Reversible modulation of a deep white matter surgical target for depression with low-intensity focused ultrasound

Current efforts to establish anatomically precise and causal deep brain circuit-symptom relationships to predict surgical responses require the insertion of intracranial electrodes. In the present study (ClinicalTrials.gov NCT05697172) we examined whether low-intensity focused ultrasound (LIFU; FDA Q220192) could modulate the white matter tracts in the anterior limb of the internal capsule (ALIC), a common surgical target for the treatment of refractory depression. We based our human study on the in vitro observation that ultrasound attenuates conduction in myelinated axons by operating mechanosensitive potassium channels in nodes of Ranvier. We employed a cross-over, randomized, sham-controlled, double-blind design to establish the ability of LIFU (80 s; 0.5 MHz; estimated peak tissue energy 2.26 Watt/cm²; 10% duty cycle) to engage a target in the ALIC in 21 patients with Major Depressive Disorder. Targets were defined as the area with highest density of thalamo-prefrontal probabilistic tractography streamlines. We measured changes in magnetic resonance functional connectivity, repetitive mentation, emotional state, and cardiac autonomic output. Compared with sham stimulation, active LIFU produced a functional disconnection of gray matter hubs connected by the sonicated tracts (d = -1.55; p < 0.001), an increase in positive emotion (d = 0.6; p = 0.04), and decreased cardiac sympathovagal balance (d = -0.57; p = 0.01). The observation that LIFU engages deep white matter tracts related to depression symptoms paves the way for rigorously investigating (1) mechanistic definitions of brain circuit-symptom relationships, (2) noninvasive, reversible, and anatomically precise probing of such circuits before surgery, and (3) potential use as a new therapy for depression.