Effects of noninvasive neuromodulation targeting the spinal cord on early learning of force control by the digits.

AIMS: Control of finger forces underlies our capacity for skilled hand movements acquired during development and reacquired after neurological injury. Learning force control by the digits, therefore, predicates our functional independence. Noninvasive neuromodulation targeting synapses that link corticospinal neurons onto the final common pathway via spike-timing-dependent mechanisms can alter distal limb motor output on a transient basis, yet these effects appear subject to individual differences. Here, we investigated how this form of noninvasive neuromodulation interacts with task repetition to influence early learning of force control during precision grip. METHODS: The unique effects of neuromodulation, task repetition, and neuromodulation coinciding with task repetition were tested in three separate conditions using a within-subject, cross-over design (n = 23). RESULTS: We found that synchronizing depolarization events within milliseconds of stabilizing precision grip accelerated learning but only after accounting for individual differences through inclusion of subjects who showed upregulated corticospinal excitability at 2 of 3 time points following conditioning stimulation (n = 19). CONCLUSIONS: Our findings provide insights into how the state of the corticospinal system can be leveraged to drive early motor skill learning, further emphasizing individual differences in the response to noninvasive neuromodulation. We interpret these findings in the context of biological mechanisms underlying the observed effects and implications for emerging therapeutic applications.

PTEN deletion in spinal pathways via retrograde transduction with AAV-RG enhances forelimb motor recovery after cervical spinal cord injury; Sex differences and late-onset pathophysiologies.

Spinal cord injuries (SCI) cause permanent functional impairments due to interruption of motor and sensory pathways. Regeneration of axons does not occur due to lack of intrinsic growth capacity of adult neurons and extrinsic inhibitory factors, especially at the injury site. However, some regeneration can be achieved via deletion of the phosphatase and tensin homolog (PTEN) in cells of origin of spinal pathways. Here, we deployed an AAV variant that is retrogradely transported (AAV-rg) to deliver gene modifying cargos to the cells of origin of multiple pathways interrupted by SCI, testing whether this promoted recovery of motor function. PTENf/f;RosatdTomato mice and control RosatdTomato mice received injections of different doses (number of genome copies, GCs) of AAV-rg/Cre into the cervical spinal cord at the time of a C5 dorsal hemisection injury. Forelimb grip strength was tested over time using a grip strength meter. PTENf/f;RosatdTomato mice with AAV-rg/Cre (PTEN-deleted) exhibited substantial improvements in forelimb gripping ability in comparison to controls. Of note, there were major sex differences in the extent of recovery, with male mice exhibiting greater recovery than females. However, at around 5-7 weeks post-injury/injection, many mice with SCI and AAV-rg-mediated PTEN deletion began to exhibit pathophysiologies involving excessive scratching of the ears and back of the neck and rigid forward extension of the hindlimbs. These pathophysiologies increased in incidence and severity over time. Our results reveal that although intra-spinal injections of AAV-rg/Cre in PTENf/f;RosatdTomato mice can enhance forelimb motor recovery after SCI, late-developing functional abnormalities occur with the experimental conditions used here. Mechanisms underlying late-developing pathophysiologies remain to be defined.

Correlation between spasticity and corticospinal/corticoreticular tract status in stroke patients after early stage.

We investigated the correlation between spasticity and the states of the corticospinal tract (CST) and corticoreticular tract (CRT) in stroke patients after early stage. Thirty-eight stroke patients and 26 healthy control subjects were recruited. The modified Ashworth scale (MAS) scale after the early stage (more than 1 month after onset) was used to determine the spasticity state of the stroke patients. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), fiber number (FN), and ipsilesional/contra-lesional ratios for diffusion tensor tractography (DTT) parameters of the CST and CRT after the early stage were measured in both ipsi- and contra-lesional hemispheres. This study was conducted retrospectively. The FA and FN CST-ratios in the patient group were significantly lower than those of the control group (P < .05), except for the ADC CST-ratio (P > .05). Regarding the DTT parameters of the CRT-ratio, the patient group FN value was significantly lower than that of the control group (P < .05), whereas the FA and ADC CRT-ratios did not show significant differences between the patient and control groups (P > .05). MAS scores showed a strong positive correlation with the ADC CRT-ratio (P < .05) and a moderate negative correlation with the FN CRT-ratio (P < .05). We observed that the injury severities of the CST and CRT were related to spasticity severity in chronic stroke patients; moreover, compared to the CST, CRT status was more closely related to spasticity severity.

Increased intensity of unintended mirror muscle contractions after cervical spinal cord injury is associated with changes in interhemispheric and corticomuscular coherences.

Mirror contractions refer to unintended contractions of the contralateral homologous muscles during voluntary unilateral contractions or movements. Exaggerated mirror contractions have been found in several neurological diseases and indicate dysfunction or lesion of the cortico-spinal pathway. The present study investigates mirror contractions and the associated interhemispheric and corticomuscular interactions in adults with spinal cord injury (SCI) - who present a lesion of the cortico-spinal tract - compared to able-bodied participants (AB). Eight right-handed adults with chronic cervical SCI and ten age-matched right-handed able-bodied volunteers performed sets of right elbow extensions at 20% of maximal voluntary contraction. Electromyographic activity (EMG) of the right and left elbow extensors, interhemispheric coherence over cerebral sensorimotor regions evaluated by electroencephalography (EEG) and corticomuscular coherence between signals over the cerebral sensorimotor regions and each extensor were quantified. Overall, results revealed that participants with SCI exhibited (1) increased EMG activity of both active and unintended active limbs, suggesting more mirror contractions, (2) reduced corticomuscular coherence between signals over the left sensorimotor region and the right active limb and increased corticomuscular coherence between the right sensorimotor region and the left unintended active limb, (3) decreased interhemispheric coherence between signals over the two sensorimotor regions. The increased corticomuscular communication and decreased interhemispheric communication may reflect a reduced inhibition leading to increased communication with the unintended active limb, possibly resulting to exacerbated mirror contractions in SCI. Finally, mirror contractions could represent changes of neural and neuromuscular communication after SCI.

Viral expression of constitutively active AKT3 induces CST axonal sprouting and regeneration, but also promotes seizures.

Increasing the intrinsic growth potential of neurons after injury has repeatedly been shown to promote some level of axonal regeneration in rodent models. One of the most studied pathways involves the activation of the PI3K/AKT/mTOR pathways, primarily by reducing the levels of PTEN, a negative regulator of PI3K. Likewise, activation of signal transducer and activator of transcription 3 (STAT3) has previously been shown to boost axonal regeneration and sprouting within the injured nervous system. Here, we examined the regeneration of the corticospinal tract (CST) after cortical expression of constitutively active (ca) Akt3 and STAT3, both separately and in combination. Overexpression of caAkt3 induced regeneration of CST axons past the injury site independent of caSTAT3 overexpression. STAT3 demonstrated improved axon sprouting compared to controls and contributed to a synergistic improvement in effects when combined with Akt3 but failed to promote axonal regeneration as an individual therapy. Despite showing impressive axonal regeneration, animals expressing Akt3 failed to show any functional improvement and deteriorated with time. During this period, we observed progressive Akt3 dose-dependent increase in behavioral seizures. Histology revealed increased phosphorylation of ribosomal S6 protein within the unilateral cortex, increased neuronal size, microglia activation and hemispheric enlargement (hemimegalencephaly).

Lateral Corticospinal Tract and Dorsal Column Damage: Predictive Relationships With Motor and Sensory Scores at Discharge From Acute Rehabilitation After Spinal Cord Injury.

OBJECTIVE: To determine if lateral corticospinal tract (LCST) integrity demonstrates a significant predictive relationship with future ipsilateral lower extremity motor function (LEMS) and if dorsal column (DC) integrity demonstrates a significant predictive relationship with future light touch (LT) sensory function post spinal cord injury (SCI) at time of discharge from inpatient rehabilitation. DESIGN: Retrospective analyses of imaging and clinical outcomes. SETTING: University and academic hospital. PARTICIPANTS: A total of 151 participants (N=151) with SCI. INTERVENTIONS: Inpatient rehabilitation. MAIN OUTCOME MEASURES: LEMS and LT scores at discharge from inpatient rehabilitation. RESULTS: In 151 participants, right LCST spared tissue demonstrated a significant predictive relationship with right LEMS percentage recovered (ß=0.56; 95% confidence interval [CI], 0.37-0.73; R=0.43; P<.001). Left LCST spared tissue demonstrated a significant predictive relationship with left LEMS percentage recovered (ß=0.66; 95% CI, 0.50-0.82; R=0.51; P<.001). DC spared tissue demonstrated a significant predictive relationship with LT percentage recovered (ß=0.69; 95% CI, 0.52-0.87; R=0.55; P<.001). When subgrouping the participants into motor complete vs incomplete SCI, motor relationships were no longer significant, but the sensory relationship remained significant. Those who had no voluntary motor function but recovered some also had significantly greater LCST spared tissue than those who did not recover motor function. CONCLUSIONS: LCST demonstrated significant moderate predictive relationships with lower extremity motor function at the time of discharge from inpatient rehabilitation, in an ipsilesional manner. DC integrity demonstrated a significant moderate predictive relationship with recovered function of LT. With further development, these neuroimaging methods might be used to predict potential deficits after SCI and to provide corresponding targeted interventions.

Laplacian-Regularized Mean Apparent Propagator-MRI in Evaluating Corticospinal Tract Injury in Patients with Brain Glioma.

OBJECTIVE: To evaluate the application of laplacian-regularized mean apparent propagator (MAPL)-MRI to brain glioma-induced corticospinal tract (CST) injury. MATERIALS AND METHODS: This study included 20 patients with glioma adjacent to the CST pathway who had undergone structural and diffusion MRI. The entire CSTs of the affected and healthy sides were reconstructed, and the peritumoral CSTs were manually segmented. The morphological characteristics of the CST (track number, average length, volume, displacement of the affected CST) were examined and the diffusion parameter values, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), mean squared displacement (MSD), q-space inverse variance (QIV), return-to-origin probability (RTOP), return-to-axis probabilities (RTAP), and return-to-plane probabilities (RTPP) along the entire and peritumoral CSTs, were calculated. The entire and peritumoral CST characteristics of the affected and healthy sides as well as those relative CST characteristics of the patients with motor weakness and normal motor function were compared. RESULTS: The track number, volume, MD, RD, MSD, QIV, RTAP, RTOP, and RTPP of the entire and peritumoral CSTs changed significantly for the affected side, whereas the AD and FA changed significantly only in the peritumoral CST (p < 0.05). In patients with motor weakness, the relative MSD of the entire CST, QIV of the entire and peritumoral CSTs, and the AD, MD, RD of the peritumoral CST were significantly higher, whereas the RTPP of the entire and peritumoral CSTs and the RTOP of the peritumoral CST were significantly lower than those in patients with normal motor function (p < 0.05 for all). In contrast, no significant changes were found in the CST morphological characteristics, FA, or RTAP (p > 0.05 for all). CONCLUSION: MAPL-MRI is an effective approach for evaluating microstructural changes after CST injury. Its sensitivity may improve when using the peritumoral CST features.

Effects of a contusive spinal cord injury on cortically-evoked spinal spiking activity in rats.

Objective.The purpose of this study was to determine the effects of spinal cord injury (SCI) on spike activity evoked in the hindlimb spinal cord of the rat from cortical electrical stimulation.Approach.Adult, male, Sprague Dawley rats were randomly assigned to a Healthy or SCI group. SCI rats were given a 175 kDyn dorsal midline contusion injury at the level of the T8 vertebrae. At 4 weeks post-SCI, intracortical microstimulation (ICMS) was delivered at several sites in the hindlimb motor cortex of anesthetized rats, and evoked neural activity was recorded from corresponding sites throughout the dorsoventral depths of the spinal cord and EMG activity from hindlimb muscles.Main results.In healthy rats, post-ICMS spike histograms showed reliable, evoked spike activity during a short-latency epoch 10-12 ms after the initiation of the ICMS pulse train (short). Longer latency spikes occurred between ∼20 and 60 ms, generally following a Gaussian distribution, rising above baseline at timeLON, followed by a peak response (Lp), and then falling below baseline at timeLOFF. EMG responses occurred betweenLONandLp( 25-27 ms). In SCI rats, short-latency responses were still present, long-latency responses were disrupted or eliminated, and EMG responses were never evoked. The retention of the short-latency responses indicates that spared descending spinal fibers, most likely via the cortico-reticulospinal pathway, can still depolarize spinal cord neurons after a dorsal midline contusion injury.Significance.This study provides novel insights into the role of alternate pathways for voluntary control of hindlimb movements after SCI that disrupts the corticospinal tract in the rat.

A preliminary study on the application of DTI in the treatment of brain tumors in motor function areas with gamma knife.

OBJECTIVES: The treatment safety and efficiency as well as the life quality of patients are still main concerns in gamma knife radiosurgery. In this study, the feasibility of applying diffusion tensor imaging (DTI) in gamma knife radiosurgery for the treatment of brain tumor in motor function areas was investigated, which aims to provide protection on the pyramidal tract and preserve the motor function in patients. PATIENTS AND METHODS: Total 74 patients with solid brain tumor were enrolled and divided into DTI group and control group. The tumor control rate was assessed at 3 months after surgery. The muscle strength of affected limb, KPS scores, ZEW scores and complications were evaluated at 3 and 6 months after gamma knife radiosurgery. RESULTS: Our results indicated that the tumor control rate, complication rate, the muscle strength of affected limb and KPS scores were not significantly different between the two groups at 3 months after surgery. At 6 months after gamma knife radiosurgery, the complication rate (0% vs 50 %, P = 0.044), KPS scores (64.9 % vs 37.8 %, P = 0.036) and ZEW scores (78.4 % vs 54.1 %, P = 0.044) of DTI group were better than the control group. Furthermore, the stability of muscle strength in patients with limb dysfunction was significantly improved in DTI group (86.4 % vs 50 %, P = 0.028). CONCLUSION: In summary, the application of DTI in gamma knife radiosurgery for the treatment of brain tumors in motor function areas can precisely define the tumor edge from pyramidal tract, which will support on designing individual treatment plan, reducing the incidence of complications, and improving long-term life quality in patients.

Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury.

Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.

Injury of Corticospinal tract and Corticoreticular pathway caused by high-voltage electrical shock: a case report.

BACKGROUND: We imaged the corticospinal tract (CST) and corticoreticular pathway (CRP) using diffusion tensor tractography (DTT) to evaluate the cause of muscle weakness in a patient who was exposed to high-voltage electricity. CASE PRESENTATION: A 39-year-old man presented with quadriparesis after high-voltage electrical shock from power lines while working about 5.8 years ago. The electrical current entered through the left hand and exited through the occipital area of the head. The degree of weakness on bilateral upper and lower extremities was 3-4 on the Medical Research Council strength scale. Diffusion tensor imaging (DTI) was performed 5.8 years after onset. The CST and CRP were depicted by placing two regions of interest for each neural tract on the two-dimensional fractional anisotropy color map. DTT of the DTI scan showed that the bilateral CST and CRP were thinned compared to those of the healthy control subject. On the nerve conduction test, abnormal findings suggesting peripheral nerve lesion were not observed. Therefore, injury of bilateral CST and CRP seems to have contributed to our patient's weakness after the electrical shock. CONCLUSION: Depiction of neural tracts in the brain using DTT can assist in the accurate and detailed evaluation of the cause of neural deficit after electrical injury.

Difference between injuries of the corticospinal tract and corticoreticulospinal tract in patients with diffuse axonal injury: a diffusion tensor tractography study.

Objectives: No studies have investigated differences in injury of the corticospinal tract (CST) and corticoreticulospinal tract (CRT) following diffuse axonal injury (DAI) to date. Therefore, we investigated differences in injury of the CST and CRT in patients with DAI using diffusion tensor tractography (DTT).Methods: Twenty consecutive patients with DAI and 20 control subjects were recruited. CST and CRT were reconstructed. Each part of the CST and CRT was analyzed in terms of DTT parameters and configuration.Results: Upon group analysis, decreased FA and TV values were observed in both the CST and CRT in the patient group compared with the control group (%) (p < .05). In the individual analysis in terms of the TV, significantly higher injury incidence was observed for the CRT (47.5%) than the CST (25.0%) (p < .05). Evaluation of the DTT configuration revealed significantly higher injury incidence for the CRT (50.0%) than the CST (17.5%) (p < .05). Specifically, the incidence of discontinuation was significantly higher for the CRT (40.0%) than the CST (10.0%) (p < .05).Conclusions: Injury of the CST and CRT was detected in patients with DAI using DTT. In terms of the incidence and severity of neural injury, the CRT appeared to be more vulnerable to DAI than the CST.

Axonal regeneration and functional recovery driven by endogenous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy.

The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration. It has been previously shown that the endogenous protein, lateral olfactory tract usher substance (LOTUS), antagonizes NgR1-mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice. However, it remained unclear whether LOTUS-mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery. Here, we generated LOTUS-overexpressing transgenic (LOTUS-Tg) rats to investigate the role of LOTUS in neuronal function after damage. After unilateral pyramidotomy, motor function in LOTUS-Tg rats recovered significantly compared to that in wild-type animals. In a retrograde tracing study, labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS-Tg rats. Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS-Tg rats. Moreover, electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS-Tg rats, which was consistent with the histological findings. According to these data, LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy. LOTUS could be a future therapeutic option for CNS injury.

Neuroprotective potential of Spirulina platensis on lesioned spinal cord corticospinal tract under experimental conditions in rat models.

Spinal cord injury (SCI) results from penetrating or compressive traumatic injury to the spine in humans or by the surgical compression of the spinal cord in experimental animals. In this study, the neuroprotective potential of Spirulina platensis was investigated on ultrastructural and functional recovery of the spinal cord following surgical-induced injury. Twenty-four Sprague-Dawley rats were divided into three groups; sham group, control (trauma) group, and experimental (S. platensis) group (180 mg/kg) of eight rats each. For each group, the rats were then subdivided into two groups to allow measurement at two different timepoints (day 14 and 28) for the microscopic analysis. Rats in the control and experimental S. platensis groups were subjected to partial crush injury at the level of T12 with Inox number 2 modified forceps by compressing on the spinal cord for 30 s. Pairwise comparisons of ultrastructural grading mean scores difference between the control and experimental S. platensis groups reveals that there were significant differences on the axonal ultrastructure, myelin sheath and BBB Score on Day 28; these correlate with the functional locomotor recovery at this timepoint. The results suggest that supplementation with S. platensis induces functional recovery and effective preservation of the spinal cord ultrastructure after SCI. These findings will open new potential avenue for further research into the mechanism of S. platensis-mediated spinal cord repair.

Alternative routes for recovery of hand functions after corticospinal tract injury in primates and rodents.

PURPOSE OF REVIEW: Recent studies on various corticospinal tract (CST) lesions have shown the plastic changes at a variety of motor systems after the lesion. This review provides the alternative routes associated with the motor functional recovery after the CST lesions at various levels in nonhuman primates and rodents. RECENT FINDINGS: In the case of the motor cortical lesions, the perilesional area compensates for the lesion. In contrast, sprouting of the corticoreticular tracts was observed after the lesions involving sensorimotor cortical areas. After the internal capsule lesion, sprouting in the cortico-rubral pathway contributes to the recovery. In case of the pyramidal lesion, rubrospinal and reticulospinal tracts play a role of the functional recovery. After the dorsolateral funiculus (DLF) lesion at C4/C5, the indirect pathway via propriospinal tract contributes to the recovery. In case of the hemisection at lower cervical cord, the CST fibers sprouted from the bilateral motor cortex and descended to the contralesional DLF and crossed below the lesion area. SUMMARY: The central pathways can change their structure and activity dynamically depending on the lesion sites and size. Revealing the difference of the alternative pathways should be crucial to understand the whole recovery mechanism and develop the further neurorehabilitative treatment.

[Quantitative characterization of risk of iatrogenic damage to pyramidal tracts based on data of intraoperative neuromonitoring during surgical correction of spinal deformities]. / Kolichestvennaia kharakteristika riska iatrogennykh povrezhdenii piramidnykh putei po dannym intraoperatsionnogo neiromonitoringa pri khirurgicheskoi korrektsii deformatsii pozvonochnika.

OBJECTIVE: Development of a quantitative indicator for the risk level of intraoperative iatrogenic motor disorders in the process of surgical correction of spinal deformity based on current neurophysiological monitoring data. MATERIAL AND METHODS: 288 patients 12.6±0.35 y.o. underwent surgical correction of spinal deformities under the control of intraoperative neuromonitoring. The nature of changes in motor evoked potentials was assessed according to the earlier proposed ranking scale. The incidence of different variants of changes in the rank values of the state of the pyramidal system during the operation and the resulting postoperative motor disturbances was calculated. RESULTS: By comparing probabilities of various changes in the conduction properties of pyramidal tracts during surgery with the incidence of the observed motor deficiencies we quantitatively assessed the possible correlation between these phenomena. We propose a method for calculating the risk index for postoperative motor disorders depending on the maximum rank of the pyramidal system's response to surgical aggression. CONCLUSION: The developed system of ranking evaluation of changes in motor evoked potentials during surgical correction of spinal deformity makes it possible to quantify the risk of postoperative motor disorders and, accordingly, to monitor the level of anxiety for a neurosurgeon during individual stages of surgical intervention.

Neuronal activity and microglial activation support corticospinal tract and proprioceptive afferent sprouting in spinal circuits after a corticospinal system lesion.

Spared corticospinal tract (CST) and proprioceptive afferent (PA) axons sprout after injury and contribute to rewiring spinal circuits, affecting motor recovery. Loss of CST connections post-injury results in corticospinal signal loss and associated reduction in spinal activity. We investigated the role of activity loss and injury on CST and PA sprouting. To understand activity-dependence after injury, we compared CST and PA sprouting after motor cortex (MCX) inactivation, produced by chronic MCX muscimol microinfusion, with sprouting after a CST lesion produced by pyramidal tract section (PTx). Activity suppression, which does not produce a lesion, is sufficient to trigger CST axon outgrowth from the active side to cross the midline and to enter the inactivated side of the spinal cord, to the same extent as PTx. Activity loss was insufficient to drive significant CST gray matter axon elongation, an effect of PTx. Activity suppression triggered presynaptic site formation, but less than PTx. Activity loss triggered PA sprouting, as PTx. To understand injury-dependent sprouting further, we blocked microglial activation and associated inflammation after PTX by chronic minocycline administration after PTx. Minocycline inhibited myelin debris phagocytosis contralateral to PTx and abolished CST axon elongation, formation of presynaptic sites, and PA sprouting, but not CST axon outgrowth from the active side to cross the midline. Our findings suggest sprouting after injury has a strong activity dependence and that microglial activation after injury supports axonal elongation and presynaptic site formation. Combining spinal activity support and inflammation control is potentially more effective in promoting functional restoration than either alone.

Automated Forelimb Tasks for Rodents: Current Advantages and Limitations, and Future Promise.

Rodent tests of function have advanced our understanding of movement, largely through the human training and testing and manual assessment. Tools such as reaching and grasping of a food pellet have been widely adopted because they are effective and simple to use. However, these tools are time-consuming, subjective, and often qualitative. Automation of training, testing, and assessment has the potential to increase efficiency while ensuring tasks are objective and quantitative. We detail new methods for automating rodent forelimb tests, including the use of pellet dispensers, sensors, computer vision, and home cage systems. We argue that limitations in existing forelimb tasks are driving the innovations in automated systems. We further argue that automated tasks partially address these limitations, and we outline necessary precautions and remaining challenges when adopting these types of tasks. Finally, we suggest attributes of future automated rodent assessment tools that can enable widespread adoption and help us better understand forelimb function in health and disease.

Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma.

After brain or spinal cord trauma, interaction of Nogo-A with neuronal NgR1 limits regenerative axonal sprouting and functional recovery. Cellular signaling by lipid-anchored NgR1 requires a coreceptor but the relevant partner in vivo is not clear. Here, we examined proteins enriched in NgR1 immunoprecipitates by Nogo-A exposure, identifying CRMP2, a cytosolic protein implicated in axon growth inhibition by Semaphorin/Plexin complexes. The Nogo-A-induced association of NgR1 with CRMP2 requires PlexinA2 as a coreceptor. Non-neuronal cells expressing both NgR1 and PlexinA2, but not either protein alone, contract upon Nogo-A exposure. Inhibition of cortical axon regeneration by Nogo-A depends on a NgR1/PlexinA2 genetic interaction because double-heterozygous NgR1+/-, PlexinA2+/- neurons, but not single-heterozygote neurons, are rescued from Nogo-A inhibition. NgR1 and PlexinA2 also interact genetically in vivo to restrict corticospinal sprouting in mouse cervical spinal cord after unilateral pyramidotomy. Greater post-injury sprouting in NgR1+/-, PlexinA2+/- mice supports enhanced neurological recovery of a mixed female and male double-heterozygous cohort. Thus, a NgR1/PlexinA2/CRMP2 ternary complex limits neural repair after adult mammalian CNS trauma.SIGNIFICANCE STATEMENT Several decades of molecular research have suggested that developmental regulation of axon growth is distinct in most regards from titration of axonal regenerative growth after adult CNS trauma. Among adult CNS pathways, the oligodendrocyte Nogo-A inhibition of growth through NgR1 is thought to have little molecular relationship to axonal guidance mechanisms active embryonically. Here, biochemical analysis of NgR1 function uncovered a physical complex with CRMP cytoplasmic mediators, and this led to appreciation of a role for PlexinA2 in concert with NgR1 after adult trauma. The data extend molecular understanding of neural repair after CNS trauma and link it to developmental processes.

Individual recovery profiles of manual dexterity, and relation to corticospinal lesion load and excitability after stroke -a longitudinal pilot study.

OBJECTIVES: In this longitudinal pilot study, we investigated how manual dexterity recovery was related to corticospinal tract (CST) injury and excitability, in six patients undergoing conventional rehabilitation. METHODS: Key components of manual dexterity, namely finger force control, finger tapping rate and independence of finger movements, were quantified. Structural MRI was obtained to calculate CST lesion load. CST excitability was assessed by measuring rest motor threshold (RMT) and the amplitude of motor evoked potentials (MEPs) using transcranial magnetic stimulation (TMS). Measurements were obtained at two weeks, three and six months post-stroke. RESULTS: At six months post-stroke, complete recovery of hand gross motor impairment (i.e., maximal Fugl-Meyer score for hand) had occurred in three patients and four patients had recovered ability to accurately control finger force. However, tapping rate and independence of finger movements remained impaired in all six patients at six months. Recovery in hand gross motor impairment and finger force control occurred in patients with smaller CST lesion load and almost complete recovery of CST excitability, although RMT or MEP size remained slightly altered in the stroke-affected hemisphere compared to the unaffected hemisphere. The two patients with poorest recovery showed persistent absence of MEPs and greatest structural injury to CST. DISCUSSION: The findings support good motor recovery being overall correlated with smaller CST lesion, and with almost complete recovery of CST excitability. However, impairment of manual dexterity persisted despite recovery in gross hand movements and grasping abilities, suggesting involvement of additional brain structures for fine manual tasks.