Neuroanatomical Basis of Coma in Acute Ischemic Stroke

Zhang, Z.; White, M.; Kim, J. A.; Torres-Lopez, V. M.; Khalaf, A.; Jin, D.; Boes, A. D.; Edlow, B. L.; English, S. W.; Fischer, D.; Geerling, J.; Halablab, S. M.; Lansberg, M. G.; McCullough-Hicks, M.; Meschia, J. F.; Michel, P. L.; Palazzo, P.; Reasoner, B. D.; Regenhardt, R. W.; Young, M. J.; Tran, A. T.; Payabvash, S.; Sheth, K. N.; Blumenfeld, H. J.

doi:10.1101/2025.08.15.670576

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bioRxiv · 10.1101/2025.08.15.670576

Neuroanatomical Basis of Coma in Acute Ischemic Stroke

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Abstract

BackgroundAcute ischemic stroke (AIS) can lead to profound disturbances in consciousness, including coma, which is associated with poor prognosis and increased mortality. Clarifying the lesion patterns that precipitate loss of consciousness can refine pathophysiological models and guide prognosis. ObjectivesIn this study, we aim to identify the brain regions most commonly affected in comatose AIS and determine whether specific combinations of lesions are necessary and sufficient to produce coma. MethodsWe retrospectively analyzed 476 AIS patients (52 comatose) using diffusion-weighted imaging. Infarcts were automatically segmented, manually verified, and normalized to MNI space. Support vector regression lesion-symptom mapping (SVR-LSM) quantified voxel-wise associations with coma, controlling for lesion volume. To assess the necessity and sufficiency of lesion combinations, we employed permutation-based nested logistic regression models comparing all subsets of four anatomical predictors: brainstem, thalamus, cerebellum, and the rest of brain lesions. ResultsSVR-LSM revealed that coma was strongly associated with lesions involving the brainstem, thalamus, and cerebellum, whereas non-comatose patients exhibited predominantly cortical infarcts. Nested model comparisons showed that concurrent lesions to both the brainstem and thalamus were necessary and sufficient for coma. Additional involvement of the cerebellum or cerebral cortex did not improve predictive performance. ConclusionsComa after AIS results from a dual-node subcortical lesion pattern involving both the brainstem and thalamus. Cerebellar and cortical lesions, even when extensive, did not induce coma in the absence of the dual-brainstem and thalamic lesions. These observations emphasize the predominant role of lesion location over lesion volume in the pathogenesis of coma. They also support mechanistic models that position the brainstem and thalamic hubs as central to the neural circuitry underlying arousal. Furthermore, these findings delineate a specific anatomical substrate that may serve as a strategic target for circuit-based neuroprotective and neuromodulatory therapies.

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Zhang, Z., White, M., Kim, J. A., Torres-Lopez, V. M., Khalaf, A., Jin, D., Boes, A. D., Edlow, B. L., English, S. W., Fischer, D., Geerling, J., Halablab, S. M., Lansberg, M. G., McCullough-Hicks, M., Meschia, J. F., Michel, P. L., Palazzo, P., Reasoner, B. D., Regenhardt, R. W., Young, M. J., Tran, A. T., Payabvash, S., Sheth, K. N., Blumenfeld, H. J.. 2025-08-18. Neuroanatomical Basis of Coma in Acute Ischemic Stroke. https://doi.org/10.1101/2025.08.15.670576

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