Ultrasound + Electrical Stimulation for Parkinson's Disease

(tbFUS-FES_PD Trial)

Overseen By Naaz Desai

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University Health Network, Toronto

Must be taking: Dopaminergic medications

Must not be taking: Antipsychotics, Antidepressants, Marijuana, others

Disqualifiers: Stroke, Seizure, Dementia, others

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

Compensation: Varies

Number of Visits: 3

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to help people with Parkinson's disease improve movement. It combines two treatments: ultrasound to the brain (Transcranial Ultrasound Stimulation, or TUS) and electrical stimulation to the muscles (Functional Electrical Stimulation, or FES). The researchers aim to determine if these treatments together can better manage Parkinson's symptoms. The trial will test various combinations to identify the most effective approach. Individuals with Parkinson's who have maintained a stable medication dose for at least four weeks might be suitable for this study. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new treatment options for Parkinson's disease.

Will I have to stop taking my current medications?

The trial requires that your Parkinson's medication dose has been stable for at least 4 weeks, so you won't need to stop taking it. However, if you are on antipsychotics, antidepressants, marijuana, or other recreational drugs that affect the nervous system, you may not be eligible to participate.

What prior data suggests that this technique is safe for Parkinson's disease patients?

Research has shown that transcranial ultrasound stimulation (TUS) is generally safe and non-invasive. It already helps alleviate some symptoms of Parkinson's disease, such as tremors. Safety studies indicate that low-intensity focused ultrasound, a type of TUS, is well-tolerated by many patients.

Studies also consider functional electrical stimulation (FES) quite safe. FES is used to improve movement and has been tested in people with conditions like Parkinson's. These studies suggest that FES can be used without major side effects.

Although TUS and FES together have not been extensively studied, the safety data for each method alone is positive in similar conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using ultrasound combined with electrical stimulation for treating Parkinson's Disease because it offers a fresh approach to managing symptoms. Typically, Parkinson's treatments focus on medications that boost dopamine levels or surgical interventions. However, this method uses Transcranial Ultrasound Stimulation (TUS) to potentially modulate brain activity non-invasively and Functional Electrical Stimulation (FES) to enhance muscle function. This combination could improve motor skills by directly influencing both the brain and muscles, offering a complementary or alternative option to current drug-based therapies. This integrated technique might provide faster and more targeted relief, which is a significant step forward in Parkinson's care.

What evidence suggests that this trial's treatments could be effective for Parkinson's disease?

This trial will evaluate the effects of Transcranial Ultrasound Stimulation (TUS) and Functional Electrical Stimulation (FES) on Parkinson's disease symptoms. Research has shown that both TUS and FES could help treat these symptoms. Studies have found that focused ultrasound can relieve symptoms, especially tremors and movement problems. TUS uses sound waves to target specific brain areas, potentially improving movement control. FES uses electrical impulses to stimulate muscles, which can enhance movement and reduce symptoms like muscle stiffness. Participants in this trial will receive either Real TUS with Sham FES, Sham TUS with Real FES, or both Real TUS and Real FES. Combining TUS and FES might enhance their effects, potentially leading to better movement control for people with Parkinson's disease. While more research is needed, early findings suggest that using these treatments together could be helpful. ^{1 2 6 7 8}

Who Is on the Research Team?

Robert Chen

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

This trial is for people aged 18-90 with confirmed Parkinson's disease who have been on a stable dose of dopaminergic medication for at least 4 weeks. It excludes those with metal implants, drug use affecting the nervous system, cardiac devices, pregnancy, severe psychiatric disorders, history of stroke or seizure, dementia, major hand disabilities, genetic mutations causing illness or infection.

Inclusion Criteria

I have been diagnosed with Parkinson's disease.

My Parkinson's medication dose has been stable for at least 4 weeks.

Exclusion Criteria

Has an implanted cardiac pacemaker or implantable cardioverter-defibrillator (ICD)

You have metal inside your body that could cause problems during certain medical tests or procedures.

I am currently using medications or substances that impact my nervous system.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combinations of Real TUS and/or Real FES across 3 study visits, each at least 7 days apart, to assess neuromodulatory effects on motor symptoms

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for changes in motor symptoms and safety after treatment using UPDRS and MEP measurements

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Real FES
• Real TUS
• Sham FES
• Sham TUS

Trial Overview The study tests combining Transcranial Ultrasound Stimulation (TUS) targeting the brain and Functional Electrical Stimulation (FES) on hand muscles to improve motor symptoms in Parkinson's patients. Participants will receive either real TUS and FES or sham (fake) versions to compare effects.

How Is the Trial Designed?

Group I: Sham TUS +Real FES Experimental Treatment 2 Interventions

The Sham tbFUS paradigm will consist of 120s train of 20ms ultrasound bursts, repeated every 200ms (Pulse Repetition Frequency (PRF)=5Hz), however the ultrasound head will be flipped so that the active side faces away from the head. This will be followed by motor point stimulation (MPS) of the right and left hand and forearm muscles i.e. Opponens Pollicis Brevis (OPB), 1st Lumbrical and First Dorsal Interosseous (FDI) muscles triggered in congruence with the voluntary effort of the participant during execution of bilateral functional tasks involving the use of two and three finger pinch grip (e.g.: picking up and moving marbles, ball bearings etc.). Parameters of stimulation will be 40 Hz frequency, 300 microsecs pulse duration, amplitude as per participant tolerance and total stimulation time 30 mins with "ON" time of 4 secs and "OFF" time of 4 secs.

Group II: Real TUS +Sham FES Experimental Treatment 2 Interventions

Participants will receive Real TUS using a 2 channel transducer with parameters' of sonication being 120s train of 20ms ultrasound bursts, repeated every 200ms (Pulse Repetition Frequency (PRF)=5Hz). The Power of Real tbFUS will be set at 20W. This will be followed by motor point stimulation (MPS) of the right and left biceps and long finger flexors triggered in congruence with the voluntary effort of the participant during execution of bilateral functional tasks involving the use of two and three finger pinch grip (e.g.: picking up and moving marbles, ball bearings etc.). Parameters of stimulation will be 40 Hz frequency, 300 microsecs pulse duration, amplitude as per participant tolerance and total stimulation time 30 mins with "ON" time of 4 secs and "OFF" time of 4 secs.

Group III: Real TUS + Real FES Experimental Treatment 2 Interventions

Participants will receive Real TUS using a 2 channel transducer with parameters' of sonication being 120s train of 20ms ultrasound bursts, repeated every 200ms (Pulse Repetition Frequency (PRF)=5Hz). The Power of Real tbFUS will be set at 20W. This will be followed by motor point stimulation (MPS) of the right and left hand and forearm muscles i.e. Opponens Pollicis Brevis (OPB), 1st Lumbrical and First Dorsal Interosseous (FDI) muscles triggered in congruence with the voluntary effort of the participant during execution of bilateral functional tasks involving the use of two and three finger pinch grip (e.g.: picking up and moving marbles, ball bearings etc.). Parameters of stimulation will be 40 Hz frequency, 300 microsecs pulse duration, amplitude as per participant tolerance and total stimulation time 30 mins with "ON" time of 4 secs and "OFF" time of 4 secs.

Real FES is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Functional Electrical Stimulation for:

• Restoration of motor function following stroke and spinal cord injury

Approved in European Union as Functional Electrical Stimulation for:

• Restoration of motor function following stroke and spinal cord injury

Approved in Canada as Functional Electrical Stimulation for:

• Restoration of motor function following stroke and spinal cord injury

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Low-intensity transcranial focused ultrasound (TUS) significantly increased motor cortex excitability in Parkinson's disease patients, as evidenced by higher TMS-elicited motor-evoked potentials (MEPs) after active stimulation compared to sham treatment.

Despite the increase in motor cortex excitability, there were no significant changes in clinical outcomes measured by the MDS-UPDRS-III scale, indicating that while a-tbTUS is a feasible neuromodulation strategy, its effects on clinical symptoms may require further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated Transcranial Ultrasound Neuromodulation in Parkinson's Disease: A Pilot Study. Samuel, N., Ding, MYR., Sarica, C., et al.[2023]

Transcranial MR-guided focused ultrasound has shown promise as a safe and effective treatment for functional neurological disorders, with clinical trials demonstrating its ability to create thermal lesions.

Preclinical studies suggest that focused ultrasound can also disrupt the blood-brain barrier and provide reversible neuromodulation, indicating potential for broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of transcranial magnetic resonance imaging-guided focused ultrasound in functional neurosurgery. Weintraub, D., Elias, WJ.[2022]

Non-invasive focused ultrasound stimulation (FUS) has been shown to be safe and beneficial in modulating motor behavior in preclinical studies of Parkinson's disease, suggesting its potential as a novel treatment option.

The review included 11 studies, primarily from China, indicating that while FUS shows promise in influencing Parkinson's disease processes, more research is needed to fully understand its mechanisms before it can be widely implemented in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focused Ultrasound Stimulation as a Neuromodulatory Tool for Parkinson's Disease: A Scoping Review. Lee, KS., Clennell, B., Steward, TGJ., et al.[2022]

Low-intensity focused ultrasound (LIFU) has shown promise in improving motor symptoms of Parkinson's disease by regulating microglia activation and promoting nerve repair, making it a potential non-invasive treatment option.

Combining LIFU with microbubbles can enhance drug delivery across the blood-brain barrier, highlighting the need for effective drug carrier systems in future Parkinson's disease therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low intensity focused ultrasound: a new prospect for the treatment of Parkinson's disease. Zhong, YX., Liao, JC., Liu, X., et al.[2023]

Magnetic resonance-guided focused ultrasound (MRgFUS) significantly improved limb tremor and daily activities in Parkinson's disease patients compared to a sham procedure, based on a pooled analysis of 2 studies with treatment durations of up to 4 months.

While MRgFUS was associated with some adverse events, such as dizziness, there were no serious side effects reported, indicating a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical application of magnetic resonance-guided focused ultrasound in Parkinson's disease: a meta-analysis of randomized clinical trials. Ge, Y., Wang, Z., Gu, F., et al.[2022]

Low intensity focused ultrasound (LIFU) is a promising non-invasive technology that can precisely modulate brain activity, offering a new approach to studying and potentially treating psychiatric illnesses.

LIFU has been shown to safely affect both cortical and subcortical brain regions, distinguishing it from other neuromodulatory techniques due to its spatial precision and reversible effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. Arulpragasam, AR., van 't Wout-Frank, M., Barredo, J., et al.[2022]

Focused ultrasound (FUS) is a feasible and safe method for creating lesions in the brain without damaging previously implanted deep brain stimulation (DBS) devices, as shown in preclinical experiments with hydrogels, cadavers, and swine.

The studies demonstrated that FUS effectively heated targeted areas to therapeutic temperatures (29-32°C) while avoiding any significant heating or damage to the DBS electrodes, indicating a promising approach for patients who cannot undergo further DBS surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and Safety of MR-Guided Focused Ultrasound Lesioning in the Setting of Deep Brain Stimulation. Dallapiazza, R., Khaled, M., Eames, M., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12414162/

Efficacy of peroneal nerve functional electrical stimulation ... This is the largest study investigating the effects of functional electrical stimulation (FES) in people with Parkinson's disease (pwPD).

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40912703/

an assessor-blinded randomised controlled trial (STEPS II ... Efficacy of peroneal nerve functional electrical stimulation (FES) for the reduction of bradykinesia in Parkinson's disease: an assessor-blinded ...

3. bmjopen.bmj.com bmjopen.bmj.com/content/bmjopen/15/9/e097010.full.pdf

Efficacy of peroneal nerve functional electrical stimulation ( ... The randomised feasibility study preceding this definitive study showed that daily FES can produce a clinically meaningful improvement in ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1094715921009156

A Pilot Study to Investigate the Feasibility of Electrical ... This study aims to investigate the effect of functional electrical stimulation (FES) on gait in people with Parkinson's disease.

5. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.795454/full

Peripherical Electrical Stimulation for Parkinsonian Tremor The outcomes of tremor suppression were varied due to various stimulation approaches, electrode locations and stimulation parameters. The FES ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06090292

NCT06090292 | Effects of Peripheral Electrical Stimulation ... To date, there are no studies that have looked at the neuro modulatory effects of combining TUS and FES on motor symptoms in patients with Parkinson's disease.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9707702/

Evaluating the validity of a functional electrical stimulation ... The FES Clinical Decision Making Tool was developed to assist clinicians with FES application and translation into clinical practice.

8. jneuroengrehab.biomedcentral.com jneuroengrehab.biomedcentral.com/articles/10.1186/s12984-021-00811-9

Peripheral electrical stimulation to reduce pathological tremor We explore peripheral electrical stimulation as an intervention for tremor reduction, identify the limitations and benefits of the current state-of-the-art ...