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The corticospinal tract (CST) forms the major descending pathway mediating voluntary hand movements in primates, and originates from ∼nine cortical subdivisions in the macaque. While the terminals of spared motor CST axons are known to sprout locally within the cord in response to spinal injury, little is known about the response of the other CST subcomponents. We previously reported that following a cervical dorsal root lesion (DRL), the primary somatosensory (S1) CST terminal projection retracts to 60% of its original terminal domain, while the primary motor (M1) projection remains robust (Darian-Smith et al., J. Neurosci., 2013). In contrast, when a dorsal column lesion (DCL) is added to the DRL, the S1 CST, in addition to the M1 CST, extends its terminal projections bilaterally and caudally, well beyond normal range (Darian-Smith et al., J. Neurosci., 2014). Are these dramatic responses linked entirely to the inclusion of a CNS injury (i.e., DCL), or do the two components summate or interact? We addressed this directly, by comparing data from monkeys that received a unilateral DCL alone, with those that received either a DRL or a combined DRL/DCL. Approximately 4 months post-lesion, the S1 hand region was mapped electrophysiologically, and anterograde tracers were injected bilaterally into the region deprived of normal input, to assess spinal terminal labeling. Using multifactorial analyses, we show that following a DCL alone (i.e., cuneate fasciculus lesion), the S1 and M1 CSTs also sprout significantly and bilaterally beyond normal range, with a termination pattern suggesting some interaction between the peripheral and central lesions., (© 2018 Wiley Periodicals, Inc.)

Focal neocortical brain injuries lead to functional alterations, which can spread beyond lesion-neighboring brain areas. The undamaged hemisphere and its associated disturbances after a unilateral lesion, so-called transhemispheric diaschisis, have been progressively disclosed over the last decades; they are strongly involved in the pathophysiology and, potentially, recovery of brain injuries. Understanding the temporal dynamics of these transhemispheric functional changes is crucial to decipher the role of the undamaged cortex in the processes of functional reorganization at different stages post-lesion. In this regard, little is known about the acute-subacute processes after 24-48 h in the brain hemisphere contralateral to injury. In the present study, we performed a controlled cortical impact to produce a unilateral traumatic brain injury (TBI) in the motor and somatosensory cortex of mice. In vitro extracellular multi-unit recordings from large neuronal populations, together with single-cell patch-clamp recordings in the cortical network contralateral to the lesion, revealed a strong, but transient, neuronal hyperactivity as early as 24-48 h post-TBI. This abnormal excitable state in the intact hemisphere was not accompanied by alterations in neuronal intrinsic properties, but it was associated with an impairment of the phasic gamma aminobutyric acid (GABA)ergic transmission and an increased expression of GABA A receptor subunits related to tonic inhibition exclusively in the contralateral hemisphere. These data unravel a series of early transhemispheric functional alterations after diffuse unilateral cortical injury, which may compensate and stabilize the disrupted brain functions. Therefore, our findings support the hypothesis that the undamaged hemisphere could play a significant role in early functional reorganization processes after a TBI.

Traumatic brain injury (TBI) induces transient or persistent dysfunction of gait and balance. Enhancement of cholinergic transmission has been reported to accelerate recovery of cognitive function after TBI, but the effects of this intervention on locomotor activity remain largely unexplored. The hypothesis that enhancement of cholinergic function by inhibition of acetylcholinesterase (AChE) improves locomotion following TBI was tested in Sprague-Dawley male rats after a unilateral controlled cortical impact (CCI) injury of the motor-sensory cortex. Locomotion was tested by time to fall on the constant speed and accelerating Rotarod, placement errors and time to cross while walking through a horizontal ladder, activity monitoring in the home cages, and rearing behavior. Assessments were performed the 1st and 2nd day and the 1st, 2nd, and 3rd week after TBI. The AChE inhibitor physostigmine hemisulfate (PHY) was administered continuously via osmotic minipumps implanted subcutaneously at the rates of 1.6-12.8 μmol/kg/day. All measures of locomotion were impaired by TBI and recovered to initial levels between 1 and 3 weeks post-TBI, with the exception of the maximum speed achievable on the accelerating Rotarod, as well as rearing in the open field. PHY improved performance in the accelerating Rotarod at 1.6 and 3.2 μmol/kg/day (AChE activity 95 and 78% of control, respectively), however, higher doses induced progressive deterioration. No effect or worsening of outcomes was observed at all PHY doses for home cage activity, rearing, and horizontal ladder walking. Potential benefits of cholinesterase inhibition on locomotor function have to be weighed against the evidence of the narrow range of useful doses.

Activated iridium microelectrodes were implanted for 450-1282 days in the sensorimotor cortex of seven adult domestic cats and then pulsed for 240 h (8 h per day for 30 days) at 50 Hz. Continuous stimulation at 2 nC/phase and with a geometric charge density of 100 microC cm(-2) produced no detectable change in neuronal density in the tissue surrounding the microelectrode tips. However, pulsing with a continuous 100% duty cycle at 4 nC/phase and with a geometric charge density of 200 microC cm(-2) induced loss of cortical neurons over a radius of at least 150 microm from the electrode tips. The same stimulus regimen but with a duty cycle of 50% (1 s of stimulation, and then 1 s without stimulation repeated for 8 h) produced neuronal loss within a smaller radius, approximately 60 microm from the center of the electrode tips. However, there also was significant loss of neurons surrounding the unpulsed electrodes, presumably as a result of mechanical injury due to their insertion into and long-term residence in the tissue, and this was responsible for most of the neuronal loss within 150 microm of the electrodes pulsed with the 50% duty cycle.

Direct evidence of the anatomical localization of brain function is provided by functional neurological changes during awake surgery combined with data from preoperative functional magnetic resonance imaging and diffusion tensor imaging studies. The goal of the present study was to analyze the etiology and mechanism of motor hemineglect using these techniques. Of 29 patients with brain tumors within and near the primary motor area (M1) in whom awake surgery was employed from April 2004 through March 2007, 2 patients evinced motor hemineglect of the left hand during awake surgery. The brain tumors in these 2 cases alone were located just beside the hand area of M1 and the primary sensory area (S1) in the right hemisphere. In case 1, the U fibers that connected the areas activated by hand clenching in M1 with S1 were compressed by the brain tumor. These results suggest that the combination of damage to the right hemispheric hand area in M1 and S1 plays a critical role in the development of motor hemineglect., (Copyright 2009 S. Karger AG, Basel.)

In response to a lesion, intact regions of cortex in both hemispheres undergo adaptive changes in network function. For example, changes in excitability and intracortical inhibition in primary motor cortex (M1) were reported after lesioning contralateral or ipsilateral brain regions. Close interactions exist between M1 and primary somatosensory cortex (S1) within one hemisphere. Therefore, we hypothesized that lasting modifications would occur in S1 excitability after lesioning ipsilateral M1. Imaging of intrinsic optical signals (IOS, at 570 nm) was used to investigate the evolution of the somatosensory cortical response evoked by contralateral median nerve stimulation during the first hour after a photothrombotic lesion to M1 (caudal motor cortex) of the rat (n=10). Control rats (n=6) received no lesion. Perfusion was monitored by Laser speckle imaging and the extent of the resulting lesion was determined histologically. Control animals did not show evidence for reduced perfusion, infarction, or changes in IOS. M1 infarction led to a significant increase in evoked response amplitude, duration, and area of activation, and a shortening of latencies. These parameters reached a plateau around 50 min after ischemia. These results indicate S1 hyperexcitability after M1 injury. Whether these adaptations contribute to functional deficits or play a role in recovery, remains to be determined.

Using different models of focal cortical injury in adult rats, the neural structural and behavioral outcomes of unilateral lesions of the forelimb representation of the sensorimotor cortex (SMC) were assessed. Lesions were produced using either electrolytic, aspiration, or combined ('electroaspiration') techniques. Measurements of dendritic arborization in layer V of the motor cortex opposite the lesion revealed a growth of pyramidal neuron dendritic processes following electrolytic lesions in comparison to shams. This effect was not found in either the aspiration or electroaspiration lesion groups. Behaviorally, animals in all lesion groups developed a hyper-reliance on the forelimb ipsilateral to the lesion and proportionate disuse of the contralateral (impaired) forelimb for postural support behaviors. In comparison to sham-operated animals, the initial asymmetries in behaviors expressed during movement were similar between lesion groups, but were less enduring following electrolytic lesions than following aspiration and electroaspiration lesions. Furthermore, both aspiration lesion groups had more prevalent adduction of the impaired forelimb than the electrolytic-only lesion rats. Thus, cortical aspiration resulted in more severe and enduring forelimb impairments than the electrolytic lesions, despite similar lesion sizes, as assessed using cortical volume measures. These findings suggest that the aspiration lesion procedures, at least as performed in the present study, exacerbate the behavioral effects of focal cortical injury and limit compensatory plasticity in the contralateral cortex.

Sensorimotor cortical reorganization after early brain lesions was studied by means of fMRI in two pairs of monozygotic twins, in each of which one member had a focal brain injury. This offered a unique opportunity to reduce the wide intersubject variability of the controls often found in similar studies. Activation images were acquired during a motor task (sequential opposition finger movements) and a sensory task (passive brushing of palm and fingers). During the tasks with the recovered hand, constant findings in the lesioned subjects were the activation of the undamaged areas adjacent to lesion site and the activation of the ipsilateral sensorimotor cortex. Bilateral activation of the primary sensorimotor cortex was never observed in the healthy co-twin controls.

The present investigation was conducted to document a role of L-threo-3,4-dihydroxyphenylserine (L-DOPS), precursor of L-norepinephrine (NE), in the functional recovery from beam-walking performance deficits in rats after unilateral sensorimotor cortex ablation. L-DOPS was administered simultaneously with benserazide (BSZ; a peripheral aromatic amino acid decarboxylase inhibitor), and the regional contents of NE in the cerebral cortex, hippocampus, and cerebellum were assayed. Behavioral recovery was demonstrated by the rats treated with L-DOPS and BSZ, and the rate of recovery was significantly different from that of either BSZ-treated or vehicle-treated control rats. The NE tissue levels in the three discrete regions of the rat brain were significantly elevated in the experimental rats receiving both L-DOPS and BSZ. The present studies indicate that increasing NE levels by the precursor L-DOPS may be responsible for facilitating behavioral recovery from beam-walking performance deficits in rats, and further suggest that L-DOPS may become one of the candidate compounds for further clinical human trials promoting functional recovery after injuries to the cerebral cortex.

Motor recovery after unilateral sensorimotor cortex ablation or sham-injury was measured in apolipoprotein E knockout and wild-type mice by testing their abilities to traverse a narrow beam. All mice trained without difficulty. Sham-operated mice performed perfectly regardless of genotype throughout testing. There was no difference in motor scores between lesioned apolipoprotein E knockout and wild-type mice on a first trial 24h after injury (P>0.05). There was a significant overall effect of lesion on motor performance (two-way repeated measures analysis of variance F(1,42)=304, P<0.0001), a significant time effect (F(17,714)=58, P<0.0001) and a lesion by time interaction (F(17,714)=58, P<0.0001). However, there was no effect of apolipoprotein E genotype group on recovery rate (i.e. there was no lesion group by genotype group by time interaction, F(17,714)=0.33, P=1.00) and no effect of genotype on the final level of motor performance 12 days after the lesion (Kruskal-Wallis H=5.79, P=0.12). These data suggest that motor recovery after unilateral injury to the sensorimotor cortex does not vary with apolipoprotein E genotype.

Object: Respiratory dysfunction including apnea frequently follows head injury in humans. The purpose of this study was to identify any structural alterations in the region of brainstem respiratory nuclei that might account for immediate postinjury respiratory abnormalities in anesthetized experimental animals., Methods: Using scanning electron microscopy, the authors examined the floor of the fourth ventricle in injured rats after a piston strike to the sensorimotor cortex that depressed the dura 1, 2, or 4 mm. The rats were killed within minutes of injury. Cortical impact depths measuring either 1 or 2 mm (eight rats) produced no respiratory abnormalities, and the structural integrity of the ependymal lining of the ventricular floor in these animals was not compromised. Thirteen rats were subjected to impact to a 4-mm depth and 10 of these exhibited immediate temporary or permanent apnea. The medullae of nine of these rats were studied using scanning electron microscopy, and the fourth ventricular floors of all nine rats showed tears. Four rats that exhibited immediate, permanent apnea had tears in the caudal fourth ventricle floor near the obex, whereas five rats with no or only transient apnea had tears located more anteriorly, near the aqueduct or laterally. Changes in cerebrospinal fluid flow or pressure dynamics may have caused these tears. Light microscopy, focused near the area postrema, revealed a shearing defect through the ependyma of the fourth ventricular floor into the subjacent neuropil with a disruption of axonal pathways., Conclusions: Respiratory neuronal network components lying within 2 mm of the area postrema may well have been disrupted by the caudal tears producing permanent apnea. A similar phenomenon could account for the transient or permanent postinjury apnea seen in humans with severe head injury.

The present work aimed at studying the participation of the homologous contralateral zone to a unilateral somatomotor cortex lesion, once the animals had showed a significant functional recovery. We studied recovery of coordinated walking after unilateral motor cortex aspiration in rats. A callosotomy was performed 20 days after the initial lesion, without significant effects. We conclude that after this time period, the intact hemisphere plays no role in the recovery process, suggesting that at this time point recovery does not depend on the integrity of corpus callosal fibers at this rostral-caudal level.

We have previously shown that lesions of the sensorimotor cortex induced by either thermocoagulation or aspiration produce different effects on axonal plasticity. We have now investigated whether these methods of lesion also influence the behavioral outcome. The behavioral effects of unilateral and bilateral lesions of the sensorimotor cortex induced by either aspiration or by thermocoagulation of pial blood vessels were examined in adult Sprague-Dawley rats. Rats were tested to determine limb use asymmetry by analyzing (1) coordinated forelimb placement and (2) paw use preference when rearing. Their responsiveness to somatosensory stimulation was tested by analyzing (1) the latency to remove sticky tape on the ventral surface of the paw, and (2) vibrissae-stimulated forelimb placing. Behavioral tests were performed prior to surgery and on day 4, 8, 12, 16, and 20 after surgery. Both unilateral lesions resulted in an over-reliance on the nonimpaired forelimb as early as 4 days after the surgery; functional recovery occurred after 16 days. Animals with bilateral lesions did not use either forelimb for support in postural support behaviors. However, this effect was more apparent in the animals with a thermocoagulatory lesion and, in contrast to the animals with an aspiration lesion, these animals did not show functional recovery. Animals with a unilateral aspiration, but not a thermocoagulatory lesion, showed a slowed response to tactile stimulation applied to the contralateral forelimb. After bilateral lesions, animals showed a slowed response to tactile stimulation applied to either forelimb at early time points after the lesion and recovery of function at later time points. These data indicate that, for the most part, lesions of the sensorimotor cortex by aspiration or thermocoagulation produce very similar effects on the behaviors examined in this study. However, unexpectedly, thermocoagulatory lesions induced a more severe (unilateral lesion) or prolonged (bilateral lesion) deficit in forelimb use than aspiration lesions. Conversely, the effect on tactile stimulation is more prominent after unilateral aspiration than thermocoagulatory lesions.

Cognitive deficits are the most enduring and disabling sequelae of human traumatic brain injury (TBI), but quantifying the magnitude, duration, and pattern of cognitive deficits produced by different types of TBI has received little emphasis in preclinical animal models. The objective of the present study was to use a battery of behavioral tests to determine if different impact sites produce different patterns of behavioral deficits and to determine how long behavioral deficits can be detected after TBI. Prior to surgery, rats were trained to criteria on delayed nonmatching to position, radial arm maze, and rotarod tasks. Rats received sham surgery (controls), midline frontal contusions (frontal TBI, 2.25 m/sec impact), or unilateral sensorimotor cortex contusions (lateral TBI, 3.22 m/sec impact) at 12 months of age and were tested throughout the next 12 months. Cognitive deficits were more robust and more enduring than sensorimotor deficits for both lateral TBI and frontal TBI groups. Lateral TBI rats exhibited transient deficits in the forelimb placing and in the rotarod test of motor/ambulatory function, but cognitive deficits were apparent throughout the 12-month postsurgery period on tests of spatial learning and memory including: (1)reacquisition of a working memory version of the radial arm maze 6-7 months post-TBI, (2) performance in water maze probe trials 8 months post-TBI, and (3) repeated acquisition of the Morris water maze 8 and 11 months post-TBI. Frontal TBI rats exhibited a different pattern of deficits, with the most robust deficits in tests of attention/orientation such as: (1) the delayed nonmatching to position task (even with no delays) 1-11 weeks post-TBI, (2) the repeated acquisition version of the water maze--especially on the first "information" trial 8 months post-TBI, (3) a test of sensorimotor neglect or inattention 8.5 months post-TBI, and (4) a DRL20 test of timing and/or sustained attention 11 months after surgery. These results suggest that long-term behavioral deficits can be detected in rodent models of TBI, that cognitive deficits seem to be more robust than sensorimotor deficits, and that different TBI impact sites produce dissociable patterns of cognitive deficits in rats.

For a period of time after unilateral brain injury, surviving neural tissue surrounding the lesion may be vulnerable to extremely high behavioral demand. Previously, we found that lesions of the forelimb representation area of the sensorimotor cortex (FL-SMC) in rats increase in size substantially when the intact forelimb is immobilized with a plaster of paris cast during the first 15 days after surgery, which forces overuse of the impaired forelimb. The present study was designed to determine whether the adult brain is more vulnerable to forced overuse of the impaired forelimb during the first 7 days post-lesion than during the second 7 days post-lesion. Using behavioral tests of forelimb use and stereological analysis of remaining tissue volume 40 days after FL-SMC lesions, we found that forced overuse of the impaired forelimb during the first 7 days after the initial damage caused expansion of neural injury and greatly interfered with restoration of function. In contrast, forced overuse of the impaired forelimb during the second 7 days had no significant effect on lesion size but nevertheless interfered with restoration of function. Thus, surviving neural tissue in the damaged hemisphere and recovery of function appear to be vulnerable to prolonged forced overuse of the impaired forelimb throughout the first 15 days, but tissue loss was detectable only when the animal was forced to use the impaired forelimb during the first 7 days after injury.

Several lines of evidence suggest that the recovery of the ability of rats to traverse a narrow beam after unilateral injury to the sensorimotor cortex is noradrenergically mediated. We tested the hypotheses that the influence of norepinephrine on beam-walking recovery occurs, at least partially, through effects in the contralateral and/or ipsilateral cerebral cortex. Rats had either a selective left or right 6-hydroxydopamine lesion or sham lesion of the dorsal noradrenergic bundle (DNB) 2 weeks before suction-ablation or sham injury of the right sensorimotor cortex. The rats' abilities to perform the beam-walking task were measured over the 10 days following cortex surgery. DNB lesions did not affect the initial severity of the beam-walking deficit and had no effect on the performance of the task in rats with sham cortex injuries. Lesions of the contralateral but not ipsilateral DNB significantly impaired recovery. Further, in cortically lesioned rats with contralateral DNB lesions, norepinephrine content in the cerebral cortex opposite to the sensorimotor cortex lesion was significantly correlated with recovery. These data suggest that the effect of norepinephrine on recovery of beam-walking ability may be partially exerted in the cerebral cortex contralateral to the injury.

These experiments on rats evaluated whether recovery of competence in certain motor tests could be enhanced by practice begun soon after traumatic brain injury (TBI). Before TBI, rats were pre-trained to cross a flat and a pegged beam. Anesthetized animals received a right sensorimotor cortex TBI. One group began task-specific testing (flat and pegged beams) on day 1 after injury and repeated 13 times in 35 days by which time functional recovery occurred. Paw preference was evaluated eight times during the 35 day period, beginning the third day after injury. A second group of injured rats remained in their home cage without any testing for 35 days after injury. From day 35 they were tested 13 times over the next 35 days on both beam tests and eight times on the paw preference test. At day 35 those rats that remained in their home cage without testing (task-specific practice) performed as well on the flat beam as the rats that began testing 1 day after injury. By day 37, their third test day, the untested rats performed as well as the tested rats on the pegged beam. Paw preference was the same in both groups of rats. These results were compared to sham-operated controls. Post-injury performance as measured by these tests indicated that most of the recovery occurred without task-specific practice. However, task-specific practice was necessary to achieve optimum performance on both beam tests. This implies that neural reorganization occurred independent of any practice. Task specific practice served to 'fine tune' the rat's performance after 35 days.

Unilateral injury to the forelimb-representation area of the sensorimotor cortex (FL-SMC) in adult rats results in use-dependent proliferation of dendritic processes, followed by partial pruning, of layer V pyramidal neurons of the contralateral homotopic cortex. In development, 'exuberant' growth of neurons is often followed by pruning, a process that has been associated with a glutamatergic-NMDA receptor mechanism. A related mechanism may play a role in injury-related pruning of dendrites in adults. The N-methyl-D-aspartate (NMDA) receptor antagonist MK801, administered throughout the pruning phase to adult animals with FL-SMC lesions, prevents dendritic pruning and disrupts behavioral recovery. Ethanol (ETOH) also acts as an NMDA receptor antagonist. It has been shown to reduce NMDA-active ion currents, inhibit NMDA-evoked electrophysiological responses, and decrease glutamate-binding in the hippocampus and cortex. ETOH also affects neuromorphology in the developing and adult cerebellum, hippocampus, and cortex. Ethanol's involvement with NMDA receptor function and its influence on dendritic morphology led us to examine its effect on dendritic pruning and behavioral recovery following unilateral FL-SMC lesions. Lesioned animals were exposed to moderate doses of ethanol in a liquid diet only during the period of dendritic pruning. As with MK801, ETOH prevented pruning and reinstated chronic behavioral asymmetries.

This study characterizes physiological, histological and behavioral effects of traumatic brain injury (TBI) produced by a controlled pneumatic impactor striking the entire right sensorimotor cortex of the anesthetized rat. Damage to both the fore- and hindlimb sensorimotor areas resulted in a hemiparetic animal which allowed us to use four sensitive behavioral/neurological tests to track the recovery sequelae after injury. Initial experiments measured cardiovascular and respiratory effects after cortical impact which depressed the dura to varying depths. Both 0.5 mm and 1 mm cortical depressions produced a momentary decrease (P < 0.05) in mean arterial blood pressure (MABP) while cortical impacts to depths of 2 mm or 3 mm produced a momentary increase (P < 0.05) in MABP. Normotension was re-established within 30 s after the initial response at all injury levels. Respiratory rate was affected only following 3 mm cortical depressions. A 1 mm cortical depression appeared ideal in terms of minimal cardiorespiratory effects, low mortality and lasting behavioral effects. For behavioral and histologic studies, therefore, additional rats were injured by a 1 mm cortical impact and tested for 8 weeks after TBI using four behavioral tests. Injured rats displayed both fore- and hindlimb deficits up to 56 days while traversing a narrow beam (P < 0.001) and up to 28 days when crossing a pegged beam (P < 0.05). Forelimb deficits evaluated on a wire grid platform were evident for 28 days (P < 0.05). Forepaw preference measured in a non-test setting indicated a bias to use the unaffected forepaw for 35 days (P < 0.05). A biphasic pattern of functional recovery was seen on all tests. A period of rapid functional recovery lasting 7 to 10 days was followed by a slower period of functional recovery lasting many weeks. Possible meanings of this biphasic recovery are discussed as issues of behavioral compensation/adaptation versus true neural recovery. Eight weeks after TBI histological analyses indicated that axonal degeneration was present in the areas adjacent to the ipsilateral cortical injury site. Degenerating fibers also extended across the corpus callosum into the homologous area in the contralateral cortex and were seen in the ipsilateral striatum, somatosensory and motor thalamic nuclei and substantia nigra. Significant axonal degeneration occurred bilaterally around the deep cerebellar nuclei. Degenerating fibers extended into the folia and terminated in the cerebellar granule cell layer. Thus the entire sensorimotor control system appeared to have been affected by a cortical injury.

Unilateral sensorimotor cortical contusion significantly decreased ipsilateral hippocampal cerebral metabolic rates of glucose utilization (CMRglu) compared to sham controls at 2 and 16 days post injury. In contrast, hippocampal CMRglu was transiently increased at 6 days post injury. Both the increased and decreased CMRglu were predominantly localized to the hippocampal CA3 subfield ipsilateral to injury and were significantly different from sham controls in the dorsal but not ventral hippocampal formation.

Measurement of the ability of rats to traverse a narrow elevated beam has been used to quantitate motor recovery after unilateral injury to the sensorimotor cortex. Lesion extent is an important variable to consider in studies of the effects of drugs on beam-walking recovery. However, traditional histologic evaluation precludes neurochemical measurements in brain tissue. The present study was carried out to determine how well the dimensions of the lesion measured at the surface of the brain correlate with subsequent motor recovery in comparison with standard histology. The maximum medial extent of the lesion (closest approximation of the lesion to the inter-hemispheric fissure) was correlated with subsequent recovery (Spearman r = 0.61, P = 0.02) whereas the lesion surface area was not correlated with recovery (Spearman r = 0.25, P = 0.30). This data compared favorably with measures that were dependent on histologic tissue preparation. Furthermore, measurements of surface lesion parameters were highly reliable (intra- and inter-observer reliability for lesion surface maximum medial extent and lesion surface area were r2 = 0.88, 0.96, 0.97, and 0.96, P = 0.0001, respectively). Lesion surface parameters provide a valid and reliable measure of lesion size and extent for studies of beam-walking recovery after injury to the sensorimotor cortex.

This study reports the effects of norepinephrine infusions into cerebellum after unilateral sensorimotor cortex injury. The results demonstrate an immediate and permanent acceleration in motor recovery in awake rats infused with 150 micrograms norepinephrine into the cerebellum contralateral to a right sensorimotor cortex ablation. A vehicle infusion or infusion of norepinephrine into the ipsilateral cerebellum produced no beneficial effects on functional recovery.

Fetal frontal cortex was transplanted into cavities formed in the right motor cortex of neonatal rats. As adults, the animals were trained to press two levers in rapid succession with their left forelimb to receive food rewards. Once they had reached an optimal level of performance, the effect of removing their transplants was assessed. Surgical removal of transplants significantly impaired the performance of 2 of 4 subjects. Placing a cross-strain skin graft to induce the immunological rejection of the transplants produced a behavioral deficit in 1 of 2 subjects with complete transplant removal. Skin grafts produced no behavioral effects in four subjects that had surviving transplants. Since the motor deficits produced by transplant removal resembled those observed following the removal of normal motor cortex, we propose that these three transplants functioned within the host brain. Histology showed that the procedures used to remove cortical grafts did not injure any host brains. Therefore, host brain damage is unlikely to account for the behavioral deterioration that followed transplant removals.

Afferent and efferent connections of the transplant, implanted in the previously damaged sensorimotor area of the mature rat cerebral cortex have been studied by means of axonal transport of horseradish peroxidase. For 5 months after transplantation neural axons of the transplant are capable to reach the caudo-putamen and thalamic structures, while connections with the spinal cord are absent. The afferent connections of the transplant are minimal and belong only to the neighbouring areas of the cortex and the caudo-putamen of the recipient brain. Presence of efferent projections to the striate and thalamic structures demonstrates specificity of the projections formed; this can be a morphological base for restoration of the functions lost after the damage of the sensorimotor area of the cortex in mature animals.

Autoradiographic and axonal degeneration staining techniques were combined in individual animals to study the distribution of corticopontine fibers. In normal animals, forelimb and hindlimb motor cortical projections terminated somatotopically within the ipsilateral pontine nuclei. Sparse crossed projections also displayed a somatotopic pattern. After unilateral sensorimotor cortical lesions in newborn rats, an increase in the crossed corticopontine fibers arising from the opposite unablated motor cortex was observed at maturity. These fibers distributed in a topographic pattern similar to the normal ipsilateral corticopontine pattern; forelimb motor cortical projections terminated rostral to hindlimb motor cortical fibers. The specific distribution of the anomalous fibers suggests that they constitute a functional pathway.

Unilateral neonatal cortical ablation induces the development of a bilateral corticorubral projection from the remaining sensorimotor cortex. The retrograde fluorescent tracers Fast blue (FB) and Nuclear yellow (NY) were used to determine if the aberrant contralateral projection arises from axon collaterals of the normal uncrossed projection. Six to 8 weeks after unilateral cortical ablation in neonatal rats, the red nuclei were injected with FB on one side and NY on the other to study the source of the normal and aberrant afferents from the cerebral cortex. In control animals, many neurons in layer V of the sensorimotor cortex were retrogradely labeled with the tracer that had been injected into the ipsilateral red nucleus. In animals with unilateral ablations, many neurons throughout the remaining sensorimotor cortex were retrogradely labeled with FB or NY. No cortical neurons were doubly labeled. In addition to demonstrating the bilaterality of the corticorubral projection in animals which had received neonatal lesions, these results indicate that the aberrant contralateral corticorubral projection does not consist of axon collaterals of the normal ipsilateral fibers.

Groups of rats were exposed to an enriched environment 2 hr per day for 30 days during the immediate pre- and/or postoperative period, or not at all. Animals in four of these groups sustained lesions in the bilateral sensorimotor cortex. One sham-operated control group was enriched pre- and postoperatively; a second control group was not. Animals were trained preoperatively to locomote across a narrow elevated runway. Testing on the locomotor task began 31 days after surgery and continued until preoperative performance levels were achieved. Preoperative enrichment had the most potent influence on initial deficit and recovery of locomotion. Animals that were enriched preoperatively failed to demonstrate any deficit postoperatively, and the topology of their hindlimb movement appeared to be normal. In preoperatively impoverished animals, postoperative enrichment reduced the degree of initial deficit and speeded recovery of locomotion when compared with animals not enriched at all. However, preoperatively impoverished rats demonstrated an aberrant topology of hindlimb movement even after they were "behaviorally recovered".