Role of remote motor cortex in recovery following an extensive motor cortical lesion in a non-human primate

Abstract

The ultimate goal in this research was to study the role of remote motor cortex in recovery from stroke in a non-human primate model in order to complement existing behavioral and anatomical findings from rodent studies and aid in the interpretation of human neuroimaging data.Transcranial magnetic stimulation (TMS) has been used extensively to study excitability of the motor cortex in normal subjects and changes in motor evoked potentials (MEPs) and in intracortical excitability (ICI) in stroke patients. The presence of ipsilateral MEPs (iMEPs) and changes in the uninjured hemisphere have been related both to good and poor motor recovery. This technique has also offered insight into the mechanisms underlying iMEPs and plasticity in the injured hemisphere in terms of the participation of ipsilateral pathways in stroke recovery.

Recent neuroimaging data seems to point to the involvement of spared ipsilesional motor areas (in the same hemisphere as the lesion). It has also been suggested that regain of function of the paretic hand occurs as a consequence of a dynamic, bihemispheric reorganization after stroke onset and that the premotor areas are especially suited to reorganize following injury to the corticospinal tract. Given that lesion location and size determine the outcome and degree of cortical plasticity after stroke, reorganization of the motor cortex may follow different mechanisms depending on whether primary motor, premotor or supplementary motor areas in the ipsilesional hemisphere are spared and depending on whether subcortical structures are included in the lesion.

In summary, there is ample evidence of plasticity in both hemispheres following stroke. However the relationship to recovery is not clear. The present studies intend to clarify whether plasticity in the injured cortex is related to recovery of function and whether there is a change in ipsilateral electromyographic (EMG) activity (from the uninjured cortex) following an extensive cortical lesion.

The aim of the present study was to address three experimental hypotheses. The first hypothesis focuses on plasticity in the ipsilesional (injured) hemisphere, stating that physiological changes in the ipsilesional SMA would be positively correlated to recovery of function. The lesion was induced by electrocoagulation of the blood vessels in the physiologically defined primary motor (M1), premotor ventral (PMv) and premotor dorsal (PMd) upper extremity representation areas. Prior to and three weeks (early time point) and three months (13 weeks, late time point) after the lesion, intracortical microstimulation (ICMS) was employed in the ipsilesional distal forelimb (DFL) supplementary motor area (SMA) to derive detailed output maps of this region at pre-lesion, early and late time points. Physiological changes were correlated with behavioral outcome. The ipsilesional DFL SMA was significantly enlarged three months post lesion. This enlargement was positively correlated to the lesion size and to the improved motor performance.

The second hypothesis stated that after an ischemic lesion in the motor cortex, maintenance of recovered motor function would depend on activity in spared motor cortex in the ipsilesional hemisphere. A secondary focal lesion in the ipsilesional SMA DFL area was performed three months after the initial lesion. Motor performance was monitored for the subsequent thirty days to determine if the original deficits were reinstated. Secondary lesions in the DFL SMA representation failed to show a significant effect on the behavior.

The third hypothesis is related to changes in the uninjured hemisphere, stating that descending control of ipsilateral muscles does not change with recovery from a lesion in the motor cortex. ICMS was employed in the uninjured cortex in M1, PMv and SMA forelimb motor areas. EMG signals were recorded from the proximal and distal ipsilateral (affected) forelimb muscles. Although ipsilateral EMG activity has been observed in normal subjects this generally requires active target muscle contraction and high stimulation intensities. Pre-lesion ipsilateral EMG activity detected in the normal squirrel monkeys was compared to contralateral activity. Post-lesion, there was an increase in the number of ipsilateral EMG events (affected arm) at both time points compared to pre-lesion. The latency of these facilitation effects increased three weeks post-lesion and decreased to pre-lesion values by three months post-lesion. Ipsilateral suppressive effects also increased at both time points, but this change was paralleled by the same pattern of changes in the contralateral side.

This study of plasticity in both hemispheres at the early and late stage in a primate model of stroke is novel and should offer insight into the mechanisms of functional recovery following stroke. (Abstract shortened by UMI.)