Using Non-invasive Brain and Spinal Cord Stimulation to Improve Arm and Hand Function After Spinal Cord Injury

Feasibility outcomes

Feasibility, which will be assessed through adherence, recruitment, retention, and adverse event rates across all groups. We will specifically document session numbers, dates and times, as well as the frequency and severity of skin irritations, abnormal blood pressure responses (e.g., autonomic dysreflexia), cardiac responses (e.g., tachycardia, bradycardia) and any symptoms. Participant safety will be monitored throughout the intervention via regular skin integrity checks and cardiovascular recordings (blood pressure and heart rate) throughout each session.

Upper limb strength

Change in upper limb strength from pre- to post-intervention using the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) strength sub-score. The GRASSP evaluates three domains: strength manual muscle testing of key upper limb muscles), sensibility (light touch and pinprick discrimination), and prehension, which includes both a qualitative analysis of grasp patterns and a performance-based component (GRASSP-Prehension Performance) that assesses functional use of the hand during object manipulation tasks. Strength will be the primary dependent measure from this measure.

Sensorimotor network connectivity

Change in functional connectivity strength of the cortical sensorimotor network from pre- to post- intervention using resting-state functional MRI (fMRI). We will use a Philips Ingenia Elition 3.0T MRI scanner with a 32-channel sensitivity head coil to scan brain and a separate 20 channel dStream head/neck coil for cervical spinal cord. We will collect T1 and resting state functional MRI scans of both brain and cervical spinal cord at baseline and post-intervention. Resting state functional MRI will be acquired to characterize functional reorganization of the brain and/or spinal cord driven by cerebellar TBS + cervical tSCS (or tSCS alone) alongside functional task practice. Brain and spinal cord functional connectivity: We will characterize properties of the sensorimotor network, particularly global efficiency, which represents the overall capacity that the network has to transfer information (i.e., quantifies the extent to which nodes of the network are integrated).

Arm and hand sensorimotor control

Arm and hand sensorimotor control will be indexed using Kinarm standard tests. Specifically, by the task score and path: length ratio during a four target visually guided reaching task using the Kinarm End-Point Lab (BKIN Technologies Ltd., Kingston, ON, Canada). These metrics take into account the spatial and temporal components of reaching, providing nuanced information regarding motor control strategies. We will also characterize proprioceptive sense by using an arm position matching task on the Kinarm and quantifying absolute matching error.

Corticospinal excitability (Motor Evoked Potentials [MEPs]):

To characterize cortical excitability, we will index resting motor threshold for corticospinal tracts. We will use single-pulse TMS delivered using a figure-of-eight coil connected to the Magstim SuperRapid2 Plus-1 stimulator (Magstim Rapid II System , Magstim Company Ltd., GB, Class II License No 69773). MEPs will be recorded from the first dorsal interosseous (FDI) muscle (Bagnoli™, Delsys Inc., Natick, USA). The motor hotspot, which is the region where a single-pulse stimulation elicits the largest and most consistent MEP in the most-affected hand, will be identified and recorded. A neuronavigation system, will be used to ensure the consistent targeting of the hotspot across sessions. Resting motor threshold is the stimulator output that elicits an MEP \>50μV in 5 of 10 trials at rest. We will quantify MEP amplitudes and latencies to evaluate corticospinal excitability.

Cerebellar-brain inhibition (CBI)

Cerebellar influences on motor evoked potentials can be assessed using a dual TMS coil approach. CBI will be elicited by applying a conditioning pulse (CS) over the lateral cerebellum (midpoint between the inion and the mastoid targets the lateral cerebellum)16 using a double-cone coil before a test stimulus (TS) over the contralateral motor cortex using a figure-of-eight coil (Magstim Rapid II System , Magstim Company Ltd., GB, Class II License No 69773). The interstimulus interval between CS and TS will be 5ms-7ms to maximize the inhibitory effect. TS intensity will be set to the minimum intensity that elicits MEPs with an average peak-to-peak amplitude of 0.5-1 mV. CS intensity will be set to 100% RMT, with a maximum intensity cut-off at 80% maximum stimulator output (MSO) to avoid discomfort. Ten conditioned and 15 unconditioned MEPs will be collected. The amplitude of the conditioning MEPs will be expressed as a ratio of the mean unconditioned stimuli.

Spinal reflex excitability (H-reflex):

H-reflex testing will be conducted by obtaining surface EMG responses (Bagnoli™, Delsys Inc., Natick, USA, not a medical device \[research purposes only\]) from the upper limb muscles (e.g., extensor/flexor carpi radialis, FDI) in response to median/radial nerve stimulation (Bio-logic aep system - stimulator, facial digitimer ds7a, natus medical incorporated dba excel-tech ltd (xltek), Oakville, Canada, Class II License No 85645). To generate a H-Reflex recruitment curve (input-output curve), square-wave pulses will be delivered starting at sub-threshold intensities for eliciting an H-reflex. Stimulations of progressively higher intensity will be delivered until a plateau in the peak-to-peak amplitude of the M-Wave is observed. We will calculate Hmax/Mmax ratio to index the percentage of the motoneuron pool that is activated.

Neurological function and injury severity

Neurological evaluations of participants with SCI will be performed using the ISNCSCI exam. The level and severity of damage to motor and sensory pathways will be determined by a trained team member using the standard ISNCSCI examination (2019 revision). In brief, this examination includes the assessment of motor function of key muscles in the upper and lower extremities using an established scale (muscle power graded as 0-5; for a total of 20 muscles in the four limbs) and sensory evaluation to light touch and pin prick in 28 dermatomes of the body. Sensory scores for each dermatome are assigned as 0=absent, 1=abnormal, and 2=normal. With this coding system, participants who perceive a pinprick as minimally sharp touch are assigned the same score as those who perceive it as almost normal. Perception of light touch stimuli is graded similarly.

Short-form (36) Health Survey (SF-36):

The SF-36 is the most commonly used generic measure of QoL. The SF-36 consists of 8 domains pertaining to the respondents' experiences in the last 4 weeks. Each of the 8 summed scores is linearly transformed onto a scale from 0 (negative health) to 100 (positive health) to provide a score for each subscale. The SF-36 is widely used to measure QOL in patients with SCI.

Autonomic Dysfunction following SCI (ADFSCI) questionnaire:

The ADFSCI assesses self-reported frequency and severity of autonomic related symptoms. The OH part of the questionnaire includes 8 items, each using a 5-point scale to score the frequency and severity of hypotensive symptoms, such as dizziness, nausea, confusion, etc., under different circumstances.