It has been demonstrated that the human lumbosacral spinal cord can be neuromodulated with epidural (ESS) and transcutaneous (TSS) spinal cord stimulation to enable recovery of standing and volitional control of the lower limbs after complete motor paralysis due to spinal cord injury (SCI). The work proposed herein will examine and identify distinct electrophysiological mechanisms underlying transcutaneous spinal stimulation (TSS) and epidural spinal stimulation (ESS) to define how these approaches determine the ability to maintain self-assisted standing after SCI.

Spinal circuitries below a paralyzing injury have a functional potential that far exceeds what has been thought possible. It has been demonstrated that task-specific motor therapy combined with epidural spinal cord stimulation (ESS) can promote improved motor function during postural, locomotor, and voluntary movement tasks, resulting in dramatic effects on the wellbeing of individuals with spinal cord injury (SCI). While these findings indicate a substantial promise for restoring mobility even after motor complete paralysis, chronic ESS is based on a high-cost implantable device, as well as an expensive and invasive surgical procedure. The investigators have developed a cost-effective alternative to ESS - non-invasive, transcutaneous electrical stimulation of the spinal cord (TSS). Preliminary works demonstrate that this neuromodulatory strategy provides sufficient specificity to selectively stimulate multisegmental dorsal nerve roots, enable stepping movements, and improve postural control during sitting and standing in individuals with motor complete SCI. The similarities between the effects of ESS and TSS are of critical importance in guiding more individually-specific neuromodulatory approaches to improve motor function and mobility after SCI, but have not been compared directly in the same subjects.

This study is focused on investigation the effects and mechanisms of each spinal neuromodulation strategy in regaining self-assisted standing. Not only is the recovery of balance control one of the most desired goals of people with paralysis, it provides the foundation necessary for regaining the ability to walk, and is critical to future therapies, involving robotic (e.g. exoskeleton) technologies. The objectives of this study are (1) to define the therapeutic potential of TSS during standing in individuals with motor complete SCI, and (2) to identify the neurophysiological and functional signatures of TSS and ESS. The central hypothesis is that each of the neuromodulatory strategies, when individually tailored, can result in significant motor recovery in individuals with chronic paralysis by reactivation and integration of networks that were clinically dormant prior to the intervention. The investigators predict that this proposal will have a high impact given that it encompasses multiple functional systems that contribute to the independence and quality of life in a broad population of individuals with SCI, and provides the first direct comparison of the invasive and non-invasive approaches. The investigators propose a progressive, mechanistic, and translational study to validate the effects of each approach, examine the neuroplastic capacity caused by activity-based training in the presence of TSS, and evaluate TSS and ESS stimulation paradigms as rehabilitative modalities after SCI.

Inclusion criteria

1. All participants must be able to provide a provision of a signed and dated informed consent form.

2. Stated willingness to comply with all study procedures and availability for the duration of the study.

3. Male or female, aged 22-75 years old.

4. Documentation from the participant's primary treating physician confirming a stable medical condition.

5. Inability to maintain standing independently without external support due to SCI AIS A-C.

6. Ability to tolerate at least 15 minutes in an upright (supported) position.

7. Able to self-transfer from the wheelchair and demonstrate active range of motion of bilateral upper extremities in gravity dependent plane.

8. Able to passively range bilateral lower extremities within normal mobility parameters including:

   1. greater than 90 degrees of hip flexion and 165 degrees of hip extension;
   2. greater than 90 degrees of knee flexion and reach neutral knee extension of 180 degrees;
   3. neutral ankle position reaching a minimum of 90 degrees of dorsiflexion.

9. Participants should be on a stable intrathecal baclofen or oral anti-spasticity regimen/dose for the period of the study unless advised otherwise by their physician.

10. 1 to 30 years post spinal cord injury.

11. Non-progressive spinal cord injury.

12. Neurological level of injury below C4 and above T12 (excluding conus injury and/or indications of lower motor neuron injury).

13. Eligible for fMRI per safety questionnaire.

14. Women of childbearing potential must agree to the use of an effective means of avoiding pregnancy for the duration of the study.

15. Able to commit to the full study.

Exclusion Criteria:

1. Ability to maintain standing independently without external support.

2. Currently involved in another rehabilitation training of the lower extremities.

3. Active pressure sores, unhealed bone fractures, peripheral neuropathies, or painful musculoskeletal dysfunction (including but not limited to contractures in the upper and lower extremities).

4. Any ongoing medical condition which would preclude participant from regular physical activity (including but not limited to: cardiopulmonary disease, uncontrollable autonomic dysreflexia or orthostatic hypotension, active urinary tract infections, pregnant or nursing).

5. Intrathecal baclofen pump therapy for spasticity not compatible with 3T MRI.

6. Must not have received Botox injections to primary lower extremity and trunk musculature within the past 3 months, resulting in absence of muscle tone and precluding response to electrical stimulation therapy.

7. Current or history of neuromuscular conditions (including but not limited to: unhealed ligament of muscular tears in the upper or lower extremities, pain in weight bearing positions for upper and lower extremities).

8. Clinically significant depression, psychiatric disorders, or ongoing drug abuse, including heavy alcohol use.

9. Any reason the PI or treating physician may deem as harmful to the participant to enroll or continue in the study.

10. Body Mass Index (BMI) over 30.

11. Pregnancy.

12. Use a ventilator or diaphragmatic pacer.

13. Participants with the following conditions will be excluded from TMS, but may take part in the overall study:

    • Personal or first-degree family history of seizures or epilepsy.
    • Metal in the head, except mouth implants.
    • History of suicide attempts.
    • History of intracranial lesions, increased intracranial pressure, or stroke.
    • Current use of tricyclic anti-depressants, selective serotonin reuptake inhibitors (SSRIs), serotonin nor-epinephrine reuptake inhibitors (SNRIs), buproprion (Wellbutrin), or tramadol.