Theta-Burst Stimulation for Post-Concussion Syndrome

Overseen By Matthew Burke, MD, FRCPC

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Anticonvulsants, Antiepileptics, Benzodiazepines

Disqualifiers: Seizure disorder, Substance dependence, Pregnancy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 1 week

26 Participants Needed

Trial Summary

What is the purpose of this trial?

TMS has been safely and reliably delivered at the Harquail Centre for over 5 years, with a primary focus on conventional rTMS protocols for treatment-resistant depression. Recently, the investgator team has gained the capability to deliver sham-controlled intermittent theta-burst stimulation (iTBS) rTMS. Unlike conventional high frequency rTMS, which was used in the previous sham-controlled rTMS PCS pilot study, iTBS is a patterned form of stimulation that recapitulates endogenous activity patterns of neural circuits pairing gamma frequency (50Hz) burst pulses coupled in a theta frequency rhythm (5Hz).12 iTBS delivers 600 pulses in just over 3 minutes with similar or greater effects on neural plasticity compared to conventional rTMS (taking over 30-45 minutes) and similar tolerability and efficacy in trials of depression. Furthermore, novel accelerated iTBS protocols stimulating the left dorsolateral prefrontal cortex (dlPFC) over 8-10 treatments, 50 minutes apart over a 5 day interval has recently demonstrated robust efficacy in depression and received recent FDA approval. Thus, accelerated iTBS can be delivered in a single week of treatment compared to 6 weeks with conventional rTMS methods. Finally, the investigators recently acquired the technology to integrate MRI neuroimage-guided stimulation, which would allow to target specific brain regions/networks implicated in PCS at high spatial resolution. No studies to date have investigated image-guided accelerated iTBS rTMS for the treatment of PCS.

Will I have to stop taking my current medications?

The trial requires that you stop taking any antiepileptic medications and limits lorazepam to no more than 2 mg daily (or its equivalent in other benzodiazepines). If you are taking these medications, you may need to adjust or stop them to participate.

What data supports the effectiveness of the treatment Theta-Burst Stimulation for Post-Concussion Syndrome?

Research suggests that intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, can aid in cognitive and motor function recovery. It has shown potential benefits in conditions like traumatic brain injury and depression, indicating it might help with post-concussion syndrome as well. ^{1 2 3 4 5}

Is theta-burst stimulation safe for humans?

Theta-burst stimulation (TBS), a type of repetitive transcranial magnetic stimulation (rTMS), is generally considered safe, with most adverse events being mild and occurring in about 5% of subjects. However, there is a theoretical risk of seizures, so it should be used with caution, especially since it is a newer technique. ^{2 6 7 8 9}

How is theta-burst stimulation treatment different from other treatments for post-concussion syndrome?

Theta-burst stimulation (TBS) is unique because it uses magnetic pulses to directly stimulate specific brain areas, potentially enhancing brain function and recovery. Unlike traditional treatments, it can be combined with other therapies like cognitive rehabilitation to improve outcomes. ^{1 2 10 11 12}

Eligibility Criteria

This trial is for adults aged 18-60 who've had a head injury leading to loss of consciousness or memory issues, with symptoms like headaches and dizziness starting within 4 weeks of the injury and lasting 3-12 months. Participants must be able to consent and follow the study plan but can't join if they have major brain damage, history of seizures (except childhood febrile seizures), are pregnant, on certain medications, or involved in personal injury lawsuits.

Inclusion Criteria

I experience at least three symptoms like headache, dizziness, or fatigue.

My symptoms started within 4 weeks after a head injury.

I have had a head injury that caused me to lose consciousness or forget things.

Exclusion Criteria

I am currently on medication for epilepsy.

Ferromagnetic, non-removable metallic implants from above the clavicle with the exception of dental work

Active personal injury litigation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive accelerated iTBS rTMS treatment targeting the left dorsolateral prefrontal cortex over 8-10 sessions within a 5-day interval

1 week

8-10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Accelerated, Theta-burst Stimulation

Trial Overview The trial tests an advanced form of brain stimulation called intermittent Theta-Burst Stimulation (iTBS) against a sham treatment. iTBS aims to improve neural plasticity using rapid bursts mimicking natural brain patterns. It's delivered over five days instead of six weeks like older methods. The technology also allows targeting specific brain areas implicated in Post-Concussion Syndrome using MRI guidance.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Group II: Sham Placebo Group 1 Intervention

Accelerated, Theta-burst Stimulation is already approved in United States for the following indications:

Approved in United States as rTMS for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Findings from Research

Intermittent theta-burst stimulation (iTBS) shows promise as a targeted treatment for cognitive and psychosocial deficits following traumatic brain injury (TBI), potentially enhancing recovery when combined with behavioral interventions like cognitive rehabilitation and psychotherapy.

This review suggests that iTBS could lead to consistent functional gains in TBI patients, and future research may explore its application in other complex neuropsychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

rTMS/iTBS and Cognitive Rehabilitation for Deficits Associated With TBI and PTSD: A Theoretical Framework and Review. Lindsey, A., Ellison, RL., Herrold, AA., et al.[2023]

In a study involving 36 multiple sclerosis patients, intermittent theta burst stimulation (iTBS) significantly improved manual dexterity, as shown by faster completion times in the nine-hole peg test and increased performance in the Box and Block Test.

However, iTBS did not have a significant impact on hand motor imagery abilities, indicating that while it can enhance physical tasks, it may not affect cognitive aspects of motor function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Intermittent Theta Burst Stimulation on Manual Dexterity and Motor Imagery in Patients with Multiple Sclerosis: A Quasi-Experimental Controlled Study. Azin, M., Zangiabadi, N., Iranmanesh, F., et al.[2020]

A 25-year-old man with chronic traumatic brain injury showed significant improvements in balance and motor function after three weeks of cerebellar intermittent theta burst stimulation (iTBS) combined with neurorehabilitation, as measured by various assessments including the Fugl-Meyer Assessment and Berg Balance Scale.

The results indicated notable enhancements in balance performance (+10.72%), motor recovery (+3.00%), step length (+3.4 cm), and walking speed (+0.04 m/sec), suggesting that combining rTMS with rehabilitation can effectively aid recovery in TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical effects of non-invasive cerebellar magnetic stimulation treatment combined with neuromotor rehabilitation in traumatic brain injury. A single case study. Martino Cinnera, A., Bonnì, S., Iosa, M., et al.[2022]

In a study involving 300 patients with treatment-resistant depression, accelerated bilateral theta burst stimulation (TBS) was found to be effective and safe, with a treatment response rate of 43.7% and a remission rate of 28.2%.

The study revealed no significant differences in efficacy between different TBS intensities or when compared to traditional unilateral 10 Hz rTMS, indicating that the accelerated TBS does not provide faster antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. Chen, L., Thomas, EHX., Kaewpijit, P., et al.[2022]

This study aims to develop and assess a combined intervention of intermittent theta burst stimulation (iTBS) and yoga for military veterans with mild traumatic brain injury (mTBI) and chronic pain, focusing on feasibility and acceptability.

The intervention will be conducted over 6 weeks with 20 participants, and it is expected to provide preliminary evidence of safety and effectiveness in improving quality of life, function, and pain management for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of a Combined Neuromodulation and Yoga Intervention for Mild Traumatic Brain Injury and Chronic Pain: Protocol for an Open-label Pilot Trial. Krese, KA., Donnelly, KZ., Etingen, B., et al.[2023]

Intermittent theta-burst stimulation (iTBS) and high-frequency rTMS (HF-rTMS) show similar efficacy in treating treatment-resistant depression (TRD), with response rates of 48.0% for iTBS and 45.5% for HF-rTMS based on two high-quality randomized controlled trials involving 474 participants.

Both iTBS and HF-rTMS have comparable safety profiles, with similar rates of discontinuation and adverse events, such as headaches, indicating that iTBS is a safe alternative to HF-rTMS for patients with TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. Lan, XJ., Yang, XH., Qin, ZJ., et al.[2023]

Theta burst stimulation (TBS) is a promising technique for altering brain excitability, with a review of studies showing that adverse events were mostly mild and occurred in only 5% of subjects, indicating a generally safe profile.

Despite its safety, TBS carries a theoretical higher risk of seizures compared to other stimulation methods, necessitating cautious application and further research into its dosing parameters to better understand seizure risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. Oberman, L., Edwards, D., Eldaief, M., et al.[2022]

Intermittent theta burst stimulation (iTBS) is as effective as standard high-frequency (10 Hz) rTMS for treating treatment-resistant depression, showing non-inferiority in improving depression scores over 4-6 weeks in a study with 414 participants.

Both iTBS and 10 Hz rTMS had similar safety profiles and dropout rates, with headaches being the most common side effect, indicating that iTBS can be a viable alternative that allows for more patients to be treated in a shorter time without losing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Blumberger, DM., Vila-Rodriguez, F., Thorpe, KE., et al.[2022]

Theta-burst stimulation (TBS) was found to be safe for children, with no serious adverse events reported among 40 participants aged under 18, including those with Tourette syndrome and typically developing children.

Only 11.6% of participants experienced mild, self-limited side effects, such as finger twitching and headaches, indicating that TBS is well tolerated in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. Wu, SW., Shahana, N., Huddleston, DA., et al.[2012]

The study found that continuous theta-burst stimulation (cTBS) can effectively reduce cortical excitability, but its effects show limited reproducibility across sessions, indicating variability in its impact.

Among the neurophysiological markers assessed, the modulation of corticospinal excitability measured 5 minutes after cTBS was the most consistent, suggesting it could be a reliable measure for future research on cTBS effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reproducibility of the effects of theta burst stimulation on motor cortical plasticity in healthy participants. Vernet, M., Bashir, S., Yoo, WK., et al.[2022]

A study involving 50 veterans with PTSD showed that intermittent theta-burst stimulation (iTBS) significantly improved social and occupational functioning after 2 weeks, indicating its potential efficacy as a treatment for PTSD.

One month after treatment, iTBS demonstrated significant reductions in both clinician- and self-rated PTSD symptoms, as well as improvements in depression and functioning, suggesting that iTBS could be a promising new approach for managing PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder. Philip, NS., Barredo, J., Aiken, E., et al.[2020]

Monophasic intermittent theta-burst stimulation (iTBS) was found to induce significantly greater increases in motor corticospinal excitability compared to biphasic iTBS, based on a study involving 30 healthy volunteers.

The study suggests that monophasic iTBS may have a stronger potential for functional impact in clinical applications, as it demonstrated a more pronounced physiological effect on motor neuron activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of pulse shape in theta-burst stimulation: Monophasic vs biphasic TMS. Wendt, K., Sorkhabi, MM., Stagg, CJ., et al.[2023]

References

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

rTMS/iTBS and Cognitive Rehabilitation for Deficits Associated With TBI and PTSD: A Theoretical Framework and Review. [2023]

2. Estonia pubmed.ncbi.nlm.nih.gov

Effects of Intermittent Theta Burst Stimulation on Manual Dexterity and Motor Imagery in Patients with Multiple Sclerosis: A Quasi-Experimental Controlled Study. [2020]

3. Italy pubmed.ncbi.nlm.nih.gov

Clinical effects of non-invasive cerebellar magnetic stimulation treatment combined with neuromotor rehabilitation in traumatic brain injury. A single case study. [2022]

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

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. [2022]

5. Canada pubmed.ncbi.nlm.nih.gov

Feasibility of a Combined Neuromodulation and Yoga Intervention for Mild Traumatic Brain Injury and Chronic Pain: Protocol for an Open-label Pilot Trial. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. [2023]

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

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. [2012]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Reproducibility of the effects of theta burst stimulation on motor cortical plasticity in healthy participants. [2022]

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

Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder. [2020]

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

The effect of pulse shape in theta-burst stimulation: Monophasic vs biphasic TMS. [2023]