ABSTRACT
An unmet need for psychiatric neuroimaging is a standard developmental frame of reference to benchmark
studies of neurodevelopmental conditions such as schizophrenia the psychosis spectrum (PS). Using a
modelling approach that has proven successful for non-imaging growth charts in clinical pediatrics, and in our
preliminary work that was focused on a limited set of global brain MRI features, we propose to leverage data
from our multi-site Brain Chart Consortium to produce computational charts of brain maturation for a far richer
set of brain morphological features across anatomical scales. Our Consortium aims to be the largest and most
inclusive possible, with preliminary data covering the entire lifespan, over 130,000 MRI scans, over 100,000
individuals and over 300 MR scanners. Using advanced, fully-reproducible pipelines for quality control, image
processing and harmonization, multi-scale brain charts will define normative trends and milestones of growth
which can be used to benchmark a new individual brain scan, or group of scans, while controlling for study-
specific technical confounds. We will create and maintain an open resource to disseminate these charts for use
by other researchers. We will use brain charts to identify clusters of developmental imaging phenotypes – brain
profiles benchmarked by growth chart norms – with similarly-shaped maturational trajectories. Longitudinal
analysis of twin datasets will specifically delineate heritable brain profiles, which we hypothesize will show
genotype-by-age effects organized along the sensory-to-association (SA) axis of cortical maturation, in
developmental epochs where risk for PS is hypothesized to emerge (Aim 1). We will perform genome- and
transcriptome-wide association studies to identify brain profiles that are influenced by functionally active
genetic variants associated with risk for PS (Aim 2). We will perform brain profile subtyping of individuals with
PS diagnoses in our Consortium case-control studies (over 2000 MRIs), to characterize a PS subtype where
deviations are most prominent along the SA axis in association cortices that undergo prolonged maturation
through adolescence. Any individual’s chart-benchmarked brain profile, in a new study, can thus be
characterized with a loading score that quantifies similarity to this PS subtype, and we will evaluate the
association of the PS subtype loading score with the evolution of PS symptoms across multiple longitudinal
follow-up studies of PS conducted at the University of Pennsylvania (over 2200 longitudinal MRIs, 800
participants, 450 with PS, age 8-35) that will be pooled and harmonized for this proposal (Aim 3). This
proposal’s overarching goal is to create a practically useful brain chart resource and to demonstrate its
transformative potential for studies of brain development in PS. This work capitalizes on the PI and assembled
team’s expertise in psychiatric and developmental brain imaging, imaging-genetics and neuroinformatics.
Cumulatively, the proposed research will provide a substantial advance in our understanding of typical brain
development and altered neurodevelopment in PS.