Neurogenic Lower Urinary Tract Dysfunction in the First Year After Spinal Cord Injury: A Descriptive Study of Urodynamic Findings.

PURPOSE: We aimed to provide a real-world description of neurogenic lower urinary tract dysfunction within the first year after spinal cord injury with a focus on unfavorable urodynamic parameters that are associated with urological morbidity. MATERIALS AND METHODS: Urodynamic investigations from 97 patients with traumatic or ischemic acute spinal cord injury and managed according to the European Association of Urology Guidelines on Neuro-Urology were analyzed at a single university spinal cord injury center at 1 month, 3 months, 6 months, and 12 months after injury. Unfavorable urodynamic parameters were defined as detrusor overactivity in combination with detrusor sphincter dyssynergia, maximum storage detrusor pressure of 40 cm H2O or higher, bladder compliance less than 20 mL/cm H2O, and vesicoureteral reflux of any grade. RESULTS: One or more unfavorable urodynamic parameter was observed in 87 out of 97 patients (90%) within the first year after spinal cord injury. Eighty-eight percent of the patients showed detrusor overactivity with detrusor sphincter dyssynergia, 39% a maximum storage detrusor pressure of 40 cm H2O or higher, and 7% vesicoureteral reflux. No patient developed a low-compliance bladder. CONCLUSIONS: Using a standardized urodynamic follow-up schedule, we found unfavorable urodynamic parameters in a majority of the population within the first year after spinal cord injury. As early treatment based on urodynamic findings might reduce the risk of deterioration of upper and lower urinary tract function, thereby improving long-term outcomes, there is need for further research regarding recommendations for a urodynamic follow-up schedule during the first year after spinal cord injury.

Temporal development of unfavourable urodynamic parameters during the first year after spinal cord injury.

OBJECTIVES: To describe the temporal development of and risk factors for the occurrence of unfavourable urodynamic parameters during the first year after spinal cord injury (SCI). PATIENTS AND METHODS: This population-based longitudinal study used data from 97 adult patients with a single-event traumatic or ischaemic SCI who underwent video-urodynamic investigation (UDI) at a university SCI centre. The first occurrences of unfavourable urodynamic parameters (detrusor overactivity combined with detrusor sphincter dyssynergia [DO-DSD], maximum storage detrusor pressure ≥40 cmH2 O, bladder compliance <20 mL/cmH2 O, vesico-ureteric reflux [VUR] and any unfavourable parameter [composite outcome]) were evaluated using time-to-event analysis. RESULTS: The majority of the population (87/97 [90%]) had at least one unfavourable urodynamic parameter. Most unfavourable urodynamic parameters were initially identified during the 1- or 3-month UDI, including 92% of the DO-DSD (78/85), 82% of the maximum storage pressure ≥40 cmH2 O (31/38), and 100% of the VUR (seven of seven) observations. No low bladder compliance was observed. The risk of DO-DSD was elevated in patients with thoracic SCI compared to those with lumbar SCI (adjusted hazard ratio [aHR] 2.38, 95% confidence interval [CI] 1.16-4.89). Risk of maximum storage detrusor pressure ≥40 cmH2 O was higher in males than females (aHR 8.33, 95% CI 2.51-27.66), in patients with a cervical SCI compared to those with lumbar SCI (aHR 14.89, 95% CI 3.28-67.55), and in patients with AIS Grade B or C compared to AIS Grade D SCI (aHR 6.17, 95% CI 1.78-21.39). No risk factors were identified for the composite outcome of any unfavourable urodynamic parameter. CONCLUSIONS: The first UDI should take place within 3 months after SCI as to facilitate early diagnosis of unfavourable urodynamic parameters and timely treatment. Neuro-urological guidelines and individualised management strategies for patients with SCI may be strengthened by considering sex and SCI characteristics in the scheduling of UDIs.

bTUNED: transcutaneous tibial nerve stimulation for neurogenic lower urinary tract dysfunction.

OBJECTIVE: To present the protocol for a randomized controlled trial (RCT) evaluating the efficacy and safety of transcutaneous tibial nerve stimulation (TTNS) for refractory neurogenic lower urinary tract dysfunction (NLUTD). STUDY DESIGN AND RESULTS: bTUNED (bladder and TranscUtaneous tibial Nerve stimulation for nEurogenic lower urinary tract Dysfunction) is an international multicentre, sham-controlled, double-blind RCT investigating the efficacy and safety of TTNS. The primary outcome is success of TTNS, defined as improvements in key bladder diary variables at study end compared to baseline values. The focus of the treatment is defined by the Self-Assessment Goal Achievement (SAGA) questionnaire. Secondary outcomes are the effect of TTNS on urodynamic, neurophysiological, and bowel function outcome measures, as well as the safety of TTNS. CONCLUSIONS: A total of 240 patients with refractory NLUTD will be included and randomized 1:1 into the verum or sham TTNS group from March 2020 until August 2026. TTNS will be performed twice a week for 30 min during 6 weeks. The patients will attend baseline assessments, 12 treatment visits and follow-up assessments at the study end.

Indwelling catheter vs intermittent catheterization: is there a difference in UTI susceptibility?

BACKGROUND: Patients with neurogenic lower urinary tract dysfunction (NLUTD) often rely on some type of catheterization for bladder emptying. Intermittent catheterization (IC) is considered the gold standard and is preferred over continuous catheterization, since it is considered to cause fewer urinary tract infections (UTIs) than indwelling catheterization. The main objective of our study was to describe UTI prevalence (at visit) and incidence (within the last 12 months) and urine culture characteristics between patients using an indwelling catheter versus (vs) those performing IC. METHODS: In this cross-sectional study, we prospectively evaluated from 02/2020 to 01/2021 patients with NLUTD undergoing urine cultures for prophylactic reasons or due to UTI symptoms. At visit, all patients underwent a standardized interview on current UTI symptoms as well as UTI history and antibiotic consumption within the past year. Patients using an indwelling catheter (n = 206) or IC (n = 299) were included in the analysis. The main outcome was between-group differences regarding UTI characteristics. RESULTS: Patients using an indwelling catheter were older (indwelling catheter vs IC: median 66 (Q1-Q3: 55-77) vs 55 (42-67) years of age) and showed a higher Charlson comorbidity index (indwelling catheter vs IC: median 4 (Q1-Q3: 2-6) vs 2 (1-4) (both p < 0·001). A total of 40 patients from both groups were diagnosed with a UTI at visit (indwelling catheters vs IC: 8% (16/206) vs 8% (24/299); p = 0·782), and the number of UTIs within the past 12 months was not significantly different between groups. Overall, Escherichia coli (21%), Enterococcus faecalis (17%), and Klebsiella spp. (12%) were the most frequently detected bacteria. CONCLUSIONS: In this cohort of patients with NLUTD, we did not find relevant differences in UTI frequency between groups. These results suggest that UTI-related concerns should not be given undue emphasis when counseling patients for catheter-related bladder emptying methods.

Sex differences in urological management during spinal cord injury rehabilitation: results from a prospective multicenter longitudinal cohort study.

STUDY DESIGN: Prospective, multicenter, longitudinal cohort study. OBJECTIVES: To describe female-male differences in first-line urological management during spinal cord injury (SCI) rehabilitation. SETTING: Inpatient specialized post-acute SCI rehabilitation in Switzerland. METHODS: Data on bladder storage medication (antimuscarinic and beta-3 agonist) use, suprapubic catheter placement, demographic and SCI characteristics was collected within 40 days of SCI and at rehabilitation discharge from May 2013-September 2021. Prevalence and indicators of bladder storage medication and suprapubic catheter use at discharge were investigated with sex-stratified descriptive and logistic regression analyses. RESULTS: In 748 patients (219 females, 29%), bladder storage medication use at discharge had a prevalence of 24% (95% CI: 18-29%) for females and 30% (95% CI: 26-34%) for males and was indicated by cervical AIS grade A, B, C and traumatic SCI in both sexes. Thoracic AIS grade A, B, C SCI (males), and lumbar/sacral AIS grade A, B, C SCI (females) predicted higher odds of bladder storage medication use (SCI characteristic*sex interaction, p < 0.01). Prevalence of suprapubic catheter use at discharge was 22% (95% CI: 17-28%) for females and 17% (95% CI: 14-20%) for males. Suprapubic catheter use was indicated by cervical AIS grade A, B, C SCI, and age >60 in both sexes. Females with thoracic grade A, B, C SCI tended to have higher odds of suprapubic catheter use (SCI characteristic*sex interaction, p = 0.013). CONCLUSIONS: We identified sex differences in urological management especially in persons with AIS grade C or higher sub-cervical SCI. There is scope for well-powered, female-specific research in SCI in order to understand the underlying mechanisms and support patient-tailored management.

Optimizing clinical trial design using prospective cohort study data: a case study in neuro-urology.

STUDY DESIGN: Simulations using data from a prospective cohort study. OBJECTIVES: To illustrate how prospective cohort data can be employed in randomized controlled trial (RCT) planning to assess feasibility and operational challenges, using TASCI (Transcutaneous tibial nerve stimulation in patients with Acute Spinal Cord Injury to prevent neurogenic detrusor overactivity: a nationwide randomized, sham-controlled, double-blind clinical trial) as a case study. SETTING: Spinal cord injury (SCI) rehabilitation centers in Switzerland. METHODS: TASCI is nested in the multicenter Swiss Spinal Cord Injury Cohort Study (SwiSCI), which prospectively includes patients with acute SCI. In simulations, data from 640 patients, collected by SwiSCI, were used to investigate different scenarios of patient eligibility and study consent, as well as the performance of the randomization list. Descriptive analysis was used to describe the population of interest and the simulation results; multivariable logistic regression analysis was performed to identify predictors of discharge within the TASCI intervention time period. RESULTS: The recruitment target of 114 patients is obtainable within the originally envisioned 3-year time period under the most favorable recruitment scenario examined. The distribution of the primary prognostic factor produced imbalance in the randomization lists and informed further discussion of the cut-off values used in stratification. Influxes of patients resulted in overlapping intervention periods for multiple participants, which guided resource allocation. Early discharge was related to the primary prognostic factor and study center, but is only anticipated in about 8% of participants. CONCLUSIONS: Prospective cohort data are a very valuable resource for planning RCTs.

Bladder emptying method is the primary determinant of urinary tract infections in patients with spinal cord injury: results from a prospective rehabilitation cohort study.

OBJECTIVE: To understand the occurrence of and risk factors for urinary tract infections (UTIs) in patients with spinal cord injury (SCI) undergoing specialized SCI rehabilitation in Switzerland. PATIENTS AND METHODS: This study used data collected from 369 patients, who participated in a nationwide rehabilitation cohort for SCI in Switzerland between 2013 and 2017. Information on UTIs as well as their potential determinants, including demographics, lesion characteristics, and time-updated data on functional independence and bladder management, was used. Multivariable regression methods were applied to perform a time-updated evaluation of determinants of UTI risk. RESULTS: The crude incidence rate (IR) of UTIs was 0.55 UTIs per 100 person-days (95% confidence interval [CI] 0.49-0.62), the cumulative IR was 43%, and the median length of stay was 122 days. The bladder emptying method at discharge was largely determined by 28 days after admission. Among those using indwelling or assisted intermittent catheterization (IC), the likelihood of self-IC at discharge was positively related to the level of self-care independence, negatively related to age at injury, and lower in women than men. Catheter users consistently had higher adjusted IRs for UTI than spontaneous voiders. The IR ratios were: indwelling catheter: 5.97 (95% CI 2.63-13.57); assisted IC: 6.05 (95% CI 2.63-13.94); self-IC: 5.16 (95% CI 2.31-11.52); test for differences across catheter groups: P = 0.82. Lesion severity and previous UTI had additional but smaller effect sizes. CONCLUSIONS: Bladder emptying method was identified as the main risk factor for UTI in patients with SCI. As spontaneous voiders had the lowest UTI rate, further research is warranted to reduce voiding dysfunction, for instance using neuromodulation procedures.

Dynamic changes in heat transducing channel TRPV1 expression regulate mechanically insensitive, heat sensitive C-fiber recruitment after axotomy and regeneration.

Peripheral injury leads to a significant increase in the prevalence of mechanically insensitive, heat-sensitive C-fibers (CH) that contain the heat transducing TRPV1 (transient receptor potential vanilloid type I) channel in mice. We have recently shown that this recruitment of CH fibers is associated with increased expression of the receptor for GDNF (glial cell line-derived neurotrophic factor) family neurotrophic factor artemin (GFRα3), and that in vivo inhibition of GFRα3 prevented the increase in TRPV1 expression normally observed following axotomy. Here we have directly tested the hypothesis that the recruitment of functional CH fibers following nerve regeneration requires enhanced TRPV1 levels. We used in vivo siRNA-mediated knockdown to inhibit the injury-induced expression of TRPV1 coupled with ex vivo recording to examine response characteristics and neurochemical phenotypes of different functionally defined cutaneous sensory neurons after regeneration. We confirmed that inhibition of TRPV1 did not affect the axotomy-induced decrease in polymodal C-fiber (CPM) heat threshold, but transiently prevented the recruitment of CH neurons. Moreover, a recovery of TRPV1 protein was observed following resolution of siRNA-mediated inhibition that was correlated with a concomitant rebound in CH neuron recruitment. Thus dynamic changes in TRPV1 expression, not absolute levels, may underlie the functional alterations observed in CH neurons and may contribute to the development of heat hyperalgesia after nerve injury.

Comprehensive phenotyping of group III and IV muscle afferents in mouse.

While much is known about the functional properties of cutaneous nociceptors, relatively little is known about the comprehensive functional properties of group III and IV muscle afferents. We have developed a mouse ex vivo forepaw muscle, median and ulnar nerve, dorsal root ganglion (DRG), spinal cord recording preparation to examine the functional response properties, neurochemical phenotypes, and spinal projections of individual muscle afferents. We found that the majority of group III and IV muscle afferents were chemosensitive (52%) while only 34% responded to mechanical stimulation and fewer (32%) responded to thermal stimuli. The chemosensitive afferents could be grouped into those that responded to a "low"-metabolite mixture containing amounts of lactate and ATP at pH 7.0 simulating levels observed in muscle during exercise (metaboreceptors) and a "high"-metabolite mixture containing lactic acid concentrations and ATP at pH 6.6 mimicking levels observed during ischemic contractions (metabo-nociceptors). While the majority of the metabo-nociceptive fibers responding to the higher concentration levels were found to contain acid-sensing ion channel 3 (ASIC3) and/or transient receptor potential vanilloid type 1 (TRPV1), metaboreceptors responding to the lower concentration levels lacked these receptors. Anatomically, group III muscle afferents were found to have projections into laminae I and IIo, and deeper laminae in the spinal cord, while all functional types of group IV muscle afferents projected primarily into both laminae I and II. These results provide novel information about the variety of sensory afferents innervating the muscle and provide insight into the types of fibers that may exhibit plasticity after injuries.

Development of a Sham Protocol to Investigate Transcutaneous Tibial Nerve Stimulation in Randomised, Sham-Controlled, Double-Blind Clinical Trials.

Transcutaneous tibial nerve stimulation (TTNS) is a promising treatment for neurogenic lower urinary tract symptoms. However, the evidence is limited due to a general lack of randomised controlled trials (RCTs) and, also, inconsistency in the sham and blinding conditions. In the context of much-needed RCTs, we aimed to develop a suitable sham-control protocol for a clinical setting to maintain blinding but avoid meaningful stimulation of the tibial nerve. Three potential electrode positions (lateral malleolus/5th metatarsal/plantar calcaneus) and two electrode sizes (diameter: 2.5 cm/3.2 cm) were tested to determine which combination provided the optimal sham configuration for a TTNS approach, based on a visible motor response. Sixteen healthy volunteers underwent sensory and motor assessments for each sham configuration. Eight out of them came back for an extra TTNS visit. Sensory thresholds were present for all sham configurations, with linear regression models revealing a significant effect regarding electrode position (highest at plantar calcaneus) but not size. In addition, motor thresholds varied with the position-lowest for the 5th metatarsal. Only using this position and 3.2 cm electrodes attained a 100% response rate. Compared to TTNS, sensory and motor thresholds were generally higher for the sham configurations; meanwhile, perceived pain was only higher at the lateral malleolus. In conclusion, using the 5th metatarsal position and 3.2 cm electrodes proved to be the most suitable sham configuration. Implemented as a four-electrode setup with standardized procedures, this appears to be a suitable RCT protocol for maintaining blinding and controlling for nonspecific TTNS effects in a clinical setting.

Urodynamics Are Essential to Predict the Risk for Upper Urinary Tract Damage after Acute Spinal Cord Injury.

We used clinical parameters to develop a prediction model for the occurrence of urodynamic risk factors for upper urinary tract (UUT) damage during the first year after acute spinal cord injury (SCI). A total of 97 patients underwent urodynamic investigation at 1, 3, 6, and 12 months after acute SCI, within the framework of a population-based longitudinal study at a single university SCI center. Candidate predictors included demographic characteristics and neurological and functional statuses 1 month after SCI. Outcomes included urodynamic risk factors for UUT damage: detrusor overactivity combined with detrusor sphincter dyssynergia, maximum storage detrusor pressure (pDetmax) ≥ 40 cmH2O, bladder compliance < 20 mL/cmH2O, and vesicoureteral reflux. Multivariable logistic regression was used for the prediction model development and internal validation, using the area under the receiver operating curve (aROC) to assess model discrimination. Two models showed fair discrimination for pDetmax ≥ 40 cmH2O: (i) upper extremity motor score and sex, aROC 0.79 (95% CI: 0.69-0.89), C-statistic 0.78 (95% CI: 0.69-0.87), and (ii) neurological level, American Spinal Injury Association Impairment Scale grade, and sex, aROC 0.78 (95% CI: 0.68-0.89), C-statistic 0.76 (95% CI: 0.68-0.85). We identified two models that provided fair predictive values for urodynamic risk factors of UUT damage during the first year after SCI. Pending external validation, these models may be useful for clinical trial planning, although less so for individual-level patient management. Therefore, urodynamics remains essential for reliably identifying patients at risk of UUT damage.

Urological Management at Discharge from Acute Spinal Cord Injury Rehabilitation: A Descriptive Analysis from a Population-based Prospective Cohort.

Background: There is limited epidemiological evidence describing contemporary neuro-urological management of persons with acute spinal cord injury (SCI). Objective: To describe neurogenic lower urinary tract dysfunction (NLUTD) management at discharge from SCI rehabilitation. Design setting and participants: The population-based Swiss Spinal Cord Injury (SwiSCI) cohort study prospectively collected data from 602 adults undergoing specialized postacute SCI rehabilitation from 2013 to 2020. The management strategy was based on the European Association of Urology (EAU) Guidelines on Neuro-Urology. Outcome measurements and statistical analysis: Data were collected at discharge using the International SCI Lower Urinary Tract Function Basic Data Set. Multivariable logistic regression adjusting for demographics, SCI characteristics, and center, with inverse probability weighting accounting for sampling bias, was used to produce prevalence estimates and identify predictors of lower urinary tract symptoms (LUTS) and NLUTD management outcomes. Results and limitations: At discharge (median time after SCI: 5.0 mo [Q1-Q3: 3.0-7.2]), the prevalence of LUTS or managed NLUTD was 82% (95% confidence interval [CI]: 79-85%). SCI completeness was the main predictor of LUTS and managed NLUTD. The risk of urinary incontinence was elevated in females (odds ratio 1.98 [95% CI: 1.18-3.32]) and with complete lesions (odds ratio 4.71 [95% CI: 2.52-8.81]). Voiding dysfunction was most commonly managed with intermittent catheterization (prevalence 39% [95% CI: 35-42%]), followed by indwelling catheterization (prevalence 22% [95% CI: 18-25%]). The prevalence of antimuscarinic or mirabegron use was 29% (95% CI: 26-33%). Urodynamic and renal function data were not collected. Conclusions: Our population-based description of urological management in Swiss SCI centers utilizing the EAU Guidelines on Neuro-Urology may be used as a reference for evaluation in other settings. Data further indicate a need for sex-specific neuro-urological management research. Patient summary: At discharge from spinal cord injury (SCI) rehabilitation, a majority of patients have lower urinary tract problems, especially those with complete SCI. Women have a higher risk of urinary incontinence.

Enhanced artemin/GFRα3 levels regulate mechanically insensitive, heat-sensitive C-fiber recruitment after axotomy and regeneration.

We have shown recently that following saphenous nerve transection and successful regeneration, cutaneous polymodal nociceptors (CPMs) lacking transient receptor potential vanilloid 1 (TRPV1) are sensitized to heat stimuli and that mechanically insensitive, heat-sensitive C-fibers (CHs) that contain TRPV1 increase in prevalence. Target-derived neurotrophic factor levels were also enhanced after axotomy and regeneration. In particular, the glial-cell line-derived neurotrophic factor (GDNF) family member artemin was found to be significantly enhanced in the hairy hindpaw skin and its receptor GDNF family receptor α3 (GFRα3) was increased in the L2/L3 dorsal root ganglia (DRGs) following nerve injury. In this study, we assessed the role of enhanced artemin/GFRα3 levels on the changes in mouse cutaneous CH neurons following saphenous nerve regeneration. We used a newly developed siRNA-mediated in vivo knockdown strategy to specifically inhibit the injury-induced expression of GFRα3 and coupled this with an ex vivo recording preparation to examine response characteristics and neurochemical phenotype of different types of functionally defined neurons after injury. We found that inhibition of GFRα3 did not affect the axotomy-induced decrease in CPM threshold, but transiently prevented the recruitment of CH neurons. Western blot and real-time PCR analysis of hairy hindpaw skin and L2/L3 DRGs after saphenous nerve regeneration suggested that inhibition of the potential initial injury-induced increase in enhanced target-derived artemin signaling resulted in dynamic changes in TRPV1 expression after regeneration. These changes in TRPV1 expression may underlie the functional alterations observed in CH neurons after nerve regeneration.

Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role of target-derived neurotrophic factor signaling.

Damage to peripheral nerves is known to contribute to chronic pain states, including mechanical and thermal hyperalgesia and allodynia. It is unknown whether the establishment of these states is attributable to peripheral changes, central modifications, or both. In this study, we used several different approaches to assess the changes in myelinated (A) and unmyelinated (C) cutaneous nociceptors after transection and regeneration of the saphenous nerve. An ex vivo recording preparation was used to examine response characteristics and neurochemical phenotype of different types of functionally defined neurons. We found that myelinated nociceptors had significantly lower mechanical and thermal thresholds after regeneration, whereas C-polymodal nociceptors (CPMs) had lower heat thresholds. There was a significant increase in the percentage of mechanically insensitive C-fibers that responded to heat (CHs) after regeneration. Immunocytochemical analysis of identified afferents revealed that most CPMs were isolectin B4 (IB4) positive and transient receptor potential vanilloid 1 (TRPV1) negative, whereas CHs were always TRPV1 positive and IB4 negative in naive animals (Lawson et al., 2008). However, after regeneration, some identified CPMs and CHs stained positively for both markers, which was apparently attributable to an increase in the total number of IB4-positive neurons. Real-time PCR analysis of L2/L3 DRGs and hairy hindpaw skin at various times after saphenous nerve axotomy suggested multiple changes in neurotrophic factor signaling that correlated with either denervation or reinnervation of the cutaneous target. These changes may underlie the functional alterations observed after nerve regeneration and may explain how nerve damage leads to chronic pain conditions.

Cutaneous C-polymodal fibers lacking TRPV1 are sensitized to heat following inflammation, but fail to drive heat hyperalgesia in the absence of TPV1 containing C-heat fibers.

BACKGROUND: Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1-/- mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced-inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. RESULTS: In wildtype mice we found that polymodal C-fibers (CPMs) lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs) were not sensitized following inflammation. However, results suggested that some of these fibers may have gained mechanical sensitivity and that some previous silent fibers gained heat sensitivity. In mice lacking TRPV1, inflammation only decreased heat threshold of CPMs but did not sensitize their responses to the heat ramp. No CH-fibers could be identified in naïve nor inflamed TRPV1-/- mice. CONCLUSIONS: Results obtained here suggest that increased heat sensitivity in TRPV1-negative CPM fibers alone following inflammation is insufficient for the induction of heat hyperalgesia. On the other hand, TRPV1-positive CH fibers appear to play an essential role in this process that may include both afferent and efferent functions.

Update from TASCI, a Nationwide, Randomized, Sham-controlled, Double-blind Clinical Trial on Transcutaneous Tibial Nerve Stimulation in Patients with Acute Spinal Cord Injury to Prevent Neurogenic Detrusor Overactivity.

Transcutaneous tibial nerve stimulation has the potential to revolutionize the management of lower urinary tract dysfunction in patients with acute spinal cord injury. TASCI is a nationwide randomized, sham-controlled, double-blind clinical trial for which the preparatory phase has been successfully completed.

TASCI-transcutaneous tibial nerve stimulation in patients with acute spinal cord injury to prevent neurogenic detrusor overactivity: protocol for a nationwide, randomised, sham-controlled, double-blind clinical trial.

INTRODUCTION: Neurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI. METHODS AND ANALYSIS: TASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5-39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30 min/day, 5 days/week, for 6-9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1 year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome. ETHICS AND DISSEMINATION: TASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03965299.

Purinergic receptor P2Y1 regulates polymodal C-fiber thermal thresholds and sensory neuron phenotypic switching during peripheral inflammation.

We have recently found that, following complete Freund's adjuvant (CFA)-induced inflammation, cutaneous polymodal nociceptors (CPM) lacking the transient receptor potential vanilloid 1 (TRPV1) are sensitized to heat stimuli. In order to determine possible mechanisms playing a role in this change, we examined gene expression in the L2/L3 sensory ganglia following CFA injection into the hairy hind paw skin and found that G-protein-coupled purinoreceptor P2Y1 expression was increased. This receptor is of particular interest, as most CPMs innervating mouse hairy skin bind isolectin B4, which co-localizes with P2Y1. Additionally, our recent findings have shown that cutaneous CPMs in P2Y1-/- mice displayed significantly reduced thermal sensitivity. Together, these findings suggested a possible role for P2Y1 in inflammation-induced heat sensitization in these fibers. To test this hypothesis, we utilized our in vivo small interfering RNA technique to knock down the inflammation-induced increase in P2Y1 expression and then examined the functional effects using ex vivo recording. We found that the normal reduction of heat thresholds in CPM fibers induced by CFA was completely blocked by inhibition of P2Y1. Surprisingly, inhibition of P2Y1 during inflammation also significantly increased the number of CPM neurons expressing TRPV1 without a change in the total number of TRPV1-positive cells in the L2 and L3 dorsal root ganglia. These results show that the inflammation-induced enhanced expression of P2Y1 is required for normal heat sensitization of cutaneous CPM fibers. They also suggest that P2Y1 plays a role in the maintenance of phenotype in cutaneous afferent fibers containing TRPV1.

Overexpression of neurotrophin-3 enhances the mechanical response properties of slowly adapting type 1 afferents and myelinated nociceptors.

Constitutive overexpression of neurotrophin-3 (NT3) in murine skin results in an increased number of sensory neurons within the dorsal root ganglia, an increase of myelinated axons in cutaneous nerves, hyperinnervation of the skin, and an increased number of Merkel cells found in flank skin. Here we used a saphenous skin/nerve preparation to determine if these anatomical changes affect the functional response characteristics of cutaneous sensory neurons. Overexpression of NT3 significantly increased the responses of slowly adapting type 1 (SA1) low-threshold mechanoreceptors and Adelta high-threshold mechanoreceptors to suprathreshold mechanical stimulation. It also resulted in significantly faster conduction velocities of SA1 fibers. In contrast to earlier findings in flank skin, no differences were noted in the numbers of Merkel cells in the touch domes in hindlimb skin of NT3-overexpressing mice. In addition, the number of dermal Merkel cells, located around hair follicles on the dorsum of the foot, was reduced by 55%. The increase in mechanical sensitivity was found to correlate with significant increases in the expression of acid-sensing ion channels (ASIC) 1 and 3. Additional experiments using intracellular recordings and staining procedures confirmed that at least some cutaneous myelinated nociceptors and SA1 mechanoreceptors stained positively for both trkC and ASIC3. These results indicate that cutaneous NT3 overexpression alters the response properties of specific cutaneous sensory neurons, and that these changes may be due to the modulation of putative mechanosensitive ion channels.