Effect of low-intensity focused ultrasound of right anteromedial cortico-subcortical circuits on repetitive negative and self-referential thinking in depression: a sham-controlled randomized feasibility trial

Abstract Background Depression (MDD) is associated with an unusually large amount of individual disability and societal costs as well as unsatisfactory outcomes with well-established therapies, including psychotropic drugs and different types of psychotherapy. Based on increasing interest in modulation of brain circuits involved in specific symptoms of depression, we chose to target a single measurable and replicable construct of depression, repetitive negative thinking (RNT), a transdiagnostic clinical manifestation that cuts across a variety of internalizing psychiatric disorders, but in the case of depression, it is associated with persistent symptoms, treatment resistance, proneness to relapse after treatment, and more suicidal ideation, behavior, and completed suicides. With the help of using low-intensity transcranial focused ultrasound (LIFU), we will modulate individually-identified neural circuits associated with (a) the generation and maintenance of repetitive negative thinking (RNT), and (b) affective processing of self-referential adjectives. Methods The study will consist of two groups/arms subjected consecutively to either LIFU sonication or sham sonication in a crossover fashion. It will be a single-site, pilot study involving 20 participants with depression (10 with low RNT and 10 with high RNT) and 10 healthy controls. This project has two phases. First, we will use advanced structural-functional connectivity analysis techniques to individually define anatomical tracts that support functional connectivity alterations associated with the intensity of RNT in each MDD patient. Informed by recent neurocircuitry evidence in MDD and obsessive-compulsive disorder we hypothesize that structural pathways linking the thalamus, the orbitofrontal cortex, and the anterior cingulate cortex in the right hemisphere will be associated with RNT. Second, by using the resulting pathways to guide the choice of the target(s) for LIFU neuromodulation, we will probe its on (1) measures of RNT (Brief State Rumination Inventory), (2) functional connectivity between regions known to have an anatomical connection in the individual participant, and (3) neural processing of self-referential affective adjectives. Discussion We anticipate this feasibility study will provide the information necessary for the design of a larger-scale clinical trial to establish 1) a definitive causal relationship between brain circuits and RNT as a symptom, and 2) a novel target to modulate RNT in the clinical setting. Trial registration: In process at ClinicalTrials.gov. FDA Non-Significant Risk determination Q220192 (November 4, 2022).