Activity-dependent plasticity improves M1 motor representation and corticospinal tract connectivity.

Motor cortex (M1) activity between postnatal weeks 5 and 7 is essential for normal development of the corticospinal tract (CST) and visually guided movements. Unilateral reversible inactivation of M1, by intracortical muscimol infusion, during this period permanently impairs development of the normal dorsoventral distribution of CST terminations and visually guided motor skills. These impairments are abrogated if this M1 inactivation is followed by inactivation of the contralateral, initially active M1, from weeks 7 to 11 (termed alternate inactivation). This later period is when the M1 motor representation normally develops. The purpose of this study was to determine the effects of alternate inactivation on the motor representation of the initially inactivated M1. We used intracortical microstimulation to map the left M1 1 to 2 mo after the end of left M1 muscimol infusion. We compared representations in the unilateral inactivation and alternate inactivation groups. Alternate inactivation converted the sparse proximal M1 motor representation produced by unilateral inactivation to a complete and high-resolution proximal-distal representation. The motor map was restored by week 11, the same age that our present and prior studies demonstrated that alternate inactivation restored CST spinal connectivity. Thus M1 motor map developmental plasticity closely parallels plasticity of CST spinal terminations. After alternate inactivation reestablished CST connections and the motor map, an additional 3 wk was required for motor skill recovery. Since motor map recovery preceded behavioral recovery, our findings suggest that the representation is necessary for recovering motor skills, but additional time, or experience, is needed to learn to take advantage of the restored CST connections and motor map.

Differential activity-dependent development of corticospinal control of movement and final limb position during visually guided locomotion.

Although we understand that activity- and use-dependent processes are important in determining corticospinal axon terminal development in the spinal cord, little is known about the role of these processes in development of skilled control of limb movements. In the present study we determined the effects of unilateral motor cortex activity blockade produced by muscimol infusion during the corticospinal axon terminal refinement period, between postnatal weeks 5-7, on visually guided locomotion. We examined stepping and forepaw placement on the rungs of a horizontal ladder and gait modifications as animals stepped over obstacles during treadmill walking. When cats traversed the horizontal ladder, the limb contralateral to inactivation was placed significantly farther forward on the rungs than the ipsilateral limb, indicating defective endpoint control. Similarly, when animals stepped over obstacles on a treadmill, the contralateral limb was placed farther in front of the obstacle, but only when it was the first (i.e., leading) limb to step over the obstacle, not when it was the second (i.e., trailing) limb. This is also indicative of an endpoint control deficit. In contrast, neither during ladder walking, nor when stepping over obstacles on the treadmill, was there any consistent evidence for a major impairment in limb trajectory. These results point to distinct and possibility independent corticospinal mechanisms for movement trajectory control and endpoint control. Although corticospinal activity during early postnatal development is needed to refine circuits for accurate endpoint control, this activity-dependent refinement is not needed for movement trajectory control.

Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery.

Although recent neurological research has shed light on the brain's mechanisms of self-repair after stroke, the role that intact tissue plays in recovery is still obscure. To explore these mechanisms further, we used microelectrode stimulation techniques to examine functional remodeling in cerebral cortex after an ischemic infarct in the hand representation of primary motor cortex in five adult squirrel monkeys. Hand preference and the motor skill of both hands were assessed periodically on a pellet retrieval task for 3 mo postinfarct. Initial postinfarct motor impairment of the contralateral hand was evident in each animal, followed by a gradual improvement in performance over 1-3 mo. Intracortical microstimulation mapping at 12 wk after infarct revealed substantial enlargements of the hand representation in a remote cortical area, the ventral premotor cortex. Increases ranged from 7.2 to 53.8% relative to the preinfarct ventral premotor hand area, with a mean increase of 36.0 +/- 20.8%. This enlargement was proportional to the amount of hand representation destroyed in primary motor cortex. That is, greater sparing of the M1 hand area resulted in less expansion of the ventral premotor cortex hand area. These results suggest that neurophysiologic reorganization of remote cortical areas occurs in response to cortical injury and that the greater the damage to reciprocal intracortical pathways, the greater the plasticity in intact areas. Reorganization in intact tissue may provide a neural substrate for adaptive motor behavior and play a critical role in postinjury recovery of function.

Role of sensory deficits in motor impairments after injury to primary motor cortex.

After a focal ischemic lesion in the hand representation of the primary motor cortex in squirrel monkeys, manual skill was mildly and transiently impaired on a reach-and-retrieval task. Performance was significantly poorer during weeks 1 and 3 post-lesion, but was normal by week 4. An unusual behavioral event was also observed after the lesion. Monkeys reached for pellets, but visually inspected the hand for the presence of the pellets, even when none were actually retrieved. This behavior, possibly indicative of a sensory deficit, was rarely observed prior to the lesion, but was observed at significantly higher levels during week one post-lesion. These results suggest that the primary motor cortex plays a significant role in somatosensory processing during the execution of motor tasks. Motor deficits heretofore identified as purely motor, may be at least partially due to a sensory deficit, or sensory-motor disconnection.

Effects of postlesion experience on behavioral recovery and neurophysiologic reorganization after cortical injury in primates.

Previous studies have shown that after injury to the hand representation in primary motor cortex (M1), size of the spared hand representation decreased dramatically unless the unimpaired hand was restrained and monkeys received daily rehabilitative training using the impaired fingers. The goal of this study was to determine if restriction of the unimpaired hand was sufficient to retain spared hand area after injury or if retention of the spared area required repetitive use of the impaired limb. After infarct to the hand area of M1 in adult squirrel monkeys, the unimpaired hand was restrained by a mesh sleeve over the unimpaired arm. Monkeys did not receive rehabilitative training. Electrophysiologic maps of M1 were derived in anesthetized monkeys before infarct and 1 month after infarct by using intracortical microstimulation. One month after the lesion, the size of the hand representation had decreased. Areal changes were significantly smaller than those in animals in a previous study that had received daily repetitive training after infarct (p < 0.05). Areal changes were not different from those in a group of animals that received neither rehabilitative intervention nor hand restraint after injury. These results suggest that retention of hand area in M1 after a lesion requires repetitive use of the impaired hand.

Factors contributing to motor impairment and recovery after stroke.

The goal of the present study was to examine factors affecting motor impairment and recovery in a primate model of cortical infarction. Microelectrode stimulation techniques were used to delineate the hand representation in the primary motor cortex (M1). Microinfarcts affecting approximately 30% of the hand representation were made by electrocoagulation of surface vessels. Electrophysiologic procedures were repeated at 1 month after the infarct to examine changes in motor map topography. Before the infarct, and at approximately 1 week (early period) and 1 month (late period) after the infarct, manual performance was assessed on a reach-and-retrieval task that required skilled use of the digits. Contrary to the expected outcome, early impairment was inversely related to the amount of digit representation destroyed by the infarct. That is, animals with less involvement of the M1 digit area demonstrated the greatest motor deficit in the early postinfarct period. In addition, improvement in motor performance between early and late postinfarct periods was directly related to a decrease in the extent of the digit + wrist/forearm area in the final postinfarct map. These results suggest that specific aspects of motor-map remodeling are expressions of adaptive mechanisms that underlie functional recovery after stroke. Further, they suggest that the adaptive mechanisms underlying postinjury recovery differ in detail from those that operate in normal motor learning. The potential role of compensatory mechanisms in these phenomena is discussed.

Cortical plasticity after stroke: implications for rehabilitation.

While adaptive processes in the cerebral cortex have long been thought to contribute to functional recovery after stroke, the precise neuronal structures and mechanisms underlying these processes have been difficult to identify. Over the past 15 years, a large number of studies conducted in human stroke patients and in experimental animal models have contributed to a more coherent picture of the brain's adaptive capacity after injury. These studies suggest that the cerebral cortex undergoes significant and functional structural plasticity for at least several weeks to months following injury. Adaptive changes have been demonstrated in the intact tissue surrounding the lesion, as well as in other cortical motor areas remote from the site of injury. Recent results from non-human primate studies of cortical reorganization after stroke demonstrate marked functional changes in the intact cortical tissue adjacent to the infarct in the weeks following an ischemic lesion. Further, intensive task-specific practice with the impaired limb has a modulatory effect on the inevitable cortical plasticity. Taken together with parallel studies of forced use in human stroke patients, it is likely that use of the impaired limb can influence adaptive reorganizational mechanisms in the intact cerebral cortex, and thus, promote functional recovery.

Recovery of motor function after focal cortical injury in primates: compensatory movement patterns used during rehabilitative training.

The recovery of skilled hand use after cortical injury was assessed in adult squirrel monkeys. Specific movement patterns used to perform a motor task requiring fine manual skill were analyzed before and after a small ischemic infarct (2.6-3.8 mm2) to the electrophysiologically identified hand area of the primary motor cortex (M1). After 1-3 weeks of pre-infarct training, each monkey stereotypically used one specific movement pattern to retrieve food pellets. After injury to the hand area of M1, the monkeys were required to retrieve the pellets using their impaired forelimb. Immediately after the injury, the number of finger flexions used by the monkeys to retrieve the pellets increased, indicating a deficit in skilled finger use. After approximately 1 month of rehabilitative training, skilled use of the fingers appeared to recover, indicated by a reduction in the number of finger flexions per retrieval. The monkeys again retrieved the pellets using one specific movement pattern in most trials. Despite the apparent recovery of skilled finger use after rehabilitative training, three of five monkeys retrieved the pellets using stereotypic movement patterns different from those used before the injury. Thus, this study provides evidence that compensatory movement patterns are used in the recovery of motor function following cortical injury, even after relatively small lesions that produce mild, transient deficits in motor performance. Examination of electrophysiological maps of evoked movements suggests that the mode of recovery (re-acquisition of pre-infarct movement strategies vs development of compensatory movement strategies) may be related to the relative size of the lesion and its specific location within the M1 hand representation.