Spinal Cord Injuries and Disorders (SCI/D)
Conditions
Keywords
Spinal cord injury, Transcutaneous Spinal Cord Stimulation, Cerebellar Theta Burst Stimulation, Arm and Hand Function, Upper Limb Motor Control, Transcranial Magnetic Stimulation, Neuroimaging, Neurophysiology
Brief summary
Cervical spinal cord injury (SCI) disrupts communication between the brain and spinal circuits, affecting voluntary movement control and contributing to arm and hand impairments, the top recovery priority for people with tetraplegia. Although rehabilitation and emerging neuromodulation approaches can support meaningful gains, many individuals experience persistent limitations in reaching and grasping. Current noninvasive stimulation strategies typically target the brain OR the spinal cord alone, despite strong reciprocal interactions between these structures. Cervical transcutaneous spinal cord stimulation (tSCS) can enhance upper limb function. Cerebellar stimulation, given its key role in sensorimotor integration and modulation of corticospinal excitability, represents a promising but underexplored therapeutic target. Theta burst stimulation (TBS), a rapid form of repetitive transcranial magnetic stimulation (TMS), induces lasting changes in cortical excitability and may promote associative plasticity when paired with spinal cord stimulation. This double-blind, randomized, sham-controlled pilot trial (n=24) will evaluate the feasibility, preliminary efficacy, and mechanisms of combined cerebellar TBS + cervical tSCS in people with chronic cervical SCI (AIS B, C or D). Participants will either receive cerebellar TBS + cervical tSCS, tSCS only, or sham stimulation while engaging in functional task practice such as pinching and grasping 3x/week for 8 weeks. Feasibility outcomes include adherence, retention, and safety. Efficacy will be assessed using the GRASSP strength sub-score and KINARM-based measures of sensorimotor control. Mechanistic outcomes will assess changes in cortical and spinal cord functional connectivity using resting state fMRI, corticospinal excitability using motor evoked potentials, and spinal excitability using the H reflex. Findings will establish whether combined cerebellar TBS and cervical tSCS is feasible, safe, and capable of enhancing upper limb recovery.
Interventions
DEVICECerebellar theta burst stimulation
Theta burst stimulation (TBS) is a pattern of repetitive transcranial magnetic stimulation that will be delivered over the lateral hemisphere of the cerebellum. Sham TBS will be delivered using a sham coil over the cerebellum.
Non-invasive electrical stimulation at 30Hz will be delivered through 2 round electrodes placed over the cervical vertebrae to target the cervical spinal cord. Sham cervical tSCS will involve briefly increasing stimulation intensity to the sensory threshold, followed by reducing the intensity to zero for the remainder of the session
BEHAVIORALFunctional task practice
All participants will complete 60-minute sessions of functional task practice three times per week for eight weeks, delivered concurrently with either real or sham stimulation. Following functional task practice guidelines, training will consist of repetitive, goal-directed upper-limb activities designed to promote functional independence in everyday tasks.
Sponsors
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. At least 19 years of age and no older than 75 years at the time of enrollment. Previous research has demonstrated the safety and efficacy of stimulation-based interventions in adults up to 75 years of age. The lower age limit reflects the legal age for independent informed consent in British Columbia.7,8 2. Non-progressive cervical SCI from C2-C8 inclusive 3. AIS classification B, C or D 4. Indicated for upper extremity training procedures by the participant's treating physician, occupational therapist, or physical therapist 5. GRASSP-Prehension score ≥10 or GRASSP-Strength score ≥30 6. Minimum 12 months after injury (i.e., chronic SCI) 7. If prescribed anti-spasticity or pain medications, must be at a stable dose for at least 4 weeks before commencing study procedures 8. Stable management of spinal cord related clinical issues (e.g., spasticity management, autonomic dysreflexia) 9. Capable of providing informed consent
Exclusion criteria
1. Has any unstable or significant medical condition that is likely to interfere with study procedures or likely to confound study endpoint evaluations, such as severe neuropathic pain, depression, mood disorders or other cognitive disorders 2. Has been diagnosed with autonomic dysreflexia that is severe, unstable and uncontrolled 3. History of additional neurologic disease, such as stroke, multiple sclerosis and traumatic brain injury 4. History of seizures (e.g. epilepsy). 5. Any implanted metal (other than dental implants) in the skull or presence of pacemakers, stimulators, or medication pumps in the trunk. 6. Participant has undergone electrode implantation surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility outcomes | From enrollment to the end of stimulation at 8 weeks | 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 | Baseline and after 8 weeks of stimulation | 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 | Baseline and after 8 weeks of stimulation | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arm and hand sensorimotor control | Baseline and after 8 weeks of stimulation | 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]): | Baseline and after 8 weeks of stimulation | 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) | Baseline and after 8 weeks of stimulation | 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): | Baseline and after 8 weeks of stimulation | 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. |
Countries
Canada
Contacts
CONTACTRaza Malik, PhD
Outcome results
None listed