Lentiviral Interleukin-10 Gene Therapy Preserves Fine Motor Circuitry and Function After a Cervical Spinal Cord Injury in Male and Female Mice.
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ABSTRACT:
SUBMITTER: Chen JY
PROVIDER: S-EPMC8116384 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coupling between cervical and lumbar spinal networks (cervico-lumbar coupling) is vital during human locomotion. Impaired cervico-lumbar coupling after neural injuries or diseases can be reengaged via simultaneous arm and leg cycling training. Sensorimotor circuitry including cervico-lumbar coupling may further be enhanced by non-invasive modulation of spinal circuity using transcutaneous spinal cord stimulation (tSCS). This project aimed to determine the effect of cervical, lumbar, or combined tSCS on spinal reflex (Hoffmann [H-]) and corticospinal (motor evoked potential [MEP]) excitability during a static or cycling cervico-lumbar coupling task. Fourteen neurologically intact study participants were seated in a recumbent leg cycling system. H-reflex and MEP amplitudes were assessed in the left flexor carpi radialis (FCR) muscle during two tasks (Static and Cycling) and four conditions: (1) No tSCS, (2) tSCS applied to the cervical enlargement (Cervical); (3) tSCS applied to the lumbar enlargement (Lumbar); (4) simultaneous cervical and lumbar tSCS (Combined). While cervical tSCS did not alter FCR H-reflex amplitude relative to No tSCS, lumbar tSCS significantly facilitated H-reflex amplitude by 11.1%, and combined cervical and lumbar tSCS significantly enhanced the facilitation to 19.6%. Neither cervical nor lumbar tSCS altered MEP amplitude alone (+4.9 and 1.8% relative to legs static, No tSCS); however, combined tSCS significantly increased MEP amplitude by 19.7% compared to No tSCS. Leg cycling alone significantly suppressed the FCR H-reflex relative to static, No tSCS by 13.6%, while facilitating MEP amplitude by 18.6%. When combined with leg cycling, tSCS was unable to alter excitability for any condition. This indicates that in neurologically intact individuals where interlimb coordination and corticospinal tract are intact, the effect of leg cycling on cervico-lumbar coupling and corticospinal drive was not impacted significantly with the tSCS intensity used. This study demonstrates, for the first time, that tonic activation of spinal cord networks through multiple sites of tSCS provides a facilitation of both spinal reflex and corticospinal pathways. It remains vital to determine if combined tSCS can influence interlimb coupling after neural injury or disease when cervico-lumbar connectivity is impaired.
| S-EPMC8093452 | biostudies-literature
Project description:Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.
| S-EPMC8657985 | biostudies-literature
Project description:BackgroundThe anti-inflammatory cytokine interleukin-10 (IL-10) has been explored previously as a treatment method for spinal cord injury (SCI) due to its ability to attenuate pro-inflammatory cytokines and reduce apoptosis. Primary limitations when using systemic injections of IL-10 are that it is rapidly cleared from the injury site and that it does not cross the blood-spinal cord barrier.ObjectiveHere, mineral-coated microparticles (MCMs) were used to obtain a local sustained delivery of IL-10 directly into the injury site after SCI.MethodsFemale Sprague-Dawley rats were contused at T10 and treated with either an intraperitoneal injection of IL-10, an intramedullary injection of IL-10, or MCMs bound with IL-10 (MCMs+IL-10). After treatment, cytokine levels were measured in the spinal cord, functional testing and electrophysiology were performed, axon tracers were injected into the brainstem and motor cortex, macrophage levels were counted using flow cytometry and immunohistochemistry, and lesion size was measured.ResultsWhen treated with MCMs+IL-10, IL-10 was significantly elevated in the injury site and inflammatory cytokines were significantly suppressed, prompting significantly less cells expressing antigens characteristic of inflammatory macrophages and significantly more cells expressing antigens characteristic of earlier stage anti-inflammatory macrophages. Significantly more axons were preserved within the rubrospinal and reticulospinal tracts through the injury site when treated with MCMs+IL-10; however, there was no significant difference in corticospinal tract axons preserved, regardless of treatment group. The rats treated with MCMs+IL-10 were the only group with a significantly higher functional score compared to injured controls 28 days post-contusion.ConclusionThese data demonstrate that MCMs can effectively deliver biologically active IL-10 for an extended period of time altering macrophage phenotype and aiding in functional recovery after SCI.
| S-EPMC6489327 | biostudies-literature
Project description:Introduction Degenerative Cervical Myelopathy [DCM] is a slow-motion spinal cord injury. Compression and dynamic compression have been considered disease hallmarks. However, this is likely an oversimplification, as compression is more commonly incidental and has only modest correlation to disease severity. MRI studies have recently suggested spinal cord oscillation could play a role. Research question To determine if spinal cord oscillation could contribute to spinal cord injury in degenerative cervical myelopathy. Material and methods A computational model of an oscillating spinal cord was developed from imaging of a healthy volunteer. Using finite element analysis, the observed implications of stress and strain, were measured in the context of a simulated disc herniation. The significance was bench marked by comparison to a more recognised dynamic injury mechanism; a flexion extension model of dynamic compression. Results Spinal cord oscillation altered both compressive and shear strain on the spinal cord. Following initial compression, compressive strain moves from within the spinal cord to the spinal cord surface, whilst shear strain is magnified by 0.1–0.2, depending on the amplitude of oscillation. These orders of magnitude are equivalent to a dynamic compression model. Discussion and conclusion Spinal cord oscillation could significantly contribute to spinal cord damage across DCM. Its repeated occurrence with every heartbeat, draws parallels to the concept of fatigue damage, which could reconcile differing theories on the origins of DCM. This remains hypothetical at this stage, and further investigations are required. Highlights • Aetiology of Degenerative Cervical Myelopathy is poorly understood• Paradigm based purely on ‘compression’ could be an oversimplification• Analysis of a computational model based on an MRI cervical spine• Loading from cord oscillation was equivalent to that from dynamic compression• Proposes a cause of ‘repetitive microtrauma’ warranting further investigation
| S-EPMC10293319 | biostudies-literature
Project description:BackgroundDegenerative cervical spinal cord compression is becoming increasingly prevalent, yet the MRI criteria that define compression are vague, and vary between studies. This contribution addresses the detection of compression by means of the Spinal Cord Toolbox (SCT) and assesses the variability of the morphometric parameters extracted with it.MethodsProspective cross-sectional study. Two types of MRI examination, 3 and 1.5 T, were performed on 66 healthy controls and 118 participants with cervical spinal cord compression. Morphometric parameters from 3T MRI obtained by Spinal Cord Toolbox (cross-sectional area, solidity, compressive ratio, torsion) were combined in multivariate logistic regression models with the outcome (binary dependent variable) being the presence of compression determined by two radiologists. Inter-trial (between 3 and 1.5 T) and inter-rater (three expert raters and SCT) variability of morphometric parameters were assessed in a subset of 35 controls and 30 participants with compression.ResultsThe logistic model combining compressive ratio, cross-sectional area, solidity, torsion and one binary indicator, whether or not the compression was set at level C6/7, demonstrated outstanding compression detection (area under curve =0.947). The single best cut-off for predicted probability calculated using a multiple regression equation was 0.451, with a sensitivity of 87.3% and a specificity of 90.2%. The inter-trial variability was better in Spinal Cord Toolbox (intraclass correlation coefficient was 0.858 for compressive ratio and 0.735 for cross-sectional area) compared to expert raters (mean coefficient for three expert raters was 0.722 for compressive ratio and 0.486 for cross-sectional area). The analysis of inter-rater variability demonstrated general agreement between SCT and three expert raters, as the correlations between SCT and raters were generally similar to those of the raters between one another.ConclusionsThis study demonstrates successful semi-automated compression detection based on four parameters. The inter-trial variability of parameters established through two MRI examinations was conclusively better for Spinal Cord Toolbox compared with that of three experts' manual ratings.
| S-EPMC8923862 | biostudies-literature
Project description:The number of elderly patients with spinal cord injury without radiographic abnormalities (SCIWORA) has been increasing in recent years and common of most cervical spinal cord injuries. Basic research has shown the effectiveness of early decompression after spinal cord injury on the spinal cord without stenosis; no studies have reported the efficacy of decompression in models with spinal cord compressive lesions. The purpose of this study was to evaluate the effects of decompression surgery after acute spinal cord injury in rats with chronic spinal cord compressive lesions, mimicking SCIWORA. A water-absorbent polymer sheet (Aquaprene DX, Sanyo Chemical Industries) was inserted dorsally into the 4-5th cervical sublaminar space in 8-week-old Sprague Dawley rats to create a rat model with a chronic spinal compressive lesion. At the age of 16 weeks, 30 mildly myelopathic or asymptomatic rats with a Basso, Beattie, and Bresnahan score (BBB score) of 19 or higher were subjected to spinal cord compression injuries. The rats were divided into three groups: an immediate decompression group (decompress immediately after injury), a sub-acute decompression group (decompress 1 week after injury), and a non-decompression group. Behavioral and histological evaluations were performed 4 weeks after the injury. At 20 weeks of age, the BBB score and FLS (Forelimb Locomotor Scale) of both the immediate and the sub-acute decompression groups were significantly higher than those of the non-decompression group. There was no significant difference between the immediate decompression group and the sub-acute decompression group. TUNEL (transferase-mediated dUTP nick end labeling) staining showed significantly fewer positive cells in both decompression groups compared to the non-decompression group. LFB (Luxol fast blue) staining showed significantly more demyelination, and GAP-43 (growth associated protein-43) staining tended to show fewer positive cells in the non-decompression group. Decompression surgery in the acute or sub-acute phase of injury is effective after mild spinal cord injury in rats with chronic compressive lesions. There was no significant difference between the immediate decompression and sub-acute decompression groups.
| S-EPMC9402533 | biostudies-literature
Project description:Sexual dysfunction is a common consequence for women with spinal cord injury (SCI); however, current treatments are ineffective, especially in the under-prioritized population of women with SCI. This case-series, a secondary analysis of the Epidural Stimulation After Neurologic Damage (E-STAND) clinical trial aimed to investigate the effect of epidural spinal cord stimulation (ESCS) on sexual function and distress in women with SCI. Three females, with chronic, thoracic, sensorimotor complete SCI received daily (24 h/day) tonic ESCS for 13 months. Questionnaires, including the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS) were collected monthly. There was a 3.2-point (13.2%) mean increase in total FSFI from baseline (24.5 ± 4.1) to post-intervention (27.8 ± 6.6), with a 4.8-50% improvement in the sub-domains of desire, arousal, orgasm and satisfaction. Sexual distress was reduced by 55%, with a mean decrease of 12 points (55.4%) from baseline (21.7 ± 17.2) to post-intervention (9.7 ± 10.8). There was a clinically meaningful change of 14 points in the International Standards for Neurological Classification of Spinal Cord Injury total sensory score from baseline (102 ± 10.5) to post-intervention (116 ± 17.4), without aggravating dyspareunia. ESCS is a promising treatment for sexual dysfunction and distress in women with severe SCI. Developing therapeutic interventions for sexual function is one of the most meaningful recovery targets for people with SCI. Additional large-scale investigations are needed to understand the long-term safety and feasibility of ESCS as a viable therapy for sexual dysfunction. Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03026816, NCT03026816.
| S-EPMC10167769 | biostudies-literature
Project description:BackgroundPrevious work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM) sleep.Methodology/principal findingsTo determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre) into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA-glycine transporter (VGAT) genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD) and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT) and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT) are not critically involved in REM sleep control.Conclusions/significanceThese findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD).
| S-EPMC3197189 | biostudies-literature
Project description:Circulating sex steroids are critical for the development of neuroplasticity in the respiratory motor system. A primary locus of inducible respiratory neuroplasticity is the phrenic motor nucleus, a column of motor neurons in the ventral cervical spinal cord (C3-C5). In specific, exposure to acute intermittent hypoxia (AIH) induces strengthened synaptic connections to phrenic motor neurons and increased motor output; a form of neuroplasticity called phrenic long-term facilitation (pLTF). Gonadectomy (surgical removal of the testes in males and ovaries in females) reduces circulating sex steroids and eliminates AIH-induced phrenic pLTF in both females and males, implicating sex steroids as critical mediators for the development of neuroplasticity. To begin interrogating mechanisms of sex steroid influence on phrenic motor neurons and to determine the effect of gonadectomy on local gene expression, we performed RNA sequencing on ventral cervical spinal cord samples containing the phrenic motor nucleus. Our findings identified sex-specific gene expression in gonadally-intact rats and suggested that gonadectomy caused greater changes to the transcriptomes of male rats compared to females.
2022-05-13 | GSE202381 | GEO
Project description:BackgroundChronic pain in head, neck, shoulders and upper limbs is debilitating, and patients usually rely on pain medications or surgery to manage their symptoms. However, given the current opioid epidemic, non-pharmacological interventions that reduce pain, such as spinal cord stimulation (SCS), are needed. The purpose of this study was to review the evidence on paresthesia-free 10 kHz SCS therapy for neck and upper extremity pain.MethodsSystematic literature search was performed for studies reporting outcomes for cervical 10 kHz SCS using date limits from May 2008 to November 2020. The study results were analyzed and described qualitatively. Additionally, when feasible, meta-analyses of the outcome data, with 95% confidence intervals (CIs), were conducted using both the fixed-effects (FE) and random-effects (RE) models.ResultsA total of 15 studies were eligible for inclusion. The proportion of patients who achieved ≥ 50% pain reduction was 83% (95% CI 77-89%) in both the FE and RE models. The proportion of patients who reduced/eliminated their opioid consumption was 39% (95% CI 31-46%) in the FE model and 39% (95% CI 31-48%) in the RE model. Pain or discomfort with the implant, lead migration, and infections were potential risks following cervical SCS. Explant rate was 0.1 (95% CI 0.0-0.2) events per 100 person-months, and no patients in the included studies experienced a neurological complication or paresthesia.ConclusionFindings suggest 10 kHz SCS is a promising, safe, minimally invasive alternative for managing chronic upper limb and neck pain.
| S-EPMC8586436 | biostudies-literature