Forelimb Motor Cortex Research Articles

Anti-Nogo-A Antibody Therapy Improves Functional Outcome Following Traumatic Brain Injury

Background Traumatic brain injury (TBI) can cause sensorimotor deficits, and recovery is slow and incomplete. There are no effective pharmacological treatments for recovery from TBI, but research indicates potential for anti-Nogo-A antibody (Ab) therapy. This Ab neutralizes Nogo-A, an endogenous transmembrane protein that inhibits neuronal plasticity and regeneration. Objective We hypothesized that anti-Nogo-A Ab treatment following TBI results in disinhibited axonal growth from the contralesional cortex, the establishment of new compensatory neuronal connections, and improved function. Methods We modeled TBI in rats using the controlled cortical impact method, resulting in focal brain damage and motor deficits like those observed in humans with a moderate cortical TBI. Rats were trained on the skilled forelimb reaching task and the horizontal ladder rung walking task. They were then given a TBI, targeting the caudal forelimb motor cortex, and randomly divided into 3 groups: TBI-only, TBI + Anti-Nogo-A Ab, and TBI + Control Ab. Testing resumed 3 days after TBI and continued for 8 weeks, when rats received an injection of the anterograde neuronal tracer, biotinylated dextran amine (BDA), into the corresponding area contralateral to the TBI. Results We observed significant improvement in rats that received anti-Nogo-A Ab treatment post-TBI compared to controls. Analysis of BDA-positive axons revealed that anti-Nogo-A Ab treatment resulted in cortico-rubral plasticity to the deafferented red nucleus. Conclusions. Anti-Nogo-A Ab treatment may improve functional recovery via neuronal plasticity to brain areas important for skilled movements, and this treatment shows promise to improve outcomes in humans who have suffered a TBI.

Enriched Rehabilitation Reduces Abnormal Motor Synergies and Enhances Motor Plasticity Following Severe Stroke in Rats.

Stroke results in loss of upper motor neuron control over voluntary movements and emergence of abnormal synergies. Presently, it is unclear to what extent poststroke recovery reflects true recovery (restitution), compensation, or some combination of these processes. Here, we investigated this question using behavioral and kinematic analyses of skilled reaching in rats subjected to severe stroke that affected both the forelimb motor cortex and dorsolateral striatum. After stroke, male rats either spontaneously recovered or received enriched rehabilitation. We assessed forelimb motor recovery using behavioral and kinematic outcome measures. To provide insights into the mechanisms underlying the effects of rehabilitation on behavior, we used intracortical microstimulation and FosB (protein fosB) immunostaining techniques. Enriched rehabilitation significantly improved food pellet retrieval in the staircase-reaching task. Rehabilitation resulted in several poststroke flexion synergies returning to prestroke patterns, and across subjects, these changes correlated with the intensity of rehabilitation. Enriched rehabilitation increased the proportion of distal movement representation in the perilesional cortex and increased use-dependent activation in the ipsilesional red nucleus. These results provide evidence that enriched rehabilitation enhances recovery, at least in part, by restitution of forelimb function following severe stroke. Furthermore, the restitution of function is associated with changes in multiple motor-related structures at different levels of the central nervous system. A better understanding of the processes that underlie improved motor performance, along with the identification of midbrain circuits activated by rehabilitation, represent new insights and potential targets for optimizing poststroke recovery.

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia

L-DOPA-induced dyskinesia (LID) in Parkinson’s disease has been linked to oscillatory neuronal activities in the cortico-basal ganglia network. We set out to examine the pattern of cortico-basal ganglia oscillations induced by selective agonists of D1 and D2 receptors in a rat model of LID. Local field potentials were recorded in freely moving rats using large-scale electrodes targeting three motor cortical regions, dorsomedial and dorsolateral striatum, external globus pallidus, and substantial nigra pars reticulata. Abnormal involuntary movements were elicited by the D1 agonist SKF82958 or the D2 agonist sumanirole, while overall motor activity was quantified using video analysis (DeepLabCut). Both SKF82958 and sumanirole induced dyskinesia, although with significant differences in temporal course, overall severity, and body distribution. The D1 agonist induced prominent narrowband oscillations in the high gamma range (70–110 Hz) in all recorded structures except for the nigra reticulata. Additionally, the D1 agonist induced strong functional connectivity between the recorded structures and the phase analysis revealed that the primary motor cortex (forelimb area) was leading a supplementary motor area and striatum. Following treatment with the D2 agonist, narrowband gamma oscillations were detected only in forelimb motor cortex and dorsolateral striatum, while prominent oscillations in the theta band occurred in the globus pallidus and nigra reticulata. Our results reveal that the dyskinetic effects of D1 and D2 receptor agonists are associated with distinct patterns of cortico-basal ganglia oscillations, suggesting a recruitment of partially distinct networks.

Complex forelimb movements and cortical topography evoked by intracortical microstimulation in male and female mice.

The motor cortex is crucial for the voluntary control of skilled movement in mammals and is topographically organized into representations of the body (motor maps). Intracortical microstimulation of the motor cortex with long-duration pulse trains (LD-ICMS; ~500ms) evokes complex movements, occurring in multiple joints or axial muscles, with characteristic movement postures and cortical topography across a variety of mammalian species. Although the laboratory mouse is extensively used in basic and pre-clinical research, high-resolution motor maps elicited with electrical LD-ICMS in both sexes of the adult mouse has yet to be reported. To address this knowledge gap, we performed LD-ICMS of the forelimb motor cortex in both male (n = 10) and naturally cycling female (n = 8) C57/BL6J mice under light ketamine-xylazine anesthesia. Complex and simple movements were evoked from historically defined caudal (CFA) and rostral (RFA) forelimb areas. Four complex forelimb movements were identified consisting of Elevate, Advance, Dig, and Retract postures with characteristic movement sequences and endpoints. Furthermore, evoked complex forelimb movements and cortical topography in mice were organized within the CFA in a unique manner relative to a qualitative comparison with the rat.

Neurons of rat motor cortex become active during both grasping execution and grasping observation

In non-human primates, a subset of frontoparietal neurons (mirror neurons) respond both when an individual executes an action and when it observes another individual performing a similar action.1-8 Mirror neurons constitute an observation and execution matching system likely involved in others' actions processing3,5,9 and in a large set of complex cognitive functions.10,11 Here, we show that the forelimb motor cortex of rats contains neurons presenting mirror properties analogous to those observed in macaques. We provide this evidence by event-related potentials acquired by microelectrocorticography and intracortical single-neuron activity, recorded from the same cortical region during grasping execution and observation. Mirror responses are highly specific, because grasping-related neurons do not respond to the observation of either grooming actions or graspable food alone. These results demonstrate that mirror neurons are present already in species phylogenetically distant from primates, suggesting for them a fundamental, albeit basic, role not necessarily related to higher cognitive functions. Moreover, because murine models have long been valued for their superior experimental accessibility and rapid life cycle, the present finding opens an avenue to new empirical studies tackling questions such as the innate or acquired origin of sensorimotor representations and the effects of social and environmental deprivation on sensorimotor development and recovery.

Gamma frequency activation of inhibitory neurons in the acute phase after stroke attenuates vascular and behavioral dysfunction

Alterations in gamma oscillations occur in several neurological disorders, and the entrainment of gamma oscillations has been recently proposed as a treatment for neurodegenerative disease. Optogenetic stimulation enhances recovery in models of stroke when applied weeks after injury; however, the benefits of acute brain stimulation have not been investigated. Here, we report beneficial effects of gamma-frequency modulation in the acute phase, within 1 h, after stroke. Transgenic VGAT-ChR2 mice are subject to awake photothrombotic stroke in an area encompassing the forelimb sensory and motor cortex. Optogenetic stimulation at 40Hz in the peri-infarct zone recovers neuronal activity 24h after stroke in motor and parietal association areas, as well as blood flow over the first week after stroke. Stimulation significantly reduces lesion volume and improves motor function. Our results suggest that acute-phase modulation of cortical oscillatory dynamics may serve as a target for neuroprotection against stroke.

Stability of motor cortex network states during learning-associated neural reorganizations.

A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.NEW & NOTEWORTHY The neural activity reorganizes throughout motor learning, but how this reorganization impacts the stability of network states is unclear. We used two-photon calcium imaging to investigate how the network states in layer 2/3 and layer 5 of forelimb motor and premotor cortex are modulated by motor learning. We show that motor cortex network states are layer-specific and constant regarding criticality during neural activity reorganization, and suggests that layer-specific constraints could be motivated by different functions.

The Home-Cage Automated Skilled Reaching Apparatus (HASRA): Individualized Training of Group-Housed Mice in a Single Pellet Reaching Task.

The single pellet reaching task is commonly used in rodents to assess the acquisition of fine motor skill and recovery of function following nervous system injury. Although this task is useful for gauging skilled forelimb use in rodents, the process of training animals is labor intensive and variable across studies and labs. To address these limitations, we developed a single pellet reaching paradigm for training and testing group housed mice within their home cage. Mice enter a training compartment attached to the outside of the cage and retrieve millet seeds presented on a motorized pedestal that can be individually positioned to present seeds to either forelimb. To identify optimal training parameters, we compared task participation and success rates between groups of animals that were presented seeds at two different heights (floor vs mouth height) and at different intervals (fixed-time vs trial-based). The mouth height/fixed interval presentation style was most effective at promoting reaching behavior as all mice reached for seeds within 5 d. Using this paradigm, we assessed stroke-induced deficits in home-cage reaching. Following three weeks of baseline training, reaching success rate was ∼40%, with most trials performed during the dark cycle. A forelimb motor cortex stroke significantly decreased interaction with presented seeds within the first 2 d and impaired reaching success rates for the first 7 d. Our data demonstrate that group-housed mice can be efficiently trained on a single pellet reaching task in the home cage and that this assay is sensitive to stroke induced motor impairments.

Motor learning promotes remyelination via new and surviving oligodendrocytes.

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activity-dependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here, we report that while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases OPC differentiation, oligodendrocyte generation, and myelin sheath remodeling in the forelimb motor cortex. Immediately followingdemyelination, neurons exhibit hyperexcitability, learning is impaired, and behavioral intervention provides no benefit to remyelination. However, partial remyelination restores neuronal and behavioral function allowing learning to enhance oligodendrogenesis, remyelination of denuded axons, and the ability of surviving oligodendrocytes to generate new myelinsheaths. Previously considered controversial, we show that sheath generation by mature oligodendrocytes is not only possible but also increases myelin pattern preservation following demyelination, presenting a new target for therapeutic interventions. Together, our findings demonstrate that precisely-timed motor learning improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.

Modeling Mixed Vascular and Alzheimer's Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD Transgenic Mice.

Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8weeks of age. Behavioral tests were done at 7, 10, 15, and 20weeks. A subset of animals underwent 18FDG-PET/CT. At 20weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.

Independent replication of motor cortex and cervical spinal cord electrical stimulation to promote forelimb motor function after spinal cord injury in rats

Cervical spinal cord injury (SCI) impairs arm and hand function largely by interrupting descending tracts. Most SCI spare some axons at the lesion, including the corticospinal tract (CST), which is critical for voluntary movement. We targeted descending motor connections with paired electrical stimulation of motor cortex and cervical spinal cord in the rat. We sought to replicate the previously published effects of intermittent theta burst stimulation of forelimb motor cortex combined with trans-spinal direct current stimulation placed on the skin over the neck to target the cervical enlargement. We hypothesized that paired stimulation would improve performance in skilled walking and food manipulation (IBB) tasks. Rats received a moderate C4 spinal cord contusion injury (200 kDynes), which ablates the main CST. They were randomized to receive paired stimulation for 10 consecutive days starting 11 days after injury, or no stimulation. Behavior was assessed weekly from weeks 4–7 after injury, and then CST axons were traced. Rats with paired cortical and spinal stimulation achieved significantly better forelimb motor function recovery, as measured by fewer stepping errors on the horizontal ladder task (34 ± 9% in stimulation group vs. 51 ± 18% in control, p = .013) and higher scores on the food manipulation task (IBB, 0–9 score; 7.2 ± 0.8 in stimulated rats vs. 5.2 ± 2.6 in controls, p = .025). The effect size for both tasks was large (Cohen's d = 1.0 and 0.92, respectively). The CST axon length in the cervical spinal cord did not differ significantly between the groups, but there was denser and broader ipsilateral axons distribution distal to the spinal cord injury. The large behavioral effect and replication in an independent laboratory validate this approach, which will be trialed in cats before being tested in people using non-invasive methods.

Abstract WP139: MRI Evaluation and Functional Assessment of Brain Injury Improvement After 3K3A-Activated Protein C Treatment for Murine White Matter Stroke

Introduction: Subcortical white matter stroke (WMS) accounts for 25% of all incidences of stroke and results in severe motor and cognitive disability. WMS stands as the second leading cause of dementia and is notably prevalent in older adults. Activated protein C (APC), a plasma serine protease with potent antithrombotic and cell-signaling activities, was engineered to reduce bleeding risk while retaining normal cell-signaling activities (anti-inflammatory, anti-apoptotic, and neuroregenerative, etc. activities). The engineered variant, 3K3A-APC, is neuroprotective in preclinical models of ischemic stroke with large infarcts involving common large arteries and gray matter. A multicenter Phase 2 randomized clinical trial enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC in acute ischemic stroke patients following endovascular treatments (NCT02222714). Methods: In this new study, a murine WMS was induced by the vasoconstrictor N5-(1-iminoethyl)-L-ornithine, dihydrochloride (L-Nio) by injection into the subcortical white matter ventral to the mouse forelimb motor cortex using the Neurostar motorized ultra-precise small animal stereotaxic instrument. Mice received intravenously 0.2 mg/kg recombinant murine 3K3A-APC or saline at 4, 24, 48 and 72 h after L-Nio. Then MRI scans were performed using a 7T PET/MRI scanner (MR Solutions) and a standard quadrature coil at 1 and 7 days after the stroke. Results: Both MRI and histological results showed that 3K3A-APC significantly reduced the lesion volume, increased the viability of oligodendrocytes and neurons, and protected against blood brain barrier damage at 1 and 7 days after stroke. Behavioral tests showed that 3K3A-APC improved functional recovery. Conclusions: These results demonstrated that 3K3A-APC might be an effective treatment for white matter stroke.

Characterizing Spontaneous Motor Recovery Following Cortical and Subcortical Stroke in the Rat

Background. Stroke is a leading cause of neurological disability, often resulting in long-term motor impairments due to damage to cortical or subcortical motor areas. Despite the high prevalence of subcortical strokes in the clinical population, preclinical research has primarily focused on investigating and treating cortical strokes. Moreover, while both humans and animals show spontaneous recovery following stroke, little is known about how injury location affects this process. Objective. To capture the heterogeneity of human stroke and examine how stroke location affects spontaneous motor recovery following damage to cortical, subcortical, or a combination of both areas. Methods. Endothelin-1 (ET-1), a potent vasoconstrictor, was used to produce focal infarcts in the forelimb motor cortex (FMC), the dorsolateral striatum (DLS) or both the FMC and DLS in male Sprague-Dawley rats. The spontaneous recovery profile of animals was followed over an 8-week period using a battery of behavioral tasks assessing motor function and limb preference. Results. All 3 groups showed significant impairments on the Montoya staircase, beam, and cylinder tests following stroke, with the combined group (FMC + DLS) having the largest and most persistent impairments. Importantly, spontaneous recovery was not simply dependent on lesion volume, but on location, and the behavioral test employed. Conclusions. Stroke location markedly and differentially influences the level of spontaneous functional recovery, which is only captured by using multiple outcome measures. These results illustrate the need for preclinical stroke models to align with the heterogeneity of human stroke, especially with respect to lesion location, size, and outcome measures.

Corticospinal Circuits from the Sensory and Motor Cortices Differentially Regulate Skilled Movements through Distinct Spinal Interneurons

Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, wemap the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects ofskilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10+ interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3+ spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3+ interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in themotor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits.

Abstract WP90: Activate Protein C Analog Protects Ischemic Injury of Subcortical White Matter in Mice

Subcortical white matter stroke constitutes up to 30% of all stroke subtypes, occurs initially as silent infarcts in the white matter (WM), and contributes significantly to the development of vascular dementia. Activated protein C (APC) is a plasma serine protease that is capable of antithrombotic, anti-inflammatory, anti-apoptotic, and cell-signaling activities. 3K3A-APC, a recombinant variant of APC with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, has shown benefits in preclinical models of ischemic stroke with big infarcts involving large brain arteries and gray matter. A multicenter Phase 2 randomized clinical trial has enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC in acute ischemic stroke patients following endovascular thrombolysis (NCT02222714). In this study, subcortical WM stroke model was induced by vasoconstrictor N5-(1-iminoethyl)-L-ornithine, dihydrochloride (L-Nio). L-Nio (Calbiochem) was injected into subcortical WM of the anterior cingulum (AC) of the corticolimbic circuit or the subcortical white matter ventral to the mouse forelimb motor cortex using the Neurostar motorized ultra-precise small animal stereotaxic instrument (Model 963SD). Mice received 0.2 mg/kg intravenously of recombinant murine 3K3A-APC or saline at 4, 24, 48 and 72 h after stroke. The results indicate that 3K3A-APC significantly reduces the lesion volume and protected blood brain barrier damage 3 days after stroke, and improves remote memory function 4 weeks after stroke, compared to vehicle. These results demonstrate that 3K3A-APC might be an effective treatment for white matter stroke.

The Clinical Features in Subarachnoid Hemorrhage of Unknown Etiology

Background: Ongoing clinical trials are testing the effect of fluoxetine delivered post-stroke where a majority of patients are taking statins. This study determined the influence of the timing of administration of fluoxetine and statin on the final infarct volume and the risk of secondary bleeding in an animal model of ischemic stroke. Methods and findings: Ischemic strokes were induced by endothelin-1 injection into two cortical sites of 10-12 month old female rats, targeting the forelimb motor cortex. Combined medications (5 mg/kg fluoxetine and 1 mg/kg simvastatin) were orally administered either beginning 6-12 hours or 20-26 hours after stroke induction and continued daily for 90 days. Infarct volumes were assessed at poststroke day 91 using Nissl stained coronal brain sections. Control animals typically had 5-13 mm3 infarct volumes following endothelin-1 induced stroke. Animals that received fluoxetine and simvastatin (FS) beginning 20- 26 hours after stroke induction showed a strong trend of reduced infarct volume (3±0.3447 mm3 SEM, P=0.0563). Earlier drug delivery (6-12 hours after stroke) resulted in significantly larger infarct volumes (15.44.260 mm3 SEM, P=0.0157) when the drug groups were directly compared. Examination of the infarcts showed that earlier drug delivery induced secondary hemorrhagic infarcts, while later delivery did not (P=0.0427; Fisher’s exact test). Conclusion: There is a danger of secondary bleeding if fluoxetine and simvastatin are combined within 6-12 hours of ischemic stroke induction in rats resulting in larger infarct volumes. Delaying fluoxetine and simvastatin delivery to 20-26 hours after stroke induction in rats, however, reduces infarct volume and significantly lowers the risk of secondary hemorrhagic infarcts.

Combining robotic training and inactivation of the healthy hemisphere restores pre-stroke motor patterns in mice.

Focal cortical stroke often leads to persistent motor deficits, prompting the need for more effective interventions. The efficacy of rehabilitation can be increased by 'plasticity-stimulating' treatments that enhance experience-dependent modifications in spared areas. Transcallosal pathways represent a promising therapeutic target, but their role in post-stroke recovery remains controversial. Here, we demonstrate that the contralesional cortex exerts an enhanced interhemispheric inhibition over the perilesional tissue after focal cortical stroke in mouse forelimb motor cortex. Accordingly, we designed a rehabilitation protocol combining intensive, repeatable exercises on a robotic platform with reversible inactivation of the contralesional cortex. This treatment promoted recovery in general motor tests and in manual dexterity with remarkable restoration of pre-lesion movement patterns, evaluated by kinematic analysis. Recovery was accompanied by a reduction of transcallosal inhibition and 'plasticity brakes' over the perilesional tissue. Our data support the use of combinatorial clinical therapies exploiting robotic devices and modulation of interhemispheric connectivity.

Cortical electrical stimulation in female rats with a cervical spinal cord injury to promote axonal outgrowth.

Electrical stimulation (ES) to promote corticospinal tract (CST) repair after spinal cord injury (SCI) is underinvestigated. This study is the first to detail intracortical ES of the injured CST. We hypothesize that cortical ES will promote CST collateralization and regeneration, prevent dieback, and improve recovery in an SCI rat model. The CST was transected at the the fourth cervical level in adult female Lewis rats trained in a stairwell grasping task. Animal groups included (a) ES333 (n = 14; 333 Hz, biphasic pulse for 0.2-ms duration every 500 ms, 30 pulses per train); (b) ES20 (n = 14; 20 Hz, biphasic pulse for 0.2-ms duration every 1 s, 60 pulses per train); (c) SCI only (n = 10); and (d) sham (n = 10). ES of the injured forelimb's motor cortex was performed for 30 min immediately prior to SCI. Comparisons between histological data were performed with a 1-way ANOVA or Kruskal-Wallis test, and grasping scores were compared using repeated-measures 2-way ANOVA. Significantly more axonal collateralization was found in ES333 animals compared with controls (p < .01). Axonal dieback analysis revealed ES20 rats to have consistently more dieback than the other groups at all points measured (p < .05). No difference in axonal regeneration was found between groups, nor was there any difference in functional recovery. Cortical ES of the injured CST results in increased collateral sprouting and influences neuroplasticity depending on the ES parameters used. Further investigation regarding optimal parameters and its functional effects is required.

The role of forelimb motor cortex areas in goal directed action in mice

Mammalian motor cortex consists of several interconnected subregions thought to play distinct roles in voluntary movements, yet their specific role in decision making and execution is not completely elucidated. Here we used transient optogenetic inactivation of the caudal forelimb area (CFA) and rostral forelimb area (RFA) in mice as they performed a directional joystick task. Based on a vibrotactile cue applied to their forepaw, mice were trained to push or pull a joystick after a delay period. We found that choice and execution are temporally segregated processes. CFA and RFA were both essential during the stimulus delivery for correct choice and during the answer period for motor execution. Fine, distal motor deficits were restricted to CFA inactivation. Surprisingly, during the delay period neither area alone, but only combined inactivation was able to affect choice. Our findings suggest transient and partially distributed neural processing of choice and execution across different subregions of the motor cortex.

Unilateral forelimb sensorimotor cortex devascularization disrupts the topographic and kinematic characteristics of hand movements while string-pulling for food in the rat

String-pulling by the rat is a bimanual act, in which an upright animal retrieves a piece of food attached to the end of the string by downward hand-over-hand movements. The present study compared the movements of string-pulling, using topographic and kinematic measures of hand movement, in control rats and rats with unilateral sensorimotor motor cortex lesion produced by removal of the pia matter. In the first week following devascularization, the rhythmicity and accuracy of string-pulling movements decomposed; however, thereafter the rhythm of bilateral alternation was restored. Over 70days of testing, distance traveled decreased for both hands in the control and lesion groups, suggesting that both groups displayed an increase in string-pulling efficiency. Nevertheless, the lesion group exhibited more missed string contacts with the (contralateral-to-lesion) hand and more grasps in which the string was hooked between the digits with both hands. In addition, an increase in mouth grasps was observed in the lesion group. Motion capture analyses revealed that the lesion group exhibited longer reach and withdraw movements and these movements were longer for the ipsilateral-to-lesion vs contralateral-to-lesion hand. Thus, although rhythmicity of string-pulling behavior recovers after sensorimotor cortex devascularization, the contralateral-to-lesion hand contributed less to string pulling and requires mouth grasps to stabilize the string for grasping. The results are discussed in relation to contemporary theories of the contributions of the forelimb motor cortex to skilled movement and the potential use of string-pulling as a therapy for brain injury.