Experiment 1: Modulation of Physiological Tremor in Healthy Volunteers Thirty healthy volunteers will undergo TUS targeting the dentate nucleus in a randomized, double-blinded crossover design. Tremor amplitude, induced by a 15 g weight, will be measured using an accelerometer, and EEG will assess neural oscillations and cerebello-thalamo-cortical connectivity. Stimulation will include short-term (1 minute on/off for 12 minutes) and long-term (30 minutes) protocols, as well as closed-loop TUS for phase-specific effects. This experiment aims to optimize stimulation parameters and explore the dentate nucleus's role in tremor generation. Experiment 2: Tremor Modulation in Essential Tremor Patients Thirty ET patients will receive TUS targeting the dentate nucleus with optimized parameters from Experiment 1 in a randomized crossover design. The best protocol from previous experiment will be tested here. Tremor amplitude and EEG will be recorded to assess short- and long-term effects of TUS on pathological tremor.
Experiment 1: Modulation of Physiological Tremor in Healthy Volunteers This is a randomized, double-blinded, crossover study involving 30 healthy volunteers. Healthy volunteers will be recruited from campus with a flyer and using social media platforms. Each participant will undergo two conditions: on-target transcranial focused ultrasound stimulation (TUS) to the dentate nucleus and off-target (sham) stimulation. Initial screening will be performed via phone, after which an informed consent will be signed. The full experiment will consist of four separate visit days, of which only the first one will take place at the UZ Leuven department of Radiology. Visit days 2-4 will entirely be performed at the KU Leuven Brainshub facility in gebouw De Nayer. * Visit 1: Imaging On the first visit, participants will undergo MRI scans to obtain structural (T1-weighted) and Ultrashort Echo Time (UTE) MRI images. These scans will help reconstruct individual head models to estimate skull characteristics and optimize the TUS target engagement. Using the MRI data, simulations will be performed to calculate the optimal position, shape, size, and pressure of the ultrasound beam. This ensures precise targeting of the dentate nucleus on an individual level during subsequent stimulation sessions. * Visit 2: Immediate effects on Tremor Modulation and Phase Entrainment During this visit, participants will perform a task to induce physiological tremor (e.g., holding a weight on their finger). Tremor amplitude will be measured using an accelerometer. TUS will be applied in two conditions: on-target stimulation to the dentate nucleus and off-target sham stimulation. The stimulation will follow a short-term protocol (1 minute on, 1 minute off, repeated for 12 minutes). EEG will be recorded to assess changes in neural oscillations and phase entrainment in the cerebello-thalamo-cortical network. This visit aims to evaluate the immediate effects of TUS on tremor modulation and neural activity. * Visit 3: Prolonged effects on Tremor Modulation This visit will evaluate the long-term effects of TUS on tremor modulation. The stimulation protocol will be extended to 30 minutes of sonication to observe whether prolonged stimulation results in stronger or sustained tremor reduction. As in Visit 2, accelerometer data will be collected to measure tremor amplitude, and EEG will be recorded to monitor changes in brain activity over the extended stimulation period. The goal is to assess the durability of the effects and refine the optimal stimulation duration. * Visit 4: Closed-loop Stimulation for Tremor Suppression On the fourth visit, a closed-loop stimulation protocol will be tested. This involves synchronizing the TUS delivery to either the peak or trough of the tremor oscillation to determine whether phase-specific stimulation enhances tremor modulation. Real-time tremor data will be collected using an accelerometer, and EEG will be used to track neural responses. This visit aims to explore whether closed-loop TUS can provide more precise control over tremor amplitude compared to standard on/off stimulation. Experiment 2: Tremor Modulation in Essential Tremor Patients Building on the results from Experiment 1, 30 ET patients will participate in a similar crossover design. Patients will be recruited by a neurologist collaborating on this project. The optimized TUS parameters from Experiment 1 will be used to target the dentate nucleus. The most optimal protocol for tremor reduction will be selected during this experiment. Thus, experiment 2 will exist of one visit day for imaging and another visit day to test the most optimal TUS protocol. Similarly, tremor amplitude will be measured using an accelerometer, and EEG will monitor neural activity during stimulation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
60
This study will look at both physiological tremor in healthy volunteers and pathological tremor in ET patients. A set of parameters will be tested in healthy volunteers and the optimal combination of pulse repetition frequency (PRF) and pulse duration (PD) will be selected. A closed-loop system will also be tested where the timing of the ultrasound pulses is locked to the peak or the trough of the measured tremor and can adjust in real-time.
This condition will serve as the active control (sham stimulation).
BrainsHub
Leuven, Vlaams-Brabant, Belgium
Tremor amplitude
Extracted from accelerometer data. The PCA component will be calculated by combining data from all three accelerometer axis (x, y and z). The power spectral density average of this PCA component will be calculated before (1min), during and after (1 min) stimulation. The primary outcome is the change in tremor amplitude (m/s²) across pre-, during-, and post-TUS conditions.
Time frame: Experiment 1 (short-term effects): 1-minute recording segments up to 10 minutes after stimulation, Experiment 1(long-term effects): Up to 30 minutes after stimulation Experiment 2 (Essential tremor): Up to 30 minutes after stimulation
Tremor frequency
Tremor frequency will be derived from the same one-dimensional signal obtained via principal component analysis (PCA) of the triaxial accelerometer data. The power spectral density (PSD) will be estimated using Welch's method for each recording segment (pre-TUS, during TUS, post-TUS). The dominant tremor frequency will be defined as the frequency corresponding to the maximum PSD value within the predefined tremor band (e.g., 4-12 Hz) (expressed in Hz)
Time frame: Experiment 1 (short-term effects): 1-minute recording segments up to 10 minutes after stimulation, Experiment 1 (long-term effects): Up to 30 minutes after stimulation Experiment 2 (Essential tremor): Up to 30 minutes after stimulation
EEG oscillatory activity
Absolute and relative power change per band (post-TUS vs baseline, and vs sham/off-target). Power spectral density will be calculated and band-limited power will be extracted: Alpha (8-12 Hz), beta (13-30 Hz),Theta (4-8 Hz) and gamma (\>30 Hz).
Time frame: Experiment 1 (short-term effects): 1-minute segments of on/off stimulation from 10 minutes before stimulation up until 10 minutes after stimulation Experiment 1 (long-term effects) & 2: 10 minutes before stimulation up until 30 minutes after stimulation
EEG Phase
EEG phase (radians) using Hilbert transform at the tremor frequency will be extracted per channel.
Time frame: Experiment 1 (short-term): During 1-minute segments of ON-stimulation Experiment 1 (long-term): During full 30-minute stimulation session. Experiment 2 (essential tremor): During full 30-minute stimulation session.
Phase-Locking Value
Alignment of the instantaneous phase of the EEG signal to TUS pulses (PRF). range 0-1 with 0 = random phase, 1 = perfect alignment
Time frame: Experiment 1 (short-term): During 1-minute segments of ON-stimulation Experiment 1 (long-term): During full 30-minute stimulation session. Experiment 2 (essential tremor): During full 30-minute stimulation session.
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