NCT07172295: Low-Intensity Focused Ultrasound for PD Tremor

NCT07172295: Low-Intensity Focused Ultrasound for Parkinson's Disease Tremor

Overview

NCT07172295: Low-Intensity Focused Ultrasound for Parkinson's Disease Tremor

Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT07172295 |
| Title | Modulate Tremor Severity With Low-intensity Focused Ultrasound Stimulation Targeting the Deep Nucleus of Patients With Refractory Hand Tremor |
| Status | Recruiting |
| Phase | Not Applicable (Device Trial) |
| Condition(s) | Parkinson Disease, Essential Tremor, Dystonic Tremor |
| Intervention | Low-Intensity Focused Ultrasound (LiFUS) Stimulation |
| Sponsor | National Taiwan University Hospital |
| Location | National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan |

Study Description

This Phase 1 clinical trial evaluates the safety and efficacy of low-intensity focused ultrasound (LiFUS) stimulation for treating refractory hand tremor in patients with Parkinson Disease, Essential Tremor, or Dystonic Tremor.

The study employs NaviFUS-ctbFUS (center-targeted beam Formed Ultrasound) technology, a novel device-based approach that delivers focused acoustic energy to specific brain targets without invasive surgery.

Intervention Details

The treatment protocol consists of:

• Three consecutive sessions with 5-minute intervals
• Target: Center of the [Ventral Intermediate Nucleus (VIM)](https://en.wikipedia.org/wiki/Ventral_intermediate_nucleus) of the thalamus
• Energy delivery: 7 stimulation points at approximately 0.5 MPa intracranial pressure
• Patients must shave their hair prior to treatment for optimal ultrasound transmission

Mechanism of Action

Focused Ultrasound in Tremor Treatment

Low-intensity focused ultrasound is a non-invasive neuromodulation technique that uses acoustic energy to temporarily modulate neuronal activity in specific brain regions. The key mechanisms include:

Target: Thalamic Vim Nucleus

The ventral intermediate nucleus (VIM) of the thalamus is a well-established target for tremor treatment. Surgical lesioning (thalamotomy) and [deep brain stimulation](/therapeutics/deep-brain-stimulation) of this region have been used for decades to treat medication-resistant tremor.

LiFUS offers a non-invasive alternative to:

• [Deep Brain Stimulation](/therapeutics/deep-brain-stimulation) (DBS)
• Radiofrequency Thalamotomy
• Gamma Knife Thalamotomy

Eligibility Criteria

Inclusion Requirements

• Age: 18-80 years
• Diagnosis: Parkinson Disease tremor, Essential Tremor, or Dystonic Tremor
• Refractory tremor: Inadequate response to standard medications
• Stable medications: No changes in tremor medications for at least 4 weeks
• Normal organ function: Normal liver and renal function
• Willingness: Must be willing to shave hair for treatment

Exclusion Criteria

• Intracranial implants (e.g., [deep brain stimulation](/therapeutics/deep-brain-stimulation) devices, cochlear implants)
• Scalp conditions that may interfere with ultrasound transmission
• Pregnancy
• Major depression
• Brain tumors
• Anticoagulant use or coagulopathy
• Insufficient skull density (poor ultrasound transmission)

Outcome Measures

Primary Outcome

| Measure | Description |
|---------|-------------|
| Incidence of Adverse Events | Safety assessment comparing adverse events to baseline |

Secondary Outcome

| Measure | Description |
|---------|-------------|
| Change in Tremor Amplitude | Efficacy measured via Archimedes spirogram |

Clinical Significance

Advantages Over Current Treatments

Challenges and Limitations

• Limited long-term data on durability of treatment effect
• Requires patient cooperation (hair removal, head stabilization)
• May not be suitable for patients with certain skull characteristics
• Efficacy may be temporary, requiring repeated sessions

Historical Context and Scientific Foundation

Evolution of Focused Ultrasound in Neurosurgery

The development of focused ultrasound for neurological applications represents a remarkable convergence of physics and medicine. The foundational work by William Fry and colleagues in the 1950s established the basic principles of using focused acoustic energy to create targeted lesions in the brain[@bauer2017]. Early experiments demonstrated that ultrasound could produce discrete thermal lesions without damaging overlying tissue, but technological limitations prevented widespread clinical adoption.

The modern era of focused ultrasound neurosurgery began with the integration of magnetic resonance imaging (MRI) for real-time guidance. This technological leap, pioneered in the 2000s, enabled clinicians to visualize the focal point of ultrasound energy and monitor temperature changes in real time. The FDA approval of MRI-guided focused ultrasound (MRgFUS) for essential tremor in 2016 marked a turning point in the field[@elias2016].

From High-Intensity to Low-Intensity Neuromodulation

While high-intensity focused ultrasound (HIFU) creates permanent thermal lesions through temperatures exceeding 55°C, low-intensity focused ultrasound (LiFUS) operates at much lower energy levels (typically below 1 MPa peak pressure) that do not produce tissue heating sufficient for ablation. This lower energy approach has attracted significant interest for its potential to modulate neural activity reversibly, without creating permanent damage.

Research has demonstrated that LiFUS can affect neuronal activity through multiple mechanisms[@kim2018]:

• Ion channel modulation: Mechanical stimulation can directly activate or inhibit voltage-gated ion channels
• Membrane effects: Changes in membrane capacitance and permeability
• Network-level effects: Alterations in synaptic transmission and neural circuitry

Technical Implementation

NaviFUS-ctbFUS System

The NaviFUS-ctbFUS (center-targeted beam Formed Ultrasound) system represents a sophisticated approach to non-invasive brain stimulation. Unlike MRI-guided focused ultrasound systems that require costly and complex MRI infrastructure, this device utilizes a multi-element ultrasound array with electronic beam steering capabilities.

Key technical features include:

• Multi-element transducer array: Enables electronic focus steering without mechanical movement
• Real-time targeting: Allows visualization and adjustment of the focal point
• Lower cost implementation: Potentially more accessible than MRI-guided systems
• Portable design: May enable use in outpatient settings

Target Selection: Ventral Intermediate Nucleus

The choice of the ventral intermediate nucleus (VIM) as the stimulation target reflects decades of neurosurgical experience. The VIM serves as a critical relay in the cerebellar-thalamo-cortical circuit that underlies tremor generation. Hyperactivity in this region is a hallmark of both Parkinsonian tremor and essential tremor.

Surgical interventions targeting the VIM include:

• Radiofrequency thalamotomy: Precise thermal lesion using implanted electrodes
• Gamma Knife thalamotomy: Radiation-based lesioning
• Deep brain stimulation: Implanted electrodes delivering electrical stimulation
• Focused ultrasound thalamotomy: Non-invasive thermal ablation

Comparison with Other Neuromodulation Approaches

Deep Brain Stimulation

[DBS](/therapeutics/deep-brain-stimulation) remains the gold standard for surgical treatment of medication-resistant tremor. The approach involves implantation of electrodes in the VIM (or related nuclei), with a subcutaneous pulse generator providing chronic electrical stimulation. DBS offers several advantages:

• Adjustability: Stimulation parameters can be optimized post-operatively
• Reversibility: Can be turned off or removed
• Established efficacy: Supported by extensive clinical data

• Surgical complications (infection, hemorrhage)
• Hardware failures (electrode breakage, battery depletion)
• Requires lifetime maintenance and replacements

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) uses magnetic fields to induce electrical currents in cortical neurons. While FDA-approved for depression and other conditions, TMS has limited penetration depth, typically affecting only superficial cortical structures. Its utility for tremor (which involves deep nuclei) is therefore limited.

Transcranial Direct Current Stimulation

tDCS applies low-intensity electrical currents through electrodes placed on the scalp. Like TMS, it primarily affects cortical regions and has not demonstrated robust efficacy for tremor treatment.

Focused Ultrasound Advantages

Compared to these alternatives, focused ultrasound offers unique advantages:

| Feature | Focused Ultrasound | DBS | TMS | tDCS |
|---------|-------------------|-----|-----|------|
| Depth penetration | Deep brain targets | Deep | Shallow | Shallow |
| Invasiveness | Non-invasive | Surgical | Non-invasive | Non-invasive |
| Precision | Millimeter-scale | Good | Limited | Poor |
| Reversibility | Fully reversible | Reversible | Fully reversible | Fully reversible |

Patient Selection Considerations

Ideal Candidates

Based on the trial's eligibility criteria and clinical experience, ideal candidates for LiFUS VIM stimulation include:

Risk Assessment

Careful patient selection is essential given the experimental nature of this approach. Key considerations include:

• Skull density assessment: Quantitative CT can evaluate ultrasound transmission properties
• Coagulation status: Patients on anticoagulation require careful risk-benefit analysis
• Neurological comorbidities: Presence of other neurological conditions may affect outcomes
• Psychological preparation: Understanding the experimental nature of the intervention

Outcome Assessment

Primary Safety Endpoints

The trial's primary focus on adverse events reflects the early-stage nature of this technology. Expected safety assessments include:

• Neurological examination: Monitoring for new neurological deficits
• Imaging studies: MRI to detect any unexpected tissue changes
• Cognitive testing: Assessing any changes in cognitive function
• Quality of life measures: Patient-reported outcomes

Secondary Efficacy Endpoints

The use of Archimedes spirography for tremor measurement represents a quantitative approach to assessing treatment effects. This technique provides:

• Objective tremor quantification: Numerical measures of tremor amplitude
• Serial comparisons: Tracking changes over time
• Blinded assessment: Can be performed by raters unaware of treatment status

• Clinical rating scales: Fahn's tremor rating scale, TRS
• Accelerometry: Objective measurement of tremor frequency and amplitude
• Functional assessments: Writing, drawing, drinking tasks

Future Directions

Technology Development

The results of NCT07172295 will inform several key technological questions:

Clinical Translation Pathways

Success in this trial could pave the way for broader clinical application:

• Expanded indications: Extension to other movement disorders
• Device optimization: Next-generation systems with improved targeting
• Regulatory pathways: FDA Breakthrough Device designation potential
• Accessibility: Development of less expensive, more widely available systems

Conclusion

NCT07172295 represents a carefully designed early-phase trial testing a novel non-invasive neuromodulation approach for tremor. The use of low-intensity focused ultrasound targeting the VIM offers a potentially transformative approach that could provide the benefits of surgical intervention without the risks of implantation. The rigorous safety focus, combined with quantitative efficacy measures, positions this study to generate meaningful data for the field.

The successful completion of this trial would represent a significant advance in the treatment of medication-resistant tremor, offering hope to patients who cannot or choose not to undergo invasive surgical procedures. The findings will inform the broader development of focused ultrasound neuromodulation and potentially expand the therapeutic toolkit available to clinicians treating movement disorders.

Cross-Linking

Related Treatment Pages

• [Focused Ultrasound Therapy](/therapeutics/focused-ultrasound)
• [Deep Brain Stimulation](/therapeutics/deep-brain-stimulation)
• [Radiofrequency Thalamotomy](/therapeutics/radiofrequency-thalamotomy)

Related Disease Pages

• [Parkinson's Disease Tremor](/diseases/parkinsons-disease)
• [Essential Tremor](/diseases/essential-tremor)
• [Dystonic Tremor](/diseases/dystonic-tremor)

Related Mechanism Pages

• [Cerebellar-Thalamic Circuit in Tremor](/mechanisms/tremor-circuit)
• [Thalamic Neuromodulation](/mechanisms/thalamic-neuromodulation)

Related Protein/Gene Pages

• [GAD1](/genes/gad1) (GABAergic neurons in thalamus)
• [Thalamus](/entities/thalamus)

External Links

• [ClinicalTrials.gov - NCT07172295](https://clinicaltrials.gov/study/NCT07172295)
• [PubMed - Focused Ultrasound](https://pubmed.ncbi.nlm.nih.gov/?term=focused+ultrasound+tremor)
• [Focused Ultrasound Foundation](https://www.fusfoundation.org/)

Emerging Applications and Future Research

Expanding Indications

The success of focused ultrasound in tremor treatment has prompted investigation into other neurological applications:

Depression and Anxiety:

• Targeting the prefrontal cortex
• Modulating limbic circuits
• Potential treatment-resistant cases

• Hippocampal targeting
• Seizure focus ablation
• Neuromodulation approaches

• Blood-brain barrier opening for drug delivery
• Thermal ablation of small tumors
• Combined with chemotherapy

• Parkinson's disease dyskinesias
• Dystonia
• Huntington's disease chorea

Technical Advances

Next-Generation Systems:

• Improved resolution
• Reduced treatment time
• Better skull penetration

• Continuous temperature monitoring
• Automated targeting adjustments
• Closed-loop control systems

• Simultaneous targeting of multiple regions
• Enhanced treatment flexibility
• Complex pattern delivery

AI is transforming focused ultrasound treatment planning:

• Automated targeting: Machine learning algorithms identify optimal targets
• Predictive modeling: AI predicts treatment outcomes
• Personalized parameters: Individualized treatment protocols
• Quality assurance: Automated verification of treatment delivery

Regulatory and reimbursement Considerations

FDA Approval Pathways

Focused ultrasound devices follow distinct regulatory pathways:

510(k) Pathway:

• Demonstrating substantial equivalence
• Predicate device comparison
• Typical for incremental improvements

• Novel devices without predicates
• Risk-based classification
• Requires extensive clinical data

• Class III devices
• Safety and efficacy demonstration
• Most rigorous pathway

Reimbursement Challenges

Coverage and reimbursement present ongoing challenges:

Current Status:

• Medicare covers essential tremor HIFU
• Limited coverage for other indications
• Geographic variations exist

• Patient advocacy groups
• Clinical society recommendations
• Health economic demonstrations

• Reduced surgical complications
• Shorter recovery times
• No implanted hardware costs

Research gaps and Unmet Needs

Knowledge Gaps

Despite significant progress, important questions remain:

• Duration of treatment effect
• Need for retreatment
• Disease progression impact

• Precise neuromodulation mechanisms
• Optimal stimulation parameters
• Network effects

• Predictors of response
• Optimal candidates
• Contraindications

Unmet Needs

Technical Needs:

• More affordable systems
• Wider accessibility
• Improved targeting accuracy

• Additional indications
• Combination therapies
• Biomarker development

• Mechanism studies
• Comparative effectiveness
• Quality of life outcomes

Practical Considerations for Patients

Treatment Process

Understanding the treatment experience helps patient preparation:

Pre-Treatment:

• Detailed imaging and mapping
• Hair removal (for transcranial approaches)
• Medical clearance
• Discussion of expectations

• Conscious sedation or local anesthesia
• Head positioned in device
• Real-time imaging guidance
• Communication with treatment team

• Short recovery period
• Monitoring for adverse effects
• Follow-up imaging
• Rehabilitation if needed

Expected Outcomes

For Patients with Tremor:

• Significant tremor reduction (often 50-80%)
• Improved daily functioning
• Enhanced quality of life
• Reduced medication dependence

• Immediate effects often noticeable
• Gradual improvement over weeks
• Stable results by 3-6 months

Cost Considerations

Treatment Costs:

• Device and facility fees
• Professional fees
• Imaging costs
• Follow-up care

• Varies by indication and insurer
• Pre-authorization often required
• Appeals process available

Conclusion and Clinical Perspective

NCT07172295 represents an innovative approach to treating medication-resistant tremor through non-invasive neuromodulation. By targeting the ventral intermediate nucleus of the thalamus with low-intensity focused ultrasound, this trial explores a technology that could revolutionize treatment for movement disorders.

The advantages of this approach are substantial: non-invasiveness, reversibility, precision targeting, and the absence of implanted hardware. For patients who cannot or do not wish to undergo deep brain stimulation surgery, this could represent a transformative therapeutic option.

The rigorous safety focus of this trial reflects the early-stage nature of the technology but also the careful approach being taken to establish a foundation for broader clinical application. The quantitative outcome measures, including Archimedes spirography, provide objective assessment of efficacy that will be critical for advancing the field.

Success in this trial would not only benefit the specific patients enrolled but would also advance the broader field of focused ultrasound neuromodulation. The knowledge gained regarding optimal stimulation parameters, treatment durability, and safety will inform future applications across a range of neurological conditions.

As the field matures, focused ultrasound may become a first-line treatment option for tremor disorders, offering an accessible and minimally invasive alternative to surgical intervention. The results of NCT07172295 will contribute meaningfully to this ongoing evolution in neurological treatment.

Comparative Effectiveness with Surgical Alternatives

Cost-Effectiveness Analysis

Healthcare systems increasingly evaluate treatments based on cost-effectiveness. Focused ultrasound thalamotomy offers potential economic advantages over traditional surgical approaches:

Direct Treatment Costs:

• HIFU: Typically $30,000-50,000 (single treatment)
• DBS: $100,000-150,000 (device, surgery, follow-up)
• Medication: Ongoing costs for pharmacotherapy

• Reduced hospitalization
• Shorter recovery time
• Less need for caregiver support
• Faster return to work

• Device maintenance (DBS battery changes)
• Medication costs
• Complications management
• Nursing home placement avoidance

Quality of Life Outcomes

Beyond clinical endpoints, treatment success should be measured by quality of life improvements:

Functional Improvements:

• Ability to eat independently
• Writing and typing
• Self-care activities
• Social participation

• Reduced anxiety about tremor
• Improved self-esteem
• Decreased social isolation
• Enhanced independence

• Reduced caregiving burden
• Less need for physical assistance
• Improved family relationships

Long-Term Follow-Up Considerations

Sustained benefit tracking is essential for treatment validation:

Monitoring Protocols:

• Clinical assessments at 1, 3, 6, 12 months
• Annual follow-up thereafter
• Imaging to assess tissue changes
• Quality of life questionnaires

• Identifying candidates for repeat procedures
• Comparing outcomes with initial treatment
• Optimizing parameters for subsequent sessions