Low-intensity focused ultrasound to human amygdala reveals a causal role in ambiguous emotion processing and alters local and network activity

The amygdala shows abnormal metabolism in depression, a disorder marked by altered emotion, motivation, and learning. Yet its causal role in these processes remains unclear because non-invasive, reversible perturbation in humans has not been possible. We used transcranial focused ultrasound stimulation (TUS) to modulate basolateral amygdala (BLA) activity. In separate sessions, healthy volunteers received offline TUS to bilateral BLA, mid-insula, or sham before completing a novel emotional learning task validated online. 7T-resting-state connectivity and metabolite measures confirmed target engagement: BLA-TUS reduced the BLA's connectivity fingerprint and lowered its excitation/inhibition balance. Behaviorally, BLA-TUS increased approach tendencies toward neutral, emotionally ambiguous faces in a stimulation-volume-dependent manner and slowed responses to neutral and happy faces. These effects were functionally and regionally specific and suggest a causal role for the amygdala in resolving emotional ambiguity. Our findings inform studies of mood disorders, where difficulty resolving ambiguity may contribute to emotional and learning biases.