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
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.
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. A similar approach was followed in a recent study by Aubry et al. (2024)
with the Insightec Exablate system. 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.