NIBS Therapy in Subacute Spinal Cord Injury

The objective of this proposal is to begin translating findings from pre-clinical studies to human motor deficits following cervical SCI (cervSCI). This HF-rTMS treatment protocol has not been previously assessed in human SCI and is qualitatively different from rTMS protocols reported to transiently modulate excitability of existing pathways, previously demonstrated in the literature. The protocol involves a daily stimulation of \~10 mins bilateral HF-rTMS for 2 weeks. SCI participants will be studied in a United States inpatient setting for this phase I study.

Given the findings in the pre-clinical model of robust axonal sprouting and functional synapse formation close to the damaged tissue using the above stimulation parameters, the transcranial magnetic stimulation treatment will target the hand-forearm region of the primary motor cortex, bilaterally. The aim is to include the cortical representation of affected muscles adjacent to the neurological level of injury. This zone often contains a mix of clinically and neurophysiologically intact, weakly innervated and denervated corticospinal pathways. Under standard sub-acute rehabilitation care, recovery of up to 1 neurological level of injury (NLI) is often the case, but improvement of 2 or more levels is far less common (<30% of patients). To examine the feasibility and safety of this novel intervention is the principal aim of the study. The associated potential clinical and neurophysiological changes will also be evaluated. These preliminary data will be used to power a subsequent efficacy trial to test the hypothesis that rTMS induced corticospinal augmentation will result in greater than typical extension of the NLI in human SCI, assessed up to the stable recovery phase at 6 months post-injury.

• Active rTMS (Device), also known as active repetitive transcranial magnetic stimulation: The stimulation protocol will comprise 15Hz pulse trains, each 50 pulses, repeated 10x, with a 60s inter-train interval. Stimulation intensity will be determined from individual MRI-modeled e-field, to achieve approximately motor threshold in the target area.
• sham rTMS (Device), also known as sham repetitive transcranial magnetic stimulation: The stimulation protocol will comprise 15Hz pulse trains, each 50 pulses, repeated 10x, with a 60s inter-train interval. Stimulation intensity will be close to zero (negligible) since sham coil will be used for the intervention

Primary outcomes

• Eligibility - (Percentage candidates eligible of screened patients) [21 months (Recruitment period)]: The proportion of patients who can take part in the study, whether they later agree to or not.
• Recruitment - (Percentage candidates enrolled of approached patients) [21 months (Recruitment period)]: The proportion of eligible patients who agree to take part in the study.
• Adherence to intervention - (Percentage candidates who dropout during the intervention period of enrolled candidates) [2 years (Duration of human subjects' involvement)]: Proportion of intervention-related dropouts.
• Adherence to outcome assessment - (Percentage candidates who do not complete outcome assessments of enrolled candidates) [2 years (Duration of human subjects' involvement)]: Proportion of patients that complete the assessments at the start and the end of the intervention.
• Retention - (Percentage candidates who do not complete 6-month follow up of enrolled candidates) [2 years (Duration of human subjects' involvement)]: The number of patients who drop out or were 'lost' at the 6-month follow-up.
• Adverse Events [2 years (Duration of human subjects' involvement)]: Rate of adverse and serious adverse events

Secondary outcomes

• Motor neurological level change (ISNCSCI assessment) [Baseline and 6 months after injury]: Proportion of patients with Improvement of 2 or more motor zone of partial preservation levels from baseline to 6 months after injury.
• Incidence of reconnectivity (Proportion: MEP absent, covert to MEP present) [Baseline and 6 months after injury]: The proportion of re-connectivity will be estimated by treatment group.
• Change in motor threshold between groups (Difference in %Maximum Stimulator Output to achieve motor threshold) [Baseline and 6 months after injury]: Change in motor threshold of key muscles will be estimated bilaterally within each group and a comparison of the change between groups.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

1. Post traumatic or non-traumatic cervical spinal cord injury (SCI) with residual upper-extremity paralysis
2. Time post-injury less than six weeks
3. Neurological Level of Injury (NLI) C4-C6
4. ASIA Impairment Scale (AIS) A-D
5. Sensory and motor zone of partial preservation (ZPP, clinically complete or incomplete)
6. Age 18 to 80 years old

Exclusion Criteria:

1. Ventilator dependence;
2. Concurrent neurological condition affecting sensory or motor pathways or otherwise limiting ability to participate in the study;
3. Evidence of trauma-related brain injury;
4. Contraindications for TMS or history of seizure or seizure risk;
5. Spinal instability;
6. Uncontrolled autonomic dysreflexia;
7. Severe muscular or skeletal or neuropathic pain;
8. Known or suspected pregnancy;
9. Medically unstable or any reason the physician may deem as inappropriate for the participant to enroll or continue in the study.

• Dylan J Edwards, PhD, Principal investigator, Albert Einstein Healthcare Network