NCT07172295: Low-Intensity Focused Ultrasound for Parkinson's Disease Tremor
Overview
Mermaid diagram (expand to render)
| 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:
Mechanical effects: Ultrasound waves produce mechanical vibrations that can modulate ion channel activity on neuronal membranes
Thermal effects: At low intensities, subtle temperature changes may influence neural excitability
Focal targeting: Modern LiFUS systems can precisely target deep brain structures like the thalamusTarget: 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
Non-invasive: No surgical incision or burr holes required
Reversible: Effects can be reassessed unlike surgical lesions
Precise targeting: Can focus energy on specific brain nuclei
Outpatient procedure: May not require hospitalization
No implant: Unlike [DBS](/therapeutics/deep-brain-stimulation), no hardware is implantedChallenges 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
The distinction between neuromodulation (temporary, reversible effects) and ablation (permanent destruction) is fundamental to understanding this trial's approach. By using intensities below the thermal ablation threshold, the investigators aim to achieve therapeutic benefit while maintaining safety.
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
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
NCT07172295 differs from these approaches by using low-intensity (non-ablative) stimulation, potentially offering therapeutic benefit with a more favorable safety profile.
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
However, DBS carries risks inherent to any implanted device:
- 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:
Medication-refractory tremor: Patients who have failed adequate trials of pharmacotherapy
Non-surgical candidates: Patients who cannot undergo DBS due to medical comorbidities or personal preference
Mild to moderate tremor severity: Patients with functional impairment but not complete disability
Intact cognitive function: Able to cooperate with the procedure and provide informed consent
Suitable skull anatomy: Adequate bone density and absence of anatomical variants that would impede ultrasound transmissionRisk 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
Additional efficacy measures commonly used in tremor trials include:
- 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:
Optimal stimulation parameters: Determining effective intensity, frequency, and duration
Treatment durability: Understanding how long benefits persist
Repeat treatment: Safety and efficacy of multiple treatment sessions
Combination approaches: Synergy with medication or other neuromodulationClinical 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
Epilepsy:
- Hippocampal targeting
- Seizure focus ablation
- Neuromodulation approaches
Brain Tumors:
- Blood-brain barrier opening for drug delivery
- Thermal ablation of small tumors
- Combined with chemotherapy
Movement Disorders Beyond Tremor:
- Parkinson's disease dyskinesias
- Dystonia
- Huntington's disease chorea
Technical Advances
Next-Generation Systems:
Higher Frequency Arrays:
- Improved resolution
- Reduced treatment time
- Better skull penetration
Real-Time Feedback:
- Continuous temperature monitoring
- Automated targeting adjustments
- Closed-loop control systems
Multi-Focus Approaches:
- Simultaneous targeting of multiple regions
- Enhanced treatment flexibility
- Complex pattern delivery
Artificial Intelligence Integration: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
De Novo Pathway:
- Novel devices without predicates
- Risk-based classification
- Requires extensive clinical data
PMA (Premarket Approval):
- 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
Advocacy Efforts:
- Patient advocacy groups
- Clinical society recommendations
- Health economic demonstrations
Value Propositions:
- Reduced surgical complications
- Shorter recovery times
- No implanted hardware costs
Research gaps and Unmet Needs
Knowledge Gaps
Despite significant progress, important questions remain:
Long-term efficacy:
- Duration of treatment effect
- Need for retreatment
- Disease progression impact
Mechanism of action:
- Precise neuromodulation mechanisms
- Optimal stimulation parameters
- Network effects
Patient selection:
- Predictors of response
- Optimal candidates
- Contraindications
Unmet Needs
Technical Needs:
- More affordable systems
- Wider accessibility
- Improved targeting accuracy
Clinical Needs:
- Additional indications
- Combination therapies
- Biomarker development
Research Needs:
- 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
During Treatment:
- Conscious sedation or local anesthesia
- Head positioned in device
- Real-time imaging guidance
- Communication with treatment team
Post-Treatment:
- 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
Timeline:
- 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
Insurance Coverage:
- 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
Indirect Cost Considerations:
- Reduced hospitalization
- Shorter recovery time
- Less need for caregiver support
- Faster return to work
Long-term Economic Impact:
- 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
Psychological Benefits:
- Reduced anxiety about tremor
- Improved self-esteem
- Decreased social isolation
- Enhanced independence
Caregiver Impact:
- 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
Retreatment Strategies:
- Identifying candidates for repeat procedures
- Comparing outcomes with initial treatment
- Optimizing parameters for subsequent sessions