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1.  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  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.
doi:10.1038/npp.2012.252
PMCID: PMC3671994  PMID: 23303059
Biological Psychiatry; biomarker; clinical Pharmacology/clinical trials; depression; unipolar/bipolar; functional MRI; Imaging; clinical or Preclinical; iSPOT-D; prefrontal cortex; standardized cognitive and emotion task protocols; not open access; functional MRI; prefrontal cortex; major depressive disorder; biomarker; standardized cognitive and emotion task protocols; iSPOT-D
2.  Tractography of the Brainstem in Major Depressive Disorder Using Diffusion Tensor Imaging 
PLoS ONE  2014;9(1):e84825.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0084825
PMCID: PMC3897382  PMID: 24465436
3.  Early Exposure to Traumatic Stressors Impairs Emotional Brain Circuitry 
PLoS ONE  2013;8(9):e75524.
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.
doi:10.1371/journal.pone.0075524
PMCID: PMC3779182  PMID: 24073270
4.  Widespread reductions in gray matter volume in depression☆ 
NeuroImage : Clinical  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.
Highlights
•Focal gray matter volume decrease in depression exceeded loss via aging 11–50 years.•Gray matter differences were found in regions with established roles in depression.•Structural change findings support the idea of depression as a network abnormality.•Hippocampal gray matter volume loss likely has no role in non-geriatric depression.•Amygdala gray matter volume loss likely plays no role in depression pathophysiology.
doi:10.1016/j.nicl.2013.08.016
PMCID: PMC3814952  PMID: 24273717
AAL, Automated Anatomical Labeling; ACC, Anterior Cingulate Cortex; BAs, Brodmann Areas; CVNA, Change in Volume expected in that region through Normal Aging; DLPFC, Dorsolateral Prefrontal Cortex; DTI, Diffusion Tensor Imaging; FDR, False Discovery Rate; fMRI, functional Magnetic Resonance Imaging; GM, Gray Matter; HRSD17, 17-Item Hamilton Rating Scale for Depression; iSPOT-D, International Study to Predict Optimized Treatment in Depression; MDD, Major Depressive Disorder; MPFC, Medial Prefrontal Cortex; MRI, Magnetic Resonance Imaging; OFC, Orbitofrontal Cortex; PFC, Prefrontal Cortex; VBM, Voxel-Based Morphometry; Gray matter; Major depressive disorder; VBM; Volume; Cortical thickness; iSPOT-D
5.  Dysregulation in cortical reactivity to emotional faces in PTSD patients with high dissociation symptoms 
European Journal of Psychotraumatology  2013;4:10.3402/ejpt.v4i0.20430.
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.3402/ejpt.v4i0.20430
PMCID: PMC3764312  PMID: 24020010
posttraumatic stress disorder (PTSD); dissociation; ERPs; faces; emotion
6.  GSK3B and MAPT Polymorphisms Are Associated with Grey Matter and Intracranial Volume in Healthy Individuals 
PLoS ONE  2013;8(8):e71750.
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.
doi:10.1371/journal.pone.0071750
PMCID: PMC3741177  PMID: 23951236
7.  Testing the white matter retrogenesis hypothesis of cognitive aging 
Neurobiology of Aging  2011;33(8):1699-1715.
Background
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.
Methods
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 two prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and two 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 to 30 years) and degenerative trajectory (ages 31 to 87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group.
Results
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.
Discussion
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.
doi:10.1016/j.neurobiolaging.2011.06.001
PMCID: PMC3222729  PMID: 21783280
MRI; diffusion tensor imaging; aging; cognition; retrogenesis; BRAINnet
8.  Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial 
Trials  2013;14:224.
Background
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.
Methods/Design
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.
Trial registration
International Study to Predict Optimized Treatment - in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849.
doi:10.1186/1745-6215-14-224
PMCID: PMC3729660  PMID: 23866851
Major depressive disorder; Antidepressant treatments; Imaging; Biomarker; iSPOT-D
9.  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  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.
doi:10.1002/brb3.76
PMCID: PMC3489810  PMID: 23139903
Depression and anxiety; emotional well-being; Internet; mental health screen; risk and resilience; sensitivity and specificity
10.  Hippocampal volume varies with educational attainment across the life-span 
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.
doi:10.3389/fnhum.2012.00307
PMCID: PMC3494123  PMID: 23162453
socioeconomic status; SES; education; hippocampus; amygdala; brain; neuroanatomy; brain reserve
11.  A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): Rationale and design 
Trials  2011;12:77.
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). 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.
Methods
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.
Results
The methodology for the ACTION study has been detailed.
Conclusions
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.
Trial registration
Australian and New Zealand Clinical Trials Registry ANZCTRN12607000535471.
doi:10.1186/1745-6215-12-77
PMCID: PMC3068100  PMID: 21396130
12.  International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol 
Trials  2011;12:4.
Background
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.
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 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.
Discussion
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.
Trial registration
International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849
URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1
doi:10.1186/1745-6215-12-4
PMCID: PMC3036635  PMID: 21208417
13.  Emotion brain alterations in anorexia nervosa: a candidate biological marker and implications for treatment 
Background
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.
Methods
In a retest design, 28 adolescent females with AN were tested at first admission 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.
Results
Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP components 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.
Limitations
This study could have been improved with a longer standardized retest interval.
Conclusion
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.
doi:10.1503/jpn.090073
PMCID: PMC2895157  PMID: 20598239
14.  Category and letter verbal fluency across the adult lifespan: relationship to EEG theta power 
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.
doi:10.1016/j.acn.2004.12.006
PMCID: PMC2758771  PMID: 15939182
Normal aging; Category fluency; Letter fluency; EEG; Theta
15.  Emotion-elicited gamma synchrony in patients with first-episode schizophrenia: a neural correlate of social cognition outcomes 
Background
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.
Methods
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.
Results
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
Limitations to our study include the lack of comparison between medicated and unmedicated patients or between types of medication.
Conclusion
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.
PMCID: PMC2702448  PMID: 19568482
16.  The DNA sequence of the human X chromosome 
Ross, Mark T. | Grafham, Darren V. | Coffey, Alison J. | Scherer, Steven | McLay, Kirsten | Muzny, Donna | Platzer, Matthias | Howell, Gareth R. | Burrows, Christine | Bird, Christine P. | Frankish, Adam | Lovell, Frances L. | Howe, Kevin L. | Ashurst, Jennifer L. | Fulton, Robert S. | Sudbrak, Ralf | Wen, Gaiping | Jones, Matthew C. | Hurles, Matthew E. | Andrews, T. Daniel | Scott, Carol E. | Searle, Stephen | Ramser, Juliane | Whittaker, Adam | Deadman, Rebecca | Carter, Nigel P. | Hunt, Sarah E. | Chen, Rui | Cree, Andrew | Gunaratne, Preethi | Havlak, Paul | Hodgson, Anne | Metzker, Michael L. | Richards, Stephen | Scott, Graham | Steffen, David | Sodergren, Erica | Wheeler, David A. | Worley, Kim C. | Ainscough, Rachael | Ambrose, Kerrie D. | Ansari-Lari, M. Ali | Aradhya, Swaroop | Ashwell, Robert I. S. | Babbage, Anne K. | Bagguley, Claire L. | Ballabio, Andrea | Banerjee, Ruby | Barker, Gary E. | Barlow, Karen F. | Barrett, Ian P. | Bates, Karen N. | Beare, David M. | Beasley, Helen | Beasley, Oliver | Beck, Alfred | Bethel, Graeme | Blechschmidt, Karin | Brady, Nicola | Bray-Allen, Sarah | Bridgeman, Anne M. | Brown, Andrew J. | Brown, Mary J. | Bonnin, David | Bruford, Elspeth A. | Buhay, Christian | Burch, Paula | Burford, Deborah | Burgess, Joanne | Burrill, Wayne | Burton, John | Bye, Jackie M. | Carder, Carol | Carrel, Laura | Chako, Joseph | Chapman, Joanne C. | Chavez, Dean | Chen, Ellson | Chen, Guan | Chen, Yuan | Chen, Zhijian | Chinault, Craig | Ciccodicola, Alfredo | Clark, Sue Y. | Clarke, Graham | Clee, Chris M. | Clegg, Sheila | Clerc-Blankenburg, Kerstin | Clifford, Karen | Cobley, Vicky | Cole, Charlotte G. | Conquer, Jen S. | Corby, Nicole | Connor, Richard E. | David, Robert | Davies, Joy | Davis, Clay | Davis, John | Delgado, Oliver | DeShazo, Denise | Dhami, Pawandeep | Ding, Yan | Dinh, Huyen | Dodsworth, Steve | Draper, Heather | Dugan-Rocha, Shannon | Dunham, Andrew | Dunn, Matthew | Durbin, K. James | Dutta, Ireena | Eades, Tamsin | Ellwood, Matthew | Emery-Cohen, Alexandra | Errington, Helen | Evans, Kathryn L. | Faulkner, Louisa | Francis, Fiona | Frankland, John | Fraser, Audrey E. | Galgoczy, Petra | Gilbert, James | Gill, Rachel | Glöckner, Gernot | Gregory, Simon G. | Gribble, Susan | Griffiths, Coline | Grocock, Russell | Gu, Yanghong | Gwilliam, Rhian | Hamilton, Cerissa | Hart, Elizabeth A. | Hawes, Alicia | Heath, Paul D. | Heitmann, Katja | Hennig, Steffen | Hernandez, Judith | Hinzmann, Bernd | Ho, Sarah | Hoffs, Michael | Howden, Phillip J. | Huckle, Elizabeth J. | Hume, Jennifer | Hunt, Paul J. | Hunt, Adrienne R. | Isherwood, Judith | Jacob, Leni | Johnson, David | Jones, Sally | de Jong, Pieter J. | Joseph, Shirin S. | Keenan, Stephen | Kelly, Susan | Kershaw, Joanne K. | Khan, Ziad | Kioschis, Petra | Klages, Sven | Knights, Andrew J. | Kosiura, Anna | Kovar-Smith, Christie | Laird, Gavin K. | Langford, Cordelia | Lawlor, Stephanie | Leversha, Margaret | Lewis, Lora | Liu, Wen | Lloyd, Christine | Lloyd, David M. | Loulseged, Hermela | Loveland, Jane E. | Lovell, Jamieson D. | Lozado, Ryan | Lu, Jing | Lyne, Rachael | Ma, Jie | Maheshwari, Manjula | Matthews, Lucy H. | McDowall, Jennifer | McLaren, Stuart | McMurray, Amanda | Meidl, Patrick | Meitinger, Thomas | Milne, Sarah | Miner, George | Mistry, Shailesh L. | Morgan, Margaret | Morris, Sidney | Müller, Ines | Mullikin, James C. | Nguyen, Ngoc | Nordsiek, Gabriele | Nyakatura, Gerald | O’Dell, Christopher N. | Okwuonu, Geoffery | Palmer, Sophie | Pandian, Richard | Parker, David | Parrish, Julia | Pasternak, Shiran | Patel, Dina | Pearce, Alex V. | Pearson, Danita M. | Pelan, Sarah E. | Perez, Lesette | Porter, Keith M. | Ramsey, Yvonne | Reichwald, Kathrin | Rhodes, Susan | Ridler, Kerry A. | Schlessinger, David | Schueler, Mary G. | Sehra, Harminder K. | Shaw-Smith, Charles | Shen, Hua | Sheridan, Elizabeth M. | Shownkeen, Ratna | Skuce, Carl D. | Smith, Michelle L. | Sotheran, Elizabeth C. | Steingruber, Helen E. | Steward, Charles A. | Storey, Roy | Swann, R. Mark | Swarbreck, David | Tabor, Paul E. | Taudien, Stefan | Taylor, Tineace | Teague, Brian | Thomas, Karen | Thorpe, Andrea | Timms, Kirsten | Tracey, Alan | Trevanion, Steve | Tromans, Anthony C. | d’Urso, Michele | Verduzco, Daniel | Villasana, Donna | Waldron, Lenee | Wall, Melanie | Wang, Qiaoyan | Warren, James | Warry, Georgina L. | Wei, Xuehong | West, Anthony | Whitehead, Siobhan L. | Whiteley, Mathew N. | Wilkinson, Jane E. | Willey, David L. | Williams, Gabrielle | Williams, Leanne | Williamson, Angela | Williamson, Helen | Wilming, Laurens | Woodmansey, Rebecca L. | Wray, Paul W. | Yen, Jennifer | Zhang, Jingkun | Zhou, Jianling | Zoghbi, Huda | Zorilla, Sara | Buck, David | Reinhardt, Richard | Poustka, Annemarie | Rosenthal, André | Lehrach, Hans | Meindl, Alfons | Minx, Patrick J. | Hillier, LaDeana W. | Willard, Huntington F. | Wilson, Richard K. | Waterston, Robert H. | Rice, Catherine M. | Vaudin, Mark | Coulson, Alan | Nelson, David L. | Weinstock, George | Sulston, John E. | Durbin, Richard | Hubbard, Tim | Gibbs, Richard A. | Beck, Stephan | Rogers, Jane | Bentley, David R.
Nature  2005;434(7031):325-337.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
doi:10.1038/nature03440
PMCID: PMC2665286  PMID: 15772651
17.  Neural synchrony in patients with a first episode of schizophrenia: tracking relations with grey matter and symptom profile 
Background
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.
Methods
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.
Results
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.
Limitations
Our study did not include unmedicated patients or normative follow-up testing.
Conclusion
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.
PMCID: PMC2612078  PMID: 19125210
18.  The neural networks of inhibitory control in posttraumatic stress disorder 
Objective
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.
Methods
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).
Results
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.
Conclusion
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.
PMCID: PMC2527717  PMID: 18787658
inhibition; stress disorders, posttraumatic; motor activity; neurophysiology
19.  The relationship between early life stress and microstructural integrity of the corpus callosum in a non-clinical population 
Background
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.
Methods
In the present study we evaluated this relationship in healthy non-clinical participants using diffusion tensor imaging (DTI) and self-reported history of ELS.
Results
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.
Conclusion
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.
PMCID: PMC2515911  PMID: 18728817
20.  Rostral anterior cingulate volume predicts treatment response to cognitive-behavioural therapy for posttraumatic stress disorder 
Objective
To index the extent to which treatment response in posttraumatic stress disorder (PTSD) is predicted by rostral anterior cingulate cortex (rACC) volume.
Method
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.
Results
According to voxel-based morphometry, treatment responders had larger rACC volume than nonresponders. Further, symptom reduction was associated with larger rACC volume.
Conclusion
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.
PMCID: PMC2265310  PMID: 18330460
stress disorders, post-traumatic; magnetic resonance imaging; cognitive therapy
21.  Associations between the COMT Val/Met polymorphism, early life stress, and personality among healthy adults 
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.
PMCID: PMC2671786  PMID: 19412467
anxiety; depression; gene-environment interaction; early life stress
22.  “Missing links” in borderline personality disorder: loss of neural synchrony relates to lack of emotion regulation and impulse control 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
PMCID: PMC1449878  PMID: 16699604
brain; borderline personality disorder; cognition; electroencephalography; gamma synchrony
23.  Comparative Secretome Analyses of Three Bacillus anthracis Strains with Variant Plasmid Contents  
Infection and Immunity  2005;73(6):3646-3658.
Bacillus anthracis, the causative agent of anthrax, secretes numerous proteins into the extracellular environment during infection. A comparative proteomic approach was employed to elucidate the differences among the extracellular proteomes (secretomes) of three isogenic strains of B. anthracis that differed solely in their plasmid contents. The strains utilized were the wild-type virulent B. anthracis RA3 (pXO1+ pXO2+) and its two nonpathogenic derivative strains: the toxigenic, nonencapsulated RA3R (pXO1+ pXO2−) and the totally cured, nontoxigenic, nonencapsulated RA3:00 (pXO1− pXO2−). Comparative proteomics using two-dimensional gel electrophoresis followed by computer-assisted gel image analysis was performed to reveal unique, up-regulated, or down-regulated secretome proteins among the strains. In total, 57 protein spots, representing 26 different proteins encoded on the chromosome or pXO1, were identified by peptide mass fingerprinting. S-layer-derived proteins, such as Sap and EA1, were most frequently observed. Many sporulation-associated enzymes were found to be overexpressed in strains containing pXO1+. This study also provides evidence that pXO2 is necessary for the maximal expression of the pXO1-encoded toxins lethal factor (LF), edema factor (EF), and protective antigen (PA). Several newly identified putative virulence factors were observed; these include enolase, a high-affinity zinc uptake transporter, the peroxide stress-related alkyl hydroperoxide reductase, isocitrate lyase, and the cell surface protein A.
doi:10.1128/IAI.73.6.3646-3658.2005
PMCID: PMC1111850  PMID: 15908394
24.  Identification of Bacillus anthracis specific chromosomal sequences by suppressive subtractive hybridization 
BMC Genomics  2004;5:15.
Background
Bacillus anthracis, Bacillus thuringiensis and Bacillus cereus are closely related members of the B. cereus-group of bacilli. Suppressive subtractive hybridization (SSH) was used to identify specific chromosomal sequences unique to B. anthracis.
Results
Two SSH libraries were generated. Genomic DNA from plasmid-cured B. anthracis was used as the tester DNA in both libraries, while genomic DNA from either B. cereus or B. thuringiensis served as the driver DNA. Progressive screening of the libraries by colony filter and Southern blot analyses identified 29 different clones that were specific for the B. anthracis chromosome relative not only to the respective driver DNAs, but also to seven other different strains of B. cereus and B. thuringiensis included in the process. The nucleotide sequences of the clones were compared with those found in genomic databases, revealing that over half of the clones were located into 2 regions on the B. anthracis chromosome.
Conclusions
Genes encoding potential cell wall synthesis proteins dominated one region, while bacteriophage-related sequences dominated the other region. The latter supports the hypothesis that acquisition of these bacteriophage sequences occurred during or after speciation of B. anthracis relative to B. cereus and B. thuringiensis. This study provides insight into the chromosomal differences between B. anthracis and its closest phylogenetic relatives.
doi:10.1186/1471-2164-5-15
PMCID: PMC368432  PMID: 15028116
25.  Molecular Characterization of Brucella abortus Chromosome II Recombination 
Journal of Bacteriology  2003;185(20):6130-6136.
Large-scale genomic rearrangements including inversions, deletions, and duplications are significant in bacterial evolution. The recently completed Brucella melitensis 16M and Brucella suis 1330 genomes have facilitated the investigation of such events in the Brucella spp. Suppressive subtractive hybridization (SSH) was employed in identifying genomic differences between B. melitensis 16M and Brucella abortus 2308. Analysis of 45 SSH clones revealed several deletions on chromosomes of B. abortus and B. melitensis that encoded proteins of various metabolic pathways. A 640-kb inversion on chromosome II of B. abortus has been reported previously (S. Michaux Charachon, G. Bourg, E. Jumas Bilak, P. Guigue Talet, A. Allardet Servent, D. O'Callaghan, and M. Ramuz, J. Bacteriol. 179:3244-3249, 1997) and is further described in this study. One end of the inverted region is located on a deleted TATGC site between open reading frames BMEII0292 and BMEII0293. The other end inserted at a GTGTC site of the cyclic-di-GMP phosphodiesterase A (PDEA) gene (BMEII1009), dividing PDEA into two unequal DNA segments of 160 and 977 bp. As a consequence of inversion, the 160-bp segment that encodes the N-terminal region of PDEA was relocated at the opposite end of the inverted chromosomal region. The splitting of the PDEA gene most likely inactivated the function of this enzyme. A recombination mechanism responsible for this inversion is proposed.
doi:10.1128/JB.185.20.6130-6136.2003
PMCID: PMC225032  PMID: 14526025

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