Themes and strategies for studying the biology of stroke recovery in the poststroke epoch

Abstract

Background and purpose: This review will focus on the emerging principles of neural repair after stroke, and on the overlap between cellular mechanisms of neural repair in stroke and clinical principles of recovery and rehabilitation.

Summary of review: Stroke induces axonal sprouting and neurogenesis. Axonal sprouting occurs in tissue adjacent to the stroke and its connected cortical areas, and from sites that are contralateral to the infarct. Neurogenesis produces newly born immature neurons in peri-infarct striatum and cortex. Stimulation of both axonal sprouting and neurogenesis is associated with improved recovery in animal models of stroke. A unique cellular environment in the poststroke brain supports neural repair: an association of angiogenic and remodeling blood vessels with newly born immature neurons in a neurovasclar niche. Controversies in the field of neural repair after stroke persist, and relate to the locations of axonal sprouting in animal models of stroke and how these correlate to patterns of human remapping and recovery, and to the different models of stroke used in studies of neurogenesis.

Conclusions: On a cellular level, the phenomenology of neural repair after stroke has been defined and unique regenerative environments in the poststroke brain identified. As the field moves toward specific studies of causal mechanisms in poststroke repair, it will need to maintain a perspective of the animal models suited to the study of neural repair after stroke as they relate to the patterns of recovery in humans in this disease.

Figure. Stroke Model Determines Degree of Surviving Tissue and Pattern of Post-Stroke Neurogenesis

A. Focal cortical stroke produced by permanent occlusion of a distal branch of the MCA and brief bilateral common carotid occlusion. Box shows the region seen in panel D. B. Large hemispheric stroke produced by 90 minutes of MCA suture occlusion¹²⁹. C. Large cortical infarct produced by permanent distal MCA and ipsilateral CCA occlusion and transient contralateral CCA occlusion¹³⁰. D. Doublecortin positive immature neurons (orange) migrate from the SVZ along the white matter dorsal to the striatum to the peri-infarct cortex (arrows) at 7 days after stroke. Box shows the region that is enlarged in panel E. E. Doublecortin positive cells migrate just ventral to the infarct (arrow) and extend into peri-infarct cortex. Within peri-infarct cortex, immature neurons extend local processes (arrowhead). A comparison of the large infarcts in panels B and D indicate that the region of migration and neurogenesis in peri-infarct cortex would not be present in these stroke models as this tissue is dead. Panel B is reprinted with permission from Brain, Oxford University Press. Panel C is reprinted with permission from Journal of Cerebral Blood Flow & Metabolism, Nature Publishing Group.