Reversible and Noninvasive Modulation of a Historical Surgical Target for Depression with Low Intensity Focused Ultrasound

Major depressive disorder has a point prevalence of 5% of the world population and is the main cause of disability, with up to a third of patients not responding to first-line treatments. Surgical neuromodulation is offered to only an anecdotal proportion of these patients, because while these methods are curative in some individuals, the proportion of responders rarely exceeds 50%. Recent efforts to establish reliable brain circuit-symptom relationships and thus predict response have involved mapping with multiple intracranial electrodes, but the impracticality of this approach currently prevents its application at scale. In the present study (ClinicalTrials.gov identifier NCT05697172; FDA Q220192) we begin to address this gap by leveraging low-intensity focused ultrasound (LIFU), a novel noninvasive technique, to modulate the anterior limb of the internal capsule, which is an established surgical deep white matter target for depression. We based our study on burgeoning in vitro evidence that LIFU attenuates axonal conduction by operating mechanosensitive channels in nodes of Ranvier. Compared with sham stimulus, active LIFU produced a functional disconnection of gray matter hubs reached by the sonicated axonal tracts, an increase in positive emotion, and top-down effects on the cardiovascular autonomic balance. Our results using LIFU of deep-brain white matter tracts in humans open three potential avenues to understand the mechanisms and improve the outcome of depression, namely attaining a personalized definition of brain circuit-symptom relationships, serving as a noninvasive probe for neuromodulation before irreversible procedures in a "try before you buy" approach, and ultimately emerging as a therapeutic intervention itself.