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Reproducible Sex Differences in Personalized Functional Network Topography in Youth.

Arielle S Keller1,2, Kevin Y Sun3,4,5, Ashley Francisco3,5

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Sex differences in brain network organization emerge during adolescence, impacting mental health. These patterns are linked to X-linked gene expression, potentially explaining female vulnerability to psychiatric disorders.

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Area of Science:

  • Neuroscience
  • Developmental Psychology
  • Genetics

Background:

  • Understanding sex-specific brain development is crucial for addressing psychiatric disorders affecting females.
  • Individual differences in functional brain network organization vary by sex and are linked to psychopathology.

Purpose of the Study:

  • To investigate the impact of sex on the spatial organization of personalized functional brain networks in adolescents.
  • To identify brain networks exhibiting significant sex-based topographical differences.

Main Methods:

  • Utilized non-negative matrix factorization to create person-specific functional brain network atlases from a large adolescent cohort (n=6437).
  • Employed generalized additive models to analyze sex-based associations with network topography and support vector machines for sex classification.
  • Correlated sex differences in network topography with gene expression data from the Allen Human Brain Atlas.

Main Results:

  • Significant sex differences in personalized functional network (PFN) topography were observed, particularly in association networks (fronto-parietal, ventral attention, default mode).
  • Machine learning models accurately classified participant sex based on PFN topography.
  • Brain regions with pronounced sex differences in PFN topography showed enrichment for X-linked genes and genes expressed in astrocytes and excitatory neurons.

Conclusions:

  • Sex differences in PFN topography are robust, reproducible, and associated with X-linked gene expression patterns.
  • These findings suggest a neurobiological basis for the increased risk of depression and anxiety in females during adolescence.
  • The study highlights the importance of considering sex as a biological variable in brain development and mental health research.