Resting-State fMRI and Post-Ischemic Stroke Functional Recovery: Unraveling Causality and Predicting Therapeutic Targets

Research on functional recovery after ischemic stroke has primarily focused on non-invasive brain stimulation and motor rehabilitation therapies, while direct pharmacological interventions are relatively underexplored. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationship between 191 resting-state functional magnetic resonance imaging (rs-fMRI) features and post-ischemic stroke functional recovery (PISFR). Significant rs-fMRI phenotypes were identified, and Mendelian randomization was employed to determine their associated proteins. Bidirectional Mendelian randomization identified four rs-fMRI phenotypes potentially associated with functional recovery after ischemic stroke. Subsequent MR analysis, using pheno12 as the outcome and plasma protein as the exposure, highlighted Fas-Associated protein with Death Domain (FADD) as a significant protein. Further exploration within the protein-protein interaction (PPI) network identified FADD, Cysteinyl Aspartate Specific Proteinase 8 (CASP8), and Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) as potential drug targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these proteins are involved in the extrinsic apoptotic pathway, providing new insights for pharmacological strategies in post-ischemic stroke recovery. This study offers genetic evidence linking rs-fMRI to functional recovery post-ischemic stroke and identifies potential drug targets that may facilitate therapeutic interventions to enhance recovery after ischemic stroke.