Beyond posterior putamen lesions in post-stroke spasticity: widespread structural and functional breakdown across brain networks

Background Post-stroke spasticity (PSS) is a common and disabling motor complication whose neuroanatomical underpinnings remain incompletely understood. Beyond focal lesion localization, PSS likely arises from large-scale network disruptions involving both cortical and subcortical systems. Here, we combined functional and structural lesion network mapping (LNM) to identify the brain networks and white-matter tracts whose dysconnection best explains the presence and severity of PSS.

We analyzed 281 patients with hemorrhagic stroke, including 88 with PSS and 193 without PSS (NPSS). After matching for age, sex, and lesion size (N=81 PSS; N=60 NPSS), we computed functional LNM using normative connectomes from 1000 healthy participants of the Human Connectome Project and structural LNM using the HCP1065 tractography template. Group-level voxel-wise and tract-wise analyses identified regions and tracts with significant dysconnectivity differences. Finally, a ridge regression model with leave-one-out cross-validation assessed the relationship between dysconnectivity (both functional and structural) and spasticity severity, quantified by the Modified Ashworth Scale (MAS).

Lesion-symptom mapping revealed that PSS was primarily associated with lesions in the posterior putamen. Structural LNM showed significantly higher tract dysconnectivity in PSS, particularly within the corticospinal, corticopontine, corticobulbar, corticostriatal, medial lemniscus, and superior thalamic radiation pathways (all pNPSS) and a Negative Dysconnected Network (PSS<NPSS). Despite these bidirectional effects, overall dysconnection was consistently higher in the PSS group. The most affected networks included the cerebellum, sensorimotor, auditory, dorsal attention, default mode, and medial visual resting-state networks. Ridge regression analysis confirmed a strong association between MAS scores and the degree of dysconnectivity across these networks (R²=0.70).

Post-stroke spasticity is not the result of damage to a single locus but rather reflects the dysconnection of a distributed structural and functional network encompassing, not only motor, but also attentional and high order cognitive networks. These findings provide a network-based framework for understanding spasticity and support the use of lesion network mapping to predict and potentially guide targeted neuromodulation in stroke rehabilitation. Competing Interest Statement The authors have declared no competing interest. Funding Statement JMC acknowledges financial support from the Spanish Ministry of Health (PI22/01118) and Basque Ministry of Health (2023111002 & 2022111031). JMC and AE are both funded by the Spanish Ministry of Science (grant PID2023-148012OB-I00). ID was supported by the Spanish Ministry of Science with the grant PID2023-150633OA-I00. AE and ID are both funded by the Spanish Ministry of Science and Innovation grants RYC2021-032390-I and RYC2022-035429-I, respectively. JMC, AE, and ID are funded by Ikerbasque: The Basque Foundation for Science. MMF acknowledges financial support from Carlos III Institute of Health (grant RICORS-Ictus RD24/0009/0004). 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: This study was approved by the Clinical Research Ethics Committee of Cruces University Hospital (code E19/52, PI: Jesus M Cortes). 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 Availability All data is available upon reasonable request.