Development of an Activity-Dependent Epidural Stimulation System in Freely Moving Spinal Cord Injured Rats: A Proof of Concept Study

Purpose: Extensive pre-clinical and clinical experimentation has yielded data on the robustness and versatility of epidural stimulation (ES) strategies to activate spinal neural circuitry to produce functional benefits. Increasing studies are now reporting that closed-loop electrical stimulation delivery methods significantly enhance the neuromodulation effects of stimulation, to in turn, improve physiological outcomes of the intervention. No studies have yet explored the feasibility and usage of closed-loop systems to neuromodulate the cervical spinal cord using ES. Methods: We developed an activity-dependent system that utilizes electromyography (EMG) activity to trigger epidural stimulation (tES) of the cervical spinal cord in awake, freely moving rats. Experiments were performed on rats that were implanted with chronic forelimb EMG and cervical epidural implants, with (n = 7) and without (n = 2) a complete C4 spinal hemisection. Results: Our results show that the EMG triggered activity-dependent system can be reliably applied and reproduced for: (i) stimulating multiple rats simultaneously throughout the night during free home-cage activity and (ii) use as a mobile system for testing and training during various short-term behavioral testing conditions. The system was able to consistently generate stimulation pulse trains in response to attempted EMG activity that crossed a user-defined threshold in all rats for all experiments, including the overnight experiments that lasts for 7 h/session for 6 days/week through the 3-month period. Conclusion: The developed closed-loop system can be considered to represent a class of bidirectional neural prostheses via a circuit that enables two-way interactions between neural activity (real-time processing of EMG activity) and external devices (such as a stimulator). It can operate autonomously for extended periods of time in unrestrained rats, allowing its use as a long-term therapeutic tool. It can also enable us to study the long-term physiological effects of incorporating electrical stimulation techniques into the nervous system. The system can also be experimented for connecting several neural systems into a Brainet by combining neural signals from multiple rats dynamically and in real-time so as to enhance motor performance. Studies are ongoing in our laboratory to test the usefulness of this system in the recovery of hand function after cervical spinal cord injuries.