Spinal cord injury (SCI) is a neurological condition that causes progressive neurodegeneration. The major symptoms of SCI are paralysis, paresthesia, pain, spasticity, bladder, bowel, and sexual dysfunction. It largely affects the young population (21-49 years); thus, the psychological impact on a healthy individual to adapt to a paraplegic or quadriplegic condition in their early life is devastating. SCI causes damage to neurons, nerves, and other surrounding cells that send and receive signals from different body parts to the brain via the spinal cord (SC) and vice versa [1]. SCI can be traumatic or nontraumatic. Traumatic SCI is a great challenge for therapeutic management considering its high morbidity. There is complete or incomplete loss of locomotor, sensory, and autonomic functions depending on the severity and level of the lesion [2]. The consequences of injury are not just a break in communication between neurons, but a cascade of events that sets up a vicious cycle and leads to widespread neuronal degeneration, cell death, and the formation of glial scars [3]. Cellular components such as proteins, phospholipids, neurotransmitters, and metabolites derived from SC neurons and glial cells diffuse from the injury site into the cerebrospinal fluid and blood [4]. These biomarkers could serve as good diagnostic markers to predict the severity of the injury. To regain functional connectivity, and attenuate gliosis and secondary injury, activity-dependent strategies have been proposed to be quite effective. The current treatment modalities for SCI include surgery, pain management, and rehabilitation. However, functional recovery by restoring connections of the corticospinal tract after a complete SCI is challenging.

High-frequency repetitive transcranial magnetic stimulation (rTMS) has decreased neuropathic pain and spasticity in incomplete SC–injured patients [5,6]. A newer form of patterned transcranial magnetic stimulation (TMS), intermittent theta burst stimulation (iTBS) is now being studied for the improvement of symptoms in incomplete SCI [7]. There is very limited literature available, showing the effect of either cortical iTBS or trans-spinal TMS in combination with a rehabilitation program to promote repair, regeneration, and recovery in patients with complete SCI (cSCI). This study aims to determine the functional outcomes of administering iTBS at the cortex as well as at SC along with intensive rehabilitation programs in patients with cSCI.

This study aims to evaluate the comparative efficacy of iTBS and rTMS in promoting motor function recovery in individuals with cSCI. In addition, it seeks to identify the most effective stimulation site—motor cortex, SC, or a combined approach—for optimizing therapeutic outcomes. The study will further assess the impact of these TMS protocols along with customized rehabilitation programs on sensory and locomotor function, cortical excitability and neuroplasticity, SCI-related biomarkers, and self-reported outcomes, including pain, anxiety, depression, and overall quality of life.

A double-blinded, prospective, randomized, placebo-controlled study will be conducted. The computer-generated sequence will be sealed in sequentially numbered envelopes, which will be opened after the patient is enrolled in the study. Both the patient and investigator will be blinded to the intervention. An experienced therapist will perform the intervention protocol. This protocol is based on the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (checklist provided in Multimedia Appendix 1).

The recruitment, intervention, and follow-up phase will be 2 years, followed by 6 months of data analysis. Patient recruitment will start in January 2023 and the trial will be completed by July 2025.

Adults aged 18 to 60 years with a thoracolumbar (T1-L5) SCI and complete motor loss below the lesion level (American Spinal Injury Association [ASIA] score A) will be screened and recruited within 1 month of injury.

Exclusion criteria include patients with osteoporotic fractures, a history of neurological or orthopedic diseases affecting the SC, head injuries, ferromagnetic metallic implants near the target stimulation area, pacemakers, cognitive impairment, pregnancy, a history of seizures, or acute eczema or bedsores.

The personal privacy of patients will be protected. The results of this study will not disclose any identifying and personal information of the patient without his or her permission.

The sample size for this study is determined based on the methodology outlined by Roy et al [8], which assessed the reduction in motor evoked potential (MEP) amplitude following intervention. Using an α level of 0.05 and a power of 90%, these parameters are incorporated into the 2-tailed formula for sample size calculation.

For a 2-sample comparison of means, the null hypothesis (H0: m1=m2) will tested, where m1 and m2 represent the means of 2 distinct populations. The assumptions for the calculation are as follows:

Based on these assumptions, the estimated required sample size is calculated to be 6 subjects per group. To account for potential dropouts, a 20% adjustment is applied, resulting in a revised sample size of 8 participants per group. Consequently, the total minimum sample size required for the study is 40 participants.

A total of 40 patients will be randomized into 5 groups using computer-generated random numbers. Patients will be categorized into placebo, rTMS, and iTBS to evaluate the efficacy of iTBS versus traditional rTMS on the primary motor cortex (MC). To determine the optimal site for iTBS application, stimulation was given at either MC or SC or combined MC+SC.

Group classification based on the mode of stimulation is listed as follows:

Group classification based on the site of stimulation is listed as follows:

This trial’s conduct and report will follow the CONSORT (Consolidated Standards of Reporting Trials) statement for randomized trials (Figure 1).

Participants will be enrolled from the Jai Prakash Narayan Apex Trauma Centre at AIIMS (All India Institute Of Medical Sciences) Delhi. Following SCI surgery, a 15-day period will be designated for vertebral stabilization, after which sutures will be removed on the 15th day. Once the sutures are removed, baseline parameters will be measured. Patients will then be randomly assigned to one of the intervention groups. After completing the intervention, postintervention parameters will be recorded and follow-up assessments will be conducted at 1, 2, and 3 months (Figure 2). To ensure consistency during the intervention, all assessments will be recorded by the blinded primary investigator.

During the intervention phase, patients will be randomly allocated to one of the interventional groups. The rTMS or iTBS will be administered using the Neurosoft - Neuro-MS 5 device (Neurosoft Ltd), a commercially available transcranial magnetic stimulator. The device will be equipped with both an angulated figure 8–shaped coil and a circular coil for stimulation. The intervention (rTMS or iTBS) will be applied to the lower-limb motor area located in M1 (to stimulate both lower limbs), with the handle of the coil aligned parallel to the interhemispheric midline (pointing occipitally) based on the vertex position according to the International 10-20 EEG system. For SC stimulation, the circular coil will be positioned over the injury site. In the placebo stimulation group, a sham coil (not generating a magnetic field but producing similar click sounds) will be used and the stimulation protocol remains akin to the iTBS group.

The standard protocol for iTBS will be used: 3-pulse bursts at 50 Hz, repeated at 5 Hz, with a 2-second train repeated every 10 seconds for 20 repetitions, amounting to a total of 600 pulses [7]. The rTMS protocol will consist of 1600 pulses at a frequency of 20 Hz, with a 2-second train repeated every 30 seconds for 20 minutes [9]. A resting motor threshold (RMT) of 90% will be used for both rTMS and iTBS stimulation intensity. RMT will be determined by recording MEP from the abductor pollicis brevis (APB). RMT will be recorded by placing figure-eight coils over the motor hotspots of the APB. The minimum stimulus intensity that causes an MEP with a peak-to-peak amplitude of at least 50 µV in at least 50% of consecutive stimuli will be considered as RMT. Interventions will be administered for 5 consecutive days, twice daily, with a total of 10 sessions [10].

All the participants will be required to fill out a TMS safety questionnaire both before and after the intervention. Briefly, the preintervention questionnaire takes care of any implants, past history of seizures, pregnancy, or head trauma, whereas the postintervention questionnaire reports any adverse effects observed by patients like headache, nausea, ear discomfort, or any seizure. Besides these, the participants will also undergo thorough screening for contraindications, continuous monitoring during and after stimulation, and adherence to standardized emergency protocols as approved by the institutional review board. If a patient experiences an adverse event during the trial, the principal investigator will provide treatment and corresponding financial compensation. Patients who are enrolled in the placebo group will also receive the conventional rehabilitation program during the study.

SCI significantly impairs the corticospinal integrity and afferent-efferent input-output circuitry. Theoretically, the pyramidal tract is the primary neural pathway that links the cortex and SC to facilitate the movement of distal extremities. The primary purpose of any treatment is to reconstruct the neural circuit immediately after SCI for functional sensory-motor recovery. To facilitate neural circuit reconstruction, it is required to stimulate nerve cell sprouting and regeneration as well as increase the strength of the existing neuronal connections. Previous research demonstrated that individuals with incomplete SCI can benefit from locomotor training to enhance their motor skills. Rehabilitation programs may use learning and relearning mechanisms, uncovering a previously inactive synapse, and forming a new synapse [24]. However, the reconstruction of the damaged neural circuit is quite difficult with locomotor training alone. Studies have shown that the functional effects of exercise along with transcranial magnetic stimulation, can activate spared neural pathways and enhance the possibility of neural reconstruction [25,26].

TMS induces electrical currents in underlying cortical areas, depolarizes neurons, and generates an action potential that modulates the activity of spinal motor neurons and target muscles via the corticospinal tract. Repetitive transcranial magnetic stimulation as well as iTBS is an intervention in various psychiatric and pain conditions. In SCI, few studies suggest improvement in locomotor function, spasticity, and pain in incomplete patients [6]. Although, the functional mechanism of rTMS or iTBS on sensorimotor recovery in patients with SCI is not fully understood, but thought to induce synaptic plasticity via LTP or LTD-like effects [27], thereby promoting functional recovery in patients with SCI.

In addition, SC stimulation can modulate the activity of the local central pattern motor generators, which promotes synaptic strengthening [28]. In rat models of complete and incomplete SCI, a significant attenuation of glial scaring, lesion volume, neurotransmitter imbalance, muscle atrophy, and facilitation of neuronal survival, axonal regeneration, and myogenesis has been shown following whole-body magnetic field exposure [29,30]. Therefore, we propose that SC stimulation along with motor cortical stimulation would attenuate secondary damage and promote regeneration even in patients with cSCI, leading to long-term functional recovery.

Various single- and paired-pulse paradigms of TMS have been used for the assessment of cortical excitability, plasticity, integrity of the corticospinal tract, and excitatory-inhibitory neural circuitry of the motor cortex. We shall use all paired-pulse paradigms (short-interval intracortical inhibition, intracortical facilitation, and long-interval intracortical inhibition) to objectively assess excitatory-inhibitory neural circuitry and single-pulse paradigms (RMT, MEP, recruitment curves, and contralateral silent period) for unraveling the excitability of corticospinal circuitry and motor units.

While this study offers valuable insights, several limitations must be acknowledged that may affect the interpretation and broader application of the findings. First, the sample size is relatively small, which could reduce the statistical power and may not fully represent the broader population of individuals with SCIs. Second, variability in the severity of SC injuries among participants may influence the outcomes, as responses to treatment could differ based on the level and completeness of the injury. Finally, the short duration of the follow-up period may not adequately capture the long-term effects of the interventions, suggesting the need for longer-term studies to assess the sustainability of the benefits observed.

An intensive individualized rehabilitation regime coupled with iTBS could be a holistic management strategy that can restore locomotor function and quality of life in patients with cSCI. TMS is also a promising tool to evaluate the cortical plasticity and excitability in SCI and thereby understand the mechanism of action of the proposed intervention and characterize the effective connectivity of neural circuits and mechanisms regulating the balance between inhibition and facilitation within the corticospinal pathway.