Background: Predicting development of cerebral palsy following neonatal stroke remains challenging. This study aimed to identify novel acute brain functional connectome-based correlates of cerebral palsy following neonatal stroke. Methods: Stroke lesions were segmented from routine clinical diffusion images of a cohort of term-born neonates with symptomatic arterial ischemic stroke, recruited to Swiss and Australian pediatric stroke registries. Lesions, and 3T resting state functional MRIs of term-born newborns from the developing Human Connectome Project, were co-registered to a template. A neonatal stroke functional connectome was created by computing voxel-wise correlations between lesions and gray matter regions. Linear regressions compared functional connections to lesions between participants who did and did not develop cerebral palsy. Results: Eighty-five newborns with stroke were included (64% male; median age at MRI of 4 days), of which 33% developed cerebral palsy at a median age of 2.1 years. Multiple gray matter regions were more highly functionally correlated to lesions in participants who developed cerebral palsy (1721 voxels; t: 5.4-7.4; all p<0.05, family-wise error rate corrected). These regions included the basal ganglia, thalamus, cerebellum, frontal regions (inferior and orbital frontal and superior frontal), temporal regions (pole, superior, and mesial temporal including hippocampus and amygdala) and the insula. Conclusions: This study identified functional networks related to the development of cerebral palsy following neonatal stroke. Building on prior individual lesion-based studies, this work suggests that development of cerebral palsy after neonatal stroke is related to disruptions of broader functional networks involving motor and extramotor regions, as opposed to only lesions in motor regions.

The authors have declared no competing interest.

Grant funding was received from the Cerebral Palsy Alliance, Australia (Grant reference PG10117) and the Australian National Health and Medical Research Council (NHMRC; Ideas Grant ID 2020902). Some data in this study were provided by the developing Human Connectome Project, KCL-Imperial-Oxford Consortium funded by the European Research Council under the European Union Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement no. [319456]. CEK received support from the Monash Early Career Postdoctoral Fellowship. JS received support from the MCRI Early Career Research Fellowship. JYMY acknowledges positional funding support from the Royal Children?s Hospital Foundation (RCHF 2022-1402). This research was supported by The Royal Children?s Hospital Foundation, Murdoch Children?s Research Institute, The University of Melbourne, Department of Paediatrics, and the Victorian Government?s Operational Infrastructure Support Program. The funding support had no role in the study design; in the collection, analysis and interpretation of data; in the writing and in the decision to submit this article for publication.

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 Royal Children's Hospital Melbourne Human Research Ethics Committee (HREC 37115). The Swiss Neuropediatric Stroke Registry was approved by the local ethics committee in Bern. The developing Human Connectome Project study was approved by the UK Health Research Authority (14/LO/1169).

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.

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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).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data for the developing Human Connectome Project are available on the NIMH Data Archive. Instructions on how to access these data are available here: https://biomedia.github.io/dHCP-release-notes/. Anonymized data for the newborn stroke cohorts can be shared upon appropriate request, subject to ethical approval and adequate data sharing agreements.