Ultrasound Neuromodulation of Circuits and Negative Valence Systems in Treatment-Resistant Depression

Overview

Approximately one third of individuals with Major Depressive Disorder (MDD) are considered treatment-resistant, subject to severe disability and risk of suicide, and exhibit symptoms anchored in abnormalities of Research Domain Criteria (RDoC) Negative Valence Systems behavioral processes. In the present study we plan to use low-intensity focused ultrasound in 120 persons with treatment-resistant MDD to modulate deep white matter tracts connecting the thalamus and different regions of the prefrontal cortex reversibly and non-invasively, with the aim of assigning a causal, mechanistic role to large scale brain circuits in the production of those critical behavioral abnormalities. A successful study will help to attain the precise definition of neuromodulation targets for this clinical population in utter need of help.

Approximately one third of individuals with depression are considered treatment-resistant (TRD) and exhibit symptoms anchored in abnormalities of RDoC Negative Valence Systems behavioral processes. For example, anhedonia and rumination contribute to significant impairment in daily functioning, high relapse rates, and a staggering global toll of over 700,000 annual suicides. One reason for inadequate treatment response is our limited understanding of causal mechanisms linking brain circuit function to Negative Valence behavior abnormalities, which impedes the development of precision neuromodulation treatments. The investigators propose to address this problem by using low-intensity focused ultrasound (LIFU), which can noninvasively and reversibly modulate deep brain circuits, to determine the mechanistic relationship between cortico-subcortical circuits and distinct Negative Valence System behaviors including reward processes and rumination. Substantial preliminary evidence suggests that aberrant connectivity between the thalamus and orbitofrontal (OFC) or anterior cingulate (ACC) cortices in the right hemisphere contribute to distinct depression-related RDoC Negative Valence system behavioral changes. In a preliminary clinical trial, which received a non-significant risk determination by the FDA (NCT05697172) the investigators observed safe modulation of deep white matter tracts using LIFU. The investigators now propose to employ advanced structural imaging techniques to tailor modulation targets to each patient's unique anatomy. The study will involve 120 TRD participants who will receive LIFU and sham stimulation to individually defined white matter tracts connecting thalamus with either OFC (n=60) or ACC (n=60). The investigators will measure resting-state functional magnetic resonance imaging (fMRI) changes, and changes in two behavioral models underlying Negative Valence manifestations (monetary incentive delay and induced rumination tasks). The investigators' hypothesis is that thalamo-OFC and thalamo-ACC hyperconnectivity, historically targeted in neuromodulation techniques useful in TRD, contributes to distortions in distinct behavioral components of the Negative Valence system. This proposal thus has the following Specific Aims: In Aim 1, the investigators will determine the anatomical specificity of LIFU when applied to thalamo-OFC and thalamo-ACC white matter tracts. The investigators predict that LIFU will lead to reduced functional connectivity in the specific cortical regions reached by the modulated white matter bundles. In Aim 2, the investigators will correlate connectivity between thalamus and OFC or ACC, with functional features of distinct behaviors pertaining to the RDoC Negative Valence. Exploratory Aim 3 will establish behavioral correlates of such neural changes. If successful, the present proposal will contribute to understanding clinically meaningful brain-behavior mechanistic relationships by parsing thalamo-prefrontal circuits and RDoC Negative Valence system behaviors. In turn, such definition of targets with a causal role in abnormal behavior processes, could inform precision therapeutic neuromodulation in a psychiatric population in utter need of innovative treatments.