Omar A. Gharbawie

Evidence for bilateral control of skilled movements: ipsilateral skilled forelimb reaching deficits and functional recovery in rats follow motor cortex and lateral frontal cortex lesions.

Unilateral damage to cortical areas in the frontal cortex produces sensorimotor deficits on the side contralateral to the lesion. Although there are anecdotal reports of bilateral deficits after stroke in humans and in experimental animals, little is known of the effects of unilateral lesions on the same side of the body. The objective of the present study was to make a systematic examination of the motor skills of the ipsilateral forelimb after frontal cortex lesions to either the motor cortex by devascularization of the surface blood vessels (pial stroke), or to the lateral cortex by electrocoagulation of the distal branches of the middle cerebral artery (MCA stroke). Plastic processes in the intact hemisphere were documented using Golgi–Cox dendritic analysis and by intracortical microstimulation analysis. Although tests of reflexive responses in forelimb placing identified a contralateral motor impairment following both cortical lesions, quantitative and qualitative measures of skilled reaching identified a severe ipsilateral impairment from which recovery was substantial but incomplete. Golgi‐impregnated pyramidal cells in the forelimb area showed an increase in dendritic length and branching. Electrophysiological mapping showed normal size forelimb representations in the lesioned rats relative to control animals. The finding of an enduring ipsilateral impairment in skilled movement is consistent with a large but more anecdotal literature in rats, nonhuman primates and humans, and suggests that plastic changes in the intact hemisphere are related to that hemispheres contribution to skilled movement.

Skilled reaching impairments from the lateral frontal cortex component of middle cerebral artery stroke: a qualitative and quantitative comparison to focal motor cortex lesions in rats

The classical approach to investigating brain contributions to behavior has been to localize function to a region. In clinical investigations, however, injury is frequently multifocal, raising the question of how individual brain regions contribute to a resulting behavioral syndrome. For example, middle cerebral artery (MCA) ischemia in humans can concurrently damage a number of cortical and subcortical areas and the same areas are damaged in rat models of MCA stroke. In the rat, MCA occlusion produces severe motor deficits, but the cortical area of damage is the lateral neocortex, sparing motor cortex. This anatomical finding raises the question of whether the rat lateral neocortex contributes to MCA-related motor impairments, a question that was investigated in the present study. Rats received unilateral neocortical lesions via electrocoagulation of the MCA and were compared to rats with standard motor cortex lesions produced by devascaulrization of the overlaying blood vessels. The MCA group was as impaired as the motor cortex group in skilled reaching movements as assessed by quantitative measures of the contralateral-to-lesion forelimb in a single pellet task and in a tray-reaching task. Although there was improvement in success scores over a 2-week period in both groups, the groups were characterized by distinctive and enduring qualitative impairments. The motor cortex deficit was exemplified by use of trunk musculature and head movements to assist the reaching limb while the MCA impairment included sensory abnormalities. The results are discussed in relation to the contribution of lateral frontal cortex injury to MCA stroke sensorimotor syndromes.

The topography of three-dimensional exploration: a new quantification of vertical and horizontal exploration, postural support, and exploratory bouts in the cylinder test.

The study of exploratory behavior in confined spaces can provide insights into both the spatial and the motor behavior of animals. In the present study, the behavior of rats placed inside of a cylinder (the cylinder test) for 5 min was examined to uncover: (1) the overall organization of exploratory behavior, (2) pattern of movement on the horizontal surface, (3) pattern of movement on the vertical surface, and (4) supporting and stepping movements. The results show that exploratory behavior is organized into a number of bouts of lateral and vertical scans with each bout ending by movement arrest and face washing. Within bouts, activity consists of alternating horizontal and vertical progressions that vary systematically over the course of a bout. Horizontal progressions consist of head scans, turning, and stepping, and decrease in amplitude across a bout. Vertical progressions consist of rears, head scans, and descent with an amplitude expressed by an inverted-U across bouts. Each horizontal and vertical progression is directed toward a different portion of the cylinder and the direction of lateral movements alternate within progressions and between progressions. For each rat, bouts tended to end in the same location suggesting the establishment of a home base. Eshkol-Wachmann movement analysis indicates that during progressions, the forepaws are mainly used for postural support and follow forequarter movements, while upward, downward, and sideward shifts in body weight are generated from the hind limbs. These findings illustrate that in even brief exploratory tests the three-dimensional exploratory behavior of rats is organized. The results are discussed in relation to the use of the cylinder test for analyzing a number of behaviors including exploration, locomotion, and supporting reactions.

Middle cerebral artery (MCA) stroke produces dysfunction in adjacent motor cortex as detected by intracortical microstimulation in rats.

Middle cerebral artery (MCA) stroke in the rat produces impairments in skilled movements. The lesion damages lateral neocortex but spares primary motor cortex (M1), raising the question of the origin of skilled movement deficits. Here, the behavioral deficits of MCA stroke were identified and then M1 was examined neurophysiologically and neuroanatomically. Rats were trained on a food skilled reaching task then the lateral frontal cortex was damaged by unilateral MCA electrocoagulation contralateral to the reaching forelimb. Reach testing and training on two tasks was conducted over 30 post-surgical days. Later, M1 and the corticospinal tract were investigated using intracortical microstimulation (ICMS), anterograde and retrograde axon tracing. A skilled reaching impairment was observed post-surgery, which partly recovered with time and training. ICMS revealed a diminished forelimb movement representation in MCA rats, but a face representation comparable in size to sham rats. Anterograde and retrograde tract tracing suggest that M1 efferents were intact. Although M1 appears to be in the main anatomically spared after MCA stroke its function as assessed electrophysiologically and behaviorally is disrupted.

Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats

The current study examines the effects of chronic administration of nicotine on motor behavior after focal stroke in rats. Animals were trained in a tray-reaching task for 2weeks and then they were divided into: (1) control+saline (2) control+nicotine (3) stroke+saline, and (4) stroke+nicotine groups. Lesions were produced by devascularization of the surface blood vessels of the sensorimotor cortex contralateral to the forepaw used for reaching. Forty-eight hours after the lesions, and for a total of 12days, animals received two daily injections of either nicotine (0.3mg/kg) or saline (0.9%). Animals were tested in a motor battery 1week after the lesions and every other week for a total of 7weeks. Pyramidal cells in forelimb and cingulate areas were then examined for dendritic length and branching using a Golgi-Cox procedure. Behavioral results demonstrated that by the end of the testing stroke+nicotine animals showed significant behavioral improvement relative to stroke+saline animals. Stroke+nicotine animals showed an increase in dendritic length and branching in pyramidal cells of the forelimb and cingulate areas. The results suggest that the behavioral enhancement in the stroke+nicotine group might be attributable to the enhanced dendritic growth in residual cortical motor regions.

Recovery of skilled reaching following motor cortex stroke : do residual corticofugal fibers mediate compensatory recovery

Motor cortex (MC) injury impairs skilled reaching in rats, but success scores are eventually restored to approximate preoperative levels. The improvement is attributed to compensatory strategies, such as substituting trunk rotations for the chronically lost rotatory movement of the forelimb, that occur during transport and withdrawal. The present study examined the contributions of the rostral motor cortex (RMC) and the caudal motor cortex (CMC) to skilled reaching performance. The study also examined the role of the ipsilateral and the contralateral hemispheres in supporting the spontaneous recovery. Rats were trained to reach for single food pellets, and their recovery from partial or complete MC injury was documented with quantitative scores and movement element measures in three experiments: (1) devascularization of the CMC, or the RMC, or both, in the hemisphere contralateral to the reaching paw; (2) additional lesions to the CMC and RMC injuries such that the conjoint damage amounted to an MC lesion; and (3) MC lesion followed by damage in the neocortex lateral to the injury or in the opposite MC. The results showed that the CMC made the main contribution to skilled reaching performance, and that there was a lesser contribution by the RMC. MC damage was exacerbated by additional damage to the ipsilateral neocortex as compared to the contralateral neocortex. The results are discussed in relation to the idea that the involvement of the neocortical areas in skilled reaching performance and its recovery is proportional to the region from which corticospinal projections originate.

Subcortical middle cerebral artery ischemia abolishes the digit flexion and closing used for grasping in rat skilled reaching

That rats reach for and grasp a food item using a single paw has prompted their use in neurobiological studies of skilled movements and modeling neural injury including middle cerebral artery stroke. Although motor system lesions have been shown to disrupt various qualitative aspects of the transport of a limb to a food target and withdrawal of the limb with the food, no lesion has been found to abolish digit flexion for grasping. Here, rats received unilateral transient middle cerebral artery ischemia that was restricted mainly to subcortical tissue of the forebrain (caudate-putamen, globus pallidus, and associated fibers) or a sham operation. Both paws were later trained and evaluated on skilled reaching using a rating scale for digit use. Middle cerebral artery rats did not flex and close their digits to grasp food when using their contralateral-to-lesion limb. The grasp impairment was not due to a failure to learn the task as middle cerebral artery rats used the ipsilateral limb as successfully as control rats and they were reinforced for reaching by raking food into the reaching box using an open paw. The impairment was also not due to an inability to move the digits, as they were flexed and closed in other phases of the reach. The paradigm should prove useful for further studies of rehabilitation in relation to the idea that digit closure may be controlled by the joint action of a number of neural systems that converge in the basal ganglia.

Attempt-dependent decrease in skilled reaching characterizes the acute postsurgical period following a forelimb motor cortex lesion: An experimental demonstration of learned nonuse in the rat

The notion that shock or diaschisis is a distinctive stage in the recovery process following brain damage has played a formative role in the characterization of brain injury. For example, damage to the forelimb region of motor cortex results in an acute period of behavioural depression in skilled reaching and other skilled actions followed by improved performance mediated by compensatory movements. Whereas the progression of improvement and the use of compensatory movements in the chronic period of recovery is well-documented, temporal aspects of behaviour during the acute period of depression of behaviour are relatively unstudied. The present study examined the temporal scheduling of reach-attempts by rats attempting to gain single pellets of food from a shelf in a skilled reaching task. Pretrained rats received contralateral-to-the-pretrained limb forelimb motor cortex lesions. Control lesions included contralateral-to-the-pretrained limb parietal cortex lesions, or ipsilateral-to-the-pretrained limb motor cortex lesions. Frame-by-frame video analysis of behaviour showed a decrease in reaching attempts as a function of successive approaches and attempts to grasp the food over the first few postsurgical days in rats with contralateral-to-the-pretrained limb motor cortex lesions. A similar approach-dependent decrease in attempts did not occur after parietal or ipsilateral-to-the-pretrained limb motor cortex lesions. The decrease in responding occurred only during acute testing and was not observed in rats first tested after 8 days of postoperative recovery. The findings are discussed in relation to the ideas that: (1) the stroke subject is an active participant in modifying behaviour to cope with injury; (2) learned nonuse contributes to behaviour in the acute postinjury period following motor cortex injury; (3) diaschisis inadequately accounts for poststoke behaviour.

Experience-dependent amelioration of motor impairments in adulthood following neonatal medial frontal cortex injury in rats is accompanied by motor map expansion.

One of the most common, and disruptive, neurological symptoms following neonatal brain injury is a motor impairment. Neonatal medial frontal cortical lesions in rats produce enduring motor impairments, and it is thought that lesion-induced abnormal cortical morphology and connectivity may underlie the motor deficits. In order to investigate the functional consequences of the lesion-induced anatomical abnormalities in adulthood, we used intracortical microstimulation to determine the neurophysiologic organization of motor maps within the lesion hemisphere. In addition, groups of neonatal lesion rats were given reach training or complex housing rehabilitation in adulthood and then mapped with intracortical microstimulation. The results demonstrate that neonatal medial frontal cortex lesions produce motor deficits in adulthood that are associated with abnormal motor maps. Further, adult behavioral treatment promoted partial recovery that was supported by reorganization of the motor maps whereby there were increases in the size of the forelimb motor maps. The experience-induced expansion of the forelimb motor maps in adulthood provides a neural mechanism for the experience-dependent improvements in motor performance.

Transient middle cerebral artery occlusion disrupts the forelimb movement representations of rat motor cortex

Infarcts from proximal middle cerebral artery (MCA) stroke can produce impairments in motor function, particularly finger movements in humans and digit flexion in rats. In rats, the extent of neural damage may be limited to basal ganglia structures or may also include portions of the frontal and parietal cortex in severe cases. Although the primary motor cortex (M1) is anatomically spared in proximal MCA occlusion, its functional integrity is suspect because even a small subcortical infarct can damage neural circuits linking M1 with basal ganglia, brainstem, and spinal cord. This motivated the present study to investigate the neurophysiological integrity of M1 after transient proximal MCA occlusion. Rats, preoperatively trained and non‐preoperatively trained to reach for food, received extensive reach training/testing with the contralateral‐to‐lesion paw for several weeks after MCA occlusion. The forelimb movement representations were assayed from the ipsilateral‐to‐lesion M1 with intracortical microstimulation approximately 10 weeks after MCA occlusion. Digit flexion was impaired during food grasping in rats with relatively small subcortical infarcts and was completely abolished in rats that sustained at least moderate subcortical damage. Corresponding forelimb movement representations ranged from abnormally small to absent. The results suggest that ischemia in subcortical territories of the MCA does not spare the neurophysiological properties of M1 despite its apparent anatomical intactness, probably because of damage sustained to its descending fibers. Thus, M1 dysfunction contributes to the impairments that ensue from proximal MCA occlusion, even when the infarct is limited to subcortical regions.