Transcranial ultrasonic stimulation of the primary motor cortex

Transcranial ultrasonic stimulation (TUS) is a non-invasive brain stimulation
(NIBS) technique characterised by its superior spatial focality and ability to
reach both superficial and deep regions of the brain. At present, it is
important to confirm the fundamental neurophysiological effects of TUS. This
can be achieved by measuring the impact of TUS on the excitability of the
primary motor cortex (M1). Previous research has combined TUS with transcranial
magnetic stimulation (TMS) and observed a reduced amplitude of TMS-elicited
muscle twitches with TUS than without TUS. Considering the fundamental nature
of these findings, independent replications are required to confirm and expand
our understanding of the fundamental neurophysiological effects of TUS.
Therefore, we hypothesize that in two replication experiments, we will solidify
previous findings on the inhibitory outcome of TUS on M1 excitability and its
relationship with TUS sonication duration. Furthermore, previous research has
found that a blocked rather than an interleaved presentation of TUS parameter
conditions resulted in more robust effects. Therefore, we further hypothesize
that in a novel experiment, we may find differences in the magnitude of effect
of varying TUS sonication durations. This effort may indicate potential
cumulative effects of TUS and will further serve to inform the experimental
design of future studies.

Our primary objective is to replicate two experiments conducted by Fomenko and
colleagues (2020), the first investigating whether TUS over M1 decreases
excitability, and the second investigating whether varying TUS sonication
duration significantly affects M1 excitability. Here, we will additionally
conduct a novel investigation of whether a more robust effect of varying TUS
sonication durations is observed when parameters are presented in a blocked
versus interleaved design.
Our secondary objective is to establish the technical feasibility of
combining TMS and TUS at Radboud University.

The present study will be a single-blind randomized sham-controlled trial. The
study consists of two sessions. In the first, participants* resting motor
threshold will be measured and structural MRI scans will be obtained. The
second session is the intervention session. There will be two within-subject
factors. The first is TUS (passive sham / active sham / verum TUS). The second
is Parameter Presentation (blocked / interleaved).

Participants will receive TMS at standard supra-threshold intensity and TUS at
standard sub-threshold intensity.

Participants will receive no direct benefit from participating, though
participants will be financially compensated where applicable. However,
participants may see benefit in gaining first-hand experience with TUS. Before
participation, all subjects will be thoroughly screened for contraindications
for NIBS and MRI. TMS is a widely used NIBS technique and is associated with
minimal risk. There have been no reports of serious adverse events in healthy
participants when using protocols in accordance with published safety
guidelines (i.e., Rossi et al., 2020; see Donders NIBS SOP). The estimated risk
for participating in TUS experiments is minimal. TUS for human neuromodulation
has never resulted in serious adverse events (Pasquinelli et al., 2019). In
fact, there have been no reports of serious adverse events related to
diagnostic ultrasound either (ter Haar, 2010). Safety is further secured by
adherence of TUS experiments to internationally recognized guidelines (e.g.,
from the Food and Drug Administration) for diagnostic ultrasound. For both TMS
and TUS, minor side effects may include light transient headache and fatigue.
All in all, the risk and burden associated with participation can be considered
minimal, and we do not expect any serious adverse events during the project.