Key points To electrophysiologically determine the predominant neural structures activated with cervical epidural stimulation (ES), well‐established electrophysiological protocols (single‐pulse, paired‐pulse and multiple frequency stimulation) were delivered at rest, during motor activity and under anaesthesia in adult rats. Cervical ES resulted in spinal evoked motor responses with three different waveforms – early response (ER), middle response (MR) and late response (LR). ERs remained unmodulated by repeated stimulation protocols. In contrast, MRs and LRs were modulated by repeated stimulation protocols and volitional motor activity. ERs are consequential to the direct activation of motor efferents; MRs are secondary to type‐I sensory afferent activation and LRs result from the engagement of wider spinal interneuronal circuitry with potential influence from supraspinal pathways. Evidence from this work is fundamental in enhancing our understanding of cervical ES, and critical in refining the design of neuromodulation‐based rehabilitative strategies and in the construction of neuroprosthetics. Abstract Epidural stimulation (ES) of the lumbar spinal cord has demonstrated significant improvements in various physiological functions after a traumatic spinal cord injury in humans. Electrophysiological evidence from rodent, human and computational studies collectively suggest that the functional recovery following lumbar ES is mediated via direct activation of sensory afferent fibres. However, the mechanisms underlying cervical ES have not been comprehensively studied, which greatly limits our understanding of its effectiveness in restoring upper limb function. In this work, we determined the predominant neural structures that are activated with cervical ES using in vivo cervical spinal evoked motor responses (SEMRs). Standard electrophysiological protocols (single‐pulse, paired‐pulse and multiple frequency stimulation) were implemented in 11 awake and anaesthetized rats in four experimental stages. Three distinct types of cervical SEMRs were identified based on latency of their appearance: early response (ER), middle response (MR) and late response (LR). ERs remained unmodulated by repeated stimulation protocols. MRs and LRs were modulated by repeated stimulation protocols and volitional motor activity. Except for LRs being completely abolished under urethane, ketamine or urethane anaesthesia did not affect the appearance of cervical SEMRs. Our data, backed by literature, suggest that ERs are secondary to the direct activation of motor efferents, MRs are elicited by activation of type‐I sensory afferents and LRs result from the engagement of interneuronal circuitry with potential influence from supraspinal pathways. The gathered information paves the way to designing motor rehabilitation strategies that can utilize cervical ES to recover upper limb function following neurological deficits.

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.

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Long-term recovery of limb function is a significant unmet need in people with paralysis. Neuromodulation of the spinal cord through epidural stimulation, when paired with intense activity-based training, has shown promising results toward restoring volitional limb control in people with spinal cord injury. Non-invasive neuromodulation of the cervical spinal cord using transcutaneous spinal cord stimulation (tSCS) has shown similar improvements in upper-limb motor control rehabilitation. However, the motor and sensory rehabilitative effects of activating specific cervical spinal segments using tSCS have largely remained unexplored. We show in two individuals with motor-complete SCI that targeted stimulation of the cervical spinal cord resulted in up to a 1,136% increase in exerted force, with weekly activity-based training. Furthermore, this is the first study to document up to a 2-point improvement in clinical assessment of tactile sensation in SCI after receiving tSCS. Lastly, participant gains persisted after a one-month period void of stimulation, suggesting that targeted tSCS may lead to persistent recovery of motor and sensory function.

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