# Using person-specific networks to uncover sex differences in vulnerability to internalizing disorders

> **NIH NIH DP5** · UNIVERSITY OF PENNSYLVANIA · 2024 · $406,250

## Abstract

PROJECT SUMMARY/ ABSTRACT
 Internalizing disorders such as major depressive disorder and generalized anxiety disorder show marked
sex differences in prevalence, presentation, and trajectory. For example, depression and anxiety disorders are
more prevalent in females than males. The neural mechanisms underlying such sex differences, however, are
not well understood. Previous studies have suggested sex differences in internalizing symptoms may be due to
abnormalities of the default mode network (DMN), a functional network that is critical for internally-directed
cognition and emotional processes. The vast majority of studies on functional networks use methods that assume
that the DMN is in the same anatomic location in every individual. However, evidence from multiple independent
groups has recently shown that there is significant inter-individual variation in the spatial distribution of functional
networks on the anatomic cortex and that person-specific networks predict aspects of cognition and
psychopathology. We recently provided the first evidence of sex differences in such personalized functional
networks and showed that sex differences in personalized networks are greatest in the DMN. Preliminary data
demonstrate that DMN representation — a measure of normalized surface area — is greater in females.
However, it is unknown if sex differences in personalized DMNs 1) evolve during development or 2) underly sex
differences in internalizing symptoms.
 The over-arching hypothesis of this proposal is that DMN representation is greater in females, which
confers a vulnerability to internalizing symptoms. Given that these symptoms typically emerge during childhood
and adolescence, this hypothesis will be evaluated using three large developmental data resources: the Healthy
Brain Network (HBN; n=5,000), the Human Connectome Project: Development (HCP-D; n=1,300), and the
Adolescent Brain and Cognitive Development Study (ABCD, n=11,572). Aim 1 will characterize developmental
sex differences in the spatial distribution of personalized functional networks, while Aim 2 will delineate how
personalized networks relates to sex differences in internalizing symptoms. Finally, Aim 3 will use baseline
variation in personalized functional networks to predict the longitudinal course of internalizing psychopathology.
 This innovative research project will establish that sex differences in personalized functional networks
underly sex differences in internalizing psychopathology. Results will help inform targeted early interventions
and trials of personalized neuromodulatory therapies. Successful completion of the proposed aims as an
independent investigator will accelerate the candidate’s ability to exert a sustained impact on the field and
advance our understanding of the contribution of sex as a biological variable to the development of internalizing
psychopathology.

## Key facts

- **NIH application ID:** 10933436
- **Project number:** 5DP5OD036142-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sheila Shanmugan
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,250
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933436

## Citation

> US National Institutes of Health, RePORTER application 10933436, Using person-specific networks to uncover sex differences in vulnerability to internalizing disorders (5DP5OD036142-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10933436. Licensed CC0.

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