Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission Status after 16 Weeks of Pharmacotherapy: A CAN-BIND Report.

Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. So far, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity associated with MDD and pharmacotherapy outcomes in a large, multisite sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior cingulate cortex, insula and dorsolateral prefrontal cortex) and all other brain voxels. Partial least squares was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission (MADRS ≤ 10) early (within 8 weeks), late (within 16 weeks), or not at all. We replicated previous findings of altered connectivity in patients. In addition, baseline connectivity of the anterior/posterior cingulate and insula seeds differentiated patients with different treatment outcomes. The stability of these differences was established in the largest single-site subsample. Our replication and extension of altered connectivity highlighted previously reported and new differences between patients and controls, and revealed features that might predict remission prior to pharmacotherapy. Trial registration:ClinicalTrials.gov: NCT01655706.

Frontal EEG asymmetry moderates the relation between borderline personality disorder features and feelings of social rejection in adolescents.

Although associations among borderline personality disorder (BPD), social rejection, and frontal EEG alpha asymmetry scores (FAA, a neural correlate of emotion regulation and approach-withdrawal motivations) have been explored in different studies, relatively little work has examined these relations during adolescence in the same study. We examined whether FAA moderated the relation between BPD features and rejection sensitivity following a validated social exclusion paradigm, Cyberball. A mixed, clinical-community sample of 64 adolescents (females = 62.5%; Mage = 14.45 years; SD = 1.6; range = 11-17 years) completed psychodiagnostic interviews and a self-report measure of BPD (Time 1). Approximately two weeks later (Time 2), participants completed a resting EEG recording followed by Cyberball. FAA moderated the relation between BPD features and overall feelings of rejection following Cyberball: individuals with greater relative left FAA had the highest and lowest feelings of social rejection depending on whether they had high and low BPD feature scores, respectively. Results remained after controlling for age, sex, gender, depression, and BPD diagnosis. These results suggest that FAA may moderate the relation between BPD features and social rejection, and that left frontal brain activity at rest may be differentially associated with those feelings in BPD. Findings are discussed in terms of the link between left frontal brain activity in the regulation and dysregulation of social approach behaviors, characteristic of BPD.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Resting state fMRI scanner instabilities revealed by longitudinal phantom scans in a multi-center study.

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.

Exploring brain connectivity changes in major depressive disorder using functional-structural data fusion: A CAN-BIND-1 study.

There is a growing interest in examining the wealth of data generated by fusing functional and structural imaging information sources. These approaches may have clinical utility in identifying disruptions in the brain networks that underlie major depressive disorder (MDD). We combined an existing software toolbox with a mathematically dense statistical method to produce a novel processing pipeline for the fast and easy implementation of data fusion analysis (FATCAT-awFC). The novel FATCAT-awFC pipeline was then utilized to identify connectivity (conventional functional, conventional structural and anatomically weighted functional connectivy) changes in MDD patients compared to healthy comparison participants (HC). Data were acquired from the Canadian Biomarker Integration Network for Depression (CAN-BIND-1) study. Large-scale resting-state networks were assessed. We found statistically significant anatomically-weighted functional connectivity (awFC) group differences in the default mode network and the ventral attention network, with a modest effect size (d < 0.4). Functional and structural connectivity seemed to overlap in significance between one region-pair within the default mode network. By combining structural and functional data, awFC served to heighten or reduce the magnitude of connectivity differences in various regions distinguishing MDD from HC. This method can help us more fully understand the interconnected nature of structural and functional connectivity as it relates to depression.

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.

Evaluating Adherence to Return to School and Activity Protocols in Children After Concussion.

OBJECTIVE: The need to have a pediatric-specific concussion management protocol on Return to School (RTS) and Return to Activity (RTA) after concussion has been recognized internationally. The first step to evaluate the protocol effectiveness is to establish whether children and youth are adhering to these recommendations. The objective of this study was to explore the prevalence and predictors of adherence to RTS and RTA concussion management protocols for children/youth. DESIGN: A prospective cohort of children/youth with concussion. SETTING: Childhood Disability Research Centre. PARTICIPANTS: One hundred thirty-nine children/youth aged 5 to 18 years, diagnosed with concussion and symptomatic upon enrollment, were followed for up to 6 months. Primary recruitment occurred from a Children's Hospital Emergency Department. INTERVENTION: Provision of RTS/RTA guidelines. MAIN OUTCOME MEASURES: Measurement of adherence came from multiple sources, including the child's and parent's knowledge of protocols, research personnel evaluations, and self-reported stages of RTS/RTA and Post-Concussion Symptom Scale (PCSS) scores. RESULTS: Spearman correlations and logistic regression were used, investigating the relationship between PCSS and progression of protocols and determining predictors of adherence. Significant negative associations between total PCSS score and stage of RTS/RTA protocols were found. Fifty-three percent and 56% of the participants adhered to the RTS and RTA protocols, respectively. CONCLUSIONS: Children's knowledge of protocols and total PCSS scores significantly predicted adherence to RTS/RTA and may be the most important factors in predicting adherence during recovery from concussion.

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants.

Task-based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood-oxygen-level dependent (BOLD) signal of such tasks is essential. We assessed test-retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra-class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub-cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task-based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.

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.

Post-concussive depression: evaluating depressive symptoms following concussion in adolescents and its effects on executive function.

Background: Post-concussive depression describes an elevation of depressive symptoms following concussion that occurs in conjunction with other symptoms of concussion. Children with concussion are more likely to diagnosed with depression. The overlapping symptoms between clinical depression and concussion make the diagnosis of depression difficult. The purpose of this study is to explore how post-concussive depression relates to post-concussion symptoms and cognition by investigating symptom-reporting in youth with post-concussive depression and executive function.Methods: Adolescents (age 10-17 years) diagnosed with concussion were divided into two groups based on depression scores on the Children's Depression Inventory (post-concussion depression; non-depression groups). Symptom reporting on the Post-Concussion Symptom Inventory and performance on Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) were compared.Results: Participants with post-concussive depression had heightened emotionality, irritability, and nervousness. Sadness and fatigue were reported by both groups. ImPACT was unable to distinguish between groups but the group overall demonstrated severe neurocognitive deficits.Conclusion: Reports of greater emotionality, irritability, and nervousness on concussion symptom scales may be indicators of post-concussion depression. It is important for clinicians to take note when an adolescent with concussion scores high on these three emotional symptoms as they may be indicative of greater emotional distress.

Testing a deep convolutional neural network for automated hippocampus segmentation in a longitudinal sample of healthy participants.

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues - Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies.

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging ­ alone or in combination with other variables ­ can predict the outcomes of various treatment modalities.

Impact of maternal adverse childhood experiences on child socioemotional function in rural Kenya: Mediating role of maternal mental health.

Mothers in low- and middle-income countries (LMIC) suffer heightened vulnerability for adverse childhood experiences (ACEs), which is exacerbated by the multitude of risk factors associated with poverty and may lead to increased risk of psychiatric disorder. The constellation of complex, co-occurring biological, environmental, social, economic and psychological risk factors are in turn transmitted to her child, conferring vulnerability for adverse development. This study examines the association between maternal intra- and extra-familial ACEs, maternal education and the mental health of her child, mediated by maternal mental health. Mother-child dyads (n = 121) in Machakos, Kenya were examined cross-sectionally using self-report measures of ACEs, maternal mental health and child internalizing and externalizing mental health problems. The four models proposed to examine the relationship between intra- and extra-familial maternal ACEs and child internalizing and externalizing problems demonstrated indirect pathways through maternal mental health. These effects were found to be conditional on levels of maternal education, which served as a protective factor at lower levels of maternal ACEs. These models demonstrate how the impact of ACEs persists across the lifespan resulting in a negative impact on maternal mental health and conferring further risk to subsequent generations. Elucidating the association between ACEs and subsequent intergenerational sequelae, especially in LMIC where risk is heightened, may improve targeted caregiver mental health programs for prevention and intervention.

Cortical thickness correlates of cognitive performance in cognitively-matched individuals with and without schizophrenia.

Schizophrenia is characterized by psychosis and, in most cases, cognitive impairment. It is unclear, however, whether these elements of the disorder represent distinct or related disease processes. Accordingly, this study investigated 3-way interactions between group, cognition and cortical thickness in cognitively-matched patients with schizophrenia and healthy control groups. Patients and healthy controls were group-matched on demographics and a broadly-based index of cognitive performance. T1-weighted images were processed using Freesurfer. Variable selection techniques were applied to determine which regions best predicted 3-way interaction effects. Independent variables included age, sex, IQ, and 87 regional cortical thickness values strongly associated with group or cognition. Antipsychotic treatment effects were also investigated. Twenty regions were selected by the best fitting model. The top 6 regions included the left pre- and post-central, left superior frontal and temporal and right rostral and caudal middle frontal cortices. No antipsychotic treatment effects were seen. Cortical thinning in schizophrenia exists even in the absence of cognitive impairment. Our findings support the separation of psychosis and cognitive impairment as independent disease processes, with distinct relations with cortical thickness in prefrontal cortical areas. Parsing out these two disease processes will increase understanding of heterogeneity in schizophrenia and may modify treatment targets.

Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS. METHODS: We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n = 22) or placebo (n = 22) for 6 weeks. At weeks 0, 6, and 10, we determined patients' levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At weeks 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters, and neurotrophin levels. RESULTS: At week 6, 14 of 22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7 of 22 patients in the placebo group (P = .04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo. CONCLUSION: In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. ClinicalTrials.gov no. NCT01276626.

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.

Executive function in teen and adult women: Association with maternal status and early adversity.

The aim of this study was to determine the impact of maternal age on executive function and the moderating effects of women's maternal status and early-life experiences. Four groups of women were assessed as a function of their age (teens vs. adults) and maternal status (mothers vs. nonmothers). Participants completed executive function tests, including Spatial Working Memory (SWM), Intra-Extra-Dimensional-Set-Shift (IED), and Stockings of Cambridge (SOC). Women also completed the Childhood Trauma Questionnaire to assess their experiences of early adversity. Results showed that for the IED-task, there were main effects of age and maternal status and an interaction between the two; adults performed better than teens, mothers performed better than nonmothers, and teen nonmothers performed the least well of all groups. For the SWM-task, adults performed better than teens. Our results indicate that although age is an important factor for proper executive functioning, different tasks are affected differently and other factors such as maternity and adverse childhood experiences moderate this functioning.

Cortical thickness in bipolar disorder: a systematic review.

OBJECTIVES: Bipolar disorder (BD) is a debilitating illness, the psychopathology of which is associated with aberrant structural and functional differences in the brain. Despite the many advances in psychiatric research, our understanding of the complex neurobiological underpinnings of BD remains incomplete. The aim of this review was to critically examine all available published magnetic resonance imaging (MRI) research reporting cortical thickness in BD with respect to a healthy population and/or other psychiatric samples. METHODS: The systematic search encompassed all relevant studies published until November 2014. Relevant papers were identified through an online search of select databases (MEDLINE and EMBASE) using key terms bipolar disorder or mania, and cortical thickness. Two independent raters determined the eligibility of papers and performed separate data extraction to ensure quality and accuracy of reporting. RESULTS: A total of 17 papers met the criteria and were included in this review. Compared to a healthy population, the majority of studies reported decreased cortical thickness in the left anterior cingulate/paracingulate and the left superior temporal gyrus, as well as several prefrontal regions bilaterally in patients with BD. Studies also show consistency of cortical thinning in individuals with BD and schizophrenia in frontal and temporal regions, suggesting some common neuropathology. CONCLUSIONS: This systematic review further supports a link between specific structural brain abnormalities and BD. Future studies should investigate cortical thickness with respect to at-risk populations to determine whether these neuropathologies develop before or after the onset of BD.

Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort.

BACKGROUND: Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. METHODS: CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. DISCUSSION: From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01655706 . Registered July 27, 2012.

Gray matter volumes in symptomatic and asymptomatic offspring of parents diagnosed with bipolar disorder.

Children of parents diagnosed with bipolar disorder (BD), termed high-risk offspring (HRO), are at greater risk of developing psychiatric disorders compared to healthy children of healthy parents (HCO). Gray matter volume (GMV) abnormalities have been observed in HRO, however, these reports are inconsistent. We posit that this variability may be attributed to differences in methodology among offspring studies; in particular, the presence of psychiatric symptoms in HRO. Here, we directly compared GMVs between symptomatic and asymptomatic HRO, and HCO. High-resolution T1-weighted MR images were collected from 31 HRO (18 symptomatic and 13 asymptomatic) and 20 age- and sex-matched HCO. HRO had at least one parent diagnosed with BD. Symptomatic HRO were defined as having a psychiatric diagnosis other than BD, while asymptomatic HRO were required to be free of any psychiatric diagnosis. Scans were processed using voxel-based morphometry methods and between group analyses were performed in SPM. Compared to HCO, the HRO group showed decreased GMV in the right inferior orbitofrontal, right middle frontal, and bilateral superior and middle temporal regions. Both symptomatic and asymptomatic HRO groups showed decreased GMV in these regions separately when compared to HCO. When comparing symptomatic and asymptomatic HRO, GMVs were comparable in all regions except the lateral occipital cortex. Our study compared symptomatic and asymptomatic HRO directly. In doing so, we provided further support for the presence of discrete GMV deficits in HRO, and confirmed that these deficits are present irrespective of the presence of symptoms in HRO.