Polygenic contributions to performance on the Balloon Analogue Risk Task.

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

An integrated brain-behavior model for working memory.

Working memory (WM) is a central construct in cognitive neuroscience because it comprises mechanisms of active information maintenance and cognitive control that underpin most complex cognitive behavior. Individual variation in WM has been associated with multiple behavioral and health features including demographic characteristics, cognitive and physical traits and lifestyle choices. In this context, we used sparse canonical correlation analyses (sCCAs) to determine the covariation between brain imaging metrics of WM-network activation and connectivity and nonimaging measures relating to sensorimotor processing, affective and nonaffective cognition, mental health and personality, physical health and lifestyle choices derived from 823 healthy participants derived from the Human Connectome Project. We conducted sCCAs at two levels: a global level, testing the overall association between the entire imaging and behavioral-health data sets; and a modular level, testing associations between subsets of the two data sets. The behavioral-health and neuroimaging data sets showed significant interdependency. Variables with positive correlation to the neuroimaging variate represented higher physical endurance and fluid intelligence as well as better function in multiple higher-order cognitive domains. Negatively correlated variables represented indicators of suboptimal cardiovascular and metabolic control and lifestyle choices such as alcohol and nicotine use. These results underscore the importance of accounting for behavioral-health factors in neuroimaging studies of WM and provide a neuroscience-informed framework for personalized and public health interventions to promote and maintain the integrity of the WM network.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Effects of an employee exercise programme on mental health.

BACKGROUND: Prior research indicates that workplace wellness programmes (WWPs) are generally associated with lowered healthcare costs and improved employee health. Despite the importance of mental well-being in workplace productivity and attendance, few WWP studies have focused on improvements in psychological well-being. AIMS: To examine the effects of the Bruin Health Improvement Program (BHIP), a 3-month exercise and nutrition WWP, on seven domains of health: physical and mental health, stress, energy level, social satisfaction, self-efficacy and quality of life. METHODS: Using data from BHIP completers, we conducted multiple one-way multivariate analyses of variance and follow-up univariate t-tests to examine changes in physical and mental health, stress, energy level, social satisfaction, self-efficacy and quality of life. Effect sizes were also calculated post hoc to determine the magnitude of each effect. RESULTS: Results for the 281 participants reveal significant improvements across all seven domains (P < 0.001). Effect sizes ranged from 0.19 to 0.67. CONCLUSIONS: This study is unique in revealing the effects of a WWP on multiple domains of psychological well-being. Given rising healthcare costs associated with mental health, targeting mental health through WWP may be an effective strategy for reducing indirect healthcare costs associated with absenteeism and presenteeism.

A phenome-wide examination of neural and cognitive function.

This data descriptor outlines a shared neuroimaging dataset from the UCLA Consortium for Neuropsychiatric Phenomics, which focused on understanding the dimensional structure of memory and cognitive control (response inhibition) functions in both healthy individuals (130 subjects) and individuals with neuropsychiatric disorders including schizophrenia (50 subjects), bipolar disorder (49 subjects), and attention deficit/hyperactivity disorder (43 subjects). The dataset includes an extensive set of task-based fMRI assessments, resting fMRI, structural MRI, and high angular resolution diffusion MRI. The dataset is shared through the OpenfMRI project, and is formatted according to the Brain Imaging Data Structure (BIDS) standard.

Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: link to impulsivity in methamphetamine users.

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.

Neural mechanisms of response inhibition and impulsivity in 22q11.2 deletion carriers and idiopathic attention deficit hyperactivity disorder.

•22q11DS offers a compelling model to understand the neural substrates of attentional dysfunction.•First study directly comparing neural function in 22q11DS vs. ADHD patients•22q11DS and ADHD patients show a shared deficit in RI-related activation.•ADHD patients showed greater activity in the middle frontal gyrus than 22q11DS during RI.•Neural activity is inversely correlated with self-reported Cognitive Impulsivity in 22q11DS.

Neural substrates of inhibitory control deficits in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is associated with elevated levels of impulsivity, inattention, and distractibility, which may be related to underlying neurobiological dysfunction due to haploinsufficiency for genes involved in dopaminergic neurotransmission (i.e. catechol-O-methyltransferase). The Stop-signal task has been employed to probe the neural circuitry involved in response inhibition (RI); findings in healthy individuals indicate that a fronto-basal ganglia network underlies successful inhibition of a prepotent motor response. However, little is known about the neurobiological substrates of RI difficulties in 22q11DS. Here, we investigated this using functional magnetic resonance imaging while 45 adult participants (15 22q11DS patients, 30 matched controls) performed the Stop-signal task. Healthy controls showed significantly greater activation than 22q11DS patients within frontal cortical and basal ganglia regions during successful RI, whereas 22q11DS patients did not show increased neural activity relative to controls in any regions. Using the Barratt Impulsivity Scale, we also investigated whether neural dysfunction during RI was associated with cognitive impulsivity in 22q11DS patients. RI-related activity within left middle frontal gyrus and basal ganglia was associated with severity of self-reported cognitive impulsivity. These results suggest reduced engagement of RI-related brain regions in 22q11DS patients, which may be relevant to characteristic behavioral manifestations of the disorder.

Challenges in phenotype definition in the whole-genome era: multivariate models of memory and intelligence.

Refining phenotypes for the study of neuropsychiatric disorders is of paramount importance in neuroscience. Poor phenotype definition provides the greatest obstacle for making progress in disorders like schizophrenia, bipolar disorder, Attention Deficit/Hyperactivity Disorder (ADHD), and autism. Using freely available informatics tools developed by the Consortium for Neuropsychiatric Phenomics (CNP), we provide a framework for defining and refining latent constructs used in neuroscience research and then apply this strategy to review known genetic contributions to memory and intelligence in healthy individuals. This approach can help us begin to build multi-level phenotype models that express the interactions between constructs necessary to understand complex neuropsychiatric diseases. These results are available online through the http://www.phenowiki.org database. Further work needs to be done in order to provide consensus-building applications for the broadly defined constructs used in neuroscience research.

Phenomics: the systematic study of phenotypes on a genome-wide scale.

Phenomics is an emerging transdiscipline dedicated to the systematic study of phenotypes on a genome-wide scale. New methods for high-throughput genotyping have changed the priority for biomedical research to phenotyping, but the human phenome is vast and its dimensionality remains unknown. Phenomics research strategies capable of linking genetic variation to public health concerns need to prioritize development of mechanistic frameworks that relate neural systems functioning to human behavior. New approaches to phenotype definition will benefit from crossing neuropsychiatric syndromal boundaries, and defining phenotypic features across multiple levels of expression from proteome to syndrome. The demand for high throughput phenotyping may stimulate a migration from conventional laboratory to web-based assessment of behavior, and this offers the promise of dynamic phenotyping-the iterative refinement of phenotype assays based on prior genotype-phenotype associations. Phenotypes that can be studied across species may provide greatest traction, particularly given rapid development in transgenic modeling. Phenomics research demands vertically integrated research teams, novel analytic strategies and informatics infrastructure to help manage complexity. The Consortium for Neuropsychiatric Phenomics at UCLA has been supported by the National Institutes of Health Roadmap Initiative to illustrate these principles, and is developing applications that may help investigators assemble, visualize, and ultimately test multi-level phenomics hypotheses. As the transdiscipline of phenomics matures, and work is extended to large-scale international collaborations, there is promise that systematic new knowledge bases will help fulfill the promise of personalized medicine and the rational diagnosis and treatment of neuropsychiatric syndromes.

Literature Mapping with PubAtlas - extending PubMed with a 'BLASTing interface'.

PubAtlas (www.pubatlas.org) is a web service and standalone program providing literature maps for the biomedical research literature. It accepts user-defined sets of terms (PubMed queries) as input, and permits 'BLASTing' of one set against another: for all terms x and y in these sets, deriving the results of the pairwise intersections x AND y. This all vs. all capability extends PubMed with a literature analysis interface. Correspondingly, the basic form of literature map that PubAtlas provides for exploring associations among sets of terms is an interactive tabular display, in heatmap/microarray format.PubAtlas supports development of specialized lexica -- hierarchies of controlled terminology that can represent sets of related concepts or a 'user-defined query language'. PubAtlas also provides historical perspectives on the literature, with temporal query features that highlight historical patterns. Generally, it is a framework for extending the PubMed interface, and an extensible platform for producing interactive literature maps.

A collaborative knowledge base for cognitive phenomics.

The human genome project has stimulated development of impressive repositories of biological knowledge at the genomic level and new knowledge bases are rapidly being developed in a 'bottom-up' fashion. In contrast, higher-level phenomics knowledge bases are underdeveloped, particularly with respect to the complex neuropsychiatric syndrome, symptom, cognitive, and neural systems phenotypes widely acknowledged as critical to advance molecular psychiatry research. This gap limits informatics strategies that could improve both the mining and representation of relevant knowledge, and help prioritize phenotypes for new research. Most existing structured knowledge bases also engage a limited set of contributors, and thus fail to leverage recent developments in social collaborative knowledge-building. We developed a collaborative annotation database to enable representation and sharing of empirical information about phenotypes important to neuropsychiatric research (www.Phenowiki.org). As a proof of concept, we focused on findings relevant to 'cognitive control', a neurocognitive construct considered important to multiple neuropsychiatric syndromes. Currently this knowledge base tabulates empirical findings about heritabilities and measurement properties of specific cognitive task and rating scale indicators (n=449 observations). It is hoped that this new open resource can serve as a starting point that enables broadly collaborative knowledge-building, and help investigators select and prioritize endophenotypes for translational research.

Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation.

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

Methods for developmental studies of fear conditioning circuitry.

Psychophysiologic studies use air puff as an aversive stimulus to document abnormal fear conditioning in children of parents with anxiety disorders. This study used functional magnetic resonance imaging (fMRI) to examine changes in amygdala activity during air-puff conditioning among adults. Blood oxygen level-dependent (BOLD) signal was monitored in seven adults during 16 alternating presentations of two different colored lights (CS+ vs. CS-), one of which was consistently paired with an aversive air puff. A region-of-interest analysis demonstrated differential change in BOLD signal in the right but not left amygdala across CS+ versus CS- viewing. The amygdala is engaged by pairing of a light with an air puff. Given that prior studies relate air-puff conditioning to risk for anxiety in children, these methods may provide an avenue for directly studying the developmental neurobiology of fear conditioning.

The timing of neurodevelopmental abnormality in schizophrenia: an integrative review of the neuroimaging literature.

In this paper we will review recent neuroimaging research in schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and the timing of the neuroanatomic abnormalities underlying the disorder. Specifically, enlargement of cerebrospinal fluid spaces, deficits in cortical gray matter, and reduced volume of mesiotemporal structures have all been reported in patients in the first episode of schizophrenia, their first-degree relatives, and individuals with schizotypal personality disorder, supporting the possibility that these abnormalities reflect a genetically mediated neurodevelopmental disorder. These findings from the empirical literature will be synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. We believe that the evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, in order to more definitively determine the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and ultimately the prevention of schizophrenia.

Neurodevelopmental models of schizophrenia: pathophysiologic synthesis and directions for intervention research.

This paper examines contemporary models of the pathophysiology of schizophrenia from a neurodevelopmental perspective. Specifically, this article reviews recent research in the neuropathology, neuroimaging, and developmental psychopathology of schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and timing of both the neuroanatomic abnormalities underlying the disorder and their behavioral manifestations. Findings from the empirical literature are synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. The evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, to determine more definitively the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and, ultimately, prevention of schizophrenia.

Cortical brain regions engaged by masked emotional faces in adolescents and adults: an fMRI study.

Face-emotion processing has shown signs of developmental change during adolescence. Functional magnetic resonance imaging (fMRI) was used on 10 adolescents and 10 adults to contrast brain regions engaged by a masked emotional-face task (viewing a fixation cross and a series of masked happy and masked fearful faces), while blood oxygen level dependent signal was monitored by a 1.5-T MRI scanner. Brain regions differentially engaged in the 2 age groups were mapped by using statistical parametric mapping. Summed across groups, the contrast of masked face versus fixation-cross viewing generated activations in occipital-temporal regions previously activated in passive face-viewing tasks. Adolescents showed higher maxima for activations in posterior association cortex for 3 of the 4 statistical contrasts. Adolescents and adults differed in the degree to which posterior hemisphere brain areas were engaged by viewing masked facial displays of emotion.

Working memory deficits in schizophrenia are not necessarily specific or associated with MRI-based estimates of area 46 volumes.

Despite substantial evidence that the prefrontal cortex does not function normally in patients diagnosed with schizophrenia, evidence for prefrontal structural abnormalities, as measured by magnetic resonance imaging (MRI), has been inconsistent. Additionally, evidence for relationships between prefrontal structural and functional measures has been limited. The inconsistencies in the MRI literature are, at least in part, due to a lack of standard and specific measurement protocols that allow delineation of functionally distinct cortical regions. In this study, reliable methods for measuring an estimate of area 46 (estimate referred to as area 46(e)), as defined by 'Cereb. Cortex 5 (1995) 323', were developed and used to examine relationships between area 46(e) volumes, working memory, and symptom severity in 23 male patients and 23 healthy male comparison subjects. Patients performed more poorly than healthy reference subjects on all cognitive measures including measures of spatial and non-spatial working memory, but showed no significant corresponding deficits in area 46(e) volumes or whole brain volumes. Moreover, there were no significant relationships between symptom severity and area 46(e) volumes. These findings suggest that the prefrontal functional abnormalities observed in schizophrenia may occur in the absence of prefrontal volume deficits, and may instead involve more widespread brain systems or prefrontal connections with other brain regions.

Reduced anterior cingulate gyrus volume correlates with executive dysfunction in men with first-episode schizophrenia.

Although frontal lobe structural and functional abnormalities have been identified in schizophrenia, their relationship remains elusive. Because the frontal lobes are both structurally and functionally heterogeneous, it is possible that some measures of frontal lobe structure may not have accurately identified relevant frontal lobe subregions. The authors hypothesized that the volumes of two dorsal, 'archicortical' subregions (i.e. superior frontal gyrus and anterior cingulate gyrus), but not a ventral, 'paleocortical' subregion (i.e. orbital frontal region) would be significantly and selectively correlated with executive and motor dysfunction in patients with schizophrenia as previously reported for the anterior hippocampal region. Volumes of these frontal lobe subregions were measured from magnetic resonance images based on sulcal anatomy in 20 men and 15 women with first-episode schizophrenia. All patients completed a comprehensive neuropsychological test battery while clinically stabilized that encompassed six domains of functioning: attention, executive, motor, visuospatial, memory and language. Findings indicated that reduced anterior cingulate gyrus volume was significantly correlated with worse executive functioning in men; among women, there were no significant correlations. Among men, anterior cingulate gyrus volume was significantly more strongly correlated with executive functioning than with attention, visuospatial, memory, language and general intellectual functioning. Neither executive nor motor functioning was significantly more strongly correlated with the dorsal 'archicortical' volumes than with orbital frontal volume. These findings suggest a link between executive deficits and dysfunction of the dorsal 'archicortical' system and implicate sex differences in their relationship in first-episode schizophrenia.