The goal of this proof-of-concept study is to examine the effects of a relatively new, non-invasive electrical current-based technique, transcranial temporal interference stimulation (tTIS), in patients with Essential Tremor (ET). TTIS is delivered via a Digitimer Ltd. stimulator, the "DS5 Isolated Bipolar Constant Current Stimulator." The method enables targeting deep cerebral structures to selectively modulate neurons. The structure of interest in the present study is the ventralis intermedius (VIM) of the thalamus, which plays a key role in tremor generation in people with essential tremor. Therefore, techniques targeting the VIM nucleus can potentially improve the tremor and the quality of life in the long term, as is the case with MRI-guided high-intensity focused ultrasound (MRgHIFU). Despite its efficiency, MRgHIFU can lead to side effects that could benefit from improved predictive modeling. In our proof-of-concept study, the investigators aim to examine whether tTIS of the VIM nucleus can alter tremor characteristics and, therefore, mimic the effects of MRgHIFU. This work would pave the way for future clinical trials to design prediction tools for MRgHIFU if the investigators can demonstrate the positive impact of tTIS.

Essential tremor (ET) represents one of the most common movement disorders worldwide, with an estimated prevalence of 1 % across all ages, increasing with age. Despite being considered a benign disease, it can nevertheless lead to significant functional impairment. Several drugs, such as beta-blockers, can be used to alleviate the tremor, but they may not be enough to improve the quality of life, and they can cause significant side effects.

The etiology and pathophysiology of ET are not yet fully understood. One pathophysiological hypothesis for ET is a deficiency in cerebellar GABAergic transmission, leading to abnormal oscillatory activity that interferes with motor function. This abnormal oscillatory activity converges on the thalamus, specifically in the ventralis intermedius (VIM) nucleus. Various surgical or disruptive medical techniques can target this nucleus in case of a drug-resistant tremor or drug intolerance.

One such technique is MRI-guided, high-intensity focused ultrasound thalamotomy (MRgHIFU), which results in a long-lasting, significant reduction of tremor in most cases. Despite the MRgHIFU's millimetric precision, the VIM is not directly visible on peri-operative MRI scans. MRgHIFU thalamotomy can also lead to side effects, such as modifications of sensations (paresthesia), speech difficulties (dysarthria), imbalance (ataxia), or even motor deficits (hemiparesis). Therefore, more accurate tools are needed to predict the effects of MRgHIFU.

One promising technique that could help clinicians predict the effects of MRgHIFU is transcranial temporal interference stimulation. This non-invasive neuromodulation technique uses two pairs of scalp electrodes, which deliver two slightly different high-frequency currents (e.g., f1 = 2.00 kHz; f2 = 2.01 kHz). Frequencies in the kHz range are too high to induce an effect on neurons and nerves. Still, due to their difference Δf = f2-f1, they both interfere in the depth of the brain to create a so-called amplitude-modulated envelope with a beat frequency falling in the physiological range (e.g., Δf = 10 Hz). This allows neuromodulation of deep structures-the VIM in this study-and avoids stimulation of the cortical structures at the same time. The investigators will use the Digitimer Ltd. "DS5 Isolated Bipolar Constant Current Stimulator" to deliver tTIS.

The goal of the proposed proof-of-concept study is to examine the effects of tTIS on tremor modulation in essential tremor patients who are candidates for MRgHIFU thermoablation of the VIM, and to compare the impact of tTIS with the "true" effect of tremor reduction after MRgHIFU. The primary outcome will be the change in tremor amplitude (in mm), as measured by Inertial Measurement Units (IMUs) comprising an accelerometer, a gyroscope, and a magnetometer. The secondary outcomes will be other quantitative tremor parameters, such as the frequency, angular and linear acceleration, and power, as well as safety outcomes.

Inclusion Criteria (for both arms):

• Informed Consent signed by the subject;
• Age ≥ 18 years;
• Diagnosis of Essential Tremor (ET) based on the proposed criteria by the Movement Disorders Society;
• Candidate for MRgHIFU thalamotomy

Exclusion Criteria (for both arms):

• Unable to provide informed consent;
• Severe sensory or cognitive impairment or musculoskeletal dysfunction that prohibits understanding instructions or performing the experimental tasks.

Only for patients undergoing the tTIS protocol (experimental arm):

• Severe neuropsychiatric (e.g., major depression, severe dementia, psychosis) or unstable systemic diseases (e.g., severe progressive and unstable cancer, life-threatening infectious disease);

• Inability to follow or non-compliance with the procedures of the study;

• Contraindications for non-invasive brain stimulation:

  • Electronic or ferromagnetic medical implants or devices
  • History of seizures

De-identified individual participant data, including demographic data, clinical characteristics, and quantitative tremor assessment data, will be shared.

Data will be available upon reasonable request to the corresponding author after publication of the primary results, in accordance with ethical approval and applicable data protection regulations.

After publication of the primary results, upon reasonable request.