International Spinal Research Trust Research Articles

Acute Intermittent Hypoxia Induces Chemoreflex-Independent Sympathetic Plasticity and Improves Cardiovascular Function in a Rodent Model of Spinal Cord Injury

Background: Cardiovascular complications are one of the leading causes of morbidity and mortality in people with spinal cord injury (SCI). Activation of spinal sympathetic circuitry is critical to offset cardiovascular dysregulation and disease in those with high-level SCI. Acute intermittent hypoxia (AIH) elicits plasticity (i.e., a gradual increase in nerve activity post-AIH exposure) in phrenic and non-phrenic spinal motor circuitry and improves motor function — yet the cardiovascular benefits of AIH after SCI are largely unexplored. Aims: Determine mechanisms (Aim 1) and potential benefits (Aim 2) of AIH-induced sympathetic plasticity post-SCI. Hypothesis: We hypothesized that AIH elicits chemoreflex-dependent sympathetic plasticity and improves cardiovascular function in rats with SCI. Methods: For Aim 1, 40 adult (10-12 weeks) male Wistar rats were subjected to a spinal cord contusion injury (T3, 300 kdyn) and randomly assigned to 5 groups of 8 each: AIH alone, AIH after carotid body denervation (CBX, no peripheral chemoreflex), time control with no intervention (TC), simulated hemorrhage (to mimic AIH-induced hypotension), and AIH plus phenylephrine (to prevent hypotension during hypoxic episodes). Two weeks post-SCI recovery, rats were anesthetized with urethane (~2.1g.kg−1 i.v.) and underwent femoral venous and arterial catheterizations to monitor blood pressure (BP), sample arterial blood gases, and enable intravenous fluid and drug delivery. Additionally, splanchnic sympathetic nerve activity (sSNA) was recorded using a suction electrode at baseline and for up to 90-min following each experimental paradigm. AIH consisted of 10 x 1 min episodes of FiO2 = 0.1 (balanced N2) interspersed with 2 min of FiO2 = 1. Hexamethonium bromide (30 mg.kg−1) was infused to subtract noise levels from each recording, after which rats were euthanized with chloral hydrate. For Aim 2, 19 additional rats were subjected to the same injury model and time post-injury and allocated to 2 groups: AIH ( n = 11) and TC ( n = 8). These rats were instrumented with left-ventricular (LV) and arterial catheters and assessed simultaneously for cardiac and peripheral hemodynamic function at baseline and 90-min post-AIH/TC. Results: Aim 1) When expressed as % change from baseline, sSNA increased at 90-min post-treatment in AIH (93±67%, P = 0.02) and CBX (193±182%, P < 0.001), but not TC rats (50±45%, P = 0.40). Preventing BP reduction during hypoxic episodes with i.v. phenylephrine blocked the increase in sSNA 90-min post-AIH (12±66%, P > 0.99). Mimicking the AIH-induced BP reduction with simulated hemorrhage (10 x 1-min BP reductions of ~20-25 mmHg equal to those during AIH, interspersed by 2-min of euvolemia), increased sSNA 90-min post-intervention (106±86%, P = 0.01). Aim 2) The changes in maximal LV pressure (AIH = 11±8 mmHg vs. TC = 2±5 mmHg, P = 0.05) and mean arterial pressure (AIH = 8±7 mmHg vs. TC = 0±4 mmHg, P = 0.05) were greater at 90-min post-AIH treatment. Conclusions: We conclude that AIH elicits sympathetic plasticity and improves cardiovascular function post-SCI. Since AIH-induced sympathetic plasticity remains in the presence of a bilateral CBX, is replicated by episodic simulated hemorrhage, and is blocked by phenylephrine, AIH-induced sympathetic plasticity is independent of carotid (peripheral) chemoreflex activation, and is closely linked to episodic hypotension. We suggest that AIH-induced sympathetic plasticity arises from episodic reductions in spinal/medullary cardiovascular centers blood flow (and oxygen delivery) post-SCI. International Spinal Research Trust and Natural Sciences, Engineering Research Council of Canada, International Collaboration on Repair Discoveries. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MP52-20 OPTIMISATION OF TRANSCUTANEOUS SPINAL CORD STIMULATION IN MODULATION OF MICTURITION REFLEXES FOLLOWING SPINAL CORD INJURY

You have accessJournal of UrologyCME1 Apr 2023MP52-20 OPTIMISATION OF TRANSCUTANEOUS SPINAL CORD STIMULATION IN MODULATION OF MICTURITION REFLEXES FOLLOWING SPINAL CORD INJURY Hannah Houliston, Richard Nobrega, Natalia Vasquez, Frank Lee, and Sarah Knight Hannah HoulistonHannah Houliston More articles by this author , Richard NobregaRichard Nobrega More articles by this author , Natalia VasquezNatalia Vasquez More articles by this author , Frank LeeFrank Lee More articles by this author , and Sarah KnightSarah Knight More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003300.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Spinal cord injury (SCI) can result in neurogenic lower urinary tract dysfunction including neurogenic detrusor over-activity (NDO) and detrusor-sphincter dyssynergia (DSD). Exciting developments in spinal cord stimulation (SCS) have demonstrated potential to improve motor function. Transcutaneous SCS (tSCS) provides a non-invasive alternative to epidural SCS, and there is preliminary evidence to suggest it can modulate spinal networks involved in micturition. However, there is ambiguity regarding optimal electrode sites and stimulation parameters. The aim of this study was to investigate optimisation of electrode site and tSCS parameters during the filling and voiding phase of the micturition cycle in people with SCI. METHODS: Ethical approval was obtained from the Research Ethics Committee. Participants were recruited if they had a supra-sacral SCI and proven NDO on most recent urodynamics. During visit 1, 1 ms tSCS pulses of increasing amplitude where administered at three randomised electrode sites; cathode between spinous process of T11-12, or L1-2, anodes at iliac crests or abdomen. External anal sphincter (EAS) and bilateral tibialis anterior EMG were recorded throughout. Optimal electrode site was selected based on motor-evoked potential response, and tolerance to stimulation. With electrodes placed at the optimal site, tSCS was applied in 5 s bursts at either 1, 15 or 30 Hz during voluntary pelvic floor contraction, relaxation and control. During visit 2, participants completed 6 cycles of urodynamics, one control cycle at the start and end, two cycles applying either 30 or 15 Hz tSCS during bladder filling, and two cycles applying either 1 or 15 Hz tSCS during voiding. RESULTS: Six participants were recruited (4 male, 2 female), with mean age 50±20 years old. 4 had an incomplete cervical and 2 an incomplete thoracic SCI. All participants tolerated the stimulation, and there were no adverse events. Optimal electrode sites were cathode L1-2, anode abdomen (n=2), cathode T11-12, anode iliac crest (n=2), cathode L1-2, anode iliac crest (n=1) and cathode T11-12, anode abdomen (n=1). Preliminary analysis of EMG data indicates that tSCS may enhance voluntary contraction of EAS. In addition, tSCS during the filling phase may increase bladder capacity. Further analysis is on-going. CONCLUSIONS: tSCS is an exciting new development which may improve bladder and bowel function following SCI. Our initial studies optimising electrode positioning and parameters will be used to investigate the use of tSCS in a further study combining it with pelvic floor muscle training. Source of Funding: International Spinal Research Trust Grant © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e710 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hannah Houliston More articles by this author Richard Nobrega More articles by this author Natalia Vasquez More articles by this author Frank Lee More articles by this author Sarah Knight More articles by this author Expand All Advertisement PDF downloadLoading ...

Translating state-of-the-art spinal cord MRI techniques to clinical use: A systematic review of clinical studies utilizing DTI, MT, MWF, MRS, and fMRI.

BackgroundA recent meeting of international imaging experts sponsored by the International Spinal Research Trust (ISRT) and the Wings for Life Foundation identified 5 state-of-the-art MRI techniques with potential to transform the field of spinal cord imaging by elucidating elements of the microstructure and function: diffusion tensor imaging (DTI), magnetization transfer (MT), myelin water fraction (MWF), MR spectroscopy (MRS), and functional MRI (fMRI). However, the progress toward clinical translation of these techniques has not been established.MethodsA systematic review of the English literature was conducted using MEDLINE, MEDLINE-in-Progress, Embase, and Cochrane databases to identify all human studies that investigated utility, in terms of diagnosis, correlation with disability, and prediction of outcomes, of these promising techniques in pathologies affecting the spinal cord. Data regarding study design, subject characteristics, MRI methods, clinical measures of impairment, and analysis techniques were extracted and tabulated to identify trends and commonalities. The studies were assessed for risk of bias, and the overall quality of evidence was assessed for each specific finding using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.ResultsA total of 6597 unique citations were identified in the database search, and after full-text review of 274 articles, a total of 104 relevant studies were identified for final inclusion (97% from the initial database search). Among these, 69 studies utilized DTI and 25 used MT, with both techniques showing an increased number of publications in recent years. The review also identified 1 MWF study, 11 MRS studies, and 8 fMRI studies. Most of the studies were exploratory in nature, lacking a priori hypotheses and showing a high (72%) or moderately high (20%) risk of bias, due to issues with study design, acquisition techniques, and analysis methods. The acquisitions for each technique varied widely across studies, rendering direct comparisons of metrics invalid. The DTI metric fractional anisotropy (FA) had the strongest evidence of utility, with moderate quality evidence for its use as a biomarker showing correlation with disability in several clinical pathologies, and a low level of evidence that it identifies tissue injury (in terms of group differences) compared with healthy controls. However, insufficient evidence exists to determine its utility as a sensitive and specific diagnostic test or as a tool to predict clinical outcomes. Very low quality evidence suggests that other metrics also show group differences compared with controls, including DTI metrics mean diffusivity (MD) and radial diffusivity (RD), the diffusional kurtosis imaging (DKI) metric mean kurtosis (MK), MT metrics MT ratio (MTR) and MT cerebrospinal fluid ratio (MTCSF), and the MRS metric of N-acetylaspartate (NAA) concentration, although these results were somewhat inconsistent.ConclusionsState-of-the-art spinal cord MRI techniques are emerging with great potential to improve the diagnosis and management of various spinal pathologies, but the current body of evidence has only showed limited clinical utility to date. Among these imaging tools DTI is the most mature, but further work is necessary to standardize and validate its use before it will be adopted in the clinical realm. Large, well-designed studies with a priori hypotheses, standardized acquisition methods, detailed clinical data collection, and robust automated analysis techniques are needed to fully demonstrate the potential of these rapidly evolving techniques.

Detection of the neuronal activity occurring caudal to the site of spinal cord injury that is elicited during lower limb movement tasks

Functional magnetic resonance imaging (fMRI) of the spinal cord (spinal fMRI) was used to detect neuronal activity elicited by passive and active lower limb movement tasks, in regions caudal to the injury site in volunteers with spinal cord injury. The objectives of this project are: (1) to assess the use of spinal fMRI as a tool for detecting neuronal function in the spinal cord below an injury, and (2) to characterize the neuronal response to active and passive movement tasks. Institute for Biodiagnostics, National Research Council of Canada, Winnipeg, Manitoba, Canada. fMRI of the spinal cord was carried out in 12 volunteers with cervical or thoracic spinal cord injuries. Spinal fMRI was carried out in a 1.5 T clinical MR system using established methods. Active and passive lower limb movement tasks were performed, and sagittal images spanning the entire lumbar spinal cord were obtained. Activity was detected in all volunteers regardless of the extent of injury. During both active and passive participation, activity was seen caudal to the injury site, although the number of active voxels detected with passive movement was less than with the active movement task. Average percent signal change was 13.6% during active participation and 15.0% during passive participation. Spinal fMRI is able to detect a neuronal response during both active and passive lower limb movement tasks in the spinal cord caudal to the injury site.

Quantitative sensory tests (perceptual thresholds) in patients with spinal cord injury

This article was presented at the Premeeting Workshop on Outcome Measures at the American Spinal Injury Association (ASIA) Annual Scientific Meeting in Dallas, Texas, in May 2005. The article summarizes preliminary findings of three quantitative sensory tests that were evaluated as part of the International Spinal Research Trust Clinical Initiative study: perceptual thresholds to electrical, vibration, and thermal stimulation. The results gathered so far suggest that the three tests are simple, reproducible, and applicable in a clinical setting. The tests seem to add resolution and sensitivity to the standard clinical testing and could be useful adjuncts in longitudinal monitoring of spinal cord injury for research purposes.

International spinal research trust research strategy. III: A discussion document

Discussion document. To review the Research Strategy of the International Spinal Research Trust (ISRT), which identifies key areas of basic and clinical research that are likely to be beneficial in developing potential treatments for spinal cord injury for funding. This strategy is intended to both guide the programme of research towards areas of priority and stimulate discussion of the different avenues of research. This latest document has been developed to take into account the scientific progress in the 6 years since publication of the previous Research Strategy. The latest scientific developments in research designed to repair the spinal cord and restore function following injury and how they might impact on spinal cord injury research are highlighted.

Perceptual threshold to cutaneous electrical stimulation in patients with spinal cord injury

Prospective experimental. The aim of this study was to develop a quantitative sensory test (QST) that could be used for assessing the level and the density (degree of impairment) of spinal cord injury (SCI) and for monitoring neurological changes in patients with SCI. National Spinal Injuries Centre, Stoke Mandeville Hospital, Buckinghamshire Hospitals NHS Trust, UK. Perceptual threshold to 3 Hz cutaneous electrical stimulation was measured in 30 control subjects and in 45 patients with SCI at American Spinal Injuries Association (ASIA) sensory key points for selected dermatomes between C3 and S2 bilaterally. Electrical perceptual threshold (EPT) was recorded as the lowest ascending stimulus intensity out of three tests at which the subject reported sensation. The level of SCI according to EPT results was established for right and left sides as the most caudal spinal segment at which patient's EPT was within the control range (mean +/- 2 standard deviation (SD)). The level of SCI, according to EPT, was then compared with clinical sensory level derived according to ASIA classification. In the control group, EPT depended on the dermatome tested and was lowest for T1 (1.01 +/- 0.23 mA, mean +/- SD) and highest for L5 (3.32 +/- 1.14 mA). There was strong correlation between corresponding right and left dermatomes and between repeated assessments. In the SCI group, the level of lesion according to EPT and clinical testing was the same in 43 of the 90 tests (48%). In 37 cases (41%), the EPT level was higher than the clinical level, and in 10 cases (11%), it was lower. Below the level of lesion in incomplete SCI and in the zone of partial preservation in complete SCI, the EPT values in most dermatomes were raised compared with the control group. EPT is a simple, reproducible QST that can assess both the level and the density of SCI. It seems to add sensitivity and resolution to the standard clinical testing and could be a useful adjunct in longitudinal monitoring of patients with SCI for research purposes during natural recovery and therapeutic interventions. International Spinal Research Trust (ISRT), UK, Grant CLI001.

Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy

Review. To highlight the value of investigating the effects of putative therapeutic interventions in clinical spinal cord injury (SCI) in domestic dogs. England, UK. Many experimental interventions in laboratory rodents have been shown to ameliorate the functional deficits caused by SCI; the challenge now is to determine whether they can be translated into useful clinical techniques. Important differences between clinical SCI in human patients and that in laboratory rodents are in the size of the spinal cord and heterogeneity of injury severity. A further key issue is whether the statistical difference in outcome in the laboratory will translate into a useful difference in clinical outcome. Here, we stress the value of investigating the effects of putative therapies in clinical SCI in domestic dogs. The causes of injury, ability to categorise the severity and methods available to measure outcome are very similar between canine and human patients. Furthermore, postmortem tissue more rapidly becomes available from dogs because of their short lifespan than from human patients. The role that investigation of canine SCI might play is illustrated by our preliminary trials on intraspinal transplantation of olfactory glial cells for severe SCI. This canine translational model provides a means of 'filtering' putative treatments before human application.

Thermal perception thresholds: assessing the level of human spinal cord injury

Controlled, cross-sectional, observational. To investigate whether quantitative sensory testing (QST) is able to reveal subclinical deficits at the neurological level of lesion in subjects with chronic spinal cord injury (SCI). National Spinal Injuries Centre, Stoke Mandeville Hospital and Imperial College London, UK. QST and clinical assessments were carried out on 18 subjects with complete SCI (American Spinal Injury Association (ASIA) grade A) and 10 subjects with incomplete SCI (ASIA grades B, C or D). A total of 10 healthy subjects acted as controls. At the level of lesion perceptual thresholds to monofilaments, cold pain and heat pain were similar to values in control subjects but cool and warm thresholds were significantly raised. A correlation between cool and warm thresholds was observed at the level of lesion in complete SCI and between heat and cold pain thresholds at the level of lesion in complete SCI, incomplete SCI and in control subjects. In the zone of partial preservation in complete SCI and below the level of lesion in incomplete SCI, thresholds for all modalities were all different compared to controls. QST reveals impaired thermal sensation in dermatomes clinically defined as normal with ASIA standards. Quantitative thermal testing therefore permits a discriminating assessment of preserved sensation and subclinical deficit and has the potential to improve upon the clinical detection of natural recovery or changes in level of injury following interventions designed to repair SCI.

Magnetic brain stimulation can improve clinical outcome in incomplete spinal cord injured patients.

Preliminary longitudinal clinical trial. To test the efficacy of repetitive transcranial magnetic stimulation (rTMS) in modulating corticospinal inhibition and improving recovery in stable incomplete spinal cord injury (iSCI). National Spinal Injuries Centre, Stoke Mandeville Hospital, Bucks, UK and Division of Neuroscience, Imperial College Faculty of Medicine, Charing Cross Hospital, London, UK. Four stable iSCI patients were treated with rTMS over the occipital cortex (sham treatment) and then over the motor cortex (real treatment). Patients were assessed using electrophysiological, clinical and functional measures before treatment, during sham treatment, during the therapeutic treatment and during a 3-week follow-up period. Cortical inhibition was reduced during the treatment week. Perceptual threshold to electrical stimulation of the skin, ASIA clinical measures of motor and sensory function and time to complete a peg-board improved and remained improved into the follow-up period. In this preliminary trial, rTMS has been shown to alter cortical inhibition in iSCI and improve the clinical and functional outcome. This work was supported by the International Spinal Research Trust.

Towards improved clinical and physiological assessments of recovery in spinal cord injury: a clinical initiative.

Clinical practice and scientific research may soon lead to treatments designed to repair spinal cord injury. Repair is likely to be partial in the first trials, extending only one or two segments below the original injury. Furthermore, treatments that are becoming available are likely to be applied to the thoracic spinal cord to minimise loss of function resulting from damage to surviving connections. These provisos have prompted research into the improvement of clinical and physiological tests designed (1) to determine the level and density of a spinal cord injury, (2) to provide reliable monitoring of recovery over one or two spinal cord segments, and (3) to provide indices of function provided by thoracic spinal root innervation, presently largely ignored in assessment of spinal cord injury. This article reviews progress of the Clinical Initiative, sponsored by the International Spinal Research Trust, to advance the clinical and physiological tests of sensory, motor and autonomic function needed to achieve these aims.

Towards therapy for spinal cord injuries.

The Fifth International Spinal Research Trust (ISRT) Research Network Meeting was held on 6–7 September 2002 in London.

Progress in spinal cord research - a refined strategy for the International Spinal Research Trust.

Achieving regeneration in the central nervous system represents one of the greatest intellectual and practical challenges in neurobiology, and yet it is an absolute requirement if spinal cord injury patients are to have any hope of recovery. The mission of the International Spinal Research Trust (ISRT), established in 1980, is to raise money specifically for spinal research, with a view to ending the permanence of paralysis caused by spinal cord injury. This review summarises some of the major steps forward made in recent years in understanding the mechanisms involved in spinal cord injury and where these discoveries fit in with the ISRT's overall objectives. We review approaches aimed at (1) preventing immediate adverse reactions to injury such as neuronal death and scar formation; (2) minimising inhibitory properties of the CNS environment and maximising the growth potential of damaged neurons; (3) understanding axonal guidance systems that will be required for directed outgrowth and functional reconnection; and (4) optimising the function of surviving systems. We also discuss 'infrastructural' prerequisites for applying knowledge gained through spinal research to the clinical condition, including basic scientific issues such as developing representative animal models of spinal cord injury and sensitive quantitative methods for assessing growth and functional restoration. In addition, we point out the importance of communication. The need to share knowledge between research groups is vital for advancing our understanding of injury and repair mechanisms. Equally important is the need for communication between basic scientists and clinicians which will be essential for what is the ultimate goal of the ISRT, the development of relevant treatment strategies that will prove beneficial to the spinal injured patient.

Distinct sites of insulin-like growth factor (IGF)-II expression and localization in lesioned rat brain: possible roles of IGF binding proteins (IGFBPs) in the mediation of IGF-II activity.

Although expression of the IGF-II has been demonstrated within the central nervous system (CNS), past studies have failed to reveal its precise roles or responses subsequent to a traumatic injury. To demonstrate that IGF-II, IGFBP, and IGF receptor (-R) expression alters in response to a penetrating CNS injury, we used the techniques of ribonuclease protection assay, in situ hybridization, immunohistochemistry, Western blotting, and RIA. Under normal physiology, IGF-II expression is restricted to the mesenchymal support structures of the brain, including the choroid plexus, where its expression is coincident with that of IGFBP-2. Between 1-7 days post lesion (dpl), in the acute phase following a penetrant wound to the CNS, IGF-II and IGF-IIR protein, but not messenger RNA, were colocalized, with IGF-I, IGF-IR, and IGFBP-1, -2, -3, and -6, to neurons, macrophages, astrocytes, and microglia within the damaged tissue. Within the cerebrospinal fluid (CSF), levels of IGF-II peptide increased to peak at 7 dpl. IGFBP-2, -3, and -6 were also observed within the CSF, with IGFBP-2 predominating and exhibiting an increase in binding efficiency from 7-10 dpl. In the chronic phase of injury (7-14 dpl), an increase in both IGF-II, IGF-IIR and IGFBP-5 messenger RNA and protein was observed specifically and focally in the marginal astrocytes forming the limiting glial membrane of the wound. Thus, our evidence suggests that there are two mechanisms of action for IGF-II within the injured rat brain. During the acute phase, the secretion of IGF-II from the choroid plexus into the CSF is up-regulated, resulting in increased transport of the peptide to the wound. In the CSF, transported IGF-II is complexed to IGFBP-2 and essentially demonstrates an endocrine mode of action with a balance of locally produced IGFBPs modulating its bioactivity in the wound. Later in the wounding response, levels of IGF-II decline in the CSF and the wound neuropil, possibly with the aid of increased IGFBP-5 levels that may help to locally sequester and down-regulate IGF-II activity. Hence, in the chronic phase of the injury response, IGF-II reasserts itself to a predominantly autocrine/paracrine role restricted to the mesenchymal support structures, including the glia limitans, which may help reestablish and maintain tissue homeostasis.

The International Spinal Research Trust's strategic approach to the development of treatments for the repair of spinal cord injury.

The International Spinal Research Trust (ISRT) has selected a sub-set of the key molecular and cellular events underlying spinal injury and nerve regeneration, to be focus of their funding and other means of research support. These priority targets are (i) to understand and to minimise the damage caused by spinal injury and the resulting inflammatory and fibrotic events, in order to prevent the establishment of a post-acute situation that is ill-placed for regeneration; and (ii) to understand and then to manipulate the integrated environment for regrowth that is created by the interplay of soluble and matrix- or membrane-associated factors, both trophic and inhibitory. Investigation and, ultimately, exploitation of these targets requires the development of standardised and representative animal models and the application of quantitative methods for assessing functional re-innervation. The ISRT will also sponsor the networking of different disciplines and technologies to apply the most productive skills to spinal repair.

Regeneration in the central nervous system and related factors. Summary of the Bermuda Paraplegia Conference, April 1994 (International Spinal Research Trust)

Keywords: central nervous system; spinal cord injury researches; regeneration in the central nervous system

Review article: the amelioration and cure of spinal cord damage. The aim of the International Spinal Research Trust

Review article: the amelioration and cure of spinal cord damage. The aim of the International Spinal Research Trust