A traumatic spinal cord injury (SCI) causes lasting damage to sensory and motor circuitry, resulting in partial or complete paralysis, loss of sensation, autonomic dysreflexia, pain, and bowel and bladder dysfunction [1]. While there has been significant investment and focus on mechanisms and methods to improve mobility of the SCI community, neurogenic lower urinary tract dysfunction (NLUTD) is a much less studied co- morbidity. This is remarkable, given that patients designate the restoration of voiding as a top priority [2]. The lower urinary tract (LUT) has two principal functions: storage and voiding. These processes rely on the synchronized activity of the LUT, which is elaborately regulated by supraspinal centers [3]. After a SCI, supraspinal control of voiding is disrupted leading to development of NLUTD. Prevailing intervention focuses on symptom relief such as chronic catheter utilization, which is associated with altered voiding dynamics and can result in infection or mal-adaptive plasticity of the spinal circuitry. Recent advances in our understanding of the potential for plasticity or regeneration of damaged micturition circuitry will not only have a dramatic impact on patients with SCI, but more broadly, in the global population for those that suffer NLUTD as well. In this study we propose an innovative approach by applying ventral epidural spinal stimulation (VES) to map the spinal circuitry involved in the neural control of micturition in a semi-chronic injury model. Understanding the adaptive nature of neural circuitry can help us better understand NULTD pathologies as well as identify potential therapeutic targets to restore bladder function.

Long Evans rats underwent a laminectomy at T9 and received a moderate contusion injury with an Ohio State Impactor. Four weeks post-SCI, we conducted terminal electrophysiology evaluations (n=4), along with age matched controls (n=3). During terminal electrophysiology experiments, a laminectomy at T9 was performed to allow for insertion of a custom spinal stimulation electrode. Next, a suprapubic catheter was inserted through the bladder dome and coupled to a three-way valve for controlled infusion of intravesical saline, and to monitoring changes in bladder pressure via an inline pressure transducer. Subsequently, flexible microelectrodes were fitted to regions of the bladder identified as dome, mid, and base, as well as the external urethral sphincter (EUS) to record electromyographic (EMG) signals. Once all LUT electrodes were in place, the spinal stimulating electrode was inserted ventrally until reaching the L1 spinal segment. Additionally, needle electrodes were placed in the gastrocnemius and tibialis anterior muscles in both hindlimbs to record motor evoked potentials. Stimulation was delivered at each spinal segment between L1 and S1 (0.1-0.5mA and 1-20Hz) with a D8SR Bipolar Constant Current Stimulator (Digitimer Ltd.), and evoked potentials from the LUT and hindlimb muscles were recorded with a PowerLab 16/35 DAQ (ADInstruments Inc.).

Analysis of the LUT recruitment curves (bladder dome, mid bladder, bladder base, and EUS) showed significantly higher (p<0.01) amplitudes of response as stimulation intensity increased in both control and SCI animals. Preliminary results also demonstrate distinct trends in response to stimulation between control and SCI groups in both bladder and EUS. More specifically stimulation at L6 recorded the strongest response at both 0.4mA and 0.5mA throughout the bladder in control animals. But this trend was not seen in SCI animals with bladder dome showing the highest response at L4, while mid bladder and bladder base both showing the highest response to S1 stimulation. Overall, each location in the bladder displayed distinct responses to not only stimulation intensity, but also with respect to the spinal level stimulated. Evoked potentials of the EUS showed significantly divergent patterns between controls and SCI groups. Amplitude of the EUS response was highest when the spinal cord was stimulated at L4-L6 in controls, with SCI animals demonstrating significantly higher response amplitudes with S1 stimulation, followed by L4-L6 (Figure 1).

Our lab has previously demonstrated the ability to record EMG signals from the LUT of SCI rodents. These results have reflected that graduated levels of bladder dysfunction are proportional to injury severity, with overall attenuated EMG activity throughout the LUT of all SCI animals when compared against controls (Figure 2). With this study we further characterize the activity seen in the LUT and the contribution of each spinal segment between L1/S1 with respect to bladder function. Our results show there is a distinct response to stimulation between SCI rats and uninjured controls. These differences could be derived from an innate plasticity of the central nervous system (CNS) to adjust after traumatic injury. By understanding how spinal circuitry adapts after a SCI, we can determine more effective targets for neuromodulation with the potential to improve storage and/or voiding, and thus restore bladder function.

Although these are preliminary results, our data suggest that CNS plasticity after a moderate thoracic SCI leads to significant reorganization of the spinal circuitry coordinating neural control of bladder function. Understanding these mechanisms will allow us to more accurately determine targets for therapeutic spinal stimulation depending on the type of NLUTD present.

Hou S, Rabchevsky AG. Autonomic consequences of spinal cord injury. Compr Physiol. Oct 2014;4(4):1419-5doi:10.1002/cphy.c130045
van Middendorp JJ, Allison HC, Ahuja S, et al. Top ten research priorities for spinal cord injury: the methodology and results of a British priority setting partnership. Spinal Cord. May 2016;54(5):341-doi:10.1038/sc.2015.199
Griffiths D. Neural control of micturition in humans: a working model. Nat Rev Urol. Dec 2015;12(12):695-70doi:10.1038/nrurol.2015.266

Continence 2S2 (2022) 100291
DOI: 10.1016/j.cont.2022.100291