Spinal Cord Injuries (SCI)
Conditions
Keywords
transcutaneous spinal cord stimulation, intermittent theta burst stimulation, repetitive transcranial magnetic stimulation, cervical spinal cord injury, upper limb rehabilitation, neuromodulation, convergent neuromodulation, tetraplegia
Brief summary
This clinical trial investigates whether combining cortical and spinal neuromodulation can improve upper limb motor recovery in adults with chronic incomplete cervical spinal cord injury (SCI). Restoring upper limb function is the top rehabilitation priority for individuals with tetraplegia, yet effective interventions remain limited. The study combines transcutaneous spinal cord stimulation (tSCS), which enhances spinal circuit excitability, with intermittent theta burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation that increases cortical excitability and strengthens descending motor pathways. While each approach has shown independent promise, their combined use has not been evaluated in a controlled trial. Eligible participants are adults aged 21-65 with chronic (\>12 months post-injury) incomplete cervical SCI (ASIA Impairment Scale grade C or D, levels C2-C8). A total of 24 participants will be randomised 1:1 to either combined iTBS and tSCS plus standardised upper limb rehabilitation, or tSCS plus rehabilitation alone, across 24 sessions over 12 weeks. The primary outcome is change in Upper Extremity Motor Score from baseline to week 12. Secondary outcomes cover functional performance, independence, spasticity, corticospinal excitability, quality of life, and goal attainment. Assessments occur at baseline, post-intervention, and at 4- and 12-week follow-up. As a pilot randomised controlled trial, this study will generate the first controlled evidence on adjunctive cortical neuromodulation alongside tSCS-based rehabilitation, while also producing feasibility data to inform the design of a future definitive multicentre trial.
Detailed description
Background: Cervical spinal cord injury (SCI) results in severe upper limb impairment, with restoration of hand and arm function ranked as the highest rehabilitation priority by individuals with tetraplegia. Transcutaneous spinal cord stimulation (tSCS) has emerged as a promising approach for enhancing upper limb recovery. Intermittent theta burst stimulation (iTBS), an efficient form of repetitive transcranial magnetic stimulation, can enhance cortical excitability and descending motor drive. However, the benefit of combining these complementary neuromodulation modalities to simultaneously target supraspinal and spinal circuits has not been evaluated in a controlled trial. Objective: This study aims to evaluate the feasibility, safety, and preliminary efficacy of combined cortical neuromodulation (iTBS) and spinal neuromodulation (tSCS) versus tSCS alone, each paired with standardized upper limb rehabilitation, for improving upper limb motor function in chronic incomplete cervical SCI. Methods: This single-center, two-arm, assessor-blinded, pilot randomized controlled trial will enroll 24 adults aged 21 to 65 years with chronic (more than 12 months post-injury) incomplete cervical SCI (American Spinal Injury Association Impairment Scale grade C or D, neurological level C2 to C8). Participants will be randomized 1:1 to receive either iTBS combined with tSCS plus standardized upper limb rehabilitation or tSCS plus upper limb rehabilitation alone. Interventions will be delivered twice weekly for 12 weeks (24 sessions). The primary outcome is the change in Upper Extremity Motor Score from baseline to 12 weeks. Secondary outcomes include measures of upper limb function, independence, spasticity, corticospinal excitability, quality of life, and goal attainment. Assessments will be conducted at baseline, post-intervention, and at 4-week and 12-week follow-up. Conclusions: This pilot trial will provide the first controlled evidence on whether adjunctive cortical neuromodulation via iTBS produces additional upper limb motor recovery beyond tSCS-based rehabilitation in chronic incomplete cervical SCI. Feasibility data and effect size estimates will inform the design of a subsequent multicenter confirmatory trial.
Interventions
DEVICETranscranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that enhances cortical excitability and corticospinal drive. Intermittent theta burst stimulation (iTBS), a brief patterned form of rTMS, produces lasting facilitatory effects and is more time-efficient. Evidence indicates rTMS improves motor function, reduces spasticity, and enhances neuroplasticity in SCI.
DEVICETranscutaneous Spinal Cord Stimulation
Transcutaneous spinal cord stimulation (tSCS) is a non-invasive neuromodulation technique that delivers electrical stimulation over the spine to activate sensory afferents and enhance spinal motor circuit excitability. Early studies showed it can enable voluntary movement even in motor-complete spinal cord injury (SCI), with subsequent research demonstrating improvements in motor function, standing, and walking in incomplete SCI. Evidence suggests tSCS modulates both spinal and corticospinal pathways, supporting neuroplasticity. The Up-LIFT trial (2024) provided strong clinical evidence, showing that tSCS combined with rehabilitation significantly improved upper limb strength and function in chronic cervical SCI, with 72% of participants meeting effectiveness endpoints and no serious adverse events. Later studies confirmed its safety in home and community settings, though standardization and larger trials remain needed.
Sponsors
National University Hospital, Singapore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Single-center, two-arm, assessor-blinded, pilot randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Chronicity: More than 12 months post-injury at enrollment * Injury type: Traumatic or non-traumatic incomplete cervical SCI, neurological level C2 to C8 * AIS classification: Grade C or D * UEMS: 10 to 20 out of 25 on the more impaired side; lower bound 10 ensures sufficient voluntary activation for task training and elicitable MEPs, upper bound avoids ceiling effects. * Grip strength: MMT grade 3 or higher in finger flexors (C8 myotome) on at least one side. * Hand function: Able to transfer at least 1 block across the partition within 60 seconds on the more impaired side. * Sitting tolerance: Able to tolerate upright seated posture in own wheelchair for at least 1 continuous hour without symptomatic orthostatic hypotension or pressure-related discomfort requiring position change. * Medical stability: No acute medical complications * Informed consent: Able to provide written informed consent and comply with the study schedule * Medications: Stable regimen for 4 weeks prior, AND participant plus clinician agreement that dosage (baclofen, tizanidine, botulinum toxin) remains unchanged throughout the 12-week intervention; any change logged as protocol deviation * Surgical clearance: Cleared by neurosurgeon or orthopedic surgeon for participation in tSCS-based rehabilitation
Exclusion criteria
* Seizure history: History of seizures or epilepsy * Implanted devices: Intracranial metallic implants, cochlear implants, cardiac pacemakers, or other implanted electronic devices. Cervical spinal instrumentation (e.g., posterior rods, plates, or screws at C2 to T1) is not an exclusion for tSCS provided overlying skin is intact; participants with hardware directly beneath planned electrode sites will undergo low-intensity test stimulation during screening, and electrode placement will be shifted by one interspace if current distortion, focal discomfort, or unexpected motor thresholds are observed. Intracranial hardware remains an absolute exclusion for iTBS. * Prior craniotomy: Prior neurosurgical procedure involving craniotomy * Pregnancy: Currently pregnant or intending to become pregnant during the study period * Psychiatric or cognitive: Active psychiatric illness (eg, untreated major depression, psychosis) or cognitive impairment precluding informed consent * Concurrent neurological disease: Progressive or degenerative neurological condition (eg, multiple sclerosis, motor neuron disease) * Concurrent trials: Participation in another interventional rehabilitation or neurostimulation trial * Skin integrity: Skin lesions or breakdown at electrode placement sites (scalp or posterior cervical spine) * Cortical excitability medications: Medications known to alter cortical excitability (eg, antiepileptic drugs, high-dose benzodiazepines) that cannot be stabilized for at least 2 weeks prior to enrollment * Severe spasticity: Modified Tardieu Scale muscle reaction grade 4 (unfatigable clonus \>10 s) at elbow or wrist flexors on the more impaired side, or spasticity judged by the treating physician as unresponsive to optimised pharmacological management.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Upper Extremity Motor Score (UEMS) | Week 0 | The UEMS is a component of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) examination and assesses the strength of 10 key muscles of the upper extremities (5 per side) on a 0 to 5 scale, yielding a score of 0 to 25 per side or 0 to 50 bilaterally. The UEMS has well-established psychometric properties, is sensitive to change in SCI populations. Higher score indicates better outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Graded and Redefined Assessment of Strength, Sensibility, and Prehension Version 2 (GRASSP-2) | Week 0 | The GRASSP V2 is an assessment for tetraplegia, typically scored across 5 specific subtests rather than a single total sum. Key maximum scores for GRASSP V2 include 50 for Strength (10 muscles x 5), 12 for Dorsal Sensation, 12 for Palmar Sensation, and 30 for Prehension Performance. A higher score indicates better outcomes. |
| Grip/Pinch Strength | Week 0 | Maximal grip force (Jamar dynamometer), lateral pinch, tip pinch, and tripod pinch (pinch gauge) |
| Nine-Hole Peg Test | Week 0 | Timed fine motor dexterity assessment. The participant is instructed to pick up the pegs one by one and place them into the holes as fast as possible. Once all pegs are in the holes, the participant immediately removes them one by one and returns them to the container, as fast as possible. The primary score is the number of seconds taken to complete the task. Shorter times indicate better fine manual dexterity. |
| Box and Block Test | Week 0 | Gross manual dexterity (number of blocks transferred in 60 seconds) |
| Capabilities of Upper Extremity Test (CUE-T) | Week 0 | CUE-T is a standardized, performance-based assessment tool designed specifically to measure functional limitations in the arms and hands of individuals with tetraplegia due to SCI. It objectively evaluates how well a person can perform basic and instrumental ADLs, such as reaching, grasping, and manipulating objects. Higher score indicates better outcome. |
| Spinal Cord Independence Measure III (SCIM-III) | Week 0 | It measures independence in daily activities across three main domains-Self-Care, Respiration/Sphincter Management, and Mobility-with a total score ranging from 0 to 100. Higher score indicates better outcome. |
| R2-R1 in Modified Tardieu Scale | Week 0 | Modified Tardieu Scale measures velocity-dependent spasticity of elbow and wrist flexors/extensors. R1 (Angle of Catch) is measured during the fast (V3) stretch, indicating when the spastic reflex is triggered. R2 (Full Range of Motion) is measured during the slow (V1) stretch, indicating the maximum joint angle. A lower R2-R1 value is better (indicating less spasticity and more normal muscle behaviour). |
| Central Motor Conduction Time (CMCT) | Week 0 | It evaluates the integrity of the corticospinal tract by subtracting peripheral motor conduction time from the total Motor Evoked Potential (MEP). As per IFCN guidelines: CMCT = MEP latency minus PCT, where PCT = (F-latency + M-latency minus 1) / 2. A shorter CMCT indicates better outcome. |
| peak-to-peak amplitude of motor evoked potential (MEP) | Week 0 | Measured by transcranial magnetic stimulation (TMS). Amplitude, latency, resting and active motor thresholds from FDI and APB will be recorded. The bigger value of peak-to peak amplitude of MEP indicates better outcome |
| EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) | Week 0 | The EQ-5D-5L is a standardized, self-reported questionnaire used to measure health-related quality of life (HRQoL) across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension scores from 1 to5, with higher score indicating worse outcome. |
| Modified goal attainment scale (GAS) | Week 0 | Patient-identified goals scored on a standardized attainment scale. Generally, a higher score indicates a better outcome. |
Countries
Singapore
Contacts
CONTACTGobinathan Chandran, MBBS
CONTACTTang Ning, PhD
PRINCIPAL_INVESTIGATORGobinathan Chandran, MBBS
NUH
Outcome results
None listed