Accelerated TMS for Hand Dystonia

Overseen By Alaa Norain, MBS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Duke University

Must not be taking: Anticholinergics, Benzodiazepines, Muscle relaxants

Disqualifiers: Other dystonia, Parkinsonism, Seizure, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 1 day

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to investigate the impact of accelerated transcranial magnetic stimulation (TMS) on brain function and behavior in patients with focal hand dystonia. Previous research demonstrated that individualized TMS improved dystonic behavior after one session. Building on this, the current study administers four TMS sessions in a day, with assessments conducted in four weeks, twelve weeks, and 20 weeks after each session. The research involves 8 in-person and 6 virtual visits focused on functional MRI brain scans and writing behavior analysis. The potential risk of seizures from TMS is mitigated through careful screening, adhering to safety guidelines. The study's main benefit is enhancing dystonic behavior and deepening the understanding of brain changes caused by TMS in focal hand dystonia, paving the way for further advancements in clinical therapy for this condition.

Will I have to stop taking my current medications?

Yes, you will need to stop taking medications used for treating dystonia symptoms, such as anticholinergics, benzodiazepines, and muscle relaxants, at least one month before the study.

What data supports the effectiveness of the treatment Accelerated TMS for Hand Dystonia?

Research shows that theta burst stimulation, a component of Accelerated TMS, can lead to improvements in dystonia symptoms by modifying brain circuits involved in movement control. In cervical dystonia, a similar condition, cerebellar theta burst stimulation resulted in a small but significant clinical improvement, suggesting potential benefits for hand dystonia as well. ^{1 2 3 4 5}

Is Accelerated TMS generally safe for humans?

Research on repetitive transcranial magnetic stimulation (rTMS) and related techniques like Theta-Burst Stimulation shows they are generally safe for humans, with studies often focusing on conditions like dystonia. While these studies primarily assess effectiveness, they also monitor safety, and no major safety concerns have been reported in the context of these treatments. ^{3 5 6 7 8}

How does the treatment Accelerated TMS differ from other treatments for hand dystonia?

Accelerated TMS (repetitive transcranial magnetic stimulation) is unique because it uses magnetic fields to stimulate specific brain areas, potentially improving brain plasticity and connectivity, which are often altered in dystonia. Unlike traditional treatments, it targets the brain's motor and sensory pathways non-invasively, offering a novel approach to managing symptoms. ^{1 2 3 5 9}

Research Team

Noreen Bukhari-Parlakturk, MD PhD

Principal Investigator

Duke Health

Eligibility Criteria

This trial is for adults over 18 with isolated focal hand dystonia, confirmed by a neurologist. Participants must be right-handed, able to give informed consent and literate. Excluded are those with other movement disorders or seizure history, recent drug use or certain treatments like TMS therapy, botulinum toxin injections, specific medications for dystonia symptoms, and recent hand therapy.

Inclusion Criteria

You primarily use your right hand for tasks.

Diagnosed with isolated focal hand by a neurologist.

Must be able to sign an informed consent

Exclusion Criteria

I have a history of seizures.

I have been diagnosed with a movement disorder other than dystonia.

You have any reasons that make it unsafe for you to have a MRI or TMS.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive accelerated TMS sessions, with four sessions administered in a single day

1 day

2 visits (in-person)

Assessment

Participants undergo functional MRI brain scans and engage in writing tasks to evaluate changes in brain function and behavior

4 weeks

6 visits (virtual), 6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 12, 20, 24, 32, and 40 weeks

40 weeks

Treatment Details

Interventions

• Accelerated TMS

Trial Overview The study tests accelerated transcranial magnetic stimulation (TMS) on patients with focal hand dystonia. It involves four TMS sessions in one day and assesses the impact on brain function and writing behavior immediately after, at two weeks and twelve weeks post-treatment using functional MRI scans.

Participant Groups

Group I: TMS to primary somatosensory cortex Active Control 1 Intervention

Participants received TMS sessions at primary somatosensory cortex

Group II: TMS at low amplitude to primary somatosensory cortex Placebo Group 1 Intervention

Participants receive TMS at a cortical target at smaller amplitude

Accelerated TMS is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as rTMS for:

• Major Depressive Disorder
• Obsessive Compulsive Disorder

Approved in European Union as rTMS for:

• Major Depressive Disorder
• Obsessive Compulsive Disorder

Approved in United Kingdom as rTMS for:

• Major Depressive Disorder
• Obsessive Compulsive Disorder
• Post-Traumatic Stress Disorder
• Depersonalization Disorder
• Borderline Personality Disorder
• Addiction

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

American Academy of Neurology

Collaborator

Trials

12

Recruited

370+

Findings from Research

Theta burst stimulation (TBS) applied to the primary somatosensory cortex (S1) can modulate somatosensory temporal discrimination threshold (STDT) in patients with focal hand dystonia (FHD), but it does not fully normalize STDT values after treatment.

While intermittent TBS (iTBS) decreased STDT values in patients, indicating some level of response, it did not improve writing performance, suggesting that the underlying mechanisms affecting sensory discrimination differ from those causing motor symptoms in FHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary somatosensory cortical plasticity and tactile temporal discrimination in focal hand dystonia. Conte, A., Rocchi, L., Ferrazzano, G., et al.[2022]

A two-week trial of cerebellar continuous theta burst stimulation (cTBS) in patients with cervical dystonia showed a small but significant clinical improvement of about 15% as measured by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).

The stimulation altered cerebellar brain inhibition (CBI) circuits and normalized patterns of cortical plasticity, suggesting that cerebellar-thalamo-cortical circuits could be a promising target for managing symptoms of dystonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients. Koch, G., Porcacchia, P., Ponzo, V., et al.[2018]

Patients with cervical dystonia show disrupted cerebellar cortical connectivity and altered cerebellar plasticity compared to healthy controls, as evidenced by transcranial magnetic stimulation results from a study involving 12 patients and 13 controls.

In healthy individuals, cerebellar stimulation can modulate motor cortex excitability, but these effects are absent in patients with cervical dystonia, indicating a significant difference in cerebellar function in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal cerebellar connectivity and plasticity in isolated cervical dystonia. Porcacchia, P., Álvarez de Toledo, P., Rodríguez-Baena, A., et al.[2020]

Cerebellar continuous theta-burst stimulation (cTBS) effectively reduced excitability in the primary motor cortex for healthy subjects and patients with cervical dystonia, but not for those with focal hand dystonia, suggesting a specific inhibitory role of the cerebellum in different types of dystonia.

The study found no correlation between changes in motor cortex excitability and movement abnormalities in patients, indicating that the cerebellar modulation may not directly influence kinematic measures in focal dystonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cerebellar theta-burst stimulation on arm and neck movement kinematics in patients with focal dystonia. Bologna, M., Paparella, G., Fabbrini, A., et al.[2018]

In a study involving 14 patients with idiopathic focal hand dystonia (FHD) and 14 healthy controls, it was found that techniques like intermittent theta burst stimulation (iTBS) and paired associative stimulation (PAS) did not produce the expected changes in motor evoked potentials (MEPs) in FHD patients, indicating altered brain plasticity.

Additionally, FHD patients showed a lack of expected improvements in motor learning tasks, suggesting that both experimentally-induced and behaviorally-induced plasticity are disrupted in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal experimentally- and behaviorally-induced LTP-like plasticity in focal hand dystonia. Belvisi, D., Suppa, A., Marsili, L., et al.[2013]

Repetitive transcranial magnetic stimulation (rTMS) significantly reduced the severity of dystonia symptoms in 66 patients, as measured by the Burke-Fahn-Marsden scale, indicating its efficacy in treating this condition.

The treatment was well-tolerated with minimal side effects, suggesting that rTMS is a safe option for patients with various forms of dystonia, supporting its broader use in rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of transcranial magnetic stimulation in the treatment of rare forms of muscular dystonia]. Likhachev, SA., Charnukha, TN., Zabrodzets, GV., et al.[2018]

In patients with dystonia who had deep brain stimulation (DBS) electrodes implanted, transcranial magnetic stimulation (TMS) of one motor cortex produced bilateral hand motor responses, indicating a complex interaction between cortical and subcortical pathways.

The study found that ipsilateral responses to TMS were smaller and faster than contralateral responses, suggesting that these responses originate from subcortical activation of corticospinal fibers, which is important for interpreting TMS results in patients with DBS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pseudo-bilateral hand motor responses evoked by transcranial magnetic stimulation in patients with deep brain stimulators. Kühn, AA., Trottenberg, T., Kupsch, A., et al.[2019]

In a study involving 30 participants, including DYT1 gene carriers with and without dystonia, it was found that those with dystonia showed a significantly prolonged response to repetitive transcranial magnetic stimulation (rTMS), indicating heightened brain plasticity.

The lack of response to rTMS in DYT1 gene carriers without dystonia suggests that abnormal brain plasticity may play a crucial role in the development of symptoms in genetically predisposed individuals, highlighting a potential mechanism in the pathogenesis of primary dystonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers. Edwards, MJ., Huang, YZ., Mir, P., et al.[2007]

Non-invasive brain stimulation techniques like transcranial magnetic stimulation (TMS) reveal that patients with dystonia exhibit reduced inhibition and increased facilitation in motor cortical excitability, indicating altered brain function in this condition.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been shown to improve symptoms of dystonia, including pain and functional disability, while also demonstrating changes in cortical evoked potentials, suggesting a mechanism for restoring motor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the connections between basal ganglia and cortex revealed by transcranial magnetic stimulation, evoked potential and deep brain stimulation in dystonia. Udupa, K., Bhattacharya, A., Chen, R.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Primary somatosensory cortical plasticity and tactile temporal discrimination in focal hand dystonia. [2022]

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

Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients. [2018]

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

Abnormal cerebellar connectivity and plasticity in isolated cervical dystonia. [2020]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of cerebellar theta-burst stimulation on arm and neck movement kinematics in patients with focal dystonia. [2018]

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

Abnormal experimentally- and behaviorally-induced LTP-like plasticity in focal hand dystonia. [2013]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of transcranial magnetic stimulation in the treatment of rare forms of muscular dystonia]. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Pseudo-bilateral hand motor responses evoked by transcranial magnetic stimulation in patients with deep brain stimulators. [2019]

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

Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers. [2007]

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

Exploring the connections between basal ganglia and cortex revealed by transcranial magnetic stimulation, evoked potential and deep brain stimulation in dystonia. [2022]