BACKGROUND: Perivascular Spaces (PVS) are a marker of cerebral small vessel disease (CSVD) that are visible on brain imaging. Larger PVS has been associated with poor quality of life and cognitive impairment post-stroke. However, the association between PVS and post-stroke sensorimotor outcomes has not been investigated. METHODS: 602 individuals with a history of stroke across 24 research cohorts from the ENIGMA Stroke Recovery Working Group were included. PVS volume fractions were obtained using a validated, automated segmentation pipeline from the basal ganglia (BG) and white matter centrum semiovale (CSO), separately. Robust mixed effects regressions were used to a) examine the cross-sectional association between PVS volume fraction and post-stroke sensorimotor outcomes and b) to examine whether PVS volume fraction was associated with other measures of CSVD and overall brain health (e.g., white matter hyperintensities [WMHs], brain age [measured by predicted age difference, brain-PAD]). RESULTS: Larger PVS volume fraction in the CSO, but not BG, was associated with worse post-stroke sensorimotor outcomes (b = -0.06, p = 0.047). Higher burden of deep WMH (b = 0.25, p <0.001), periventricular WMH (b = 0.16, p <0.001) and higher brain-PAD (b = 0.09, p <0.001) were associated with larger PVS volume fraction in the CSO. CONCLUSIONS: Our data show that PVS volume fraction in the CSO is cross-sectionally associated with sensorimotor outcomes after stroke, above and beyond standard lesion metrics. PVS may provide insight into how the overall vascular health of the brain impacts inter-individual differences in post-stroke sensorimotor outcomes.

1.Jeiran Choupan has a published patent for the PVS segmentation method used in this work. 2.Adriana B. Conforto reports one consultancy for Boehringer-Ingelheim. 3.Steven C. Cramer reports being or having been a consultant at Constant Therapeutics, BrainQ, Myomo, MicroTransponder, Panaxium, Beren Therapeutics, Medtronic, NeuroTrauma Sciences, BlueRock Therapeutics, Simcere, and TRCare. 4.Brenton Hordacre holds a paid consultancy role for Recovery VR and has a clinical partnership with Fourier Intelligence. 5.Carolee J. Winstein reports being a consultant for Microtransponder, and MedRhythms; a member of the data safety and monitoring board for Enspire DBS Therapy; and receives publishing royalties for Stroke Recovery and Rehabilitation, 2nd Edition, published in 2015, Demos Medical Publishers; Motor Control and Learning, 6th Edition, published in 2019, Human Kinetics, Inc. 6.George F. Wittenberg reports scientific Advisory Boards: (1) Myomo, Inc. (2) Neuro-Innovators, LLC. 7.Lars T. Westlye reports being a shareholder of Baba. Vision. 8.Sook-Lei Liew reports being a consultant for Synchron and co-owner of Ardist Inc.

This study was funded by the National Institutes of Health, USA [R01NS115845,P2CHD086844, U24NS107234, R01NS090677, R21HD067906-01A1, NIH R01 NS076348, NIH UH3-NS121565, NIH U01 NS120910, R01NS115845, U01 NS086872, R01 HD062744, HD095457, P20 GM109040, R01AG059874, R01MH117601, R01NS090677, R01MH131806, R01MH129742, NIH/NICHD HD065438]; Canadian Institutes of Health Research, Canada [PTJ-148535, MOP- 130269, MOP-106651]; Michael Smith Foundation for Health Research, Canada; Centre for Progress in Stroke Recovery, Canada; California Rehabilitation Institute, USA [20214600]; Lone Star Stroke Clinical Trial Network supported by the Texas Legislature, USA; Italiana Ministry of Health, Italy; European Research Council, [ERC NGBMI, 759370, ERC StG Grant No. 802998]; Federal Ministry of Research and Education [BMBF SSMART, 01DR21025A]; Deutsche Forschungsgemeinschaft, Germany [DFG SO932/7-1]; and the Department of Veterans Affairs, USA [1IK6RX003075, 1I01RX001935, 36C24E21P0147].

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Ethical approvals for the data used in this study were collected in accordance with the Declaration of Helsinki and in compliance with the local ethics boards at each institute. Written informed consent was obtained from all study participants.

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The primary and corresponding authors of this study had full access to the data and take responsibility for data integrity and analyses. Publicly sharing the full data is limited by data sharing restrictions imposed by some of the (i) ethical review boards of the participating research cohorts, and consent documents; (ii) national and trans-national data sharing laws; and (iii) institutional processes, which may require a signed data transfer agreement for limited and predefined data use. However, similar to other ENIGMA working groups, we support data sharing among members of the ENIGMA Stroke Recovery Working Group3 who submit an analysis plan for a secondary project for group review. Following approval of the analysis plan, access to the relevant data will be provided, contingent on data availability, local PI approval and compliance with all supervising regulatory boards.