From Toxin to Treatment: A Narrative Review on the Use of Botulinum Toxin for Autonomic Dysfunction.

Since its regulatory approval over a half-century ago, botulinum toxin has evolved from one of the most potent neurotoxins known to becoming routinely adopted in clinical practice. Botulinum toxin, a highly potent neurotoxin produced by Clostridium botulinum, can cause botulism illness, characterized by widespread muscle weakness due to inhibition of acetylcholine transmission at neuromuscular junctions. The observation of botulinum toxin's anticholinergic properties led to the investigation of its potential benefits for conditions with an underlying etiology of cholinergic transmission, including autonomic nervous system dysfunction. These conditions range from disorders of the integument to gastrointestinal and urinary systems. Several formulations of botulinum toxin have been developed and tested over time, significantly increasing the availability of this treatment for appropriate clinical use. Despite the accelerated and expanded use of botulinum toxin, there lacks an updated comprehensive review on its therapeutic use, particularly to treat autonomic dysfunction. This narrative review provides an overview of the effect of botulinum toxin in the treatment of autonomic dysfunction and summarizes the different formulations and dosages most widely studied, while highlighting reported outcomes and the occurrence of any adverse events.

REPORT-SCS: minimum reporting standards for spinal cord stimulation studies in spinal cord injury.

Objective.Electrical spinal cord stimulation (SCS) has emerged as a promising therapy for recovery of motor and autonomic dysfunctions following spinal cord injury (SCI). Despite the rise in studies using SCS for SCI complications, there are no standard guidelines for reporting SCS parameters in research publications, making it challenging to compare, interpret or reproduce reported effects across experimental studies.Approach.To develop guidelines for minimum reporting standards for SCS parameters in pre-clinical and clinical SCI research, we gathered an international panel of expert clinicians and scientists. Using a Delphi approach, we developed guideline items and surveyed the panel on their level of agreement for each item.Main results.There was strong agreement on 26 of the 29 items identified for establishing minimum reporting standards for SCS studies. The guidelines encompass three major SCS categories: hardware, configuration and current parameters, and the intervention.Significance.Standardized reporting of stimulation parameters will ensure that SCS studies can be easily analyzed, replicated, and interpreted by the scientific community, thereby expanding the SCS knowledge base and fostering transparency in reporting.

Heart Rate Variability-Based Prediction of Autonomic Dysreflexia After Spinal Cord Injury.

Autonomic dysreflexia (AD) is a common autonomic complication of spinal cord injury (SCI) characterized by a sudden increase is blood pressure triggered by peripheral stimulation, such as bladder distention. Iatrogenic AD events often occur during various medical procedures including urodynamic assessments (UDSs) used to evaluate lower urinary tract (LUT) function in individuals with SCI. To date, there are no established clinical practices that would allow early detection of the development of episodes of AD. Heart rate variability (HRV) is a reliable and non-invasive metric for evaluating autonomic regulation of the cardiovascular system, with demonstrated utility in people with SCI during UDSs. We aim to provide a comprehensive evaluation of cardiovascular function during UDS-induced AD using ultra-short-term HRV analysis and identify changes in cardiovascular dynamics to predict the onset of AD. We assessed cardiovascular data in a total of 24 participants with sensorimotor complete SCI above T6 (17 males, 7 females, median age = 43 [36-50] years) who experienced AD during UDS. We used continuous electrocardiographic recordings to evaluate HRV in 60 sec overlapping windows during filling cystometry. The mean of "normal-to-normal" heartbeats (meanNN), its standard deviation (SDNN), and the root mean square of successive differences (RMSSD) were calculated and used in all subsequent analyses. We found that SDNN and RMSSD diminished during the early phase of bladder filling and sharply increased during AD. Using the lowest point of statistical variability in heart rate (i.e., SDNN), we were able to predict AD events within 240 sec (percentile 25-percentile 75: 172-339 sec) before the first systolic blood pressure peak after AD onset (sensitivity = 0.667; specificity = 0.875). Our results indicated a temporary increase in sympathetic activity during the early phase of bladder filling, which is followed by an increase in parasympathetic outflow to the heart when AD occurs. These findings have significant clinical implications that extend beyond the context of UDS and demonstrate the importance of identifying early changes in HRV in order to accurately predict AD episodes in people living with SCI.

Motor and autonomic concomitant health improvements with neuromodulation and exercise (MACHINE) training: a randomised controlled trial in individuals with spinal cord injury.

INTRODUCTION: Motor and autonomic dysfunctions are widespread among people with spinal cord injury (SCI), leading to poor health and reduced quality of life. Exercise interventions, such as locomotor training (LT), can promote sensorimotor and autonomic recovery post SCI. Recently, breakthroughs in SCI research have reported beneficial effects of electrical spinal cord stimulation (SCS) on motor and autonomic functions. Despite literature supporting the independent benefits of transcutaneous SCS (TSCS) and LT, the effect of pairing TSCS with LT is unknown. These therapies are non-invasive, customisable and have the potential to simultaneously benefit both sensorimotor and autonomic functions. The aim of this study is to assess the effects of LT paired with TSCS in people with chronic SCI on outcomes of sensorimotor and autonomic function. METHODS AND ANALYSIS: Twelve eligible participants with chronic (>1 year) motor-complete SCI, at or above the sixth thoracic segment, will be enrolled in this single-blinded, randomised sham-controlled trial. Participants will undergo mapping for optimisation of stimulation parameters and baseline assessments of motor and autonomic functions. Participants will then be randomly assigned to either LT+TSCS or LT+Sham stimulation for 12 weeks, after which postintervention assessments will be performed to determine the effect of TSCS on motor and autonomic functions. The primary outcome of interest is attempted voluntary muscle activation using surface electromyography. The secondary outcomes relate to sensorimotor function, cardiovascular function, pelvic organ function and health-related quality of life. Statistical analysis will be performed using two-way repeated measures Analysis of variance (ANOVAs) or Kruskal-Wallis and Cohen's effect sizes. ETHICS AND DISSEMINATION: This study has been approved after full ethical review by the University of British Columbia's Research Ethics Board. The stimulator used in this trial has received Investigation Testing Authorisation from Health Canada. Trial results will be disseminated through peer-reviewed publications, conference presentations and seminars. TRIAL REGISTRATION NUMBER: NCT04726059.

The Microbiological Burden of Short-Term Catheter Reuse in Individuals with Spinal Cord Injury: A Prospective Study.

Despite the risk of developing catheter-associated urinary tract infections (CAUTI), catheter reuse is common among people with spinal cord injury (SCI). This study examined the microbiological burden and catheter surface changes associated with short-term reuse. Ten individuals with chronic SCI reused their catheters over 3 days. Urine and catheter swab cultures were collected daily for analysis. Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) analyses were used to assess catheter surface changes. Catheter swab cultures showed no growth after 48 h (47.8%), skin flora (28.9%), mixed flora (17.8%), or bacterial growth (5.5%). Asymptomatic bacteriuria was found for most participants at baseline (n = 9) and all at follow-up (n = 10). Urine samples contained Escherichia coli (58%), Klebsiella pneumoniae (30%), Enterococcus faecalis (26%), Acinetobacter calcoaceticus-baumannii (10%), Pseudomonas aeruginosa (6%) or Proteus vulgaris (2%). Most urine cultures showed resistance to one or more antibiotics (62%). SEM images demonstrated structural damage, biofilm and/or bacteria on all reused catheter surfaces. XPS analyses also confirmed the deposition of bacterial biofilm on reused catheters. Catheter surface changes and the presence of antibiotic-resistant bacteria were evident following short-term reuse, which may increase susceptibility to CAUTI in individuals with SCI despite asymptomatic bacteriuria.

Spinal Cord Stimulation Prevents Autonomic Dysreflexia in Individuals with Spinal Cord Injury: A Case Series.

Spinal cord injury (SCI) results in severe cardiovascular dysfunction due to the disruption of supraspinal control. Autonomic dysreflexia (AD), an uncontrolled rise in blood pressure in response to peripheral stimuli including common bowel routine, digital anorectal stimulation (DARS), reduces the quality of life, and increases morbidity and mortality. Recently, spinal cord stimulation (SCS) has emerged as a potential intervention to mitigate unstable blood pressure following SCI. The objective of this case series was to test the real-time effect of epidural SCS (eSCS) at the lumbosacral spinal cord, the most common implant location, on mitigating AD in individuals with SCI. We recruited three individuals with cervical and upper thoracic motor-complete SCI who have an implanted epidural stimulator. We demonstrated that eSCS can reduce the elevation in blood pressure and prevent DARS-induced AD. The blood pressure variability analysis indicated that eSCS potentially reduced vascular sympathetic nervous system activity during DARS, compared to without eSCS. This case series provides evidence to support the use of eSCS to prevent AD episodes during routine bowel procedures, improving the quality of life for individuals with SCI and potentially reducing cardiovascular risks.

Effects of non-invasive spinal cord stimulation on lower urinary tract, bowel, and sexual functions in individuals with chronic motor-complete spinal cord injury: Protocol for a pilot clinical trial.

INTRODUCTION: Electrical spinal cord neuromodulation has emerged as a leading intervention for restoring autonomic functions, such as blood pressure, lower urinary tract (LUT), bowel, and sexual functions, following spinal cord injury (SCI). While a few preliminary studies have shown the potential effect of non-invasive transcutaneous spinal cord stimulation (tSCS) on autonomic recovery following SCI, the optimal stimulation parameters, as well as real-time and long-term functional benefits of tSCS are understudied. This trial entitled "Non-invasive Neuromodulation to Treat Bladder, Bowel, and Sexual Dysfunction following Spinal Cord Injury" is a pilot trial to examine the feasibility, dosage effect and safety of tSCS on pelvic organ function for future large-scale randomized controlled trials. METHODS AND ANALYSIS: Forty eligible participants with chronic cervical or upper thoracic motor-complete SCI will undergo stimulation mapping and assessment batteries to determine the real-time effect of tSCS on autonomic functions. Thereafter, participants will be randomly assigned to either moderate or intensive tSCS groups to test the dosage effect of long-term stimulation on autonomic parameters. Participants in each group will receive 60 minutes of tSCS per session either twice (moderate) or five (intensive) times per week, over a period of six weeks. Outcome measures include: (a) changes in bladder capacity through urodynamic studies during real-time and after long-term tSCS, and (b) resting anorectal pressure determined via anorectal manometry during real-time tSCS. We also measure assessments of sexual function, neurological impairments, and health-related quality of life using validated questionnaires and semi-structured interviews. ETHICS AND DISSEMINATION: Ethical approval has been obtained (CREB H20-01163). All primary and secondary outcome data will be submitted to peer-reviewed journals and disseminated among the broader scientific community and stakeholders.

Probing the deployment of peripheral visual attention during obstacle-crossing planning.

Gaze is directed to one location at a time, making peripheral visual input important for planning how to negotiate different terrain during walking. Whether and how the brain attends to this input is unclear. We developed a novel paradigm to probe the deployment of sustained covert visual attention by testing orientation discrimination of a Gabor patch at stepping and non-stepping locations during obstacle-crossing planning. Compared to remaining stationary, obstacle-crossing planning decreased visual performance (percent correct) and sensitivity (d') at only the first of two stepping locations. Given the timing of the first and second steps before obstacle crossing relative to the Gabor patch presentation, the results suggest the brain uses peripheral vision to plan one step at a time during obstacle crossing, in contrast to how it uses central vision to plan two or more steps in advance. We propose that this protocol, along with multiple possible variations, presents a novel behavioral approach to identify the role of covert visual attention during obstacle-crossing planning and other goal-directed walking tasks.

Arm crank ergometer "spin" training improves seated balance and aerobic capacity in people with spinal cord injury.

BACKGROUND: There is some evidence that upper-body training modalities can improve not only aerobic capacity but also seated balance in people with spinal cord injury (SCI), even in those classified with motor-complete paralysis above T6. Here, we evaluated the effect of arm crank ergometry (ACE) "spin" training on trunk muscle recruitment and its effects on seated balance and aerobic capacity. METHODS: Eight individuals with high-level complete and 6 with either a low-level complete or a motor-incomplete SCI participated in this study. Participants completed 5 weeks of a group ACE "spin" training protocol which featured modulations in cadence and resistance as well as back-supported and unsupported bouts. Surface electromyography was used to confirm trunk muscle recruitment during unsupported ACE. Changes in aerobic capacity (peak oxygen consumption) and seated balance control (center of pressure parameters) were assessed at pre- and post-intervention. RESULTS: Unsupported ACE was effective for eliciting trunk muscle activity (P < .05). Following training, peak oxygen consumption significantly improved by an average of 16% (P = .005). Static sitting balance significantly improved from pre- to post-intervention, but only when tested with eyes closed as measured by a reduction in area (P = .047) and velocity of center of pressure (P = .013). No significant changes were observed in static sitting balance with eyes open or in dynamic sitting balance. CONCLUSION: Group ACE "spin" classes may benefit not only aerobic fitness but also static seated balance control in people with SCI.

Improvements in skilled walking associated with kinematic adaptations in people with spinal cord injury.

INTRODUCTION: Individuals with motor-incomplete SCI (m-iSCI) remain limited community ambulators, partly because they have difficulty with the skilled walking requirements of everyday life that require adaptations in inter-joint coordination and range of motion of the lower limbs. Following locomotor training, individuals with SCI show improvements in skilled walking and walking speed, however there is limited understanding of how adaptations in lower limb kinematics following training contribute to improvements in walking. OBJECTIVE: To determine the relationship between changes in lower limb kinematics (range of motion and inter-joint coordination) and improvements in walking function (walking speed and skilled walking) following locomotor training. METHODS: Lower limb kinematics were recorded from 8 individuals with chronic m-iSCI during treadmill walking before and after a 3-month locomotor training program. Data were also collected from 5 able-bodied individuals to provide normative values. In individuals with SCI, muscle strength was used to define the stronger and weaker limb. Motion analysis was used to determine, hip, knee and ankle angles. Joint angle-angle plots (cyclograms) were used to quantify inter-joint coordination. Shape differences between pre-and post-training cyclograms were used to assess the changes in coordination and their relation to improvements in walking function. Walking function was assessed using the 10MWT for walking speed and the SCI-FAP for skilled walking. Comparing pre- and post-training cyclograms to the able-bodied pattern was used to understand the extent to which changes in coordination involved the recovery of normative motor patterns. RESULTS: Following training, improvements in skilled walking were significantly related to changes in hip-ankle coordination (ρ = - .833, p = 0.010) and knee range of motion (ρ = .833, p = 0.010) of the weaker limb. Inter-joint coordination tended to revert towards normative patterns, but not completely. No relationships were observed with walking speed. CONCLUSION: Larger changes in hip-ankle coordination and a decrease in knee range of motion in the weaker limb during treadmill walking were related to improvements in skilled walking following locomotor training in individuals with SCI. The changes in coordination seem to reflect some restoration of normative patterns and the adoption of compensatory strategies, depending on the participant.

Training with robot-applied resistance in people with motor-incomplete spinal cord injury: Pilot study.

UNLABELLED: People with motor-incomplete spinal cord injury (m-iSCI) can recover basic walking function but still have difficulty performing the skilled walking required for everyday environments. We hypothesized that a robotic-based gait rehabilitation strategy founded on principles of motor learning would be a feasible and potentially effective approach for improving skilled walking in people with m-iSCI. Fifteen individuals with chronic (>1 yr) m-iSCI were randomly allocated to body weight-supported treadmill training (BWSTT) with Lokomat-applied resistance (Loko-R) or conventional Lokomat-assisted BWSTT (Control). Training sessions were 45 min, 3 times/week for 3 mo. Tolerance to training was assessed by ratings of perceived exertion and reports of pain/soreness. Overground skilled walking capacity (Spinal Cord Injury-Functional Ambulation Profile [SCI-FAP]), as well as walking speed and distance were measured at baseline, posttraining, and 1 and 6 mo follow-up. Our results indicate that Loko-R training could be feasibly applied for people with m-iSCI, although participants in Loko-R tended to report higher levels of perceived exertion during training. Participants in the Loko-R group performed significantly better in the SCI-FAP than Control at posttraining and in follow-up assessments. This study provides evidence that Loko-R training is feasible in people with m-iSCI. Furthermore, there is preliminary evidence suggesting that Loko-R may help improve performance in skilled overground walking tasks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT00610974. "Enhancing Walking in People With Incomplete Spinal Cord Injury: a Pilot Study"; https://clinicaltrials.gov/ct2/show/NCT00610974.