The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Using structural MRI to identify bipolar disorders - 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group.

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

Western Star, 1905-02-01

The Western Star began publication on Newfoundland's west coast on 4 April 1900, appearing weekly with brief semiweekly periods up to 1952, when it became a daily. As of 17 April 2019 it continues as a free weekly community paper

Self-monitoring in patients with schizophrenia

Item does not contain fulltextBackground. The present study investigated whether a failure of self-monitoring contributes to core syndromes of schizophrenia. Method. Three groups of patients with a DSM-IV diagnosis of schizophrenia (n = 27), with either prominent paranoid hallucinatory or disorganization syndrome, or without these symptoms, and a matched healthy control group (n = 23) drew circles on a writing pad connected to a PC monitor. Subjects were instructed to continuously monitor the relationship between their hand movements and their visual consequences. They were asked to detect gain changes in the mapping. Self-monitoring ability and the ability to automatically correct movements were assessed. Results. Patients with either paranoid-hallucinatory syndrome or formal thought disorder were selectively impaired in their ability to detect a mismatch between a self-generated movement and its consequences, but not impaired in their ability to automatically compensate for the gain change. Conclusions. These results support the claim that a failure of self-monitoring may underlie the core symptoms of schizophrenia

Neural correlates of syntax production in schizophrenia

10.1192/bjp.186.3.209British Journal of Psychiatry186MAR.209-21

The neural basis of disturbed efference copy mechanism in patients with schizophrenia

Item does not contain fulltextCore psychopathological symptoms in patients with schizophrenia suggest that their sense of self may be disturbed. A disturbance in predictive motor mechanisms may be the cause of such symptoms. Ten patients with schizophrenia and ten healthy right-handed control subjects opened and closed their hand. This movement was filmed with an MRI compatible video camera and projected online onto a monitor. BOLD contrast was measured with fMRI. The temporal delay between movement and feedback was parametrically varied. Participants judged whether or not there was a delay. Patients were less sensitive to these delays than a matched control group. Comparing neural activation between the two groups showed a reduced attenuation of movement-sensitive perceptual areas in patients with increasing delay and a higher activation in the putamen in controls. The results provide further evidence that impaired efference copy mechanisms may contribute to the pathogenesis of schizophrenia and its first rank symptoms

Supramodal representation of emotions

Supramodal representation of emotion and its neural substrates have recently attracted attention as a marker of social cognition. However, the question whether perceptual integration of facial and vocal emotions takes place in primary sensory areas, multimodal cortices, or in affective structures remains unanswered yet. Using novel computer-generated stimuli, we combined emotional faces and voices in congruent and incongruent ways and assessed functional brain data (fMRI) during an emotional classification task. Both congruent and incongruent audiovisual stimuli evoked larger responses in thalamus and superior temporal regions compared with unimodal conditions. Congruent emotions were characterized by activation in amygdala, insula, ventral posterior cingulate (vPCC), temporo-occipital, and auditory cortices; incongruent emotions activated a frontoparietal network and bilateral caudate nucleus, indicating a greater processing load in working memory and emotion-encoding areas. The vPCC alone exhibited differential reactions to congruency and incongruency for all emotion categories and can thus be considered a central structure for supramodal representation of complex emotional information. Moreover, the left amygdala reflected supramodal representation of happy stimuli. These findings document that emotional information does not merge at the perceptual audiovisual integration level in unimodal or multimodal areas, but in vPCC and amygdala

Mismatch Negativity Responses in Schizophrenia: A Combined fMRI and Whole-Head MEG Study

OBJECTIVE: Mismatch negativity is an event-related brain response sensitive to deviations within a sequence of repetitive auditory stimuli. It is thought to reflect short-term sensory memory and is independent of higher-level cognitive processes. Mismatch negativity response is diminished in patients with schizophrenia. Little is known about the mechanisms of this decreased response, the contribution of the different hemispheres, and its locus of generation. METHOD: Patients with schizophrenia (N=12) and matched comparison subjects (N=12) were studied. A novel design to measure mismatch negativity responses to deviant auditory stimuli was generated by using the switching noises from the functional magnetic resonance imaging (fMRI) scanner, thus avoiding any interfering background sound. Stimuli included deviants of amplitude (9 dB lower) and duration (76 msec shorter) presented in a random sequence. The scanner noise was recorded and applied to the same subjects in a whole-head magnetoencephalography (MEG) device. Neuromagnetic and hemodynamic responses to the identical stimuli were compared between the patients and comparison subjects. RESULTS: As expected, neuromagnetic mismatch fields were smaller in the patient group. More specifically, a lateralization to the right for duration deviance was only found in comparison subjects. For the relative amplitude of the blood-oxygen-level-dependent signal (measured with fMRI), differences emerged in the secondary (planum temporale), but not primary (Heschl’s gyrus), auditory cortex. Duration deviants achieved a right hemispheric advantage only in the comparison group. A significantly stronger lateralization to the left was found for the deviant amplitude stimuli in the patients. CONCLUSIONS: The data support the view of altered hemispheric interactions in the formation of the short-term memory traces necessary for the integration of auditory stimuli. This process is predominantly mediated by the planum temporale (secondary auditory cortex). Altered interaction of regions within the superior temporal plane and across hemispheres could be in part responsible for language-mediated cognitive (e.g., verbal memory) and psychopathological (hallucinations, formal thought disorder) symptoms in schizophrenia