Depression phenotypes in spinal cord injury and impact on post-injury healthcare utilization and cost: Analysis using a large claim database.

CONTEXT/OBJECTIVE: Depression is the most common psychological comorbidity associated with spinal cord injury (SCI) and affects healthcare utilization and costs. This study aimed to use an International Classification of Disease (ICD) and prescription drug-based depression phenotypes to classify people with SCI, and to evaluate the prevalence of those phenotypes, associated risk factors, and healthcare utilization. DESIGN: Retrospective Observational Study. SETTING: Marketscan Database (2000-2019). PARTICIPANTS: Individuals with SCI were classified into six ICD-9/10, and prescription drugs defined phenotypes: Major Depressive Disorder (MDD), Other Depression (OthDep), Antidepressants for Other Psychiatric Conditions (PsychRx), Antidepressants for non-psychiatric condition (NoPsychRx), Other Non-depression Psychiatric conditions only (NonDepPsych), and No Depression (NoDep). Except for the latter, all the other groups were referred to as "depressed phenotypes". Data were screened for 24 months pre- and 24 months post-injury depression. INTERVENTIONS: None. OUTCOME MEASURES: Healthcare utilization and payments. RESULTS: There were 9,291 patients with SCI classified as follows: 16% MDD, 11% OthDep, 13% PsychRx, 13% NonPsychRx, 14% NonDepPsych, 33% NoDep. Compared with the NoDep group, the MDD group was younger (54 vs. 57 years old), predominantly female (55% vs. 42%), with Medicaid coverage (42% vs. 12%), had increased comorbidities (69% vs. 54%), had fewer traumatic injuries (51% vs. 54%) and had higher chronic 12-month pre-SCI opioid use (19% vs. 9%) (all P < 0.0001). Classification into a depressed phenotype before SCI was found to be significantly associated with depression phenotype post-SCI, as evidenced by those who experienced a negative change (37%) vs. a positive change (15%, P < 0.0001). Patients in the MDD cohort had higher healthcare utilization and associated payments at 12 and 24 months after SCI. CONCLUSION: Increasing awareness of psychiatric history and MDD risk factors may improve identifying and managing higher-risk patients with SCI, ultimately optimizing their post-injury healthcare utilization and cost. This method of classifying depression phenotypes provides a simple and practical way to obtain this information by screening through pre-injury medical records.

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.

Health Care Utilization and Cost Associated With Urinary Tract Infections in a Privately Insured Spinal Cord Injury Population.

Background: Urinary tract infections (UTIs) are the most common secondary medical complication following spinal cord injury (SCI), significantly impacting health care resource utilization and costs. Objectives: To characterize risk factors and health care utilization costs associated with UTIs in the setting of SCI. Methods: IBM's Marketscan Database from 2000-2019 was utilized to identify individuals with traumatic SCI. Relevant ICD-9 and ICD-10 codes classified individuals into two analysis groups: having ≥ 1 UTI episode or no UTI episodes within 2 years following injury. Demographics (age, sex), insurance type, comorbidities, level of injury (cervical, thoracic, lumbar/sacral), and health care utilization/payments were evaluated. Results: Of the 6762 individuals retained, 1860 had ≥ 1 UTI with an average of three episodes (SD 2). Younger age, female sex, thoracic level of injury, noncommercial insurance, and having at least one comorbidity were associated with increased odds of UTI. Individuals with a UTI in year 1 were 11 times more likely to experience a UTI in year 2. As expected, those with a UTI had a higher rate and associated cost of hospital admission, use of outpatient services, and prescription refills. UTIs were associated with 2.48 times higher cumulated health care resource use payments over 2 years after injury. Conclusions: In addition to bladder management-related causes, several factors are associated with an increased risk of UTIs following SCI. UTI incidence substantially increases health care utilization costs. An increased understanding of UTI-associated risk factors may improve the ability to identify and manage higher risk individuals with SCI and ultimately optimize their health care utilization.

Opioid Dependence and Associated Health Care Utilization and Cost in Traumatic Spinal Cord Injury Population: Analysis Using Marketscan Database.

Background: Postinjury pain is a well-known debilitating complication of spinal cord injury (SCI), often resulting in long-term, high-dose opioid use with the potential for dependence. There is a gap in knowledge about the risk of opioid dependence and the associated health care utilization and cost in SCI. Objectives: To evaluate the association of SCI with postinjury opioid use and dependence and evaluate the effect of this opioid dependence on postinjury health care utilization. Methods: Using the MarketScan Database, health care utilization claims data were queried to extract 7187 adults with traumatic SCI from 2000 to 2019. Factors associated with post-SCI opioid use and dependence, postinjury health care utilization, and payments were analyzed with generalized linear regression models. Results: After SCI, individuals were more likely to become opioid users or transition from nondependent to dependent users (negative change: 31%) than become nonusers or transition from dependent to nondependent users (positive change: 14%, p < .0001). Individuals who were opioid-dependent users pre-SCI had more than 30 times greater odds of becoming dependent after versus not (OR 34; 95% CI, 26-43). Dependent users after injury (regardless of prior use status) had 2 times higher utilization payments and 1.2 to 6 times more health care utilization than nonusers. Conclusion: Opioid use and dependence were associated with high health care utilization and cost after SCI. Pre-SCI opioid users were more likely to remain users post-SCI and were heavier consumers of health care. Pre- and postopioid use history should be considered for treatment decision-making in all individuals with SCI.

Neuroanatomical mapping of the lumbosacral spinal cord in individuals with chronic spinal cord injury.

With emerging applications of spinal cord electrical stimulation in restoring autonomic and motor function after spinal cord injury, understanding the neuroanatomical substrates of the human spinal cord after spinal cord injury using neuroimaging techniques can play a critical role in optimizing the outcomes of these stimulation-based interventions. In this study, we have introduced a neuroimaging acquisition and analysis protocol of the spinal cord in order to identify: (i) spinal cord levels at the lumbosacral enlargement using nerve root tracing; (ii) variability in the neuroanatomical characteristics of the spinal cord among individuals; (iii) location of the epidural stimulation paddle electrode and contacts with respect to the spinal cord levels at lumbosacral enlargement; and (iv) the links between the anatomical levels of stimulation and the corresponding neurophysiological motor responses. Twelve individuals with chronic, motor complete spinal cord injury implanted with a spinal cord epidural stimulator were included in the study (age: 34 ± 10.9 years, sex: 10 males, 2 females, time since injury: 8.2 ± 9.9 years, American Spinal Injury Association Impairment Scale: 6 A, 6 B). High-resolution MRI scans of the spinal cord were recorded pre-implant. An analysis of neuroanatomical substrates indicates that the length of the spinal column and spinal cord, location of the conus tip and the relationship between the spinal cord levels and vertebral levels, particularly at the lumbosacral enlargement, are variable across individuals. There is no statistically significant correlation between the length of the spinal column and the length of the spinal cord. The percentage of volumetric coverage of the lumbosacral spinal cord by the epidural stimulation paddle electrode ranges from 33.4 to 90.4% across participants. The location of the spinal cord levels with respect to the electrode contacts varies across individuals and impacts the recruitment patterns of neurophysiological responses. Finally, MRI-based spinal cord modelling can be used as a guide for the prediction and preplanning of optimum epidural stimulation paddle placement prior to the implant surgery to ensure maximizing functional outcomes. These findings highlight the crucial role that the neuroanatomical characteristics of the spinal cord specific to each individual play in achieving maximum functional benefits with spinal cord electrical stimulation.

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.

Retrospective trends in length of stay and bowel management at discharge from inpatient rehabilitation among individuals with spinal cord injury.

STUDY DESIGN: Retrospective observational cohort study. OBJECTIVES: To describe the trend in length of stay (LOS) and its association with the rate of individuals needing total assistance with bowel management upon discharge from inpatient spinal cord injury (SCI) rehabilitation facilities. SETTING: Participants enrolled in the National Spinal Cord Injury Model Systems (NSCIMS) database. METHODS: The NSCIMS database was used to obtain bowel management characteristics from individuals (n = 15,975) aged 15 years or older discharged from inpatient rehabilitation facilities between 1988 and 2016 with known demographic factors and LOS. Levels of bowel management were defined from the functional independence measure (FIM) based on the level of assistance required to complete a bowel program. To control for changes in participant population and injury characteristics over the study period, the inverse probability of treatment weight (IPTW) technique was used. Linear and logistic regressions and the Spearman correlation coefficient were used for statistical analyses. RESULTS: The LOS significantly decreased more than ¾ of a day on average each year from 1988 (LOS: 83.16 days) to 2016 (LOS: 50.53 days). Concurrently, the odds of needing total assistance in bowel management at discharge increased 4.1% each year. The correlation between these trends was moderate (-0.63). Association analyses yielded that a 1-day decrease in average LOS was associated with a 0.53% increase in those needing total assistance for bowel management at discharge. CONCLUSION: Over the years, as inpatient rehabilitation LOS decreased, rates of those needing total assistance for bowel management at discharge increased.

Longitudinal Trends and Prevalence of Bowel Management in Individuals With Spinal Cord Injury.

Background: Neurogenic bowel dysfunction (NBD) following spinal cord injury (SCI) represents a major source of morbidity, negatively impacting quality of life and overall independence. The long-term changes in bowel care needs are not well-reported, preventing consensus on the natural course and optimal management of NBD following injury. Objectives: To understand the changes in bowel management needs over time following SCI. Methods: A retrospective observational study using the National Spinal Cord Injury Model Systems database evaluated the degree of independence with bowel management at discharge from inpatient rehabilitation across time (1988-2016). The prevalence and consecutive trajectory of bowel management was also evaluated at discharge and at each 5-year follow-up period, for 25 years. Results: The majority of individuals discharged from inpatient rehabilitation (n = 17,492) required total assistance with bowel management, a trend that significantly increased over time. However, by 5-years post injury, there was a significant shift in bowel management needs from total assistance to modified independence. In those with consecutive 25-year follow-up data (n = 11,131), a similar shift in bowel management to a less dependent strategy occurred even at chronic time points post injury, primarily in individuals with paraplegia and classified as motor and sensory complete. Conclusion: The findings of this study highlight the need for providing continued multipronged interventions (e.g., rehabilitative, educational, psycho-social) at the different stages of SCI to support individuals not only in the immediate years after discharge but also well into the chronic stages after injury.

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.

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.

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.

A Two-decade Assessment of Changing Practice for Surgical Decompression and Fixation after Traumatic Spinal Cord Injury - Impact on Healthcare Utilization and Cost.

Early surgery after traumatic spinal cord injury (TSCI) has been associated with a greater neurological recovery and reduced secondary complications. In this study, we aimed to evaluate the trend of early TSCI surgery (within 24 hours) over two decades and the effect on length of hospitalization, complications, and hospital charges. We extracted emergency admissions of adults diagnosed with TSCI from the National Inpatient Sample database (1998-2016). We analyzed the trend of early surgery and concurrent trends of complication rate, length of stay (LOS) and hospital charges. These outcomes were then compared between early and late surgery cohorts. There were 3942 (53%) TSCI patients who underwent early surgery, and 3446 (47%) were operated after 24 hours. The combined patient group characteristics consisted of median age 43 years (IQR: 29-59), 73% males, 72% white, 44% private payer, 18% Medicare, 17% Medicaid, 51% cervical, 30% thoracic, 75% from large hospitals, and 79% from teaching hospitals. The trend of early surgery, adjusted for annual case-mix, increased from 45% in 1998 to 64% in 2016. Each year was associated with 1.60% more patients undergoing early surgery than the previous year (p-value <0.05). During these years, the total LOS decreased, while hospital charges increased. Patients who underwent early surgery spent four fewer days in the hospital, accrued $28,705 lower in hospital charges and had 2.8% fewer complications than those with delay surgery. We found that the rate of early surgery has significantly increased from 1998 to 2016. However, as of 2016, one-third of patients still did not undergo spinal surgery within 24 hours. Late surgery is associated with higher complications, longer stays, and higher charges. The causes of delayed surgery are undoubtedly justified in some situations but require further delineation. Surgeons should consider performing surgery within 24 hours on patients with TSCI whenever feasible.

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.

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.

Identification of bladder and colon afferents in the nodose ganglia of male rats.

The sensory neurons innervating the urinary bladder and distal colon project to similar regions of the central nervous system and often are affected simultaneously by various diseases and disorders, including spinal cord injury. Anatomical and physiological commonalities between the two organs involve the participation of shared spinally derived pathways, allowing mechanisms of communication between the bladder and colon. Prior electrophysiological data from our laboratory suggest that the bladder also may receive sensory innervation from a nonspinal source through the vagus nerve, which innervates the distal colon as well. The present study therefore aimed to determine whether anatomical evidence exists for vagal innervation of the male rat urinary bladder and to assess whether those vagal afferents also innervate the colon. Additionally, the relative contribution to bladder and colon sensory innervation of spinal and vagal sources was determined. By using lipophilic tracers, neurons that innervated the bladder and colon in both the nodose ganglia (NG) and L6/S1 and L1/L2 dorsal root ganglia (DRG) were quantified. Some single vagal and spinal neurons provided dual innervation to both organs. The proportions of NG afferents labeled from the bladder did not differ from spinal afferents labeled from the bladder when considering the collective population of total neurons from either group. Our results demonstrate evidence for vagal innervation of the bladder and colon and suggest that dichotomizing vagal afferents may provide a neural mechanism for cross-talk between the organs.

Novel multi-system functional gains via task specific training in spinal cord injured male rats.

Locomotor training (LT) after spinal cord injury (SCI) is a rehabilitative therapy used to enhance locomotor recovery. There is evidence, primarily anecdotal, also associating LT with improvements in bladder function and reduction in some types of SCI-related pain. In the present study, we determined if a step training paradigm could improve outcome measures of locomotion, bladder function, and pain/allodynia. After a T10 contusive SCI trained animals (adult male Wistar rats), trained animals began quadrupedal step training beginning 2 weeks post-SCI for 1 h/day. End of study experiments (3 months of training) revealed significant changes in limb kinematics, gait, and hindlimb flexor-extensor bursting patterns relative to non-trained controls. Importantly, micturition function, evaluated with terminal transvesical cystometry, was significantly improved in the step trained group (increased voiding efficiency, intercontraction interval, and contraction amplitude). Because both SCI and LT affect neurotrophin signaling, and neurotrophins are involved with post-SCI plasticity in micturition pathways, we measured bladder neurotrophin mRNA. Training regulated the expression of nerve growth factor (NGF) but not BDNF or NT3. Bladder NGF mRNA levels were inversely related to bladder function in the trained group. Monitoring of overground locomotion and neuropathic pain throughout the study revealed significant improvements, beginning after 3 weeks of training, which in both cases remained consistent for the study duration. These novel findings, improving non-locomotor in addition to locomotor functions, demonstrate that step training post-SCI could contribute to multiple quality of life gains, targeting patient-centered high priority deficits.