Neuroimaging of Brain Circuits and Molecular Mechanisms in Normal Cognition

National Institute Of Mental Health

Investigators

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Abstract

The Clinical and Translational Neuroscience Branch continues to make advances on several fronts to delineate the neurochemical, neurogenetic, and neuropsychological contributions to neural systems function and development relevant to mental illness. We have devoted extensive efforts building two unprecedented scientific resources: first, a unique multimodal neuroimaging dataset in adults that includes neuropsychological testing, extensive dopaminergic PET imaging as well as functional and structural MRI; and, second, a longitudinal, neurodevelopmental dataset in children 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. In addition, we have engaged in novel imaging experiments assessing the neural effects of ovarian steroid hormones in women with and without premenstrual dysphoric disorder. Recent progress has focused on dissecting genetic, neurochemical and hormonal contributions to cognitive functions and neural circuits that are implicated in neuropsychiatric illness and also show substantial variation over the lifespan and across individuals even in health. In our adult studies, we and collaborators meta-analyzed results from two recent genome-wide association studies, which identified numerous locations in the genome that have statistically reliable associations to cognitive performance. By implicating important biological pathways for cognition and establishing a basis for quantification of cumulative polygenic cognitive scoring that may further drive discovery in independent cohorts, this work has been an important step for the field. Building on this discovery, we employed several complementary transcriptomic methods to identify genes in these locations that are credibly associated with cognition and further annotate the resulting genes using multiple databases to identify druggable targets. Using a meta-analytic data set (N=373,617), we identified 241 independent cognition-associated locations(29 novel), and 76 genes were identified by two or more methods of gene identification. Several novel pathways were recognized that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing. (Lam et al., 2021). Additionally, we have found that cumulative effects of certain ancient DNA variants that an individual harbors relates to skull shape, brain structure, and functional connectivity in a manner that may have relevance for neuropsychiatric illness (Gregory et al., 2022). In our longitudinal neurodevelopmental neuroimaging and endocrinological studies of children from age eight to 18, much of our focus in the past year has been on data collection. In this project (Cole et al., 2021), our extensive battery of imaging, cognitive, and hormonal measurements allows us to investigate endocrine-driven trajectories of neurobiological development in a comprehensive manner that will permit not only a more integrated view of puberty in the human brain than is currently available, but also will provide an unprecedented opportunity to trace the natural course and endocrinological dependence of key neuroimaging phenotypes established (by us and others) to be perturbed in neuropsychiatric illness. We have recently begun a planned interim analysis of these data to establish the effect sizes and variance for our endocrine and neuroimaging data. Additionally, we are focused on understanding the neurobiological correlates of the onset of adrenarche, an early pubertal event associated with a marked increase in adrenal androgens that may impact brain development. Our study provides a rare and exciting opportunity to capture the onset of this pubertal event and isolate the effects of adrenal hormones from those of other puberty-related hormones typically associated with puberty such as estradiol and testosterone. Additionally, we have developed and provided to the scientific community analytical methods and tools to facilitate sophisticated non-linear mixed-effects modeling approaches to the dataset once complete (Chen et al. 2021). In addition to our work with the pubertal transition dataset, we continue to further our efforts toward understanding hormonal contributions to cognitive operations in adult women. To this end we have completed a series of studies identifying an important neuroanatomical hub for regulating affective state in women with premenstrual dysphoric disorder (PMDD) compared with healthy women. These studies employed a rigorous hormone manipulation protocol involving leuprolide acetate induced ovarian suppression and add-back conditions with estrogen and progesterone separately. This work revealed that in women with PMDD, the subgenual cingulate cortex, an important affective regulatory region that is a treatment target in major depression, showed abnormal reductions in resting regional cerebral blood flow, measured by PET, during both estradiol and progesterone add-back conditions relative to ovarian suppression (Wei et al. 2021). Data such as these may add to a better understanding of complex, hormonally-related changes in brain function in health and disease.