Poststroke Impairment and Recovery Are Predicted by Task-Specific Regionalization of Injury

Abstract

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 (N = 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.

Enhanced Spontaneous Motor Recovery After Stroke in Mice Treated With Cerebrolysin

“…31 The reasons for this difference between rats and humans is not clear but may be related to the following: (1) inherent differences between rat and human neuroanatomy; (2) rat rehabilitation is better suited to capitalize on SBR with enriched environments, increased time on task, and rehabilitation specifically suited to the outcome measure; and/or (3) a pairing of lesion location and rehabilitation that is better suited to influence recovery in rodents compared with humans. 33 Here, we report recovery of function independent of poststroke training in mice that receive Cerebrolysin (see Figure 1A), similar to the spontaneous recovery seen in stroke patients. Such recovery cannot be because mice receiving Cerebrolysin injections had reduced poststroke deficits immediately after the stroke because our data show that mice tested immediately after stroke (Figures 1A and 1C) had reduced prehension success, similar to prior reports.…”

“…31 The reasons for this difference between rats and humans is not clear but may be related to the following: (1) inherent differences between rat and human neuroanatomy; (2) rat rehabilitation is better suited to capitalize on SBR with enriched environments, increased time on task, and rehabilitation specifically suited to the outcome measure; and/or (3) a pairing of lesion location and rehabilitation that is better suited to influence recovery in rodents compared with humans. 33…”

More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke

“…41 This was accompanied by the recovery of performance on a skilled reaching task, although interestingly, in contrast to the current study, deficits on both the cylinder and grid-walking task remained evident, suggesting that different types of sensorimotor function may recover at different rates depending on stroke size and location. 42 Promisingly, emerging studies Ab expression switches from a scattered distribution in the parenchyma of the brain up to 28 days post-stroke to a localisation around the vessels at 84 days post-stroke in the peri-infarct region and in the CA1 sub-region of the hippocampus. At day 84, Ab was observed to accumulate around the cerebral vessels in the peri-infarct region, and a lesser degree in the CA1 subregion of the hippocampus.…”

“…41 This was accompanied by the recovery of performance on a skilled reaching task, although interestingly, in contrast to the current study, deficits on both the cylinder and grid-walking task remained evident, suggesting that different types of sensorimotor function may recover at different rates depending on stroke size and location. 42 Promisingly, emerging studies have shown that the modulation of GABAergic signalling using pharmacological approaches 37,43 or optogenetic stimulation 44 after stroke can promote motor recovery.…”

Lesion Area in the Cerebral Cortex Determines the Patterns of Axon Rewiring of Motor and Sensory Corticospinal Tracts After Stroke

“…Predictions of poststroke outcomes in patients are useful to develop more effective therapies in individuals such as the rehabilitation with appropriate intensity and dose. Prognostic factors in lesion size and location were systematically examined in a rat model ( Jeffers et al, 2020 ). Our present study demonstrates potential neural substrates that could determine the recovery process among different CST and lesion types.…”