Dose-Dependent Functional Connectivity Effects of Low-Intensity Focused Ultrasound Applied to Deep White Matter Tracts in Humans

PROJECT ABSTRACT Low intensity focused ultrasound (LIFU) is a novel technique producing noninvasive, reversible, and anatomically precise neuromodulation of deep structures in the brain. Thus far, it has been successfully employed in humans to modulate the activity of gray matter hubs, including amygdala, thalamus, and cerebral cortex. Burgeoning in vitro data shows that LIFU is also a powerful modulator of axonal conduction, by operating mechanosensitive TRAAK potassium channels in nodes of Ranvier. In a recently completed pilot study (NCT 05697172; FDA non-significant risk), we translated those findings to human subjects by applying LIFU to deep brain white matter tracts, reasoning that a successful study would allow the modulation of large- scale brain circuits and thus potentially explore their mechanistic relationship with normal and abnormal behavior. Specifically, we observed that a single sonication applied to tracts traversing the anterior limb of the internal capsule (ALIC) produces a functional disconnection of the connected gray matter regions, as assessed with resting-state functional magnetic resonance imaging (fMRI). Now we propose to define the dose- dependent effects of LIFU applied to white matter tracts regarding both intensity and duration of its neuromodulatory effects. We plan to study 60 healthy adults who will be randomly exposed to two different doses of LIFU applied to tracts connecting the thalamus with the subgenual cingulate (SGCC) and orbitofrontal (OFC) cortices, namely one and three LIFU epochs (as employed in our pilot study: 80 s duration; 2.26 Watt/cm2 derated tissue peak pulse average intensity; 10% duty cycle, 500 kHz). The target white matter tracts will be defined in each individual participant by means of probabilistic tractography. The Aim 1 of this proposal is to determine the relationship between LIFU dose and intensity of target engagement in terms of decreased fMRI functional connectivity between the gray matter regions connected by the sonicated white matter tracts (i.e., thalamus and both SGCC and OFC). Aim 2 is to determine the influence of baseline structural (number of connecting streamlines) and functional (fMRI connectivity) on the dose-dependent LIFU modulation effects. In Aim 3 we will determine the duration of the neuromodulation effect of the two different doses of LIFU. A successful study will result in the definition of dose-response relationships between white matter LIFU modulation and engagement of the targeted brain circuit. This will pave the way for the development of mechanistic studies consistently linking aberrant function of large-scale brain circuits and basic behavioral processes, with the long-term goal of improving the definition of precision neuromodulation targets in treatment-resistant depression and other psychiatric disorders.