Impact of Activity-Based Training on Bowel Function in a Rat Model of Spinal Cord Injury.

Significant bowel-related issues after spinal cord injury (SCI) that affect morbidity and quality of life (QOL) include diminished bowel motility, loss of sphincter control, gastric ulcers, autonomic dysreflexia, pain, diarrhea, constipation, and fecal incontinence. Clinical diagnoses and research in humans have largely relied on anorectal manometry (ARM) procedures to increase understanding of the functional effects of SCI on colorectal motility and defecation physiology. Recent pre-clinical rodent studies have also used ARM to further our understanding of bowel-related dysfunctions post-SCI. In the present study, the benefits of different activity-based training (ABT) durations on bowel function were examined. Six groups of male rats including two non-training (NT; uninjured and SCI) and four ABT (quadrupedal [Quad or Q] stepping on a treadmill) groups. All ABT animals received 4 weeks of 1-h daily stepping beginning 2 weeks post-SCI followed by variable amounts for 4 additional weeks (none; daily; once a week; daily for final 4th week only). Outcome measures included fecal output (home cage; metabolic cage) throughout the study and terminal measurements (post 8-week ABT) of external anal sphincter (EAS) electromyography, resting anorectal pressure, and giant contraction (GC) activation under urethane anesthesia. The results indicate that treadmill training normalized defecation amount based on feces weight and food intake, as well as GC frequency, EAS latency and amplitude during fecal expulsion, and resting pressure in specific areas within the colorectum. The two intermittent training groups consistently showed recorded metrics comparable to the non-injured group. The results demonstrate bowel dysfunction in the rodent SCI contusion model with improvements in functional outcomes following ABT. Importantly, the benefits to bowel-related functions with versus without intermittent ABT illustrate the need for periodic therapy to maintain the functional gains of ABT.

Mid-lumbar (L3) epidural stimulation effects on bladder and external urethral sphincter in non-injured and chronically transected urethane-anesthetized rats.

Recent pre-clinical and clinical spinal cord epidural stimulation (scES) experiments specifically targeting the thoracolumbar and lumbosacral circuitries mediating lower urinary tract (LUT) function have shown improvements in storage, detrusor pressure, and emptying. With the existence of a lumbar spinal coordinating center in rats that is involved with external urethral sphincter (EUS) functionality during micturition, the mid-lumbar spinal cord (specifically L3) was targeted in the current study with scES to determine if the EUS and thus the void pattern could be modulated, using both intact and chronic complete spinal cord injured female rats under urethane anesthesia. L3 scES at select frequencies and intensities of stimulation produced a reduction in void volumes and EUS burst duration in intact rats. After chronic transection, three different subgroups of LUT dysfunction were identified and the response to L3 scES promoted different cystometry outcomes, including changes in EUS bursting. The current findings suggest that scES at the L3 level can generate functional neuromodulation of both the urinary bladder and the EUS in intact and SCI rats to enhance voiding in a variety of clinical scenarios.

Impact of activity-based recovery training and desmopressin on spinal cord injury-induced polyuria in Wistar rats.

Activity-based recovery training (ABRT) reverses spinal cord injury (SCI) induced polyuria and alterations of biomarkers involved with fluid balance, including expression levels of kidney vasopressin 2 receptors. However, void volumes do not return to pre-injury baseline levels, indicating a combinatorial approach may be necessary.In the current study, acute effects of a pharmacological intervention versus placebo were examined in male rats that had received 70 daily ABRT sessions. The treatment, desmopressin (DDAVP - synthetic analogue of arginine vasopressin), an antidiuretic therapy used for the management of bedwetting in children and central diabetes insipidus, has previously shown some promise in a few limited cohorts of SCI individuals having nocturnal polyuria.A total of 70 sessions of ABRT over a 10-week timeframe again reduced the overproduction of urine, but not completely to pre-SCI baseline levels. DDAVP treatment maintained but did not further reduce the level of urine output in the ABRT group without continuous exercise, demonstrating either intervention/treatment alone is effective, despite no additive effect. Although intake did not change from pre-injury levels despite polyuria, DDAVP treatment also reduced drink volume.Further studies are needed as the mechanisms underlying changes in fluid and solute balance are likely multi-factorial involving a complex interaction between the neural (both central and peripheral) control of systems mediating thirst, urinary output, and cardiovascular regulation.

Targeting bladder function with network-specific epidural stimulation after chronic spinal cord injury.

Profound dysfunctional reorganization of spinal networks and extensive loss of functional continuity after spinal cord injury (SCI) has not precluded individuals from achieving coordinated voluntary activity and gaining multi-systemic autonomic control. Bladder function is enhanced by approaches, such as spinal cord epidural stimulation (scES) that modulates and strengthens spared circuitry, even in cases of clinically complete SCI. It is unknown whether scES parameters specifically configured for modulating the activity of the lower urinary tract (LUT) could improve both bladder storage and emptying. Functional bladder mapping studies, conducted during filling cystometry, identified specific scES parameters that improved bladder compliance, while maintaining stable blood pressure, and enabled the initiation of voiding in seven individuals with motor complete SCI. Using high-resolution magnetic resonance imaging and finite element modeling, specific neuroanatomical structures responsible for modulating bladder function were identified and plotted as heat maps. Data from this pilot clinical trial indicate that scES neuromodulation that targets bladder compliance reduces incidences of urinary incontinence and provides a means for mitigating autonomic dysreflexia associated with bladder distention. The ability to initiate voiding with targeted scES is a key step towards regaining volitional control of LUT function, advancing the application and adaptability of scES for autonomic function.

Effect of T3 Spinal Contusion Injury on Upper Urinary Tract Function.

Spinal cord injury (SCI) significantly impacts many systems attributable to disrupted autonomic regulation of the body. Of these disruptions, excessive production/passage of urine (polyuria) has been understudied. Pre-clinical animal studies investigating SCI-induced polyuria have been carried out in T8-T10 spinal-level contusive injuries, which directly impacts both supraspinal sympathetic inputs to the spinal circuitry mediating kidney function as well as local networks including pre-ganglionic sympathetic fibers to the kidney. The current study utilizes a higher-level (T3) contusion to narrow the potential source(s) of damage that induce(s) polyuria. Metabolic cage 24-h urine collections demonstrated that, starting 1 week post-SCI and lasting chronically through 6 weeks post-SCI, T3 contused adult male rats had a significant increase in void volume relative to pre-injury and surgical sham controls. Subsequent examination of previously identified biomarkers revealed levels reflecting the presence of polyuria. For example, urine atrial natriuretic peptide levels were significantly increased at 6 weeks post-SCI compared to baseline, and serum arginine vasopressin (AVP) levels were significantly decreased. Further, there was a significant decrease post-injury relative to shams in the number of AVP-labeled cells within the suprachiasmatic nucleus, a hypothalamic region responsible for significant disruptions of circadian rhythmicity post-SCI, including loss of the diurnal variation of AVP production, which clinical studies have identified as contributing to the emergence of nocturia after SCI. Together, the current results demonstrate that SCI-induced polyuria is present after a T3-level SCI, indicating that damage of descending supraspinal circuitries precipitates dysfunction of homeostatic mechanisms involved in salt and water balance.

Thoracolumbar epidural stimulation effects on bladder and bowel function in uninjured and chronic transected anesthetized rats.

Pre-clinical studies have shown that spinal cord epidural stimulation (scES) at the level of pelvic and pudendal nerve inputs/outputs (L5-S1) alters storage and/or emptying functions of both the bladder and bowel. The current mapping experiments were conducted to investigate scES efficacy at the level of hypogastric nerve inputs/outputs (T13-L2) in male and female rats under urethane anesthesia. As found with L5-S1 scES, T13-L2 scES at select frequencies and intensities of stimulation produced an increase in inter-contraction interval (ICI) in non-injured female rats but a short-latency void in chronic T9 transected rats, as well as reduced rectal activity in all groups. However, the detrusor pressure during the lengthened ICI (i.e., urinary hold) remained at a low pressure and was not elevated as seen with L5-S1 scES, an effect that's critical for translation to the clinic as high fill pressures can damage the kidneys. Furthermore, T13-L2 scES was shown to stimulate voiding post-transection by increasing bladder activity while also directly inhibiting the external urethral sphincter, a pattern necessary to overcome detrusor-sphincter dyssynergia. Additionally, select scES parameters at T13-L2 also increased distal colon activity in all groups. Together, the current findings suggest that optimization of scES for bladder and bowel will likely require multiple electrode cohorts at different locations that target circuitries coordinating sympathetic, parasympathetic and somatic outputs.

Timeline of Changes in Biomarkers Associated with Spinal Cord Injury-Induced Polyuria.

Deficits in upper and lower urinary tract function, which include detrusor overactivity, urinary incontinence, detrusor-sphincter dyssynergia, and polyuria, are among the leading issues that arise after spinal cord injury (SCI) affecting quality of life. Given that overproduction of urine (polyuria) has been shown to be associated with an imbalance in key regulators of body fluid homeostasis, the current study examined the timing of changes in levels of various relevant hormones, peptides, receptors, and channels post-contusion injury in adult male Wistar rats. The results show significant up- or downregulation at various time points, beginning at 7 days post-injury, in levels of urinary atrial natriuretic peptide, serum arginine vasopressin (AVP), kidney natriuretic peptide receptor-A, kidney vasopressin-2 receptor, kidney aquaporin-2 channels, and kidney epithelial sodium channels (ß- and γ-, but not α-, subunits). The number of AVP-labeled neurons in the hypothalamus (supraoptic and -chiasmatic, but not paraventricular, nuclei) was also significantly altered at one or more time points. These data show significant fluctuations in key biomarkers involved in body fluid homeostasis during the post-SCI secondary injury phase, suggesting that therapeutic interventions (e.g., desmopressin, a synthetic analogue of AVP) should be considered early post-SCI.

Bladder and bowel responses to lumbosacral epidural stimulation in uninjured and transected anesthetized rats.

Spinal cord epidural stimulation (scES) mapping at L5-S1 was performed to identify parameters for bladder and bowel inhibition and/or contraction. Using spinally intact and chronic transected rats of both sexes in acute urethane-anesthetized terminal preparations, scES was systematically applied using a modified Specify 5-6-5 (Medtronic) electrode during bladder filling/emptying cycles while recording bladder and colorectal pressures and external urethral and anal sphincter electromyography activity. The results indicate frequency-dependent effects on void volume, micturition, bowel peristalsis, and sphincter activity just above visualized movement threshold intensities that differed depending upon neurological intactness, with some sex-dependent differences. Thereafter, a custom-designed miniature 15-electrode array designed for greater selectivity was tested and exhibited the same frequency-dependent urinary effects over a much smaller surface area without any concurrent movements. Thus, select activation of autonomic nervous system circuitries with scES is a promising neuromodulation approach for expedient translation to individuals with SCI and potentially other neurologic disorders.

Choice of cystometric technique impacts detrusor contractile dynamics in wistar rats.

The objective of the current animal study was to investigate factors contributing to the different phases of the cystometrogram (CMG) in order to address disparities in research data reported in the current literature. Three experiments in 20 female Wistar rats were designed to investigate (1) the effects of anesthesia on the contractile pattern of the bladder during micturition; (2) the impact of the physical characteristics of the CMG technique upon the accuracy of intra-vesical pressure recordings; and (3) identification of physiological and methodological factors associated with the emptying and rebound phases during CMG. Variables tested included awake versus urethane-anesthetized conditions, use of a single catheter for both filling and intra-vesical pressure (Pves) recording versus a separate two catheter approach, and comparisons between ureter, bladder dome, and urethral catheter placements. Both awake and anesthetized conditions contributed to variations in the shape and magnitude of the CMG pressure curves. In addition, catheter size, acute incision of the bladder dome for catheter placement, use of the same catheter for filling and Pves recordings, as well as the placement and positioning of the tubing, all contributed to alterations of the physiological properties and characteristic of the various CMG phases, including the frequent occurrence of an artificial rebound during the third phase of micturition. The present results demonstrate how different experimental conditions lead not only to variability in Pves curves, but consistency of the measurements as well, which needs to be accounted for when interpreting CMG outcome data.

Kinematic analysis of penile reflexes in a rat model of spinal cord injury.

The ex-copula penile dorsiflexion reflex (PDFR) is an established measure of sexual dysfunction in male rat models of spinal cord injury. Although the PDFR after complete spinal transection is well described, information regarding the more clinically relevant incomplete spinal contusion injury model is limited. This study examined, using two-dimensional (2D) kinematic analysis, the relationship between the PDFR and degree of white matter sparing (WMS). Male Wistar rats received a T9 contusion with varying degrees of impactor forces. Weekly kinematic recordings of the PDFR were made 3-8 weeks postinjury. Sexual reflex components examined included maximum angle of penile dorsiflexion, total penile event duration, and penile ascent speed. Post hoc comparison between animals grouped based upon injury severity (moderate-severe: 13.33%-17.15% WMS vs moderate: 20.85%-33.50% WMS) indicated PDFR effects. Specifically, the numbers of animals with more moderate contusions having data points above the median in both maximum angle of penile dorsiflexion and penile ascent speed were significantly lower than animals with more severe injuries. Total penile event duration was also affected but only at more chronic time points (6-8 weeks). Thus, 2D kinematic analysis of the PDFR allows for more consistent and quantifiable analysis of the subtle differences that can occur between injury severity groups in the rat contusion model.

Effect of Different Forms of Activity-Based Recovery Training on Bladder, Bowel, and Sexual Function After Spinal Cord Injury.

OBJECTIVES: To investigate whether the urogenital and bowel functional gains previously demonstrated post-locomotor step training after chronic spinal cord injury could have been derived due to weight-bearing alone or from exercise in general. DESIGN: Prospective cohort study; pilot trial with small sample size. SETTING: Urogenital and bowel scientific core facility at a rehabilitation institute and spinal cord injury research center in the United States. PARTICIPANTS: Men and women (N=22) with spinal cord injury (American Spinal Injury Association Impairment Scale grades of A-D) participated in this study. INTERVENTIONS: Approximately 80 daily 1-hour sessions of either stand training or nonweight-bearing arm crank ergometry. Comparisons were made with previously published locomotor training data (step; N=7). MAIN OUTCOME MEASURES: Assessments at both pre- and post-training timepoints included cystometry for bladder function and International Data Set Questionnaires for bowel and sexual functions. RESULTS: Cystometry measurements revealed a significant decrease in bladder pressure and limited improvement in compliance with nonweight-bearing exercise but not with standing. Although International Data Set questionnaires revealed profound bowel dysfunction and marked deficits in sexual function pretraining, no differences were identified poststand or after nonweight-bearing exercise. CONCLUSIONS: These pilot trial results suggest that, although stand and weight-bearing alone do not benefit pelvic organ functions after spinal cord injury, exercise in general may contribute at least partially to the lowering of bladder pressure and the increase in compliance that was seen previously with locomotor training, potentially through metabolic, humoral, and/or cardiovascular mechanisms. Thus, to maximize activity-based recovery training benefits for functions related to storage and emptying, an appropriate level of sensory input to the spinal cord neural circuitries controlling bladder and bowel requires task-specific stepping.

Investigation of Bowel Function with Anorectal Manometry in a Rat Spinal Cord Contusion Model.

Bowel dysfunction after chronic spinal cord injury (SCI) is a common source of morbidity and rehospitalization. Typical complications include constipation, fecal impaction, incontinence, abdominal distention, autonomic dysreflexia, and the necessity of interventions (i.e., suppositories, digital stimulation) to defecate. Numerous surveys have confirmed that the remediation of bowel complications is more highly valued for quality of life than improvements in walking. Much of what is known about bowel function after SCI for diagnosis and research in humans has been gained using anorectal manometry (ARM) procedures. However, ARM has been underutilized in pre-clinical animal work. Therefore, a novel combination of outcome measures was examined in the current study that incorporates functional output of the bowel (weekly fecal measurements), weight gain (pre-injury to terminal weight), and terminal ARM measurement with external anal sphincter electromyography under urethane anesthesia. The results indicate higher fecal output after contusion during the sub-acute period (4-7 days) post-injury, changes in the composition of the feces, and functionally obstructive responses in a specific section of the rectum (increased baseline pressure, increased frequency of contraction, and reduced ability to trigger a giant contraction to a distension stimulus). These results demonstrate significant bowel dysfunction in the rodent SCI contusion model that is consistent with data from human research. Thus, the combined measurement protocol enables the detection of changes and can be used, with minimal cost, to assess effectiveness of therapeutic interventions on bowel complications.

Improvements in Bladder Function Following Activity-Based Recovery Training With Epidural Stimulation After Chronic Spinal Cord Injury.

Spinal cord injury (SCI) results in profound neurologic impairment with widespread deficits in sensorimotor and autonomic systems. Voluntary and autonomic control of bladder function is disrupted resulting in possible detrusor overactivity, low compliance, and uncoordinated bladder and external urethral sphincter contractions impairing storage and/or voiding. Conservative treatments managing neurogenic bladder post-injury, such as oral pharmacotherapy and catheterization, are important components of urological surveillance and clinical care. However, as urinary complications continue to impact long-term morbidity in this population, additional therapeutic and rehabilitative approaches are needed that aim to improve function by targeting the recovery of underlying impairments. Several human and animal studies, including our previously published reports, have documented gains in bladder function due to activity-based recovery strategies, such as locomotor training. Furthermore, epidural stimulation of the spinal cord (scES) combined with intense activity-based recovery training has been shown to produce volitional lower extremity movement, standing, as well as improve the regulation of cardiovascular function. In our center, several participants anecdotally reported improvements in bladder function as a result of training with epidural stimulation configured for motor systems. Thus, in this study, the effects of activity-based recovery training in combination with scES were tested on bladder function, resulting in improvements in overall bladder storage parameters relative to a control cohort (no intervention). However, elevated blood pressure elicited during bladder distention, characteristic of autonomic dysreflexia, was not attenuated with training. We then examined, in a separate, large cross-sectional cohort, the interaction between detrusor pressure and blood pressure at maximum capacity, and found that the functional relationship between urinary bladder distention and blood pressure regulation is disrupted. Regardless of one's bladder emptying method (indwelling suprapubic catheter vs. intermittent catheterization), autonomic instability can play a critical role in the ability to improve bladder storage, with SCI enhancing the vesico-vascular reflex. These results support the role of intersystem stimulation, integrating scES for both bladder and cardiovascular function to further improve bladder storage.

Recommendations for evaluation of bladder and bowel function in pre-clinical spinal cord injury research.

Objective: In order to encourage the inclusion of bladder and bowel outcome measures in preclinical spinal cord injury (SCI) research, this paper identifies and categorizes 1) fundamental, 2) recommended, 3) supplemental and 4) exploratory sets of outcome measures for pre-clinical assessment of bladder and bowel function with broad applicability to animal models of SCI.Methods: Drawing upon the collective research experience of autonomic physiologists and informed in consultation with clinical experts, a critical assessment of currently available bladder and bowel outcome measures (histological, biochemical, in vivo functional, ex vivo physiological and electrophysiological tests) was made to identify the strengths, deficiencies and ease of inclusion for future studies of experimental SCI.Results: Based upon pre-established criteria generated by the Neurogenic Bladder and Bowel Working Group that included history of use in experimental settings, citations in the literature by multiple independent groups, ease of general use, reproducibility and sensitivity to change, three fundamental measures each for bladder and bowel assessments were identified. Briefly defined, these assessments centered upon tissue morphology, voiding efficiency/volume and smooth muscle-mediated pressure studies. Additional assessment measures were categorized as recommended, supplemental or exploratory based upon the balance between technical requirements and potential mechanistic insights to be gained by the study.Conclusion: Several fundamental assessments share reasonable levels of technical and material investment, including some that could assess bladder and bowel function non-invasively and simultaneously. Such measures used more inclusively across SCI studies would advance progress in this high priority area. When complemented with a few additional investigator-selected study-relevant supplemental measures, they are highly recommended for research programs investigating the efficacy of therapeutic interventions in preclinical animal models of SCI that have a bladder and/or bowel focus.

Activity-Based Training Reverses Spinal Cord Injury-Induced Changes in Kidney Receptor Densities and Membrane Proteins.

Complications in upper and lower urinary function arise after spinal cord injury (SCI), which creates a significant impact on quality of life for those affected. One upper urinary complication is SCI-induced polyuria, or the overproduction of urine, of which the underlying mechanisms have yet to be elucidated. Activity-based training (ABT) has been utilized in both animal and clinical settings as a rehabilitative therapy to improve many issues that arise after SCI, including more recently urogenital function. The goal of the current study was to identify potential mechanisms contributing to previously identified improvements in polyuria with ABT, using a male rat moderate-severe spinal contusion model. Although ABT had no significant effect on reversing injury-induced alterations of serum arginine vasopressin and urinary atrial natriuretic peptide levels, there was a dramatic effect upon the receptors of these fluid balance hormones (vasopressin receptor 2 and natriuretic peptide A receptor), as well as kidney aquaporin 2 and sodium channels. ABT changes in densities of key receptors and kidney membrane proteins involved in fluid balance after chronic SCI support the likelihood of multiple mechanisms through which exercise can positively influence urinary tract function after SCI. By understanding the mechanisms, amount, and timing regarding how ABT improves different aspects of urinary function, more targeted training strategies can be developed to optimize the functional gains within the SCI population.

Telemetric monitoring of penile pressure during mating in rats after chronic spinal cord injury.

In men with a spinal cord injury (SCI), erectile function, ejaculation, and fertility are severely impaired. The present study utilized a telemetric pressure transducer implanted into the corpus cavernosum of the penis to examine sexual function during awake mating behavior in a rat contusion model with a range of Infinite Horizon Impactor forces distributed between 150 and 215 kdyn. The mating behavior paradigm included examination of the counts, average pressure, and average duration for mounts, intromissions, and ejaculations. Male Wistar rats were mated with receptive females in 30-min sessions preinjury (sexual acclimation) and once per week for 6 wk beginning after a 2-wk recovery period post-SCI. All SCI animals had significant deficits in sexual function in the parameters measured. These deficiencies were more prevalent in a subset having less than 20% white matter sparing, likely a reflection of the extent of bilateral spino-bulbo-spinal sexual circuitry disruption at the lesion epicenter. The resulting discoordination of the autonomic and somatic reflex control of erection and ejaculation recorded using telemetry devices in an awake, behaving animal model provides an effective means of gauging sexual function deficits after SCI and could have utility for quantifying recovery after a therapeutic intervention.

Activity-Based Training Alters Penile Reflex Responses in a Rat Model of Spinal Cord Injury.

INTRODUCTION: Multisystem functional gains have been reported in males with spinal cord injury (SCI) after undergoing activity-based training (ABT), including increases in scoring of sexual function and reports of improved erectile function. AIM: This study aims to examine the effect of daily 60-minute locomotor training and exercise in general on sexual function in a rat SCI contusion model. METHODS: Male Wistar rats received a T9 contusion SCI. Animals were randomized into 4 groups: a quadrupedal stepping group (SCI + QT), a forelimb-only exercise group (SCI + FT), a non-trained harnessed group (SCI + NT), and a home cage non-trained group (SCI + HC). The 2 non-trained groups were combined (SCI) post hoc. Daily training sessions were 60 minutes in duration for 8 weeks. Urine samples were collected during bi-weekly 24-hour metabolic cage behavioral testing. Latency, numbers of penile dorsiflexion, and glans cupping were recorded during bi-weekly penile dorsiflexion reflex (PDFR) testing. Terminal electromyography (EMG) recordings of the bulbospongiosus muscle (BSM) were recorded in response to stimulation of the dorsal nerve of the penis (DNP). OUTCOMES: ABT after SCI had a significant effect on PDFR, as well as BSM EMG latency and burst duration. RESULTS: SCI causes a significant decrease in the latency to onset of PDFR. After 8 weeks of ABT, SCI + QT animals had a significantly increased latency relative to the post-SCI baseline. BSM EMG response to DNP stimulation had a significantly decreased latency and increase in average and maximum amplitude in SCI + QT animals. SCI animals had a significantly longer burst duration than trained animals. Time between PDFR events, penile dorsiflexion, glans cupping, and urine testosterone were not affected by ABT. CLINICAL IMPLICATIONS: ABT has a positive influence on sexual function and provides a potential therapy to enhance the efficacy of current sexual dysfunction therapies in the male SCI population. STRENGTHS AND LIMITATIONS: Several significant small improvements in sexual function were found in a clinically relevant rat model of SCI using a readily available rehabilitative therapy. The limited findings could reflect insensitivity of the PDFR as a measure of erectile function. CONCLUSIONS: These results indicate that task-specific stepping and/or loading provide sensory input to the spinal cord impacting the neural circuitry responsible for sexual function. Steadman CJ, Hoey RF, Montgomery LR, et al. Activity-Based Training Alters Penile Reflex Responses in a Rat Model of Spinal Cord Injury. J Sex Med 2019; 16:1143-1154.

Activity-based Training on a Treadmill with Spinal Cord Injured Wistar Rats.

Spinal cord injury (SCI) results in lasting deficits that include both mobility and a multitude of autonomic-related dysfunctions. Locomotor training (LT) on a treadmill is widely used as a rehabilitation tool in the SCI population with many benefits and improvements to daily life. We utilize this method of activity-based task-specific training (ABT) in rodents after SCI to both elucidate the mechanisms behind such improvements and to enhance and improve upon existing clinical rehabilitation protocols. Our current goal is to determine the mechanisms underlying ABT-induced improvements in urinary, bowel, and sexual function in SCI rats after a moderate to severe level of contusion. After securing each individual animal in a custom-made adjustable vest, they are secured to a versatile body weight support mechanism, lowered to a modified three-lane treadmill and assisted in step-training for 58 minutes, once a day for 10 weeks. This setup allows for the training of both quadrupedal and forelimb-only animals, alongside two different non-trained groups. Quadrupedal-trained animals with body weight support are aided by a technician present to assist in stepping with proper hind limb placement as necessary, while forelimb-only trained animals are raised at the caudal end to ensure no hind limb contact with the treadmill and no weight-bearing. One non-trained SCI group of animals is placed in a harness and rests next to the treadmill, while the other control SCI group remains in its home cage in the training room nearby. This paradigm allows for the training of multiple SCI animals at once, thus making it more time-efficient in addition to ensuring that our pre-clinical animal model mimics the clinical representation as close as possible, particularly with respect to the body weight support with manual assistance.

Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury.

OBJECTIVE: Locomotor training (LT) as a therapeutic intervention following spinal cord injury (SCI) is an effective rehabilitation strategy for improving motor outcomes, but its impact on non-locomotor functions is unknown. Given recent results of our labs' pre-clinical animal SCI LT studies and existing overlap of lumbosacral spinal circuitries controlling pelvic-visceral and locomotor functions, we addressed whether LT can improve bladder, bowel and sexual function in humans at chronic SCI time-points (> two years post-injury). STUDY DESIGN: Prospective cohort study; pilot trial with small sample size. METHODS: Eight SCI research participants who were undergoing 80 daily one-hour sessions of LT on a treadmill using body-weight support, or one-hour of LT and stand training on alternate days, as part of another research study conducted at the Kentucky Spinal Cord Injury Research Center, University of Louisville, were enrolled in this pilot trial. Urodynamic assessments were performed and International Data Set questionnaire forms completed for bladder, bowel and sexual functions at pre-and post-training time points. Four usual care (non-trained; regular at-home routine) research participants were also enrolled in this study and had the same assessments collected twice, at least 3 months apart. RESULTS: Filling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. No significant differences were found for usual care research participants. CONCLUSIONS: These results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03036527.