Transplantable human motor networks as a neuron-directed strategy for spinal cord injury.
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ABSTRACT:
SUBMITTER: Olmsted ZT
PROVIDER: S-EPMC8333163 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Combined interventions for neuromodulation leading to neurorecovery have gained great attention by researchers to resemble clinical rehabilitation approaches. In this randomized clinical trial, we established changes in the net output of motoneurons innervating multiple leg muscles during stepping when transcranial magnetic stimulation (TMS) of the primary motor cortex was paired with transcutaneous spinal (transspinal) stimulation over the thoracolumbar region during locomotor training. TMS was delivered before (TMS-transspinal) or after (transspinal-TMS) transspinal stimulation during the stance phase of the less impaired leg. Ten individuals with chronic incomplete or complete SCI received at least 20 sessions of training. Each session consisted of 240 paired stimuli delivered over 10-min blocks for 1 h during robotic assisted step training on a motorized treadmill. Body weight support, leg guidance force and treadmill speed were adjusted based on each subject's ability to step without knee buckling or toe dragging. Most transspinal evoked potentials (TEPs) recorded before and after each intervention from ankle and knee muscles during assisted stepping were modulated in a phase-dependent pattern. Transspinal-TMS and locomotor training affected motor neuron output of knee and ankle muscles with ankle TEPs to be modulated in a phase-dependent manner. TMS-transspinal and locomotor training increased motor neuron output for knee but not for ankle muscles. Our results support that targeted brain and spinal cord stimulation alters responsiveness of neurons over multiple spinal segments in people with chronic SCI. Noninvasive stimulation of the brain and spinal cord along with locomotor training is a novel neuromodulation method that can become a promising modality for rehabilitation in humans after SCI.
| S-EPMC9612520 | biostudies-literature
Project description:Restoring muscle function to patients with spinal cord injuries (SCIs) will invariably require a functioning lower motor neuron (LMN). As techniques such as nerve transfer surgery emerge, characterizing the extent of LMN damage associated with SCIs becomes clinically important. Current methods of LMN diagnosis have inherent limitations that could potentially be overcome by the development of magnetic resonance imaging (MRI) biomarkers: specific features on MRI that are indicative of LMN integrity. To identify research on MRI biomarkers of LMN damage in the acute phase after SCI, we searched PubMed, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials for articles published from inception to April 27, 2021. Overall, 2 of 58 unique articles screened met our inclusion criteria, both of which were small studies. We therefore identify MRI biomarkers of LMN damage overlying SCI as a notable gap in the literature. Because of the lack of existing literature on this specific problem, we further our discussion by examining concepts explored in research characterizing MRI biomarkers of spinal cord and neuronal damage in different contexts that may provide value in future work to identify a biomarker for LMN damage in SCI. We conclude that MRI biomarkers of LMN damage in SCI is an underexplored, but promising, area of research as emerging, function-restoring therapies requiring this information continue to advance.
| S-EPMC8655802 | biostudies-literature
Project description:Spinal cord injury is associated with chronic sensorimotor deficits due to the interruption of ascending and descending tracts between the brain and spinal cord. Functional recovery after anatomically complete spinal cord injury is limited due to the lack of long-distance axonal regeneration of severed fibers in the adult central nervous system. Most spinal cord injuries in humans, however, are anatomically incomplete. Although restorative treatment options for spinal cord injury remain currently limited, research from experimental models of spinal cord injury have revealed a tremendous capability for both spontaneous and treatment-induced plasticity of the corticospinal system that supports functional recovery. We review recent advances in the understanding of corticospinal circuit plasticity after spinal cord injury and concentrate mainly on the hindlimb motor cortex, its corticospinal projections, and the role of spinal mechanisms that support locomotor recovery. First, we discuss plasticity that occurs at the level of motor cortex and the reorganization of cortical movement representations. Next, we explore downstream plasticity in corticospinal projections. We then review the role of spinal mechanisms in locomotor recovery. We conclude with a perspective on harnessing neuroplasticity with therapeutic interventions to promote functional recovery.
| S-EPMC6788232 | biostudies-literature
Project description:Increased use of epidural Spinal Cord Stimulation (eSCS) for the rehabilitation of spinal cord injury (SCI) has highlighted the need for a greater understanding of the properties of reflex circuits in the isolated spinal cord, particularly in response to repetitive stimulation. Here, we investigate the frequency-dependence of modulation of short- and long-latency EMG responses of lower limb muscles in patients with SCI at rest. Single stimuli could evoke short-latency responses as well as long-latency (likely polysynaptic) responses. The short-latency component was enhanced at low frequencies and declined at higher rates. In all muscles, the effects of eSCS were more complex if polysynaptic activity was elicited, making the motor output become an active process expressed either as suppression, tonic or rhythmical activity. The polysynaptic activity threshold is not constant and might vary with different stimulation frequencies, which speaks for its temporal dependency. Polysynaptic components can be observed as direct responses, neuromodulation of monosynaptic responses or driving the muscle activity by themselves, depending on the frequency level. We suggest that the presence of polysynaptic activity could be a potential predictor for appropriate stimulation conditions. This work studies the complex behaviour of spinal circuits deprived of voluntary motor control from the brain and in the absence of any other inputs. This is done by describing the monosynaptic responses, polysynaptic activity, and its interaction through its input-output interaction with sustain stimulation that, unlike single stimuli used to study the reflex pathway, can strongly influence the interneuron circuitry and reveal a broader spectrum of connectivity.
| S-EPMC8354937 | biostudies-literature
Project description:Implantable spinal-cord-neuroprostheses aiming to restore standing and walking after paralysis have been extensively studied in animal models (mainly cats) and have shown promising outcomes. This study aimed to take a critical step along the clinical translation path of these neuroprostheses, and investigated the organization of the neural networks targeted by these implants in a non-human primate. This was accomplished by advancing a microelectrode into various locations of the lumbar enlargement of the spinal cord, targeting the ventral horn of the gray matter. Microstimulation in these locations produced a variety of functional movements in the hindlimb. The resulting functional map of the spinal cord in monkeys was found to have a similar overall organization along the length of the spinal cord to that in cats. This suggests that the human spinal cord may also be organized similarly. The obtained spinal cord maps in monkeys provide important knowledge that will guide the very first testing of these implants in humans.
| S-EPMC6753145 | biostudies-literature
Project description:The developing spinal cord builds a boundary between the CNS and the periphery, in the form of a basement membrane. The spinal cord basement membrane is a barrier that retains CNS neuron cell bodies, while being selectively permeable to specific axon types. Spinal motor neuron cell bodies are located in the ventral neural tube next to the floor plate and project their axons out through the basement membrane to peripheral targets. However, little is known about how spinal motor neuron cell bodies are retained inside the ventral neural tube, while their axons can exit. In previous work, we found that disruption of Slit/Robo signals caused motor neuron emigration outside the spinal cord. In the current study, we investigate how Slit/Robo signals are necessary to keep spinal motor neurons within the neural tube. Our findings show that when Slit/Robo signals were removed from motor neurons, they migrated outside the spinal cord. Furthermore, this emigration was associated with abnormal basement membrane protein expression in the ventral spinal cord. Using Robo2 and Slit2 conditional mutants, we found that motor neuron-derived Slit/Robo signals were required to set up a normal basement membrane in the spinal cord. Together, our results suggest that motor neurons produce Slit signals that are required for the basement membrane assembly to retain motor neuron cell bodies within the spinal cord.
| S-EPMC6842423 | biostudies-literature
Project description:BackgroundTranscutaneous spinal cord stimulation (tSCS) is a non-invasive modality in which electrodes can stimulate spinal circuitries and facilitate a motor response. This review aimed to evaluate the methodology of studies using tSCS to generate motor activity in persons with spinal cord injury (SCI) and to appraise the quality of included trials.MethodsA systematic search for studies published until May 2021 was made of the following databases: EMBASE, Medline (Ovid) and Web of Science. Two reviewers independently screened the studies, extracted the data, and evaluated the quality of included trials. The electrical characteristics of stimulation were summarised to allow for comparison across studies. In addition, the surface electromyography (EMG) recording methods were evaluated.ResultsA total of 3753 articles were initially screened, of which 25 met the criteria for inclusion. Studies were divided into those using tSCS for neurophysiological investigations of reflex responses (n = 9) and therapeutic investigations of motor recovery (n = 16). The overall quality of evidence was deemed to be poor-to-fair (10.5 ± 4.9) based on the Downs and Black Quality Checklist criteria. The electrical characteristics were collated to establish the dosage range across stimulation trials. The methods employed by included studies relating to stimulation parameters and outcome measurement varied extensively, although some trends are beginning to appear in relation to electrode configuration and EMG outcomes.ConclusionThis review outlines the parameters currently employed for tSCS of the cervicothoracic and thoracolumbar regions to produce motor responses. However, to establish standardised procedures for neurophysiological assessments and therapeutic investigations of tSCS, further high-quality investigations are required, ideally utilizing consistent electrophysiological recording methods, and reporting common characteristics of the electrical stimulation administered.
| S-EPMC8601579 | biostudies-literature
Project description:ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Although much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. In the present work, we have deeply sequenced whole transcriptome from spinal cord ventral horns of post-mortem ALS human donors affected by the sporadic form of the disease (which comprises ~90% of the cases but which is less investigated than the inherited form of the disease). We observe 1160 deregulated genes including 18 miRNAs and show that down regulated genes are mainly of neuronal derivation while up regulated genes have glial origin and tend to be involved in neuroinflammation or cell death. Remarkably, we find strong deregulation of SNAP25 and STX1B at both mRNA and protein levels suggesting impaired synaptic function through SNAP25 reduction as a possible cause of calcium elevation and glutamate excitotoxicity. We also note aberrant alternative splicing but not disrupted RNA editing.
| S-EPMC5577269 | biostudies-literature
Project description:Spontaneous, acute, complete thoracolumbar spinal cord injury (TL-SCI) in dogs frequently results in permanent deficits modeling chronic paralysis in people. Recovery of walking without recovery of sensation has been interpreted in dogs as reflexive spinal walking. To evaluate this assumption, this study characterized the electrophysiological status of motor and sensory long tracts and local reflex circuitry in dogs with absent recovery of sensation after acute TL-SCI and correlated findings to gait scores. Twenty dogs with permanent deficits after acute, clinically complete TL-SCI and 6 normal dogs were prospectively enrolled. Transcranial magnetic motor evoked potentials (MEPs), somatosensory evoked potentials (SSEPs), H-reflex, and F-waves were evaluated. Gait was quantified using an ordinal, open field scale (OFS) and treadmill-based stepping and coordination scores (SS, RI). MEP latency and H-reflex variables were compared between cases and controls. Associations between presence of MEPs, SSEPs, F-waves or H-reflex variables, and gait scores were determined. Pelvic limb MEPs were detected in 4 cases; no case had trans-lesional sensory conduction. Latency was longer and conduction velocity slower in cases than controls (pa = 0.0064, 0.0023, respectively). Three of 4 cases with pelvic limb MEPs were ambulatory, and gait scores (OFS, SS, RI) were each associated with presence of trans-lesional conduction (pa = 0.006, 0.006, 0.003, respectively). H threshold in cases (mean, 3.2mA ±2.5) was lower than controls (mean, 7.9mA ±3.1; pa = 0.011) and was inversely associated with treadmill-based scores, SS, and RI (pa = 0.042, 0.043, respectively). The association between pelvic limb MEPs and gait scores supports the importance of descending influence on regaining walking after severe TL-SCI in dogs rather than just activation of spinal walking. The inverse association between H-reflex threshold and gait scores implies that increases in motor neuron pool excitability might also contribute to motor recovery.
| S-EPMC6436022 | biostudies-literature
Project description:The primary aim of this work was to investigage the proteomic differences across spinal cord injury (SCI) patients who experience significant functional recovery relative to those who do not, to both better understand the pathophysiology and to identify potentially useful biomarkers of recovery. Blood samples were taken, following informed consent, from ASIA impairment scale (AIS) grade C "Improvers" (AIS grade improvement) (n=10 & n=9) and "Non-Improvers" (No AIS change) (n=7 & n=6), and AIS grade A (n=11 & n= 9) and D (n=11 & n=10) at <2 weeks ("Acute") and approx. 3 months ("Sub-acute") post-injury for a total of 73 samples. The samples were treated with ProteoMiner™ beads. Data dependent label-free LC-MSMS was used to characterise the proteome of the samples.
2022-07-14 | PXD035072 | Pride