New Funding to Determine the Mechanism TNS in the Context of SCI

Congrats to lab on a new 5 year R01 “Mechanisms and Optimization of Tibial Nerve Stimulation in Treating Neurogenic Bladder Dysfunction”. Jim Hokanson (PI) will be leading the effort with co-investigators Aaron Mickle, Nikki Lytle, Cory O’Conner, and Kajana Satkunendrarajah (Miami Project) to uncover the mechanism by which tibial nerve stimulation can improve bladder function following spinal cord injury. Congrats to all involved in the project! This was a team effort to gather their preliminary data and submit this large proposal!

PROJECT SUMMARY Lower urinary tract dysfunction is one of the most desired areas of improvement for people with spinal cord injury (SCI). Evidence is increasing that tibial nerve stimulation may be effective in improving bladder function for those with bladder dysfunction due to SCI. However, despite decades of clinical use, particularly for non-neurogenic bladder dysfunction, it is still unclear how stimulating a nerve (tibial) at the ankle impacts the bladder and whether changes to the stimulation parameters could improve therapeutic efficacy. Mechanistic work thus far, which has largely focused on indirect evidence for the involvement of neurotransmitters involved in tibial nerve stimulation, has not led to changes in the way tibial nerve stimulation is delivered. As an alternative approach we will map the neural connections between the tibial nerve and the lower urinary tract to understand circuits that may contribute to the efficacy of tibial nerve stimulation. This will be done in naïve rats, as well as those that received a T9 contusion, as we expect that SCI may change the neural circuitry of the spinal cord. In addition to virus-based anatomical mapping, we will conduct functional mapping by examining stimulation-induced c-Fos activity. We will also conduct snRNA-seq in conjunction with a machine learning approach to understand cell types in the spinal cord that are responsive to chronic tibial nerve stimulation. Overall we expect that these mapping and cell-type classification efforts will enable future studies that dissect these circuits to understand how specific components of the pathway impact bladder function. Importantly, these efforts could lead to an improved understanding of how various neuromodulation approaches differ and how to choose the best neuromodulation strategies for individuals. In addition to this mechanistic work we will also attempt to improve tibial nerve stimulation outcomes by varying stimulation parameters delivered chronically to rats with a T9 contusion. Stimulation parameters have been carefully chosen based on data from animals and human studies, as well as first-principles, with the expectation that the new parameters will improve tibial nerve stimulation outcomes. We expect that these stimulation parameters, which are clinically feasible, would help inform clinical studies of tibial nerve stimulation in those with SCI.