamma synchrony, calculated relative to a pre-stimulus baseline, in schizophrenia. The results an excess of absolute GPS in schizophrenia may contribute to an inability to effectively integrate task-relevant information, which underlie psychotic symptoms.

    View details for DOI 10.1016/j.schres.2008.05.029

    View details for Web of Science ID 000260591900029

    View details for PubMedID 18603413

  • The integrate model of emotion, thinking and self regulation: an application to the "paradox of aging". Journal of integrative neuroscience Williams, L. M., Gatt, J. M., Hatch, A., Palmer, D. M., Nagy, M., Rennie, C., Cooper, N. J., Morris, C., Grieve, S., Dobson-Stone, C., Schofield, P., Clark, C. R., Gordon, E., Arns, M., Paul, R. H. 2008; 7 (3): 367-404


    This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.

    View details for PubMedID 18988298

  • An "integrative neuroscience" platform: application to profiles of negativity and positivity bias. Journal of integrative neuroscience Gordon, E., Barnett, K. J., Cooper, N. J., Tran, N., Williams, L. M. 2008; 7 (3): 345-366


    The aim of the paper is to describe a standardized "Integrative Neuroscience" Platform that can be applied to elucidate brain-body mechanisms. This infrastructure includes a theoretical integration (the INTEGRATE Model). To demonstrate this infrastructure, hypotheses from the INTEGRATE Model are applied in an example investigation of the cognitive, brain and body markers of individual differences in the trait characteristic of Negativity Bias (the tendency to see oneself and one's world as negative). A sample of 270 healthy participants (18-65 years old) were grouped into equal sized matched subsets of high "Negativity Bias" and high "Positivity Bias" (n = 135 in each group). Participants were assessed using a standardized battery of psychological traits, cognition and brain and body (autonomic) activity. Greater "Negativity Bias" relative to "Positivity Bias" was characterized by greater autonomic reactivity and early neural excitation to signals of potential danger, at the timescale of Emotion (< 200 ms). Concomitantly, there was a relatively lower level of "Thinking", reflected in cognitive dimensions and associated electrical brain measures of working memory and EEG Theta power. By contrast, Negativity and Positivity Bias did not differ in levels of emotional resilience and social skills at the longer time scale of Self Regulation. This paper provides a demonstration of how an Integrative Neuroscience infrastructure can be used to elucidate the brain-body basis of trait characteristics, such as Negativity Bias, that are key indicators of risk for poor well-being and psychopathology.

    View details for PubMedID 18988297

  • The neural networks of inhibitory control in posttraumatic stress disorder JOURNAL OF PSYCHIATRY & NEUROSCIENCE Falconer, E., Bryant, R., Felmingham, K. L., Kemp, A. H., Gordon, E., Peduto, A., Olivieri, G., Williams, L. M. 2008; 33 (5): 413-422


    Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD.Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17).Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions.The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms.

    View details for Web of Science ID 000259500500004

    View details for PubMedID 18787658

  • Developing an integrated brain, behavior and biological response profile in posttraumatic stress disorder (PTSD). Journal of integrative neuroscience Falconer, E. M., Felmingham, K. L., Allen, A., Clark, C. R., McFarlane, A. C., Williams, L. M., Bryant, R. A. 2008; 7 (3): 439-456


    The present study sought to determine a profile of integrated behavioral, brain and autonomic alterations in PTSD. Previous findings suggest that PTSD is associated with changes across electrophysiological (EEG and ERP), autonomic and cognitive/behavioral measures. In particular, PTSD has been associated with reduced cognitive performance, altered cortical arousal (measured by EEG), diminished late ERP component to oddball task targets (reduced P3 amplitude) and increased autonomic arousal relative to healthy controls. The present study examined measures of cognitive function, auditory oddball ERP components, autonomic function (heart rate and skin conductance) and EEG during resting conditions in 44 individuals with PTSD and 44 non-trauma-exposed controls, and predicted that an integrated profile of changes across a number of these measures would show a high level of sensitivity and specificity in discriminating PTSD from controls. Nine variables showing strongly significant (p < 0.002) between-group differences were entered into a discriminant function analysis. Four of these measures successfully discriminated the PTSD and non-PTSD groups: change in tonic arousal, duration of attention switching, working memory reaction time and errors of commission during visuospatial maze learning. Tonic arousal change contributed the most variance in predicting group membership. These results extend previous findings and provide an integrated biomarker profile that characterizes both PTSD and non-PTSD groups with a high degree of sensitivity and specificity. This outcome provides a platform for future studies to test how this profile of disturbances in autonomic and information processing may be unique to PTSD or may occur generically across clinical and/or other anxiety disorders.

    View details for PubMedID 18988301

  • Investigating models of affect: Relationships among EEG alpha asymmetry, depression, and anxiety EMOTION Mathersul, D., Williams, L. M., Hopkinson, P. J., Kemp, A. H. 2008; 8 (4): 560-572


    The approach-withdrawal and valence-arousal models both predict that depressive and anxious profiles will be associated with relatively reduced left frontal and increased right frontal activity respectively, while the valence-arousal model also proposes a dissociation by lower and higher right parietotemporal activity, respectively. Recent work further suggests that subtypes of anxiety disorders may be characterized by distinctive patterns of activity depending on their type of arousal (anxious arousal/apprehension). The aim of this study was to investigate the relationships among nonclinical depression/anxiety and lateralized frontal/parietotemporal activity by categorizing participants (N=428) on the basis of both negative mood and alpha EEG. Key findings include: (i) greater right frontal lateralization in anxious participants, symmetrical frontal activity in depressed/comorbid, and left frontal lateralization in healthy controls; (ii) right frontal lateralization in anxious arousal participants, left frontal and right parietotemporal lateralization in anxious apprehension; (iii) bilateral increase in frontal and increased right parietotemporal activity in depressed/comorbid participants. Findings support predictions for frontal but not posterior regions. Grouping on the basis of EEG may not be reciprocally predictive of negative mood groupings, suggesting involvement of additional factors.

    View details for DOI 10.1037/a0012811

    View details for Web of Science ID 000257974200012

    View details for PubMedID 18729586

  • Voxel-based morphometry in schizophrenia: implications for neurodevelopmental connectivity models, cognition and affect. Expert review of neurotherapeutics Williams, L. M. 2008; 8 (7): 1049-1065


    Voxel-based morphometry (VBM) studies have provided valuable data on the nature and distribution of gray and white matter abnormalities in schizophrenia relative to the whole brain. Most VBM studies have focused on chronic patients, but there are accumulating studies of first-episode schizophrenia and other high-risk groups such as first-degree relatives. This review outlines the evidence from VBM studies of both chronic and first-episode/high-risk groups. The most consistent reduction revealed in chronic patients is in the superior temporal cortex, and in first-episode/high-risk individuals, in frontal brain regions. These findings are reviewed in relation to complementary evidence for neurodevelopmental deviation, and functional associations with both neuroimaging and behavioral measures of general and social cognition.

    View details for DOI 10.1586/14737175.8.7.1049

    View details for PubMedID 18590476

  • Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: An fMRI study HUMAN BRAIN MAPPING Bryant, R. A., Kemp, A. H., Felmingham, K. L., Liddell, B., Olivieri, G., Peduto, A., Gordon, E., Williams, L. M. 2008; 29 (5): 517-523


    Biological models of posttraumatic stress disorder (PTSD) suggest that patients will display heightened amygdala but decreased medial prefrontal activity during processing of fear stimuli. However, a rapid and automatic alerting mechanism for responding to nonconscious signals of fear suggests that PTSD may display heightened rather than decreased MPFC under nonconscious processing of fear stimuli. This study used functional magnetic resonance imaging to examine blood oxygenation level-dependent signal changes during nonconscious presentation (16.7 ms, masked) of fearful and neutral faces in 15 participants with PTSD and 15 age and sex-matched healthy control participants. Results indicate that PTSD participants display increased amygdala and MPFC activity during nonconscious processing of fearful faces. These data extend existing models by suggesting that the impaired MPFC activation in PTSD may be limited to conscious fear processing. Hum Brain Mapp, 2008. (c) 2007 Wiley-Liss, Inc.

    View details for DOI 10.1002/hbm.20415

    View details for Web of Science ID 000255673900002

    View details for PubMedID 17525984

  • Resting electroencephalogram asymmetry and posttraumatic stress disorder JOURNAL OF TRAUMATIC STRESS Shankman, S. A., Silverstein, S. M., Williams, L. M., Hopkinson, P. J., Kemp, A. H., Felmingham, K. L., Bryant, R. A., McFarlane, A., Clark, C. R. 2008; 21 (2): 190-198


    The valence-arousal (W. Heller, 1993) and approach-withdrawal (R. J. Davidson, 1998a) models hypothesize that particular patterns of hemispheric brain activity are associated with specific motivational tendencies and psychopathologies. We tested several of these predictions in two groups-a posttraumatic stress disorder (PTSD) and a "supercontrol" group, selected to be maximally different from those with PTSD. Contrary to almost all hypotheses, individuals with PTSD did not differ from controls on resting electroencephalogram (EEG) asymmetry. Particular aspects of PTSD were also not related to EEG hemisphere differences. Our null findings are consistent with the few studies that have examined resting EEG asymmetries in PTSD and suggest that PTSD may be associated with different processes than psychopathologies previously examined in studies of hemispheric brain activity (e.g., major depressive disorder, panic disorder).

    View details for DOI 10.1002/jts.20319

    View details for Web of Science ID 000255446600009

    View details for PubMedID 18404640

  • Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behaviour therapy for post-traumatic stress disorder PSYCHOLOGICAL MEDICINE Bryant, R. A., Felmingham, K., Kemp, A., Das, P., Hughes, G., Peduto, A., Williams, L. 2008; 38 (4): 555-561


    Although cognitive behaviour therapy (CBT) is the treatment of choice for post-traumatic stress disorder (PTSD), approximately half of patients do not respond to CBT. No studies have investigated the capacity for neural responses during fear processing to predict treatment response in PTSD.Functional magnetic resonance imaging (fMRI) responses of the brain were examined in individuals with PTSD (n=14). fMRI was examined in response to fearful and neutral facial expressions presented rapidly in a backwards masking paradigm adapted for a 1.5 T scanner. Patients then received eight sessions of CBT that comprised education, imaginal and in vivo exposure, and cognitive therapy. Treatment response was assessed 6 months after therapy completion.Seven patients were treatment responders (defined as a reduction of 50% of pretreatment scores) and seven were non-responders. Poor improvement after treatment was associated with greater bilateral amygdala and ventral anterior cingulate activation in response to masked fearful faces.Excessive fear responses in response to fear-eliciting stimuli may be a key factor in limiting responses to CBT for PTSD. This excessive amygdala response to fear may reflect difficulty in managing anxiety reactions elicited during CBT, and this factor may limit optimal response to therapy.

    View details for DOI 10.1017/S0033291707002231

    View details for Web of Science ID 000254497300009

    View details for PubMedID 18005496

  • Rostral anterior cingulate volume predicts treatment response to cognitive-behavioural therapy for posttraumatic stress disorder JOURNAL OF PSYCHIATRY & NEUROSCIENCE Bryant, R. A., Felmingham, K., Whitford, T. J., Kemp, A., Hughes, G., Peduto, A., Williams, L. M. 2008; 33 (2): 142-146


    To index the extent to which treatment response in posttraumatic stress disorder (PTSD) is predicted by rostral anterior cingulate cortex (rACC) volume.We used structural magnetic resonance imaging in a 1.5 T scanner to examine subjects with PTSD (n = 13), traumatized control subjects (n = 13) and nontraumatized control subjects (n = 13). Subjects with PTSD then participated in 8 sessions of cognitive-behavioural therapy, after which we reassessed them for PTSD.According to voxel-based morphometry, treatment responders had larger rACC volume than nonresponders. Further, symptom reduction was associated with larger rACC volume.Consistent with evidence for the neural bases of extinction learning, PTSD patients with larger rACC volume may be better able to regulate fear during cognitive-behavioural therapy and thus achieve greater treatment gains.

    View details for Web of Science ID 000253761400007

    View details for PubMedID 18330460

  • Early Life Stress on Brain Structure and Function Across the Lifespan: A Preliminary Study BRAIN IMAGING AND BEHAVIOR Seckfort, D. L., Paul, R., Grieve, S. M., Vandenberg, B., Bryant, R. A., Williams, L. M., Clark, C. R., Cohen, R. A., Bruce, S., Gordon, E. 2008; 2 (1): 49-58
  • Body mass index and neuropsychological function in healthy children and adolescents APPETITE Gunstad, J., Spitznagel, M. B., Paul, R. H., Cohen, R. A., Kohn, M., Luyster, F. S., Clark, R., Williams, L. M., Gordon, E. 2008; 50 (2-3): 246-251


    Elevated body mass index (BMI) is associated with adverse neurocognitive outcome in adults, including reduced neuropsychological test performance. It is unknown whether this relationship also exists in children and adolescents. A total of 478 children and adolescents (age 6-19) without significant medical or psychiatric history provided demographic information and completed a computerized cognitive test battery. Participants were categorized using clinical criteria into underweight, normal weight, at risk for overweight and overweight groups based on age and gender. Partial correlation and MANCOVA analyses adjusting for age and intellectual function found no relationship between BMI and cognitive test performance in the full sample. However, analyses performed separately by gender showed that underweight females exhibited poorer memory performance than other female BMI groups. These findings suggest that elevated BMI is not associated with cognitive function in healthy children and adolescents, though underweight might be a risk factor for reduced memory performance in females. Further work is needed to clarify the inconsistent findings between adults and minors.

    View details for DOI 10.1016/j.appet.2007.07.008

    View details for Web of Science ID 000254126600008

    View details for PubMedID 17761359

  • Investigating the neuropsychological and neuroanatomical changes that occur over the first 2-3 years of illness in patients with first-episode schizophrenia PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Zipparo, L., Whitford, T. J., Hodge, M. A., Lucas, S., Farrow, T. F., Brennan, J., Gomes, L., Williams, L. M., Harris, A. W. 2008; 32 (2): 531-538


    This study explored the concurrent courses of the neuroanatomical and neuropsychological changes that occurred over the first 2-3 years of illness in patients with first-episode schizophrenia (FES).Fifty-two patients with FES underwent neuropsychological testing and a structural magnetic resonance imaging (sMRI) scan within three months of their first presentation to mental health services with psychotic symptoms (time1). Patients' cognitive performance was evaluated via an extensive neuropsychological test battery, which assessed 9 cognitive domains. Of the 52 patients at time1, 32 returned 2-3 years later (time2) for follow-up neuropsychological testing, and 20 of these also underwent follow-up sMRI. MR images were preprocessed in SPM99. Grey matter volumes of patients' whole-brain, frontal lobes and temporal lobes were calculated by convolving the preprocessed images with manually-drawn binary masks.Patients exhibited longitudinal improvements in full-scale IQ, performance IQ and visual memory. In contrast, concurrent reductions in grey matter were observed for the whole-brain (3% reduction) and the frontal lobe (3.65% reduction). Furthermore, the extent of patients' whole-brain and frontal-lobe grey matter changes were positively correlated with longitudinal changes in verbal learning and memory.The results of this study suggest that while the early stages of schizophrenia are associated with a mild improvement in patients' overall cognitive functioning, they are also associated with progressive grey matter atrophy.

    View details for DOI 10.1016/j.pnpbp.2007.10.011

    View details for Web of Science ID 000253847000031

    View details for PubMedID 18061326

  • The relationship between early life stress and microstructural integrity of the corpus callosum in a non-clinical population. Neuropsychiatric disease and treatment Paul, R., Henry, L., Grieve, S. M., Guilmette, T. J., Niaura, R., Bryant, R., Bruce, S., Williams, L. M., Richard, C. C., Cohen, R. A., Gordon, E. 2008; 4 (1): 193-201


    Previous studies have examined the impact of early life stress (ELS) on the gross morphometry of brain regions, including the corpus callosum. However, studies have not examined the relationship between ELS and the microstructural integrity of the brain.In the present study we evaluated this relationship in healthy non-clinical participants using diffusion tensor imaging (DTI) and self-reported history of ELS.Regression analyses revealed significant reductions in fractional anisotropy (FA) within the genu of the corpus callosum among those exposed to the greatest number of early life stressors, suggesting reduced microstructural integrity associated with increased ELS. These effects were most pronounced in the genu of the corpus callosum compared to the body and splenium, and were evident for females rather than males despite no differences in total ELS exposure between the sexes. In addition, a further comparison of those participants who were exposed to no ELS vs. three or more ELS events revealed lower FA in the genu of the corpus callosum among the ELS-exposed group, with trends of FA reduction in the body and the whole corpus callosum. By contrast, there were no relationships between ELS and volumetric analysis of the CC regions. The two group did not differ significantly on measures of current depression, stress or anxiety.Our results reveal that greater exposure to ELS is associated with microstructural alterations in the white matter in the absence of significant volumetric changes. Importantly, our results indicate that exposure to ELS is associated with abnormalities on DTI despite the absence of clinically significant psychiatric symptoms. Future studies are needed to determine whether specific types of ELS are more likely to impact brain structure and function.

    View details for PubMedID 18728817

  • General and social cognition in first episode schizophrenia: Identification of separable factors and prediction of functional outcome using the IntegNeuro, test battery SCHIZOPHRENIA RESEARCH Williams, L. M., Whitford, T. J., Flynn, G., Wong, W., Liddell, B. J., Silverstein, S., Galletly, C., Harris, A. W., Gordon, E. 2008; 99 (1-3): 182-191


    It is increasingly recognized that cognitive assessments, unlike symptom ratings, provide a reliable predictor of functional outcome in schizophrenia. This study evaluated the utility of the 'IntegNeuro' computerized test battery for assessing cognition in first episode schizophrenia. We determined the presence of separable factors of general and social cognition, their equivalence to the consensus domains identified by the NIMH MATRICS project, and their effectiveness in predicting real world functional outcomes.Fifty six first episode schizophrenia (FES) patients and 112 matched healthy controls were assessed on the touchscreen-based 'IntegNeuro' cognitive test battery and FES patients for social functioning (SOFAS) and quality of life (WHOQOL-BREF).Principal components analysis identified i) six factors corresponding to MATRICS domains of general cognition ('Information Processing Speed', 'Verbal Recall', 'Working Memory Capacity', 'Sustained Attention/Vigilance', 'Verbal Processing', 'Executive Function'), ii) an 'Emotional Intelligence' factor corresponding to the MATRICS social cognition domain, and iii) an additional 'Sensori-Motor Function' factor of general cognition and 'Negativity' factor of social cognition. Patients showed impairments relative to controls across all factors, but especially for Working Memory Capacity, followed by Verbal Memory, Sustained Attention/Vigilance and Negativity. These factors strongly predicted poorer social functioning in FES, along with poorer quality of life in psychological, social, and health satisfaction facets.The IntegNeuro battery has utility for assessing separable domains of general and social cognition in FES, which are predictive of real world outcomes. Thus, it may be appropriate for clinical application, including in multi-center trials targeting new treatments for cognition in schizophrenia.

    View details for DOI 10.1016/j.schres.2007.10.019

    View details for Web of Science ID 000254306600023

    View details for PubMedID 18053688

  • ERP indices of working memory updating in AD/HD: Differential aspects of development, subtype, and medication JOURNAL OF CLINICAL NEUROPHYSIOLOGY Keage, H. A., Clark, C. R., Hermens, D. F., Williams, L. M., Kohn, M. R., Clarke, S., Lamb, C., Crewther, D., Gordon, E. 2008; 25 (1): 32-41


    This study investigated whether children and adolescents diagnosed with the predominantly inattentive and combined subtypes of attention deficit/hyperactivity disorder (AD/HD-in and AD/HD-com, respectively) differed on psychophysiological indices of working memory updating off- and on-stimulant medication, as compared with control subjects and each other. ERPs were recorded in AD/HD and control participants during a one-back working memory task. The N100 (discrimination), P150 (selection), N300 (memory retrieval), and P450wm (updating) components after nontarget stimuli, which served to update working memory with target identity, were assessed. Premedication abnormalities were obtained for the N300 component, delayed in the child AD/HD-com group, and attenuated in the adolescent AD/HD-in group and P450wm component for all AD/HD groups, expressed as either delayed latency and/or attenuated amplitude. ERP abnormalities were predominantly ameliorated after stimulant medication. There were no psychophysiological differences between the subtypes. A general feature of the disorder relates to a deficit in the conscious updating of working memory systems with newly relevant information (P450wm), which varies with age and subtype. Children with AD/HD-com and adolescents with AD/HD-in also exhibit abnormalities in the retrieval of relevant prior memories (N300). This study indicates that AD/HD is related to abnormalities in the capacity to modulate the content of working memory stores.

    View details for Web of Science ID 000253100600005

    View details for PubMedID 18303558

  • Putative biomarker of working memory systems development during childhood and adolescence NEUROREPORT Keage, H. A., Clark, C. R., Hermens, D. F., Williams, L. M., Kohn, M. R., Clarke, S., Lamb, C., Crewther, D., Gordon, E. 2008; 19 (2): 197-201


    The study aimed to identify brain functional indicators of working memory systems development between 6 and 18 years. Event-related potentials (ERPs) were recorded from 251 normally developing children to stimuli requiring the updating of working memory. Cluster analysis of event-related potential componentry divided the sample into three clusters (mean ages 9, 12 and 16 years), with ascending cluster membership independently associated with improved task performance. The clusters correspond to periods of grey matter loss and white matter increase observed in developing children, supporting the view that the clusters delineate three key qualitative stages in advancing cognitive capability during the maturation of higher brain systems function. This outcome identifies a biomarker with the potential for assessing abnormalities in the rate of brain development.

    View details for Web of Science ID 000252645000013

    View details for PubMedID 18185108

  • Event-related wave activity in the EEG provides new marker of ADHD CLINICAL NEUROPHYSIOLOGY Alexander, D. M., Hermens, D. F., Keage, H. A., Clark, C. R., Williams, L. M., Kohn, M. R., Clarke, S. D., Lamb, C., Gordon, E. 2008; 119 (1): 163-179


    This study examines the utility of new measures of event-related spatio-temporal waves in the EEG as a marker of ADHD, previously shown to be closely related to the P3 ERP in an adult sample.Wave activity in the EEG was assessed during both an auditory Oddball and a visual continuous performance task (CPT) for an ADHD group ranging in age from 6 to 18 years and comprising mostly Combined and Inattentive subtypes, and for an age and gender matched control group.The ADHD subjects had less wave activity at low frequencies ( approximately 1 Hz) during both tasks. For auditory Oddball targets, this effect was shown to be related to smaller P3 ERP amplitudes. During CPT, the approximately 1 Hz wave activity in the ADHD subjects was inversely related to clinical and behavioral measures of hyperactivity and impulsivity. CPT wave activity at approximately 1 Hz was seen to "normalise" following treatment with stimulant medication.The results identify a deficit in low frequency wave activity as a new marker for ADHD associated with levels of hyperactivity and impulsivity.The marker is evident across a range of tasks and may be specific to ADHD. While lower approximately 1 Hz activity partly accounts for reduced P3 ERPs in ADHD, the effect also arises for tasks that do not elicit a P3. Deficits in behavioral inhibition are hypothesized to arise from underlying dysregulation of cortical inhibition.

    View details for DOI 10.1016/j.clinph.2007.09.119

    View details for Web of Science ID 000252644300017

    View details for PubMedID 18054279

  • Effect of age on startle and on prepulse inhibition of startle 48th Annual Meeting of the Society-for-Psychophysiological-Research Lipp, O. V., Blumenthal, T. D., Mallan, K. M., Williams, L. M., Gordon, E. WILEY-BLACKWELL. 2008: S78–S78
  • Development and validation of a World-Wide-Web-based neurocognitive assessment battery WebNeuro BEHAVIOR RESEARCH METHODS Selverstein, S. M., Berten, S., Olson, P., Paul, R., Williams, L. M., Cooper, N., Gordon, E. 2007; 39 (4): 940-949


    Assessment of neurocognitive functioning is a critical task in many clinical, educational, service, and industrial settings. We report on descriptive and validation data of a new, World-Wide-Web-based, comprehensive battery of neurocognitive functioning, WebNeuro, that can be used in both applied and research contexts. Fifty healthy control participants completed both WebNeuro, and an established non-Internet-based computerized cognitive assessment battery, IntegNeuro, that uses a touchscreen platform. Results indicated comparability across the two batteries, in terms of critical single test scores, factor analysis derived indices,overall performance scores, and sex differences. These results support the validity of WebNeuro as a neurocognitive assessment measure. Advantages of its use in applied and research settings are discussed.

    View details for Web of Science ID 000251492800030

    View details for PubMedID 18183911

  • Neural biases to covert and overt signals of fear: Dissociation by trait anxiety and depression JOURNAL OF COGNITIVE NEUROSCIENCE Williams, L. M., Kemp, A. H., Felmingham, K., Liddell, B. J., Palmer, D. M., Bryant, R. A. 2007; 19 (10): 1595-1608


    Although biases toward signals of fear may be an evolutionary adaptation necessary for survival, heightened biases may be maladaptive and associated with anxiety or depression. In this study, event-related potentials (ERPs) were used to examine the time course of neural responses to facial fear stimuli (versus neutral) presented overtly (for 500 msec with conscious attention) and covertly (for 10 msec with immediate masking to preclude conscious awareness) in 257 nonclinical subjects. We also examined the impact of trait anxiety and depression, assessed using psychometric ratings, on the time course of ERPs. In the total subject group, controlled biases to overtly processed fear were reflected in an enhancement of ERPs associated with structural encoding (120-220 msec) and sustained evaluation persisting from 250 msec and beyond, following a temporo-occipital to frontal topography. By contrast, covert fear processing elicited automatic biases, reflected in an enhancement of ERPs prior to structural encoding (80-180 msec) and again in the period associated with automatic orienting and emotion encoding (230-330 msec), which followed the reverse frontal to temporo-occipital topography. Higher levels of trait anxiety (in the clinical range) were distinguished by a heightened bias to covert fear (speeding of early ERPs), compared to higher depression which was associated with an opposing bias to overt fear (slowing of later ERPs). Anxiety also heightened early responses to covert fear, and depression to overt fear, with subsequent deficits in emotion encoding in each case. These findings are consistent with neural biases to signals of fear which operate automatically and during controlled processing, feasibly supported by parallel networks. Heightened automatic biases in anxiety may contribute to a cycle of hypervigilance and anxious thoughts, whereas depression may represent a "burnt out" emotional state in which evaluation of fear stimuli is prolonged only when conscious attention is allocated.

    View details for Web of Science ID 000249763900003

    View details for PubMedID 17854280

  • Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort NEUROIMAGE Dobson-Stone, C., Gatt, J. M., Kuan, S. A., Grieve, S. M., Gordon, E., Williams, L. M., Schofield, P. R. 2007; 37 (2): 394-400


    Loss-of-function mutations in MCPH1 and ASPM are responsible for some cases of autosomal recessive primary microcephaly. Recent studies have indicated that certain common variants of these genes have been positively selected for during the evolution of modern humans. It is therefore possible that these variants may predispose to an increase in brain size in the normal human population. We genotyped the MCPH1 G37995C and ASPM A44871G polymorphisms in a cohort of 118 healthy people who had undergone structural magnetic resonance imaging analysis. We did not detect significant association of either MCPH1 G37995C or ASPM A44871G genotype with whole brain volume, cerebral cortical volume or proportion of grey matter in this cohort. Nor did we detect an association of combined MCPH1 37995C and ASPM 44871G allele dosage with these brain measurements. These results were also confirmed in an age-restricted subcohort of 94 individuals. This study suggests that phenotypes other than brain size may have been selected for in ASPM and MCPH1 variants during evolution of modern humans.

    View details for DOI 10.1016/j.neuroimage.2007.05.011

    View details for Web of Science ID 000248585400003

    View details for PubMedID 17566767

  • Influence of comorbid depression on fear in posttraurnatic stress disorder: An fMRI study PSYCHIATRY RESEARCH-NEUROIMAGING Kemp, A. H., Felmingham, K., Das, P., Hughes, G., Peduto, A. S., Bryant, R. A., Williams, L. M. 2007; 155 (3): 265-269


    Posttraumatic Stress Disorder (PTSD) is thought to involve a dysregulation of medial prefrontal-amygdala activity in response to fear. PTSD studies, however, have been confounded by comorbid depression, which shows similar dysregulation. Amygdala and medial prefrontal activity was reduced in PTSD-depression compared to PTSD-alone samples, highlighting the need to account for comorbidity.

    View details for DOI 10.1016/j.pscychresns.2007.01.010

    View details for Web of Science ID 000248971800009

    View details for PubMedID 17572075

  • Dynamic organization of the emotional brain: Responsivity, stability, and instability NEUROSCIENTIST Williams, L. M., Gordon, E. 2007; 13 (4): 349-370


    Models of emotion processing have commonly been formulated as dichotomies such as approach versus avoidance. These models and associated research on evolutionary adaptation, awareness, motivational arousal, and cortical-subcortical brain systems are reviewed. A continuum model of emotional-significance processing is proposed to integrate current dichotomies and reflect the highly interconnected nature of brain systems. This model highlights a spectrum from "mismatches," signifying potential danger, to "matches," signifying safety and the expectation of reward. Subcortical-cortical interactions and autonomic arousal modulation support mismatch and match processing across a temporal continuum from milliseconds (in which processing is automatic and arguably nonconscious) to tenths of a second (in which responses are facilitated and contextual evaluation commences) to minutes and hours (when memory consolidation and neural plasticity occur). Variations at distinct points along this continuum, with contributions from constitutional and genetic factors, may contribute to individual differences in emotional stability and instability in neuropsychiatric disorders.

    View details for DOI 10.1177/1073858407303429

    View details for Web of Science ID 000248224200013

    View details for PubMedID 17644766

  • The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades BIOLOGICAL PSYCHOLOGY Alexander, D. M., Williams, L. M., Gatt, J. M., Dobson-Stone, C., Kuan, S. A., Todd, E. G., Schofield, P. R., Cooper, N. J., Gordon, E. 2007; 75 (3): 229-238


    Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.

    View details for DOI 10.1016/j.biopsycho.2007.03.001

    View details for Web of Science ID 000248113400002

    View details for PubMedID 17433528

  • Distinguishing symptom profiles in adolescent ADHD using an objective cognitive test battery. International journal of adolescent medicine and health Clarke, S. D., Kohn, M. R., Hermens, D. F., Rabbinge, M., Clark, C. R., Gordon, E., Williams, L. M. 2007; 19 (3): 355-367


    Currently diagnosis and assessment of ADHD relies on clinical interview and subjective ratings. Standardized objective cognitive tests can provide additional information about ADHD and help distinguish symptom profiles.To assess the cognition of adolescent ADHD subtypes using a standardized cognitive test battery.Seventy-two ADHD combined subtype, 58 ADHD predominantly inattentive subtype and 130 age- and sex-matched healthy controls.Cognitive differences between ADHD subtypes were examined according to 1. symptom dimensions (inattentive versus hyperactivity/impulsivity scores) and 2. category (ADHDcom vs. ADHDin). We examined whether cognitive performance would discriminate symptom profiles (from each other and from healthy controls), and whether these profiles could predict test performance. All subjects completed the standardized and fully computerized IntegNeuro test battery using a touch-screen protocol. These tests span the domains of sensori-motor, attention, executive function, language and memory, and have robust construct validity compared to traditional paper-and-pencil tests. The results highlighted the consistency with which performance varied across symptom profiles, irrespective of categorical or dimensional definitions. ADHDcom was primarily distinguished from ADHDin by increased errors and response variability in response inhibition and (to a lesser extent) selective attention tasks. Inattentive symptoms were more likely to predict cognitive performance and there is an indication that despite the same criteria, these symptoms may be more severe in the ADHDcom subtype.These findings highlight the specificity of cognitive deficits, which differentiate ADHD subtypes in adolescence. This study provides consistent evidence that accuracy and response variability in an executive function (response inhibition) task may best distinguish the common ADHD subtypes.

    View details for PubMedID 17937152

  • Volumetric white matter abnormalities in first-episode schizophrenia: A longitudinal, tensor-based morphometry study Australasian Schizophrenia Conference Whitford, T. J., Grieve, S. M., Farrow, T. F., Gomes, L., Brennan, J., Harris, A. W., Gordon, E., Williams, L. M. AMER PSYCHIATRIC PUBLISHING, INC. 2007: 1082–89


    While schizophrenia has long been considered a disorder of brain connectivity, few studies have investigated white matter abnormalities in patients with first-episode schizophrenia, and even fewer studies have investigated whether there is progressive white matter pathology in the disease.The authors obtained a T1-weighted structural magnetic resonance imaging (MRI) scan on 41 patients with first-episode schizophrenia. These first-episode schizophrenia patients were analyzed relative to 47 age- and sex-matched healthy comparison subjects who also underwent an MRI scan. Of the baseline participants, 25 first-episode schizophrenia patients and 26 comparison subjects returned 2 to 3 years later for a follow-up scan. To identify regional volumetric white matter differences between the two groups at baseline, voxel-based morphometry in statistical parametric mapping-2 (SPM2) was used, while tensor-based morphometry was used to identify the longitudinal changes over the follow-up interval.The first-episode schizophrenia patients exhibited volumetric deficits in the white matter of the frontal and temporal lobes at baseline, as well as volumetric increases in the white matter of the frontoparietal junction bilaterally. Furthermore, these first-episode schizophrenia patients lost considerably more white matter over the follow-up interval relative to comparison subjects in the middle and inferior temporal cortex bilaterally.These results indicate that patients with schizophrenia exhibit white matter abnormalities at the time of their first presentation of psychotic symptoms to mental health services and that these abnormalities degenerate further over the initial years of illness. Given the role that white matter plays in neural communication, the authors suggest that these white matter abnormalities may be a cause of the dysfunctional neural connectivity that has been proposed to underlie the symptoms of schizophrenia.

    View details for Web of Science ID 000247872700019

    View details for PubMedID 17606660

  • Diffusion tensor imaging of the corpus callosum: a cross-sectional study across the lifespan INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE McLaughlin, N. C., Paul, R. H., Grieve, S. M., Williams, L. M., Laidlaw, D., DiCarlo, M., Clark, C. R., Whelihan, W., Cohen, R. A., Whitford, T. J., Gordon, E. 2007; 25 (4): 215-221


    Previous studies have demonstrated strong developmental trends of white matter using in vivo neuroimaging. However, few studies have examined white matter using diffusion tensor imaging across the lifespan. In the present study we examined fractional anisotropy and volume in the corpus callosum in four groups (children, adolescents, young adults, and elderly). Results revealed a curvilinear relationship in the analysis of the fractional anisotropy values for these four groups, with fractional anisotropy values increasing in childhood and adolescence, reaching their peak in young adulthood, followed by a non-significant decline in the elderly. Volumetric analysis of corpus callosum regions revealed a similar pattern, with an increase in volume from childhood and adolescence through young adulthood, and a non-significant decrease in volume in the elderly group. These results define the microstructural development of the white matter across the lifespan. Future studies are required to examine the neurobehavioral correlates of these neuroimaging indices.

    View details for DOI 10.1016/j.ijdevneu.2007.03.008

    View details for Web of Science ID 000247548900003

    View details for PubMedID 17524591

  • Fronto-limbic and autonomic disjunctions to negative emotion distinguish schizophrenia subtypes PSYCHIATRY RESEARCH-NEUROIMAGING Williams, L. (., Das, P., Liddell, B. J., Olivieri, G., Peduto, A. S., David, A. S., Gordon, E., Harris, A. W. 2007; 155 (1): 29-44


    Schizophrenia patients show a disconnection in amygdala-medial prefrontal cortex and autonomic arousal systems for processing fear. Concurrent functional magnetic resonance imaging [fMRI] and skin conductance recording were used to determine whether these disturbances are specific to fear, or present in response to other signals of danger. We also examined whether these disturbances distinguish a specific symptom profile. During scanning, 27 schizophrenia (13 paranoid, 14 nonparanoid) and 22 matched healthy control subjects viewed standardized facial expressions of fear, anger and disgust (versus neutral). Skin conductance responses [SCRs]were acquired simultaneously to assess phasic increases in arousal. 'With-arousal' versus 'without-arousal' responses were analysed using non-parametric methods. For controls, 'with-arousal' responses were associated with emotion-specific activity for fear (amygdala), disgust (insula) and anger (anterior cingulate), together with common medial prefrontal cortex [MPFC] engagement, as predicted. Schizophrenia patients displayed abnormally increased phasic arousal, with concomitant reductions in emotion-specific regions and MPFC. These findings may reflect a general disconnection between central and autonomic systems for processing signals of danger. This disjunction was most apparent in patients with a profile of paranoia, coupled with poor social function and insight. Heightened autonomic sensitivity to signals of fear, threat or contamination, without effective neural mechanisms for appraisal, may underlie paranoid delusions which concern threat and contamination, and associated social and interpersonal difficulties.

    View details for DOI 10.1016/j.psychresns.2006.12.018

    View details for Web of Science ID 000246515400004

    View details for PubMedID 17398080

  • Genotypes and neural binding in negative affect: The contribution of genetic polymorphisms to 40 hz gamma phase synchrony 62nd Annual Meeting of the Society-of-Biological-Psychiatry Williams, L. M., Gatt, J. M., Kuan, S., Dobson-Stone, C., Paul, R. H., Schofield, P. R., Gordon, E. ELSEVIER SCIENCE INC. 2007: 265S–265S
  • Longitudinal changes in neuroanatomy and neural activity in early schizophrenia NEUROREPORT Whitford, T. J., Farrow, T. F., Rennie, C. J., Grieve, S. M., Gomes, L., Brennan, J., Harris, A. W., Williams, L. M. 2007; 18 (5): 435-439


    Although there is substantial evidence indicating that patients with first-episode schizophrenia exhibit both anatomical and electrophysiological abnormalities, there has been little research investigating the relationship between these two indices. We acquired structural magnetic resonance images and resting electroencephalographic recordings from 19 patients with schizophrenia, both at the time of their first presentation to mental health services and 2-3 years subsequently. Patients' grey matter images were parcellated into four brain lobes, and slow-wave, alpha- and beta-electroencephalographic power was calculated in four corresponding cortical regions. Although grey matter volume decreased longitudinally, particularly fronto-parietally, electroencephalographic power increased in the slow-wave and beta-frequency bands. These results suggest that first-episode schizophrenia may be associated with abnormally elevated levels of neural synchrony.

    View details for Web of Science ID 000245440900008

    View details for PubMedID 17496799

  • Integrating "brain" and "body" measures: correlations between EEG and metabolic changes over the human lifespan. Journal of integrative neuroscience Boord, P. R., Rennie, C. J., Williams, L. M. 2007; 6 (1): 205-218


    This study investigated the relationship between electroencephalograph (EEG) power and basal metabolic rate (BMR) over the human lifespan, to better understand the mechanisms involved in the decline of neural activity with age.Eyes-open EEG power was calculated in standard frequency bands and averaged across recording sites in 1831 healthy subjects aged 6 to 86 years, from the Brain Resource International Database. In a subset of 175 subjects, structural MRI scans were also undertaken to determine the role of grey matter. Cerebral metabolic rate (CMR) was estimated using two models of EEG power, based on: (1) normalization of BMR by total body mass, and (2) scaling by cortical grey matter.Regression analysis revealed a linear relationship between the CMR estimates and EEG power under both models. In the full sample, CMR explained 65% of the variance in delta power, and 53% of the variance in theta power over the age span.The results demonstrate that the large EEG signals in early childhood are associated with a higher BMR during that age. INTEGRATIVE SIGNIFICANCE: The use of cross-modal measurements in this study highlights the utility of capturing data in an integrative framework to reveal fundamental physiological relationships.

    View details for PubMedID 17472230

  • Brain maturation in adolescence: Concurrent changes in neuroanatomy and neurophysiology HUMAN BRAIN MAPPING Whitford, T. J., Rennie, C. J., Grieve, S. M., Clark, C. R., Gordon, E., Williams, L. M. 2007; 28 (3): 228-237


    Adolescence to early adulthood is a period of dramatic transformation in the healthy human brain. However, the relationship between the concurrent structural and functional changes remains unclear. We investigated the impact of age on both neuroanatomy and neurophysiology in the same healthy subjects (n = 138) aged 10 to 30 years using magnetic resonance imaging (MRI) and resting electroencephalography (EEG) recordings. MRI data were segmented into gray and white matter images and parcellated into large-scale regions of interest. Absolute EEG power was quantified for each lobe for the slow-wave, alpha and beta frequency bands. Gray matter volume was found to decrease across the age bracket in the frontal and parietal cortices, with the greatest change occurring in adolescence. EEG activity, particularly in the slow-wave band, showed a similar curvilinear decline to gray matter volume in corresponding cortical regions. An inverse pattern of curvilinearly increasing white matter volume was observed in the parietal lobe. We suggest that the reduction in gray matter primarily reflects a reduction of neuropil, and that the corresponding elimination of active synapses is responsible for the observed reduction in EEG power.

    View details for DOI 10.1002/hbm.20273

    View details for Web of Science ID 000244259100007

    View details for PubMedID 16767769

  • A genotype-endophenotype-phenotype path model of depressed mood: integrating cognitive and emotional markers. Journal of integrative neuroscience Gatt, J. M., Clark, C. R., Kemp, A. H., Liddell, B. J., Dobson-Stone, C., Kuan, S. A., Schofield, P. R., Williams, L. M. 2007; 6 (1): 75-104


    Following an integrative neuroscience perspective, we propose that cognitive and emotional functions are integrally linked, and that genetic polymorphisms which impact upon neural processes may have complementary effects on these functions. The brain-derived neurotrophic factor (BDNF) 66Met allele may contribute to both cognitive and emotional aspects of the depression phenotype.In 374 nonclinical subjects, BDNF genotype differences in task-related ERPs, emotion, memory, and EEG cortical arousal were examined.Using path modeling, higher negative affect in Met homozygotes was predicted by slow-wave EEG via the mediating effects of neuroticism. Both negative affect and working memory deficits were predicted by disturbances in emotion- and cognitive-related ERPs. This model held across groups with varying levels of depressed mood.Since impairments in emotion and working memory are core features of major depression, the BDNF Met allele may contribute to vulnerability for this disorder. An integrative approach in which genotypes are considered in combination with brain function and behavioral measures may be important in identifying profile markers of depression. INTEGRATIVE SIGNIFICANCE: This study directly demonstrates that cognitive and emotional neural networks are not parallel independent systems, but rather highly integrated with effects on both cognitive performance and emotional behavior.

    View details for PubMedID 17472225

  • An integrative approach to determine the best behavioral and biological markers of methylphenidate. Journal of integrative neuroscience Hermens, D. F., Cooper, N. J., Clark, C. R., Debrota, D., Clarke, S. D., Williams, L. M. 2007; 6 (1): 105-140


    To distinguish the most sensitive markers of methylphenidate (MPH) effects on behavior and underlying biology using an integrated cognitive and brain function test battery.A randomized placebo-controlled trial with 32 healthy adult males. Subjects were tested on MPH doses across 18 sessions with subjective mood, objective behavioral and biological endpoints. From a computerized battery of tests, behavioral measures were cognitive performance scores, while biological measures of brain function included electroencephalographs (EEG) and event-related potentials (ERPs) with complementary measures of autonomic arousal. Using mixed modeling analyses; we determined which measures were most affected by MPH dose and correlation analyses determined the associations among them.MPH dose had the most pronounced effect on cognitive performance (sustained attention/vigilance), baseline autonomic arousal (heart rate, blood pressure) and baseline brain activity (EEG theta power). The faster reaction time, reduced errors, increased autonomic arousal and reductions in theta showed strong to moderate inter-correlations. MPH least affected subjective mood measures and early sensory ERP components.These findings suggest that MPH increases cortical and autonomic arousal, facilitating vigilance. The combination of behavioral and biological measures may provide an objective set of markers of MPH response. INTEGRATIVE SIGNIFICANCE: This approach has provided additional insight into the mechanism of the stimulant medication, MPH, which would not be achieved by using such measures in isolation.

    View details for PubMedID 17472226

  • Brain structure and function correlates of general and social cognition. Journal of integrative neuroscience Rowe, D. L., Cooper, N. J., Liddell, B. J., Clark, C. R., Gordon, E., Williams, L. M. 2007; 6 (1): 35-74


    To examine how general (e.g., memory, attention) and social (emotional and interpersonal processes) cognition relate to measures of brain function and structure.PCA was used to identify general and social cognitive factors from Brain Resource International Database in 1,316 subjects. The identified factors were correlated with each subject's corresponding brain structure (MRI) and function (EEG/ERP) data.Seven core cognitive factors were identified for general and three for social. General cognition was correlated with global grey matter, while social cognition was negatively correlated with grey matter in fronto-temporal-somatosensory regions. Executive function, information processing speed and verbal memory performance were correlated with delta-theta qEEG, while most general cognitive factors negatively correlated with beta qEEG. Faster information processing speed was correlated with alpha qEEG. Executive function and information processing speed was correlated with negative-going ERP amplitude and slower ERP latency at frontal sites, but at posterior sites negative correlations were found.In contrast to general cognition, social cognition is identified by different functional (automated) activity and more localized neural structures. Only general cognition, requiring more effortful, controlled processing is related to brain function measures, particularly in frontal cortices. INTEGRATIVE SIGNIFICANCE: Recording measures from multiple modalities including MRI, EEG/ERP, social and general cognition within the same subject provides a method of brain profiling for use in cognitive-neurotherapy and pharmacological studies.

    View details for PubMedID 17472224

  • Integrating objective gene-brain-behavior markers of psychiatric disorders. Journal of integrative neuroscience Gordon, E., Liddell, B. J., Brown, K. J., Bryant, R., Clark, C. R., Das, P., Dobson-Stone, C., Falconer, E., Felmingham, K., Flynn, G., Gatt, J. M., Harris, A., Hermens, D. F., Hopkinson, P. J., Kemp, A. H., Kuan, S. A., Lazzaro, I., Moyle, J., Paul, R. H., Rennie, C. J., Schofield, P., Whitford, T., Williams, L. M. 2007; 6 (1): 1-34


    There is little consensus about which objective markers should be used to assess major psychiatric disorders, and predict/evaluate treatment response for these disorders. Clinical practice relies instead on subjective signs and symptoms, such that there is a "translational gap" between research findings and clinical practice. This gap arises from: a) a lack of integrative theoretical models which provide a basis for understanding links between gene-brain-behavior mechanisms and clinical entities; b) the reliance on studying one measure at a time so that linkages between markers are their specificity are not established; and c) the lack of a definitive understanding of what constitutes normative function. Here, we draw on a standardized methodology for acquiring multiple sources of genomic, brain and behavioral data in the same subjects, to propose candidate markers of selected psychiatric disorders: depression, post-traumatic stress disorder, schizophrenia, attention-deficit/hyperactivity disorder and dementia disorders. This methodology has been used to establish a standardized international database which provides a comprehensive framework and the basis for testing hypotheses derived from an integrative theoretical model of the brain. Using this normative base, we present preliminary findings for a number of disorders in relation to the proposed markers. Establishing these objective markers will be the first step towards determining their sensitivity, specificity and treatment prediction in individual patients.

    View details for PubMedID 17472223

  • Rates of decline distinguish Alzheimer's disease and mild cognitive impairment relative to normal aging: integrating cognition and brain function. Journal of integrative neuroscience Liddell, B. J., Paul, R. H., Arns, M., Gordon, N., Kukla, M., Rowe, D., Cooper, N., Moyle, J., Williams, L. M. 2007; 6 (1): 141-174


    Increasing age is the strongest risk factor for Alzheimer's disease (AD). Yet, departure from normal age-related decline for established markers of AD including memory, cognitive decline and brain function deficits, has not been quantified.We examined the cross-sectional estimates of the "rate of decline" in cognitive performance and psychophysiological measures of brain function over age in AD, preclinical (subjective memory complaint-SMC, Mild Cognitive Impairment-MCI) and healthy groups. Correlations between memory performance and indices of brain function were also conducted.The rate of cognitive decline increased between groups: AD showed advanced decline, and SMC/MCI groups represented intermediate stages of decline relative to normal aging expectations. In AD, advanced EEG alterations (excessive slow-wave/reduced fast-wave EEG, decreased working memory P450 component) were observed over age, which were coupled with memory decline. By contrast, MCI group showed less severe cognitive changes but specific decreases in the working memory N300 component and slow-wave (delta) EEG, associated with decline in memory. DISCUSSION AND INTEGRATIVE SIGNIFICANCE: While the cognitive data suggests a continuum of deterioration associated with increasing symptom severity across groups, integration with brain function measures points to possible distinct compensatory strategies in MCI and AD groups. An integrative approach offers the potential for objective markers of the critical turning point, with age as a potential factor, from mild memory problems to disease.

    View details for PubMedID 17472227

  • Mapping frontal-limbic correlates of orienting to change detection NEUROREPORT Williams, L. M., Felmingham, K., Kemp, A. H., Rennie, C., Brown, K. J., Bryant, R. A., Gordon, E. 2007; 18 (3): 197-202


    Orienting responses are elicited by salient stimuli, and may be indexed by skin conductance responses. Concurrent functional magnetic resonance imaging and skin conductance response recording was used to identify neural correlates of orienting to abrupt sensory change (infrequent high pitch oddball 'target' tones embedded in frequent lower pitch 'standard' tones) in 16 healthy participants. 'With skin conductance response' responses to targets were distinguished by preferentially greater activity in the amygdala and ventral medial and lateral frontal cortical regions. By contrast, 'without skin conductance response' responses elicited distinctive activity in the dorsal lateral frontal cortex and supramarginal gyrus. These findings suggest that orienting to unexpected sensory change elicits a network for appraising salience and novelty, whereas, in the absence of orienting, a parallel network for sensory and context evaluation is preferentially engaged.

    View details for Web of Science ID 000245013400001

    View details for PubMedID 17314656

  • Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia SCHIZOPHRENIA RESEARCH Das, P., Kemp, A. H., Flynn, G., Harris, A. W., Liddell, B. J., Whitford, T. J., Peduto, A., Gordon, E., Williams, L. M. 2007; 90 (1-3): 284-294


    Schizophrenia patients show reduced neural activity, relative to controls, in the amygdala and its projection to the medial prefrontal cortex (MPFC) in response to fear perception. In this study we tested the hypothesis that schizophrenia is characterized by abnormal functional connectivity in the amygdala network underlying fear perception.Functional MRI images were acquired from 14 schizophrenia patients and 14 matched healthy control subjects during an emotion perception task, in which fearful and neutral facial expression stimuli were presented pseudorandomly under nonconscious (using masking) and conscious conditions. Both subtraction and functional connectivity analyses were undertaken using a region of interest approach.In response to fearful facial expressions, schizophrenia patients displayed reduced amygdala activity, compared to controls, in both the conscious and nonconscious conditions. The amygdala displayed a reversal of the normal pattern of connectivity with the brainstem, visual cortex, and also with the dorsal and ventral divisions of the MPFC in the schizophrenia patients.The presence of functional disconnections in amygdala pathways suggests that schizophrenia patients have a failure in coordinating their automatic orienting to salient signals and the associated prefrontal monitoring of these signals.

    View details for DOI 10.1016/j.schres.2006.11.023

    View details for Web of Science ID 000245152900034

    View details for PubMedID 17222539

  • Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder PSYCHOLOGICAL SCIENCE Felmingham, K., Kemp, A., Williams, L., Das, P., Hughes, G., Peduto, A., Bryant, R. 2007; 18 (2): 127-129

    View details for Web of Science ID 000245157900007

    View details for PubMedID 17425531

  • A profile of cognitive and brain function markers for diagnostic use in ADHD Hermens, D. F., Clarke, S. D., Kohn, M. R., Clark, R., Cooper, N. J., Keage, H. A., Gordon, E., Williams, L. M. ELSEVIER SCIENCE INC. 2007: S11–S11
  • Cognitive aging, executive function, and fractional anisotropy: A diffusion tensor MR imaging study AMERICAN JOURNAL OF NEURORADIOLOGY Grieve, S. M., Williams, L. M., Paul, R. H., Clark, C. R., Gordon, E. 2007; 28 (2): 226-235


    Fractional anisotropy (FA) is a useful measure of connectivity in the brain that can be derived from the diffusion tensor imaging (DTI) dataset. This study investigated the relationship between FA and selected measures of cognition across a broad age group to explore a possible structural basis for cognitive changes with age.FA images were generated from DTI data acquired at 1.5T in 87 healthy subjects (age range, 20-73 years). Relationships between a range of cognitive measures and FA were explored using regional and voxel-based analysis.Age and regional average FA were significantly associated in the frontal, parietal, and temporal lobes but not in the occipital lobe. This negative relationship was especially prominent in the prefrontal regions of the frontal lobe, where FA declined at a rate of approximately 3% per decade. Decreased FA in the frontal, temporal, and parietal lobes was associated with poorer cognitive performance in executive maze and in an attention-switching task. A voxel-level analysis of these data revealed that the executive function-FA association was particularly strong and regionally delineated over 2 continuous, bilateral areas extending from the prefrontal cortex to the parietal lobe, with projections to the anterior portions of the thalamus.We demonstrate a relationship between FA and a measure of executive function-a core cognitive component that is a key feature of cognitive aging. We propose that that FA may provide an early means for the detection of age-related cognitive change and suggest a need for prospective data to explore this association.

    View details for Web of Science ID 000244263200012

    View details for PubMedID 17296985

  • Cross-cultural assessment of neuropsychological performance and electrical brain function measures: Additional validation of an international brain database INTERNATIONAL JOURNAL OF NEUROSCIENCE Paul, R. H., Gunstad, J., Cooper, N., Williams, L. M., Clark, C. R., Cohen, R. A., Lawrence, J. J., Gordon, E. 2007; 117 (4): 549-568


    Previous studies have revealed significant differences in performance on nonlanguage dependent cognitive tests across international settings among younger individuals, with less pronounced differences evident among older individuals (>54 years of age). The present study examined a broad range of cognitive performance as well as electrophysiological indices of brain function in a multisite and international context. A total of 200 individuals in the United States, 233 individuals in Europe, and 829 individuals in Australia were administered a standardized computerized neuropsychological battery, and complementary electroencephalogram (EEG) recordings were completed. Results revealed no significant differences in cognitive function or electrophysiology across the three continents. Similarly, although there was a main effect for age, the interaction between age and continent was not significant in any of the omnibus analyses. These findings indicate a high degree of similarity in neurocognitive and electrophysiological function among individuals residing in developed Western cultures, consistent with a traitlike status and the high heritability of the EEG.

    View details for DOI 10.1080/00207450600773665

    View details for Web of Science ID 000244944000012

    View details for PubMedID 17365135

  • The relationship between frontal gray matter volume and cognition varies across the healthy adult lifespan AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Zimmerman, M. E., Brickman, A. M., Pau, R. H., Grieve, S. M., Tate, D. F., Gunstad, J., Cohen, R. A., Aloia, M. S., Williams, L. M., Clark, C. R., Whitord, T. J., Gordon, E. 2006; 14 (10): 823-833


    Age-associated decline in gray matter brain volume and cognitive function in healthy adults has been reported in the literature. The goal of the current study is to examine the relationship between age-related changes in regional gray matter volumes and cognitive function in a large, cross-sectional sample of healthy adults across the lifespan.Magnetic resonance imaging and cognitive assessment were conducted on 148 adults aged 21-76 years. Multiple regression analyses examining the effect of age were performed on magnetic resonance image-derived gray matter brain volumes and standardized cognitive summary scores of attention and executive function. Regression was also performed to test the effect of age, gray matter volumes, and their interaction on the prediction of cognitive performance.Age significantly predicted performance on tests of attention (F [1, 146]=50.97, p <0.01, R2=0.26) and executive function (F [1, 146]=126.19, p <0.01, R2=0.46) and gray matter volumes for frontal subregions (lateral, medial, orbital), hippocampus, amygdala, and putamen (F [2, 145]=45.34-23.96, p <0.01-0.02). Lateral frontal (beta=-1.53, t=-2.16, df=131, p <0.03) and orbital frontal (beta=1.24, t=2.08, df=131, p <0.04) regions significantly predicted performance on tests of attention. Lateral frontal (beta=-1.69, t=-2.83, df=131, p <0.01) and the interaction between age and lateral frontal volume (beta=3.76, t=2.49, df=131, p <0.02) significantly predicted executive function.The findings confirm age-associated decline in cognitive function and gray matter volumes, particularly in anterior cortical brain regions. Furthermore, the association between lateral frontal gray matter volume and the ability to successfully plan, organize, and execute strategies varies as a function of age across the healthy adult lifespan.

    View details for Web of Science ID 000241457700003

    View details for PubMedID 17001022

  • Regional white matter and neuropsychological functioning across the adult lifespan 33rd Annual Meeting of the International-Neuropsychological-Society Brickman, A. M., Zimmerman, M. E., Paul, R. H., Grieve, S. M., Tate, D. F., Cohen, R. A., Williams, L. M., Clark, C. R., Gordon, E. ELSEVIER SCIENCE INC. 2006: 444–53


    The current study utilized magnetic resonance imaging (MRI) to more fully elucidate the relationship among age, regional white matter, and neuropsychological functioning.One hundred ninety-nine neurologically healthy adults received MRI and standardized neuropsychological assessment. MR images were spatially normalized and segmented by tissue type; relative white matter values in each of the four cerebral lobes in each hemisphere were computed. Subjects were divided into Younger (ages 21-30), Middle (ages 31-54), and Older (ages 55-79) age groups.The Older group had significantly less overall relative white matter than the Middle group, who had significantly less overall relative white matter than the Younger participants (F (2, 193) = 5.42, p = 0.005). Differences in frontal lobe white matter were of largest magnitude, followed by temporal lobe (F (6, 579) = 3.32, p = 0.003). Age and frontal and temporal lobe white matter were primarily associated with performance on neuropsychological tests of executive functioning and memory. Mediational analysis suggested that frontal lobe white matter mediated the relationship between age and performance on tasks of executive functioning and memory.The results confirm age-associated decline in frontal and temporal white matter, and age-related cognitive decline in several domains. Decline in neuropsychological functioning is, in part, mediated by a relative age-related reduction in frontal white matter.

    View details for DOI 10.1016/j.biopsych.2006.01.011

    View details for Web of Science ID 000240506000004

    View details for PubMedID 16616725

  • Progressive grey matter atrophy over the first 2-3 years of illness in first-episode schizophrenia: A tensor-based morphometry study NEUROIMAGE Whitford, T. J., Grieve, S. M., Farrow, T. F., Gomes, L., Brennan, J., Harris, A. W., Gordon, E., Williams, L. M. 2006; 32 (2): 511-519


    Little is known about the structural brain changes that occur over the first few years of schizophrenia, or how these changes differ from those associated with healthy brain development in adolescence and early adulthood. In this study, we aimed to identify regional differences in grey matter (GM) volume between patients with first-episode schizophrenia (FES) and matched healthy controls, both at the time of the patients' first psychotic episode (baseline condition) and 2-3 years subsequently (follow-up condition). Forty-one patients with FES and 47 matched healthy controls underwent a T1-weighted structural MRI scan. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. Voxel-based morphometry in SPM2 was used to identify the regions of GM difference between the groups in the baseline condition, while tensor-based morphometry was used to identify the longitudinal change within subject over the follow-up interval. The FES patients exhibited widespread GM reductions in the frontal, parietal, and temporal cortices and cerebellum in the baseline condition, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES subjects were observed to lose considerably more GM over the follow-up interval than the controls, especially in the parietal and temporal cortices. We argue that the progressive GM atrophy we have found to be associated with the onset of schizophrenia arises from a dysfunction in the dramatic period of healthy brain development typically associated with adolescence.

    View details for DOI 10.1016/j.neuroimage.2006.03.041

    View details for Web of Science ID 000239848700004

    View details for PubMedID 16677830

  • Standardized assessment of cognitive functioning during development and aging using an automated touchscreen battery ARCHIVES OF CLINICAL NEUROPSYCHOLOGY Clark, C. R., Paul, R. H., Williams, L. A., Arns, M., Fallahpour, K., Handmer, C., Gordon, E. 2006; 21 (5): 449-467


    This study examined the effects of age, gender and education on subjects spanning nine decades on a new cognitive battery of 12 tests. One thousand and seven participants between 6 and 82 completed the battery under standardized conditions using an automated, computerized touchscreen. Sensitive indicators of change were obtained on measures of attention and working memory, learning and memory retrieval, and language, visuospatial function, sensori-motor and executive function. Improvement tended to occur through to the third and fourth decade of life, followed by gradual decrement and/or stabilized performance thereafter. Gender differences were obtained on measures of sustained attention, verbal learning and memory, visuospatial processing and dexterity. Years of education in adults was reflected in performance on measures of verbal function. Overall, the test battery provided sensitive indicators on a range of cognitive functions suitable for the assessment of abnormal cognition, the evaluation of treatment effects and for longitudinal case management.

    View details for DOI 10.1016/j.acn.2006.06.005

    View details for Web of Science ID 000240502800009

    View details for PubMedID 16904862

  • Longitudinal changes in regional grey matter volume and corresponding EEG power in first-episode psychosis Whitford, T. J., Farrow, T. F., Rennie, C. J., Grieve, S. M., Gomes, L., Brennan, J., Williams, L. M., Harris, A. W. INFORMA HEALTHCARE. 2006: A122–A123
  • Automated and controlled processing of fear facial expression display dysfunctions in the amygdala pathways in schizophrenia: a functional connectivity approach Das, P., Flynn, G., Harris, A. W., Kemp, A. H., Liddell, B. J., Whitford, T., Peduto, A., Gordon, E., Williams, L. M. INFORMA HEALTHCARE. 2006: A118–A119
  • Structural MRI evidence of differences between first episode bipolar disorder and first episode schizophrenia 2nd Biennial Conference of the International-Society-for-Bipolar-Disorders Farrow, T. F., Whitford, T. J., Williams, L. M., Gomes, L., Harris, A. W. WILEY-BLACKWELL. 2006: 18–18
  • Volumetric white matter abnormalities in first-episode schizophrenia: a longitudinal MRI study Whitford, T. J., Grieve, S. M., Farrow, T. F., Gomes, L., Brennan, J., Harris, A. W., Gordon, E., Williams, L. M. INFORMA HEALTHCARE. 2006: A122–A122
  • Event-related potential correlates of depression, insight and negative symptoms in males with recent-onset psychosis CLINICAL NEUROPHYSIOLOGY Sumich, A., Harris, A., Flynn, G., Whitford, T., Tunstall, N., Kumari, V., Brammer, M., Gordon, E., Williams, L. M. 2006; 117 (8): 1715-1727


    The neurobiology of clinical characteristics -in particular depression, insight and negative symptoms- in recent-onset psychosis (ROP) was studied using event-related potentials (ERPs).Twenty right-handed ROP men and 20 controls completed an auditory-oddball task. ROP men had minimum exposure to antipsychotic medication. N100, N200 and P300 were studied to ascertain the effects of (a) diagnosis (patients versus controls), and (b) clinical characteristics.ROP men had significantly lower anterior N100, enhanced N200 at T3, and lower P300 at Pz than controls. Lower right-anterior N100 and enhanced right-anterior N200 amplitude explained 47.7% of negative symptoms. Left-central N100 amplitude explained 30.28% of negative symptoms. Lower left-posterior and higher right-posterior P300 amplitude explained 65.99% of total symptoms. Lower left-central N100, enhanced left-central N200 and depression explained 78.8% of impairments in insight and judgement. Impaired insight/judgement correlated positively with right-anterior N200 and was identified as the most significant co-efficient for depression.Disturbed selective-attention and executive function indexed by N100 and N200, respectively, are associated with poor insight and negative symptoms. A complex interaction exists between insight and depression.The current results demonstrate a biological basis of insight and depression and a complex interaction between the two, perhaps mediated by executive function, in early psychosis.

    View details for DOI 10.1016/j.clinph.2006.04.017

    View details for Web of Science ID 000239876700011

    View details for PubMedID 16807100

  • Amygdala-prefrontal dissociation of subliminal and supraliminal fear HUMAN BRAIN MAPPING Williams, L. M., Liddell, B. J., Kemp, A. H., Bryant, R. A., Meares, R. A., Peduto, A. S., Gordon, E. 2006; 27 (8): 652-661


    Facial expressions of fear are universally recognized signals of potential threat. Humans may have evolved specialized neural systems for responding to fear in the absence of conscious stimulus detection. We used functional neuroimaging to establish whether the amygdala and the medial prefrontal regions to which it projects are engaged by subliminal fearful faces and whether responses to subliminal fear are distinguished from those to supraliminal fear. We also examined the time course of amygdala-medial prefrontal responses to supraliminal and subliminal fear. Stimuli were fearful and neutral baseline faces, presented under subliminal (16.7 ms and masked) or supraliminal (500 ms) conditions. Skin conductance responses (SCRs) were recorded simultaneously as an objective index of fear perception. SPM2 was used to undertake search region-of-interest (ROI) analyses for the amygdala and medial prefrontal (including anterior cingulate) cortex, and complementary whole-brain analyses. Time series data were extracted from ROIs to examine activity across early versus late phases of the experiment. SCRs and amygdala activity were enhanced in response to both subliminal and supraliminal fear perception. Time series analysis showed a trend toward greater right amygdala responses to subliminal fear, but left-sided responses to supraliminal fear. Cortically, subliminal fear was distinguished by right ventral anterior cingulate activity and supraliminal fear by dorsal anterior cingulate and medial prefrontal activity. Although subcortical amygdala activity was relatively persistent for subliminal fear, supraliminal fear showed more sustained cortical activity. The findings suggest that preverbal processing of fear may occur via a direct rostral-ventral amygdala pathway without the need for conscious surveillance, whereas elaboration of consciously attended signals of fear may rely on higher-order processing within a dorsal cortico-amygdala pathway.

    View details for DOI 10.1002/hbm.20208

    View details for Web of Science ID 000239316700003

    View details for PubMedID 16281289

  • Identifying brain and cognition markers of dose effects for methylphenidate and prediction of treatment response in ADHD 25th Congress of the Collegium-Internationale-Neuro-Psychopharmacologicum (CINP)/29th Annual Meeting of the Canadian-College-of-Neuropsychopharmacology Gordon, E., Hermens, D., Cooper, N. J., Kohn, M., Clark, C. R., Connell, K., Mason, M., Cohen, M., Williams, L. M. CAMBRIDGE UNIV PRESS. 2006: S241–S241
  • The mellow years?: Neural basis of improving emotional stability over age JOURNAL OF NEUROSCIENCE Williams, L. M., Brown, K. J., Palmer, D., Liddell, B. J., Kemp, A. H., Olivieri, G., Peduto, A., Gordon, E. 2006; 26 (24): 6422-6430


    Contrary to the pervasive negative stereotypes of human aging, emotional functions may improve with advancing age. However, the brain mechanisms underlying changes in emotional function over age remain unknown. Here, we demonstrate that emotional stability improves linearly over seven decades (12-79 years) of the human lifespan. We used both functional magnetic resonance imaging and event-related potential recording to examine the neural basis of this improvement. With these multimodal techniques, we show that better stability is predicted by a shift toward greater medial prefrontal control over negative emotional input associated with increased activity later in the processing sequence (beyond 200 ms after stimulus) and less control over positive input, related to a decrease in early activity (within 150 ms). This shift was independent from gray matter loss, indexed by structural magnetic resonance data. We propose an integrative model in which accumulated life experience and the motivation for meaning over acquisition in older age contribute to plasticity of medial prefrontal systems, achieving a greater selective control over emotional functions.

    View details for DOI 10.1523/JNEUROSCI.0022-06.2006

    View details for Web of Science ID 000238375900005

    View details for PubMedID 16775129

  • Associations between the COMT Val/Met polymorphism, early life stress, and personality among healthy adults. Neuropsychiatric disease and treatment Hoth, K. F., Paul, R. H., Williams, L. M., Dobson-Stone, C., Todd, E., Schofield, P. R., Gunstad, J., Cohen, R. A., Gordon, E. 2006; 2 (2): 219-225


    Efforts to identify genetic factors that confer an increased risk for the expression of psychiatric symptoms have focused on polymorphisms in variety of candidate genes, including the catechol-O-methyltransferase (COMT) gene. Results from previous studies that have examined associations between the functional COMT polymorphism (Val158Met) and mental health have been mixed. In the present study, we examined the relationships between COMT, early life stress, and personality in a healthy adult sample. Consistent with previous studies, we hypothesized that individuals with the low-activity genotype would have higher neuroticism and lower extraversion and that this effect would be more pronounced in females. In addition, we extended the previous literature by investigating the potential influence of early life stress. A total of 486 healthy adults underwent genetic testing and personality assessment. Results revealed that individuals homozygous for the COMT low enzyme activity allele had lower extraversion on the NEO-FFI and demonstrated a trend toward greater neuroticism. These relationships were not influenced by sex or the presence of reported early life stress. The finding that COMT genotype was associated with extraversion, and more weakly with neuroticism, is consistent with previous studies. Future research to clarify the influence of sex and gene-environmental interactions is warranted.

    View details for PubMedID 19412467

  • Exposure to early life trauma is associated with adult obesity PSYCHIATRY RESEARCH Gunstad, J., Paul, R. H., Spitznagel, M. B., Cohen, R. A., Williams, L. M., Kohn, M., Gordon, E. 2006; 142 (1): 31-37


    Exposure to traumatic events during childhood is associated with an elevated risk of adult obesity. It has been hypothesized that the psychological sequelae from childhood trauma account for this risk, though no study has examined whether an increased risk of obesity is found in persons without psychological disorders. We examined exposure to early life stressors and body mass index (BMI) in 696 adults without significant medical or psychiatric history. Bivariate correlation showed that the total number of early life stressors (r=0.08), age (r=0.19), and sex (r=0.16) were significantly related to adult BMI. Given the relationship between sex and BMI, we examined the contribution of early life stressors to adult obesity separately for men and women. In men, hierarchical regression showed that exposure to early life stressors predicted adult obesity. Specifically, history of being bullied/rejected (Obese 31%, Normal weight, 9%) and emotional abuse (Obese, 17%; Normal weight, 2%) predicted adult obesity after controlling for the effects of age. In women, no relationship between early life stressors and adult obesity was found. These findings suggest that multiple processes mediate the relationship between early life stress and adult obesity and that their relative contributions may differ between men and women.

    View details for DOI 10.1016/j.psychres.2005.11.007

    View details for Web of Science ID 000238430700004

    View details for PubMedID 16713630

  • Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei BIOLOGICAL PSYCHIATRY Cohen, R. A., Grieve, S., Hoth, K. F., Paul, R. H., Sweet, L., Tate, D., Gunstad, J., Stroud, L., McCaffery, J., Hitsman, B., Niaura, R., Clark, C. R., MacFarlane, A., Bryant, R., Gordon, E., Williams, L. M. 2006; 59 (10): 975-982


    Early life stress (ELS) is linked to adult psychopathology and may contribute to long-term brain alterations, as suggested by studies of women who suffered childhood sexual abuse. We examine whether reported adverse ELS defined as stressful and/or traumatic adverse childhood events (ACEs) is associated with smaller limbic and basal ganglia volumes.265 healthy Australian men and women without psychopathology or brain disorders were studied. ACEs were assessed by the ELSQ and current emotional state by the DASS. Anterior cingulate cortex (ACC), hippocampus, amygdala, and caudate nucleus volumes were measured from T1-weighted MRI. Analyses examined ROI volumetric associations with reported ACEs and DASS scores.Participants with greater than two ACEs had smaller ACC and caudate nuclei than those without ACEs. A significant association between total ACEs and ROI volumes for these structures was observed. Regression analysis also revealed that ELS was more strongly associated than current emotional state (DASS) with these ROI volumes.Reported ELS is associated with smaller ACC and caudate volumes, but not the hippocampal or amygdala volumes. The reasons for these brain effects are not entirely clear, but may reflect the influence of early stress and traumatic events on the developing brain.

    View details for DOI 10.1016/j.biopsych.2005.12.016

    View details for Web of Science ID 000237676100012

    View details for PubMedID 16616722

  • The 'when' and 'where' of perceiving signals of threat versus non-threat NEUROIMAGE Williams, L. M., Palmer, D., Liddell, B. J., Song, L., Gordon, E. 2006; 31 (1): 458-467


    We tested the proposal that signals of potential threat are given precedence over positive and neutral signals, reflected in earlier and more pronounced changes in neural activity. The temporal sequence ('when') and source localization ('where') of event-related potentials (ERPs) elicited by fearful and happy facial expressions, compared to neutral control expressions, were examined for 219 healthy subjects. We scored ERPs over occipito-temporal sites (N80, 50-120 ms; P120, 80-180 ms; N170, 120-220 ms; P230, 180-290 ms; N250, 230-350 ms) and their polarity-reversed counterparts over medial sites (P80, 40-120 ms; N120, 80-150 ms; VPP, 120-220 ms; N200, 150-280 ms; P300, 280-450 ms). In addition to scoring peak amplitude and latency, the anatomical sources of activity were determined using low resolution brain electromagnetic tomography (LORETA). Fearful faces were distinguished by persistent increases in positivity, associated with a dynamical shift from temporo-frontal (first 120 ms) to more distributed cortical sources (120-220 ms) and back (220-450 ms). By contrast, expressions of happiness produced a discrete enhancement of negativity, later in the time course (230-350 ms) and localized to the fusiform region of the temporal cortex. In common, fear and happiness modulated the face-related N170, and produced generally greater right hemisphere activity. These findings support the proposal that fear signals are given precedence in the neural processing systems, such that processing of positive signals may be suppressed until vigilance for potential danger is completed. While fear may be processed via parallel pathways (one initiated prior to structural encoding), neural systems supporting positively valenced input may be more localized and rely on structural encoding.

    View details for DOI 10.1016/j.neuroimage.2005.12.009

    View details for Web of Science ID 000238012200044

    View details for PubMedID 16460966

  • The multiscale character of evoked cortical activity NEUROIMAGE Breakspear, M., Bullmore, E. T., Aquino, K., Das, P., Williams, L. M. 2006; 30 (4): 1230-1242


    Both the architecture and the dynamics of the brain have characteristic features at different spatial scales. However, the existence, nature and function of dynamical interdependencies between such scales have not been investigated. We studied the multiscale properties of functional magnetic resonance imaging (fMRI) data acquired while human subjects viewed a visual image. Traditional "region of interest" analysis of this data set revealed evoked activity in primary and extrastriate visual cortex. Wavelet transform in the spatial domain provides a multiscale representation of this evoked brain activity. Studying the correlation structure of this representation revealed strong and novel interdependencies in these data within and between different spatial scales. We found that such correlations are stronger than those evident in the original data and comparable in magnitude to those obtained after Gaussian smoothing. However, analysis of the data in the wavelet domain revealed additional structure such as positive correlations, strong anti-correlations and phase-lagged interdependencies. Statistical significance of these effects was inferred through nonparametric bootstrap techniques. We conclude that the spatial analysis of functional neuroimaging data in the wavelet domain provides novel information which may reflect complex spatiotemporal neuronal activity and information encoding. It also affords a quantitative means of testing hierarchical and multiscale models of cortical activity.

    View details for DOI 10.1016/j.neuroimage.2005.10.041

    View details for Web of Science ID 000237601500016

    View details for PubMedID 16403656

  • Integrative neuroscience approach to predict ADHD stimulant response. Expert review of neurotherapeutics Hermens, D. F., Rowe, D. L., Gordon, E., Williams, L. M. 2006; 6 (5): 753-763


    Despite high rates of prescription, little is known about the long-term consequences of stimulant medication therapy for attention-deficit hyperactivity disorder (ADHD) sufferers. Historically, the clinical use of stimulants for ADHD has been based on trial and error before optimal therapy is reached. Concurrently, scientific research on the mechanism of action of stimulants has influenced neurobiological models of ADHD, but has not always informed their prescription. Whilst the two main stimulant types (methylphenidate and dexamphetamine) have numerous similarities, they also differ (slightly) in mechanism and possibly individual response. A further issue relates to differences in cost and availability compounded by the expectation for stimulants to be effective in ameliorating a broad spectrum of ADHD-related symptoms. Thus, there is an increasing need for treating clinicians to prescribe not only the most effective drug, but also the most appropriate dose with the associated release mechanism and schedule for each ADHD patient presented. In this regard, the field is witnessing an emergence of the personalized medicine approach to ADHD, in which treatment decisions are tailored to each individual. This shift requires a new approach to research into treatment response prediction. Given the heterogeneity of ADHD, a profile of information may be required to capture the most sensitive predictors of treatment response in individuals. These profiles will also benefit from the integration of data from clinical rating scales with more direct measures of cognition and brain function. In conclusion, there is a need to establish a more robust normative framework as the baseline for treatment, as well as diagnostic decisions, and as discussed, the growth of integrated neuroscience databases will be important in this regard.

    View details for PubMedID 16734523

  • Integrative neuroscience approach to predict ADHD stimulant response EXPERT REVIEW OF NEUROTHERAPEUTICS Hermens, D. F., Rowe, D. L., Gordon, E., Williams, L. M. 2006; 6 (5): 753-763
  • Cognitive status of young and older cigarette smokers: Data from the international brain database JOURNAL OF CLINICAL NEUROSCIENCE Paul, R. H., Brickman, A. M., Cohen, R. A., Williams, L. M., Niaura, R., Pogun, S., Clark, C. R., Gunstad, J., Gordon, E. 2006; 13 (4): 457-465


    Previous studies that have examined the impact of cigarette smoking on cognition have revealed mixed results; some studies report no impact and others report detrimental effects, especially in older individuals. Few studies, however, have examined the effects of cigarette smoking on both young and old healthy individuals using highly robust and standardized methods of cognitive assessment. This study draws on an international database to contrast cognitive differences between younger and older individuals who regularly smoke cigarettes and non-smokers. Data were sampled from 1000 highly screened healthy individuals free of medical or psychiatric health complications. A cohort of 62 regular smokers (n = 45 < 45 years of age; n = 1745 years) with a Fagerstrom nicotine dependency score of 1 or more were identified and matched to a cohort of 62 healthy nonsmokers (n = 43 < 45 years; n = 1945 years) on demographic variables and estimated intelligence. Performances on cognitive measures of attention, reaction time, cognitive flexibility, psychomotor speed, and memory were considered for analysis. As a group, smokers performed more poorly than nonsmokers on one measure of executive function. A significant age and smoking status interaction was identified with older smokers performing more poorly than older nonsmokers and younger smokers on a measure of long-delayed recall of new information. Cigarette smoking is associated with isolated and subtle cognitive difficulties among very healthy individuals.

    View details for DOI 10.1016/j.jocn.2005.04.012

    View details for Web of Science ID 000237703200010

    View details for PubMedID 16678725

  • "Missing links" in borderline personality disorder: loss of neural synchrony relates to lack of emotion regulation and impulse control JOURNAL OF PSYCHIATRY & NEUROSCIENCE Williams, L. M., Sidis, A., Gordon, E., Meares, R. A. 2006; 31 (3): 181-188


    Symptoms of borderline personality disorder (BPD) may reflect distinct breakdowns in the integration of posterior and frontal brain networks. We used a high temporal resolution measure (40-Hz gamma phase synchrony) of brain activity to examine the connectivity of brain function in BPD.Unmedicated patients with BPD (n = 15) and age-and sex-matched healthy control subjects (n = 15) undertook a task requiring discrimination of salient from background tones. In response to salient stimuli, the magnitude and latency of peak gamma phase synchrony for early (0-150 ms post stimulus) and late (250-500 ms post stimulus) phases were calculated for frontal and posterior regions and for left and right hemispheres. We recorded skin conductance responses (SCRs) and reaction time (RT) simultaneously to examine the contribution of arousal and performance.Compared with controls, patients with BPD had a significant delay in early posterior gamma synchrony and a reduction in right hemisphere late gamma synchrony in response to salient stimuli. Both SCR onset and RT were also delayed in BPD, but independently from differences in synchrony. The delay in posterior synchrony was associated with cognitive symptoms, and reduced right hemisphere synchrony was associated with impulsivity.These findings suggest that distinct impairments in the functional connectivity of neural systems for orienting to salient input underlie core dimensions of cognitive disturbance and poor impulse control in BPD.

    View details for Web of Science ID 000237107900005

    View details for PubMedID 16699604

  • An integrative neuroscience model of "significance" processing. Journal of integrative neuroscience Williams, L. M. 2006; 5 (1): 1-47


    The Gordon [37-40] framework of Integrative Neuroscience is used to develop a continuum model for understanding the central role of motivationally-determined "significance" in organizing human information processing. Significance is defined as the property which gives a stimulus relevance to our core motivation to minimize danger and maximize pleasure. Within this framework, the areas of cognition and emotion, theories of motivational arousal and orienting, and the current understanding of neural systems are brought together. The basis of integration is a temporal continuum in which significance processing extends from the most rapid millisecond time scale of automatic, nonconscious mechanisms to the time scale of seconds, in which memory is shaped, to the controlled and conscious mechanisms unfolding over minutes. Over this continuum, significant stimuli are associated with a spectrum of defensive (or consumptive) behaviors through to volitional regulatory behaviors for danger (versus pleasure) and associated brainstem, limbic, medial forebrain bundle and prefrontal circuits, all of which reflect a balance of excitatory (predominant at rapid time scales) to inhibitory mechanisms. Across the lifespan, the negative and positive outcomes of significance processing, coupled with constitutional and genetic factors, will contribute to plasticity, shaping individual adaptations and maladaptions in the balance of excitatory-inhibitory mechanisms.

    View details for PubMedID 16544365

  • EEG markers for cognitive decline in elderly subjects with subjective memory complaints. Journal of integrative neuroscience Alexander, D. M., Arns, M. W., Paul, R. H., Rowe, D. L., Cooper, N., Esser, A. H., Fallahpour, K., Stephan, B. C., Heesen, E., Breteler, R., Williams, L. M., Gordon, E. 2006; 5 (1): 49-74


    New treatments for Alzheimer's disease require early detection of cognitive decline. Most studies seeking to identify markers of early cognitive decline have focused on a limited number of measures. We sought to establish the profile of brain function measures which best define early neuropsychological decline. We compared subjects with subjective memory complaints to normative controls on a wide range of EEG derived measures, including a new measure of event-related spatio-temporal waves and biophysical modeling, which derives anatomical and physiological parameters based on subject's EEG measurements. Measures that distinguished the groups were then related to cognitive performance on a variety of learning and executive function tasks. The EEG measures include standard power measures, peak alpha frequency, EEG desynchronization to eyes-opening, and global phase synchrony. The most prominent differences in subjective memory complaint subjects were elevated alpha power and an increased number of spatio-temporal wave events. Higher alpha power and changes in wave activity related most strongly to a decline in verbal memory performance in subjects with subjective memory complaints, and also declines in maze performance and working memory reaction time. Interestingly, higher alpha power and wave activity were correlated with improved performance in reverse digit span in the subjective memory complaint group. The modeling results suggest that differences in the subjective memory complaint subjects were due to a decrease in cortical and thalamic inhibitory gains and slowed dendritic time-constants. The complementary profile that emerges from the variety of measures and analyses points to a nonlinear progression in electrophysiological changes from early neuropsychological decline to late-stage dementia, and electrophysiological changes in subjective memory complaint that vary in their relationships to a range of memory-related tasks.

    View details for PubMedID 16544366

  • Distractibility in AD/HD predominantly inattentive and combined subtypes: the P3a ERP component, heart rate and performance. Journal of integrative neuroscience Keage, H. A., Clark, C. R., Hermens, D. F., Kohn, M. R., Clarke, S., Williams, L. M., Crewther, D., Lamb, C., Gordon, E. 2006; 5 (1): 139-158


    The current study aimed to investigate whether children and adolescents diagnosed with Attention Deficit/Hyperactivity Disorder Predominantly Inattentive (AD/HD-in; Child n = 24, Adolescent n = 33) and Combined (AD/HD-com; Child n = 30, Adolescent n = 42) subtypes were more distractible than controls (Child n = 54; Adolescents n = 75), by assessing event-related potential (ERP), performance and peripheral arousal measures. All AD/HD groups displayed smaller amplitudes and/or shorter latencies of the P3a ERP component - thought to reflect involuntary attention switching - following task-deviant novel stimuli (checkerboard patterns) embedded in a Working Memory (WM) task. The P3a results suggested that both AD/HD-in and AD/HD-com subtypes ineffectively evaluate deviant stimuli and are hence more "distractible". These abnormalities were most pronounced over the central areas. AD/HD groups did not display any abnormalities in averaged heart rate over the WM task, a measure of peripheral arousal. They did display abnormalities in performance measures from the task, but these were unrelated to P3a abnormalities. AD/HD groups also displayed a number of deficits on Switching of Attention and Verbal Memory tasks, however, the pattern of abnormality mostly reflected general cognitive deficits rather than resulting from distraction.

    View details for PubMedID 16544371

  • Dynamic spectral analysis findings in first episode and chronic schizophrenia INTERNATIONAL JOURNAL OF NEUROSCIENCE Harris, A., Melkonian, D., Williams, L., Gordon, E. 2006; 116 (3): 223-246


    The quantified analysis of the electroencephalogram (qEEG) has enabled the extraction of additional psychophysiological information from the raw EEG, but in turn has introduced a number of distortions. This study compared Dynamic Spectral Analysis (DSA), a novel and mathematically stringent technique for the evaluation of qEEG activity with conventional power spectral analysis in subjects with both first episode and chronic schizophrenia and matched controls. Advantages of the technique in the automated processing of data, rejection of artefact, avoidance of artefact introduced by the mathematical trans-formation of the data and the identification of irregular low frequency artefactual activity "pi" are discussed in detail. Using this method, the study has confirmed past observations of increased slow wave activity in schizophrenia, and identified a decrease in peak frequency in the alpha band in the subjects with chronic schizophrenia. The two clinical groups differed in mean peak frequency in the delta band with the first episode schizophrenia subjects having a raised mean peak frequency and the subjects with chronic schizophrenia having a lowered mean peak frequency. The results suggest continued change in the EEG with illness chronicity in schizophrenia. These changes were most evident in the frequency domain emphasizing the importance of routine measurement of mean band frequencies in qEEG studies.

    View details for DOI 10.1080/00207450500402977

    View details for Web of Science ID 000235683500002

    View details for PubMedID 16484051

  • Predicting severity of non-clinical depression: preliminary findings using an integrated approach. Journal of integrative neuroscience Kemp, A. H., Hopkinson, P. J., Stephan, B. C., Clark, C. R., Gordon, E., Bryant, R. A., Williams, L. M. 2006; 5 (1): 89-110


    Depression is characterized by disturbances in affect, cognition, brain and body function, yet studies have tended to focus on single domains of dysfunction. An integrated approach may provide a more complete profile of the range of deficits characterized by depressed individuals, but it is unclear whether this approach is able to predict depression severity over and above that predicted by single tasks or domains of function. In this study, we examined the value of combining multiple domains of function in predicting depression severity.Participants contained in the International Brain Database, ( had completed three testing components including a web-based questionnaire of Personal History, the Brain Resource Cognition battery of Neuropsychological tests, Personality assessment and Psychophysiological testing. Two hundred and sixty six of these participants were able to be classified as either non-depressed, mild-moderately or severely (non-clinically) depressed, based on a depression screening questionnaire. Analysis of variance identified variables on which the categorized participants differed. Significant variables were then entered into a series of stepwise regressions to examine their ability to predict depression scores.An integrated model including measures of affect (increased Neuroticism; decreased Emotional Intelligence), cognition (increased variability of reaction time during a working memory task; decreased "name the word component score" in the verbal interference task), brain (decreased left-lateralized P150 ERP component during a working memory task) and body function (increased negative skin conductance level gradient) were found to predict more of the variation in depression severity than any single domain of function.On the basis of behavioral as well as Psychophysiological findings reported in this study, it was suggested that deficits in subclinically depressed individuals are more pronounced during automatic stages of stimulus processing, and that performance in these individuals may improve (to the level displayed by controls) when task demands are increased. Findings also suggest that it is important to consider disturbances across different domains of function in order to elucidate depression severity. Each domain may contribute unique explanatory information consistent with an integrative model of depression, taking into account the role of both behavior and underlying neural changes.

    View details for PubMedID 16544368

  • Trauma modulates amygdala and medial prefrontal responses to consciously attended fear NEUROIMAGE Williams, L. M., Kemp, A. H., Felmingham, K., Barton, M., Olivieri, G., Peduto, A., Gordon, E., Bryant, R. A. 2006; 29 (2): 347-357


    Effective fear processing relies on the amygdala and medial prefrontal cortex (MPFC). Post-trauma reactions provide a compelling model for examining how the heightened experience of fear impacts these systems. Post-traumatic stress disorder (PTSD) has been associated with excessive amygdala and a lack of MPFC activity in response to nonconscious facial signals of fear, but responses to consciously processed facial fear stimuli have not been examined. We used functional MRI to elucidate the effect of trauma reactions on amygdala-MPFC function during an overt fear perception task. Subjects with PTSD (n = 13) and matched non-traumatized healthy subjects (n = 13) viewed 15 blocks of eight fearful face stimuli alternating pseudorandomly with 15 blocks of neutral faces (stimulus duration 500 ms; ISI 767 ms). We used random effects analyses in SPM2 to examine within- and between-group differences in the MPFC and amygdala search regions of interest. Time series data were used to examine amygdala-MPFC associations and changes across the first (Early) versus second (Late) phases of the experiment. Relative to non-traumatized subjects, PTSD subjects showed a marked bilateral reduction in MPFC activity (in particular, right anterior cingulate cortex, ACC), which showed a different Early-Late pattern to non-traumatized subjects and was more pronounced with greater trauma impact and symptomatology. PTSD subjects also showed a small but significant enhancement in left amygdala activity, most apparent during the Late phase, but reduction in Early right amygdala response. Over the time course, trauma was related to a distinct pattern of ACC and amygdala connections. The findings suggest that major life trauma may disrupt the normal pattern of medial prefrontal and amygdala regulation.

    View details for DOI 10.1016/j.neuroimage.2005.03.047

    View details for Web of Science ID 000234841200001

    View details for PubMedID 16216534

  • ADHD and schizophrenia phenomenology: Visual scanpaths to emotional faces as a potential psychophysiological marker? NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Marsh, P. J., Williams, L. M. 2006; 30 (5): 651-665


    Commonalities in the clinical phenomenology and psychopharmacology of ADHD and schizophrenia are reviewed. The potential of psychostimulants to produce psychotic symptoms emphasizes the need for objective psychophysiological distinctions between these disorders. Impaired emotion perception in both disorders is discussed. It is proposed that visual scanpaths to facial expressions of emotion might prove a potentially useful psychophysiological distinction between ADHD and schizophrenia. There is consistent evidence that both facial affect recognition and scanpaths to facial expressions are impaired in schizophrenia, with emerging empirical evidence showing that facial affect recognition is impaired in ADHD also. Brain imaging studies show reduced activity in the medial prefrontal and limbic (amygdala) brain regions required to process emotional faces in schizophrenia, but suggest more localized loss of activity in these regions in ADHD. As amygdala activity in particular has been linked to effective visual scanning of face stimuli, it is postulated that condition-specific breakdowns in these brain regions that subserve emotional behavior might manifest as distinct scanpath aberrations to facial expressions of emotion in schizophrenia and ADHD.

    View details for DOI 10.1016/j.neubiorev.2005.11.004

    View details for Web of Science ID 000238771200004

    View details for PubMedID 16466794

  • Intelligence and the tuning-in of brain networks LEARNING AND INDIVIDUAL DIFFERENCES Stankov, L., Danthiir, V., Williams, L. M., Pallier, G., Roberts, R. D., Gordon, E. 2006; 16 (3): 217-233
  • BDNF Va166Met polymorphism is associated with body mass index in healthy adults NEUROPSYCHOBIOLOGY Gunstad, J., Schofield, P., Paul, R. H., Spitznagel, M. B., Cohen, R. A., Williams, L. M., Kohn, M., Gordon, E. 2006; 53 (3): 153-156


    Although recent studies suggest a possible relationship between the brain-derived neurotrophic factor Val66Met polymorphism and eating disorders, no study has examined the possibility that the Met-Met genotype is associated with a lower body mass index (BMI) in healthy individuals. We examined this possibility in 481 adults (age range 18-82 years) without significant medical or psychiatric history. After adjusting for gender, analysis of covariance showed that persons with the Met-Met genotype had a lower BMI than those with the Val-Met/Val-Val genotypes (22.28 +/-3.77 vs. 24.72+/-4.81). A similar, though nonsignificant, trend emerged when comparing all three genotypes separately. These findings suggest a possible relationship between Val66Met polymorphism and BMI in healthy adults. Further work is needed to clarify possible mechanisms for this relationship.

    View details for DOI 10.1159/000093341

    View details for Web of Science ID 000238188900007

    View details for PubMedID 16707914

  • The test-retest reliability of a standardized neurocognitive and neurophysiological test battery: "Neuromarker" INTERNATIONAL JOURNAL OF NEUROSCIENCE Williams, L. M., Simms, E., Clark, C. R., Paul, R. H., Rowe, D., Gordon, E. 2005; 115 (12): 1605-1630


    NeuroMarker combines EEG and ERP measures with neurocognitive tests in a fully computerized and standardized testing system. It is designed for use across the lifespan and has a large normative database of over 1,000 subjects. This study was a preliminary evaluation of "NeuroMarker" in subjects spanning four decades. Twenty-one healthy subjects (12-57 years) were tested at baseline and four weeks later. From the "Neuromarker" battery, the authors analyzed EEG data (eyes open and closed) and ERPs elicited during auditory oddball (N100, P200, N200, P300) and working memory (P150, P300) tasks. Concomitant neuropsychological data, acquired using a touch-screen system, comprised measures of sensori-motor, attention, verbal, executive, and memory function. Test-retest data were examined using analyses of variance and correlational procedures (corrected for multiple comparisons), with parallel analyses of age. EEG data did not differ across sessions, and showed high test-retest reliability (.71-.95), particularly for theta and delta (>.85). ERP components also showed sound reliability, particularly for sites where components are maximal: fronto-central N100 (.76-.77), centro-parietal P300 (.78-.81) to oddball targets, N100 and P200 (.74-.86) to oddball non-targets, and P150 amplitude and latency (.84-.93) to working memory stimuli. Neuropsychological tests showed a similarly sound level of consistency (on average, .70), with the most consistent tests tapping simple motor function, estimated intelligence, switching of attention (Part 2), verbal interference response time and memory intrusions (.71-.89). Age and sex did not have a differential impact on reliability for EEG, ERP, or neuropsychology measures. These findings provide preliminary evidence that the "NeuroMarker" battery is reliable for test-retest assessments. The results suggest that the standardized approach has utility for providing sensitive clinical and treatment evaluations across age groups.

    View details for DOI 10.1080/00207450590958475

    View details for Web of Science ID 000233300100001

    View details for PubMedID 16287629

  • Distinct amygdala-autonomic arousal profiles in response to fear signals in healthy males and females NEUROIMAGE Williams, L. M., Barton, M. J., Kemp, A. H., Liddell, B. J., Peduto, A., Gordon, E., Bryant, R. A. 2005; 28 (3): 618-626


    The amygdala has a key role in regulating arousal and vigilance, and responds to both visual and vocal signals of fear, including facial expressions of fear. In this study, we used functional MRI to examine sex differences in the magnitude, extent, lateralization and time course of amygdala responses to facial signals of fear, in a relatively large sample of males and females. Skin conductance was recorded simultaneously with functional imaging to examine concomitant changes in emotional arousal, and to provide an independent index of response attenuation. Scanning and skin conductance recording was undertaken during perception of facial fear stimuli. Sex differences were apparent in the laterality and time course of fear perception. In males, the right amygdala and autonomic arousal attenuated over the late half of the experiment. By contrast, females showed persistent bilateral amygdala responses, with a tendency towards greater left amygdala engagement during the late phase. Females also showed a greater general extent of amygdala response. We suggest that distinct evolutionary pressures might contribute to a lower threshold for vigilance to signals of danger in females, reflected in a profile of sustained amygdala-arousal interaction.

    View details for DOI 10.1016/j.neuroimage.2005.06.035

    View details for Web of Science ID 000233257000010

    View details for PubMedID 16081303

  • Diagnosis-related regional gray matter loss over two years in first episode schizophrenia and bipolar disorder BIOLOGICAL PSYCHIATRY Farrow, T. F., Whitford, T. J., Williams, L. M., Gomes, L., Harris, A. W. 2005; 58 (9): 713-723


    We examined gray- and white-matter brain volumes in first episode psychosis (FEP) at initial presentation and at two-year follow-up. We predicted that FEP subjects would show longitudinal reductions in fronto-temporal gray- and white-matter volumes compared with controls. Furthermore, we expected groups to be differentiated by diagnosis-related reductions.Twenty-five schizophrenia and 8 bipolar disorder FEP patients underwent a structural MRI scan at first presentation and 2 years later. Matched healthy subjects (n = 22) underwent a single identical scan.At initial presentation FEP subjects had significantly less gray- and white-matter than healthy subjects. Diagnostic dissociations were revealed both at first presentation and at follow-up. In schizophrenia patients, gray-matter deficits were observed in lateral and medial frontal regions and in bilateral posterior temporal lobe regions, with additional extensive losses over time in lateral fronto-temporal regions and left anterior cingulate gyrus. By contrast, gray matter deficit in bipolar patients was localized to bilateral inferior temporal gyri with additional loss over time observed only in the anterior cingulate cortex.The results are consistent with a dual process model of psychosis, in which the diagnosis-related gray matter loss is determined by neurodevelopmental gray-matter volumetric differences which predate symptom onset, and diagnosis-related neurodegenerative gray-matter loss over time.

    View details for DOI 10.1016/j.biopsych.2005.04.033

    View details for Web of Science ID 000233207300006

    View details for PubMedID 15993858

  • Preliminary validity of "IntegNeuro (TM)": A new computerized battery of neurocognitive tests INTERNATIONAL JOURNAL OF NEUROSCIENCE Paul, R. H., Lawrence, J., Williams, L. M., Richard, C. C., Cooper, N., Gordon, E. 2005; 115 (11): 1549-1567


    The purpose of this study was to examine the preliminary validity of a newly developed battery of computerized cognitive measures, IntegNeuro. This standardized and semi-automated computerized battery assesses sensori-motor function, attention, new learning and memory, language fluency, executive function, and estimated intelligence. A total of 50 healthy individuals (aged 22-80 years) were included in the study. Correlational analyses revealed highly significant associations between the two cognitive batteries. These results support the use of IntegNeuro as a computerized cognitive system. Additional studies are needed to examine the clinical utility of the battery.

    View details for DOI 10.1080/00207450590957890

    View details for Web of Science ID 000233300000006

    View details for PubMedID 16223701

  • Responses to methylphenidate in adolescent AD/HD: Evidence from concurrently recorded autonomic (EDA) and central (EEG and ERP) measures INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY Hermens, D. F., Williams, L. M., Clarke, S., Kohn, M., Cooper, N., Gordon, E. 2005; 58 (1): 21-33


    This paper aims to examine the effects of methylphenidate (MPH) on integrated baseline and event-related psychophysiological measures in AD/HD. Thirty-four unmedicated AD/HD adolescents (11-17 years; 6 females) were first compared to 34 age- and sex-matched controls, and then re-tested at least 4 weeks after methylphenidate (MPH) medication. In each testing session, EDA was recorded simultaneously with EEG during a resting eyes open condition, and with ERPs during an auditory oddball task. Unmedicated AD/HD subjects were compared to controls and then AD/HD subjects were compared pre- and post-medication. Correlations between the change in EEG theta and the remaining psychophysiological variables were undertaken to provide information about post MPH treatment changes. In the unmedicated state, AD/HD was characterized by abnormally enhanced theta, across fronto-central sites, generally reduced P2 responses, with larger non-specific and oddball-elicited SCRs and poor behavioural performance on the oddball task. Following treatment, AD/HD showed a 'normalization' of theta activity (particularly in the right hemisphere), a reduction in the rate of decrement of EDA and a general increase in P3 amplitude. These findings suggest that methylphenidate is associated with a robust 'normalization' of low frequency EEG activity during the resting brain state, but has less impact on task-related brain activity or phasic changes in autonomic function. This dissociation of resting and task-related activity may prove to be useful in elucidating the effects of stimulant versus new non-stimulant medications in AD/HD.

    View details for DOI 10.1016/j.ijpsycho.2005.03.006

    View details for Web of Science ID 000231913800004

    View details for PubMedID 15936104

  • Neurophysiological markers of contextual processing: The relationship between P3b and Gamma synchrony and their modulation by arousal, performance and individual differences COGNITIVE BRAIN RESEARCH Kang, K., Williams, L. M., Hermens, D., Gordon, E. 2005; 25 (2): 472-483


    The ability to identify and respond to significant events in the environment is a vital aspect of human cognition and yet is poorly understood as a dynamic neural process. While the response to a contextually-relevant stimulus involves a number of complimentary processes, including selective attention and neural binding, it is also subject to modulation by factors like arousal, age and sex. Adopting an integrative approach, we investigated contextual processing (as indexed by P3b and Gamma phase synchrony) in 120 healthy subjects performing an auditory oddball task while controlling for these other modulating factors. Results suggest a relationship between P3b and Gamma-2 synchrony in posterior regions only, with phasic anterior processing seemingly unrelated to that in posterior regions. However, only the P3b was significantly correlated to central and autonomic arousal. Further, while age and sex were associated with variation in individual measures, they did not strongly affect the relationship between the measures. We concluded that, in simple contextual processing, global and local elements of target stimuli are processed in parallel with little variation being shown between the sexes or resulting from increasing age.

    View details for DOI 10.1016/j.cogbrainres.2005.07.008

    View details for Web of Science ID 000233076400007

    View details for PubMedID 16154729

  • Selective errors in declarative memory and hippocampal function associated with brain derived neurotrophic factor polymorphism 13th World Congress on Psychiatric Genetics Schofield, P. R., Williams, L. M., Luty, A., Cooper, N., BROWN, K., Grieve, S., Gordon, E. WILEY-BLACKWELL. 2005: 91–91
  • Biophysical modeling of tonic cortical electrical activity in attention deficit hyperactivity disorder INTERNATIONAL JOURNAL OF NEUROSCIENCE Rowe, D. L., Robinson, P. A., Lazzaro, L., Powles, R. C., Gordon, E., Williams, L. M. 2005; 115 (9): 1273-1305


    Psychophysiological theories characterize Attention Deficit Hyperactivity Disorder (ADHD) in terms of cortical hypoarousal and a lack of inhibition of irrelevant sensory input, drawing on evidence of abnormal electroencephalographic (EEG) delta-theta activity. To investigate the mechanisms underlying this disorder a biophysical model of the cortex was used to fit and replicate the EEGs from 54 ADHD adolescents and their control subjects. The EEG abnormalities in ADHD were accounted for by the model's neurophysiological parameters as follows: (i) dendritic response times were increased, (ii) intrathalamic activity involving the thalamic reticular nucleus (TRN) was increased, consistent with enhanced delta-theta activity, and (iii) intracortical activity was increased, consistent with slow wave (<1 Hz) abnormalities. The longer dendritic response time is consistent with the increase in the activity of inhibitory cells types, particularly in the TRN, and therefore reduced arousal. The increase in intracortical activity may also reflect an increase in background activity or cortical noise within neocortical circuits. In terms of neurochemistry, these findings may be accounted for by disturbances in the cholinergic and/or noradrenergic systems. To the knowledge of the authors, this is the first study to use a detailed biophysical model of the brain to elucidate the neurophysiological mechanisms underlying tonic abnormalities in ADHD.

    View details for DOI 10.1080/00207450590934499

    View details for Web of Science ID 000231267400003

    View details for PubMedID 16048806

  • Grey matter deficits and symptom profile in first episode schizophrenia PSYCHIATRY RESEARCH-NEUROIMAGING Whitford, T. J., Farrow, T. F., Gomes, L., Brennan, J., Harris, A. W., Williams, L. M. 2005; 139 (3): 229-238


    Several studies have investigated grey matter reductions in first episode schizophrenia (FES), but few have examined the relationship between grey matter reduction and clinical profile. A group of 31 patients with strictly defined FES and 30 healthy controls underwent T1-weighted magnetic resonance imaging (MRI) scan. Voxel-based morphometry in SPM99 was used to identify four distinct regions of grey matter reduction in the FES subjects. The regions of interest (ROIs) were in the left ventral prefrontal cortex (ROI 1), left parietal and temporal cortices (ROI 2), right cerebellum (ROI 3), and right frontal and parietal cortices (ROI 4). These regions of reduction were transformed into binary masks, which were convolved with patients' pre-processed grey matter images. Patients' grey matter volumes in these regions were correlated with their composite scores on the following three symptom dimensions: Psychomotor Poverty, Disorganization and Reality Distortion. The volumes of ROIs 1, 2 and 4 were found to be significantly correlated with the Reality Distortion syndrome score. Our findings indicate that distinct, widespread grey matter reductions are present very early in the course of schizophrenia. The results also suggest a possible structural underpinning for the abnormal brain activity typically associated with symptoms of Reality Distortion.

    View details for DOI 10.1016/j.pscychresns.2005.05.010

    View details for Web of Science ID 000231605500006

    View details for PubMedID 16055311

  • Preservation of limbic and paralimbic structures in aging HUMAN BRAIN MAPPING Grieve, S. M., Clark, C. R., Williams, L. M., Peduto, A. J., Gordon, E. 2005; 25 (4): 391-401


    Patterns of gray matter (GM) loss were measured in 223 healthy subjects spanning eight decades. We observed significant clusters of accelerated loss in focal regions of the frontal and parietal cortices, including the dorsolateral frontal cortex, pre- and postcentral gyrus, and the inferior and superior parietal lobes. The rate of loss in these clusters was approximately twice that of the global average. By contrast, clusters of significant GM preservation were found in limbic and paralimbic structures, including the amygdala, hippocampus, thalamus, and the cingulate gyrus. In these clusters, GM loss was attenuated significantly relative to the global rate. The preservation of these structures is consistent with the functional importance of the thalamo-limbic circuits in sensory integration, arousal, emotion, and memory, and lends credence to the idea that later-maturing cortical regions are more vulnerable to age-related morphologic changes. Moreover, the limbic findings act as a frame of reference to explore further the effects of stress and learning on these structures in an evidence-based manner across age.

    View details for DOI 10.1002/hbm.20115

    View details for Web of Science ID 000230971000004

    View details for PubMedID 15852381

  • Neural networks of information processing in posttraumatic stress disorder: A functional magnetic resonance imaging study BIOLOGICAL PSYCHIATRY Bryant, R. A., Felmingham, K. L., Kemp, A. H., Barton, M., Peduto, A. S., Rennie, C., Gordon, E., Williams, L. M. 2005; 58 (2): 111-118


    Neuroimaging studies report reduced medial prefrontal cortical (particularly anterior cingulate) but enhanced amygdala response to fear signals in posttraumatic Stress Disorder (PTSD). We investigated whether anterior cingulate-amygdala dysregulation in PTSD would generalize to salient, but nonthreat related signals.Individuals with PTSD (n = 14) and age and sex-matched nontraumatized controls (n = 14) completed an auditory oddball paradigm adapted to functional magnetic resonance imaging at a 1.5-T field strength.Controls displayed bilateral activation in ventral anterior cingulate and amygdala networks, and PTSD subjects showed bilateral dorsal anterior cingulate and amygdala activation to targets relative to nontargets. Compared to controls, PTSD subjects showed enhanced responses to targets in the dorsal and rostral anterior cingulate, and left amygdala. Whole-brain analyses confirmed the expected pattern of distributed prefrontal-parietal responses to targets in the oddball task. Greater activity in posterior parietal somatosensory regions was observed in PTSD.Our findings of enhanced anterior cingulate responses in PTSD contrast with reports of reduced activity for threat stimuli, suggesting that the latter may be specific to processing of threat-related content. Activation in rostral and dorsal anterior cingulate, left amygdala and posterior parietal networks in response to salient, nonthreatening stimuli may reflect generalized hypervigilance.

    View details for DOI 10.1016/j.biopsych.2005.03.021

    View details for Web of Science ID 000230605300004

    View details for PubMedID 16038681

  • Category and letter verbal fluency across the adult lifespan: relationship to EEG theta power ARCHIVES OF CLINICAL NEUROPSYCHOLOGY Brickman, A. M., Paul, R. H., Cohen, R. A., Williams, L. M., MacGregor, K. L., Jefferson, A. L., Tate, D. F., Gunstad, J., Gordon, E. 2005; 20 (5): 561-573


    The purpose of this study was to examine the impact of age, sex, and education on category and letter verbal fluency task performance. A secondary goal was to examine whether resting EEG theta power in bilateral frontal and temporal lobes impacts age-associated decline in verbal fluency task performance. A large sample (N = 471) of healthy, normal participants, age 21-82, was assessed for letter fluency (i.e., FAS), and for category fluency (i.e., Animal Naming), and with a 32-channel EEG system for 'eyes-open' resting theta power. The effects of age, sex, and education were examined using analyses of variance. Correlation analyses were used to test the impact of theta power on age and fluency performance by controlling for the effects of theta when examining the relationship between the other two variables. The results indicated that performance on both fluency tests declined linearly with age, but that the rate of decline was greater for category fluency. These age changes were not associated with education level, and there were no sex differences. While theta power was negatively associated with age and positively associated with Animal Naming performance, it did not moderate the relationship between the two. The differential age-associated decline between category and letter fluency suggests separate neurobiological substrates underlying the two domains of performance, which is not related to theta activity.

    View details for DOI 10.1016/j.acn.2004.12.006

    View details for Web of Science ID 000230266900001

    View details for PubMedID 15939182

  • Sex differences in adolescent ADHD: findings from concurrent EEG and EDA CLINICAL NEUROPHYSIOLOGY Hermens, D. F., Kohn, M. R., Clarke, S. D., Gordon, E., Williams, L. M. 2005; 116 (6): 1455-1463


    Attention Deficit Hyperactivity Disorder (ADHD) occurs more frequently in male children and adolescents than in females, with a ratio of approximately 3 to 1. We determined whether psychophysiological differences are associated with the expression of ADHD in males and females, using simultaneously recorded electroencephalography (EEG) and electrodermal activity (EDA).Quantitative EEG and EDA measures were acquired simultaneously and continuously (2min) during an eyes closed resting condition for 70 ADHD adolescents (48 males, 22 females) and their age- and sex-matched controls.Males and females with ADHD were differentiated by both EEG theta activity and EDA. ADHD males showed increased theta (widespread), whereas ADHD females showed a localised frontal enhancement of theta with reduced rate of EDA decrement. These sex differences were unrelated to ADHD subtype.These findings suggest that different psychophysiological processes may underlie ADHD in each sex. The profile of theta enhancement in ADHD males is consistent with a developmental deviation model of ADHD, whereas ADHD in females may be better understood within an arousal model, which emphasizes both central and autonomic function.These findings highlight the potential for concurrent EDA measures to inform EEG studies of ADHD, particularly in regard to sex differences.

    View details for DOI 10.1016/j.clinph.2005.02.012

    View details for Web of Science ID 000229984300025

    View details for PubMedID 15978508

  • Pathways for fear perception: Modulation of amygdala activity by thalamo-cortical systems NEUROIMAGE Das, P., Kemp, A. H., Liddell, B. J., Brown, K. J., Olivieri, G., Peduto, A., Gordon, E., Williams, L. M. 2005; 26 (1): 141-148


    Effective perception of fear signals is crucial for human survival and the importance of the amygdala in this process is well documented. Animal, lesion and neuroimaging studies indicate that incoming sensory signals of fear travel from thalamus to amygdala via two neural pathways: a direct subcortical route and an indirect pathway via the sensory cortex. Other lines of research have demonstrated prefrontal modulation of the amygdala. However, no study to date has examined the prefrontal modulation of the thalamo-cortico-amygdala pathways in vivo. We used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamus, amygdala and sensory (inferior occipital, fusiform) cortices, and the modulation of these networks by the anterior cingulate cortex (ACC). Functional magnetic resonance imaging (fMRI) data were acquired for 28 healthy control subjects during a fear perception task, with neutral as the 'baseline' control condition. Main effect analysis, using a region of interest (ROI) approach, confirmed that these regions are part of a distributed neural system for fear perception. Psychophysiological interactions revealed an inverse functional connectivity between occipito-temporal visual regions and the left amygdala, but a positive connectivity between these visual region and the right amygdala, suggesting that there is a hemispheric specialization in the transfer of fear signals from sensory cortices to amygdala. Physiophysiological interactions revealed a dorsal-ventral division in ACC modulation of the thalamus-sensory cortex pathway. While the dorsal ACC showed a positive modulation of this pathway, the ventral ACC exhibited an inverse relationship. In addition, both the dorsal and ventral ACC showed an inverse interaction with the direct thalamus-amygdala pathway. These findings suggest that thalamo-amygdala and cortical regions are involved in a dynamic interplay, with functional differentiation in both lateralized and ventral/dorsal gradients. Breakdowns in these interactions may give rise to affect-related symptoms seen in a range of neuropsychiatric disorders.

    View details for DOI 10.1016/j.neuroimage.2005.01.049

    View details for Web of Science ID 000228915800016

    View details for PubMedID 15862214

  • Integrative neuroscience: The role of a standardized database CLINICAL EEG AND NEUROSCIENCE Gordon, E., Cooper, N., Rennie, C., Hermens, D., Williams, L. M. 2005; 36 (2): 64-75


    Most brain related databases bring together specialized information, with a growing number that include neuroimaging measures. This article outlines the potential use and insights from the first entirely standardized and centralized database, which integrates information from neuroimaging measures (EEG, event related potential (ERP), structural/functional MRI), arousal (skin conductance responses (SCR)s, heart rate, respiration), neuropsychological and personality tests, genomics and demographics: The Brain Resource International Database. It comprises data from over 2000 "normative" subjects and a growing number of patients with neurological and psychiatric illnesses, acquired from over 50 laboratories (in the U.S.A, United Kingdom, Holland, South Africa, Israel and Australia), all with identical equipment and experimental procedures. Three primary goals of this database are to quantify individual differences in normative brain function, to compare an individual's performance to their database peers, and to provide a robust normative framework for clinical assessment and treatment prediction. We present three example demonstrations in relation to these goals. First, we show how consistent age differences may be quantified when large subject numbers are available, using EEG and ERP data from nearly 2000 stringently screened. normative subjects. Second, the use of a normalization technique provides a means to compare clinical subjects (50 ADHD subjects in this study) to the normative database with the effects of age and gender taken into account. Third, we show how a profile of EEG/ERP and autonomic measures potentially provides a means to predict treatment response in ADHD subjects. The example data consists of EEG under eyes open and eyes closed and ERP data for auditory oddball, working memory and Go-NoGo paradigms. Autonomic measures of skin conductance (tonic skin conductance level, SCL, and phasic skin conductance responses, SCRs) were acquired simultaneously with central EEG/ERP measures. The findings show that the power of large samples, tested using standardized protocols, allows for the quantification of individual differences that can subsequently be used to control such variation and to enhance the sensitivity and specificity of comparisons between normative and clinical groups. In terms of broader significance, the combination of size and multidimensional measures tapping the brain's core cognitive competencies, may provide a normative and evidence-based framework for individually-based assessments in "Personalized Medicine."

    View details for Web of Science ID 000202980500003

    View details for PubMedID 15999901

  • Resting EEG theta activity predicts cognitive performance in attention-deficit hyperactivity disorder PEDIATRIC NEUROLOGY Hermens, D. F., Soei, E. X., Clarke, S. D., Kohn, M. R., Gordon, E., Williams, L. M. 2005; 32 (4): 248-256


    Quantitative electroencephalography has contributed significantly to elucidating the neurobiologic mechanisms of attention-deficit hyperactivity disorder. The most consistent and robust electroencephalographic disturbance in attention-deficit hyperactivity disorder has been abnormally increased theta band during resting conditions. Separate research using attention-demanding tests has elucidated cognitive disturbances that differentiate attention-deficit hyperactivity disorder. This study attempts to integrate electroencephalographic and neuropsychological indices to determine whether cognitive performance is specifically related to increased theta. Theta activity was recorded during a resting condition for 46 children/adolescents with attention-deficit hyperactivity disorder and their sex- and age-matched control subjects. Accuracy and reaction time during an auditory oddball and a visual continuous performance test were then recorded. Compared with control subjects, the attention-deficit hyperactivity disorder group manifested significantly increased (primarily left) frontal theta. Furthermore, the attention-deficit hyperactivity disorder group scored significantly delayed reaction time and decreased accuracy in both tasks. Correlation analysis revealed a significant relationship between frontal (primarily left) theta and oddball accuracy for the attention-deficit hyperactivity disorder group compared with a significant relationship between posterior (primarily right) theta and reaction time in the continuous performance test for the control group. These results indicate that spatial neurophysiologic deficits in attention-deficit hyperactivity disorder may be related to disturbances in signal detection. This observation has important implications for the role of trait-like biologic deficits in attention-deficit hyperactivity disorder predicting performance in information processing.

    View details for DOI 10.1016/j.pediatrneurol.2004.11.009

    View details for Web of Science ID 000228472600005

    View details for PubMedID 15797181

  • The dose-dependent effect of methylphenidate on performance, cognition and psychophysiology. Journal of integrative neuroscience Cooper, N. J., Keage, H., Hermens, D., Williams, L. M., Debrota, D., Clark, C. R., Gordon, E. 2005; 4 (1): 123-144


    The effects of methylphenidate (MPH) on 32 healthy human male volunteers (aged 18 to 25 years, mean age=22.26) were examined using a within-subject design. Each participant attended six testing periods, held once per week. Within each testing period, three repeat testing sessions were undertaken: pre-medication, on-medication and two hours post-medication. In these sessions, dose was manipulated (placebo, 5 mg, 15 mg or 45 mg) according a double-blind placebo design. In this report, we focus on behavioral, autonomic arousal (heart rate, skin conductance) and psychophysiological (ERP) data acquired during the working memory task. We found increased autonomic arousal (heart rate, skin conductance and blood pressure) with MPH. A linear reduction in reaction time, omission errors and target P3 latency, and a corresponding increase in background P3 amplitude was observed with increased MPH dose. The relationship between these measures supported an increase in performance and underlying brain function with MPH. To our knowledge, this is the first paper to use behavioral, arousal and electrophysiological measures in an integrative approach to study the effects of MPH on healthy adults.

    View details for PubMedID 16035144

  • Age-dependent change in executive function and gamma 40 Hz phase synchrony. Journal of integrative neuroscience Paul, R. H., Clark, C. R., Lawrence, J., Goldberg, E., Williams, L. M., Cooper, N., Cohen, R. A., Brickman, A. M., Gordon, E. 2005; 4 (1): 63-76


    Decline in cognitive function is well recognized, yet few neurophysiological correlates of age-related cognitive decline have been identified. In this study we examined the impact of age on neurocognitive function and Gamma phase synchrony among 550 normal subjects (aged 11-70). Gamma phase synchrony was acquired to targets in the auditory oddball paradigm. The two tasks of executive function were switching of attention and an electronic maze. Subjects were divided into four age groups, which were balanced for sex. We hypothesized that reduced cognitive performance among older healthy individuals would be associated with age-related changes in gamma phase synchrony. Results showed a significant decrease in executive function in the oldest (51-70 years) age group. ANOVAs of age-by-frontal Gamma synchrony also showed a significant effect of age on Gamma phase synchrony in the left frontal region that corresponded modestly to the age effect found on executive task performance, with reduced performance associated with increased gamma synchrony. The results indicate that age-related changes in cognitive function evident among elderly individuals may in part be related to decreased ability to integrate information and this may be reflected as a compensatory increase in gamma synchrony in frontal regions of the brain.

    View details for PubMedID 16035141

  • Toward an integrated profile of emotional intelligence: introducing a brief measure. Journal of integrative neuroscience Kemp, A. H., Cooper, N. J., Hermens, G., Gordon, E., Bryant, R., Williams, L. M. 2005; 4 (1): 41-61


    Over the last decade, an increasing number of research studies have focused on the construct of Emotional Intelligence (EI), which may be broadly defined as the capacity to perceive and regulate emotions in oneself as well as those of others. Researchers have generally adopted an organizational or management focus to the study of EI, however studies which adopt a more integrated perspective by combining psychological with biological measures, may help in further elucidating this relatively abstract construct. The first objective of this paper was to report on the psychometric properties of a brief, self-report measure of EI (Brain Resource Inventory for Emotional intelligence Factors or BRIEF), comprising internal emotional capacity (IEC), external emotional capacity (EEC) and self concept (SELF). Second, we further explored the validity of the measure by assessing the relationships between the BRIEF and variables considered relevant to the understanding of EI (including gender, age, personality, cognitive intelligence and resting state electroencephalography, EEG). The BRIEF possessed sound psychometric properties (internal consistency, r=0.68-0.81; test-retest reliability, r=0.92; construct validity with the Self Report Emotional Intelligence Test, r=0.70). As hypothesized, females were found to score higher than males on EI. EI was associated more with personality than with cognitive ability, and EEG was found to explain a significant portion of the variance in EI scores. The finding that low EI is related to underarousal of the left-frontal cortex (increased theta EEG) is consistent with research on patients with depression, as well as attention deficit hyperactivity disorder. Although EI did not display age-related increases, this might relate to the exclusion of adolescents from our sample. In conclusion, examination of the way in which EI measures relate to a complementary range of psychological and biological measures may help to further elucidate this construct.

    View details for PubMedID 16035140

  • The impact of early life stress on psychophysiological, personality and behavioral measures in 740 non-clinical subjects. Journal of integrative neuroscience McFarlane, A., Clark, C. R., Bryant, R. A., Williams, L. M., Niaura, R., Paul, R. H., Hitsman, B. L., Stroud, L., Alexander, D. M., Gordon, E. 2005; 4 (1): 27-40


    Early Life Stress (ELS) has been associated with a range of adverse outcomes in adults, including abnormalities in electrical brain activity [1], personality dimensions [40], increased vulnerability to substance abuse and depression [14]. The present study seeks to quantify these proposed effects in a large sample of non-clinical subjects. Data for the study was obtained from The Brain Resource International Database (six laboratories: two in USA, two in Europe, two in Australia). This study analyzed scalp electrophysiological data (EEG eyes open, closed and target auditory oddball data) and personality (NEO-FFI), history of addictive substance use and ELS) data that was acquired from 740 healthy volunteers. The ELS measures were collected via a self-report measure and covered a broad range of events from childhood sexual and physical abuse, to first-hand experience of traumatizing accidents and sustained domestic conflict [41]. Analysis of covariance, controlling for age and gender, compared EEG data from subjects exposed to ELS with those who were unexposed. ELS was associated with significantly decreased power across the EEG spectrum. The between group differences were strongest in the eyes closed paradigm, where subjects who experienced ELS showed significantly reduced beta (F1,405=12.37, p=.000), theta (F1,405=20.48, p=.000), alpha (F1,405=9.65, p=.002) and delta power (F1,450=36.22, p=.000). ELS exposed subjects also showed a significantly higher alpha peak frequency (F1,405=6.39, p=.012) in the eyes closed paradigm. Analysis of covariance on ERP components revealed that subjects who experienced ELS had significantly decreased N2 amplitude (F1,405=7.73, p=.006). Analyses of variance conducted on measures of personality revealed that subjects who experienced ELS had significantly higher levels of neuroticism (F1,264=13.39, p=.000) and openness (F1,264=17.11, p=.000), but lower levels of conscientiousness, than controls (F1,264=4.08, p=.044). The number of ELS events experienced was shown to be a significant predictor of scores on the DASS questionnaire [27], which rates subjects on symptoms of depression (F3,688=16.44, p=.000, R2=.07), anxiety (F3,688=14.32, p=.000, R2=.06) and stress (F3,688=20.02, p=.000, R2=.08). Each additional early life stressor was associated with an increase in these scores independent of age, gender and the type of stressor. Furthermore, the number of ELS experiences among smokers was also found to be a positive predictor of the nicotine dependency score (Faegstrom Test For Nicotine Dependence, [19]) (F3,104=10.99, p=.000, R2=.24), independent of age, gender and type of stressor. In conclusion, we highlight the impact of a history of ELS showed significant effects on brain function (EEG and ERP activity), personality dimensions and nicotine dependence.

    View details for PubMedID 16035139

  • Neural synchrony and gray matter variation in human males and females: integration of 40 Hz gamma synchrony and MRI measures. Journal of integrative neuroscience Williams, L. M., Grieve, S. M., Whitford, T. J., Clark, C. R., Gur, R. C., Goldberg, E., Flor-Henry, P., Peduto, A. S., Gordon, E. 2005; 4 (1): 77-93


    Coherent cognition requires activity to be brought together across diverse brain networks. Synchronous, in-phase oscillations in the high-frequency (40 Hz) Gamma range are thought to be one mechanism underlying the functional integration of brain networks. While sex differences have been observed across a range of cognitive functions, their role in normal cortical synchronization has not been elucidated. We recorded Gamma phase synchrony in 500 male and 500 female subjects during an auditory oddball task, which taps discrimination of task-relevant signals. Results revealed a marked sex-linked dissociation in the spatio-temporal pattern of cortical synchronization. Females showed increased Gamma synchrony in the frontal brain, while males showed enhanced synchrony in the parieto-occipital region. These differences were not accounted for by sex differences in whole brain MRI volume. However, there were positive associations between Gamma synchrony and gray matter for females, while these relationships were negative for males. Sex differences in the profile of cortical synchronization may reflect distinct aspects of evolutionary advantage.

    View details for PubMedID 16035142

  • Toward an integrated profile of depression: evidence from the brain resource international database. Journal of integrative neuroscience Kemp, A. H., Stephan, B. C., Hopkinson, P., Sumich, A. L., Paul, R. H., Clark, C. R., Gordon, E., Bryant, R. A., Williams, L. M. 2005; 4 (1): 95-106


    Clinical depression is one of the most common psychiatric disorders in adults, yet non-clinical depression in the community may go unnoticed, despite high prevalence rates and significant psychosocial impairment. The aim of the current study was to classify 1,226 individuals from a community sample on the basis of depression scores (using the Depression Anxiety Stress Scales, DASS) and to determine whether depression in a non-clinical sample differed significantly from healthy controls on a profile of multimodal measures. The data analyzed in this study included personality, emotional intelligence, cognition and psychophysiology. It was predicted that non-clinically depressed participants would differ from healthy controls on measures of personality (increased neuroticism; decreased extraversion), emotional intelligence (decreased), cognition (impairments in executive dysfunction and memory impairment), psychophysiology (increased resting-state, right-frontal activation; diminished skin conductance) after controlling for gender, age, handedness and years of education. Findings provide support for the majority of hypotheses, though no evidence was found for memory impairment or frontal hemispheric asymmetry. Longitudinal studies are needed to determine the extent to which of these findings will have utility for the prediction of depression onset and treatment response/non-response.

    View details for PubMedID 16035143

  • Distinct pattern of P3a event-related potential in borderline personality disorder NEUROREPORT Meares, R., Melkonian, D., Gordon, E., Williams, L. 2005; 16 (3): 289-293


    P3a and P3b event-related brain potentials to auditory stimuli were recorded for 17 unmedicated patients with borderline personality disorder, 17 matched healthy controls and 100 healthy control participants spanning five decades. Using high-resolution fragmentary decomposition for single-trial event-related potential analysis, distinctive disturbances in P3a in borderline personality disorder patients were found: abnormally enhanced amplitude, failure to habituate and a loss of temporal locking with P3b. Normative age dependencies from 100 controls suggest that natural age-related decline in P3a amplitude is reduced in borderline personality disorder patients and is likely to indicate failure of frontal maturation. On the basis of the theories of Hughlings Jackson, this conceptualization of borderline personality disorder is consistent with an aetiological model of borderline personality disorder.

    View details for Web of Science ID 000227620100018

    View details for PubMedID 15706238

  • BOLD, sweat and fears: fMRI and skin conductance distinguish facial fear signals NEUROREPORT Williams, L. M., Das, P., Liddell, B., Olivieri, G., Peduto, A., Brammer, M. J., Gordon, E. 2005; 16 (1): 49-52


    It is not known how the brain and autonomic systems interact during perception of facial signals of danger. We recorded blood-oxygen-level-dependent (BOLD) activity using fMRI and simultaneous skin conductance measures of autonomic arousal in healthy subjects. Distinct response profiles were elicited for fear (enhanced arousal with amygdala activity), anger (rapid onset, slow recovery arousal responses with anterior cingulate) and disgust (delayed arousal responses with insula and basal ganglia activity). The findings suggest that fear, anger and disgust perception involves specific interactions in the neural arousal systems for emotion and motivation.

    View details for Web of Science ID 000226737000012

    View details for PubMedID 15618889

  • Examining the time course of subliminal emotion perception Liddell, B., Palmer, D., Gordon, E., Williams, L. M. WILEY-BLACKWELL. 2005: 29–29
  • A direct brainstem-amygdala-cortical 'alarm' system for subliminal signals of fear NEUROIMAGE Liddell, B. J., Brown, K. J., Kemp, A. H., Barton, M. J., Das, P., Peduto, A., Gordon, E., Williams, L. M. 2005; 24 (1): 235-243


    We examined whether consciously undetected fear signals engage a collateral brainstem pathway to the amygdala and prefrontal cortex in the intact human brain, using functional neuroimaging. 'Blindsight' lesion patients can respond to visual fear signals independently from conscious experience, suggesting that these signals reach the amygdala via a direct pathway that bypasses the primary visual cortex. Electrophysiological evidence points to concomitant involvement of prefrontal regions in automatic orienting to subliminal signals of fear, which may reflect innervation arising from brainstem arousal systems. To approximate blindsight in 22 healthy subjects, facial signals of fear were presented briefly (16.7 ms) and masked such that conscious detection was prevented. Results revealed that subliminal fear signals elicited activity in the brainstem region encompassing the superior colliculus and locus coeruleus, pulvinar and amygdala, and in fronto-temporal regions associated with orienting. These findings suggest that crude sensory input from the superior colliculo-pulvinar visual pathway to the amygdala may allow for sufficient appraisal of fear signals to innervate the locus coeruleus. The engagement of the locus coeruleus could explain the observation of diffuse fronto-temporal cortical activity, given its role in evoking collateral ascending noradrenergic efferents to the subcortical amygdala and prefrontal cortex. This network may represent an evolutionary adaptive neural 'alarm' system for rapid alerting to sources of threat, without the need for conscious appraisal.

    View details for DOI 10.1016/neuroimage.2004.08.016

    View details for Web of Science ID 000225811800025

    View details for PubMedID 15588615

  • The problem of comorbidity: Using event-related potentials to delineate temporal markers for PTSD above comorbid depression Terpening, Z., Felmingham, K., Bryant, R., Gordon, E., Williams, L. M. WILEY-BLACKWELL. 2005: 38–38
  • Age-related changes in the processing of facial stimuli: An ERP study Palmer, D. M., Williams, L. M., Liddell, B. J., Gordon, E. WILEY-BLACKWELL. 2005: 33–34
  • Gamma phase synchrony in children with attention deficit/hyperactivity disorder Keage, H. A., Clark, C. R., Hermens, D. F., Clarke, S., Kohn, M., Williams, L. M., Crewther, D. P., Gordon, E. WILEY-BLACKWELL. 2005: 27–27
  • The dynamics of cortico-amygdala and autonomic activity over the experimental time course of fear perception COGNITIVE BRAIN RESEARCH Williams, L. M., Brown, K. J., Das, P., Boucsein, W., Sokolov, E. N., Brammer, M. J., Olivieri, G., Peduto, A., Gordon, E. 2004; 21 (1): 114-123


    Human neuroimaging studies implicate the amygdala, medial prefrontal and somatosensory-related cortices as key neural components in the perception of facial fear signals. Yet, their temporal sequence and interaction with autonomic arousal is not known. We used simultaneous functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) recording in 22 healthy subjects to examine central and autonomic responses to repeated fearful expressions. Phasic SCRs followed a U-shape pattern across early, middle and late presentations of fear stimuli. fMRI data revealed a concomitant temporal sequence of preferential somatosensory insula, dorsomedial prefrontal cortex and left amygdala engagement. These findings suggest that sustained cortico-amygdala and autonomic responses may serve to prime the emotional content of fear signals, and differentiate them from initial stimulus novelty.

    View details for DOI 10.1016/j.cogbrainres.2004.06.005

    View details for Web of Science ID 000224336200012

    View details for PubMedID 15325419

  • Sex differences in functional connectivity in first-episode and chronic schizophrenia patients AMERICAN JOURNAL OF PSYCHIATRY Slewa-Younan, S., Gordon, E., Harris, A. W., Haig, A. R., Brown, K. J., Flor-Henry, P., Williams, L. M. 2004; 161 (9): 1595-1602


    There has been consistent evidence for a lower incidence and milder course of schizophrenia in women, yet there have been very few investigations of sex differences in brain function in this disorder. This study used a new high-temporal-resolution measure of functional brain connectivity to test the prediction that female patients would show relatively greater inter- and intrahemispheric connectivity than male patients, particularly in the early stage of schizophrenia.Forty patients with chronic schizophrenia (20 women and 20 men) and 24 patients with first-episode schizophrenia (12 women and 12 men) and their respective matched comparison groups completed a conventional auditory oddball task. Phase synchronous gamma (40 Hz) activity was extracted from EEG recording during the task and time-locked to the oddball (target) stimuli.Chronic schizophrenia subjects showed a reduction in global functional connectivity (lower gamma phase synchrony) relative to their matched healthy subjects. Unexpectedly, this reduction was most apparent in female patients. By contrast, while first-episode patients showed a general reduction in the speed of frontal connectivity, the speed of global connectivity was relatively faster in female patients.This is the first study to investigate sex differences in schizophrenia that used the functional connectivity measure of gamma phase synchrony. The results suggest that in female patients with schizophrenia, additional breakdowns in brain network connectivity may develop with illness chronicity.

    View details for Web of Science ID 000223800600012

    View details for PubMedID 15337649

  • Spatiotemporal wavelet resampling for functional neuroimaging data HUMAN BRAIN MAPPING Breakspear, M., Brammer, M. J., Bullmore, E. T., Das, P., Williams, L. M. 2004; 23 (1): 1-25


    The study of dynamic interdependences between brain regions is currently a very active research field. For any connectivity study, it is important to determine whether correlations between two selected brain regions are statistically significant or only chance effects due to non-specific correlations present throughout the data. In this report, we present a wavelet-based non-parametric technique for testing the null hypothesis that the correlations are typical of the data set and not unique to the regions of interest. This is achieved through spatiotemporal resampling of the data in the wavelet domain. Two functional MRI data sets were analysed: (1) Data from 8 healthy human subjects viewing a checkerboard image, and (2) "Null" data obtained from 3 healthy human subjects, resting with eyes closed. It was demonstrated that constrained resampling of the data in the wavelet domain allows construction of bootstrapped data with four essential properties: (1) Spatial and temporal correlations within and between slices are preserved, (2) The irregular geometry of the intracranial images is maintained, (3) There is adequate type I error control, and (4) Expected experiment-induced correlations are identified. The limitations and possible extensions of the proposed technique are discussed.

    View details for DOI 10.1002/hbm.20045

    View details for Web of Science ID 000223541400001

    View details for PubMedID 15281138

  • Sex differences in adult ADHD: a double dissociation in brain activity and autonomic arousal BIOLOGICAL PSYCHOLOGY Hermens, D. F., Williams, L. M., Lazzaro, I., Whitmont, S., Melkonian, D., Gordon, E. 2004; 66 (3): 221-233


    It is now estimated that up to one-half of attention deficit hyperactivity disorder (ADHD) children continue to manifest symptoms in adulthood. A striking discrepancy between juvenile and adult populations is the increasing proportion of females with an ADHD diagnosis. To shed light on the psychophysiological mechanisms underlying adult ADHD, electroencephalography (EEG) and electrodermal index of arousal (skin conductance level or SCL) measures were employed under conditions of eyes-closed resting activity. Quantitative EEG (QEEG) and SCL were measured simultaneously and continuously (2 min) in 35 ADHD adults (21 males, 14 females) and their age- and sex-matched controls. As a group ADHD adults were found to have EEG and SCL deviations consistent with previous adolescent and juvenile studies. However, adult males (but not females) with ADHD showed increased EEG theta activity. By contrast, adult females (but not males) with ADHD were autonomically hypo-aroused (decreased SCL). These results suggest that distinct mechanisms may underpin adult ADHD in males and females.

    View details for DOI 10.1016/j.biopsycho.2003.10.006

    View details for Web of Science ID 000222123900002

    View details for PubMedID 15099695

  • Face to face: visual scanpath evidence for abnormal processing of facial expressions in social phobia PSYCHIATRY RESEARCH Horley, K., Williams, L. M., Gonsalvez, C., Gordon, E. 2004; 127 (1-2): 43-53


    Cognitive models of social phobia propose that cognitive biases and fears regarding negative evaluation by others result in preferential attention to interpersonal sources of threat. These fears may account for the hypervigilance and avoidance of eye contact commonly reported by clinicians. This study provides the first objective examination of threat-related processing in social phobia. It was predicted that hyperscanning (hypervigilance) and eye avoidance would be most apparent in social phobia for overt expressions of threat. An infrared corneal reflection technique was used to record visual scanpaths in response to angry, sad, and happy vs. neutral facial expressions. Twenty-two subjects with social phobia were compared with age- and sex-matched normal controls. As predicted, social phobia subjects displayed hyperscanning, (increased scanpath length) and avoidance (reduced foveal fixations) of the eyes, particularly evident for angry faces. The results could not be explained by either medication or co-morbid depression. These findings are consistent with theories emphasising the role of information processing biases in social phobia, and show promise in the application to treatment evaluation in this disorder.

    View details for DOI 10.1016/j.psychres.2004.02.016

    View details for Web of Science ID 000222952700006

    View details for PubMedID 15261704

  • Differential neural responses to overt and covert presentations of facial expressions of fear and disgust NEUROIMAGE Phillips, M. L., Williams, L. M., Heining, M., Herba, C. M., Russell, T., Andrew, C., Brammer, M. J., Williams, S. C., Morgan, M., Young, A. W., Gray, J. A. 2004; 21 (4): 1484-1496


    There is debate in cognitive neuroscience whether conscious versus unconscious processing represents a categorical or a quantitative distinction. The purpose of the study was to explore this matter using functional magnetic resonance imaging (fMRI). We first established objective thresholds of the critical temporal parameters for overt and covert presentations of fear and disgust. Next we applied these stimulus parameters in an fMRI experiment to determine whether non-consciously perceived (covert) facial expressions of fear and disgust show the same double dissociation (amygdala response to fear, insula to disgust) observed with consciously perceived (overt) stimuli. A backward masking paradigm was used. In the psychophysics experiment, the following parameters were established: 30-ms target duration for the covert condition, and 170-ms target duration for the overt condition. Results of the block-design fMRI study indicated substantial differences underlying the perception of fearful and disgusted facial expressions, with significant effects of both emotion and target duration. Findings for the overt condition (170 ms) confirm previous evidence of amygdala activation to fearful faces, and insula activation to disgusted faces, and a double dissociation between these two emotions. In the covert condition (30 ms), the amygdala was not activated to fear, nor was the insula activated to disgust. Overall, findings demonstrate significant differences between the neural responses to fear and to disgust, and between the covert presentations of these two emotions. These results therefore suggest distinct neural correlates of conscious and unconscious emotion perception.

    View details for DOI 10.1016/j.neuroimage.2003.12.013

    View details for Web of Science ID 000220723900027

    View details for PubMedID 15050573

  • A temporal dissociation of subliminal versus supraliminal fear perception: An event-related potential study JOURNAL OF COGNITIVE NEUROSCIENCE Liddell, B. J., Williams, L. M., Rathjen, J., Shevrin, H., Gordon, E. 2004; 16 (3): 479-486


    Current theories of emotion suggest that threat-related stimuli are first processed via an automatically engaged neural mechanism, which occurs outside conscious awareness. This mechanism operates in conjunction with a slower and more comprehensive process that allows a detailed evaluation of the potentially harmful stimulus (LeDoux, 1998). We drew on the Halgren and Marinkovic (1995) model to examine these processes using event-related potentials (ERPs) within a backward masking paradigm. Stimuli used were faces with fear and neutral (as baseline control) expressions, presented above (supraliminal) and below (subliminal) the threshold for conscious detection. ERP data revealed a double dissociation for the supraliminal versus subliminal perception of fear. In the subliminal condition, responses to the perception of fear stimuli were enhanced relative to neutral for the N2 "excitatory" component, which is thought to represent orienting and automatic aspects of face processing. By contrast, supraliminal perception of fear was associated with relatively enhanced responses for the late P3 "inhibitory" component, implicated in the integration of emotional processes. These findings provide evidence in support of Halgren and Marinkovic's temporal model of emotion processing, and indicate that the neural mechanisms for appraising signals of threat may be initiated, not only automatically, but also without the need for conscious detection of these signals.

    View details for Web of Science ID 000220490700012

    View details for PubMedID 15072682

  • An investigation of individual typologies of attention-deficit hyperactivity disorder using cluster analysis of DSM-IV criteria PERSONALITY AND INDIVIDUAL DIFFERENCES Marsh, P. J., Williams, L. M. 2004; 36 (5): 1187-1195
  • Visual scanpath dysfunction in first-degree relatives of schizophrenia probands: evidence for a vulnerability marker? SCHIZOPHRENIA RESEARCH Loughland, C. M., Williams, L. M., Harris, A. W. 2004; 67 (1): 11-21


    Previous research demonstrates that people with schizophrenia have abnormally 'restricted' visual scanpaths to face and facial expression stimuli, which appear to be diagnostically specific to schizophrenia [Schizophr. Res. 55 (2002) 159; Biol. Psychiatry 52 (2002) 338]. This study examined the familial transmission of 'restricted' scanpaths in first-degree relatives of schizophrenia subjects. We recorded visual scanpaths for 65 schizophrenia subjects, 37 biological first-degree relatives and 61 nonrelated 'healthy' control subjects in two experiments: 'face recognition' and 'facial affect recognition'. Concurrent behavioral tasks were face matching and expression matching, each under two multiple-choice conditions (seven or three options). As predicted, first-degree relatives generally showed an attenuated form of the markedly 'restricted' scanpaths of schizophrenia subjects across all face stimuli. The notable exception to this pattern was the relatives' extreme avoidance of facial features (compared to both schizophrenia and healthy control groups). Our results offer the first evidence that some components of visual scanpath dysfunction may represent a trait marker in the familial transmission of schizophrenia, but that first-degree relatives may have additional disturbances in social cognition associated with the perception of facial features.

    View details for DOI 10.1016/S0920-9964(03)00094-X

    View details for Web of Science ID 000188738800002

    View details for PubMedID 14741320

  • Mapping the time course of nonconscious and conscious perception of fear: An integration of central and peripheral measures HUMAN BRAIN MAPPING Williams, L. M., Liddell, B. J., Rathjen, J., Brown, K. J., Gray, J., Phillips, M., Young, A., Gordon, E. 2004; 21 (2): 64-74


    Neuroimaging studies using backward masking suggest that conscious and nonconscious responses to complex signals of fear (facial expressions) occur via parallel cortical and subcortical circuits. Little is known, however, about the temporal differentiation of these responses. Psychophysics procedures were first used to determine objective thresholds for both nonconscious detection (face vs. blank screen) and discrimination (fear vs. neutral face) in a backward masking paradigm. Event-related potentials (ERPs) were then recorded (n = 20) using these thresholds. Ten blocks of masked fear and neutral faces were presented under each threshold condition. Simultaneously recorded skin conductance responses (SCRs) provided an independent index of stimulus perception. It was found that Fear stimuli evoked faster SCR rise times than did neutral stimuli across all conditions, indicating that emotional content influenced responses, regardless of awareness. In the first 400 msec of processing, ERPs dissociated the time course of conscious (enhanced N4 component) from nonconscious (enhanced N2 component) perception of fear, relative to neutral. Nonconscious detection of fear also elicited relatively faster P1 responses within 100 msec post-stimulus. The N2 may provide a temporal correlate of the initial sensory processing of salient facial configurations, which is enhanced when top-down cortical feedback is precluded. By contrast, the N4 may index the conscious integration of emotion stimuli in working memory, subserved by greater cortical engagement. Hum. Brain Mapping 21:64-74, 2004.

    View details for DOI 10.1002/hbm.10154

    View details for Web of Science ID 000188505900002

    View details for PubMedID 14755594

  • A novel method for the topographic analysis of neural activity reveals formation and dissolution of 'dynamic cell assemblies' JOURNAL OF COMPUTATIONAL NEUROSCIENCE Breakspear, M., Williams, L. M., Stam, C. J. 2004; 16 (1): 49-68


    The study of synchronous oscillations in neural systems is a very active area of research. However, cognitive function may depend more crucially upon a dynamic alternation between synchronous and desynchronous activity rather than synchronous behaviour per se. The principle aim of this study is to develop and validate a novel method of quantifying this complex process. The method permits a direct mapping of phase synchronous dynamics and desynchronizing bursts in the spatial and temporal domains. Two data sets are analyzed: Numeric data from a model of a sparsely coupled neural cell assembly and experimental data consisting of scalp-recorded EEG from 40 human subjects. In the numeric data, the approach enables the demonstration of complex relationships between cluster size and temporal duration that cannot be detected with other methods. Dynamic patterns of phase-clustering and desynchronization are also demonstrated in the experimental data. It is further shown that in a significant proportion of the recordings, the pattern of dynamics exhibits nonlinear structure. We argue that this procedure provides a 'natural partitioning' of ongoing brain dynamics into topographically distinct synchronous epochs which may be integral to the brain's adaptive function. In particular, the character of transitions between consecutive synchronous epochs may reflect important aspects of information processing and cognitive flexibility.

    View details for Web of Science ID 000186692800005

    View details for PubMedID 14707544

  • Perception of facial signals of emotion: An ERP study Palmer, D., Liddell, B., Gordon, E., Williams, L. M. WILEY-BLACKWELL. 2004: 50–50
  • Processing salient nonthreatening stimuli in posttraumatic stress disorder: An fMRI investigation Felmingham, K. L., Bryant, R. A., Williams, L. M., Kemp, A., BROWN, K., Peduto, A. WILEY-BLACKWELL. 2004: 42–42
  • Do sex differences in emotionality mediate sex differences in traits of psychosis-proneness? COGNITION & EMOTION Williams, L. M., Barry, J. 2003; 17 (5): 747-758
  • In the face of danger: Specific viewing strategies for facial expressions of threat? COGNITION & EMOTION Green, M. J., Williams, L. M., Davidson, D. 2003; 17 (5): 779-786
  • A disturbance of nonlinear interdependence in scalp EEG of subjects with first episode schizophrenia NEUROIMAGE Breakspear, M., Terry, J. R., Friston, K. J., Harris, A. W., Williams, L. M., BROWN, K., Brennan, J., Gordon, E. 2003; 20 (1): 466-478


    It has been proposed that schizophrenia arises through a disturbance of coupling between large-scale cortical systems. This "disconnection hypothesis" is tested by applying a measure of dynamical interdependence to scalp EEG data. EEG data were collected from 40 subjects with a first episode of schizophrenia and 40 matched healthy controls. An algorithm for the detection of dynamical interdependence was applied to six pairs of bipolar electrodes in each subject. The topographic organization of the interdependence was calculated and served as the principle measure of cortical integration. The rate of occurrence of dynamical interdependence did not statistically differ between subject groups at any of the sites. However, the topography across the scalp was significantly different between the two groups. Specifically, nonlinear interdependence tended to occur in larger concurrent "clusters" across the scalp in schizophrenia than in the healthy subjects. This disturbance was reflected most strongly in left intrahemispheric coupling and did not differ significantly according to symptomatology. Medication dose and subject arousal were not observed to be confounding factors. The study of dynamical interdependence in scalp EEG data does not support a straightforward interpretation of the disconnection hypothesis-that there is a decrease in the strength of functional coupling between adjacent cortical regions. Rather, it suggests a dysregulation in the organization of dynamical interactions across supraregional brain systems.

    View details for DOI 10.1016/S1053-8119(03)00332-X

    View details for Web of Science ID 000185746400043

    View details for PubMedID 14527607

  • The five symptom dimensions and depression in schizophrenia PSYCHOPATHOLOGY Lee, K. H., Harris, A. W., Loughland, C. M., Williams, L. M. 2003; 36 (5): 226-233


    The aim of this study was to investigate the relationship between the five-factor model of psychopathology and depression in schizophrenia. Symptoms were rated using the Positive and Negative Syndrome Scale (PANSS) and the Montgomery and Asberg Depression Rating Scale (MADRS) in 105 chronic patients with schizophrenia. Principal-component analysis (PCA) produced a five-factor solution for the PANSS (psychomotor poverty, disorganisation, reality distortion, excitement, and depression), and a two-factor solution for the MADRS (psychological and behavioural depression). The PANSS depression factor was highly associated with the MADRS psychological depression factor but not with MADRS behavioural depression. By contrast, the PANSS excitement factor showed a strong positive correlation with the behavioural depression factor but not with psychological depression. These MADRS factors were not associated significantly with the core PANSS factors, including psychomotor poverty. It is suggested that depression exists as an independent domain, differentiated from negative symptoms, in the structure of schizophrenia symptomatology.

    View details for DOI 10.1159/000073447

    View details for Web of Science ID 000186516600002

    View details for PubMedID 14571051

  • Emotion perception in schizophrenia: an eye movement study comparing the effectiveness of risperidone vs. haloperidol PSYCHIATRY RESEARCH Williams, L. M., Loughland, C. M., Green, M. J., Harris, A. W., Gordon, E. 2003; 120 (1): 13-27


    We used a psychophysiological marker of visual attention (the visual scanpath) to investigate the effects of atypical (risperidone) vs. typical (haloperidol) antipsychotic medication on facial emotion perception in schizophrenia (n=28) and healthy control (n=28) groups. Of the schizophrenia subjects, 15 were prescribed risperidone. Visual scanpaths to 'happy', 'sad' and 'neutral' faces were recorded using video-oculography, and concurrent emotion-recognition accuracy was assessed using multiple-option tasks. Compared to control subjects, both schizophrenia subgroups showed a restriction in visual scanning (reduced total fixation number and decreased scanpath length). Haloperidol-treated schizophrenia subjects exhibited an additional and consistent pattern of reduced attention (fixation) to salient features for neutral and happy. By contrast, risperidone-treated subjects showed a relatively greater attention to salient features for these expressions, in which they did not differ from controls. Recognition accuracy for happy and neutral showed a similar lack of impairment. These findings suggest that risperidone may play a specific role in schizophrenia in the ability to attend to salient features, and to integrate this information into an accurate percept for neutral and positive expressions in particular.

    View details for DOI 10.1016/S0165-1781(03)00166-5

    View details for Web of Science ID 000185709900002

    View details for PubMedID 14500110

  • Visual scanpaths to threat-related faces in deluded schizophrenia PSYCHIATRY RESEARCH Green, M. J., Williams, L. M., Davidson, D. 2003; 119 (3): 271-285


    This study examined visuo-cognitive processing of threat-related (anger, fear) and non-threat faces (happy, sad, neutral) in deluded schizophrenia (n=11), non-deluded schizophrenia (n=8), and healthy control (n=22) participants. Focal analyses examined scanpath aberrations for particular facial expressions in sub-groups of schizophrenia patients determined by the presence or absence of overt delusions. Deluded schizophrenia subjects exhibited significantly fewer fixations of shorter duration for all faces, and fewer fixations of reduced duration to the feature areas of negative facial expressions (anger, sad), compared with healthy controls. Compared with non-deluded schizophrenia subjects, deluded subjects exhibited fewer fixations to fear expressions and more fixations to the feature areas of happy expressions. These findings were revealed in the context of restricted scanning (reduced number and duration of fixations, shorter scanpath length and shorter duration of fixations to facial features) in the entire schizophrenia group (n=19) compared with healthy controls. The findings suggest a controlled attentional bias away from the feature areas of negative facial expressions in deluded schizophrenia, that is, specific to threat-related expressions compared with non-deluded schizophrenia subjects. This controlled bias away from negative social stimuli in deluded schizophrenia is discussed in terms of an attentional style of 'vigilance-avoidance' operating across early and late stages of information processing.

    View details for DOI 10.1016/S0165-1781(03)00129-X

    View details for Web of Science ID 000184726800008

    View details for PubMedID 12914898

  • Visual processing of threat-related faces in deluded schizophrenia 9th International Congress on Schizophrenia Research Green, M. J., Williams, L. M. ELSEVIER SCIENCE BV. 2003: 266–66
  • High-frequency synchronisation in schizophrenia: Too much or too little? BEHAVIORAL AND BRAIN SCIENCES Williams, L. M., Lee, K. H., Haig, A., Gordon, E. 2003; 26 (1): 109-?
  • "Gamma (40 Hz) phase synchronicity" and symptom dimensions in schizophrenia. Cognitive neuropsychiatry Lee, K., Williams, L. M., Haig, A., Gordon, E. 2003; 8 (1): 57-71


    The failure of integrative brain function is a fundamental characteristic of schizophrenia. Synchronous Gamma (40 Hz) activity, proposed as a candidate mechanism underlying the integration ("binding") of distributed brain activities, may provide a direct window into schizophrenic disintegration.40 schizophrenia and 40 age/gender-matched control subjects participated in an auditory oddball paradigm. We examined both early (Gamma 1) and later Gamma (Gamma 2) phase synchrony to target stimuli. Factor analysis scores were used to examine the associations between Gamma synchrony and three syndromes (Psychomotor Poverty, Reality Distortion, and Disorganisation).Multiple analyses of variance revealed an overall decrease in frontal and left hemisphere Gamma synchrony, but increased posterior Gamma 2 synchrony in schizophrenia compared to controls. Schizophrenia syndromes were differentiated by distinct patterns of Gamma disturbances: Psychomotor Poverty showed decreased left hemisphere synchrony; Reality Distortion was associated with increased right synchrony; Disorganisation showed a widespread enhancement with a delay in frontal Gamma synchrony.These findings are consistent with previous evidence for left hemisphere and frontal disturbances in the schizophrenia group. However, the syndrome results point to more distinctive patterns of dysregulation in network integration: widespread and excessive in Disorganisation, localised and enhanced in Reality Distortion, versus localised and diminished in Psychomotor Poverty.

    View details for PubMedID 16571550

  • Task instructions modulate neural responses to fearful facial expressions BIOLOGICAL PSYCHIATRY Lange, K., Williams, L. M., Young, A. W., Bullmore, E. T., Brammer, M. J., Williams, S. C., Gray, J. A., Phillips, M. L. 2003; 53 (3): 226-232


    The amygdala, hippocampus, ventral, and dorsal prefrontal cortices have been demonstrated to be involved in the response to fearful facial expressions. Little is known, however, about the effect of task instructions upon the intensity of responses within these regions to fear-inducing stimuli.Using functional magnetic resonance imaging, we examined neural responses to alternating, 30-sec blocks of fearful and neutral expressions in nine right-handed male volunteers during three different 5-min conditions: 1) passive viewing; 2) performance of a gender-decision task, with no explicit judgment of facial emotion; 3) performance of an emotionality judgment task - an explicitly emotional task.There was a significant effect of task upon activation within the left hippocampus and the left inferior occipital gyrus, and upon the magnitude of response within the left hippocampus, with maximal activation in these regions occurring during passive viewing, and minimal during performance of the explicit task. Performance of the gender-decision and explicit tasks, but not passive viewing, was also associated with activation within ventral frontal cortex.Neural responses to fearful facial expressions are modulated by task instructions.

    View details for DOI 10.1016/S0006-3223(02)01455-5

    View details for Web of Science ID 000180692800005

    View details for PubMedID 12559655

  • Electrodermal responsivity distinguishes ERP activity and symptom profile in schizophrenia SCHIZOPHRENIA RESEARCH Williams, L. M., Bahramali, H., Hemsley, D. R., Harris, A. W., BROWN, K., Gordon, E. 2003; 59 (2-3): 115-125


    Traditional averaging of late component Event Related Potentials (ERPs) might obscure important psychophysiological subprocesses underlying schizophrenia disturbances in cognitive functioning. One such subprocess could be the active orientation of attention to significant or novel stimuli. In this study, we used skin conductance responses (SCRs) to index orienting responses (ORs). ERP activity was examined in relation to concomitant ORs in a schizophrenia and nonpsychiatric control group. Schizophrenia responses were considered with respect to the Reality Distortion, Disorganisation and Psychomotor Poverty syndromes.Forty schizophrenia and 40 age and sex matched control subjects were tested. The three schizophrenia syndromes were derived from a principal component analysis of Positive and Negative Syndrome Scale (PANSS) ratings. Auditory ERPs (N100, N200, P200, P300) were elicited using a conventional auditory oddball paradigm, and electrodermal SCR data were acquired simultaneously.ERP data were sub-averaged according to the presence/absence of an OR. For both 'with-' and 'without-OR' ERPs, schizophrenia subjects as a group showed reduced N100 (associated with vigilance level) and N200 (associated with response selection) amplitude, and for with-OR responses, they showed an additional reduction in P300 (context processing). Concerning schizophrenia syndromes, Reality Distortion was related primarily to frontal disturbances (earlier N100/N200 latency and decreased P200/P300 amplitude), and Psychomotor Poverty to a generally delayed P300 latency. Similarly delayed P300 in Disorganisation was explained by medication effects. There were no associations with syndromes for without-OR ERPs.These results suggest that schizophrenia syndromes are dissociated with regard to both the direction and nature of speed of information processing disturbances, in relation to task-relevant information that produces active orientation.

    View details for Web of Science ID 000181043200002

    View details for PubMedID 12414068

  • Specificity of target, nontarget ERP disturbance in schizophrenia: A comparison of first episode schizophrenia and attention deficit hyperactivity disorder Brown, K. J., Gonsalvez, C. J., Harris, A. W., Lazzaro, I., Williams, L. M., Gordon, E. WILEY-BLACKWELL. 2003: 13–13
  • Regionally specific grey-matter volume reductions in first-episode schizophrenia and affective-disorder Farrow, T. F., Whitford, T. J., Williams, L. M., Gomes, L., Winter, V., Harris, A. W. WILEY-BLACKWELL. 2003: 17–17
  • Social phobics do not see eye to eye: A visual scanpath study of emotional expression processing JOURNAL OF ANXIETY DISORDERS Horley, K., Williams, L. M., Gonsalvez, C., Gordon, E. 2003; 17 (1): 33-44


    Clinical observation suggests that social phobia is characterised by eye avoidance in social interaction, reflecting an exaggerated social sensitivity. These reports are consistent with cognitive models of social phobia that emphasize the role of interpersonal processing biases. Yet, these observations have not been verified empirically, nor has the psychophysiological basis of eye avoidance been examined. This is the first study to use an objective psychophysiological marker of visual attention (the visual scanpath) to examine directly how social phobia subjects process interpersonal (facial expression) stimuli. An infra-red corneal reflection technique was used to record visual scanpaths in response to neutral, happy and sad face stimuli in 15 subjects with social phobia, and 15 age and sex-matched normal controls. The social phobia subjects showed an avoidance of facial features, particularly the eyes, but extensive scanning of non-features, compared with the controls. These findings suggest that attentional strategies for the active avoidance of salient facial features are an important marker of interpersonal cues in social phobia. Visual scanpath evidence may, therefore, have important implications for clinical intervention.

    View details for Web of Science ID 000180205600002

    View details for PubMedID 12464287

  • Gender differences in fear perception: Evidence from concurrent fMRI and skin conductance acquisition Barton, M. J., Brown, K. J., Hughes, G. L., Liddell, B. J., Olivieri, G., Peduto, A., Gordon, E., Williams, L. M. WILEY-BLACKWELL. 2003: 11–12
  • The N2 distinguishes sub- versus supra-threshold perception of fear and happy faces: An event-related potential study Liddell, B. J., Williams, L. M., Gordon, E. WILEY-BLACKWELL. 2003: 22–22
  • Sex differences in adult ADHD: An event-related psychophysiology study Hermens, D., Williams, L. M., Lazzaro, I., Whitmont, S., Gordon, E. WILEY-BLACKWELL. 2003: 20–20
  • Sex differences in gamma '40 Hz' synchrony: A comparison of first episode and chronic schizophrenia Slewa-Younan, S., Williams, L. M., Harris, A. W., Haig, A. R., Gordon, E. WILEY-BLACKWELL. 2003: 27–27
  • Synchronous Gamma activity: a review and contribution to an integrative neuroscience model of schizophrenia BRAIN RESEARCH REVIEWS Lee, K. H., Williams, L. M., Breakspear, M., Gordon, E. 2003; 41 (1): 57-78


    Synchronous high frequency (Gamma band) activity has been proposed as a candidate mechanism for the integration or 'binding' of distributed brain activities. Since the first descriptions of schizophrenia, attempts to characterize this disorder have focused on disturbances in such integrative processing. Here, we review both micro- and macroscopic neuroscience research into Gamma synchrony, and its application to understanding schizophrenia. The review encompasses evidence from both animal and human studies for the functional significance of Gamma activity, the association between Gamma dysfunction and information processing disturbances, and the relevance of specific Gamma dysfunctions to the integration and extension of previous disconnection models of schizophrenia. Attention is given to the relationship between Gamma activity and the heterogeneous symptoms of schizophrenia. Existing studies show that measures of Gamma activity have the potential to explain far more of the variance in schizophrenia performance than previous neurophysiological measures. It is concluded that measures of Gamma synchrony offer a valuable window into the core integrative disturbance in schizophrenia cognition.

    View details for Web of Science ID 000180570700005

    View details for PubMedID 12505648

  • Brain volume as a marker for age of psychosis onset in schizophrenia Whitford, T. J., Williams, L. M., Farrow, T. F., Gomes, L., Harris, A. W. WILEY-BLACKWELL. 2003: 30–30
  • A novel method of quantifying the topography of phase-desynchronisation in scalp EEG data Breakspear, M., Stam, C. J., Williams, L. M. WILEY-BLACKWELL. 2003: 12–12
  • Target and non-target ERP disturbances in first episode vs. chronic schizophrenia CLINICAL NEUROPHYSIOLOGY Brown, K. J., Gonsalvez, C. J., Harris, A. W., Williams, L. M., Gordon, E. 2002; 113 (11): 1754-1763


    Event-related potential (ERP) abnormalities to target stimuli are reliably found in schizophrenia. However, as people with schizophrenia are thought to have difficulty discerning the relevance of incoming sensory stimuli it is also important to examine ERPs to non-targets. To differentiate between potential trait markers of the disease and deficits that might be associated with the consequence of illness chronicity, this study investigated ERPs to both target and non-target stimuli in groups of people with either first episode or chronic schizophrenia (CSz).Using an auditory oddball paradigm, ERPs to target, non-target before target (Nt before) and non-target after target (Nt after) stimuli were analysed for 40 patients with CSz, 40 patients with first episode schizophrenia (FESz) and two groups of normal controls matched for age and sex with their patient counterparts.The FESz group showed the same pattern of amplitude disturbance as the CSz group to both targets (reduced N100, N200, P300 and increased P200) and non-targets (reduced N100) compared to controls. Both CSz and FESz groups also failed to show the changes to the P200-N200 component between targets and non-target stimuli that was exhibited by controls (smaller earlier P200 to targets vs. increased delayed P200 to non-targets) or the reduction in N100 amplitude of ERPs to the Nt after stimuli compared with ERPs to the Nt before stimuli. Previous literature has focussed on the sensitivity of P300 deficits in classifying persons into schizophrenia and non-schizophrenia groups. This study demonstrated improved accuracy in the classification of patients with schizophrenia from controls using discriminant analysis of target and non-target N100 and P200 components.The results suggest that ERP disturbances are evident at the time of first referral to mental health services and may be a potential trait (rather than secondary effect) of the illness. It is important to include both target and non-target stimuli processing, and their interrelationship in future research.

    View details for Web of Science ID 000179270700012

    View details for PubMedID 12417228

  • Schizophrenia and affective disorder show different visual scanning behavior for faces: A trait versus state-based distinction? BIOLOGICAL PSYCHIATRY Loughland, C. M., Williams, L. M., Gordon, E. 2002; 52 (4): 338-348


    Abnormal visual scanpaths to faces and facial expressions in schizophrenia may underlie schizophrenic subjects' disturbed interpersonal communication. This study is the first to examine the specificity of these impairments to schizophrenia, by including an affective disorder psychiatric control group.The visual scanpath performance of 65 schizophrenia, 52 affective disordered, and 61 control subjects were compared in two experiments. In the "face recognition" experiment, subjects viewed four identifiable (non-degraded) neutral faces versus four matched non-identifiable (degraded) control faces. In the "facial affect recognition" experiment, subjects viewed positive (happy), negative (sad), and neutral (control) facial emotion stimuli. Concurrent behavioral tasks were face matching (face recognition) and expression matching (facial affect recognition), each under two multiple-choice conditions (7 or 3 options).Scanpath disturbances were most apparent in schizophrenia subjects, who maintained a comparatively "restricted" scanpath style to all face stimuli. Schizophrenics subjects also showed the greatest recognition difficulties, particularly for neutral and happy faces. Scanpath parameters for affective disorder subjects differed only from the schizophrenia (but not the control) group, except for attention to facial features where they generally avoided facial features in all expressions and showed the greatest attentional problems of all groups for degraded faces.Our results suggest that a global restriction of visual scanpaths is specific to schizophrenic psychosis and might be a trait marker for this disorder, whereas scanpath abnormalities in affective disorder might instead reflect severe state-based (or discrete) attentional disturbances.

    View details for Web of Science ID 000177702300005

    View details for PubMedID 12208641

  • EEG, ERP, gamma synchrony and SCL: Towards an integrative approach to ADHD and schizophrenia Hermens, D., Williams, L. M., Lazzaro, I., Clarke, S., Harris, A., Gordon, E. ELSEVIER SCIENCE BV. 2002: 80–80
  • Towards an integrative neuroscience of orienting and emotion Williams, L. M. ELSEVIER SCIENCE BV. 2002: 14–15
  • Visual scanpaths to positive and negative facial emotions in an outpatient schizophrenia sample SCHIZOPHRENIA RESEARCH Loughland, C. M., Williams, L. M., Gordon, E. 2002; 55 (1-2): 159-170


    We used a psychophysiological marker of visual attention (visual scanpath) to investigate facial emotion processing in schizophrenia (n= 65) and healthy control (n = 61) groups. Visual scanpaths to 'happy', *sad' and 'neutral' faces (two exposures each) were recorded using video-oculography. Emotion recognition accuracy was assessed under both 'difficult' (exposure 1) and 'limited choice' (exposure 2) conditions. Compared to controls, schizophrenia subjects showed 'restricted' scanning and reduced attention to salient facial features (eyes, nose, mouth), that was particularly apparent for happy and neutral faces: accuracy was correspondingly reduced for the 'difficult' condition. The schizophrenia deficit in positive emotion perception may reflect a failure to integrate salient features due to dysfunctions in local processing of detailed, relevant information (fewer fixations, less attention to facial features), and in the networks that synchronise local and global processing of biologically-relevant face stimuli (generally restricted scanning style).

    View details for Web of Science ID 000175307500018

    View details for PubMedID 11955975

  • Arousal dissociates amygdala and hippocampal fear responses: Evidence from simultaneous fMRI and skin conductance recording NEUROIMAGE Williams, L. M., Phillips, M. L., Brammer, M. J., Skerrett, D., Lagopoulos, J., Rennie, C., Bahramali, H., Olivieri, G., David, A. S., Peduto, A., Gordon, E. 2001; 14 (5): 1070-1079


    The experience and appraisal of threat is essential to human and animal survival. Lesion evidence suggests that the subjective experience of fear relies upon amygdala-medial frontal activity (as well as autonomic arousal), whereas the factual context of threat stimuli depends upon hippocampal-lateral frontal activity. This amygdala-hippocampus dissociation has not previously been demonstrated in vivo. To explore this differentiation, we employed functional magnetic resonance imaging (fMRI) and simultaneous skin conductance response (SCR) measures of phasic arousal, while subjects viewed fearful versus neutral faces. fMRI activity was subaveraged according to whether or not the subject evoked an arousal SCR to each discrete face stimulus. The fMRI-with arousal and fMRI-without arousal data provided a distinct differentiation of amygdala and hippocampal networks. Amygdala-medial frontal activity was observed only with SCRs, whereas hippocampus-lateral frontal activity occurred only in the absence of SCRs. The findings provide direct evidence for a dissociation between human amygdala and hippocampus networks in the visceral experience versus declarative fact processing of fear.

    View details for DOI 10.1006/nimg.2001.0904

    View details for Web of Science ID 000172063100012

    View details for PubMedID 11697938

  • An integration of 40 Hz Gamma and phasic arousal: novelty and routinization processing in schizophrenia CLINICAL NEUROPHYSIOLOGY Lee, K. H., Williams, L. M., Haig, A., Goldberg, E., Gordon, E. 2001; 112 (8): 1499-1507


    Frontal and lateralized schizophrenia disturbances were examined in terms of arousal-modulated changes in 40 Hz Gamma activity.Forty patients with schizophrenia and 40 age- and gender-matched controls were studied in a conventional auditory ERP oddball paradigm. We investigated sub-averaged Gamma activity based upon a simultaneous measure of electrodemal skin conductance response (phasic arousal) to differentiate novelty (large responses) from routinization (small or no responses). Both early Gamma (Gamma 1) and later induced Gamma (Gamma 2) activities were examined.Patients with schizophrenia (compared with controls) had significantly reduced Gamma 1 amplitude in the right hemisphere for novelty processing and delayed Gamma 2 latency in the left hemisphere for both novelty and routinization. Overall, reduced Gamma 1 amplitude in patients with schizophrenia was also evident.These findings indicate that the normal laterality of Gamma activity is specifically disturbed in schizophrenia in response to novel, but not routine (familiar) stimuli. The distinct pattern of findings suggests a dysregulation of activation across left and right hemispheres during initial attention and preparatory phases of information processing, in particular, in patients with schizophrenia.

    View details for Web of Science ID 000170253600016

    View details for PubMedID 11459690

  • Time courses of left and right amygdalar responses to fearful facial expressions HUMAN BRAIN MAPPING Phillips, M. L., Medford, N., Young, A. W., Williams, L., Williams, S. C., Bullmore, E. T., Gray, J. A., Brammer, M. J. 2001; 12 (4): 193-202


    Despite the many studies highlighting the role of the amygdala in fear perception, few have examined differences between right and left amygdalar responses. Using functional magnetic resonance imaging (fMRI), we examined neural responses in three groups of healthy volunteers (n = 18) to alternating blocks of fearful and neutral faces. Initial observation of extracted time series of both amygdalae to these stimuli indicated more rapid decreases of right than left amygdalar responses to fearful faces, and increasing magnitudes of right amygdalar responses to neutral faces with time. We compared right and left responses statistically by modeling each time series with (1) a stationary fit model (assuming a constant magnitude of amygdalar response to consecutive blocks of fearful faces) and (2) an adaptive model (no assumptions). Areas of significant sustained nonstationarity (time series points with significantly greater adaptive than stationary model fits) were demonstrated for both amygdalae. There was more significant nonstationarity of right than left amygdalar responses to neutral, and left than right amygdalar responses to fearful faces. These findings indicate significant variability over time of both right and left amygdalar responses to fearful and neutral facial expressions and are the first demonstration of specific differences in time courses of right and left amygdalar responses to these stimuli.

    View details for Web of Science ID 000167688500001

    View details for PubMedID 11241871

  • Syndromes of schizophrenia and smooth-pursuit eye movement dysfunction PSYCHIATRY RESEARCH Lee, K. H., Williams, L. M., Loughland, C. M., Davidson, D. J., Gordon, E. 2001; 101 (1): 11-21


    There have been a number of studies on smooth pursuit eye movement (SPEM) dysfunction in schizophrenia. However, the association between SPEM dysfunction and particular clinical symptoms remains unclear. We examined SPEM dysfunction in relation to schizophrenic symptoms using both the positive/negative dichotomy and the three-syndrome model. Subjects included 78 patients with schizophrenia and 60 healthy control subjects. SPEM performance was indexed by root mean square error. Symptom profiles were assessed using the Positive and Negative Syndrome Scale (PANSS), and the three-primary syndromes were identified by factor analysis of PANSS ratings (Psychomotor poverty: deficit negative symptoms; Disorganization: defined primarily by thought disorder; and Reality distortion: hallucinations and delusions). Compared with controls, the schizophrenia group showed significant impairment in global SPEM function. The three-syndrome approach produced more specific findings than the dichotomous model. Of the three syndromes, only the Disorganization dimension showed a significant association with increased global SPEM dysfunction. The specificity of SPEM dysfunction to Disorganization was verified in comparisons among schizophrenia subgroups and the control group. By contrast, the general domains of positive and negative symptoms were both found to be modestly associated with SPEM dysfunction. The separation of positive and negative symptoms that contribute to Disorganization from those that define Reality Distortion and Psychomotor Poverty has revealed significant new associations between SPEM and schizophrenic symptoms. These findings are interpreted in light of the proposal that the Disorganization syndrome is the central form of pathology in schizophrenia.

    View details for Web of Science ID 000167609300002

    View details for PubMedID 11223115

  • Sex differences, gamma activity and schizophrenia INTERNATIONAL JOURNAL OF NEUROSCIENCE Slewa-Younan, S., Gordon, E., Williams, L., Haig, A. R., Goldberg, E. 2001; 107 (1-2): 131-144


    This study explores the possibility that the more favourable clinical prognosis in females with schizophrenia may be associated with their greater network interconnectedness, which is possibly reflected in enhanced "Gamma" (40 Hz) electrical brain activity. An auditory "oddball" task was administered to 35 patients with schizophrenia and 35 age and sex matched controls (25 males and 10 females). Peak Gamma amplitude (from a time series of Gamma activity averaged for 40 target stimuli, as well as the immediately preceding 40 background tones) was examined across 19 sites. Peak Gamma activity occurred 250 to 450 ms in targets and 350 to 550 ms in backgrounds. Multiple within and between group MANOVAs were undertaken analysing both Peak Gamma amplitude (microvolts) and latency (milliseconds). Within-group, the control males showed a pattern of earlier Gamma latency in the right compared with the left hemisphere (F(1, 33)=3.70, p<.06), while control females exhibited delayed latency frontally compared with the posterior region (F(1, 33)=6.25, p<.04). This male lateralization finding and the anterior/posterior gradient in females is consistent with Goldberg's model. The patient group however, failed to show this male lateralized and female frontal-posterior pattern of Gamma activity, suggesting suboptimal network integration in the patient group, in both males and females.

    View details for Web of Science ID 000168444600009

    View details for PubMedID 11328687

  • In search of the "Duchenne smile": Evidence from eye movements JOURNAL OF PSYCHOPHYSIOLOGY Williams, L. M., Senior, C., David, A. S., Loughland, C. M., Gordon, E. 2001; 15 (2): 122-127
  • Event-related potentials to threat-related faces in schizophrenia INTERNATIONAL JOURNAL OF NEUROSCIENCE Horley, K., Gonsalvez, C., Williams, L., Lazzaro, I., Bahramali, H., Gordon, E. 2001; 107 (1-2): 113-130


    Specialised network disturbances such as abnormalities in processing faces, may be associated with functional disturbances of interpersonal communication in schizophrenia. This study focused on the temporal dimension, investigating facial processing deficits in patients with schizophrenia (and non-patient controls) in a passive event-related potential (ERP) paradigm. ERPs invoked to an angry and neutral face stimulus were recorded in 27 patients with schizophrenia and 27 age and sex matched normal controls. Patients with schizophrenia showed a significant generalised delay, and diminished P200 amplitude (primarily frontal) for both stimuli-with more widespread regions of disturbance associated with the angry face. Normal controls, on the other hand, showed relatively reduced posterior P200 amplitude for angry compared to neutral faces, and a lateralised pattern of engagement in response to both stimuli. These findings indicate suboptimal processing of neutral faces in patients with schizophrenia, further exacerbated for affect laden angry faces.

    View details for Web of Science ID 000168444600008

    View details for PubMedID 11328686

  • The topography of quantified electroencephalography in three syndromes of schizophrenia INTERNATIONAL JOURNAL OF NEUROSCIENCE Harris, A. W., Bahramali, H., Slewa-Younan, S., Gordon, E., Williams, L., LI, W. M. 2001; 107 (3-4): 265-278


    This study investigated the association between quantified electroencephalography (qEEG) and three psychopathological syndromes, derived by a factor analysis of the symptom profile of a group of 40 subjects diagnosed with schizophrenia. An initial comparison with aged and sex matched normal controls showed an overall increase in slow wave activity in subjects with schizophrenia. The symptomatology of the subjects with schizophrenia was then factor analysed into three psychopathological syndromes that closely resembled Liddle's (1987b) original delineation. Correlations were undertaken between the three syndrome scores and qEEG. The "psychomotor poverty" factor was associated with increased beta activity most marked posteriorly and increased delta activity (accounted for by the effects of medication). The "disorganisation" factor was associated with widespread negative correlations in the alpha and beta bands and the "reality distortion" factor was associated positively with left anterior alpha activity. These distinct patterns of qEEG that clearly differentiate between the three syndromes, may contribute towards elucidating the underlying pathophysiological processes in schizophrenia. The results support the use of symptom based syndromes in reducing the diversity of findings in schizophrenia.

    View details for Web of Science ID 000168444800008

    View details for PubMedID 11328695

  • Misattribution of sensory input reflected in dysfunctional target: non-target ERPs in schizophrenia PSYCHOLOGICAL MEDICINE BROWN, K., Gordon, E., Williams, L., Bahramali, H., Harris, A., Gray, J., Gonsalvez, C., Meares, R. 2000; 30 (6): 1443-1449


    While numerous studies have found disturbances in the Event-Related Potentials (ERPs) of patients with schizophrenia linked to task relevant target stimuli (most notably a reduction in P300 amplitude), few have examined ERPs to task irrelevant non-targets. We hypothesize, from current models of dysfunction in information processing in schizophrenia, that there will be less difference between ERPs to targets and non-targets in patients with schizophrenia than in controls.EEGs were recorded for 40 subjects with schizophrenia and 40 age and sex matched controls during an auditory oddball reaction time task. ERPs to the targets and non-targets immediately preceding the targets were averaged separately.There was a disturbance in ERPs to targets but also to non-targets (reduced N100 amplitude and earlier P200 latency) and the difference between target and non-target ERP components (N100 and P200 amplitude and P200 latency), was significantly reduced in the schizophrenic group compared with controls.These findings suggest a disturbance in processing task relevant and irrelevant stimuli, consistent with Gray's (1998) hypothesis of misattributions in the 'match:mismatch' of novel (target) and familiar (non-target) sensory input compared with stored information.

    View details for Web of Science ID 000165285000019

    View details for PubMedID 11097084

  • The neural correlates of orienting: An integration of fMRI and skin conductance orienting NEUROREPORT Williams, L. M., Brammer, M. J., Skerrett, D., Lagopolous, J., Rennie, C., Kozek, K., Olivieri, G., Peduto, T., Gordon, E. 2000; 11 (13): 3011-3015


    In fMRI studies, the averaging of neural activity across multiple trials might obscure important psychophysiological subprocesses. The orienting response (OR) is a distinctive subprocess signalling the active orientation of attention towards potentially significant events. We sought to elucidate fMRI activity associated with visual stimuli that did or did not evoke simultaneously recorded electrodermal ORs (using customised skin conductance recording). 'With-OR' stimuli were associated with significant activity in the hippocampus, anterior cingulate and ventromedial prefrontal cortex. Averaged analysis revealed activity only in the expected visual circuits. Our results suggest that potentially significant stimuli (with-OR) activate different functional networks to familiar (without-OR) stimuli, and that orienting may therefore be an informative subprocess to consider in cognitive fMRI studies.

    View details for Web of Science ID 000089360300037

    View details for PubMedID 11006985

  • Late component ERPs are associated with three syndromes in schizophrenia INTERNATIONAL JOURNAL OF NEUROSCIENCE Williams, L. M., Gordon, E., Wright, J., Bahramali, H. 2000; 105 (1-4): 37-52


    Previous studies have revealed various abnormalities in late-component ERP amplitude and latency in schizophrenia, considered as a diagnostic category. The aim of this study was to investigate the within-sample associations between late-component ERPs and three primary syndromes of schizophrenia Reality Distortion, Psychomotor Poverty and Disorganisation. Subjects included 40 schizophrenics and 40 age and sex matched nonpsychiatric controls. Auditory ERPs (N100, N200, P200, P300) were elicited using an auditory oddball paradigm. Between-group analyses of target data showed reduced N100, N200 and P300 amplitude, increased P200 amplitude and delayed N200 latency in schizophrenics compared to controls. For non-target data, schizophrenics showed similarly reduced N100 amplitude and delayed N200 latency. Within-group analyses of target data showed that the three syndromes (determined by principal component analysis of PANSS ratings) were differentiated by ERP latency, but not amplitude (Disorganisation delayed left hemisphere P200 and P300 latency; Reality Distortion earlier global, midline and left hemisphere N200 latency; Psychomotor Poverty delayed posterior N100 latency). Notably, only Disorganisation showed a divergent pattern of associations with non-target ERP data: reduced P200 amplitude and delayed N100 latency.

    View details for Web of Science ID 000090042600004

    View details for PubMedID 11069045

  • Visual scanpaths in schizophrenia: is there a deficit in face recognition? SCHIZOPHRENIA RESEARCH Williams, L. M., Loughland, C. M., Gordon, E., Davidson, D. 1999; 40 (3): 189-199


    There is substantial evidence that schizophrenics have deficits in face processing. We hypothesised that this difficulty is due to abnormalities in the visual scanning of faces. The specificity of these abnormalities to recognisable faces, the effect of task difficulty and their relationships to three primary symptom dimensions were examined. An infrared corneal reflection technique was used to record the visual scanpaths of 63 schizophrenics and 60 non-psychiatric controls while viewing non-degraded ('recognisable') and degraded ('not recognisable') faces. In the concurrent recognition task, subjects were asked to select the previously viewed face from among seven (exposure 1) or three (exposure 2) options. Both groups were unable to accurately recognise degraded faces, but schizophrenics were less accurate than controls for non-degraded faces in the more difficult task condition. Schizophrenics maintained a relatively 'restricted' scanpath style across both faces, but scanpath disturbances were most apparent for non-degraded faces. Analysis of fixation distribution to non-degraded faces showed that, unlike controls, schizophrenics did not concentrate their fixations on salient features. Scanpath aberrations showed only minimal associations with symptom dimensions. These results suggest that schizophrenic individuals have a specific deficit in the visual scanning of faces, that is a distinct case of a fundamental problem in complex object processing.

    View details for Web of Science ID 000084023000003

    View details for PubMedID 10638857

  • A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics PSYCHIATRY RESEARCH-NEUROIMAGING Phillips, M. L., Williams, L., Senior, C., Bullmore, E. T., Brammer, M. J., Andrew, C., Williams, S. C., David, A. S. 1999; 92 (1): 11-31


    Several studies have demonstrated impaired facial expression recognition in schizophrenia. Few have examined the neural basis for this; none have compared the neural correlates of facial expression perception in different schizophrenic patient subgroups. We compared neural responses to facial expressions in 10 right-handed schizophrenic patients (five paranoid and five non-paranoid) and five normal volunteers using functional Magnetic Resonance Imaging (fMRI). In three 5-min experiments, subjects viewed alternating 30-s blocks of black-and-white facial expressions of either fear, anger or disgust contrasted with expressions of mild happiness. After scanning, subjects categorised each expression. All patients were less accurate in identifying expressions, and showed less activation to these stimuli than normals. Non-paranoids performed poorly in the identification task and failed to activate neural regions that are normally linked with perception of these stimuli. They categorised disgust as either anger or fear more frequently than paranoids, and demonstrated in response to disgust expressions activation in the amygdala, a region associated with perception of fearful faces. Paranoids were more accurate in recognising expressions, and demonstrated greater activation than non-paranoids to most stimuli. We provide the first evidence for a distinction between two schizophrenic patient subgroups on the basis of recognition of and neural response to different negative facial expressions.

    View details for Web of Science ID 000083752000002

    View details for PubMedID 10688157

  • Eye movements reflect impaired face processing in patients with schizophrenia BIOLOGICAL PSYCHIATRY Manor, B. R., Gordon, E., Williams, L. M., Rennie, C. J., Bahramali, H., Latimer, C. R., Barry, R. J., Meares, R. A. 1999; 46 (7): 963-969


    Impaired processing of faces in patients with schizophrenia may underlie aspects of disturbance in their social interaction. This study examined patterns of eye fixation in subjects with schizophrenia and non-psychiatric controls, while processing a high resolution picture of a neutral face and a nonbiological complex geometric stimulus.Ten-second sequences of eye movement were recorded video-oculographically (50 samples/sec) while subjects were "free-viewing" the stimuli. An essential element of the study was customized software that ensured stimulus presentation on a video display only after subjects were fixated upon a centre-screen cue, so that all subjects began stimulus processing from the same point.Compared with the control group, subjects with schizophrenia exhibited reduced scanpath lengths and a tendency toward fewer fixations for the face stimulus. They also showed an initial relative right spatial hemineglect (for the first voluntary fixation) when viewing the Rey figure, but not when viewing the face stimulus. Overall, there were no significant differences between the schizophrenia and control groups in the lateral distribution of subsequent fixations for either stimulus.Disturbed spatial and temporal patterns of eye movement in some people with schizophrenia may reflect sub-optimal processing of face stimuli, that may predispose these individuals to dysfunctional interpretation of facial communication cues.

    View details for Web of Science ID 000082782800011

    View details for PubMedID 10509179

  • Different psychopathological models and quantified EEG in schizophrenia PSYCHOLOGICAL MEDICINE Harris, A. W., Williams, L., Gordon, E., Bahramali, H., Slewa-Younan, S. 1999; 29 (5): 1175-1181


    This study compared the ability of two different models of psychopathology in schizophrenia to account for findings in the quantified electroencephalogram (qEEG) recorded from midline sites in a group of 40 subjects with schizophrenia. The first model was based on the positive and negative syndrome dichotomy, the second was a tripartite model that resembled Liddle's syndromes of psychomotor poverty, disorganization and reality distortion (Liddle, 1987a).A group of 40 subjects with predominantly chronic schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS) prior to the acquisition of their quantified electroencephalogram. The relationship between EEG data and symptomatology was explored, initially with the PANSS positive and negative subscales and then with a tripartite model derived From a principal component analysis of the 14 positive and negative subscale items.The tripartite syndrome model showed a greater concordance with the qEEG of the subjects than the dichotomous model. 'Psychomotor poverty' was significantly positively correlated with both delta and beta power and 'reality distortion' was significantly positively correlated with alpha-2 power. No significant correlations between the positive and negative syndrome dichotomy and the qEEG were observed.This study lends support to the factor analysis of psychopathology, and specifically the tripartite syndrome model of schizophrenia, as a step in explicating the biological dimensions of the disorder.

    View details for Web of Science ID 000083034400016

    View details for PubMedID 10576309

  • A cluster analytic study of schizotypal trait dimensions PERSONALITY AND INDIVIDUAL DIFFERENCES Loughland, C. M., Williams, L. M. 1997; 23 (5): 877-883