| 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 |
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.
The treatment protocol consists of:
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:
The ventral intermediate nucleus (VIM) of the thalamus is a well-established target for tremor treatment. Surgical lesioning (thalamotomy) and deep brain stimulation of this region have been used for decades to treat medication-resistant tremor.
LiFUS offers a non-invasive alternative to:
| Measure | Description |
|---|---|
| Incidence of Adverse Events | Safety assessment comparing adverse events to baseline |
| Measure | Description |
|---|---|
| Change in Tremor Amplitude | Efficacy measured via Archimedes spirogram |
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[1]. 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[2].
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[3]:
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.
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:
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:
NCT07172295 differs from these approaches by using low-intensity (non-ablative) stimulation, potentially offering therapeutic benefit with a more favorable safety profile.
DBS 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:
However, DBS carries risks inherent to any implanted device:
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.
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.
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 |
Based on the trial's eligibility criteria and clinical experience, ideal candidates for LiFUS VIM stimulation include:
Careful patient selection is essential given the experimental nature of this approach. Key considerations include:
The trial's primary focus on adverse events reflects the early-stage nature of this technology. Expected safety assessments include:
The use of Archimedes spirography for tremor measurement represents a quantitative approach to assessing treatment effects. This technique provides:
Additional efficacy measures commonly used in tremor trials include:
The results of NCT07172295 will inform several key technological questions:
Success in this trial could pave the way for broader clinical application:
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.
The success of focused ultrasound in tremor treatment has prompted investigation into other neurological applications:
Depression and Anxiety:
Epilepsy:
Brain Tumors:
Movement Disorders Beyond Tremor:
Next-Generation Systems:
Higher Frequency Arrays:
Real-Time Feedback:
Multi-Focus Approaches:
Artificial Intelligence Integration:
AI is transforming focused ultrasound treatment planning:
Focused ultrasound devices follow distinct regulatory pathways:
510(k) Pathway:
De Novo Pathway:
PMA (Premarket Approval):
Coverage and reimbursement present ongoing challenges:
Current Status:
Advocacy Efforts:
Value Propositions:
Despite significant progress, important questions remain:
Long-term efficacy:
Mechanism of action:
Patient selection:
Technical Needs:
Clinical Needs:
Research Needs:
Understanding the treatment experience helps patient preparation:
Pre-Treatment:
During Treatment:
Post-Treatment:
For Patients with Tremor:
Timeline:
Treatment Costs:
Insurance Coverage:
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.
Healthcare systems increasingly evaluate treatments based on cost-effectiveness. Focused ultrasound thalamotomy offers potential economic advantages over traditional surgical approaches:
Direct Treatment Costs:
Indirect Cost Considerations:
Long-term Economic Impact:
Beyond clinical endpoints, treatment success should be measured by quality of life improvements:
Functional Improvements:
Psychological Benefits:
Caregiver Impact:
Sustained benefit tracking is essential for treatment validation:
Monitoring Protocols:
Retreatment Strategies: