Brain charts of sex as a biological variable for precision structural neuroimaging of the psychosis spectrum

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY Many neuropsychiatric disorders, including psychosis spectrum conditions, display consistent sex-biases in their clinical presentation and illness course. Yet whether sex and the related process of puberty influence neurodevelopment—and thus potentially risk or resilience to the disease-processes associated with psychosis— remains hotly debated. Much of this ambiguity can be attributed to pervasive methodological limitations, such as small sample sizes and inflexible statistical approaches, that have led to heterogeneous results. This proposal aims to overcome these limitations by deriving normative growth models from a massive, global dataset of structural MRIs (n>120k MRIs, 0-100 years), testing the overarching hypothesis that sex, puberty, and age have interactive effects on neuroanatomy that together are critical for identifying structural phenotypes of psychosis spectrum symptoms and diagnoses. This approach extends recent “brain charts” literature in several key ways. Aim 1 will (1) use brain charts to quantify how sex-differences in neuroanatomy vary across the lifespan, then apply these normative models to (2) benchmark sensitive biomarkers of schizophrenia-spectrum disorders and (3) explore how these disease effects differ in males and females. Aim 2 will (1) derive neurodevelopmental growth charts (n>15k MRIs, 5-25 years) that deliniate puberty’s relationship with brain structure development and (2) assess how these pubertal effects align with local transcription of sex-hormone receptor genes. Finally, these puberty-informed brain charts will be used to (3) uncover whether individuals’ deviations from normative brain development are associated with psychosis spectrum symptoms. The results of this proposal will significantly advance the NIH’s objective to understand sex as a biological variable in the context of brain morphology, identify sensitive structural biomarkers of psychosis spectrum pathology in females and males, and provide a resource for future studies to contextualize brain structure across the lifespan. The proposal will also enable the applicant to complete rigorous training in statistical neuroimaging techniques and applications; the neuroscience of biological sex; psychosis spectrum neurobiology; and scientific communication and leadership. This research and training will be supported by a team of expert mentors comprised of Dr. Aaron Alexander- Bloch, Dr. Russell T. Shinohara, Dr. Raquel Gur, and Dr. Armin Raznahan, with additional support from contributor Dr. Benjamin Risk. The world-class informatics resources, didactic trainings, and intellectual environment provided by the University of Pennsylvania and the Children’s Hospital of Philadelphia will further ensure the feasibility of the proposed research and prepare the applicant for a career as an independent academic researcher.