TMS for Parkinson's Disease Apathy

(PDTMSAPATHY Trial)

Recruiting at 1 trial location

Overseen By Miriam Sklerov, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of North Carolina, Chapel Hill

Must be taking: Dopaminergic, SSRIs, Stimulants

Must not be taking: Anti-dopaminergic

Disqualifiers: Dementia, Epilepsy, Brain surgery, 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: 3

Duration: 6 weeks

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

No, you will not have to stop taking your current medications. Participants must be stable on their Parkinson's medication and any other medications that may influence apathy for at least 4 weeks before the study and remain stable throughout the study.

What data supports the effectiveness of the treatment Transcranial Magnetic Stimulation (TMS) for Parkinson's Disease?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can improve motor function in Parkinson's disease by modulating brain activity. Studies have demonstrated that rTMS can shorten reaction and movement times in patients, and high-frequency rTMS has shown long-lasting benefits in clinical trials. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) safe for humans?

TMS, including its variations like rTMS and TBS, is generally considered safe for humans, with a slight risk of seizures and other minor side effects. Studies have shown it to be well-tolerated in both healthy individuals and those with conditions like Parkinson's disease and major depression. ^{6 7 8 9 10}

How is the treatment TMS for Parkinson's Disease Apathy different from other treatments?

TMS (Transcranial Magnetic Stimulation) is unique because it is a non-invasive treatment that directly stimulates brain neurons using magnetic fields, unlike traditional medications that often involve oral or injectable drugs. It has shown promise in improving both motor and non-motor symptoms, such as apathy, in Parkinson's disease, which is not typically addressed by standard treatments. ^{3 11 12 13 14}

What is the purpose of this trial?

The goal of this clinical trial is to develop non-invasive brain stimulation targets for the treatment of apathy, or motivation problems, in Parkinson Disease. The main questions the study aims to answer are: 1. Does transcranial magnetic stimulation change effort task performance in Parkinson's Disease patients? 2. Is there a link between brain signals and apathy? Participants will * complete questionnaires and assessments * perform an effort task * have their brain activity recorded (EEG) * receive non-invasive brain stimulation (TMS) Researchers will compare two stimulation locations (experimental site and control site) to see if TMS of the experimental site has an effect on apathy. Participants will receive stimulation of both sites (during separate visits).

Research Team

Miriam Sklerov, MD

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

This trial is for Parkinson's Disease patients who've had symptoms for at least 5 years, are on stable dopaminergic medication, and can consent in English. Women must be postmenopausal or use contraception. Excluded are those with dementia, epilepsy, brain surgery history, metal implants like pacemakers or deep brain stimulators, severe tremor affecting EEG readings, other causes of parkinsonism or CNS diseases.

Inclusion Criteria

I can understand and consent to the study in English.

I am a woman who has not had a period in over 12 months or will use birth control during the study.

I have been diagnosed with Parkinson's Disease.

Exclusion Criteria

Presence of dementia (Montreal Cognitive Assessment (MoCA) score < 21)

Inability to provide informed consent

I cannot perform certain physical tasks as determined in a test.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-3 hours

1 visit (in-person)

Treatment

Participants receive transcranial magnetic stimulation (TMS) at two different sites with a 3-week washout period between sessions

6 weeks

2 visits (in-person)

Follow-up

Participants are monitored for changes in goal-directed behavior and reward evaluation after TMS

4 weeks

Treatment Details

Interventions

• Transcranial Magnetic Stimulation (TMS)

Trial Overview The study tests if Transcranial Magnetic Stimulation (TMS) affects motivation in Parkinson's patients by comparing the effects of stimulating two different brain areas. Participants will do tasks to measure effort and have their brain activity recorded before and after TMS sessions at both sites.

Participant Groups

Group I: Medial Prefrontal Cortex - Control Site Experimental Treatment 1 Intervention

Participants first undergo transcranial magnetic stimulation to the medial prefrontal cortex. After a 3-week washout period, participants then undergo transcranial magnetic stimulation to the control site.

Group II: Control Site - Medial Prefrontal Cortex Experimental Treatment 1 Intervention

Participants first undergo transcranial magnetic stimulation to the control site. After a 3-week washout period, participants then undergo transcranial magnetic stimulation to the medial prefrontal cortex.

Transcranial Magnetic Stimulation (TMS) is already approved in United States, European Union for the following indications:

Approved in United States as Transcranial Magnetic Stimulation (TMS) for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Migraine Headache Symptoms

Approved in European Union as Transcranial Magnetic Stimulation (TMS) for:

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

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a study involving 22 patients with Parkinson's disease, various rTMS protocols were tested over 5 days, but none showed significant improvement over placebo in enhancing motor function.

The only notable result was in the Purdue Pegboard Test, where all active rTMS protocols performed slightly better than sham stimulation, indicating that while rTMS may have some effects, motor training and medication likely played a larger role in observed improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Training effects outweigh effects of single-session conventional rTMS and theta burst stimulation in PD patients. Rothkegel, H., Sommer, M., Rammsayer, T., et al.[2019]

Repetitive transcranial magnetic stimulation (rTMS) has shown long-lasting efficacy in treating Parkinson's disease, based on two clinical trials focused on the supplementary motor area.

Animal studies and a meta-analysis support the effectiveness of high-frequency rTMS, indicating it could become a significant treatment option for various neurological and psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation (rTMS) therapy for Parkinson disease]. Shirota, Y.[2019]

In a study involving 6 patients with Parkinson's disease and 10 normal controls, repetitive transcranial magnetic stimulation (rTMS) significantly improved choice reaction time and movement time in patients without affecting their error rate, suggesting enhanced motor function.

The rTMS treatment also improved performance on a grooved peg-board test in Parkinson's patients, particularly when they were not on medication, indicating its potential as a therapeutic intervention for motor symptoms in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Akinesia in Parkinson's disease. II. Effects of subthreshold repetitive transcranial motor cortex stimulation. Pascual-Leone, A., Valls-Solé, J., Brasil-Neto, JP., et al.[2019]

In a study involving 27 patients with Parkinson's disease, repetitive deep transcranial magnetic stimulation (rDTMS) using H-coils was found to be safe, with no adverse events reported during 12 treatment sessions.

Patients experienced a significant improvement in motor symptoms, with an average reduction of 10.8 points on the motor UPDRS scale after treatment, indicating the potential efficacy of rDTMS as an add-on therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Excitatory deep repetitive transcranial magnetic stimulation with H-coil as add-on treatment of motor symptoms in Parkinson's disease: an open label, pilot study. Spagnolo, F., Volonté, MA., Fichera, M., et al.[2018]

Repetitive transcranial magnetic stimulation (rTMS), particularly at 5 Hz over the supplementary motor area, has been shown to effectively improve motor symptoms in Parkinson's disease, as demonstrated in multiple randomized, double-blind, sham-controlled studies conducted in Japan.

The mechanism of action for rTMS involves normalizing excitability in the supplementary motor area, which may help restore function in the basal ganglia, and ongoing phase III trials suggest that rTMS could soon be a standard treatment option for Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Repetitive Transcranial Magnetic Stimulation for Parkinson's Disease: A Review]. Matsumoto, H., Ugawa, Y.[2017]

A review of 84 single pulse and paired-pulse TMS studies with 1091 Parkinson's disease patients, and 77 repetitive TMS studies with 1137 patients, found a very low risk of adverse events, with no seizures reported.

The overall risk of adverse events from rTMS was 0.040 per patient, with common side effects being mild and transient, such as headaches and scalp pain, indicating that TMS is generally safe for Parkinson's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcranial magnetic stimulation in Parkinson's disease: a review of the literature. Vonloh, M., Chen, R., Kluger, B.[2021]

Theta-burst transcranial magnetic stimulation (TBS) is safe and well tolerated in patients with major depression, based on a study involving 33 participants over 10 consecutive days.

The study suggests that TBS may have antidepressant effects, and increasing stimulation parameters does not lead to more side effects, potentially enhancing its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Chistyakov, AV., Rubicsek, O., Kaplan, B., et al.[2019]

Transcranial magnetic stimulation (TMS) is safe to use with implanted deep brain stimulation (DBS) devices at low to moderate intensities, as no movement or temperature increase was observed during stimulation at 0.2 Hz with 100% intensity for 1 hour.

However, caution is advised when using high-intensity TMS (over 50%) near looped DBS leads, as it can exceed the safety limit for charge density, potentially leading to electrical tissue injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of transcranial magnetic stimulation with deep brain stimulation instruments. Shimojima, Y., Morita, H., Nishikawa, N., et al.[2010]

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

In a study involving 26 patients with mild to moderate Parkinson's disease, 50-Hz repetitive transcranial magnetic stimulation (rTMS) was found to be safe, with no adverse effects or increased risk of cortical excitability.

However, the treatment did not lead to significant improvements in motor symptoms such as gait and bradykinesia, although there was a brief improvement in daily living activities, suggesting that longer or different rTMS protocols may be needed for better efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled study of 50-Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease. Benninger, DH., Iseki, K., Kranick, S., et al.[2021]

High-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improved motor symptoms in 21 patients with Parkinson's disease, as measured by various scales including the Unified Parkinson's Disease Rating Scale (UPDRS-III) and walking tests.

However, rTMS did not show significant effects on non-motor symptoms like depression and apathy, and daily sessions did not provide additional benefits over a single session, indicating that while rTMS is effective for motor symptoms, its impact on non-motor symptoms remains limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-frequency repetitive transcranial magnetic stimulation over the primary foot motor area in Parkinson's disease. Maruo, T., Hosomi, K., Shimokawa, T., et al.[2016]

Repetitive transcranial magnetic stimulation (rTMS) significantly reduced depression scores in Parkinson's disease patients, showing lasting effects even two weeks after treatment ended, indicating its potential as an effective antidepressant intervention.

The study involved 8 patients with Parkinson's disease and demonstrated that rTMS is a safe and painless method for alleviating depressive symptoms, which is crucial given the limitations of traditional antidepressant medications in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson 's disease]. Potrebić, A., Dragasević, N., Svetel, M., et al.[2009]

Patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) exhibit motor cortex disinhibition, characterized by larger response amplitudes and reduced intracortical inhibition during transcranial magnetic stimulation (TMS).

In contrast, patients with corticobasal-ganglionic degeneration (CBGD) show hypoexcitability in the motor cortex, indicated by increased motor thresholds and smaller response amplitudes, suggesting more severe neuronal loss in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes. Kühn, AA., Grosse, P., Holtz, K., et al.[2008]

Repetitive transcranial magnetic stimulation (rTMS) significantly reduced depression scores in Parkinson's disease patients, showing lasting effects even two weeks after treatment ended, indicating its potential as an effective antidepressant intervention.

The study involved 8 patients with Parkinson's disease and demonstrated that rTMS is a safe and painless method, with no significant changes in Parkinson's symptoms, highlighting its suitability for managing depression in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson disease]. Potrebić, A., Dragasević, N., Svetel, M., et al.[2009]

References

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

Training effects outweigh effects of single-session conventional rTMS and theta burst stimulation in PD patients. [2019]

2. Japan pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation (rTMS) therapy for Parkinson disease]. [2019]

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

Akinesia in Parkinson's disease. II. Effects of subthreshold repetitive transcranial motor cortex stimulation. [2019]

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

Excitatory deep repetitive transcranial magnetic stimulation with H-coil as add-on treatment of motor symptoms in Parkinson's disease: an open label, pilot study. [2018]

5. Japan pubmed.ncbi.nlm.nih.gov

[Repetitive Transcranial Magnetic Stimulation for Parkinson's Disease: A Review]. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Safety of transcranial magnetic stimulation in Parkinson's disease: a review of the literature. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. [2019]

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

The safety of transcranial magnetic stimulation with deep brain stimulation instruments. [2010]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

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

Controlled study of 50-Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease. [2021]

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

High-frequency repetitive transcranial magnetic stimulation over the primary foot motor area in Parkinson's disease. [2016]

12. Serbia pubmed.ncbi.nlm.nih.gov

[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson 's disease]. [2009]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes. [2008]

14. Serbia pubmed.ncbi.nlm.nih.gov

[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson disease]. [2009]