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Physical activity is beneficial for human physical health and well-being. Accordingly, the association between physical activity and mood in everyday life has been a subject of several Ambulatory Assessment studies. This mechanism has been studied in children, adults, and the elderly, but neglected in adolescents. It is critical to examine this mechanism in adolescents because adolescence plays a key role in human development and adolescents’ physical activity behavior translates into their behavior in adulthood. We investigated adolescents’ mood in relation to distinct physical activities: incidental activity such as climbing stairs; exercise activity, such as skating; and sports, such as playing soccer. We equipped 134 adolescents aged 12-17 years with accelerometers and GPS-triggered electronic diaries to use in their everyday life. Adolescents reported on mood repeatedly in real time across 7 days, and these data were analyzed using multilevel-modeling. After incidental activity, adolescents felt better and more energized. After exercise, adolescents felt better but less calm. After sports, adolescents felt less energized. Analyses of the time course of the effects confirmed our findings. Physical activity influences mood in adolescents’ everyday life, but has distinct effects depending on the kind of physical activity. Our results suggest incidental and exercise activities entail higher post-bout valence compared to sports in competitive settings. These findings may serve as an important empirical basis for the targeted application of distinct physical activities to foster well-being in adolescence.

Rapid worldwide urbanization benefits humans in many aspects, but the prevalence of common psychiatric disorders is increased in urban populations. While the impact of city living and urban upbringing on mental health is well established, it remains elusive which of the multiple factors of urban living convey risk and resilience for mental disorders. For example, air pollutants, traffic noises and fragmented social networks are some of the highly interdependent and complex influences of city living suggested to be detrimental for mental health. In contrast, urban green spaces, social contacts and physical activity have been associated with increased well-being. Knowledge on underlying mechanisms of these associations is crucial for both city planning and healthcare as it informs on how to build environments and to intervene in a way that fosters mental health yet reduces psychiatric disorders. Thus, real-life studies in urban contexts have been launched making use of recent methodological advancements: Mobile devices (e.g. smartphones) to gather intensive longitudinal mental health data, stationary sensor output providing specific context information (e.g. on weather conditions and air pollution), combinations with traditional and modern neuroimaging techniques (e.g. functional near-infrared spectroscopy and portable magnetic-encephalogram caps) and modern virtual reality setups allowing for increasingly realistic and ecological valid simulation of complex urban environments. Here we review selected methodological developments, state-of-the-art approaches as well as technological frontiers and provide examples for their application, highlighting promising potential of these novel methods for tackling the urgent urbanicity societal issue of the 21st century with a view to improve urban contexts conducive to mental health.

Background:Social integration is a major resilience factor for staying healthy. However, the COVID-19-pandemic led to unprecedented restrictions in social life. The consequences of these social lockdowns on momentary well-being are yet not fully understood.Method:We investigated the individual affective benefit from social interactions in a longitudinal birth cohort study. We used two real-time, real-life ecological momentary assessments once before and once during the initial lockdown of the pandemic (N~6800 total observations) to determine the protective role of social interactions on well-being. Moreover, we used a multimethod approach combining the ecological assessment data with individual risk and resilience factors to analyze the moderating mechanisms of personality, neurobiology and genes.Results:Social contacts were linked to higher positive affect both during normal times and during the COVID-19 pandemic, highlighting the beneficial role of social embedding. Moreover, this relationship was moderated by amygdala volume, neuroticism and polygenic risk for schizophrenia. In detail, participants with a larger left amygdala volume and higher trait neuroticism exhibited an affective benefit from more social interactions prior to the pandemic. This pattern changed during the pandemic with participants with smaller amygdala volumes and lower neurotic traits showing a social affective gain during the pandemic. Moreover, participants with low genetic risk for schizophrenia showed an affective benefit from social interactions irrespective of the time point.Conclusion:Our results highlight the protective role of social integration on momentary well-being. Thereby, we offer new insights into how this relationship is differently affected by a person’s, neurobiology, personality, and genes under adverse circumstances.

Die atemberaubende technologische Entwicklung im Bereich des mobilen Computings, der Smartphones und Wearables eroffnet fur die psychiatrische Forschung und Therapie neue Moglichkeiten. Wearables erlauben nicht nur, objektive Auspragungen psychischer Symptomatik im Alltag und in Echtzeit zu erfassen, sondern sie konnen uber kontinuierliches Monitoring und die Analyse relevanter Parameter bedeutsame Situationen/Kontexte und Zeitpunkte definieren, bei denen dann erweiterte Assessments oder Interventionen implementiert werden konnen. Am Beispiel der grunflacheninduzierten Stimmungsverbesserung, dem motivationsfordernden Verhaltensfeedback und dem Geofencing zur Detektion beginnender Trinkepisoden zeigen wir auf, wie Echtzeitanalysen und -feedback von Wearables in der psychiatrischen Forschung und Versorgung genutzt werden konnen.

The relationship between transdiagnostic, dimensional, and categorical approaches to psychiatric nosology is under intense debate. To inform this discussion, we studied neural systems linked to reward anticipation across a range of disorders and behavioral dimensions. We assessed brain responses to reward expectancy in a large sample of 221 participants, including patients with schizophrenia (SZ; n = 27), bipolar disorder (BP; n = 28), major depressive disorder (MD; n = 31), autism spectrum disorder (ASD; n = 25), and healthy controls (n = 110). We also characterized all subjects with an extensive test battery from which a cognitive, affective, and social functioning factor was constructed. These factors were subsequently related to functional responses in the ventral striatum (vST) and neural networks linked to it. We found that blunted vST responses were present in SZ, BP, and ASD but not in MD. Activation within the vST predicted individual differences in affective, cognitive, and social functioning across diagnostic boundaries. Network alterations extended beyond the reward network to include regions implicated in executive control. We further confirmed the robustness of our results in various control analyses. Our findings suggest that altered brain responses during reward anticipation show transdiagnostic alterations that can be mapped onto dimensional measures of functioning. They also highlight the role of executive control of reward and salience signaling in the disorders we study and show the power of systems-level neuroscience to account for clinically relevant behaviors., Schizophrenia Bulletin, 46 (3), ISSN:0586-7614, ISSN:1745-1701

Social interactions are essential to our daily life. We tested the hypothesis that social interactions during joint attention (JA) require bidirectional communication, each with a different mechanism. We used a novel multivariate functional connectivity analysis, which enables obtaining directed pathways between four regions at each time-frequency point, with hyper-scanning MRI data of real-time JA interaction. Constructing multiple “4-regional directed pathways” and counting the number of times, regions engaged in feedforward or feedback processes in the ‘sender’ or the ‘receiver brains, we obtained the following. (1) There were more regions in feedforward than in feedback processes (125 versus 99). (2) The right hemisphere was more involved in feedforward (74 versus 33), while the left hemisphere in feedback (66 versus 51). (3) The dmPFC was more engaged in feedforward (73 versus 44) while the TPJ in both (49 versus 45). (4) The dmPFC was more involved in the sending processes (i.e. initiation of feedforward and feedback) while the TPJ in the receiving processes. (5) JA interaction was involved with high MRI frequencies (0.04–0.1 Hz), while continues interactions by low MRI frequencies (0.01–0.04 Hz). (6) Initiation and responding to JA (i.e. IJA and RJA) evolved with composite neural systems: similar systems for pathways that included the dmPFC, vmPFC and the STS, and different systems for pathways that included the TPJ, vmPFC, PCC and the STS. These findings have important consequences in the basic understanding of social interaction and could help in diagnose and follow-up of social impairments.

Psychiatric morbidity is high in cities, so identifying potential modifiable urban protective factors is important. We show that exposure to urban green space improves well-being in naturally behaving male and female city dwellers, particularly in districts with higher psychiatric incidence and fewer green resources. Higher green-related affective benefit was related to lower prefrontal activity during negative-emotion processing, which suggests that urban green space exposure may compensate for reduced neural regulatory capacity. Tost et al. show that urban green space exposure improves well-being, particularly in people dwelling in relatively deprived areas and showing less prefrontal activity during emotion processing, a neural signature that is linked to mental health risk.

This cohort study examines the association of daily-life social affective benefit with brain structure and psychiatric risk and resilience measures in 2 independent community-based samples.

BackgroundAberrant brain connectivity during emotional processing, especially within the fronto-limbic pathway, is one of the hallmarks of major depressive disorder (MDD). However, a lack of systematic approaches in previous studies made it difficult to determine whether a specific alteration in brain connectivity reflects a cause, correlate, or effect of the disorder. The current study aimed to investigate neural mechanisms that correspond to disease, risk and resilience in major depression during implicit processing of emotion cues.MethodsForty-eight patients with MDD, 49 first-degree relatives of patients with MDD and 103 healthy controls performed a face-matching task during functional magnetic resonance imaging. We used dynamic causal modelling to estimate task-dependent effective connectivity at the subject level. Parametric empirical Bayes was then performed to quantify group differences in effective connectivity.ResultsDepressive pathology was associated with decreased effective connectivity from the left amygdala and left dorsolateral prefrontal cortex to the right fusiform gyrus, whereas familial risk for depression corresponded to decreased connectivity from the right orbitofrontal cortex to the left insula and from the left orbitofrontal cortex to the right fusiform gyrus. Resilience for depression was related to increased connectivity from the anterior cingulate cortex to the left dorsolateral prefrontal cortex.ConclusionsOur results suggest that the depressive state alters top-down control of higher visual regions during the processing of emotional faces, whereas increased connectivity within the cognitive control network promotes resilience to depression.

Among research disciplines, neuroscience has introduced the most fundamental changes in the way in which mental disease states are conceptualized and pursued. Nowhere is this more obvious than in translational medicine. The slow, arduous empirical process of finding new treatments must be properly incentivized for this work to be done by the current and next generation of psychiatric neuroscientists. Here, the toolboxes such as evolving biomarkers (e.g., imaging, transomic and functional biomarkers) genetics are discussed in relation to translational issues in mental diseases.

Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory performance entails brain-wide switching between activity states using a combination of functional magnetic resonance imaging in healthy controls and individuals with schizophrenia, pharmacological fMRI, genetic analyses and network control theory. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Individuals with schizophrenia show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations. Our results demonstrate the relevance of dopamine signaling for the steering of whole-brain network dynamics during working memory and link these processes to schizophrenia pathophysiology., Working memory requires the brain to switch between cognitive states and activity patterns. Here, the authors show that the steering of these neural network dynamics is influenced by dopamine D1- and D2-receptor function and altered in schizophrenia.

Purpose Perigenual anterior cingulate cortex (pACC) is a neural convergence site for social stress-related risk factors for mental health, including ethnic minority status. Current social status, a strong predictor of mental and somatic health, has been related to gray matter volume in this region, but the effects of social mobility over the lifespan are unknown and may differ in minorities. Recent studies suggest a diminished health return of upward social mobility for ethnic minority individuals, potentially due to sustained stress-associated experiences and subsequent activation of the neural stress response system. Methods To address this issue, we studied an ethnic minority sample with strong upward social mobility. In a cross-sectional design, we examined 64 young adult native German and 76 ethnic minority individuals with comparable sociodemographic attributes using whole-brain structural magnetic resonance imaging. Results Results showed a significant group-dependent interaction between perceived upward social mobility and pACC gray matter volume, with a significant negative association in the ethnic minority individuals. Post-hoc analysis showed a significant mediation of the relationship between perceived upward social mobility and pACC volume by perceived chronic stress, a variable that was significantly correlated with perceived discrimination in our ethnic minority group. Conclusion Our findings extend prior work by pointing to a biological signature of the “allostatic costs” of socioeconomic attainment in socially disadvantaged upwardly mobile individuals in a key neural node implicated in the regulation of stress and negative affect.

BackgroundReward processing has been proposed to underpin atypical social behavior, a core feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social rewards in ASD. Utilizing a large sample, we aimed to assess altered reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.MethodsFunctional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.5 years) and 181 typically developing (TD) participants (7.6-30.8 years).ResultsAcross social and monetary reward anticipation, whole-brain analyses (pConclusionsOur results do not support current theories linking atypical social interaction in ASD to specific alterations in processing of social rewards. Instead, they point towards a generalized hypoactivity of VS in ASD during anticipation of both social and monetary rewards. We suggest that this indicates attenuated subjective reward value in ASD independent of social content and ADHD symptoms.

Background Autism spectrum disorder (“autism”) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, but its potential as a neural stratification marker has not been widely examined. Methods In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS (European Autism Interventions—A Multicentre Study for Developing New Medications) Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical control subjects as well as a replication dataset from ABIDE (Autism Brain Imaging Data Exchange) (513 individuals with autism, 691 neurotypical subjects) using a promising approach that moves beyond mean group comparisons. We derived gray matter voxelwise laterality values for each subject and modeled individual deviations from the normative pattern of brain laterality across age using normative modeling. Results Individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language, motor, and visuospatial regions, associated with symptom severity. Language delay explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged, with individuals with autism with language delay showing more pronounced rightward deviations than individuals with autism without language delay. Conclusions Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism and indicate that atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.

One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12-year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism-based interventions. These goals will be achieved by: (i) using mobile health (m-health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real-life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal-directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.

Background Sociocommunicative difficulties, including abnormalities in eye contact, are core diagnostic features of autism spectrum disorder (ASD). Many studies have used eye tracking to measure reduced attention to faces in autistic people; however, most of this work has not taken advantage of eye-tracking temporal resolution to examine temporal profiles of attention. Methods We used growth curve analysis to model attention to static social scenes as a function of time in a large (N = 650) sample of autistic participants and neurotypical participants across a wide age range (6–30 years). Results The model yielded distinct temporal profiles of attention to faces in the groups. Initially, both groups showed a relatively high probability of attending to faces, followed by decline after several seconds. The neurotypical participants, however, were significantly more likely to return their attention to faces in the latter part of each 20-second trial, with increasing probability with age. In contrast, the probability of returning to the face in the autistic participants remained low across development. In participants with ASD, more atypical profiles of attention were associated with lower Vineland Adaptive Behavior Scales communication scores and a higher curvature in one data-driven cluster correlated with symptom severity. Conclusions These findings show that social attention not only is reduced in ASD, but also differs in its temporal dynamics. The neurotypical participants became more sophisticated in how they deployed their social attention across age, a pattern that was significantly reduced in the participants with ASD, possibly reflecting delayed acquisition of social expertise.

Graph theoretical functional magnetic resonance imaging (fMRI) studies have demonstrated that brain networks reorganize significantly during motor skill acquisition, yet the associations between motor learning ability, brain network features, and the underlying biological mechanisms remain unclear. In the current study, we applied a visually guided sequential pinch force learning task and graph theoretical analyses to investigate the associations between short-term motor learning ability and resting-state brain network metrics in 60 healthy subjects. We further probed the test-retest reliability (n = 26) and potential effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine (n = 19) in independent healthy volunteers. Our results show that the improvement of motor performance after short-term training was positively correlated with small-worldness (p = 0.032) and global efficiency (p = 0.025), whereas negatively correlated with characteristic path length (p = 0.014) and transitivity (p = 0.025). In addition, using network-based statistics (NBS), we identified a learning ability–associated (p = 0.037) and ketamine-susceptible (p = 0.027) cerebellar-cortical network with fair to good reliability (intraclass correlation coefficient [ICC] > 0.7) and higher functional connectivity in better learners. Our results provide new evidence for the association of intrinsic brain network features with motor learning and suggest a role of NMDA-related glutamatergic processes in learning-associated subnetworks. Learning a new motor skill prompts immediate reconfigurations of distributed brain networks followed by adaptive changes in intrinsic brain circuits related to synaptic plasticity. Here, we identify global brain network properties and a cerebellar-cortical functional subnetwork that are both significantly associated with motor learning ability in a previously trained visuomotor task in humans. We further show that the associated functional subnetwork connectivity but not the global brain network properties are susceptible to ketamine. Our findings suggest a distinct functional role for learning-related global versus local network metrics and support the idea of a preferential susceptibility of learning-associated subnetworks to N-methyl-d-aspartate antagonist and plasticity-related consolidation effects.

Precision psychiatry stands to benefit from the latest digital technologies for assessment and analyses to tailor treatment towards individuals. Insights into dynamic psychological processes as they unfold in humans' everyday life can critically add value in understanding symptomatology and environmental stressors to provide individualized treatment where and when needed. Towards this goal, ambulatory assessment encompasses methodological approaches to investigate behavioral, physiological, and biological processes in humans' everyday life. It combines repeated assessments of symptomatology over time, e.g., via Ecological Momentary Assessment (e.g., smartphone-diaries), with monitoring of physical behavior, environmental characteristics (such as geolocations, social interactions) and physiological function via sensors, e.g., mobile accelerometers, global-positioning-systems, and electrocardiography. In this review, we expand on promises of ambulatory assessment in the investigation of mental states (e.g., real-life, dynamical and contextual perspective), on chances for precision psychiatry such as the prediction of courses of psychiatric disorders, detection of tipping points and critical windows of relapse, and treatment effects as exemplified by ongoing projects, and on future avenues of how ambulatory interventions can benefit personalized care for psychiatric patients (e.g., through real-time feedback in everyday life). Ambulatory assessment is a key contributor to precision psychiatry, opening up promising avenues in research, diagnoses, prevention and treatment.

The serotonin transporter-linked polymorphic region 5-HTTLPR is a key genetic regulator of 5-HTT expression in the human brain where the short allele S has been implicated in emotion dysregulation. However, the neural mechanism underlying the association between this variant and emotion processing is still unclear. Earlier studies suggested an effect of 5-HTTLPR on amygdala activation during emotional face processing. However, this association has been questioned in recent studies employing larger sample sizes and meta-analyses. Here, we examined a sample of 223 healthy subjects with a well-established fMRI emotional face processing task to (1) re-evaluate the association between 5-HTTLPR and amygdala activation, (2) explore potential network-based functional connectivity phenotypes for associations with 5-HTTLPR, and (3) probe the reliability, behavioral significance and potential structural confounds of the identified network phenotype. Our results revealed no significant effect of 5-HTTLPR on amygdala activation (P40.79). However, the number of S alleles was significantly correlated with functional connectivity of a visual-limbic subnetwork (PFWE= 0.03). The subnetwork cluster included brain regions that are pivotal to emotion regulation such as the hippocampus, orbitofrontal cortex, anterior cingulate gyrus, fusiform gyrus, and subcortex. Notably, individuals with lower subnetwork connectivity had significantly higher emotion suppression scores (P= 0.01). Further, the connectivity metrics were test-retest reliable and independent from subnetwork gray matter volume and white matter anisotropy. Our data provide evidence for a functional network-based phenotype linking genetic variation in 5-HTTLPR to emotion regulation, and suggest that further critical evaluations of the association between 5-HTTLPR and amygdala activation are warranted.

Previous research suggests a role of the dorsomedial prefrontal cortex (dmPFC) in metacognitive representation of social information, while the right posterior superior temporal sulcus (pSTS) has been linked to social perception. This study targeted these functional roles in the context of spontaneous mentalizing. An animated shapes task was presented to 46 subjects during functional magnetic resonance imaging. Stimuli consisted of video clips depicting animated shapes whose movement patterns prompt spontaneous mentalizing or simple intention attribution. Based on their differential response during spontaneous mentalizing, both regions were characterized with respect to their task-dependent connectivity profiles and their associations with autistic traits. Functional network analyses revealed highly localized coupling of the right pSTS with visual areas in the lateral occipital cortex, while the dmPFC showed extensive coupling with instances of large-scale control networks and temporal areas including the right pSTS. Autistic traits were related to mentalizing-specific activation of the dmPFC and to the strength of connectivity between the dmPFC and posterior temporal regions. These results are in good agreement with the hypothesized roles of the dmPFC and right pSTS for metacognitive representation and perception-based processing of social information, respectively, and further inform their implication in social behavior linked to autism. Hum Brain Mapp 38:3791-3803, 2017. © 2017 Wiley Periodicals, Inc.

The association between physical activity and mood is of major importance to increase physical activity as a prevention strategy for noncommunicable diseases and to improve mental health. Unfortunately, existing studies examining how physical activity and mood wax and wane within persons over time in everyday life do show ambiguous findings. Taking a closer look at these studies reveals that the aggregation levels differ tremendously. Whereas mood is conceptualized as a three-dimensional construct, physical activity is treated as a global construct not taking into account its distinct components like exercise (such as jogging) and nonexercise activity (NEA; such as climbing stairs).To overcome these limitations, we conducted an ambulatory assessment study on the everyday life of 106 adults over 7 d continuously measuring NEA via accelerometers and repeatedly querying for mood in real time via GPS-triggered e-diaries. We used multilevel modeling to derive differential within-subject effects of exercise versus NEA on mood and to conduct analyses on the temporal course of effects.Analyses revealed that exercise increased valence (beta = 0.023; P0.05) and calmness (beta = 0.022; P0.05). A tendency of decreasing energetic arousal (beta = -0.029) lacked significance. NEA, parameterized as 15-min episodes of physical activity intensity in everyday life, increased energetic arousal (beta = 0.135; P0.001) and decreased calmness (stand. beta = -0.080; P0.001). A tendency of increasing valence (beta = 0.014) lacked significance. Using longer time intervals for NEA revealed similar findings, thus confirming our findings.Exercise and NEA differed regarding their within-subject effects on mood, whereas exercise increased valence and calmness, NEA increased energetic arousal and decreased calmness. Therefore, it appears necessary to clearly differentiate between exercise and NEA regarding their within-subject effects on mood dimensions in both research and treatment.

Threshold-free cluster enhancement (TFCE) is a sensitive means to incorporate spatial neighborhood information in neuroimaging studies without using arbitrary thresholds. The majority of methods have applied TFCE to voxelwise data. The need to understand the relationship among multiple variables and imaging modalities has become critical. We propose a new method of applying TFCE to vertexwise statistical images as well as cortexwise (either voxel- or vertexwise) mediation analysis. Here we present TFCE_mediation, a toolbox that can be used for cortexwise multiple regression analysis with TFCE, and additionally cortexwise mediation using TFCE. The toolbox is open source and publicly available (https://github.com/trislett/TFCE_mediation). We validated TFCE_mediation in healthy controls from two independent multimodal neuroimaging samples (N = 199 and N = 183). We found a consistent structure-function relationship between surface area and the first independent component (IC1) of the N-back task, that white matter fractional anisotropy is strongly associated with IC1 N-back, and that our voxel-based results are essentially identical to FSL randomise using TFCE (all PFWE

Given the high prevalence and burden of mental disorders, fostering the understanding of protective factors is an urgent issue for translational medicine in psychiatry. The concept of resilience describes individual and environmental protective factors against the backdrop of established adversities linked to mental illness. There is convergent evidence for a crucial role of direct as well as indirect adversity impacting the developing brain, with persisting effects until adulthood. Direct adversity may include childhood maltreatment and family adversity, while indirect social adversity can include factors such as urban living or ethnic minority status. Recently, research has begun to examine protective factors which may be able to buffer against or even reverse these influences. First evidence indicates that supportive social environments as well as trait-like individual protective characteristics might impact on similar neural substrates, thus strengthening the capacity to actively cope with stress exposure in order to counteract the detrimental effects evoked by social adversity. Here, we provide an overview of the current literature investigating the neural mechanisms of resilience with a putative social background, including studies on individual traits and genetic variation linked to resilience. We argue that the regulatory perigenual anterior cingulate cortex and limbic regions, including the amygdala and the ventral striatum, play a key role as crucial convergence sites of protective factors. Further, we discuss possible prevention and early intervention approaches targeting both the individual and the social environment to reduce the risk of psychiatric disorders and foster resilience.

BackgroundResting-state functional magnetic resonance imaging–based studies on functional connectivity in autism spectrum disorder (ASD) have generated inconsistent results. Interpretation of findings is further hampered by small samples and a focus on a limited number of networks, with networks underlying sensory processing being largely underexamined. We aimed to comprehensively characterize ASD-related alterations within and between 20 well-characterized resting-state networks using baseline data from the EU-AIMS (European Autism Interventions—A Multicentre Study for Developing New Medications) Longitudinal European Autism Project.MethodsResting-state functional magnetic resonance imaging data was available for 265 individuals with ASD (7.5–30.3 years; 73.2% male) and 218 typically developing individuals (6.9–29.8 years; 64.2% male), all with IQ > 70. We compared functional connectivity within 20 networks—obtained using independent component analysis—between the ASD and typically developing groups, and related functional connectivity within these networks to continuous (overall) autism trait severity scores derived from the Social Responsiveness Scale Second Edition across all participants. Furthermore, we investigated case-control differences and autism trait–related alterations in between-network connectivity.ResultsHigher autism traits were associated with increased connectivity within salience, medial motor, and orbitofrontal networks. However, we did not replicate previously reported case-control differences within these networks. The between-network analysis did reveal case-control differences showing on average 1) decreased connectivity of the visual association network with somatosensory, medial, and lateral motor networks, and 2) increased connectivity of the cerebellum with these sensory and motor networks in ASD compared with typically developing subjects.ConclusionsWe demonstrate ASD-related alterations in within- and between-network connectivity. The between-network alterations broadly affect connectivity between cerebellum, visual, and sensory-motor networks, potentially underlying impairments in multisensory and visual-motor integration frequently observed in ASD.

Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.

Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12-15 Hz) and slow (9-12 Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.

Genetic risk for schizophrenia is associated with impairments in the initiation and performance of executive control of cognition and action. The nature of these impairments and of the neural dysfunction that underlies them has been extensively investigated using experimental psychology and neuroimaging methods. In this article, we review schizophrenia-associated functional connectivity and activation abnormalities found in subjects performing experimental tasks that engage different aspects of executive function, such as working memory, cognitive control, and response inhibition. We focus on heritable traits associated with schizophrenia risk (intermediate phenotypes or endophenotypes) that have been revealed using imaging genetics approaches. These data suggest that genetic risk for schizophrenia is associated with dysfunction in systems supporting the initiation and application of executive control in neural circuits involving the anterior cingulate and dorsolateral prefrontal cortex. This article discusses current findings and limitations and their potential relevance to symptoms and disease pathogenesis.

Summary Background: Psychiatric research is increasingly interested in the influence of social and environmental contexts on human health. According to recent findings, specific impacts of urban upbringing relate to the heightened prevalence of mental disorders. Although this is a major societal problem, it remains unknown which environmental components (e.g., psychosocial stressors, rare nature exposure) are responsible. Method: We introduce Ambulatory Assessment (AA) as a methodological approach to investigate contextual influences. GPS-triggered electronic diaries are suitable to capture data in everyday life, gathering information on both context and mental states to assess dynamic processes in real-life and real-time. Result: A longitudinal study at the Central Institute for Mental Health in Mannheim combines AA, fMRI and epigenetic approaches to investigate environmental factors influencing mental health. The findings might be incorporated in urban planning to reduce mental disorders.

The search for quantifiable biological mediators of genetic risk or 'intermediate phenotypes' is an essential strategy in psychiatric neuroscience and a useful tool for exploring the complex relationships between genes, neural circuits and behaviors. In recent years, the examination of connectivity-based intermediate phenotypes has gained increasing popularity in the study of schizophrenia, a brain disorder that manifests in early adulthood and disturbs a wide range of neural network functions. To date, several potential connectivity phenotypes have been identified that link neuroimaging measures of neural circuit interaction to genetic susceptibility for schizophrenia. This paper briefly reviews recent advances, current limitations and future directions in the search for functional connectivity intermediate phenotypes for schizophrenia across different cognitive domains.

Physical activity is known to preserve both physical and mental health. However, the physical activity levels of a large proportion of adolescents are insufficient. This is critical, since physical activity levels in youth have been shown to translate into adulthood. Whereas in adult populations, mood has been supposed to be one important psychological factor that drives physical activity in everyday life, this issue has been poorly studied in adolescent populations. Ambulatory Assessment is the state-of-the-art approach to investigate how mood and non-exercise activity fluctuate within persons in everyday life. Through assessments in real time and real life, this method provides ecological validity, bypassing several limitations of traditional assessment methods (e.g., recall biases). To investigate whether mood is associated with non-exercise activity in adolescents, we equipped a community-based sample comprising 113 participants, aged 12–17 years, with GPS-triggered e-diaries querying for valence, energetic arousal, and calmness, and with accelerometers continuously measuring physical activity in their everyday lives for 1 week. We excluded all acceleration data due to participants' exercise activities and thereafter we parameterized non-exercise activity as the mean value across 10-min intervals of movement acceleration intensity following each e-diary prompt. We used multilevel analyses to compute the effects of the mood dimensions on non-exercise activity within 10-min intervals directly following each e-diary prompt. Additionally, we conducted explorative analyses of the time course of the effects, i.e., on different timeframes of non-exercise activity up to 300 min following the mood assessment. The results showed that valence (p < 0.001) and energetic arousal (p < 0.001) were positively associated with non-exercise activity within the 10 min interval, whereas calmness (p < 0.001) was negatively associated with non-exercise activity. Specifically, adolescents who felt more content, full of energy, or less calm were more physically active in subsequent timeframes. Overall, our results demonstrate significant associations of mood with non-exercise activity in younger ages and converge with the previously observed association between mood and physical activity in adults. This knowledge on distinct associations of mood-dimensions with non-exercise activity may help to foster physical activity levels in adolescents.

The developing human brain is shaped by environmental exposures--for better or worse. Many exposures relevant to mental health are genuinely social in nature or believed to have social subcomponents, even those related to more complex societal or area-level influences. The nature of how these social experiences are embedded into the environment may be crucial. Here we review select neuroscience evidence on the neural correlates of adverse and protective social exposures in their environmental context, focusing on human neuroimaging data and supporting cellular and molecular studies in laboratory animals. We also propose the inclusion of innovative methods in social neuroscience research that may provide new and ecologically more valid insight into the social-environmental risk architecture of the human brain.

As evidenced by a multitude of studies, abnormalities in Theory of Mind (ToM) and its neural processing might constitute an intermediate phenotype of schizophrenia. If so, neural alterations during ToM should be observable in unaffected relatives of patients as well, since they share a considerable amount of genetic risk. While behaviorally, impaired ToM function is confirmed meta-analytically in relatives, evidence on aberrant function of the neural ToM network is sparse and inconclusive. The present study therefore aimed to further explore the neural correlates of ToM in relatives of schizophrenia. About 297 controls and 63 unaffected first-degree relatives of patients with schizophrenia performed a ToM task during functional magnetic resonance imaging. Consistent with the literature relatives exhibited decreased activity of the medial prefrontal cortex. Additionally, increased recruitment of the right middle temporal gyrus and posterior cingulate cortex was found, which was related to subclinical paranoid symptoms in relatives. These results further support decreased medial prefrontal activation during ToM as an intermediate phenotype of genetic risk for schizophrenia. Enhanced recruitment of posterior ToM areas in relatives might indicate inefficiency mechanisms in the presence of genetic risk.

The brain is an inherently dynamic system, and executive cognition requires dynamically reconfiguring, highly evolving networks of brain regions that interact in complex and transient communication patterns. However, a precise characterization of these reconfiguration processes during cognitive function in humans remains elusive. Here, we use a series of techniques developed in the field of "dynamic network neuroscience" to investigate the dynamics of functional brain networks in 344 healthy subjects during a working-memory challenge (the "n-back" task). In contrast to a control condition, in which dynamic changes in cortical networks were spread evenly across systems, the effortful working-memory condition was characterized by a reconfiguration of frontoparietal and frontotemporal networks. This reconfiguration, which characterizes "network flexibility," employs transient and heterogeneous connectivity between frontal systems, which we refer to as "integration." Frontal integration predicted neuropsychological measures requiring working memory and executive cognition, suggesting that dynamic network reconfiguration between frontal systems supports those functions. Our results characterize dynamic reconfiguration of large-scale distributed neural circuits during executive cognition in humans and have implications for understanding impaired cognitive function in disorders affecting connectivity, such as schizophrenia or dementia.

Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-d-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders. We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe. Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity. In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia. This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.

The application of global signal regression (GSR) to resting-state functional magnetic resonance imaging data and its usefulness is a widely discussed topic. In this article, we report an observation of segregated distribution of amygdala resting-state functional connectivity (rs-FC) within the fusiform gyrus (FFG) as an effect of GSR in a multi-center-sample of 276 healthy subjects. Specifically, we observed that amygdala rs-FC was distributed within the FFG as distinct anterior versus posterior clusters delineated by positive versus negative rs-FC polarity when GSR was performed. To characterize this effect in more detail, post hoc analyses revealed the following: first, direct overlays of task-functional magnetic resonance imaging derived face sensitive areas and clusters of positive versus negative amygdala rs-FC showed that the positive amygdala rs-FC cluster corresponded best with the fusiform face area, whereas the occipital face area corresponded to the negative amygdala rs-FC cluster. Second, as expected from a hierarchical face perception model, these amygdala rs-FC defined clusters showed differential rs-FC with other regions of the visual stream. Third, dynamic connectivity analyses revealed that these amygdala rs-FC defined clusters also differed in their rs-FC variance across time to the amygdala. Furthermore, subsample analyses of three independent research sites confirmed reliability of the effect of GSR, as revealed by similar patterns of distinct amygdala rs-FC polarity within the FFG. In this article, we discuss the potential of GSR to segregate face sensitive areas within the FFG and furthermore discuss how our results may relate to the functional organization of the face-perception circuit.

The cortisol rise after awakening (cortisol awakening response, CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation related to psychosocial stress and stress-related psychiatric disorders. However, the neural regulation of the CAR has not been examined in humans. Here, we studied neural regulation related to the CAR in a sample of 25 healthy human participants using an established psychosocial stress paradigm together with multimodal functional and structural (voxel-based morphometry) magnetic resonance imaging. Across subjects, a smaller CAR was associated with reduced grey matter volume and increased stress-related brain activity in the perigenual ACC, a region which inhibits HPA axis activity during stress that is implicated in risk mechanisms and pathophysiology of stress-related mental diseases. Moreover, functional connectivity between the perigenual ACC and the hypothalamus, the primary controller of HPA axis activity, was associated with the CAR. Our findings provide support for a role of the perigenual ACC in regulating the CAR in humans and may aid future research on the pathophysiology of stress-related illnesses, such as depression, and environmental risk for illnesses such as schizophrenia.

Hippocampal-prefrontal cortex (HC-PFC) interactions are implicated in working memory (WM) and altered in psychiatric conditions with cognitive impairment such as schizophrenia. While coupling between both structures is crucial for WM performance in rodents, evidence from human studies is conflicting and translation of findings is complicated by the use of differing paradigms across species. We therefore used functional magnetic resonance imaging together with a spatial WM paradigm adapted from rodent research to examine HC-PFC coupling in humans. A PFC-parietal network was functionally connected to hippocampus (HC) during task stages requiring high levels of executive control but not during a matched control condition. The magnitude of coupling in a network comprising HC, bilateral dorsolateral PFC (DLPFC), and right supramarginal gyrus explained one-fourth of the variability in an independent spatial WM task but was unrelated to visual WM performance. HC-DLPFC coupling may thus represent a systems-level mechanism specific to spatial WM that is conserved across species, suggesting its utility for modeling cognitive dysfunction in translational neuroscience.

Migration status is one of the best-established risk factors for schizophrenia. An increase in risk is observed in both first- and second-generation immigrants, with a varying magnitude depending on the ethnic background of the individuals. The underlying mechanisms for the increased risk are only recently coming into focus. A causal role for social stress has been widely proposed, and recent work indicated altered neural stress processing in the perigenual anterior cingulate cortex (pACC) in migrants. Since previous work shows that social stress may lead to enduring changes in the gray matter volume of vulnerable brain regions, we investigated the impact of migration background on brain structure. We studied healthy young adults (N = 124), native Germans and second-generation migrants, using whole-brain structural magnetic resonance imaging. Groups were matched for a broad range of sociodemographic characteristics including age, gender, urban exposure, and education. We found a significant group by sex interaction effect in pACC gray matter volume, which was reduced in males with migration background only. This mirrors previous findings in urban upbringing, another risk factor for schizophrenia. Our results provide convergent evidence for an impact of environmental risk factors linked to schizophrenia on gray matter volume and extend prior data by highlighting the possibility that the pACC structure may be particularly sensitive to the convergent risk factors linked to schizophrenia.

The functional role of the basal ganglia (BG) in the gating of suitable motor responses to the cortex is well established. Growing evidence supports an analogous role of the BG during working memory encoding, a task phase in which the “input-gating” of relevant materials (or filtering of irrelevant information) is an important mechanism supporting cognitive capacity and the updating of working memory buffers. One important aspect of stimulus relevance is the novelty of working memory items, a quality that is understudied with respect to its effects on corticostriatal function and connectivity. To this end, we used functional magnetic resonance imaging (fMRI) in 74 healthy volunteers performing an established Sternberg working memory task with different task phases (encoding vs. retrieval) and degrees of stimulus familiarity (novel vs. previously trained). Activation analyses demonstrated a highly significant engagement of the anterior striatum, in particular during the encoding of novel working memory items. Dynamic causal modeling (DCM) of corticostriatal circuit connectivity identified a selective positive modulatory influence of novelty encoding on the connection from the dorsolateral prefrontal cortex (DLPFC) to the anterior striatum. These data extend prior research by further underscoring the relevance of the BG for human cognitive function and provide a mechanistic account of the DLPFC as a plausible top-down regulatory element of striatal function that may facilitate the “input-gating” of novel working memory materials. Electronic supplementary material The online version of this article (10.1007/s00429-018-1679-0) contains supplementary material, which is available to authorized users.

Importance Although borderline personality disorder (BPD)—one of the most common, burdensome, and costly psychiatric conditions—is characterized by repeated interpersonal conflict and instable relationships, the neurobiological mechanism of social interactive deficits remains poorly understood. Objective To apply recent advancements in the investigation of 2-person human social interaction to investigate interaction difficulties among people with BPD. Design, Setting, and Participants Cross-brain information flow in BPD was examined from May 25, 2012, to December 4, 2015, in pairs of participants studied in 2 linked functional magnetic resonance imaging scanners in a university setting. Participants performed a joint attention task. Each pair included a healthy control individual (HC) and either a patient currently fulfilling DSM-IV criteria for BPD (cBPD) (n = 23), a patient in remission for 2 years or more (rBPD) (n = 17), or a second HC (n = 20). Groups were matched for age and educational level. Main Outcomes and Measures A measure of cross-brain neural coupling was computed following previously published work to indicate synchronized flow between right temporoparietal junction networks (previously shown to host neural coupling abilities in health). This measure is derived from an independent component analysis contrasting the time courses of components between pairs of truly interacting participants compared with bootstrapped control pairs. Results In the sample including 23 women with cBPD (mean [SD] age, 26.8 [5.7] years), 17 women with rBPD (mean [SD] age, 28.5 [4.3] years), and 80 HCs (mean [SD] age, 24.0 [3.4] years]) investigated as dyads, neural coupling was found to be associated with disorder state ( η 2 = 0.17; P = .007): while HC-HC pairs showed synchronized neural responses, cBPD-HC pairs exhibited significantly lower neural coupling just above permutation-based data levels (η 2 = 0.16; P = .009). No difference was found between neural coupling in rBPD-HC and HC-HC pairs. The neural coupling in patients was significantly associated with childhood adversity ( T = 2.3; P = .03). Conclusions and Relevance This study provides a neural correlate for a core diagnostic and clinical feature of BPD. Results indicate that hyperscanning may deliver state-associated biomarkers for clinical social neuroscience. In addition, at least some neural deficits of BPD may be more reversible than is currently assumed for personality disorders.

Background The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. Methods LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. Results Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some ‘lessons learnt’. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). Conclusion We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies. Electronic supplementary material The online version of this article (doi:10.1186/s13229-017-0146-8) contains supplementary material, which is available to authorized users.

The rs1625579 variant near the microRNA-137 (MIR137) gene is one of the best-supported schizophrenia variants in genome-wide association studies (GWAS), and microRNA-137 functionally regulates other GWAS identified schizophrenia risk variants. Schizophrenia patients with the MIR137 rs1625579 risk genotype (homozygous for the schizophrenia risk variant) also have aberrant brain structure. It is unclear if the effect of MIR137 among schizophrenia patients is due to potential epistasis with genetic risk for schizophrenia or other factors of the disorder. Here, we investigated the effect of MIR137 genotype on white matter fractional anisotropy (FA), cortical thickness (CT), and surface area (SA) in a sample comprising healthy control subjects, and individuals with familial risk for psychosis (first-degree relatives of patients with schizophrenia or bipolar disorder; N=426). In voxel-wise analyses of FA, we observed a significant genotype-by-group interaction (PFWE

Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10−4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)

BACKGROUND: Variation in CACNA1C has consistently been associated with psychiatric disease in genome-wide association studies. We have previously shown that healthy carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate (pgACC) dysfunction during episodic memory recall. To test whether this brain systems-level abnormality is a potential intermediate phenotype for psychiatric disorder, we studied unaffected relatives of patients with bipolar disorder, major depression, and schizophrenia. METHODS: The study population comprised 188 healthy first-degree relatives of patients with bipolar disorder (n=59), major depression (n=73), and schizophrenia (n=56) and 110 comparison subjects from our discovery study who were genotyped for rs1006737 and underwent functional magnetic resonance imaging while performing an episodic memory task and psychological testing. Group comparisons were analyzed using SPM8 and PASW Statistics 20. RESULTS: Similar to risk allele carriers in the discovery sample, relatives of index patients exhibited hippocampal and pgACC dysfunction as well as increased scores in depression and anxiety measures, correlating negatively with hippocampal activation. Carrying the rs1006737 risk variant resulted in a stronger decrease of hippocampal and pgACC activation in relatives, indicating an additive effect of CACNA1C variation on familial risk. CONCLUSIONS: Our findings implicate abnormal perigenual and hippocampal activation as a promising intermediate phenotype for psychiatric disease and suggest a pathophysiologic mechanism conferred by a CACNA1C variant being implicated in risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.

Schizophrenia is a severe and complex brain disorder that usually manifests in early adulthood and disturbs a wide range of human functions. More than 100 years after its initial description, the pathophysiology of the disorder is still incompletely understood. Many epidemiological studies strongly suggest a complex interaction between genetic and environmental risk factors for the development of the disorder. While there is considerable evidence for a social environmental component of this risk, the links between adverse social factors and altered brain function have just come into focus. In the present review, we first summarize epidemiological evidence for the significance of social environmental risk factors, outline the role of altered social stress processing in mental illness, and review the latest experimental evidence for the neural correlates of social environmental risk for schizophrenia. The studies we have discussed in this review provide a selection of the current work in the field. We suggest that many of the social environmental risk factors may impact on perceived social stress and engage neural circuits in the brain whose functional and structural architecture undergoes detrimental change in response to prolonged exposure. We conclude that multidisciplinary approaches involving various fields and thoroughly constructed longitudinal designs are necessary to capture complex structure of social environmental risks.

Objective Although a heritable contribution to risk for major depressive disorder (MDD) has been established and neural alterations in patients have been identified through neuroimaging, it is unclear which brain abnormalities are related to genetic risk. Studies on brain structure of high-risk subjects – such as individuals carrying a familial liability for the development of MDD – can provide information on the potential usefulness of these measures as intermediate phenotypes of MDD. Methods 63 healthy first-degree relatives of patients with MDD and 63 healthy controls underwent structural magnetic resonance imaging. Regional gray matter volumes were analyzed via voxel-based morphometry (VBM). Results Whole-brain analysis revealed significantly larger gray matter volume in the bilateral amygdala in first-degree relatives of patients with MDD. Furthermore, relatives showed significantly larger gray matter volume in anatomical structures found relevant to MDD in previous literature, specifically in the bilateral hippocampus and amygdala as well as the left dorsolateral prefrontal cortex (DLPFC). Bilateral DLPFC volume correlated positively with the experience of negative affect. Conclusions Larger gray matter volume in healthy relatives of MDD patients point to a possible vulnerability mechanism in MDD etiology and therefore extend knowledge in the field of high-risk approaches in MDD., Highlights • Brain structure of high-risk subjects might indicate intermediate phenotypes of MDD • 63 first-degree relatives of MDD patients/ 63 healthy controls were studied • Local gray matter volumes were analyzed via VBM • Analysis revealed larger volume in bilateral amygdalae in relatives of MDD patients • Brain volume differences point to a vulnerability mechanism in MDD etiology