Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
Canadian Partnership for Stroke Recovery, Ottawa, Ontario, Canada, K1G 5Z3.
J Neurosci. 2020 Jul 29;40(31):6082-6097. doi: 10.1523/JNEUROSCI.0057-20.2020. Epub 2020 Jun 30.
Lesion size and location affect the magnitude of impairment and recovery following stroke, but the precise relationship between these variables and functional outcome is unknown. Herein, we systematically varied the size of strokes in motor cortex and surrounding regions to assess effects on impairment and recovery of function. Female Sprague Dawley rats ( = 64) were evaluated for skilled reaching, spontaneous limb use, and limb placement over a 7 week period after stroke. Exploration and reaching were also tested in a free ranging, more naturalistic, environment. MRI voxel-based analysis of injury volume and its likelihood of including the caudal forelimb area (CFA), rostral forelimb area (RFA), hindlimb (HL) cortex (based on intracranial microstimulation), or their bordering regions were related to both impairment and recovery. Severity of impairment on each task was best predicted by injury in unique regions: impaired reaching, by damage in voxels encompassing CFA/RFA; hindlimb placement, by damage in HL; and spontaneous forelimb use, by damage in CFA. An entirely different set of voxels predicted recovery of function: damage lateral to RFA reduced recovery of reaching, damage medial to HL reduced recovery of hindlimb placing, and damage lateral to CFA reduced recovery of spontaneous limb use. Precise lesion location is an important, but heretofore relatively neglected, prognostic factor in both preclinical and clinical stroke studies, especially those using region-specific therapies, such as transcranial magnetic stimulation. By estimating lesion location relative to cortical motor representations, we established the relationship between individualized lesion location, and functional impairment and recovery in reaching/grasping, spontaneous limb use, and hindlimb placement during walking. We confirmed that stroke results in impairments to specific motor domains linked to the damaged cortical subregion and that damage encroaching on adjacent regions reduces the ability to recover from initial lesion-induced impairments. Each motor domain encompasses unique brain regions that are most associated with recovery and likely represent targets where beneficial reorganization is taking place. Future clinical trials should use individualized therapies (e.g., transcranial magnetic stimulation, intracerebral stem/progenitor cells) that consider precise lesion location and the specific functional impairments of each subject since these variables can markedly affect therapeutic efficacy.
病灶大小和位置影响中风后的损伤程度和恢复，但这些变量与功能结果的确切关系尚不清楚。在此，我们系统性地改变运动皮层及其周围区域的病灶大小，以评估其对功能损伤和恢复的影响。雌性 Sprague Dawley 大鼠（=64 只）在中风后 7 周内进行了熟练抓握、自发肢体使用和肢体放置评估。还在更自然的自由活动环境中测试了探索和抓握。基于损伤体积及其包含尾侧前肢区（CFA）、前肢区（RFA）、后肢（HL）皮层的可能性的 MRI 体素分析（基于颅内微刺激），与损伤和恢复均相关。每项任务损伤的严重程度均由其特定区域的损伤最佳预测：损伤包括 CFA/RFA 的体素会导致抓握受损；损伤 HL 会导致后肢放置受损；损伤 CFA 会导致自发前肢使用受损。而功能恢复则由完全不同的体素预测：RFA 外侧的损伤会减少抓握的恢复；HL 内侧的损伤会减少后肢放置的恢复；CFA 外侧的损伤会减少自发肢体使用的恢复。病灶位置的精确性是临床前和临床中风研究中，特别是在使用特定区域治疗（如经颅磁刺激）的研究中，一个重要但迄今相对被忽视的预后因素。通过估计相对于皮质运动代表的病灶位置，我们确定了个体化病灶位置与抓握/抓握、自发肢体使用和后肢行走时放置之间的功能损伤和恢复的关系。我们证实，中风会导致与受损皮质亚区相关的特定运动域受损，并且损伤侵犯相邻区域会降低从初始损伤引起的损伤中恢复的能力。每个运动域都包含与恢复最相关的独特脑区，并且可能代表正在进行有益重组的目标。未来的临床试验应使用个体化治疗（例如，经颅磁刺激、脑内干细胞/祖细胞），考虑精确的病灶位置和每个患者的特定功能损伤，因为这些变量会显著影响治疗效果。
