Non-invasive Cervical Electrical Stimulation for SCI

Most spinal cord injuries are anatomically incomplete - some nerve circuits remain intact, even if the individual cannot feel or control them. Activating spared nerve circuits may improve functional recovery. With this goal, the Investigators have developed a form of electrical stimulation over the cervical spinal cord that can activate muscles in both hands simultaneously and comfortably. This technique, called cervical electrical stimulation (CES), works at the skin surface - no surgery or other invasive procedures are required. The long-term goal is to use CES to strengthen residual circuits to hand muscles after SCI. Regaining control over hand function represents the top priority for individuals with cervical SCI. In the current study, the Investigators first need to better understand how CES works. In the first half of this study, the Investigators will take a systematic approach to determining how CES interacts with other circuits in the spinal cord and the brain. In the second half of the study, the Investigators will test combinations of CES with active hand and wrist movements to find ways to enhance physical movement with CES. These experiments will improve understanding of electrical stimulation in SCI, and may set the table for future treatments to prolong any short-term benefits observed in this study.

Roughly 60% of spinal cord injuries occur at the cervical level. Most injuries are anatomically incomplete. Activating spared nerve circuits augments functional recovery of the damaged nervous system. With this goal, the Investigators have developed a novel method of non-invasive cervical electrical stimulation (CES). Preliminary data show that CES triggers afferent sensory or efferent motor nerve roots depending on stimulus intensity, resulting in concurrent activation of multiple muscles on both upper limbs. the Investigators aim to use CES to strengthen residual circuits to hand muscles after SCI. Regaining control over hand function represents the top priority for individuals with cervical SCI. However, much more work needs to be done to better understand underlying CES mechanisms, its interactions with segmental and supraspinal circuits, and its optimal stimulation parameters for improving neural transmission to the hands. This proposal will address these issues. Mechanistic experiments: 15 able-bodied volunteers and 15 subjects with motor-incomplete cervical spinal cord injury will undergo systematic combinations of CES with transcranial magnetic stimulation or peripheral nerve stimuli at varying intensities, sites, and interstimulus intervals. Mechanistic hypotheses: Conditioning subthreshold CES pulses will potentiate responses to test pulses of TMS and peripheral nerve F-wave stimulation, will reduce responses to test pulses of peripheral nerve H-reflex stimulation, and will modulate response to test suprathreshold CES pulses in either direction depending on conditioning stimulus interval and intensity. These experiments will elucidate CES circuit interactions at both the segmental and supraspinal levels. Combined CES-volitional movement experiments: 15 able-bodied volunteers and 15 subjects with motor-incomplete cervical spinal cord injury will undergo systematic combinations of CES with volitional wrist and hand movements at varying intensity and effort level. Combined CES-volitional movement hypotheses: Conditioning subthreshold CES pulses will facilitate concurrent volitional wrist and hand muscle activation. Suprathreshold CES will transiently inhibit concurrent volitional wrist and hand muscle activation. These experiments will shed light on the clinically relevant possibility of using CES to enhance response to physical exercise therapy. Completion of the proposed studies will characterize CES circuit timing and distribution, and will demonstrate in principle the potential for CES to enhance physical therapy for wrist and hand muscles. Furthermore, this approach is compatible with other interventions, including drug and cell-based treatments.

All subjects undergo same full protocol, including CES at rest and CES plus active hand or wrist movements.

CES will be delivered at rest at various intensities, in combination with either electrical stimulation over peripheral nerves or magnetic stimulation over the motor cortex. This is an experiment designed to measure CES interactions with other central and peripheral nerve circuits.

CES will be delivered while the participant performs specific finger or wrist tasks at different degrees of effort. This is an experiment designed to detect momentary changes in muscle function.

Response to electrical and magnetic stimulation, singly or in combination, will be measured via peak-to-peak amplitude (millivolts) in first dorsal interosseous and abductor pollicis brevis muscles of conditioned relative to non-conditioned stimuli.

Effect of CES on concurrent finger or wrist active movements will be measured via root-mean-square of ongoing muscle activity in various hand and forearm muscles.

Inclusion Criteria: Age between 18 and 75 years; Chronic (more than 12 months since injury) incomplete SCI between levels C2-C8. Incomplete weakness of left or right hand muscles: score of 2, 3, or 4 (out of 5) on manual muscle testing of finger extension, finger flexion, or finger abduction; Detectable F-wave responses of the left or right abductor pollicis brevis muscle to median nerve stimulation. US Veteran or non-Veteran Exclusion Criteria: History of other serious injury or disease of central or peripheral nervous system History of seizures Ventilator dependence or patent tracheostomy site Use of medications that significantly lower seizure threshold History of head trauma with evidence of brain contusion or hemorrhage or depressed skull fracture on prior imaging History of implanted: brain/spine/nerve stimulators aneurysm clips ferromagnetic metallic implants or cardiac pacemaker/defibrillator Significant coronary artery or cardiac conduction disease Recent history (within past 6 months) of recurrent autonomic dysreflexia, defined as a syndrome of sudden rise in systolic pressure greater than 20 mm Hg or diastolic pressure greater than 10 mm Hg, without rise in heart rate, accompanied by symptoms such as headache, facial flushing, sweating, nasal congestion, and blurry vision (this will be closely monitored during all screening and testing procedures); History of bipolar disorder or suicide attempt or active psychosis Heavy alcohol consumption (> equivalent of 5 oz of liquor) within previous 48 hours Open skin lesions over the face, neck, shoulders, or arms Pregnancy Unsuitable for study participation as determined by study physician

A Limited Dataset (LDS), with individual electrophysiological and physiological outcome measures, will be shared in electronic format pursuant to a VA-approved Data Use Agreement. Individually Identifiable Data will be shared pursuant to valid HIPAA Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions as described in the authorization and consent, and a written assurance from the recipient that the information will be maintained in accordance with the security requirements of 38 CFR Part 1.466.

A Limited Dataset (LDS) will be shared in electronic format pursuant to a VA-approved Data Use Agreement. Individually Identifiable Data will be shared pursuant to valid HIPAA Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions as described in the authorization and consent, and a written assurance from the recipient that the information will be maintained in accordance with the security requirements of 38 CFR Part 1.466.

Wu YK, Levine JM, Wecht JR, Maher MT, LiMonta JM, Saeed S, Santiago TM, Bailey E, Kastuar S, Guber KS, Yung L, Weir JP, Carmel JB, Harel NY. Posteroanterior cervical transcutaneous spinal stimulation targets ventral and dorsal nerve roots. Clin Neurophysiol. 2020 Feb;131(2):451-460. doi: 10.1016/j.clinph.2019.11.056. Epub 2019 Dec 13.

Wecht JR, Savage WM, Famodimu GO, Mendez GA, Levine JM, Maher MT, Weir JP, Wecht JM, Carmel JB, Wu YK, Harel NY. Posteroanterior Cervical Transcutaneous Spinal Cord Stimulation: Interactions with Cortical and Peripheral Nerve Stimulation. J Clin Med. 2021 Nov 15;10(22):5304. doi: 10.3390/jcm10225304.