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BackgroundClarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.MethodsThe study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse (‘baseline’) and the longitudinal Vietnam Era Twin Study of Aging (‘follow-up’). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].ResultsTotal depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07–1.57), erectile dysfunction (OR 1.32, 95% CI 1.10–1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04–1.53), and sleep apnea (OR 1.40, 95% CI 1.13–1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09–1.60).ConclusionsA history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness., This review discusses the major challenges facing neuroimaging research of bipolar disorder and highlights the major accomplishments, ongoing challenges and future goals of the ENIGMA Bipolar Disorder Working Group.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

Background and aims Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early mid-life would have older than predicted brain age 16-28 years later. Design Prospective cohort observational study, utilizing smoking pack years data from average age 40 (early mid-life) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later mid-life) and 68 years (early old age). Early mid-life alcohol use was also evaluated. Setting Population-based United States sample. Participants/cases Participants were male twins of predominantly European ancestry who served in the United States military between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves. Measurements Self-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the Brain-Age Regression Analysis and Computation Utility software (BARACUS) program to create PBAD scores (chronological age-predicted brain age) acquired at average ages 56 (n = 493; 2002-08), 62 (n = 408; 2009-14) and 68 (n = 499; 2016-19). Findings In structural equation modeling, age 40 pack years predicted more advanced age 56 PBAD [β = -0.144, P = 0.012, 95% confidence interval (CI) = -0.257, -0.032]. Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking × alcohol interaction, predicted more advanced PBAD at age 56 (β = -0.166, P = 0.001, 95% CI = -0.261, -0.070) with additional influences at age 62 (β = -0.115, P = 0.005, 95% CI = -0.195, -0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin-pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD. Conclusions Heavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.

OBJECTIVE: Neuropsychological impairments are observed in individuals with Bipolar Disorder (BD), yet knowledge of how cognitive deficits unfold in real-time remains limited. Given intraindividual variability in mood observed in people with BD, and the potential for mood and cognition to be mutually influential, we employed ambulatory assessment technologies to examine potential contemporaneous (same survey) and lagged (next survey) relationships of congition and mood. METHODS: Outpatients with BD (n=46) or no psychiatric disorders (heathy volunteers [HV]; n=20) completed in-laboratory neurobehavioral assessments and 14 days of smartphone-administered mobile cognitive tests and ratings of affective variables. Linear mixed effects models were used to analyze real-time relationships between mobile cognitive test performance and mood. RESULTS: On in-laboratory tests, participants with BD showed worse cognitive performance than HVs as well as mild depression severity; mood and cognitive performance were unrelated. On mobile cognitive tests and surveys, participants with BD showed somewhat worse cognitive performance and ratings of lower energy and greater sadness relative to HV participants. Among those with BD, mania and sadness earlier in the day related to worse processing speed and better working memory performance, respectively, on the next survey. In contrast, same survey ratings of greater stress related to better working memory, and greater happiness related to better processing speed. CONCLUSIONS: Real-time assessments of mood and cognition provide incremental information beyond what can be gleaned from laboratory assessments. Understanding how these affect-related changes in processing speed emerge and play out in daily life may provide clinically useful information for treatment planning.

BackgroundWrist-worn actigraphy can objectively measure sleep, and has advantages over self-report, particularly for people with Bipolar Disorder (BD) for whom self-reports might be influenced by affect. Clinically useful data reduction approaches are needed to explore these complex data.MethodsWe created a composite score of sleep metrics in BD based on 51 BD and 80 healthy comparison (HC) participants. Subjects wore an actigraph for up to 14 consecutive 24-h periods, and we assessed total sleep time (TST), wake after sleep onset (WASO), percent sleep (PS), and number of awakenings (NA). We focused on participants who had at least 5 nights of actigraphy data. We computed z-scores for within-person means of sleep measures for BD subjects versus HCs, which were averaged to create a composite measure. We correlated this composite with participant characteristics, and used LASSO regression to identify sleep measures best explaining variability in identified correlates.ResultsSleep measures and the composite did not differ between BDs and HCs; however, there was considerable variability in z-scores among those with BD. In BDs, the composite score was higher in women (t(49)=2.28, p=0.027) and those who were employed (t(34)=2.34, p=0.025), and positively correlated with medication load (r=0.41, p=0.003) while negatively correlated with Young Mania Rating Scale (YMRS; r=-0.35, p=0.030). In LASSO regression, TST and NA best explained medication load while PS best explained employment and YMRS.ConclusionWhile a composite score of sleep metrics may provide useful information about sleep quality globally, our findings suggest that selection of theory-driven sleep measures may be more clinically meaningful.

Background Peripheral levels of pro-inflammatory biomarkers have been shown to be altered in schizophrenia (SZ) and associated with cognitive impairments, but their relevance to specific cognitive domains remains unclear. Methods Plasma levels of cytokines, chemokines, and vascular biomarkers were quantified and compared between SZ and healthy comparison (HC) groups. Cognition was assessed using the Delis-Kaplan Executive Function System Trail Making (TM) and Color Word Interference (CWI) tests. Linear regression analyses examined differential relationships of inflammatory biomarkers with executive function between groups. Results Plasma levels of TNFα, ICAM1, and MCP1 were higher in individuals with SZ compared to HCs. Higher level of MCP1 was associated with increased CWI Inhibition Switching Errors in SZ but not HCs. Conclusion Like other studies, we found evidence for increased peripheral inflammation in SZ. We also showed that SZ with particularly high MCP1 levels had poor cognitive flexibility. Interventions to reduce chemokine elevations might prove beneficial for cognitive performance.

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

Premature mortality and increased physical comorbidity associated with bipolar disorder (BD) may be related to accelerated biological aging. Sleep disturbances and inflammation may be key mechanisms underlying accelerated aging in adults with BD. To our knowledge, these relationships have not been examined rigorously. This cross-sectional study included 50 adults with BD and 73 age- and sex-comparable non-psychiatric comparison (NC) subjects, age 26–65 years. Participants were assessed with wrist-worn actigraphy for total sleep time (TST), percent sleep (PS), and bed/wake times for 7 consecutive nights as well as completing scales for subjective sleep quality. Within-individual variability in sleep measures included intra-individual standard deviation (iSD) and atypicality of one evening's sleep. Blood-based inflammatory biomarkers included interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). Linear regression analyses tested relationships of mean and iSD sleep variables with inflammatory marker levels; time-lagged analyses tested the influence of the previous evening's sleep on inflammation. BD participants had worse subjective sleep quality, as well as greater TST iSD and wake time iSD compared to the NC group. In all participants, higher TST iSD and lower mean PS were associated with higher IL-6 levels (p = 0.04, ηp2 = 0.042; p = 0.05, ηp2 = 0.039, respectively). Lower mean PS was associated with higher CRP levels (p = 0.05, ηp2 = 0.039). Atypicality of the previous night's TST predicted next day IL-6 levels (p = 0.05, ηp2 = 0.04). All of these relationships were present in both BD and NC groups and remained significant even after controlling for sleep medications. Overall, sleep measures and their variability may influence inflammatory markers in all adults. Thus, sleep may be linked to the inflammatory processes believed to underlie accelerated aging in BD.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 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).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging 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 predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

Objective: Literature on older-age bipolar disorder (OABD) is limited. This first-ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated associations among age, BD symptoms, comorbidity, and functioning. Methods: This analysis used harmonized, baseline, cross-sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF). Results: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate-to-severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47–67.00, ROC-AUC = 71.49%, 95% CI = 69.39–73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70–60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen’s Kappa = 0.83, 95% CI = 0.829–0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

The locus coeruleus (LC) is a brainstem region involved in regulating pain. Chronic pain is common in older adulthood, but no studies have examined its association with the LC in humans. We used neuromelanin-sensitive imaging to study differences in LC integrity in older adults with and without chronic pain. Chronic pain was assessed in community-dwelling men from the Vietnam Era Twin Study of Aging (VETSA) in 3 study waves covering an average of 12 years. Pain was self-reported on the SF-36 Bodily Pain Scale. Chronic pain was defined as moderate to severe pain severity at the current and at least one prior wave; 17% had chronic pain (n=80). At the third wave, 481 participants (mean age=67.57) underwent neuromelanin-sensitive MRI scans from which we calculated an LC contrast-to-noise ratio (LCCNR) – an index of LC integrity. We examined associations between chronic pain and LCCNR (in the rostral LC and caudal regions) with generalized estimating equations after adjusting for age, race, education, depressive symptoms, medical comorbidities, and opioid medication use. Individuals with chronic pain had .35 standard deviation lower rostral LCCNR (95% CI: -.62 to -.05) compared to those without chronic pain. No differences in the caudal LCCNR were detected. Chronic pain was associated with decreased rostral LC integrity in older adults. Differences in the rostral LC, rather than caudal LC, suggest the association between lower LC integrity and chronic pain may be related to pain processing in cortical regions where rostral LC projections typically connect.

Social and language abilities are closely intertwined during early development. Yet, it is still unknown how neural features underlying early social and language deficits are linked in toddlers with autism spectrum disorders (ASD). We examined functional connectivity of left and right temporal language regions and its correlations with language and social abilities in a cohort of 1– 4 years old toddlers (52 ASD/34 non-ASD). Further, ASD toddlers were stratified into those who strongly prefer social visual stimuli (ASDSoc) vs. those who do not (ASDnonSoc) based on performance on an eye-tracking paradigm. In non-ASD toddlers, connectivity between temporal regions and other language- and social-related cortical regions was significantly correlated with language, communication, and social scores. Conversely, ASD toddlers showed atypical correlations between temporal–visual cortex (cuneus) connectivity and communication ability. This temporal–visual connectivity was also correlated with social visual attention in ASDnonSocbut not in ASDSoctoddlers. These findings suggest language- and social-related functional connectivity was not correlated with language and social functions in ASD toddlers. Abnormal engagement of temporal–visual cortex connectivity may be an early-age signature of ASD and may help explain why interventions targeting social skills and language are so challenging, particularly in those with poor social engagement.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer’s disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer’s disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246–367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51–60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer’s disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61–71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer’s disease risk and the potential value of mean diffusivity and/or multimodal brain signatures., Among cognitively normal adults in their 50 s, an Alzheimer’s brain signature based on grey matter mean diffusivity—but not cortical thickness—significantly improved prediction of progression to mild cognitive impairment 12 years later. Grey matter mean diffusivity signatures may be sensitive to Alzheimer-related changes as early as middle age., Graphical Abstract Graphical Abstract

Objective: There is a dearth of research about the aging process among individuals with bipolar disorder (BD). One potential strategy to overcome the challenge of interpreting findings from existing limited older-age bipolar disorder (OABD) research studies is to pool or integrate data, taking advantage of potential overlap or similarities in assessment methods and harmonizing or cross-walking measurements where different measurement tools are used to evaluate overlapping construct domains. This report describes the methods and initial start-up activities of a first-ever initiative to create an integrated OABD-focused database, the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project. Methods: Building on preliminary work conducted by members of the International Society for Bipolar Disorders OABD taskforce, the GAGE-BD project will be operationalized in four stages intended to ready the dataset for hypothesis-driven analyses, establish a consortium of investigators to guide exploration, and set the stage for prospective investigation using a common dataset that will facilitate a high degree of generalizability. Results: Initial efforts in GAGE-BD have brought together 14 international investigators representing a broad geographic distribution and data on over 1,000 OABD. Start-up efforts include communication and guidance on meeting regulatory requirements, establishing a Steering Committee to guide an incremental analysis strategy, and learning from existing multisite data collaborations and other support resources. Discussion: The GAGE-BD project aims to advance understanding of associations between age, BD symptoms, medical burden, cognition and functioning across the life span and set the stage for future prospective research that can advance the understanding of OABD.

Objectives Persons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. The sleep-inflammation link has been reported to be stronger in women within the general population. This study sought to examine the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical and cognitive variables. Design Cross-sectional case-control study. Participants Community-dwelling outpatients with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26-65 years. Measurements Reported sleep disturbances (sleep quality and duration), and mental and physical health were assessed. Cognitive assessments included executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status - modified.) Inflammatory biomarkers included pro-inflammatory cytokines [high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-α (TNF-α)] and an anti-inflammatory cytokine (IL-10). Results The schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-α compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels. Conclusions Sleep disturbances and increased inflammation, which were common in schizophrenia, were associated in persons with schizophrenia. Moreover, women with schizophrenia had worse sleep quality and inflammation than men. Further examination of the sleep-inflammation links, their contribution to clinical outcomes, and sex-specific factors is warranted.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

ImportanceBoth cognitive reserve and modifiable lifestyle behaviors are associated with dementia risk. The effect of early lifestyle behaviors and cognitive reserve on late midlife brain aging could inform early identification and risk reduction of future dementia.ObjectiveDetermine associations of young adult cognitive reserve, early midlife lifestyle behaviors, and the reserve-by-lifestyle interaction on late midlife brain age. Examine the relationship between mild cognitive impairment (MCI) and brain age.DesignParticipants were from the nationally representative Vietnam Era Twin Study of Aging (VETSA). Cognitive reserve was assessed at median age 20 years (IQR=1.38) with the Armed Forces Qualification Test (AFQT). Lifestyle behaviors (smoking, alcohol consumption, and social engagement) were assessed at median age 41 (IQR=5.00). Structural brain imaging conducted at median age 69 (IQR=4.74) was used to construct predicted brain age difference scores (PBAD=chronological age minus predicted brain age) and MCI was ascertained.SettingIn-person cognitive testing (ages 20 and 69); mailed survey (age 41); structural MRI, MCI diagnosis at University of California, San Diego (age 69).Participants431 community-dwelling men.ExposuresAFQT; self-reported health and lifestyle behaviors.Main outcomes and measuresPBAD scores; MCI.ResultsIn fully adjusted mixed linear models, age 20 cognitive reserve and the age 41 lifestyle composite were associated with age 69 PBAD [t (104)=2.62, p=0.01, 95%CI 0.874, 6.285; t (104)=3.37, p=0.001, 95%CI 0.583, 2.249 respectively] as was the reserve-by-lifestyle interaction [t (104) = −2.29, p=0.02, 95%CI −2.330, −0.167]. Unfavorable lifestyle predicted more advanced brain age, but only for those with lower young adult cognitive reserve. The MCI group had more advanced brain age (F (2,130) = 3.13; p=0.05).Conclusions and relevanceFavorable lifestyle behaviors promoted resistance to accelerated brain aging 3 decades later for those with lower young adult cognitive reserve. High reserve appeared to be protective regardless of lifestyle. The association with MCI suggests that advanced PBAD scores reflect poorer brain integrity, although it is unclear if PBAD is related to Alzheimer’s dementia specifically. Lower cognitive reserve increases risk for dementia, but early lifestyle modification may promote healthier brain aging and dementia risk reduction, particularly in those with lower reserve.Study TypeCohort StudyKey PointsQuestionDo modifiable lifestyle behaviors in early midlife predict later accelerated brain aging and is that association moderated by cognitive reserve?FindingsA lifestyle composite of smoking, alcohol consumption and social engagement at age 41 was associated with estimated brain age in late midlife. There was a significant moderation effect whereby more unfavorable lifestyle behaviors predicted more advanced brain aging, but only in those with low-to-moderate cognitive reserve.MeaningFavorable lifestyle behaviors appear to be protective for brain integrity especially among those with lower cognitive reserve. Early midlife efforts at prevention could be prioritized among those with lower cognitive reserve.

Cortical regional identities develop through anterior-posterior (A-P) and dorsal-ventral (D-V) prenatal genomic patterning gradients. Here we find that A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) is intact in typically developing and autistic toddlers with good language outcome, but is absent in autistic toddlers with poor early language outcome. Genes driving this effect are prominent in midgestational A-P and D-V gene expression gradients and prenatal cell types driving SA and CT variation (e.g., progenitor cells versus excitatory neurons). These genes are also important for vocal learning, human-specific evolution, and prenatal co-expression networks enriched for high-penetrance autism risk genes. Autism with poor early language outcome may be linked to atypical genomic cortical patterning starting in prenatal periods and which impacts later development of regional functional specialization and circuit formation.One Sentence SummaryGenomic patterning of the cortex is atypical in autistic toddlers with poor early language outcome.

Author(s): Goldstein, Benjamin I; Baune, Bernhard T; Bond, David J; Chen, Pao-Huan; Eyler, Lisa; Fagiolini, Andrea; Gomes, Fabiano; Hajek, Tomas; Hatch, Jessica; McElroy, Susan L; McIntyre, Roger S; Prieto, Miguel; Sylvia, Louisa G; Tsai, Shang-Ying; Kcomt, Andrew; Fiedorowicz, Jess G | Abstract: ObjectivesThe association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular-bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment.MethodsAn international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps.ResultsThe association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular-bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets.ConclusionsFurther research focused on the vascular-bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

Objectives: Bipolar disorder (BD) is a debilitating psychiatric illness affecting 2%-5% of the population. Although mania is the cardinal feature of BD, inattention and related cognitive dysfunction are observed across all stages. Since cognitive dysfunction confers poor functional outcome in patients, understanding the relevant neural mechanisms remains key to developing novel-targeted therapeutics. Methods: The 5-choice continuous performance test (5C-CPT) is a mouse and fMRI-compatible human attentional task, requiring responding to target stimuli while inhibiting responding to nontarget stimuli, as in clinical CPTs. This task was used to delineate systems-level neural deficits in BD contributing to inattentive performance in human subjects with BD as well as mouse models with either parietal cortex (PC) lesions or reduced dopamine transporter (DAT) expression. Results: Mania BD participants exhibited severe 5C-CPT impairment. Euthymic BD patients exhibited modestly impaired 5C-CPT. High impulsivity BD subjects exhibited reduced PC activation during target and nontarget responding compared with healthy participants. In mice, bilateral PC lesions impaired both target and nontarget responding. In the DAT knockdown mouse model of BD mania, knockdown mice exhibited severely impaired 5C-CPT performance versus wildtype littermates. Conclusions: These data support the role of the PC in inattention in BD—specifically regarding identifying the appropriate response to target vs nontarget stimuli. Moreover, the findings indicate that severely reduced DAT function/hyperdopaminergia recreates the attentional deficits observed in BD mania patients. Determining the contribution of DAT in the PC to attention may provide a future target for treatment development.

Bipolar disorder (BD) is a serious mental illness affecting up to 1% of the elderly population. As the population ages and awareness surrounding BD increases, the prevalence of older-age bipolar disorder (OABD) is expected to rise. OABD is marked by high rates of functional impairment, physical comorbidity, cognitive deficits, and mortality, pointing to the need for an integrative biopsychosocial approach to care. Further research is needed to elucidate the etiology of early- versus late-onset BD to better understand the effects of psychotropic medications amongst people with OABD through clinical trials and to investigate brain aging and peripheral inflammation in this population through longitudinal studies. In addition, global consortia are needed to conduct prospective studies and trials with standardized measures relevant to OABD.

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between ‘social brain’ circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals., eLife digest Many parents of children with autism spectrum disorder (ASD) spot the first signs when their child is still a toddler, by noticing that their child is less interested than other toddlers in people and in social play. These early differences in behavior can have long-term implications for brain development. The brains of toddlers with little interest in social stimuli will receive less social input than those of other toddlers. This will make it even harder for the brain to develop the circuits required to support social skills. But even among children with ASD, there are large differences in children's interest in the social world. One way of measuring these differences is to track eye movements. Lombardo et al. presented toddlers with and without ASD with images of moving colorful geometric shapes next to videos of dancing children. The majority of toddlers, including most of those with ASD, spent more time looking at the children than the shapes. But about 20% of the toddlers with ASD spent most of their time looking at the shapes. These toddlers also had the most severe social symptoms. To find out why, Lombardo et al. measured the toddlers' brain activity while they slept. During sleep, or when at rest, the brain shows stereotyped patterns of activity. Groups of brain regions that work together – such as those involved in vision – fire in synchrony. Lombardo et al. found that toddlers who preferred looking at shapes over people showed different patterns of brain activity while asleep compared to other children. In the toddlers who preferred shapes, brain networks involved in social skills were less likely to coordinate their activity with networks that support vision and attention. These findings suggest there may be multiple subtypes of ASD, with different symptoms resulting from different patterns of brain activity. At present, all children who receive a diagnosis of ASD receive much the same behavioral therapy. But in the future, studies of brain networks could allow children to receive more specific diagnoses. This could in turn lead to more effective and personalized treatments.

Insomnia is prevalent in bipolar disorder (BD) even during periods of euthymic mood. We compared resting state brain activity and cognitive function between euthymic BD with and without insomnia, and secondarily to healthy individuals. BD patients with insomnia symptoms showed a significantly lower functional connectivity within the task-positive network, compared to those without insomnia. They also showed significantly slower cognitive processing speed. These two features of BD with insomnia appeared relatively independent of each other. Preliminary findings suggest that exploration of the mechanisms of sleep disturbance in BD could lead to improved understanding and treatment of inattention in BD.

Introduction The coronavirus pandemic and resulting restrictions of social activity have the potential to differentially affect older adults. People over 65 years old are at increased vulnerability to COVID-19 compared to younger adults, which may increase anxiety and efforts to socially isolate. In addition, older adults may be uniquely affected by smaller social networks or less access to technological substitutes for social interactions. While a recent study on mental well-being among older adults with pre-existing major depressive disorder found no changes in depression and anxiety associated with the early months of the coronavirus pandemic, it is unclear whether the same will be seen among community-dwelling older adults over an extended course of the pandemic. It is also important to understand whether and how some older adults are able to maintain wellness under social restrictions. We enrolled participants who took part in a pre-pandemic clinical trial (MEDEX) comparing the ability of Mindfulness-Based Stress Reduction (MBSR), aerobic exercise, the combination, or health education to reduce cognitive decline. Participants in MEDEX were assessed for levels of depression, anxiety, and compassion prior to the start of the pandemic. In a new study called StayWELL, we conducted follow-up assessments starting in June 2020, using online and mobile surveys, and examined the difference and relationship of pre- and during-pandemic measures of mental health symptoms and compassion. Methods Participant inclusion criteria: 1) older than 65 years, 2) participated in the MEDEX study, and 3) possess a mobile device with touch screen and internet access. Design: Fully virtual ecological momentary assessment (EMA) study: Using a web-based survey, we measured compassion with the Santa Clara Brief Compassion Scale and mental health symptoms using PROMIS depression and anxiety scores. StayWELL participants complete four two-week intensive sampling bursts throughout the pandemic. Data from the first burst – June 2020 – was analyzed in this study. General linear models are used to investigate the relationship of pre- and during-pandemic measures of depression, anxiety and compassion. Results Seventy-six participants are actively enrolled in our study (mean age=70 years, SD=4.3). Seventy-eight percent are women, and the mean (SD) education is 16.6 (2.0) years. The racial distribution is 84% White, 8% Black/African American, 4% Asian, and 3% More than One Race; five percent of participants identify as Hispanic. Preliminary analysis to examine change in mental health and compassion from pre-pandemic (MEDEX data) to during-pandemic (StayWELL baseline) indicate that depressive and anxiety symptoms were significantly higher three months into the pandemic compared to pre-pandemic measures, while compassion for others remained unchanged and high in this sample. Scores at the two timepoints were correlated, particularly for compassion (see Figure 1). Conclusions In this sample of older adults, anxiety and depressive symptom levels increased from before to during the pandemic. Our preliminary results support the role of compassion as a stable, individual trait marker. This ongoing longitudinal project will allow us to understand trajectories of change in mental health and well-being across the pandemic, how this relates to the degree of social isolation, and how positive psychological traits such as compassion may buffer changes in well-being brought on by the stress of living through a global health and economic crisis. Additional data is collected to further characterize mental health and wellbeing throughout the course of the pandemic using smart-phone based assessments of empathy, social isolation, loneliness, resilience, and mindfulness at similar timepoints with EMA and GPS location tracking and mobile keystroke activity (BiAffect app) on a daily basis. Funding Early Postdoc Mobility Fellowship of the Swiss National Science Foundation (SNSF) to FK.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case-control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A "vascular endothelial index" (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

Author(s): Nguyen, Tanya T; Eyler, Lisa T; Jeste, Dilip V | Abstract: BACKGROUND:Schizophrenia is associated with increased physical morbidity and early mortality, suggesting that the aging process may be accelerated in schizophrenia. However, the biological underpinnings of these alterations in aging in schizophrenia are unclear. METHOD:We conducted a detailed search of peer-reviewed empirical studies to evaluate evidence for accelerated biological aging in schizophrenia based on systemic, age-related biomarkers. We included studies that investigated differences between persons with schizophrenia and healthy comparison subjects in levels of biomarkers known to be associated with aging and examined the relationship of these biomarkers to age in the 2 groups. RESULTS:Forty-two articles that met our selection criteria were reviewed. Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia, including indices of inflammation, cytotoxicity, oxidative stress, metabolic health, gene expression, and receptor/synaptic function, with medium to large effect sizes reported in many studies. Twenty-nine percent of the studies observed differential age-related decline in schizophrenia. Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia. Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length. CONCLUSIONS:Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging. Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis.

Objectives Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. Design Cross-sectional study. Setting University of California San Diego and the Veterans Administration San Diego Healthcare System. Participants 33 euthymic BD and 38 HC participants. Measurements Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. Results BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. Conclusions Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

Objective Inflammation may play a role in the accelerated physical aging reported in schizophrenia, though biomarker findings and associations with demographic and clinical factors are inconsistent. Methods In a cross-sectional, case-control design, 95 outpatients with schizophrenia (mean age ± SD: 48.1 ± 10.2 years) and 95 demographically comparable healthy comparison subjects (HCs) (mean age ± SD: 48.1 ± 12.1 years) were studied. Sociodemographic and clinical data were collected, and plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed. The authors compared cytokine levels, examined demographic and clinical associations, and adjusted for relevant variables with linear models. Results Individuals with schizophrenia had higher levels of TNF-α and IL-6 but not IFN-γ than HCs. Age was not related to cytokine levels, and age relationships did not differ between diagnostic groups. Women had higher levels of IL-6. TNF-α and IL-6 levels were significantly correlated with depressive symptoms, and adjustment for depression reduced the group effect for both. Within the HCs, TNF-α levels were associated with physical comorbidity and body mass index. IL-6 levels were significantly correlated with body mass index and within schizophrenia patients, with worse mental and physical well-being. Accounting for physical morbidity and mental well-being reduced group differences in TNF-α and IL-6 levels, respectively. Worse positive symptoms were associated with higher IL-6 levels. Conclusion Higher TNF-α and IL-6 levels in schizophrenia patients were associated with depression, physical comorbidity, and mental well-being. Further longitudinal studies are warranted to assess inflammation as a potential treatment target for a subgroup of schizophrenia.

Background Persons with schizophrenia and schizoaffective disorder (PwS) have high rates of cardiometabolic pathology that contributes to premature mortality. Adiponectin is a metabolic hormone affecting insulin sensitivity and inflammation, and is active in the brain. High-molecular weight (HMW) adiponectin is considered a more sensitive marker of metabolic dysfunction than total adiponectin, but has been poorly studied in schizophrenia. Methods This was a cross-sectional study of 100 PwS, age range 26–68 years (46 women), and 93 age- and sex-comparable non-psychiatric comparison (NC) subjects. Assessments included measures of psychopathology, physical health, cognitive function, and circulating biomarkers of metabolic dysfunction (HMW adiponectin, lipids, insulin resistance) and inflammation (high-sensitivity C-reactive protein or hs-CRP, Tumor Necrosis Factor-α, Interleukin-6, and Interleukin-10). Results HMW adiponectin levels were lower in PwS compared to NCs. Lower HMW adiponectin levels were associated with higher body mass index (BMI), higher Framingham risk for coronary heart disease, higher number of metabolic syndrome criteria, greater insulin resistance, lower HDL cholesterol, and higher hs-CRP in both groups. Only in PwS, lower HMW adiponectin correlated with younger age. In the best-fit regression models of HMW adiponectin, lower levels were associated with lower HDL cholesterol and minority race/ethnicity in both groups; but with younger age, non-smoking, higher insulin resistance, and a diagnosis of schizoaffective disorder only among PwS, and with male sex, better cognitive functioning, and higher hs-CRP levels in NCs only. Discussion HMW adiponectin may be a promising biomarker of cardiometabolic health, especially among PwS. Adiponectin is a potential target for lifestyle and pharmacological interventions. Research on the possible role of HMW adiponectin in modifying cardiometabolic pathology in schizophrenia is needed.

Background Sleep disturbances are common in bipolar disorder (BD) and are often assessed by self-report at clinic visits over the course of BD treatment. Self-report may be subject to recall bias based upon current mood/affect states. This study sought to identify the degree of inaccuracy between subjective and objective measures of sleep duration in those with and without BD, and to assess the demographic and clinical correlates of this inaccuracy. Methods Thirty-one individuals with BD and 54 healthy control (HC) participants reported on the number of hours slept a night over the past month and subsequently completed up to 14 days/nights of wrist actigraphy which provided an objective measure of sleep duration. We compared the subjective rating to the average of all nights of objective sleep duration, and correlated the magnitude of inaccuracy with demographic and clinical characteristics in the BD and HC groups. Results On average, both BD and HC groups overestimated their sleep, and there were no differences in inaccuracy between groups. In the BD group, greater inaccuracy was associated with lower functioning, even after controlling individually for objective and subjective sleep measures. Limitations Cross-sectional study, only focus on sleep duration, and less severe bipolar symptoms of sample. Conclusions Inaccuracy in reports of sleep duration was associated with lower functioning among BD patients. Better identifying discrepancies in reports of sleep duration in clinical practice could help in more efficient monitoring and management of BD symptoms.

Objective Although 25% of people with bipolar disorder (BD) are over age 60, there is a dearth of research on older age bipolar disorder (OABD). This report describes an initial effort to create an integrated OABD database using the U.S. National Institute of Mental Health Data Archive (NDA). Goals were to: 1) combine data from three BD studies in the United States that included overlapping data elements; 2) investigate research questions related to aims of the original studies; and 3) take an important first step toward combining existing datasets relevant to aging and BD. Methods Data were prepared and uploaded to the NDA, with a focus on data elements common to all studies. As appropriate, data were harmonized to select or collapse categories suitable for cross-walk analysis. Associations between age, BD symptoms, functioning, medication load, medication adherence, and medical comorbidities were assessed. The total sample comprised 451 individuals, mean age 57.7 (standard deviation: 13.1) years. Results Medical comorbidity was not significantly associated with either age or functioning and there did not appear to be an association between medication load, comorbidity, age, and adherence. Men and African-Americans were significantly more likely to have poor adherence. Both BD mania and depression symptoms were associated with functioning, but this differed across studies. Conclusion Despite limitations including heterogeneity in study design and samples and cross-sectional methodology, integrated datasets represent an opportunity to better understand how aging may impact the presentation and evolution of chronic mental health disorders across the lifespan.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD);\ud however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical\ud heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with\ud BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered\ud individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean\ud fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and\ud meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD\ud compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and\ud cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to\ud higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities\ud in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD.\ud These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

Impulsivity is frequently linked with bipolar disorder and is associated with mania and negative outcomes. The temporal dynamics of subjective impulsivity are unclear, in particular whether impulsivity precedes or follows changes in positive or negative affect.A total of 41 outpatients with bipolar disorder (I or II) were provided with mobile devices for 11 weeks and completed twice-daily surveys about affective states and subjective impulsivity. We examined the association between aggregate subjective impulsivity with baseline global cognitive function, suicide risk ratings, and medication adherence, as well as concurrent and lagged associations with momentary positive and negative affect ratings.A total of 2902 ratings were available across study subjects. Higher aggregate mean ratings of impulsivity were associated with worse baseline global cognitive function, prior suicide attempts, and self-reported problems with medication adherence, as well as more severe manic (but not depressive) symptoms. Time-lagged models indicated that greater negative affect, but not positive affect, predicted subsequent increases in subjective impulsivity, which, in turn, predicted diminished positive affect.Other measures of impulsivity with which to validate subjective ratings were unavailable and the sample was restricted to generally clinically stable outpatients.Subjective impulsivity as measured by daily monitoring was associated with worse cognitive function and self-rated medication adherence, and higher suicide risk ratings. Impulsivity may be a maladaptive strategy to regulate negative affect in bipolar disorder.

Depression and cognitive impairment are pervasive and highly disabling aspects of bipolar disorder. Although cognitive impairment is partially independent from mood episodes, depressive symptoms may increase the risk of cognitive impairment in bipolar disorder through inflammatory processes as well as health risks such as obesity and sedentary behavior. Novel treatment avenues at the intersection of bipolar depression and cognitive impairment target inflammation directly or indirectly health behaviors such as diet, physical activity, and sleep hygiene.

Schizophrenia and bipolar disorder are among the leading causes of disability, morbidity, and mortality worldwide. In addition to being serious mental illnesses, these disorders are associated with considerable systemic physiological dysfunction, including chronic inflammation and elevated oxidative stress. The advent of sophisticated sequencing techniques has led to a growing interest in the potential role of gut microbiota in human health and disease. Advances in this area have transformed our understanding of a number of medical conditions and have generated a new perspective suggesting that gut microbiota might be involved in the development and maintenance of brain/mental health. Animal models have demonstrated strong though indirect evidence for a contributory role of intestinal microbiota in psychiatric symptomatology and have linked the microbiome with neuropsychiatric conditions. We present a systematic review of clinical studies of microbiome in schizophrenia and bipolar disorder. The published literature has a number of limitations; however, the investigations suggest that these disorders are associated with reduced microbial diversity and show global community differences compared to non-psychiatric comparison samples. In some reports, specific microbial taxa were associated with clinical disease characteristics, including physical health, depressive and psychotic symptoms, and sleep, but little information on the functional potential of those community changes. Studies also suggest increased intestinal inflammation and permeability, which may be among the principal mechanisms by which microbial dysbiosis impacts systemic physiological functioning. We highlight gaps in the current literature and implications for diagnosis and therapeutic interventions, and outline future directions for microbiome research in psychiatry.

ObjectivePositive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors with mental and physical health in schizophrenia.MethodOne hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26-65years, were evaluated with scales of resilience, optimism, happiness, and perceived stress. Measures of mental and physical health were also obtained. Regression analyses examined associations of a PPF composite with health variables.ResultsRelative to the HCs, the schizophrenia group had lower levels of PPFs. However, there was considerable heterogeneity, with over one-third of schizophrenia participants having values within the 'normative' range. The PPF composite was positively related to mental and physical health variables and with biomarkers of inflammation and insulin resistance. The relationship between PPFs and mental health was particularly strong for individuals with schizophrenia.ConclusionA sizable minority of adults with chronic schizophrenia have levels of resilience, optimism, happiness, and perceived stress similar to HCs. Psychosocial interventions to enhance PPFs should be tested in patients with serious mental illnesses, with the goal of improving their mental health (beyond controlling symptoms of psychosis) and their physical health.

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56–66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9–28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage., Highlights • In middle-aged men brain white matter metrics differed by amount of alcohol intake. • Fractional anisotropy (FA) was highest among moderate drinkers. • FA decreased with heavier drinking (>2 drinks/day, on average). • Never drinkers and heavy drinkers had highest white matter lesion burden. • Light to moderate drinking is associated with indices of better white matter health.

Introduction Mixed affective states in bipolar disorder have been associated with increased number of mood episodes, increased suicidality, higher rates of co-occurring conditions, and poorer response to treatments. In order to better understand mixed symptomatology in bipolar disorder, here we examine the prevalence and associations of subjectively reported states of simultaneously high sadness and high energy as well as objectively rated concurrently high depressive and manic symptoms. Methods We used baseline data from an ongoing longitudinal study of subjects with Bipolar Disorder (BDs) and Healthy Controls (HCs). Our mixed-age sample (mean age 48.5, SD 7.7) included 50 BDs and 91 HCs. Baseline evaluation consisted of a 2-week burst of data collection. All subjects underwent objective tests of cognitive performance, lab tests for inflammatory markers, and BDs were assessed for suicidal ideation (SI) and suicidal behavior (SB) using Columbia-Suicide Severity Rating Scale (C-SSRS) at baseline, middle and end of the 2-week period. The proportion of ratings in which SI or SB was reported (P-SI and P-SB respectively) was used as a measure of degree of SI and SB. Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Brief Psychiatric Rating Scale (BPRS), and 36-Item Short Form Health Survey (SF-36) were administered to BD subjects at baseline. Participants were given a mobile phone and affective ratings were gathered 3 times per day for 14 days at random intervals approximating morning, mid-day, and evening. Ratings were scored on a scale of 0-7 across domains such as sad/depressed, happy, energetic, etc. Short Lived Mixed Affective States (SLMAS) were defined as instances of affective ratings with simultaneously high sadness/depression (≥4) and high energy (≥4). The proportion of total reported ratings with SLMAS (P-SLMAS) were calculated for all subjects. A group with objective mixed states (group M, N=15 [30.6%]) was defined as BDs with concurrently high HAM-D and YMRS scores (HAM-D ≥ median score of 17, YMRS ≥ median score of 6). These were compared to BD patients with both HAM-D and YMRS scores lower than median (group L; N=13 [26.5%]), with high depression/low mania (group D; N=20 [20.4%]), and with high mania/low depression (group Y; N=11 [22.4%]). We examined the association of subjective mixed affect (P-SLMAS) and objective mood state group with age, suicidality, symptom severity, cognition and inflammation and to each other using correlations and ANOVAs. Results Groups were well-matched on age and sex. In terms of subjective affective ratings, while both groups had low P-SLMAS overall, BDs had significantly higher P-SLMAS compared to HCs: 9.7% (SD 13.1%) vs 3.5% (SD 7.3%), p In the BD group, P-SLMAS was significantly correlated with BPRS total score (r=0.373, p=0.012), BPRS item-3/depression score (r=0.41, p=0.004), HAM-D total score (r=0.413, r=0.004), and SF-36 mental component score (r=-0.430, p=0.011), while no significant correlation was found with YMRS total score (r=0.079, p=0.598). Significant correlations were also noted with Cognitive Failures Questionnaire-25 score (r=0.347, p=0.048) and Brief Symptom Inventory Anxiety Scale score (r=0.349, p=0.043). These significant correlations remained significant on linear regression even when proportion of ratings with high-sadness and high-energy as separate variables were taken into consideration, indicating that these significant associations with P-SLMAS were not being driven by high-sadness or high-energy individually. No correlation was found between P-SLMAS and P-SI (r=0.104, p=0.525) and P-SB (r=0.062, r=0.668). No correlation was found between age and P-SLMAS (r=0.055, p=0.520), nor were there associations of P-SLMAS with gender, race, marital status or living situation. Furthermore, no correlation was found between P-SLMAS and objective tests of cognitive performance or inflammatory markers. In terms of objectively rated mixed states, Group M had significantly higher P-SI compared to groups L, D and Y (50% vs 0%, 21% and 5% respectively, p=0.003). Group M also had higher P-SB (10% compared to 0% for all other groups), however, this did not reach statistical significance (p=0.098). No significant difference was found between groups L, D, Y and M with regards to age and other demographic variables. No differences were found with regards to CFQ-25 score, BSIAS score, objective tests of cognitive performance, or inflammatory markers. Subjectively rated mixed affect and objectively rated mixed states were not strongly associated. P-SLMAS were not significantly different across L, D, Y and M groups (p=0.103), with groups D and M showing similarly high P-SLMAS (13.4% and 14.6% respectively) and groups L and Y showing similarly low P-SLMAS (4.5% and 4.8% respectively). Conclusions SLMAS, subjectively reported short-lived states of high sadness and high energy, are reported with greater frequency in BDs compared to HCs. SLMAS appear to be a marker of depressive pathology (akin to ‘agitated depression’) and are associated with greater symptom severity. SLMAS do not show a relationship with manic symptom severity, and therefore do not show a relationship with objectively defined mixed states. While SLMAS are not associated with suicidality, objectively rated concurrently high depressive and manic symptoms are associated with greater frequency of suicidal ideation. Future work will examine relationship with psychiatric comorbidities and treatment response. This research was funded by This work was supported by NIMH grant R01 MH103318 and the Desert-Pacific Mental Illness Research, Education, and Clinical Center.