Targeted Selection of Stimulation Parameters for Restoration of Motor and Autonomic Function in Individuals With Spinal Cord Injury.

STUDY DESIGN: This is a report of methods and tools for selection of task and individual configurations targeted for voluntary movement, standing, stepping, blood pressure stabilization, and facilitation of bladder storage and emptying using tonic-interleaved excitation of the lumbosacral spinal cord. OBJECTIVES: This study aimed to present strategies used for selection of stimulation parameters for various motor and autonomic functions. CONCLUSIONS: Tonic-interleaved functionally focused neuromodulation targets a myriad of consequences from spinal cord injury with surgical implantation of the epidural electrode at a single location. This approach indicates the sophistication of the human spinal cord circuitry and its important role in the regulation of motor and autonomic functions in humans.

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.

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.

Altered vasopressin and natriuretic peptide levels in a rat model of spinal cord injury: implications for the development of polyuria.

Urinary dysfunction is a common complaint following spinal cord injury (SCI) and is a leading issue for individuals with SCI that impacts their quality of life. One urinary complication that has received little attention is SCI-induced polyuria, even though individuals with SCI will significantly restrict their fluid intake to decrease urine production, leading to sequelae of medical complications. Understanding the mechanisms instigating the development of polyuria will allow us to target interventions that may alleviate polyuria symptoms, leading to significant improvements in the quality of life and urinary health of individuals with SCI. In a rat SCI contusion model, an increase in the amount of urine excreted over a 24-h period ( P ≤ 0.001) was found at 2 wk postinjury. The urine excreted was more dilute with decreased urinary creatinine and specific gravity ( P ≤ 0.001). Several factors important in fluid balance regulation, vasopressin (AVP), natriuretic peptides, and corticosterone (CORT), also changed significantly postinjury. AVP levels decreased ( P = 0.042), whereas atrial natriuretic peptide (ANP) and CORT increased ( P = 0.005 and P = 0.031, respectively) at 2 wk postinjury. There was also a positive correlation between the increase in ANP and urine volume postinjury ( P = 0.033). The changes in AVP, ANP, and CORT are conducive to producing polyuria, and the timing of these changes coincides with the development of SCI-induced polyuria. This study identifies several therapeutic targets that could be used to ameliorate polyuria symptoms and improve quality of life in individuals with SCI.

Effects of exercise training on urinary tract function after spinal cord injury.

Spinal cord injury (SCI) causes dramatic changes in the quality of life, including coping with bladder dysfunction which requires repeated daily and nightly catheterizations. Our laboratory has recently demonstrated in a rat SCI model that repetitive sensory information generated through task-specific stepping and/or loading can improve nonlocomotor functions, including bladder function (Ward PJ, Herrity AN, Smith RR, Willhite A, Harrison BJ, Petruska JC, Harkema SJ, Hubscher CH. J Neurotrauma 31: 819-833, 2014). To target potential underlying mechanisms, the current study included a forelimb-only exercise group to ascertain whether improvements may be attributed to general activity effects that impact target organ-neural interactions or to plasticity of the lumbosacral circuitry that receives convergent somatovisceral inputs. Male Wistar rats received a T9 contusion injury and were randomly assigned to three groups 2 wk postinjury: quadrupedal locomotion, forelimb exercise, or a nontrained group. Throughout the study (including preinjury), all animals were placed in metabolic cages once a week for 24 h to monitor water intake and urine output. Following the 10-wk period of daily 1-h treadmill training, awake cystometry data were collected and bladder and kidney tissue harvested for analysis. Metabolic cage frequency-volume measurements of voiding and cystometry reveal an impact of exercise training on multiple SCI-induced impairments related to various aspects of urinary tract function. Improvements in both the quadrupedal and forelimb-trained groups implicate underlying mechanisms beyond repetitive sensory information from the hindlimbs driving spinal network excitability of the lumbosacral urogenital neural circuitry. Furthermore, the impact of exercise training on the upper urinary tract (kidney) underscores the health benefit of activity-based training on the entire urinary system within the SCI population.

The effect of spinal cord injury on the neurochemical properties of vagal sensory neurons.

The vagus nerve is composed primarily of nonmyelinated sensory neurons whose cell bodies are located in the nodose ganglion (NG). The vagus has widespread projections that supply most visceral organs, including the bladder. Because of its nonspinal route, the vagus nerve itself is not directly damaged from spinal cord injury (SCI). Because most viscera, including bladder, are dually innervated by spinal and vagal sensory neurons, an impact of SCI on the sensory component of vagal circuitry may contribute to post-SCI visceral pathologies. To determine whether SCI, in male Wistar rats, might impact neurochemical characteristics of NG neurons, immunohistochemical assessments were performed for P2X3 receptor expression, isolectin B4 (IB4) binding, and substance P expression, three known injury-responsive markers in sensory neuronal subpopulations. In addition to examining the overall population of NG neurons, those innervating the urinary bladder also were assessed separately. All three of the molecular markers were represented in the NG from noninjured animals, with the majority of the neurons binding IB4. In the chronically injured rats, there was a significant increase in the number of NG neurons expressing P2X3 and a significant decrease in the number binding IB4 compared with noninjured animals, a finding that held true also for the bladder-innervating population. Overall, these results indicate that vagal afferents, including those innervating the bladder, display neurochemical plasticity post-SCI that may have implications for visceral homeostatic mechanisms and nociceptive signaling.

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.

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.

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.

Predictive values of spinal cord diffusion magnetic resonance imaging to characterize outcomes after contusion injury.

OBJECTIVES: To explore filtered diffusion-weighted imaging (fDWI), in comparison with conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), as a predictor for long-term locomotor and urodynamic (UD) outcomes in Yucatan minipig model of spinal cord injury (SCI). Additionally, electrical conductivity of neural tissue using D-waves above and below the injury was measured to assess correlations between fDWI and D-waves data. METHODS: Eleven minipigs with contusion SCI at T8-T10 level underwent MRI at 3T 4 h. post-SCI. Parameters extracted from region of interest analysis included Daxial from fDWI at injury site, fractional anisotropy and radial diffusivity from DTI above the injury site along with measures of edema length and cord width at injury site from T2 -weighted images. Locomotor recovery was assessed pre- and weekly post-SCI through porcine thoracic injury behavior scale (PTIBS) and UD were performed pre- and at 12 weeks of SCI. D-waves latency and amplitude differences were recorded before and immediately after SCI. RESULTS: Two groups of pigs were found based on the PTIBS at week 12 (p < 0.0001) post-SCI and were labeled "poor" and "good" recovery. D-waves amplitude decreased below injury and increased above injury. UD outcomes pre/post SCI changed significantly. Conventional MRI metrics from T2 -weighted images were significantly correlated with diffusion MRI metrics. Daxial at injury epicenter was diminished by over 50% shortly after SCI, and it differentiated between good and poor locomotor recovery and UD outcomes. INTERPRETATION: Similar to small animal studies, fDWI from acute imaging after SCI is a promising predictor for functional outcomes in large animals.

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.

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.

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.

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.

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.

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.

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.

Characterization of Lower Urinary Tract Dysfunction after Thoracic Spinal Cord Injury in Yucatan Minipigs.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.

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.