rTMS Dosing for Depression Post-Spinal Cord Injury

Overseen By Catherine J VanDerwerker, PhD DPT PT

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Must not be taking: Antidepressants, Anti-seizure, others

Disqualifiers: Neurologic diseases, Dementia, Psychosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 32

Duration: 6 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

Depression is a leading cause of disability worldwide and is more commonly seen in individual's post-spinal cord injury (SCI) than in the general population. Depression post-SCI impacts an individuals' quality of life and recovery. It has been reported that among Veterans with an SCI, those without depression live longer than those with depression. Thus, depression must be treated appropriately. Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, but dosing is based on a motor response or movement in the thumb. Over half of individuals with SCI have some degree of arm or hand impairment, so these individuals might not be eligible for rTMS, or they may receive the wrong dose. This study proposes clinical trial in individuals with depression post-SCI to assess the anti-depressant effect of a novel technique to dose rTMS that does not require a motor response in the thumb. By gaining a better understanding of the application of rTMS for depression post-SCI, the investigators aim to advance the rehabilitative care of Veterans.

Will I have to stop taking my current medications?

The trial requires that you are not taking antidepressant medications or that there has been no change in doses of psychotropic medications for at least 4 weeks before the study (6 weeks if you started a new medication).

What data supports the effectiveness of the treatment rTMS for depression post-spinal cord injury?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can help improve motor function, reduce spasticity, and modulate nerve pathways in people with spinal cord injuries. While these studies focus on motor recovery, they suggest that rTMS may have potential benefits for other conditions like depression by influencing brain activity. ^{1 2 3 4 5}

Is rTMS safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) has been used in various studies for conditions like spinal cord injury, and while it shows potential benefits, the safety data is limited. More research is needed to fully understand its safety profile, but it is generally considered non-invasive and has been used in humans without major safety concerns reported. ^{1 3 5 6 7}

How is rTMS treatment for depression after spinal cord injury different from other treatments?

rTMS (repetitive transcranial magnetic stimulation) is unique because it uses magnetic fields to stimulate specific areas of the brain, which can help improve depression symptoms without the need for medication. Unlike traditional drug treatments, rTMS is non-invasive and has been shown to be well-tolerated with few side effects, making it a novel option for those who may not respond well to antidepressants. ^{8 9 10 11 12}

Research Team

Catherine VanDerwerker, PT DPT PhD

Principal Investigator

Ralph H. Johnson VA Medical Center, Charleston, SC

Eligibility Criteria

This trial is for adults aged 18-60 with major depressive disorder and a spinal cord injury (cervical or thoracic) of at least 6 months duration. Candidates should not be on antidepressants, or have stable doses for at least 4 weeks. They must not have cognitive impairments, psychosis, metallic implants, seizure history, pregnancy, high suicide risk, other neurological disorders/dementia or claustrophobia.

Inclusion Criteria

Hamilton Depression Rating Scale-17 score greater than 18

I have been diagnosed with major depressive disorder.

I haven't changed my mental health medication doses for at least 4 weeks.

Exclusion Criteria

Cognitive impairment (Montreal Cognitive Assessment score less than 17)

History of psychosis or other primary Axis I disorder

I have a neurological condition or dementia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active or sham rTMS treatment for depression post-SCI, administered 5 days/week for 6 weeks

6 weeks

30 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 12 and 24 weeks post-intervention

24 weeks

2 visits (in-person)

Treatment Details

Interventions

• rTMS

Trial Overview The study tests a new way to dose repetitive transcranial magnetic stimulation (rTMS), an FDA-approved depression treatment that doesn't rely on thumb movement responses—important for those with arm/hand impairment post-spinal cord injury. It compares active rTMS against sham (placebo-like) treatment to assess its effect on depression in these individuals.

Participant Groups

Group I: Active rTMS Experimental Treatment 1 Intervention

Active repetitive transcranial magnetic stimulation (rTMS) that will be administered 5 days/week for 6 weeks. Intensity will be individualized based on reverse-calculation electric-field modeling.

Group II: Sham rTMS Placebo Group 1 Intervention

Sham repetitive transcranial magnetic stimulation (rTMS) that will be administered 5 days/week for 6 weeks. Intensity will be individualized based on reverse-calculation electric-field modeling, but a sham treatment coil will be used; thus, no active treatment will be administered.

rTMS is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Obsessive-Compulsive Disorder (OCD)
• Major Depressive Disorder
• Migraines
• Smoking cessation

Approved in European Union as rTMS for:

• Obsessive-Compulsive Disorder (OCD)
• Major Depressive Disorder

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

Repetitive transcranial magnetic stimulation (rTMS) shows promise as a non-invasive treatment to enhance recovery and functional outcomes in individuals with spinal cord injury (SCI), with potential benefits for motor function and spasticity based on a review of 16 studies.

Future research should focus on optimizing rTMS parameters, such as timing and dosage, and emphasize the need for more rigorous studies comparing real versus sham rTMS to strengthen the evidence for its efficacy in SCI rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulation Parameters Used During Repetitive Transcranial Magnetic Stimulation for Motor Recovery and Corticospinal Excitability Modulation in SCI: A Scoping Review. Brihmat, N., Allexandre, D., Saleh, S., et al.[2022]

In a study involving subjects with spinal cord injury (SCI), real repetitive transcranial magnetic stimulation (rTMS) did not show significant differences in the ASIA impairment scale compared to sham treatment, indicating limited efficacy in this specific measure.

However, rTMS did lead to short-term improvements in upper limb function as measured by the Action Research Arm Test (ARAT) and increased motor thresholds, suggesting that electrophysiological measures could be valuable in assessing functional changes in SCI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury. Kuppuswamy, A., Balasubramaniam, AV., Maksimovic, R., et al.[2011]

Repetitive transcranial magnetic stimulation (rTMS) has been explored as a noninvasive method to enhance recovery of motor and sensory functions in patients with spinal cord injury (SCI), but results have been mixed, with some studies showing improvements while others did not.

The effectiveness of rTMS may depend on specific parameters of the treatment and the extent of post-injury reorganization in the nervous system, indicating a need for more research to optimize its use in rehabilitation for SCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of repetitive transcranial magnetic stimulation on recovery of function after spinal cord injury. Tazoe, T., Perez, MA.[2021]

In a study involving 60 rats with partial spinal cord injury, the combination of repetitive transcranial magnetic stimulation (rTMS) and treadmill training (TT) significantly improved motor function compared to other treatment groups, indicating enhanced recovery.

The combined rTMS and TT treatment also led to increased levels of brain-derived neurotrophic factor (BDNF), synapsin I (SYN), and postsynaptic density protein-95 (PSD-95) in both the motor cortex and spinal cord, suggesting that this approach promotes neuroplasticity essential for motor recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) and Treadmill Training on Recovery of Motor Function in a Rat Model of Partial Spinal Cord Injury. Wang, P., Yin, R., Wang, S., et al.[2022]

In a proof-of-concept study involving three adults with cervical spinal cord injury, repetitive QuadroPulse transcranial magnetic stimulation (rTMS(QP)) showed functional benefits, particularly in improving walking speed and cortical excitability without any adverse effects.

The combination of rTMS(QP) with targeted exercises led to even greater improvements in motor function, suggesting that this approach could be effective and warrants further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: Three case studies. Alexeeva, N., Calancie, B.[2018]

High-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the leg motor area significantly reduced lower limb spasticity in patients with incomplete spinal cord injury, with effects lasting for at least one week after treatment.

The study involved 15 patients who underwent 5 days of rTMS sessions, showing that active stimulation led to clinical improvements compared to sham stimulation, although neurophysiological measures did not show changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury. Kumru, H., Murillo, N., Samso, JV., et al.[2021]

High-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improved lower extremities motor score (LEMS) and various gait parameters in 17 patients with motor incomplete spinal cord injury after 15 sessions, with effects lasting for at least 2 weeks.

The active rTMS group showed notable improvements in spasticity and gait metrics, while the sham group did not demonstrate significant changes, highlighting the efficacy of rTMS as a therapeutic intervention for enhancing motor function in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor and gait improvement in patients with incomplete spinal cord injury induced by high-frequency repetitive transcranial magnetic stimulation. Benito, J., Kumru, H., Murillo, N., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) can be safely administered to individuals with traumatic brain injury (TBI) when following specific guidelines, minimizing risks such as seizures.

In a case study of a 48-year-old man with severe TBI, rTMS treatment for post-TBI depression over 6 weeks led to a 49% reduction in depression symptoms, demonstrating its potential efficacy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury. Nielson, DM., McKnight, CA., Patel, RN., et al.[2022]

A case study of a 71-year-old stroke survivor showed that repetitive transcranial magnetic stimulation (rTMS) significantly reduced depression symptoms after 10 sessions, indicating its efficacy for post-stroke depression.

Ongoing maintenance rTMS treatments helped sustain the improvements in depressive symptoms for at least 3 months after the initial treatment, suggesting that continued therapy may enhance long-term benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended Repetitive Transcranial Magnetic Stimulation Therapy for Post-stroke Depression in a Patient With a Pre-frontal Cortical Lesion: A Case Study. Hordacre, B., Chau, A., Graetz, L., et al.[2022]

In a pilot trial with 29 participants suffering from major depressive disorder, different doses of repetitive transcranial magnetic stimulation (rTMS) were tested, showing that all doses led to significant reductions in depression severity after 4 weeks, with no serious adverse events reported.

The highest dose of 4000 pulses showed the most substantial improvement in depression scores during the first two weeks, suggesting that higher doses may lead to a quicker antidepressant effect, warranting further investigation in a larger definitive trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation in major depression: A three-arm parallel-group dose-response randomized pilot trial. Johansson, K., Adler, M., Båve, U., et al.[2023]

A study of 77 military patients receiving rTMS treatment showed significant reductions in depression and PTSD symptoms, with over 44% of patients experiencing a notable decrease in depression scores after treatment.

Most patients had previously tried multiple antidepressants (average of 2.7 trials), indicating that rTMS may be an effective alternative for those with treatment-resistant depression and comorbid PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility. Wilkes, S., Ona, C., Yang, M., et al.[2021]

In a study involving 300 patients with treatment-resistant depression, different doses of repetitive transcranial magnetic stimulation (rTMS) did not show significant differences in response rates, with all groups exceeding a 45% response rate.

While increasing the number of TMS pulses did not correlate with better overall outcomes, higher doses of left-sided rTMS were associated with improved remission rates when considering the duration of illness, suggesting that other factors may influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression. Fitzgerald, PB., Hoy, KE., Reynolds, J., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Stimulation Parameters Used During Repetitive Transcranial Magnetic Stimulation for Motor Recovery and Corticospinal Excitability Modulation in SCI: A Scoping Review. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury. [2011]

3. United States pubmed.ncbi.nlm.nih.gov

Effects of repetitive transcranial magnetic stimulation on recovery of function after spinal cord injury. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) and Treadmill Training on Recovery of Motor Function in a Rat Model of Partial Spinal Cord Injury. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: Three case studies. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Motor and gait improvement in patients with incomplete spinal cord injury induced by high-frequency repetitive transcranial magnetic stimulation. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Extended Repetitive Transcranial Magnetic Stimulation Therapy for Post-stroke Depression in a Patient With a Pre-frontal Cortical Lesion: A Case Study. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation in major depression: A three-arm parallel-group dose-response randomized pilot trial. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression. [2020]