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.

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.

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.

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.

Objectives: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.Methods: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.Results: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).Conclusions: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.

WHAT IS KNOWN AND OBJECTIVE: Worldwide studies have shown that significant proportions of patients with type 2 diabetes (T2DM) do not meet targets for glycaemic control, blood pressure (BP) and lipids, putting them at higher risk of developing complications. However, little is known about medicines management in Australian primary care populations with T2DM. The aim of this study was to (i) describe the management of a large group of patients in primary care, (ii) identify areas for improvement in management and (iii) determine any relationship between adherence and glycaemic, BP and lipid control. METHODS: This was a retrospective, epidemiological study of primary care patients with T2DM diabetes, with HbA(1c) of >7%, recruited in 90 Australian community pharmacies. Data collected included demographic details, diabetes history, current medication regimen, height, weight, BP, physical activity and smoking status. RESULTS AND DISCUSSION: Of the 430 patients, 98% used antidiabetics, 80% antihypertensives, 73% lipid lowering drugs and 38% aspirin. BP and all lipid targets were met by only 21% and 14% of the treated patients and 21% and 12% of the untreated patients respectively. Medication adherence was related to better glycaemic control (P = 0.04). WHAT IS NEW AND CONCLUSIONS: An evidence-base prescribing practice gap was seen in this Australian primary care population of T2DM patients. Patients were undertreated with antihypertensive and lipid lowering medication, and several subgroups with co-morbidities were not receiving the recommended pharmacotherapy. Interventions are required to redress the current evidence-base prescribing practice gap in disease management in primary care.

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.

Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson's disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.

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.

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.

ABSTRACT: 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: 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) naive 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.

OBJECTIVE:: To examine resting awake EEG in adolescent AN participants before and after refeeding to determine if EEG abnormalities in Anorexia Nervosa (AN) are reversible. METHOD:: 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. RESULTS:: 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. DISCUSSION:: 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. (c) 2010 by Wiley Periodicals, Inc. (Int J Eat Disord 2010).

Array

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.

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.

Aim. To examine the efficacy of a six-month Kung Fu (KF) program on physical fitness in overweight/obese adolescents. Methods. Subjects were randomly assigned to the KF or sham exercise (Tai Chi, TC) control group. Physical measurements in cardiovascular fitness and muscle fitness occurred at baseline and after 6 months of training thrice weekly. Results. Twenty subjects were recruited. One subject was lost to follow-up, although overall compliance to the training sessions was 46.7 +/- 27.8%. At follow-up, the cohort improved in absolute upper (P = .002) and lower (P = .04) body strength, and upper body muscle endurance (P = .02), without group differences. KF training resulted in significantly greater improvements in submaximal cardiovascular fitness (P = .03), lower body muscle endurance (P = .28; significant 95% CI: 0.37-2.49), and upper body muscle velocity (P = .03) relative to TC training. Conclusions. This short-term KF program improved submaximal cardiovascular fitness, lower body muscle endurance, and muscle velocity, in overweight/obese adolescents with very low baseline fitness.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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 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. RESULTS: 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. 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.

Recent studies suggest that resting posterior versus frontal EEG delta/theta activity (delta/theta Pz-Fz) is both sensitive to pharmacological manipulations of neural dopamine and associated with the agency facet of extraversion (i.e., a motivational disposition comprising enthusiasm, energy, assertiveness, achievement striving and social dominance). These observations suggest that posterior versus frontal resting EEG delta/theta activity may represent a useful marker for investigating the molecular genetic basis of extraversion. The present study aimed to test the novel hypothesis of an association between delta/theta Pz-Fz and a functional polymorphism of the enzyme catechol-O-methyltransferase (COMT VAL(158)MET) involved in dopamine catabolism. This was conducted in a large EEG data set from the Brain Resource International Database (BRID; resting EEG from N=1093 healthy individuals, 382 of which also genotyped for COMT VAL(158)MET). In summary, we (1) showed for the first time that the VAL allele is associated with increased delta/theta Pz-Fz; (2) replicated the association between extraversion and delta/theta Pz-Fz in a large, heterogeneous sample including both genders; and (3) documented that the VAL allele of the COMT VAL(158)MET is associated with increased extraversion scores, as previously reported for an overlapping BRID sample. This coherent pattern of findings adds further support to the suggestion that the posterior-anterior distribution of resting EEG slow wave activity in the delta/theta range represents a useful tool for probing the dopaminergic basis of extraversion.