Upper Limb Rehabilitation Using Non-invasive Spinal Cord Stimulation

This RCT study is led by Dorothy Barthélemy (Ph.D, pht, Principal Investigator (PI)), Marika Demers (Ph.D, erg., co-PI), Diana Zidarov (Ph.D, co-PI) and Sujata Sinha (PhD, postdoctoral fellow, project lead). Collaborator includes Victoria Duda (PhD).

Population: individuals with SCI with injury level between C5 and T2, falling into American Spinal Injury Association (ASIA) categories A to D, in the sub-acute phase, and of minimum age of 16 years. These participants are in-patients admitted in the Institut de réadaptation Gingras-Lindsay de Montréal, Canada.

Participants will be randomized (1:1 ratio) into two equal groups, ABT + tSCS and ABT + sham stimulation and stratified based on ASIA level, age and sex.

During the training session, the ABT + tSCS group will receive ABT combined with tSCS. The tSCS will be delivered using surface electrode placed between C4 and T1 as a cathode and self-adhesive surface electrodes placed in the clavicular region on both sides as anodes. tSCS will deliver tonic pulses (30 - 100 Hz) and at an intensity that facilitates voluntary movements (usually 15 mA and up), determined prior to the first training session. Each ABT session will include 5 parts:

1. 'Motor control strengthening: equipped with an electronic goniometer, participants control muscle contraction of one joint by following a pattern on a computer screen. 2. Cardiovascular warm-up exercises: using equipment that will allow the participant to train their cardiovascular system. 3. Weight bearing and stretching exercises: exercises to prepare their upper body muscles for the strengthening exercises. 4. Muscle strengthening exercises: exercises to increase their strength, with adapted equipment if necessary. 5. Activity-based exercises: exercises composed of repetitive that are present in the participant's daily life.

In the ABT+ sham stimulation group, intensity will be set at sensory threshold that will not facilitate any movement (usually 2-3mA). The ABT will be similar to the other group.

Prior to the training, clinical tests will be conducted to assess assess their muscle strength, sensations, and the quality of movements participants can make with their arms. Specifically, the primary measure will consist of the Upper Extremity Motor Score from the with American Spinal Injury Association Impairment Exam. The secondary clinical measures will include the following assessments: the Prehension subtest of the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP-version 2) , Monofilaments test, Sensory function of the upper limb dermatomes from C4 to T1, Grip and pinch strength with a dynamometer, Proprioception subtest of the Fugl Meyer Assessment, the finger-to-nose test and the Tetraplegic Upper Limb Activity Questionnaire (TUAQ). More details of the measures are in the Outcome Measures section.

For neurophysiological measures, electrophysiological assessments will include transspinal evoked potential (TEP), motor evoked potentials (MEPs) using transcranial magnetic stimulation (TMS) and somatosensory evoked potentials (SSEPs) using electroencephalogram (EEG).

These assessments will be conducted before the training, immediately after the training and one month later.

As for the experiment, 40 participants will be recruited, as determined by a priori power analysis.

For the neuroplasticity evaluation, TEP, TMS and EEG will be used.

1. To assess the excitability of spinal pathways, the non-invasive procedure of single-pulse transcutaneous spinal stimulation (tSCS) will be used. Participants will be comfortably seated in a chair or in their wheelchair. Self-adhesive surface electrodes will be placed over the cervical spine, with the cathode (Dura stick plus double wire, Dura stick, USA) over C4-T1 and anodes over the external part of the clavicles (TENS electrodes, ROHVEMJ). Single-pulse tSCS will be delivered using a constant-current stimulator (DS8R, Digitimer, UK) to induce Transspinal evoked potentials (TEPs). Responses will be recorded from surface electromyography. More details of the measurement are in the Outcome Measures section. 2. To assess changes along the corticospinal tract (motor cortex projections to the spinal cord), a magnetic field using the TMS will be applied to the primary motor cortex (M1) over the representation area of the contralateral bicep brachii muscle (this is the target muscle). This response will be recorded painlessly using surface electromyography (EMG) electrodes placed over the targeted muscle. The entire evaluation, including setup, will take approximately one hour. The responses evoked by TMS, that is, the motor evoked potentials, (MEPs) will be compared across the 3 time frames in each group. Particularly, latency and peak-to-peak amplitude of MEPs will be measured. More details of the measurement are in the Outcome Measures section. Participants with specific contraindications to TMS (epilepsy, non-union cranial fracture and increased intracranial pressure) will be able to participate in the study, but will not take part in the TMS assessment..

2\. To assess changes in brain mechanisms, particularly those related to sensory function, EEG recordings will be performed using Brain Vision's 32-electrode cap, with the Fz electrode used as the reference. Recordings will be obtained using a Brain Vision 32-channel EEG cap referenced to Fz. The median nerve of the upper limb (at the wrist site) will be electrically stimulated to elicit cortical responses. The entire evaluation duration will be for 90 minutes including the setup.

EEG activity from C3 and C4 corresponding to the contralateral sensorimotor cortex, will be analyzed, focusing on the N20 and P25 somatosensory evoked potential (SSEP) components, which occur approximately 20 ms and 25 ms post-stimulus, respectively. The N20-P25 complex reflects transmission through ascending somatosensory pathways.

N20 refers to the negative-deflecting SSEP peaking approximately 20 ms after the onset of electrical stimulation at the median nerve. P25 follows the N20, deflecting in a positive direction peaking around 25 ms after stimulus onset. Together, these form the N20-P25 complex, which reflects the transmission along ascending neuronal pathways. In addition to these two SSEPs that occur in the early time-window, P50 and the N70 SSEPs that peak approximately around 50ms and 70 ms , respectively, after the stimulus onset. The amplitude and latency of the SSEPs will be compared across the 3 time frames in each group. In addition to C3 and C4, the neighboring electrode regions will also be inspected to identify any additional SSEPs that may emerge. More details of the measurement are in the Outcome Measures section.

• The Prehension subtest of the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP- version 2) [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Upper-limb sensory score of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Monofilament test [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Force (Grip and Pinch Strength) test [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Proprioception [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Coordination test [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Transspinal evoked potentials (TEPs) [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Transcranial magnetic stimulation (TMS)- motor evoked potentials [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]
• Electrophysiology (EEG)-Somatosensory evoked potentials (SSEPs) [Срок оценки: 3 time points: Pre-intervention (Day 0, prior to the first training session), Post-intervention (+/-1 week) and one-month post-intervention (+/- 1 week).]