Post-ischemic reorganization of sensory responses in cerebral cortex.

Introduction: Sensorimotor integration is critical for generating skilled, volitional movements. While stroke tends to impact motor function, there are also often associated sensory deficits that contribute to overall behavioral deficits. Because many of the cortico-cortical projections participating in the generation of volitional movement either target or pass-through primary motor cortex (in rats, caudal forelimb area; CFA), any damage to CFA can lead to a subsequent disruption in information flow. As a result, the loss of sensory feedback is thought to contribute to motor dysfunction even when sensory areas are spared from injury. Previous research has suggested that the restoration of sensorimotor integration through reorganization or de novo neuronal connections is important for restoring function. Our goal was to determine if there was crosstalk between sensorimotor cortical areas with recovery from a primary motor cortex injury. First, we investigated if peripheral sensory stimulation would evoke responses in the rostral forelimb area (RFA), a rodent homologue to premotor cortex. We then sought to identify whether intracortical microstimulation-evoked activity in RFA would reciprocally modify the sensory response. Methods: We used seven rats with an ischemic lesion of CFA. Four weeks after injury, the rats' forepaw was mechanically stimulated under anesthesia and neural activity was recorded in the cortex. In a subset of trials, a small intracortical stimulation pulse was delivered in RFA either individually or paired with peripheral sensory stimulation. Results: Our results point to post-ischemic connectivity between premotor and sensory cortex that may be related to functional recovery. Premotor recruitment during the sensory response was seen with a peak in spiking within RFA after the peripheral solenoid stimulation despite the damage to CFA. Furthermore, stimulation in RFA modulated and disrupted the sensory response in sensory cortex. Discussion: The presence of a sensory response in RFA and the sensitivity of S1 to modulation by intracortical stimulation provides additional evidence for functional connectivity between premotor and somatosensory cortex. The strength of the modulatory effect may be related to the extent of the injury and the subsequent reshaping of cortical connections in response to network disruption.

Post-Ischemic Reorganization of Sensory Responses in Cerebral Cortex.

Sensorimotor integration is critical for generating skilled, volitional movements. While stroke tends to impact motor function, there are also often associated sensory deficits that contribute to overall behavioral deficits. Because many of the cortico-cortical projections participating in the generation of volitional movement either target or pass-through primary motor cortex (in rats, caudal forelimb area; CFA), any damage to CFA can lead to a subsequent disruption in information flow. As a result, the loss of sensory feedback is thought to contribute to motor dysfunction even when sensory areas are spared from injury. Previous research has suggested that the restoration of sensorimotor integration through reorganization or de novo neuronal connections is important for restoring function. Our goal was to determine if there was crosstalk between sensorimotor cortical areas with recovery from a primary motor cortex injury. First, we investigated if peripheral sensory stimulation would evoke responses in the rostral forelimb area (RFA), a rodent homologue to premotor cortex. We then sought to identify whether intracortical microstimulation-evoked activity in RFA would reciprocally modify the sensory response. We used seven rats with an ischemic lesion of CFA. Four weeks after injury, the rats' forepaw was mechanically stimulated under anesthesia and neural activity was recorded in the cortex. In a subset of trials, a small intracortical stimulation pulse was delivered in RFA either individually or paired with peripheral sensory stimulation. Our results point to post-ischemic connectivity between premotor and sensory cortex that may be related to functional recovery. Premotor recruitment during the sensory response was seen with a peak in spiking within RFA after the peripheral solenoid stimulation despite the damage to CFA. Furthermore, stimulation evoked activity in RFA modulated and disrupted the sensory response in sensory cortex, providing additional evidence for the transmission of premotor activity to sensory cortex and the sensitivity of sensory cortex to premotor cortex's influence. The strength of the modulatory effect may be related to the extent of the injury and the subsequent reshaping of cortical connections in response to network disruption.

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 adaptive plasticity in recovery of function after damage to motor cortex.

Based upon neurophysiologic, neuroanatomic, and neuroimaging studies conducted over the past two decades, the cerebral cortex can now be viewed as functionally and structurally dynamic. More specifically, the functional topography of the motor cortex (commonly called the motor homunculus or motor map), can be modified by a variety of experimental manipulations, including peripheral or central injury, electrical stimulation, pharmacologic treatment, and behavioral experience. The specific types of behavioral experiences that induce long-term plasticity in motor maps appear to be limited to those that entail the development of new motor skills. Moreover, recent evidence demonstrates that functional alterations in motor cortex organization are accompanied by changes in dendritic and synaptic structure, as well as alterations in the regulation of cortical neurotransmitter systems. These findings have strong clinical relevance as it has recently been shown that after injury to the motor cortex, as might occur in stroke, post-injury behavioral experience may play an adaptive role in modifying the functional organization of the remaining, intact cortical tissue.

Effects of repetitive motor training on movement representations in adult squirrel monkeys: role of use versus learning.

Current evidence indicates that repetitive motor behavior during motor learning paradigms can produce changes in representational organization in motor cortex. In a previous study, we trained adult squirrel monkeys on a repetitive motor task that required the retrieval of food pellets from a small-diameter well. It was found that training produced consistent task-related changes in movement representations in primary motor cortex (M1) in conjunction with the acquisition of a new motor skill. In the present study, we trained adult squirrel monkeys on a similar motor task that required pellet retrievals from a much larger diameter well. This large-well retrieval task was designed to produce repetitive use of a limited set of distal forelimb movements in the absence of motor skill acquisition. Motor activity levels, estimated by the total number of finger flexions performed during training, were matched between the two training groups. This experiment was intended to evaluate whether simple, repetitive motor activity alone is sufficient to produce representational plasticity in cortical motor maps. Detailed analysis of the motor behavior of the monkeys indicates that their retrieval behavior was highly successful and stereotypical throughout the training period, suggesting that no new motor skills were learned during the performance of the large-well retrieval task. Comparisons between pretraining and posttraining maps of M1 movement representations revealed no task-related changes in the cortical area devoted to individual distal forelimb movement representations. We conclude that repetitive motor activity alone does not produce functional reorganization of cortical maps. Instead, we propose that motor skill acquisition, or motor learning, is a prerequisite factor in driving representational plasticity in M1.

Somatosensory and motor representations in cerebral cortex of a primitive mammal (Monodelphis domestica): a window into the early evolution of sensorimotor cortex.

To examine the potential early stages in the evolution of sensorimotor cortex, electrophysiological studies were conducted in the primitive South American marsupial opossum, Monodelphis domestica. Somatosensory maps derived from multiunit microelectrode recordings revealed a complete somatosensory representation of the contralateral body surface within a large region of midrostral cortex (primary somatosensory cortex, or S1). A large proportion ( approximately 51%) of S1 was devoted to representation of the glaborous snout, mystacial vibrissae, lower jaw, and oral cavity (the rostrum). A second representation, the second somatosensory area (or S2), was found adjacent and caudolateral to S1 as a mirror image reversed along the representation of the glabrous snout. A reversal of somatotopic order and an enlargement of receptive fields marked the transition from S1 to S2. Mapping of excitable cortex was conducted by using intracortical microstimulation (ICMS) techniques, as well as low-impedance depth stimulation and bipolar surface stimulation. In all three procedures, electrical stimulation resulted in movements confined strictly to the face. Specifically, at virtually all sites from which movements could be evoked, stimulation resulted in only vibrissae movement. ICMS-evoked vibrissae movements typically occurred at sites within S1 with receptive fields of the mystacial vibrissae, lower jaw, and glaborous snout. Results were similar using low-impedance depth stimulation and bipolar surface stimulation techniques except that the motor response maps were generally larger in area. There was no evidence of a motor representation rostral to S1. Examination of the cytoarchitecture in this cortical region (reminiscent of typical mammalian somatosensory cortex) and the high levels of stimulation needed for vibrissae movement suggest that the parietal neocortex of Monodelphis is representative of a primitive sensorimotor condition. It possesses a complete S1 representation with an incomplete motor component overlapping the S1 representation of the face. It contains no primary motor representation. Completion of the motor representations within S1 (trunk, limbs, tail) as well as the emergence of a primary motor cortex rostral to S1 may have occurred relatively late in mammalian phylogeny.

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.

Recovery after damage to motor cortical areas.

Until recently, the neural bases underlying recovery of function after damage to the cerebral cortex were largely unknown. Recent results from neuroanatomical and neurophysiological studies in animal models have demonstrated that after cortical damage, long-term and widespread structural and functional alterations take place in the spared cortical tissue. These presumably adaptive changes may play an important role in functional recovery.

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.

Sensitivity of neurons in somatosensory cortex (S1) to cutaneous stimulation of the hindlimb immediately following a sciatic nerve crush.

While a large number of studies have examined receptive field alterations in the cerebral cortex after peripheral nerve injury, descriptions of neuronal sensitivity have been largely qualitative. In the present study, quantitative changes in minimal force thresholds evoking cortical responses were examined in somatosensory cortex (S1) of the rat after peripheral nerve injury. Cutaneous receptive fields were defined by conventional multi-unit recording techniques. Thresholds for evoking cortical responses were defined using Semmes-Weinstein monofilaments to stimulate the skin over the distal and proximal hindlimb, and over the adjacent tail, lower back and abdomen. Then minimal force thresholds and representational areas were compared. Receptive fields were recorded before and within 3 h after a sciatic nerve crush injury. Group comparisons were also made with intact (control) rats in which more detailed maps were derived. The results show that the minimal force thresholds for activation of newly emerged responses were not statistically different from thresholds for evoking pre-crush responses. These quantitative data provide strong support for the notion that functional boundaries in S1 between saphenous and sciatic representations and between distal and proximal hindlimb representations are actively maintained by selective inhibition of subsets of overlapping inputs. Formerly inhibited responses can be activated by low-threshold cutaneous stimulation immediately following peripheral nerve injury.

Functional reorganization of the rat motor cortex following motor skill learning.

Functional reorganization of the rat motor cortex following motor skill learning. J. Neurophysiol. 80: 3321-3325, 1998. Adult rats were allocated to either a skilled or unskilled reaching condition (SRC and URC, respectively). SRC animals were trained for 10 days on a skilled reaching task while URC animals were trained on a simple bar pressing task. After training, microelectrode stimulation was used to derive high resolution maps of the forelimb and hindlimb representations within the motor cortex. In comparison with URC animals, SRC animals exhibited a significant increase in mean area of the wrist and digit representations but a decrease in elbow/shoulder representation within the caudal forelimb area. No between-group differences in areal representation were found in either the hindlimb or rostral forelimb areas. These results demonstrate that motor skill learning is associated with a reorganization of movement representations within the rodent motor cortex.

Dissociation of visual and auditory pattern discrimination functions within the cat's temporal cortex.

In ablation-behavior experiments performed in adult cats, a double dissociation was demonstrated between ventral posterior suprasylvian cortex (vPS) and temporo-insular cortex (TI) lesions on complex visual and auditory tasks. Lesions of the vPS cortex resulted in deficits at visual pattern discrimination, but not at a difficult auditory discrimination. By contrast, TI lesions resulted in profound deficits at discriminating complex sounds, but not at discriminating visual patterns. This pattern of dissociation of deficits in cats parallels the dissociation of deficits after inferior temporal versus superior temporal lesions in monkeys and humans.

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.

Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct.

Substantial functional reorganization takes place in the motor cortex of adult primates after a focal ischemic infarct, as might occur in stroke. A subtotal lesion confined to a small portion of the representation of one hand was previously shown to result in a further loss of hand territory in the adjacent, undamaged cortex of adult squirrel monkeys. In the present study, retraining of skilled hand use after similar infarcts resulted in prevention of the loss of hand territory adjacent to the infarct. In some instances, the hand representations expanded into regions formerly occupied by representations of the elbow and shoulder. Functional reorganization in the undamaged motor cortex was accompanied by behavioral recovery of skilled hand function. These results suggest that, after local damage to the motor cortex, rehabilitative training can shape subsequent reorganization in the adjacent intact cortex, and that the undamaged motor cortex may play an important role in motor recovery.

Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys.

1. Intracortical microstimulation (ICMS) techniques were used to derive detailed maps of distal forelimb movement representations in primary motor cortex (area 4) of adult squirrel monkeys before and a few months after a focal ischemic infarct. 2. Infarcts caused a marked but transient deficit in use of the contralateral hand, as evidenced by increased use of the ipsilateral hand, and reduced performance on a task requiring skilled digit use. 3. Infarcts resulted in a widespread reduction in the areal extent of digit representations adjacent to the lesion, and apparent increases in adjacent proximal representations. 4. We conclude that substantial functional reorganization occurs in primary motor cortex of adult primates following a focal ischemic infarct, but at least in the absence of postinfarct training, the movements formerly represented in the infarcted zone do not reappear in adjacent cortical regions.

Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys.

This study was undertaken to document plastic changes in the functional topography of primary motor cortex (M1) that are generated in motor skill learning in the normal, intact primate. Intracortical microstimulation mapping techniques were used to derive detailed maps of the representation of movements in the distal forelimb zone of M1 of squirrel monkeys, before and after behavioral training on two different tasks that differentially encouraged specific sets of forelimb movements. After training on a small-object retrieval task, which required skilled use of the digits, their evoked-movement digit representations expanded, whereas their evoked-movement wrist/forearm representational zones contracted. These changes were progressive and reversible. In a second motor skill exercise, a monkey pronated and supinated the forearm in a key (eyebolt)-turning task. In this case, the representation of the forearm expanded, whereas the digit representational zones contracted. These results show that M1 is alterable by use throughout the life of an animal. These studies also revealed that after digit training there was an areal expansion of dual-response representations, that is, cortical sectors over which stimulation produced movements about two or more joints. Movement combinations that were used more frequently after training were selectively magnified in their cortical representations. This close correspondence between changes in behavioral performance and electrophysiologically defined motor representations indicates that a neurophysiological correlate of a motor skill resides in M1 for at least several days after acquisition. The finding that cocontracting muscles in the behavior come to be represented together in the cortex argues that, as in sensory cortices, temporal correlations drive emergent changes in distributed motor cortex representations.

Variation and evolution of mammalian corticospinal somata with special reference to primates.

The morphology of the somata originating the corticospinal tract was examined in 24 species of mammals to identify commonalities and major sources of variation among the different species. Horseradish peroxidase was applied to a hemisection of the spinal cord at the C1-C2 junction. After tetramethylbenzidine processing, the labeled somata throughout the cerebral cortex were plotted and counted. Then, 23 morphological characteristics of the corticospinal somata were examined, including their number, size, and density across the cortical surface. The results show that morphological characteristics of corticospinal somata are closely related to an animal's body, brain, and cerebral cortex size. That is, mammals with large neocortical surfaces tend to have larger as well as more corticospinal somata; mammals with large bodies tend to have corticospinal somata that are less densely distributed. Moreover, the probable increase in the ratio of local noncorticospinal somata to corticospinal somata implies that the evolution of the corticospinal tract was accomplished by an increase in "support" or "server" cells as well as an increase in the size of the tract itself. The results also show that several characteristics are reliably related to an animal's taxonomic classification and hence its ancestry. Comparisons among three mammalian lineages indicate that some characteristics may have changed uniquely in the anthropoid primate lineage, and thus, presumably, in the human lineage. The results suggest that if morphological characteristics of the corticospinal tract important in the evolution of the specialized motor abilities in anthropoid primates are sought, then examination of the role of changes in soma diameter, rostral (motor)/caudal (sensory) ratios of density, concentration, surface density, and volume density may be more instructive than examination of the total number of corticospinal neurons alone.