Parsing Mechanistic Relationships Between Circuits and Negative Valence System Behaviors in Treatment-Resistant Depression with Ultrasound Neuromodulation - PROJECT SUMMARY 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 abnor- malities, which impedes the development of precision neuromodulation treatments. We 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 evi- dence 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 sys- tem behavioral changes. In a preliminary clinical trial, which received a non-significant risk determination by the FDA (NCT05697172) we observed safe modulation of deep white matter tracts using LIFU. We now propose to employ advanced structural imaging techniques to tailor modulation targets to each patient's unique anatomy. Our 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). We 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). Our 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, we will determine the anatomical specificity of LIFU when applied to thalamo-OFC and thalamo-ACC white matter tracts. We predict that LIFU will lead to re- duced functional connectivity in the specific cortical regions reached by the modulated white matter bundles. In Aim 2, we 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. 1
