Functional repair of the corticospinal tract by delayed transplantation of olfactory ensheathing cells in adult rats

Adult rats were trained to use their forepaws to retrieve a piece of food. Destruction of the dorsal corticospinal tract on one side at the level of the first cervical segment abolished the use of the ipsilateral forepaw for retrieval for at least 6 months after operation. Where a variable amount of the corticospinal tract was spared, there was a proportionate persistence of retrieval. In lesioned rats that had shown no retrieval for 8 weeks after operation, a suspension of olfactory ensheathing cells was injected into the lesion site. Starting between 1 and 3 weeks after transplantation, all rats with transplants bridging the lesion site resumed retrieval by the ipsilateral forepaw. Biotin dextran anterograde tracing shows regenerating corticospinal axons crossing the bridge, traveling caudally for ~10 mm in the distal part of the corticospinal tract and forming terminal arborizations in the spinal gray matter. Functional recovery can occur when only ~1% of the corticospinal tract axons are present

Effects of lipopolysaccharide-induced inflammation on expression of growth-associated genes by corticospinal neurons

Background: Inflammation around cell bodies of primary sensory neurons and retinal ganglion cells enhances expression of neuronal growth-associated genes and stimulates axonal regeneration. We have asked if inflammation would have similar effects on corticospinal neurons, which normally show little response to spinal cord injury. Lipopolysaccharide (LPS) was applied onto the pial surface of the motor cortex of adult rats with or without concomitant injury of the corticospinal tract at C4. Inflammation around corticospinal tract cell bodies in the motor cortex was assessed by immunohistochemistry for OX42 ( a microglia and macrophage marker). Expression of growth-associated genes c-jun, ATF3, SCG10 and GAP-43 was investigated by immunohistochemistry or in situ hybridisation.Results: Application of LPS induced a gradient of inflammation through the full depth of the motor cortex and promoted c-Jun and SCG10 expression for up to 2 weeks, and GAP-43 upregulation for 3 days by many corticospinal neurons, but had very limited effects on neuronal ATF3 expression. However, many glial cells in the subcortical white matter upregulated ATF3. LPS did not promote sprouting of anterogradely labelled corticospinal axons, which did not grow into or beyond a cervical lesion site.Conclusion: Inflammation produced by topical application of LPS promoted increased expression of some growth-associated genes in the cell bodies of corticospinal neurons, but was insufficient to promote regeneration of the corticospinal tract

Diffusion Tensor Imaging-Based Research on Human White Matter Anatomy

The aim of this study is to investigate the white matter by the diffusion tensor imaging and the Chinese visible human dataset and to provide the 3D anatomical data of the corticospinal tract for the neurosurgical planning by studying the probabilistic maps and the reproducibility of the corticospinal tract. Diffusion tensor images and high-resolution T1-weighted images of 15 healthy volunteers were acquired; the DTI data were processed using DtiStudio and FSL software. The FA and color FA maps were compared with the sectional images of the Chinese visible human dataset. The probability maps of the corticospinal tract were generated as a quantitative measure of reproducibility for each voxel of the stereotaxic space. The fibers displayed by the diffusion tensor imaging were well consistent with the sectional images of the Chinese visible human dataset and the existing anatomical knowledge. The three-dimensional architecture of the white matter fibers could be clearly visualized on the diffusion tensor tractography. The diffusion tensor tractography can establish the 3D probability maps of the corticospinal tract, in which the degree of intersubject reproducibility of the corticospinal tract is consistent with the previous architectonic report. DTI is a reliable method of studying the fiber connectivity in human brain, but it is difficult to identify the tiny fibers. The probability maps are useful for evaluating and identifying the corticospinal tract in the DTI, providing anatomical information for the preoperative planning and improving the accuracy of surgical risk assessments preoperatively

Corticospinal Tract (CST) reconstruction based on fiber orientation distributions(FODs) tractography

The Corticospinal Tract (CST) is a part of pyramidal tract (PT), and it can innervate the voluntary movement of skeletal muscle through spinal interneurons (the 4th layer of the Rexed gray board layers), and anterior horn motorneurons (which control trunk and proximal limb muscles). Spinal cord injury (SCI) is a highly disabling disease often caused by traffic accidents. The recovery of CST and the functional reconstruction of spinal anterior horn motor neurons play an essential role in the treatment of SCI. However, the localization and reconstruction of CST are still challenging issues; the accuracy of the geometric reconstruction can directly affect the results of the surgery. The main contribution of this paper is the reconstruction of the CST based on the fiber orientation distributions (FODs) tractography. Differing from tensor-based tractography in which the primary direction is a determined orientation, the direction of FODs tractography is determined by the probability. The spherical harmonics (SPHARM) can be used to approximate the efficiency of FODs tractography. We manually delineate the three ROIs (the posterior limb of the internal capsule, the cerebral peduncle, and the anterior pontine area) by the ITK-SNAP software, and use the pipeline software to reconstruct both the left and right sides of the CST fibers. Our results demonstrate that FOD-based tractography can show more and correct anatomical CST fiber bundles

Physical Activity Modulates Corticospinal Excitability of the Lower Limb in Young and Old Adults

Aging is associated with reduced neuromuscular function, which may be due in part to altered corticospinal excitability. Regular physical activity (PA) may ameliorate these age-related declines, but the influence of PA on corticospinal excitability is unknown. The purpose of this study was to determine the influence of age, sex, and PA on corticospinal excitability by comparing the stimulus-response curves of motor evoked potentials (MEP) in 28 young (22.4 ± 2.2 yr; 14 women and 14 men) and 50 old adults (70.2 ± 6.1 yr; 22 women and 28 men) who varied in activity levels. Transcranial magnetic stimulation was used to elicit MEPs in the active vastus lateralis muscle (10% maximal voluntary contraction) with 5% increments in stimulator intensity until the maximum MEP amplitude. Stimulus-response curves of MEP amplitudes were fit with a four-parameter sigmoidal curve and the maximal slope calculated (slopemax). Habitual PA was assessed with tri-axial accelerometry and participants categorized into either those meeting the recommended PA guidelines for optimal health benefits (\u3e10,000 steps/day, high-PA; n = 21) or those not meeting the guidelines (n = 41). The MEP amplitudes and slopemax were greater in the low-PA compared with the high-PA group (P \u3c 0.05). Neither age nor sex influenced the stimulus-response curve parameters (P \u3e 0.05), suggesting that habitual PA influenced the excitability of the corticospinal tract projecting to the lower limb similarly in both young and old adults. These findings provide evidence that achieving the recommended PA guidelines for optimal health may mediate its effects on the nervous system by decreasing corticospinal excitability

Occasional essay: upper motor neuron syndrome in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) requires recognition of both lower (LMN) and upper motor neuron (UMN) dysfunction.1 However, classical UMN signs are frequently difficult to identify in ALS.2 LMN involvement is sensitively detected by electromyography (EMG)3 but, as yet, there are no generally accepted markers for monitoring UMN abnormalities,4 the neurobiology of ALS itself, and disease spread through the brain and spinal cord,.5 Full clinical assessment is therefore necessary to exclude other diagnoses and to monitor disease progression. In part, this difficulty regarding detection of UMN involvement in ALS derives from the definition of ‘the UMN syndrome’. Abnormalities of motor control in ALS require reformulation within an expanded concept of the UMN, together with the neuropathological, neuro-imaging and neurophysiological abnormalities in ALS. We review these issues here

Impaired transmission in the corticospinal tract and gait disability in spinal cord injured persons

Rehabilitation following spinal cord injury is likely to depend on recovery of corticospinal systems. Here we investigate whether transmission in the corticospinal tract may explain foot drop (inability to dorsiflex ankle) in persons with spinal cord lesion. The study was performed in 24 persons with incomplete spinal cord lesion (C1 to L1) and 15 healthy controls. Coherence in the 10- to 20-Hz frequency band between paired tibialis anterior muscle (TA) electromyographic recordings obtained in the swing phase of walking, which was taken as a measure of motor unit synchronization. It was significantly correlated with the degree of foot drop, as measured by toe elevation and ankle angle excursion in the first part of swing. Transcranial magnetic stimulation was used to elicit motor-evoked potentials (MEPs) in the TA. The amplitude of the MEPs at rest and their latency during contraction were correlated to the degree of foot drop. Spinal cord injured participants who exhibited a large foot drop had little or no MEP at rest in the TA muscle and had little or no coherence in the same muscle during walking. Gait speed was correlated to foot drop, and was the lowest in participants with no MEP at rest. The data confirm that transmission in the corticospinal tract is of importance for lifting the foot during the swing phase of human gait

Task‐specific strength increases after lower‐limb compound resistance training occurred in the absence of corticospinal changes in vastus lateralis

Neural adaptations subserving strength increases have been shown to be task‐specific, but responses and adaptation to lower‐limb compound exercises such as the squat are commonly assessed in a single‐limb isometric task. This two‐part study assessed neuromuscular responses to an acute bout (Study A) and 4 weeks (Study B) of squat resistance training at 80% of one‐repetition‐maximum, with measures taken during a task‐specific isometric squat (IS) and non‐specific isometric knee extension (KE). Eighteen healthy volunteers (25 ± 5 years) were randomised into either a training (n = 10) or a control (n = 8) group. Neural responses were evoked at the intracortical, corticospinal and spinal levels, and muscle thickness was assessed using ultrasound. The results of Study A showed that the acute bout of squat resistance training decreased maximum voluntary contraction (MVC) for up to 45 min post‐exercise (−23%, P < 0.001). From 15–45 min post‐exercise, spinally evoked responses were increased in both tasks (P = 0.008); however, no other evoked responses were affected (P ≥ 0.240). Study B demonstrated that following short‐term resistance training, participants improved their one repetition maximum squat (+35%, P < 0.001), which was reflected by a task‐specific increase in IS MVC (+49%, P = 0.001), but not KE (+1%, P = 0.882). However, no training‐induced changes were observed in muscle thickness (P = 0.468) or any evoked responses (P = 0.141). Adjustments in spinal motoneuronal excitability are evident after acute resistance training. After a period of short‐term training, there were no changes in the responses to central nervous system stimulation, which suggests that alterations in corticospinal properties of the vastus lateralis might not contribute to increases in strength

Global Connectivity and Function of Descending Spinal Input Revealed by 3D Microscopy and Retrograde Transduction

The brain communicates with the spinal cord through numerous axon tracts that arise from discrete nuclei, transmit distinct functions, and often collateralize to facilitate the coordination of descending commands. This complexity presents a major challenge to interpreting functional outcomes from therapies that target supraspinal connectivity after injury or disease, while the wide distribution of supraspinal nuclei complicates the delivery of therapeutics. Here we harness retrograde viral vectors to overcome these challenges. We demonstrate that injection of AAV2-Retro to the cervical spinal cord of adult female mice results in highly efficient transduction of supraspinal populations throughout the brainstem, midbrain, and cortex. Some supraspinal populations, including corticospinal and rubrospinal neurons, were transduced with \u3e90% efficiency, with robust transgene expression within 3 d of injection. In contrast, propriospinal and raphe spinal neurons showed much lower rates of retrograde transduction. Using tissue clearing and light-sheet microscopy we present detailed visualizations of descending axons tracts and create a mesoscopic projectome for the spinal cord. Moreover, chemogenetic silencing of supraspinal neurons with retrograde vectors resulted in complete and reversible forelimb paralysis, illustrating effective modulation of supraspinal function. Retrograde vectors were also highly efficient when injected after spinal injury, highlighting therapeutic potential. These data provide a global view of supraspinal connectivity and illustrate the potential of retrograde vectors to parse the functional contributions of supraspinal inputs

Physical Activity Modulates Corticospinal Excitability of the Lower Limb in Young and Old Adults

Aging is associated with reduced neuromuscular function, which may be due in part to altered corticospinal excitability. Regular physical activity (PA) may ameliorate these age-related declines, but the influence of PA on corticospinal excitability is unknown. The purpose of this study was to determine the influence of age, sex, and PA on corticospinal excitability by comparing the stimulus-response curves of motor evoked potentials (MEP) in 28 young (22.4 ± 2.2 yr; 14 women and 14 men) and 50 old adults (70.2 ± 6.1 yr; 22 women and 28 men) who varied in activity levels. Transcranial magnetic stimulation was used to elicit MEPs in the active vastus lateralis muscle (10% maximal voluntary contraction) with 5% increments in stimulator intensity until the maximum MEP amplitude. Stimulus-response curves of MEP amplitudes were fit with a four-parameter sigmoidal curve and the maximal slope calculated (slopemax). Habitual PA was assessed with tri-axial accelerometry and participants categorized into either those meeting the recommended PA guidelines for optimal health benefits (\u3e10,000 steps/day, high-PA; n = 21) or those not meeting the guidelines (n = 41). The MEP amplitudes and slopemax were greater in the low-PA compared with the high-PA group (P \u3c 0.05). Neither age nor sex influenced the stimulus-response curve parameters (P \u3e 0.05), suggesting that habitual PA influenced the excitability of the corticospinal tract projecting to the lower limb similarly in both young and old adults. These findings provide evidence that achieving the recommended PA guidelines for optimal health may mediate its effects on the nervous system by decreasing corticospinal excitability