Localized network damage related to white matter hyperintensities is linked to worse outcome after severe stroke

White matter hyperintensities of presumed vascular origin (WMH), a manifestation of cerebral small vessel disease, are associated with various clinical sequelae. In stroke patients, total WMH burden is linked to recurrent cerebrovascular events and worse clinical outcome. As WMH also affect the integrity of structural large-scale brain networks, we hypothesize that the extent of WMH-related network damage carries relevant information to explain outcome variability in addition to global WMH volume. Clinical and structural brain imaging data of 33 severely affected acute stroke patients were analyzed from two independent cohorts. Imaging data were acquired within the first two weeks after stroke. WMH-related localized and global network damage was derived, involving cortical and subcortical brain regions of an extended motor network. Using ordinal logistic regression analyses, network damage was associated with functional outcome, operationalized by the modified Rankin Scale, at follow-up after three to six months. WMH were linked to a significant disconnection of multiple ipsilesional and contralesional cortical and subcortical brain regions. Global as well as localized periventricular WMH-related network damage affecting distinct brain regions of both hemispheres, including the precentral and the inferior frontal gyrus, areas of the dorsolateral prefrontal cortex, the insula, and multiple subcortical nuclei, was independently associated with a worse outcome after adjustment for baseline symptom burden, age, brain infarct volume and total WMH volume. Total and deep WMH-related network disturbances did not show similar associations. This study shows that periventricular WMH-related network damage affecting specific brain regions of the frontal and insular lobe, and subcortical nuclei is linked to functional outcome in acute stroke patients. This supports the evolving concept of structural brain reserve and underscores the potential significance of pre-existing WMH-related network damage as a crucial factor in comprehending outcome variability after severe stroke. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB 936 178316478 projects C1 to C.G., C2 to G.T. and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and the National Science Foundation of China (NSFC) in project Crossmodal Learning, TRR-169/A3 to F.H. and C.G., and the Else Kroener-Fresenius-Stiftung (2016\_A214 to R.S.). R.S. and C.U.C. are supported by an Else Kroener Exzellenzstipendium from the Else Kroener-Fresenius-Stiftung (2020\_EKES.16 to R.S., 2018_EKES.04 to C.U.C.). F.Q. is supported by the Gemeinnuetzige Hertie-Stiftung (Hertie Network of Excellence in Clinical Neuroscience). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The original studies were conducted in line with the ethical declaration of Helsinki and were granted permission by the local ethics committee of the Chamber of Physicians Hamburg. All participants or their legal guardian provided informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available by the authors upon reasonable request.