Ultrasound Neuromodulation in Essential Tremor

Hypothesis

Precisely targeted low-intensity focused ultrasound (LIFU) modulation of the dentatorubrothalamic tract (DRTT) results in transient improvement of essential tremor (ET). DRTT LIFU neuromodulation produces functional connectivity changes that mirror brain network changes after MR-guided high-intensity focused ultrasound (HIFU) thalamotomy.

Aims

1. To determine the optimal stimulation parameters for DRTT LIFU neuromodulation: the investigators will record wrist accelerometer signals while systematically varying pulse repetition frequency, duty cycle, and acoustic intensity. 2. To map network effects of DRTT LIFU neuromodulation: the investigators will record resting state fMRI (rs-fMRI) immediately after DRTT LIFU neuromodulation with the parameters most effective at reducing tremor in each patient.

Design

This is a within-subject repeated-measures interventional study designed to determine the set of LIFU stimulation parameters that are maximally effective at producing a temporary tremor reduction when applied to the DRTT - the white matter circuit in the brain in which abnormal activity causes essential tremor.

The investigators will recruit patients from the established MR-guided high-intensity focused ultrasound (HIFU) ET program at UCSF (which treats 6-9 patients/month). Due to the logistical complexity of performing MRI in patients with MR-conditional pacemakers (need for device and patient monitoring), patients with pacemakers will be excluded from enrollment. Study inclusion criteria will otherwise be similar to those for the HIFU procedure itself, namely medically refractory tremor that is expected to improve with HIFU thalamotomy without contraindications to MRI or inability to stop anticoagulation. As part of their routine pre-procedure evaluation these patients receive a dedicated head CT for calculation of skull density ratio (SDR) and a 3T brain MRI that includes high resolution diffusion imaging for tractography to identify the DRTT, as well as specialized anatomic scans (including proton density (PD) and white matter nulled T1 (wm-null T1) sequences to define adjacent thalamic anatomy.

Study participants will undergo a single LIFU session lasting 3-4 hours, generally in the 1-2 days prior to their HIFU treatment. The investigators will perform LIFU stimulation using a commercially available, portable, neuronavigated focused ultrasound system (NeuroFUS PRO, BrainBox, Cardiff, UK) and will target LIFU stimulation using the same image-guided protocol used for the patient's subsequent HIFU treatment. Wrist-based accelerometers (MP160 + TSD109A; BIOPAC Systems, Inc.) will be used to provide a quantitative behavioral readout of the LIFU effect. The investigators will use power spectrum density analysis of accelerometer signals to quantify the severity of tremor before and after LIFU and HIFU sonications. To evaluate the effect of DRTT LIFU on tremor severity and the contribution of the different acoustic parameters tested, the investigators will perform individual- and group-level statistical analyses on the quantified tremor power in the characteristic ET range of 4-12 Hz. The hair on the participant's head will be shave at the start of the session to facilitate the passage of the ultrasound energy (an existing requirement of the subsequent HIFU treatment).

The transient nature of LIFU tremor reduction (on the order of 10-20 minutes) will facilitate high-throughput parameter screening through repeated sonications within the same session (up to 25, depending on patient response). Stimulation protocols consisting of 5 seconds of active stimulation followed by 10 seconds of no stimulation repeated four times (total 60 s) will be delivered using a range of sample parameters. Stimulation parameters will be shuffled in each session to control for carryover effects at the group level. After each 60-s stimulation, there will be a 3 minute inter-stimulation period, during which tremor severity will be monitored every 60 seconds through quantitative accelerometer recordings. If a change in tremor severity greater than 50% is found in the post-LIFU period compared to the pre-LIFU baseline, the investigators will wait until tremor returns to a level comparable to baseline before proceeding with additional stimulations. The entire LIFU stimulation session will last approximately 100 minutes, sufficient to screen up to 25 stimulation protocols (1 min sonication + 3 min wait per protocol) depending on tremor response.

At the end of the session, the investigators will identify the stimulation parameters that produced the largest tremor suppression compared to the respective pre-LIFU baseline. They will then deliver a sham (off-target or defocused) sonication using these maximally effective parameters to control for nonspecific sensory and auditory effects evoked by the ultrasound stimulation. Following this, the investigators will perform a final active sonication targeting the DRTT with the maximally effective parameters, this final stimulation will be immediately followed by a brief (\~20-30 minute) MRI scan to measure the effects of LIFU on brain functional connectivity derived from rs-fMRI.

Patients will then proceed with their scheduled HIFU treatment, which will include similar intra-procedure wrist-base accelerometer measurements to document behavioral effects of HIFU on ET, as well as post treatment MRI to evaluate for post-treatment complications and to measure the effects of HIFU on brain functional connectivity as assessed with rs-fMRI.

• Increases or decreases in functional connectivity of brain networks [Time frame: 20-30 minute MRI scan at the end of the 3-4 hour experimental session]