Noninvasive suppression of responses to threat using focused ultrasonic waves.

The processing of threat- and fear-related responses is known to involve the amygdala and the bed nucleus of the stria terminalis (BNST). Malignant activity in these nuclei is associated with several important disorders, including generalized anxiety disorder and post-traumatic stress disorder. A noninvasive approach to modulate these deep brain circuits could provide novel treatment options for these disorders, but current noninvasive approaches cannot access these targets directly. This study modulated these nuclei using transcranial low-intensity focused ultrasound in non-human primates. The ultrasound was delivered into these circuits prior to an emotional stimulus (neutral, submissive, or threatening monkey faces or snake images) while quantifying the system's autonomic response using the pupil size. We found that the ultrasound stimulation substantially reduced the pupillary responses to threat images in male macaques. The effect was observed specifically for threat face images and specifically for focused ultrasound; not for other types of images or for unfocused or no ultrasound. Thus, focused ultrasound targeting fear circuits can suppress responses to threat images. This approach could be developed into noninvasive treatments of disorders that affect these circuits.<b>Significance statement</b> Responses to threat often become maladaptive, leading to disorders that include generalized anxiety disorder and post-traumatic stress disorder. The neural circuitry underlying fear processing is situated deep in the brain, and has thus been difficult to access using existing neuromodulation approaches. This study shows that low-intensity focused ultrasound targeting these deep brain circuits in non-human primates specifically suppresses responses to threat images. This approach could provide a non-invasive way to modulate processing of fear.