Sustained Reduction of Essential Tremor with Low-Power Non-Thermal Transcranial Focused Ultrasound Stimulation in Humans

Background

Essential Tremor (ET) is one of the most common neurological disorders, primarily characterized by bilateral upper limb action tremor that persists for more than three years. For ET unresponsive to medication, neurosurgical treatments like Deep Brain Stimulation (DBS) and ablation are often used. Although DBS is considered the gold standard for treating various movement disorders, its invasiveness and limited spatial specificity necessitate the search for more precise and less side-effect-prone treatment methods.

In recent years, Transcranial Ultrasound Stimulation (TUS) has emerged as a non-invasive brain stimulation technology capable of achieving millimeter-level precision by compensating for cranial bone distortion. This technique bypasses the invasive procedures associated with DBS and overcomes the spatial specificity limitations of Transcranial Magnetic Stimulation (TMS). This paper hypothesizes that MR-guided low-power TUS can induce a sustained reduction in tremor amplitude in medication-refractory ET patients.

Paper Source

The paper, titled “Sustained Reduction of Essential Tremor with Low-Power Non-Thermal Transcranial Focused Ultrasound Stimulations in Humans,” is authored by Thomas Bancel, Benoît Béranger, Maxime Daniel, among others, from well-known research institutions such as Physics for Medicine Paris, Insightec, and ICM-Paris Brain Institute. This paper was published in the 2024 edition of the journal “Brain Stimulation” and went online on May 9, 2024.

Research Procedure

Methods

1. Patient Inclusion and Ethical Review:

   • All patients (9 in total) participated in the ULTRABRAIN study (ClinicalTrial.gov ID: NCT04074031), which was approved by an ethics committee.
   • Patients signed a written informed consent and underwent thalamotomy immediately after the neurostimulation study.

2. Motor Assessment:

   • Baseline tremors were assessed using the Clinical Rating Scale for Tremor (CRST), developed by Fahn, Tolosa, and Marin.
   • The severity of the tremor was assessed by attaching 3D MR-compatible accelerometers to the back of both hands in standard tremor assessment postures.

3. Anatomical Targeting:

   • After obtaining anatomical and Diffusion Tensor Imaging (DTI) sequence images using a 3T Siemens Prisma MRI system, neurosurgeons used the Guiot Atlas for anatomical target localization of VIM and DRT.

4. Neurostimulation Protocol:

   • Low-power ultrasound stimulation was performed using the Insightec Exablate Neuro device, which features a 15 cm radius, 1024 element array, targeting the dominant hand of each patient.
   • Different ultrasound stimulation modes were tested, including Mode 1, high-duty cycle Mode 2, and low-duty cycle Modes 3 and 4, to investigate their neurostimulation effects on specific tremor target areas.

5. Tremor Data Collection and Analysis:

   • Tremor data were recorded before and after each stimulation session and analyzed using custom MATLAB software to determine changes in tremor power.

Results

1. Overall Tremor Power Reduction:

   • VIM neurostimulation combined with low-duty cycle (5%) DRT stimulation significantly reduced tremor power in four patients, with the lowest reduction reaching 89.9%.
   • Patients with VIM low-duty cycle (5%) stimulation alone saw reductions as high as 93.4%.
   • Four patients showed no response.
   • The target area temperature only slightly increased to 37.2 ± 1.4°C, indicating no significant thermal effects.

2. Statistical Analysis:

   • Most patients experienced significant tremor power reductions under specific ultrasound stimulation modes, with individual variability. However, overall data show that appropriate ultrasound parameters and targeting can produce significant tremor improvement.

Conclusion and Value

This experimental clinical study demonstrated the feasibility and efficacy of MR-guided low-power TUS in reducing essential tremor. Results indicate that TUS can substantially reduce tremor power in a short time, with effects lasting up to 30 minutes in some patients. This study not only lays the foundation for non-invasive treatments for ET but also offers new insights into the use of TUS in neuro-stimulation applications.

Highlights

1. Innovation and Uniqueness:

   • This study is the first to clinically validate the significant control effect of low-power, non-thermal TUS on ET, offering new directions for future research and clinical applications.

2. Precise Targeting:

   • Utilizing advanced MR imaging technology and precise ultrasound targeting equipment achieved high-precision tremor target localization, showcasing clear advantages over traditional TMS and DBS.

3. Non-Thermal Mechanism:

   • The tremor improvement observed in this study was not caused by thermal effects, supporting the main mechanism of action as non-thermal, thus highlighting the safety and controllability advantages of TUS.

4. Future Research Directions:

   • This study paves the way for the extensive application of TUS in neuro-stimulation, particularly for disorders involving deep brain structures. Future research should focus on exploring the effects of different ultrasound parameters on tremor control and include comparative studies to further verify and refine the findings.

This paper showcases the great potential of TUS in the field of neuroscience, looking forward to more in-depth scientific explorations into its mechanisms and application value.