The genetic architecture of the human cerebral cortex.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Female adolescents with severe substance and conduct problems have substantially less brain gray matter volume.

OBJECTIVE: Structural neuroimaging studies have demonstrated lower regional gray matter volume in adolescents with severe substance and conduct problems. These research studies, including ours, have generally focused on male-only or mixed-sex samples of adolescents with conduct and/or substance problems. Here we compare gray matter volume between female adolescents with severe substance and conduct problems and female healthy controls of similar ages. HYPOTHESES: Female adolescents with severe substance and conduct problems will show significantly less gray matter volume in frontal regions critical to inhibition (i.e. dorsolateral prefrontal cortex and ventrolateral prefrontal cortex), conflict processing (i.e., anterior cingulate), valuation of expected outcomes (i.e., medial orbitofrontal cortex) and the dopamine reward system (i.e. striatum). METHODS: We conducted whole-brain voxel-based morphometric comparison of structural MR images of 22 patients (14-18 years) with severe substance and conduct problems and 21 controls of similar age using statistical parametric mapping (SPM) and voxel-based morphometric (VBM8) toolbox. We tested group differences in regional gray matter volume with analyses of covariance, adjusting for age and IQ at p<0.05, corrected for multiple comparisons at whole-brain cluster-level threshold. RESULTS: Female adolescents with severe substance and conduct problems compared to controls showed significantly less gray matter volume in right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, bilateral somatosensory cortex, left supramarginal gyrus, and bilateral angular gyrus. Considering the entire brain, patients had 9.5% less overall gray matter volume compared to controls. CONCLUSIONS: Female adolescents with severe substance and conduct problems in comparison to similarly aged female healthy controls showed substantially lower gray matter volume in brain regions involved in inhibition, conflict processing, valuation of outcomes, decision-making, reward, risk-taking, and rule-breaking antisocial behavior.

Neural Correlates of Schizophrenia Negative Symptoms: Distinct Subtypes Impact Dissociable Brain Circuits.

BACKGROUND: The negative symptoms of schizophrenia include deficits in emotional expression and motivation. These deficits are stable over the course of illness and respond poorly to current medications. Previous studies have focused on negative symptoms as a single category; however, individual symptoms might be related to separate neurological disturbances. We analyzed data from the Functional Biomedical Informatics Research Network dataset to explore the relationship between individual negative symptoms and functional brain activity during an auditory oddball task. METHODS: Functional magnetic resonance imaging was conducted on 89 schizophrenia patients and 106 healthy controls during a two-tone auditory oddball task. Blood oxygenation level-dependent (BOLD) signal during the target tone was correlated with severity of five negative symptom domains from the Scale for the Assessment of Negative Symptoms. RESULTS: The severity of alogia, avolition/apathy and anhedonia/asociality was negatively correlated with BOLD activity in distinct sets of brain regions associated with processing of the target tone, including basal ganglia, thalamus, insular cortex, prefrontal cortex, posterior cingulate and parietal cortex. CONCLUSIONS: Individual symptoms were related to different patterns of functional activation during the oddball task, suggesting that individual symptoms might arise from distinct neural mechanisms. This work has potential to inform interventions that target these symptom-related neural disruptions.

Altered fronto-limbic activity in children and adolescents with familial high risk for schizophrenia.

Early symptoms of schizophrenia tend to emerge during adolescence, hich is a critical period for development of executive and emotional processing. While individuals with familial high risk (FHR) for schizophrenia may show cognitive and emotional changes, the neural mechanisms underlying the development of these changes remain unclear. The goal of this study was to identify functional differences in fronto-striato-limbic regions in children with FHR. Functional magnetic resonance imaging (MRI) data were collected from 21 children with a first-degree family member with schizophrenia and 21 controls without FHR. Participants performed an emotional oddball task requiring both selective attention and suppression of task-irrelevant emotional information. During selective attention, the group with FHR showed enhanced activation in the inferior frontal gyrus and caudate, with decreases in middle frontal gyrus and insular activation. The FHR group also showed greater age-related recruitment of anterior cingulate, temporal and occipital cortical areas during selective attention. During emotional processing, the FHR group showed decreased anterior cingulate activation, with decreased age-related recruitment of inferior frontal, parietal and occipital areas. The results suggest that FHR for schizophrenia may be associated with abnormal hyperactivation and hypoactivation of the neural circuitry engaged during executive and emotional processing and with age-related changes in neural recruitment during adolescence.