Genetic evidence for causal relationships between brain functional networks and domain-specific recovery after...

Intrinsic brain networks are crucial for post-stroke recovery, but the causal relationships between specific networks and domain-specific recovery outcomes, as well as the role of lipid metabolism, remain unclear. This study leveraged Mendelian randomization (MR) to evaluate 191 resting-state functional magnetic resonance imaging (rs-fMRI) BOLD-derived phenotypes in relation to post-stroke recovery after nondisabling ischemic stroke. Genetic instruments for rs-fMRI phenotypes were derived from a UK Biobank genome-wide association study (n = 34,691). Outcomes included motor, cognitive, and global recovery after nondisabling ischemic stroke, assessed using longitudinal National Institutes of Health Stroke Scale subscales over 2 years (n = 1,270). Primary analyses used the multiplicative random-effects inverse-variance weighted method. A two-step MR analysis investigated whether brain networks mediate the effects of lipids on post-stroke outcomes. Higher BOLD-derived functional connectivity within the triple network (default mode network, central executive network, and salience network) was associated with better motor and cognitive outcomes. Higher genetically predicted orbitofrontal node amplitude in the limbic network correlated with better motor recovery, while stronger parieto-frontal connectivity was associated with cognitive recovery. Genetically proxied higher low-density lipoprotein cholesterol (LDL-C) was associated with poorer cognitive recovery, with evidence suggesting partial mediation through differences in BOLD-derived triple-network connectivity. This MR study supports a potential causal role of BOLD-derived functional network phenotypes, particularly the triple network, in motor and cognitive recovery, and further suggests that differences in triple-network connectivity act as a partial mediator linking elevated LDL-C liability to impaired cognitive recovery. These findings provide hypothesis-generating evidence for future mechanistic studies and for exploring whether specific brain network-targeted interventions could have a role in stroke recovery.