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Low-intensity transcranial focused ultrasound amygdala neuromodulation

Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. Non-invasive neuromodulation is a second-line treatment approach, but current methods rely on cortical targets to indirectly modulate subcortical structures, e.g., the amygdala, implicated in MATRDs. Low-intensity transcranial focused ultrasound (tFUS) is a non-invasive technique for direct subcortical neuromodulation, but its safety, feasibility, and promise as a potential treatment is largely unknown. In a target engagement study, magnetic resonance imaging (MRI)-guided tFUS to the left amygdala was administered during functional MRI (tFUS/fMRI) to test for acute modulation of blood oxygenation level dependent (BOLD) signal in a double-blind, within-subject, sham-controlled design in patients with MATRDs (N = 29) and healthy comparison subjects (N = 23). In an unblinded treatment trial, the same patients then underwent 3-week daily (15 sessions) MRI-guided repetitive tFUS (rtFUS) to the left amygdala to examine safety, feasibility, symptom change, and change in amygdala reactivity to emotional faces. Active vs. sham tFUS/fMRI reduced, on average, left amygdala BOLD signal and produced patient-related differences in hippocampal and insular responses. rtFUS was well-tolerated with no serious adverse events. There were significant reductions on the primary outcome (Mood and Anxiety Symptom Questionnaire General Distress subscale; p = 0.001, Cohen’s d = 0.77), secondary outcomes (Cohen’s d of 0.43–1.50), and amygdala activation to emotional stimuli. Findings provide initial evidence of tFUS capability to modulate amygdala function, rtFUS safety and feasibility in MATRDs, and motivate double-blind randomized controlled trials to examine efficacy. ClinicalTrials.gov registration: NCT05228964

Figure depicts mean individual pre- and post-rtFUS activation values averaged over suprathreshold voxels in the portion of the left amygdala identified by the linear mixed effects model as demonstrating a significant time x task condition interaction. Additional causal modeling may be helpful to better support one or the other hypothesis, though a temporally and spatially precise method of neuronal recording (such as intracranial depth electrodes) in both structures (where time-lagged analyses could produce findings with a high degree of confidence) would be needed to definitively tease apart the possible contributions. Mahoney JJ, Haut MW, Carpenter J, Ranjan M, Thompson-Lake DGY, Marton JL, et al. Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial.

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