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The climate crisis, loss of biodiversity and increasing global pollution are a threat to mental health. Comprehensive transformations are needed to overcome these crises, which will also affect the mental healthcare system. If done correctly these change processes can seize the chance to improve mental health while at the same time addressing the crises. This includes avoiding the need for psychiatric treatment by strengthening the focus on mental health promotion and prevention, and also considering environmental aspects when targetting therapy procedures. In addition, by focusing on nutrition, mobility and the effects of nature, patients can be empowered to increase their mental resilience whilst reducing the negative effects on the environment. At the same time, the mental healthcare system must adapt to changing environmental conditions: increasing heat waves make protective measures necessary, especially for people with mental illnesses and increasing extreme weather events can lead to shifts in the spectrum of illnesses. Appropriate funding mechanisms will have to be established to support mental healthcare throughout this transformation. [ABSTRACT FROM AUTHOR]

Climate change and the resulting higher frequency of extreme weather events have a direct negative impact on mental health. Natural disasters are particularly associated with an increase in the prevalence of depression, anxiety and posttraumatic stress disorder. Indirect consequences of climate change, such as food shortages, economic crises, violent conflicts and forced migration, additionally represent severe psychological risk and stress factors. Climate anxiety and solastalgia, the distress induced by environmental change, are new psychological syndromes in the face of the existential threat posed by the climate crisis. Accordingly, a sustainable psychiatry must prepare for increasing and changing demands. The principles of psychiatric treatment need to focus more on prevention to reduce the overall burden on the healthcare system. Waste of resources and CO2 emissions in psychiatric treatment processes as well as infrastructure must be perceived and prevented. Psychiatric education, training and continuing education concepts should be expanded to include the topic of climate change in order to comprehensively inform and sensitize professionals, those affected and the public and to encourage climate-friendly and health-promoting behavior. More in-depth research is needed on the impact of climate change on mental health. The DGPPN becomes a sponsor and aims for climate neutrality by 2030 by committing to climate-friendly and energy-saving measures in the area of finance, in relation to the DGPPN congress as well as the DGPPN office. [ABSTRACT FROM AUTHOR]

• Lu AF11167 is a selective, high affinity inhibitor of PDE10A. • Treatment with Lu AF11167 did not reduce negative symptoms in schizophrenia. • Lu AF11167 was safe and generally well tolerated. • Placebo-controlled monotherapy studies for prominent negative symptoms are safe. Lu AF11167 is a selective, high-affinity inhibitor of PDE10A that modulates dopamine D1 and D2 receptor-mediated intraneuronal signalling without binding to these receptors. This randomized, double-blind, parallel-group, placebo-controlled study (NCT03793712) with open-label extension (NCT03929497) evaluated the efficacy of two fixed-flexible doses (1-2mg/day and 3-4mg/day) of Lu AF11167 in stable, non-acute patients with schizophrenia and persistent prominent negative symptoms. The studies were discontinued following a futility analysis of the double-blind study, and we report data collected up to study termination. Of the 210 patients screened, 162 were randomized, 111 completed the double-blind study and 96 entered the open-label study before early termination. The withdrawal rate due to impending relapse was low and comparable across treatment groups (n = 2-4 per group in the double-blind study and n = 1 in the open-label extension). Double-blind treatment with Lu AF11167 3-4mg was not superior to placebo in the reduction of Brief Negative Symptom Scale (BNSS) total scores from Baseline to Week 12 (primary endpoint); adjusted mean changes were -6.8 with placebo, -5.7 with Lu AF11167 1-2 mg group and -6.0 with Lu AF11167 3-4mg. Treatment with Lu AF11167 1-2mg also failed to separate from placebo on the primary endpoint. Neither dose group showed significant improvements versus placebo on any of the secondary efficacy measures exploring effect of treatment on overall symptomology, negative symptoms, positive symptoms, or functioning. Administration of Lu AF11167 was safe and well tolerated and adverse events were not a major reason for withdrawal from the study. [ABSTRACT FROM AUTHOR]

Background: During the last 2 years of the coronavirus disease 2019 (COVID-19) pandemic, knowledge about the long-term effects of the disease, the so-called long COVID, has rapidly grown; however, many questions remain unanswered, especially regarding the causes of persistent symptoms and their prognosis. Cognitive disorders and sleep disturbances are among the most frequent complaints. Both are associated with severe suffering and significant impairment in everyday functioning. Objective: What is known about the occurrence of cognitive disorders and sleep disturbances in long COVID? What are the influencing factors and what is known about the course over time and possible underlying mechanisms? What treatment options are available? Material and method: In a narrative review, the most important findings on cognitive disorders and sleep disturbances in long COVID are presented. An overview of cohort studies with data on the prevalence and influencing factors of both symptom complexes is given. Current knowledge and hypotheses on pathophysiological mechanisms are presented and an outlook on treatment approaches is given. Results: About one in five of those affected report cognitive impairment more than 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and about one third report sleep disturbances. The latter comprise symptoms of insomnia as well as hypersomnia. Cognitive impairment and sleep disturbances occur in patients with all levels of initial disease severity. There are indications of an improvement of cognitive deficits over time but further longitudinal studies are needed. Conclusion: In addition to the prognosis, the underlying disease mechanisms are still insufficiently understood. Furthermore, there is a great need for research on the efficacy and specific effective factors of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Substance-induced psychotic disorders (SIPD) are frequent and account for about 25% of the first admissions to a psychiatric hospital. From a clinical point of view the differential diagnosis of SIPD vs. primary (genuine or cryptogenic) psychotic disorders is often a challenge due to the similar psychopathology. This is complicated by the fact that SIPDs associated with cannabis, hallucinogens and amphetamines have a significant risk of transition to manifest psychotic disorder (e.g. schizophrenia). In the first section of this paper two case reports from general psychiatric and forensic practice are presented. Then, in a narrative review the relevance of the differential diagnostic distinction between both disorders is examined from the perspective of general and forensic psychiatry with respect to therapy, prognosis and judicial decisions regarding the placement in forensic commitment (§ 63 vs. § 64 German Penal Code, StGB). The last section aims to develop a structured procedure for the differentiation between SIPD and primary psychotic disorders. The concepts and findings presented and discussed in this paper are intended to help psychiatrists and psychologists make a diagnosis in a general and a forensic context. [ABSTRACT FROM AUTHOR]

This overview addresses some opportunities and risks of digital transformation in their significance for the diagnostics and therapy of mental illnesses under the aspect of the convergence of new digital technologies. Possibilities of smartphone-based technologies for the recording of the lifeworld context are explained and the application of this approach to the investigation of resilience mechanisms for improving mental well-being is presented on the basis of two current research results. Subsequently, the increasing networking of the environmental context itself is taken into account against the background of the so-called internet of things (IoT). These converging technologies, combined with new developments in artificial intelligence, enable a new generation of ecological momentary interventions (EMI) based on innovative sensors, local assessment of the lifeworld context and their evaluation using artificial intelligence. [ABSTRACT FROM AUTHOR]

Background: The social brain is dysfunctional in numerous stress-related psychiatric disorders. Objective: The definition of social brain networks and their susceptibility for social environmental stress. It is also reviewed how social brain networks are disrupted in schizophrenia, autism and conduct disorder. Material and methods: Literature search in PubMed. Results: The social brain consists of several subnetworks that act in concert to foster empathy. Interestingly, except for the mirror neuron system, the neural networks of the social brain have been reported to be vulnerable to social environmental stress and have also been highlighted as being compromised in psychiatric disorders. As an example, schizophrenia is related to dysfunction in social perception, mentalizing, and affiliation, whereas the most pronounced deficits in autism are seen during social perception and mentalizing. Patients with conduct disorder are more prone to dysfunction in perception, affiliation and aversion. Conclusion: Social stress affects subnetworks also compromised in psychiatric disorders. Therefore, it is plausible that the social brain might mediate the association between social stress and psychiatric disorders. To advance ecological validity in social neuroscience, recent research has highlighted the role of hyperscanning and virtual reality as means by which a more naturalistic assessment of social interactions might be feasible. [ABSTRACT FROM AUTHOR]

Mental health and well-being are consistently influenced-directly or indirectly-by multiple environmental exposures. In this review, we have attempted to address some of the most common exposures of the biophysical environment, with a goal of demonstrating how those factors interact with central structures and functions of the brain and thus influence the neurobiology of depression. We emphasize biochemical mechanisms, observational evidence, and areas for future research. Finally, we include aspects of contextual environments-city living, nature, natural disasters, and climate change-and call for improved integration of environmental issues in public health science, policies, and activities. This integration is necessary for reducing the global pandemic of depression. [ABSTRACT FROM AUTHOR]

Trust pervades nearly every social aspect of our daily lives, and its disruption is a significant factor in mental illness. Research in the field of neuroeconomics has gained a deeper understanding of the neuropsychoeconomic (NPE) underpinnings of trust by combining complementary methodologies from neuroscience, psychology, and economics. However, a coherent model of trust that integrates separate findings under a conceptual framework is still lacking. Here, we sketch out an integrative NPE model that explains how the interactions of psychoeconomic components engage domain-general large-scale brain networks in shaping trust behavior over time. We also point out caveats of current research approaches and outline open questions that can help guide future transdisciplinary investigations for a better understanding of the neuropsychology of trust. Highlights Human societies are unique in the level to which interpersonal trust penetrates every facet of our private and public social lives. Theoretical and empirical work has made tremendous strides over the last decade in investigating the neuropsychology of interpersonal trust, but a conceptual framework integrating separate research findings into a neuropsychological model of trust is still lacking. A neuropsychoeconomic framework – combining complementary methodologies from the fields of economics, psychology, and neuroscience – can help to assimilate findings across behavioral, psychological, and neural levels. An integrative model of interpersonal trust is proposed that explains how the interactions of psychoeconomic components engage domain-general large-scale brain networks in shaping trust behavior over time. As the transdisciplinary trust research matures, the proposed framework and model might help to guide future investigations to overcome current research limitations toward a better understanding of the neuropsychological underpinnings of trust. [ABSTRACT FROM AUTHOR]

Highlights • GMA are present in psychiatric disorders with neurodevelopmental origin. • Motor dysfunction reflects vulnerability for the development of mental disorders. • This analysis will help promoting RDoC Motor System construct. Abstract Although genuine motor abnormalities (GMA) are frequently found in schizophrenia, they are also considered as an intrinsic feature of bipolar, obsessive-compulsive, and neurodevelopmental disorders with early onset such as autism, ADHD, and Tourette syndrome. Such transnosological observations strongly suggest a common neural pathophysiology. This systematic review highlights the evidence on GMA and their neuroanatomical substrates in bipolar, obsessive-compulsive, and neurodevelopmental disorders. The data lends support for a common pattern contributing to GMA expression in these diseases that seems to be related to cerebello-thalamo-cortical, fronto-parietal, and cortico-subcortical motor circuit dysfunction. The identified studies provide first evidence for a motor network dysfunction as a correlate of early neurodevelopmental deviance prior to clinical symptom expression. There are also first hints for a developmental risk factor model of these mental disorders. An in-depth analysis of motor networks and related patho-(physiological) mechanisms will not only help promoting Research Domain Criteria (RDoC) Motor System construct, but also facilitate the development of novel psychopharmacological models, as well as the identification of neurobiologically plausible target sites for non-invasive brain stimulation. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe behavioral syndrome of neurodevelopmental nature marked by primary or genuine motor abnormalities (GMA), which refer to spontaneous and medication-independent motor phenomena. Since motor dysfunction thus might be a consequence of events occurring during early childhood and adolescence, GMA can be detected in the period preceding manifest schizophrenia. However, the question whether motor system dysfunction might be a promising motor intermediate phenotype for schizophrenia remains unanswered. In this review, we systematically evaluate the evidence on GMA in healthy persons, individuals with schizotypal personality traits, persons at ultra-high risk for psychosis, and unaffected first-degree relatives of schizophrenia patients. What becomes evident is a continuum of GMA expression, which appears to be linked to abnormalities of cerebello-thalamo-cortical, fronto-parietal, and cortico-subcortical motor circuits. According to current evidence, motor dysfunction is a key aspect of the neurodevelopmental risk factor model of schizophrenia. Insights provided by this research will help promoting the RDoC Motor System construct and expand the clinical relevance of the motor domain in the period preceding manifest schizophrenia. [ABSTRACT FROM AUTHOR]

Finding novel biological targets in psychiatry has been difficult, partly because current diagnostic categories are not defined by pathophysiology and difficult to model in animals. The study of species-conserved systems-level mechanisms implicated in psychiatric disease could be a promising strategy to address some of these difficulties. Altered hippocampal–prefrontal (HC-PFC) connectivity during working memory (WM) processing is a candidate for such a translational phenotype as it has been repeatedly associated with impaired cognition in schizophrenia patients and animal models for psychiatric risk factors. Specifically, persistent hippocampus-dorsolateral prefrontal cortex (HC-DLPFC) coupling during WM is an intermediate phenotype for schizophrenia that has been observed in patients, healthy relatives and carriers of two different risk polymorphisms identified in genome-wide association studies. Rodent studies report reduced coherence between HC and PFC during anesthesia, sleep and task performance in both genetic, environmental and neurodevelopmental models for schizophrenia. We discuss several challenges for translation including differences in anatomy, recording modalities and WM paradigms and suggest that a better understanding of HC-PFC coupling across species can be achieved if translational neuroimaging is used to control for task differences. The evidence for potential neurobiological substrates underlying HC-PFC dysconnectivity is evaluated and research strategies are proposed that aim to bridge the gap between findings from large-scale association studies and disease mechanisms. [ABSTRACT FROM AUTHOR]

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. Hum Brain Mapp 36:4089-4103, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This commentary suggests that neuroscience research on young healthy heavy cannabis users and patients with cannabis-induced psychosis using multimodal assessment of sensorimotor dysfunction (e.g. neuroimaging, clinical rating scales, and instrumental assessments) may help to identify both biological resistance and vulnerability without constraints and confounder factors imposed by antipsychotic treatment or disease chronicity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia. [Copyright &y& Elsevier]

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia. [ABSTRACT FROM AUTHOR]

Schizophrenia is a frequent and highly heritable brain disorder that typically manifests around or after puberty and has a fluctuating course. Multiple lines of evidence point to a neurodevelopmental origin of the illness and suggest that its (post) pubertal manifestation is related to genetic and environmental risk factors that interfere with the structural and functional reorganization of neural networks at this time. Longitudinal structural neuroimaging studies point to a progressive reduction in gray matter volume in many brain regions in schizophrenia. It has been proposed that these neuroimaging observations reflect an enduring disturbance of experience-dependent synaptic plasticity arising from developmental abnormalities in key neural circuits implicated in schizophrenia, including dorsolateral prefrontal cortex and hippocampal formation. Recent work has identified genetic variants linked to neural plasticity that are associated with changes in these circuits. Furthermore, non-invasive interventions such as transcranial magnetic stimulation have been shown to impact some of these systems-level intermediate phenotypes, suggesting a modifiability of these core pathophysiological processes of schizophrenia that may be exploited by therapy. [ABSTRACT FROM AUTHOR]

The number of neuroimaging studies on movement disorders, sensorimotor, and psychomotor functioning in schizophrenia spectrum disorders (SSD) has steadily increased over the last two decades. Accelerated by the addition of the "sensorimotor domain" to the Research Domain Criteria (RDoC) framework in January 2019, neuroscience research on the role of sensorimotor dysfunction in SSD has gained greater scientific and clinical relevance. To draw attention to recent rapid progress in the field, we performed a triennial systematic review (PubMed search from January 1st, 2018 through December 31st, 2020), in which we highlight recent neuroimaging findings and discuss methodological pitfalls as well as challenges for future research. The identified magnetic resonance imaging (MRI) studies suggest that sensorimotor abnormalities in SSD are related to cerebello-thalamo-cortico-cerebellar network dysfunction. Longitudinal and interventional studies highlight the translational potential of the sensorimotor domain as putative biomarkers for treatment response and as targets for non-invasive neurostimulation techniques in SSD. • Sensorimotor neuroscience is growing rapidly. • CTCC dysfunction might lead to sensorimotor abnormalities in SSD. • Sensorimotor neuroscience exhibits diagnostic and therapeutic relevance. [ABSTRACT FROM AUTHOR]

Abstract: I provide a brief and subjective view of where the field of imaging genetics is heading. After recapitulating early debates between imagers and geneticists revolving around the topic of candidate gene studies, I point out the importance of genome-wide significant, rare and common variants. I propose that the next stages will be dominated by large-scale multi-site studies that will enable the examination of rare-high penetrance variants and methodological developments that will be required to properly assess the effects of pleiotropy, epistasis, and gene-by environment interactions. The incorporation of new sources of biological information such as whole genome sequencing, proteomic, lipidomic and expression profiles and cellular models derived from induced pluripotent stem cells opens new vistas for imaging genetics in a translational enterprise that is ultimately hoped to improve and create therapeutic options for psychiatric disorders. [Copyright &y& Elsevier]

The panoply of cognitive, affective, motivational, and social functions that underpin everyday human experience requires precisely choreographed patterns of interaction between networked brain regions. Perhaps not surprisingly, diverse forms of psychopathology are characterized by breakdowns in these interregional relationships. Here, we discuss how functional brain imaging has provided insights into the nature of brain dysconnectivity in mental illness. Synthesizing work to date, we propose that genetic and environmental risk factors impinge upon systems-level circuits for several core dimensions of cognition, producing transdiagnostic symptoms. We argue that risk-associated disruption of these circuits mediates susceptibility to broad domains of psychopathology rather than discrete disorders. [ABSTRACT FROM AUTHOR]

Mental health and social life are intimately inter-related, as demonstrated by the frequent social deficits of psychiatric patients and the increased rate of psychiatric disorders in people exposed to social environmental adversity. Here, we review emerging evidence that combines epidemiology, social psychology and neuroscience to bring neural mechanisms of social risk factors for mental illness into focus. In doing so, we discuss existing evidence on the effects of common genetic risk factors in social neural pathways and outline the need for integrative approaches to identify the converging mechanisms of social environmental and genetic risk in brain. [ABSTRACT FROM AUTHOR]

Abstract: The neuropeptides oxytocin and vasopressin have increasingly been identified as modulators of human social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction, such as autism. Identifying the human brain regions that are impacted by oxytocin and vasopressin in a social context is essential to fully characterize the role of oxytocin and vasopressin in complex human social cognition. Advances in human non-invasive neuroimaging techniques and genetics have enabled scientists to begin to elucidate the neurobiological basis of the influence of oxytocin and vasopressin on human social behaviors. Here we review the findings to-date from investigations of the acute and chronic effects of oxytocin and vasopressin on neural activity underlying social cognitive processes using “pharmacological fMRI” and “imaging genetics”, respectively. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. [Copyright &y& Elsevier]

Alzheimer's disease is a devastating, common, progressive dementia with considerable heritability. Recently, a genetic variant associated with the disease was discovered at CLU (rs11136000) with genome-wide support. Here we show, using an imaging genetics approach in a large genotyped sample, that healthy carriers of the variant exhibit altered coupling between hippocampus and prefrontal cortex during memory processing, mirroring clinical evidence of disturbed connectivity in patients and providing a neurogenetic mechanism for CLU-associated risk and protection. [ABSTRACT FROM AUTHOR]

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are evolutionarily highly conserved mediators in the regulation of complex social cognition and behaviour. Recent studies have investigated the effects of OXT and AVP on human social interaction, the genetic mechanisms of inter-individual variation in social neuropeptide signalling and the actions of OXT and AVP in the human brain as revealed by neuroimaging. These data have advanced our understanding of the mechanisms by which these neuropeptides contribute to human social behaviour. OXT and AVP are emerging as targets for novel treatment approaches--particularly in synergistic combination with psychotherapy--for mental disorders characterized by social dysfunction, such as autism, social anxiety disorder, borderline personality disorder and schizophrenia. [ABSTRACT FROM AUTHOR]

Functional and structural brain imaging has identified neural and neurotransmitter systems involved in schizophrenia and their link to cognitive and behavioural disturbances such as psychosis. Mapping such abnormalities in patients, however, cannot fully capture the strong neurodevelopmental component of schizophrenia that pre-dates manifest illness. A recent strategy to address this issue has been to focus on mechanisms of disease risk. Imaging genetics techniques have made it possible to define neural systems that mediate heritable risk linked to candidate and genome-wide-supported common variants, and mechanisms for environmental risk and gene-environment interactions are emerging. Characterizing the neural risk architecture of schizophrenia provides a translational research strategy for future treatments. [ABSTRACT FROM AUTHOR]

Abstract: Williams syndrome (WS) is a rare genetic disorder caused by the deletion of ∼25 genes on chromosome 7q11.23 and is characterized by both hypersociability and increases in specific phobia and anticipatory anxiety regarding non-social entities or circumstances. Alterations in amygdala reactivity and prefrontal regulation consistent with the observed behavioral pattern of social versus non-social abnormalities have been previously demonstrated in individuals with WS (). However, in that study, the social stimulus (faces) matching task was more difficult than the non-social scene (IAPS stimuli) matching task, making it impossible to disambiguate the relative contributions of task difficulty and stimulus type (social versus non-social). In the present study, we examined the performance of the same group of participants with WS and normal IQs during a more cognitively demanding task using the same scene stimuli as in the prior study. Confirming previous findings, the results indicated (a) a differential response of prefrontal regions as a function of task difficulty and (b) a persistently increased activation of the amygdala to non-social scenes by individuals with WS regardless of cognitive load. These data provide further evidence of disruption in amygdala-prefrontal circuitry in individuals with WS. [Copyright &y& Elsevier]

Recent evidence suggests that default mode connectivity characterizes neural states that account for a sizable proportion of brain activity and energy expenditure, and therefore represent a plausible neural intermediate phenotype. This implies the possibility of genetic control over systems-level connectivity features. Imaging genetics is an approach to combine genetic assessment with multimodal neuroimaging to discover neural systems linked to genetic abnormalities or variation. In the present contribution, we report results obtained from applying this strategy to both structural connectivity and functional connectivity data. Using data for serotonergic (5-HTTLPR, MAO-A) and dopaminergic (DARPP-32) genes as examples, we show that systems-level connectivity networks under genetic control can be identified. Remarkable similarities are observed across modalities and scales of description. Features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure. These data provide convergent evidence for genetic control in humans over connectivity systems, whose characterization has promise for identifying neural systems mediating genetic risk for complex human behavior and psychiatric disease. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals. a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans. although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and rewardrelated neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[[sup18]F)FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRl) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging. [ABSTRACT FROM AUTHOR]

Abstract: Imaging genetics provides an enormous amount of functional–structural data on gene effects in living brain, but the sheer quantity of potential phenotypes raises concerns about false discovery. Here, we provide the first empirical results on false positive rates in imaging genetics. We analyzed 720 frequent coding SNPs without significant association with schizophrenia and a subset of 492 of these without association with cognitive function. Effects on brain structure (using voxel-based morphometry, VBM) and brain function, using two archival imaging tasks, the n-back working memory task and an emotional face matching task, were studied in whole brain and regions of interest and corrected for multiple comparisons using standard neuroimaging procedures. Since these variants are unlikely to impact relevant brain function, positives obtained provide an upper empirical estimate of the false positive association rate. In a separate analysis, we randomly permuted genotype labels across subjects, removing any true genotype–phenotype association in the data, to derive a lower empirical estimate. At a set correction level of 0.05, in each region of interest and data set used, the rate of positive findings was well below 5% (0.2–4.1%). There was no relationship between the region of interest and the false positive rate. Permutation results were in the same range as empirically derived rates. The observed low rates of positives provide empirical evidence that the type I error rate is well controlled by current commonly used correction procedures in imaging genetics, at least in the context of the imaging paradigms we have used. In fact, our observations indicate that these statistical thresholds are conservative. [Copyright &y& Elsevier]

Background: Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. Methods: We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. Results: Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. Conclusions: Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia. [Copyright &y& Elsevier]

Antisocial aggression is a widespread and expensive social problem. Although aggressive behaviors and temperament are highly heritable, clinical and trait associations for the most promising candidate gene for aggression, MAOA, have been largely inconsistent. We suggest that limitations inherent to that approach might be overcome by using multimodal neuroimaging to characterize neural mechanisms of genetic risk. Herein, we detail functional, structural and connectivity findings implicating the low-expressing allele of the MAOA u-VNTR (MAOA-L) in adversely prejudicing information processing within a corticolimbic circuit composed of amygdala, rostral cingulate and medial prefrontal cortex. We propose that the MAOA-L, by causing an ontogenic excess of 5-hydroxytryptamine, labilizes critical neural circuitry for social evaluation and emotion regulation (the ‘socioaffective scaffold’), thereby amplifying the effects of adverse early-life experience and creating deleterious sociocognitive biases. Our construct provides a neurobiologically consistent model for gene–environment interactions in impulsive aggression. [Copyright &y& Elsevier]

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of Gα-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness. [ABSTRACT FROM AUTHOR]

Brain function depends on adaptive self-organization of large-scale neural assemblies, but little is known about quantitative network parameters governing these processes in humans. Here, we describe the topology and synchronizability of frequency-specific brain functional networks using wavelet decomposition of magnetoencephalographic time series, followed by construction and analysis of undirected graphs. Magnetoencephalographic data were acquired from 22 subjects, half of whom performed a finger-tapping task, whereas the other half were studied at rest. We found that brain functional networks were characterized by small-world properties at all six wavelet scales considered, corresponding approximately to classical δ (low and high), θ, α, β, and γ frequency bands. Global topological parameters (path length, clustering) were conserved across scales, most consistently in the frequency range 2-37 Hz, implying a scale-invariant or fractal small-world organization. Dynamical analysis showed that net- works were located close to the threshold of order/disorder transition in all frequency bands. The highest-frequency γ network had greater synchronizability, greater clustering of connections, and shorter path length than networks in the scaling regime of (lower) frequencies. Behavioral state did not strongly influence global topology or synchronizability; however, motor task performance was associated with emergence of long-range connections in both β and γ networks. Long-range connectivity, e.g., between frontal and parietal cortex, at high frequencies during a motor task may facilitate sensorimotor binding. Human brain functional networks demonstrate a fractal small-world architecture that supports critical dynamics and task-related spatial reconfiguration while pre- serving global topological parameters. [ABSTRACT FROM AUTHOR]

Background: Although the major principles of dopamine (DA) signaling have been well described previously, its precise modulatory impact on the prefrontal cortex (PFC) in humans is poorly understood. Two major neurophysiological models propose segregated functional circuits on the systems level as well as D1 and D2 receptor-dependent processing states on the cellular level (two-state model). Methods: We examined the predictive validity of these models in 10 healthy male volunteers with a haloperidol challenge (HLP). Cortico-striatal-thalamo-cortical (CSTC) motor loop functions were examined during functional magnetic resonance imaging (fMRI) with a sequential finger opposition task. Neuropsychological implications of the two-state model were evaluated with a test battery of D1- or D2-sensitive prefrontal measures. Results: Analysis of fMRI data revealed a significant HLP-induced blood oxygen level dependent–signal decrease in the sensorimotor striatum and a lateralized activation loss of ipsilateral higher order motor cortices and contralateral cerebellum. Neuropsychological evaluation demonstrated a preferential impairment of D2-sensitive functions, whereas D1 or non-dopaminergic domains were unaffected. Conclusions: Our data support the hypothesis that mesocortical D1 and D2 receptors exert differential influences in the PFC for cognitive function, but the nigrostriatal CSTC network model for the motor domain could not be confirmed. [Copyright &y& Elsevier]

Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion. [ABSTRACT FROM AUTHOR]

Williams syndrome, a rare disorder caused by hemizygous microdeletion of about 28 genes on chromosome 7q11.23, has long intrigued neuroscientists with its unique combination of striking behavioural abnormalities, such as hypersociability, and characteristic neurocognitive profile. Williams syndrome, therefore, raises fundamental questions about the neural mechanisms of social behaviour, the modularity of mind and brain development, and provides a privileged setting to understand genetic influences on complex brain functions in a 'bottom-up' way. We review recent advances in uncovering the functional and structural neural substrates of Williams syndrome that provide an emerging understanding of how these are related to dissociable genetic contributions characterized both in special participant populations and animal models. [ABSTRACT FROM AUTHOR]

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAQA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence. [ABSTRACT FROM AUTHOR]

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS. [ABSTRACT FROM AUTHOR]

Carriers of the short allele of a functional 5'promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression. [ABSTRACT FROM AUTHOR]