Severe asymptomatic carotid stenosis is associated with robust reductions in homotopic functional connectivity

•SACS is associated with robust homotopic FC reductions in the Perisylvian fissure;•These involved regions are characteristically considered to be at the lower end of the functional hierarchy;•The significantly reduced homotopic FC can be partially explained by white matter hyperintensity size;•Decreased homotopic FC is most closely associated with delayed memory recall, sensorimotor processing, and other simple cognitive functions;•Homotopy FC analysis may be a clinically useful assessment of functional reserve in brain stenosis patients. Severe (>70% narrowing) asymptomatic carotid stenosis (SACS) is associated with cognitive impairment and future strokes, and connectivity basis for the remote brain consequences is poorly understood. Here we explored homotopic connectivity and parenchymal lesions measured by multimodal magnetic resonance imaging (MRI) parameters in patients with SACS. Twenty-four patients with SACS (19 males/5 females; 64.25 ± 7.18 years), 24 comorbidities-matched controls (19 males/5 females; 67.16 ± 6.10 years), and an independent sample of elderly healthy controls (39 females/45 males; 57.92 ± 4.94 years) were included. Homotopic functional connectivity (FC) of resting-state functional MRI and structural connectivity (SC) of deterministic tractography were assessed. Arterial spin labeling based cerebral perfusion, susceptibility weighted imaging based microhemorrhagic lesions, and T2-weighted white matter hyperintensities were also quantified. Significant and robust homotopic reductions (validated by the independent dataset and support vector machine-based machine learning) were identified in the Perisylvian fissure in patients with SACS (false discovery rate corrected, voxel p