Post-Stroke Depression Is Associated With Shared Neurodevelopmental Risk and Circuit Disruption

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Post-stroke depression (PSD) impacts ~30% of stroke survivors, worsening outcomes.
• The biological underpinnings of PSD remain largely unknown.

Purpose of the Study:

• To investigate the genetic and neurobiological basis of post-stroke depression.
• To identify shared genetic factors and brain circuit alterations in PSD.

Main Methods:

• Integrated cross-disorder genomics, spatial transcriptomics, and causal neuroimaging.
• Analyzed genetic overlap using MiXeR and condFDR.
• Mapped shared risk variants onto the embryonic mouse brain using gsMap.
• Utilized resting-state fMRI, ICA, FNC, and spDCM to assess brain circuit function.

Main Results:

• Found significant polygenic overlap between stroke and depression.
• Identified five pleiotropic loci linked to neuroinflammation and cardio-cerebral signaling.
• Discovered shared genetic risk enrichment in developing cortical regions.
• Observed default mode network (DMN)-sensorimotor network (SMN) decoupling and altered auditory network (AN) connectivity in PSD patients.
• Effective connectivity from AN to DMN correlated with depressive severity.

Conclusions:

• PSD exhibits a unified pathophysiology combining developmental genetic vulnerability and acquired circuit decompensation.
• HDAC9/PITX2 pathways and AN-DMN circuitry represent potential therapeutic targets for PSD.
• Findings support biomarker development and circuit-informed interventions for PSD.