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Sebastian Volkmer1,2,3, Stefan Fritze1,3, Dilsa Akkoc Altinok1,3

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Resting-state functional connectivity (rs-FC) brain-age models reveal elevated brain age in schizophrenia spectrum disorders (SSD). Within SSD, a younger functional brain age correlates with worse outcomes, suggesting developmental heterogeneity.

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Area of Science:

  • Neuroscience
  • Psychiatry
  • Brain Imaging

Background:

  • Brain-age models predict chronological age using neuroimaging, with the brain-age gap (BAG) quantifying deviations.
  • Structural brain-age acceleration is known in schizophrenia spectrum disorders (SSD), but the role of functional connectivity (FC) is unclear.

Purpose of the Study:

  • To investigate the utility of resting-state functional connectivity (rs-FC)-based brain-age models in SSD.
  • To determine if rs-FC brain age reflects clinical characteristics and illness progression in SSD.

Main Methods:

  • Trained rs-FC brain-age models on healthy control data (N≈2,200).
  • Evaluated models in four independent SSD case-control cohorts.
  • Assessed associations between rs-FC brain-age gap (BAG) and clinical variables (cognition, illness duration, neurological soft signs [NSS]) and changes over time.

Main Results:

  • SSD exhibited a higher FC-based BAG than controls, indicating modest group-level functional brain-age elevation.
  • Within SSD, a more negative (delayed maturation) BAG correlated with poorer cognition, longer illness duration, and higher NSS.
  • Increases in BAG over 12-24 weeks were linked to improvements in NSS motor coordination and hard signs.

Conclusions:

  • rs-FC brain age captures a subtle case-control difference and a clinically meaningful dimension within SSD.
  • FC-based BAG may reflect heterogeneity in neurodevelopment and network reorganization in SSD.
  • Younger functional brain age in SSD may indicate greater neurodevelopmental burden and network disruption.