NON-INVASIVE AMYGDALA NEUROMODULATION IN HUMANS WITH FOCUSED ULTRASOUND: NEUROBIOLOGICAL AND CLINICAL EFFECTS IN MOOD, ANXIETY, AND TRAUMA-RELATED DISORDERS

Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. The amygdala plays a critical role in reactivity to emotional stimuli, and amygdala hyperactivity is implicated across MATRDs in pathophysiology and treatment response. 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). Participants also completed a resting state scan and an emotional face processing paradigm before and after each active/sham in-scanner sonication to assess acute effects on amgydala intrinsic connectivity and responses to naturalistic emotional stimuli. Then, 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 during sonication. Following sonication, active (vs. sham) tFUS induced emotion non-specific attenuated activation in the left amygdala target, as well as right amygdala, bilateral anterior insula, and dorsal anterior cingulate (dACC) (time x session corrected p’s < 0.05). Greater emotion non-specific activation attenuations were observed for MATRD patients in more lateral portions of bilateral amygdala and bilateral mid/posterior insula (group x time x session corrected p’s < 0.05). Active (vs. sham) tFUS attenuated left amygdala intrinsic connectivity with right amygdala (time x session corrected p’s < 0.05) and produced increased left amygdala connectivity with right dACC in the MATRD but not HC group (group x time x session corrected p’s < 0.05). Daily rtFUS treatment 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 at post-treatment. Findings provide initial evidence of tFUS capability to rapidly and durably modulate amygdala function, safety and feasibility of rtFUS treatment in MATRDs, and impetus for future double-blind randomized controlled trials to examine efficacy. Additional work is needed to optimize energy delivery to subcortical targets, define optimal sonication parameters for desired effects, and examine durability of benefits beyond the acute treatment phase.

References

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