Objective: The objective of the proposed research is to decrease neural transmission in spinal pain pathways that become overactive after spinal cord injury (SCI) and contribute to the persistent SCI-related neuropathic pain (SCI-NP). To accomplish this objective, we propose to develop a neurobehavioral training in which people with SCI-NP learn over time to restore a more appropriate balance of pain and non-pain-related spinal neural transmission. This approach harnesses the remarkable intrinsic ability of the nervous system to reorganize and modify its function, known as neural plasticity. The proposed training approach is non-invasive, non- pharmacologic, and is rehabilitative – i.e., its benefits are intended to far outlast the duration of intervention.

Rationale: Neuropathic pain impacts up to 70% of people with SCI, and the direct and indirect consequences of SCI-NP are severe. Current SCI-NP treatments typically result only in temporary, incomplete relief. Common strategies are pharmacologic (e.g., opioids) or invasive (e.g., spinal stimulation), and often do not correct the underlying causes of the pain itself; rather, they address only the symptoms. This lack of mechanistic specificity also leads to unwanted side effects that can force individuals to discontinue therapy. Related, most SCI-NP treatments do not directly address the problem of pathologically increased transmission in spinal pain pathways below the lesion, although such maladaptive changes do contribute to the development of SCI-NP. On the flip side of the same coin, this ability of the nervous system to change even after SCI can and should be harnessed to alleviate SCI-NP; indeed, similar trainings have produced lasting gains in motor rehabilitation after SCI.

What populations will this work help, and how will it do so? The proposed work is directed toward people living with SCI-NP. The proposed work will help these people by laying the foundation for a new class of SCI- NP therapy that holds considerable promise for delivering long-lasting relief.

What are the potential clinical applications, benefits, and risks? The primary clinical application is the alleviation of neuropathic pain arising in regions of body below the injury level. The proposed approach is likely to be especially effective at alleviating allodynia (the perception of pain in response to something non-painful, e.g., the touch of clothing to the skin may feel like a burning sensation) and hyperalgesia (the perception of increased pain intensity in response to something already painful, e.g., a mild burn from a hot pot on the stove may be excruciating), two of the most common symptoms of SCI-NP. Once translated to the clinic, the benefits of the proposed approach are that it is non-invasive, non-pharmacologic, and its therapeutic gains are expected to outlast the intervention itself. The proposed approach would not require a specialized care facility for treatment, and it could be administered either by physician or non-physician healthcare providers (e.g., physical therapist), markedly increasing access. Each of these features distinguishes the proposed work from currently available options. Risks are no greater than standard physical therapy.

How will the pilot clinical trial advance research along the translational spectrum? Currently, there is no targeted plasticity-promoting, neurobehavioral training approach available for SCI-NP. This project will enhance scientific knowledge of spinal pain pathways, mechanisms of their modulation, and lay the foundation for a new class of training approach to relieve SCI-NP. A successful outcome of this project would enable rapid scaling to larger clinical trials specifically intended to optimize dosing and therapeutic efficacy. The reflex conditioning system that is currently developed (NIH U44 NS114420) or a similar system may be used for that.

What is the projected time to person-related outcomes? Within the course of this grant (less than 3 years).

Describe any interim outcomes: Aim 1 of this study utilizes a validated animal model of SCI-NP that allows for detailed neural recordings to be made directly from the spinal neurons proposed to be targeted with neurobehavioral training in people with SCI-NP. The results of these studies will be made available prior to completion of the pilot clinical study (Aim 3), enabling other researchers to capitalize on this new knowledge.

What are likely contributions of the work to advancing SCI research, patient care, and quality of life? On SCI research: the proposed work will reveal previously uncharacterized aspects of neural activity in regions of the spinal cord from which SCI-NP arises. This information will advance the knowledge of neural mechanisms that maintain the neuropathic pain state and provide the foundation for a new avenue of pain management strategies to be developed by basic and translational scientists.

On patient care: this approach has the potential to reframe the way SCI-NP is treated; neurobehavioral training to change the activity of pain and non-pain pathways to addresses the underlying causes of SCI-NP rather than merely temporarily managing its symptoms.

On quality of life: Because patients actively participate in the proposed neurobehavioral training, they typically remain able to recall how to control their neural activity for many months (to years) after training ends. Thus, there is a good possibility that long-term reductions in SCI-NP may be achieved through the proposed intervention approach.