Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BACKGROUND: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. METHODS: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. RESULTS: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (ß = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (ß = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. LIMITATIONS: The relatively small sample size and age differences between the main and replication cohorts were limitations. CONCLUSION: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review.

BACKGROUND: Bipolar disorder is chronic and debilitating. Studies investigating resting-state functional connectivity in individuals with bipolar disorder may help to inform neurobiological models of illness. METHODS: We conducted a systematic review with the following goals: to summarize the literature on resting-state functional connectivity in bipolar disorder during clinical remission (euthymia) compared with healthy controls; to critically appraise the literature and research gaps; and to propose directions for future research. We searched PubMed/MEDLINE, Embase, PsycINFO, CINAHL and grey literature up to April 2017. RESULTS: Twenty-three studies were included. The most consistent finding was the absence of differences in resting-state functional connectivity of the default mode network (DMN), frontoparietal network (FPN) and salience network (SN) between people with bipolar disorder and controls, using independent component analysis. However, 2 studies in people with bipolar disorder who were positive for psychosis history reported DMN hypoconnectivity. Studies using seed-based analysis largely reported aberrant resting-state functional connectivity with the amygdala, ventrolateral prefrontal cortex, cingulate cortex and medial prefrontal cortex in people with bipolar disorder compared with controls. Few studies used regional homogeneity or amplitude of low-frequency fluctuations. LIMITATIONS: We found heterogeneity in the analysis methods used. CONCLUSION: Stability of the DMN, FPN and SN may reflect a state of remission. Further, DMN hypoconnectivity may reflect a positive history of psychosis in patients with bipolar disorder compared with controls, highlighting a potentially different neural phenotype of psychosis in people with bipolar disorder. Resting-state functional connectivity changes between the amygdala, prefrontal cortex and cingulate cortex may reflect a neural correlate of subthreshold symptoms experienced in bipolar disorder euthymia, the trait-based pathophysiology of bipolar disorder and/or a compensatory mechanism to maintain a state of euthymia.

An fMRI study of reward circuitry in patients with minimal or extensive history of major depression.

Functional abnormalities in regions associated with reward processing are apparent in people with depression, but the extent to which disease burden impacts on the processing of reward is unknown. This research examined the neural correlates of reward processing in patients with major depressive disorder and varying degrees of past illness burden. Twenty-nine depressed patients and twenty-five healthy subjects with no lifetime history of psychiatric illness completed the study. Subsets of fourteen patients were presenting for first lifetime treatment of a depressive episode, and fifteen patients had at least three treated episodes of depression. We used functional magnetic resonance imaging to study blood oxygen level-dependent signals during the performance of a contingency reversal reward paradigm. The results identified group differences in the response to punishers bilaterally in the orbitofrontal and medial prefrontal regions. In addition, areas such as the nucleus accumbens, anterior cingulate and ventral prefrontal cortices were activated greatest by controls during reward processing, less by patients early in the course of illness and least by patients with highly recurrent illness-suggesting that these areas are sensitive to the impact of disease burden and repeated episodes of depression. Reward processing in people with depression may be associated with diminished signaling of incentive salience, a reduction in the formation of reward-related associations and heightened sensitivities for negatively valenced stimuli, all of which could contribute to symptoms of depression.

Brain structure and function in the fourth decade of life after extremely low birth weight: An MRI and EEG study.

OBJECTIVE: To examine potential long-term effects of extremely low birth weight (ELBW; ≤ 1000 g) on adult brain structure, brain function, and cognitive-behavioral performance. METHODS: A subset of survivors from the prospectively-followed McMaster ELBW Cohort (n = 23, MBW = 816 g) and their peers born at normal birth weight (NBW; ≥ 2500 g; n = 14, MBW = 3361 g) provided T1-weighted magnetic resonance imaging (MRI) brain scans, resting electroencephalographic (EEG) recordings, and behavioral responses to a face-processing task in their early thirties. RESULTS: Visual discrimination accuracy for human faces, resting EEG alpha power, and long-distance alpha coherence were lower in ELBW survivors than NBW adults, and volumes of white matter hypointensities (WMH) were higher. Across groups, face-processing performance was correlated positively with posterior EEG spectral power and long-distance alpha and theta coherence, and negatively with WMH. The associations between face-processing scores and parietal alpha power and theta coherence were reduced after adjustment for WMH. CONCLUSIONS: Electrocortical activity, brain functional connectivity, and higher-order processing ability may be negatively affected by WMH burden, which is greater in adults born extremely preterm. SIGNIFICANCE: Decrements in electrocortical activity and behavioral performance in adult ELBW survivors may be partly explained by increased WMH volumes in this vulnerable population.

Abnormal hippocampal activation in patients with extensive history of major depression: an fMRI study.

BACKGROUND: Impairment of recollection memory is consistently reported in patients with major depressive disorder (MDD) and may reflect underlying functional hippocampal changes, particularly in those with extensive histories of illness. We hypothesized that relative to controls, patients with a protracted course of illness would show diminished hippocampal activation on functional magnetic resonance imaging (fMRI) during a recollection memory task. METHODS: Patients who experienced 3 or more previously treated depressive episodes were compared with age- and sex-matched controls. We acquired fMRI data while participants performed a recollection memory process dissociation task. RESULTS: Using bilateral regions of interest (ROIs) prescribed for the right and left hippocampal/parahippocampal complex, we observed increased activation of the right hippocampal and left parahippocampal gyrus in controls compared with patients with MDD during recollection memory trials. Within-group comparisons revealed heightened engagement of the hippocampal head (R/L) for controls during recollection trials, and greater activation of the hippocampal body/tail (R/L) during the learn-list encoding period in both the MDD and control groups. Recollection memory performance was significantly correlated with changes in blood oxygen level-dependent signal during recollection trials in the ROIs of the right hippocampus and right hippocampal head. LIMITATIONS: This study was limited by the inclusion of patients taking antidepressant medication, raising the possibility that the reported findings were treatment effects. CONCLUSION: The findings of decreased recruitment of the right hippocampal and left parahippocampalgyrus in patients with MDD suggest that these regions may be sensitive to the impact of disease burden and repeated episodes of MDD. This attenuated activation may represent stable changes in hippocampal function that occur over the course of illness in patients with MDD. The findings from within-group comparisons show that the group differences in the activation of the right hippocampal head were driven by greater engagement of this region among controls during recollection memory performance. These results also associate recollection performance impairments in patients with MDD with diminished hippocampal engagement.

Cognitive Development and Brain Gray Matter Susceptibility to Prenatal Adversities: Moderation by the Prefrontal Cortex Brain-Derived Neurotrophic Factor Gene Co-expression Network.

Background: Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and prenatal adversity conditions on cognitive development trajectories and gray matter density. Methods: We analyzed the moderation effects of an expression polygenic score (ePRS) for the Brain-derived Neurotrophic Factor gene network (BDNF ePRS) on the association between prenatal adversity and child cognitive development. A score based on genes co-expressed with the prefrontal cortex (PFC) BDNF was created, using the effect size of the association between the individual single nucleotide polymorphisms (SNP) and the BDNF expression in the PFC. Cognitive development trajectories of 157 young children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort were assessed longitudinally in 4-time points (6, 12, 18, and 36 months) using the Bayley-II mental scales. Results: Linear mixed-effects modeling indicated that BDNF ePRS moderates the effects of prenatal adversity on cognitive growth. In children with high BDNF ePRS, higher prenatal adversity was associated with slower cognitive development in comparison with those exposed to lower prenatal adversity. Parallel-Independent Component Analysis (pICA) suggested that associations of expression-based SNPs and gray matter density significantly differed between low and high prenatal adversity groups. The brain IC included areas involved in visual association processes (Brodmann area 19 and 18), reallocation of attention, and integration of information across the supramodal cortex (Brodmann area 10). Conclusion: Cognitive development trajectories and brain gray matter seem to be influenced by the interplay of prenatal environmental conditions and the expression of an important BDNF gene network that guides the growth and plasticity of neurons and synapses.

Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes.

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.

Hippocampal metabolic abnormalities at first onset and with recurrent episodes of a major depressive disorder: a proton magnetic resonance spectroscopy study.

The neural underpinnings of major depressive disorder (MDD) are unknown but there is evidence for structural alteration in the hippocampus that may become more pronounced over the course of illness. The aim of the present study was to examine metabolite levels of N-acetyl-aspartate (NAA), Myo-inositol (MI), Glutamate-glutamine (Glx) and choline-containing compounds (GPC and GPC+PCh) in patients presenting for first treatment of a depressive episode compared to those with multiple past episodes and age and sex matched controls. We used single voxel proton magnetic resonance spectroscopy ((1)H-MRS) centered on the hippocampus. Choline-containing compounds were significantly increased in patients with a high past illness burden relative to controls after controlling for hippocampal volume. The group presenting for first treatment had only increases in MI levels compared with matched controls. These results suggest that abnormal membrane turnover in the hippocampus is greater in patients with highly recurrent illness, and provide support for the hypothesis that there are neuronal changes in this region over the course of illness.

Cortical serotonin type-2 receptor density in parents of children with autism spectrum disorders.

Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [(18)F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [(18)F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.

Increased choline-containing compounds in the orbitofrontal cortex and hippocampus in euthymic patients with bipolar disorder: a proton magnetic resonance spectroscopy study.

The neuronal mechanisms underlying the pathophysiology of bipolar disorder (BD) have not been fully characterized. The aim of this study was to compare metabolite levels in the hippocampus and the orbitofrontal cortex in a homogenous population of 12 euthymic patients with well-established BD and 12 age- and sex-matched healthy comparison subjects. Using a GE Signa, 3-Tesla scanner, we performed proton magnetic resonance spectroscopy (H-MRS) to examine levels of N-acetyl aspartate, glutamate and choline-containing compounds. Choline-containing compounds were significantly increased in the hippocampus and the orbitofrontal cortex in BD patients relative to control subjects. Significant elevations of glycerophosphocholine+phosphocholine (GPC+PCh) were measured in the hippocampus and the orbitofrontal cortex of patients. As choline is a marker of membrane phospholipid metabolism, the elevated choline in patients may indicate increased membrane breakdown in the brain regions examined. Abnormal neuronal loss within the hippocampus and orbitofrontal cortex further supports previous work suggesting that these regions are involved in the pathophysiology of BD.

Prefrontal Cortex Dopamine Transporter Gene Network Moderates the Effect of Perinatal Hypoxic-Ischemic Conditions on Cognitive Flexibility and Brain Gray Matter Density in Children.

BACKGROUND: Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. METHODS: We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic-associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts-MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). RESULTS: A history of exposure to several perinatal hypoxic-ischemic-associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism-based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic-associated conditions. CONCLUSIONS: These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.

Neural and behavioural correlates of autobiographical memory retrieval in patients with major depressive disorder and a history of trauma exposure.

Alterations in autobiographical memory (AM) performance have been identified in major depressive disorder (MDD) and in trauma-related disorders, however, the neural and behavioural correlates of AM retrieval in patients with MDD and a co-morbid history of trauma remain unexplored. Here, we used behavioural and neuroimaging techniques to investigate AM in this patient group and in matched healthy comparison subjects (HCs). Twenty patients with MDD and trauma exposure and 20 HCs underwent fMRI scanning while recalling positive, negative, and neutral events. Participants were subsequently administered the Autobiographical Interview (Levine et al., 2002), allowing for separation of episodic and non-episodic details of memories. Key clinical variables, including illness severity, dissociative (e.g., depersonalization, derealization) symptoms, and history of parental bonding, were assessed. Compared to controls, patients showed reduced activation in the left parahippocampus and left anterior insula during retrieval of positive memories. Among patients, greater specificity of positive AM recall on the Autobiographical Interview was related to reduced activation of the left anterior insula during retrieval of positive memories. Moreover, increased left parahippocampal activation during negative memory recall was related to heightened levels of paternal care among the patient group. Taken together, these findings point towards potential alterations in key neural processes (e.g., episodic vividness and embodiment) associated with AM retrieval among MDD patients with a history of co-morbid trauma exposure. These alterations appear unrelated to illness severity, but instead are associated with parental bonding.

A novel task for examining the neural basis of Theory of Mind deficits in bipolar disorder.

Deficits in theory of mind (ToM) processing have been observed in people with bipolar disorder (BD), but the neural basis of these deficits remains unclear. Here, we studied the relations between neural activation, dysfunctional beliefs and behavioral responses in people with BD during a second-order ToM task. Twenty-five patients and 25 healthy-control participants (HC) underwent functional magnetic resonance imaging (fMRI) while performing a novel ToM task. The Dysfunctional Attitudes scale (DAS) and the Brief Hypomanic Attitudes and Positive Predictions Inventory (BHAPPI) were used to assess dysfunctional beliefs. Significant differences in neural activation were observed between HC and BD patients in regions associated with ToM processing: medial frontal, cingulate, anterior cingulate and superior temporal gyri. Correlations between DAS scores and neural activity in medial frontal and cingulate gyri were observed for HC only. Increased activation in brain regions associated with ToM processing in patients compared to HC provides further evidence of disruption in networks controlling social-cognitive processes. Whether this results from compensatory responses to maintain appropriate behavior is unknown.

Subtle persistent working memory and selective attention deficits in women with premenstrual syndrome.

As a recurrent, cyclical phenomenon, premenstrual syndrome (PMS) affects a significant proportion of women of the reproductive age, and leads to regular monthly days of functional impairment. Symptoms of PMS include somatic and psychological symptoms, such as headaches, sleep disturbances, social withdrawal and mood changes, during the late luteal phase of the menstrual cycle, which alleviate during the follicular phase. This study investigated neurocognitive functioning in women with moderate to severe PMS symptoms (n=13) compared to women with mild/no PMS (n=27) through administration of a battery of neuropsychological tests during the asymptomatic follicular phase of the menstrual cycle. Relative to women with mild/no PMS symptoms, women with moderate to severe PMS showed significantly poorer accuracy and more errors of omission on the N-0-back, as well as more errors of omission on the N-2-back task, indicating the presence of impairment in selective attention and working memory. This study provides evidence of persistent, subtle working memory and selective attention difficulties in those with moderate to severe PMS during the follicular phase of the menstrual cycle.

Influence of endogenous estradiol, progesterone, allopregnanolone, and dehydroepiandrosterone sulfate on brain resting state functional connectivity across the menstrual cycle.

OBJECTIVE: To [1] study brain resting state functional connectivity (Rs-FC) in a well-characterized sample of healthy women in the mid-follicular and late luteal phases of the menstrual cycle; and [2] examine the correlation between endogenous E2, P, allopregnanolone, and DHEAS and patterns of Rs-FC across the menstrual cycle. DESIGN: We studied the Rs-FC of the default mode network, salience network, meso-paralimbic network, fronto-parietal network, visual network, and sensorimotor network in the mid-follicular and late luteal phases. Serum levels of E2, P, allopregnanolone, and DHEAS were correlated to patterns of functional connectivity. SETTING: University medical center. PATIENT(S): Twenty-five healthy women with regular menstrual cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Functional connectivity of key brain networks at rest and correlations of hormones to Rs-FC in the mid-follcuar and late luteal menstrual phases. RESULT(S): There were no differences in Rs-FC between the mid-follicular and late luteal menstrual phases using either independent component analysis or seed-based analysis. However, specific correlations between each hormone and patterns of functional connectivity were found in both menstrual cycle phases. CONCLUSION(S): It seems that the association between female sex hormones and brain Rs-FC is menstrual cycle phase-dependent. Future studies should examine the cognitive and behavioral correlates of this association in regularly cycling women.

Brain Structure and Function in Women with Comorbid Bipolar and Premenstrual Dysphoric Disorder.

INTRODUCTION: Hormonal fluctuations associated with female reproductive life events may precipitate or worsen affective episodes in women with bipolar disorder (BD). Previous studies have shown that women with BD report higher rates of premenstrual dysphoric disorder (PMDD) than controls. Further, bipolar women who report premenstrual worsening of mood display a worse course of their bipolar illness. Despite this, the neural correlates of comorbid BD and PMDD have not been investigated. METHODOLOGY: Eighty-five [CTRL, n = 25; PMDD, n = 20; BD, n = 21; BD with comorbid PMDD (BDPMDD), n = 19], regularly cycling women, not on hormonal contraception, underwent two MRI scans: during their mid-follicular and late luteal menstrual phases. We investigated resting-state functional connectivity (Rs-FC), cortical thickness, and subcortical volumes of brain regions associated with the pathophysiology of BD and PMDD between groups, in the mid-follicular and late luteal phases of the menstrual cycle. All BD subjects were euthymic for at least 2 months prior to study entry. RESULTS: Women in the BDPMDD group displayed greater disruption in biological rhythms and more subthreshold depressive and anxious symptoms through the menstrual cycle compared to other groups. Rs-FC was increased between the L-hippocampus and R-frontal cortex and decreased between the R-hippocampus and R-premotor cortex in BDPMDD vs. BD (FDR-corrected, p < 0.05). Cortical thickness analysis revealed decreased cortical thickness of the L-pericalcarine, L-superior parietal, R-middle temporal, R-rostral middle frontal, and L-superior frontal, as well as increased cortical thickness of the L-superior temporal gyri in BDPMDD compared to BD. We also found increased left-caudate volume in BDPMDD vs. BD (pCORR < 0.05). CONCLUSION: Women with BD and comorbid PMDD display a distinct clinical and neurobiological phenotype of BD, which suggests differential sensitivity to endogenous hormones.

Design and Implementation of an fMRI Study Examining Thought Suppression in Young Women with, and At-risk, for Depression.

Ruminative brooding is associated with increased vulnerability to major depression. Individuals who regularly ruminate will often try to reduce the frequency of their negative thoughts by actively suppressing them. We aim to identify the neural correlates underlying thought suppression in at-risk and depressed individuals. Three groups of women were studied; a major depressive disorder group, an at-risk group (having a first degree relative with depression) and controls. Participants performed a mixed block-event fMRI paradigm involving thought suppression, free thought and motor control periods. Participants identified the re-emergence of "to-be-suppressed" thoughts ("popping" back into conscious awareness) with a button press. During thought suppression the control group showed the greatest activation of the dorsolateral prefrontal cortex, followed by the at-risk, then depressed group. During the re-emergence of intrusive thoughts compared to successful re-suppression of those thoughts, the control group showed the greatest activation of the anterior cingulate cortices, followed by the at-risk, then depressed group. At-risk participants displayed anomalies in the neural regulation of thought suppression resembling the dysregulation found in depressed individuals. The predictive value of these changes in the onset of depression remains to be determined.

Effects of electroconvulsive therapy on cognitive functioning in patients with depression: protocol for a systematic review and meta-analysis.

INTRODUCTION: Depression is the leading cause of disability worldwide, affecting approximately 350 million people. Evidence indicates that only 60-70% of persons with major depressive disorder who tolerate antidepressants respond to first-line drug treatment; the remainder become treatment resistant. Electroconvulsive therapy (ECT) is considered an effective therapy in persons with treatment-resistant depression. The use of ECT is controversial due to concerns about temporary cognitive impairment in the acute post-treatment period. We will conduct a meta-analysis to examine the effects of ECT on cognition in persons with depression. METHODS: This systematic review and meta-analysis has been registered with PROSPERO (registration number: CRD42014009100). We developed our methods following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We are searching MEDLINE, PsychINFO, EMBASE, CINAHL and Cochrane from the date of database inception to the end of October 2014. We are also searching the reference lists of published reviews and evidence reports for additional citations. Comparative studies (randomised controlled trials, cohort and case-control) published in English will be included in the meta-analysis. Three clinical neuropsychologists will group the cognitive tests in each included article into a set of mutually exclusive cognitive subdomains. The risk of bias of randomised controlled trials will be assessed using the Jadad scale. We will supplement the Jadad scale with additional questions based on the Cochrane risk of bias tool. The risk of bias of cohort and case-control studies will be assessed using the Newcastle-Ottawa Scale. We will employ the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess the strength of evidence. STATISTICAL ANALYSIS: Separate meta-analyses will be conducted for each ECT treatment modality and cognitive subdomain using Comprehensive Meta-Analysis V.2.0.

Enhanced salience and emotion recognition in Autism: a PET study.

OBJECTIVE: This study examined neural activation of facial stimuli in autism when the salience of emotional cues was increased by prosodic information. METHOD: Regional cerebral blood flow (rCBF) was measured while eight high-functioning men with autism and eight men without autism performed an emotion-recognition task in which facial emotion stimuli were matched with prosodic voices and a baseline gender-recognition task. RESULTS: Emotion processing in autistic subjects, compared to that in comparison subjects, resulted in lower rCBF in the inferior frontal and fusiform areas and higher rCBF in the right anterior temporal pole, the anterior cingulate, and the thalamus. CONCLUSIONS: Even with the enhanced emotional salience of facial stimuli, adults with autism showed lower activity in the fusiform cortex and differed from the comparison subjects in activation of other brain regions. The authors suggested that the recognition of emotion by adults with autism is achieved through recruitment of brain regions concerned with allocation of attention, sensory gating, the referencing of perceptual knowledge, and categorization.