The Clinical and Translational Neuroscience Branch continues to make advances on several fronts in order to delineate the neurochemical, neurogenetic, and neuropsychological contributions to neural systems function and development relevant to mental illness. We have embarked on data collection for two unprecedented scientific resources: first, a unique multimodal neuroimaging dataset in adults that includes neuropsychological testing, extensive dopaminergic PET imaging as well as MR spectroscopy, functional and structural MRI; and, second, a longitudinal, neurodevelopmental dataset that incorporates structural and functional magnetic resonance-based brain imaging, neuropsychological measures, and, in conjunction with the Section on Behavioral Endocrinology, precise, state-of-the-art endocrinological measurements of pubertal status. These comprehensive ongoing data acquisition efforts have resulted in a growing repository of integrated information about the brain, which will permit both novel analyses synthesizing disparate but interrelated indices of neurochemical (e.g., dopamine, GABA, and glutamate) functioning and discovery of critical genetic and endocrinological factors guiding neurodevelopment. Recent work under this project has been extensive, with experiments aimed at identifying important structural, functional and neurochemical brain characteristics potentially underpinning general and social cognitive abilities, testing relevant genetic associations with these phenotypes, and generating knowledge regarding interactions between risk genetics and anxiety traits. In studies of novel brain phenotypes relevant to cognition, for instance, we have applied emerging methodologies to investigate a promising new phenotype regional differences in brain gyrification (cortical folding) in healthy subjects. We showed that localized gyrification patterns are associated with general cognitive ability. More specifically, we found that greater gyrification in fronto-parietal regions predicts better cognitive performance. We observed the pattern in large and entirely independent samples of children and adults; showed that it held true across age, sex, and different indexes of cognitive ability; and showed that regional gyrification accounted for variance in cognition beyond the influence of overall brain volume. Our findings fit well with leading hypotheses regarding the neural basis of cognitive ability and provide a foundation for the use of this new brain structure phenotype in investigations of clinical groups. Regarding insights into neurochemical processes underlying cognitive health and variability, we have also found that GABA levels measured with MR spectroscopy in the dorsal anterior cingulate mediate the effects of aging on cognitive performance in middle aged individuals. This finding adds a potential biological mechanism of brain aging to the already well described effect of atrophy. Additional efforts to understand the dopaminergic underpinnings of reward processing, decision making, and aspects of working memory are underway. In a series of multimodal experiments focused on socioemotional cognition using magnetoencephalography, positron emission tomography, and magnetic resonance imaging methods, we identified heretofore unappreciated links between midbrain dopamine stores and how social neural networks react to viewing emotional faces. We then dissected how specific types of such brain activity modulate over time as expressions emerge on a viewed face, and we discovered genetic association between the Williams syndrome region gene, GTF2I, and relationships between trait neuroticism and neural activity during social cognition. Additionally, we have extended our work on anxiety-related traits to demonstrate a link between limbic resting regional cerebral blood flow (rCBF) and harm avoidance that is modulated by BDNF genotype, lending novel empirical support for the genetic regulation of trait anxiety-limbic system neurophysiology relationships. We also remain engaged in studies characterizing the genetic determinants of key neurochemical phenotypes (i.e., MRS- and PET-based signals) and functional (i.e., cognitive and fMRI-based measurements) that have been linked with neuropsychiatric illness. For example, we have shown that a common haplotype in the DOPA decarboxylase gene (DDC) is functional in the living human striatum, such that it predicts DDC enzymatic activity previously shown to be abnormal in schizophrenia. This is not only important for understanding variability in DDC neuroimaging, an important assay in schizophrenia as well as Parkinson's disease, but also potentially for treatments (e.g., L-DOPA) that require this enzyme for efficacy. We have likewise linked a heritable schizophrenia-associated phenotype first described by this group - prefrontal inefficiency during the working memory N-back task - to promising schizophrenia risk variants in the SCN2A, NRG3, and NKCC1 genes. Collaborative studies have now confirmed genetic associations between variation in the SCN2A gene and both cognitive ability and interregional brain connectivity in a large cohort of healthy individuals. In parallel, recent collaborative work has uncovered links between a genetic locus previously associated with educational attainment and broad cognitive ability, and continuing work is pursuing genome-wide associations to the same phenotype. NRG3, linked to schizophrenia since the era of linkage studies, was found associated with fMRI abnormalities in healthy subjects, unaffected siblings, and patients with schizophrenia in a gene-diagnosis interaction. Following on work linking NKCC1 to hippocampal physiology, NKCC1 was tied to gene expression, working memory, general cognition, and variation in fMRI measures during working memory.
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