Section on Developmental Neurogenomics

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

This work is conducted under protocol 89-M-0006 (NCT00001246) and falls into two broad research themes: Theme 1: Studies of behavior and brain organization in typically-developing groups Work in this theme uses large-scale neuroimaging studies in health to advance our basic understanding of human brain organization, and guide the selection and application of imaging phenotypes for disease studies. We have so far emphasized structural magnetic resonance imaging (sMRI) because it offers intermediate in vivo phenotypes that can be reliably measured at scale, and are highly heritable, developmentally dynamic, sensitive to disease states, and amenable to translational study in mice. During the last year, our published work within this theme has fallen into two areas. First, we were a contributing group to a landmark paper (Bethlehem, Seidlitz, White et al, Nature, 2022) providing brain growth charts for the human lifespan. Normative and clinical brain scans from our group were part of this large dataset of 120,000 scans upon which these growth charts were generated. Our being part of this project sets the stage for ongoing studies providing a new benchmark for estimation of altered brain growth trajectories in patients (e.g., Alexander-Bloch et al., JAMA Psych, 2022). The second area of our research in normative brain organization in the last year as been part of an ongoing collaboration on spatial coupling between different properties of the human brain. For example, we have contributed to papers on development of statistical tests for spatial coupling between different features of the brain (Weinstein et al, Human Brain Mapping, 2021; Hu et al, Human Brain Mapping, 2022) and developmental coupling between cerebral blood flow and resting state fMRI fluctuations (Baller et al, Cell Reports, 2022). Alongside these two areas of published collaborative research, our group has also been investing in large-scale independent studies on the spatial patterning of cortical gene expression in health, and sex differences in cortical gene expression at bulk and single cell levels of analyses. These studies are current either under review, or in preparation. Theme 2: Deep phenotypic studies of participants with sex chromosome aneuploidy syndromes (SCAs) Work in this theme seeks to understand brain and behavioral changes in individuals with genetically defined neurodevelopmental disorders focusing on sex chromosome aneuploidy syndromes (SCAs) in particular. Collectively, these studies are designed to expand on past work in SCA by gathering more comprehensive measures of brain structure and function, as well as providing more fine-grained information regarding the cognitive and behavioral variations that can be seen in SCA. These data will ultimately help to better define the developmental risks and resiliencies associated with X- and Y-chromosome dosage variation in humans, and identify neurobiological systems that might underpin these associations. We hope these insights will (i) improve accurate public and professional awareness of SCAs, (ii) help clinicians provide more targeted assessment and counseling to patients and families with SCA, and (iii) begin to identify biological markers with the potential to ultimately improve assessment, prediction and treatment of neurodevelopmental issues in SCA. More broadly, this work in the specific case of SCA will shed light on (i) the principles that organize genetic influences on brain and behavior in the context of neuropsychiatric impairment, and (ii) genetic contributions to sex-differences in the brain, which are relevant for understanding the well-documented male-bias in risk for neurodevelopmental disorders more generally. During the last year, we have published work in three main areas. First, we have published a major review on convergences and divergences in the outcomes of gene dosage disorders (GDDs) in humans (Raznahan et al, JAMA Psychiatry, 2022). Gene dosage disorders - including aneuploidies like SCA and smaller genomic copy number variations (CNVs) are a major class of risk for psychiatric illness and our review surveys evidence for overlaps and difference between outcomes for distinct GDDs. This issue has importance for biological and clinical aspects of psychiatry. We also consider methodological and neurobiological factors that might shape observed convergences and divergences between different GDDs, before providing a roadmap for future research. Second, in addition to this review, our Section has published a series of data papers which directly compare psychiatric profiles between different GDDs (Lee et al, Trans Psych, 2022: Rau et al, JNDD, 2022), as well as collaborative with colleagues in Denmark to compare GDD outcomes using population-level data that are protected from ascertainment biases (Calle Snchez et al, JAMA Psychiatry, 2022). Third, we have continued our comparison of GDDs at biological levels, including for example analysis of SCA effects on regional white matter volume (Warling et al, Cerebral Cortex, 2021).