Transcranial Ultrasonic Stimulation of the Human Amygdala during Threat Learning

Abstract

Transcranial Ultrasonic Stimulation (TUS) is a novel non-invasive neuromodulation technique that can achieve focal modulation of deep brain structures such as the amygdala. In this study, we combined TUS with well-validated fear conditioning procedures, exploiting the unique opportunity for a causal test of amygdala-dependent threat learning processes in healthy humans. Ten healthy participants received online bilateral amygdala-TUS during a standard fear conditioning procedure known to involve the amygdala. We stimulated at 250kHz, with a 1000Hz pulse repetition frequency and 30% duty cycle, and with an intracranial spatial-peak pulse-averaged intensity (Isppa) below 20W/cm2. TUS was delivered on a trial-by-trial basis and at the same time as presentation of the conditioned stimulus. The fear conditioning procedure was composed of an acquisition phase, followed by a distractor task, and a recall phase, which included spontaneous recall and recall following a reinstatement procedure. Neuronavigation was used throughout the entire procedure for accurate TUS targeting. We assessed the neuromodulatory effects of amygdala-TUS using a comprehensive set of physiological markers of threat learning and recall, including skin-conductance (SCR) and heart rate response (HRR). We found a significant effect of online TUS on SCR, though this did not seem to affect threat learning. No effects of TUS were found during recall or on expression to the aversive stimulus. In light of our findings, we speculate on the idea that the human amygdala might in fact not have a crucial role in threat learning, though, we strongly emphasize that more robust and consistent evidence, which the field currently lacks, is necessary. Key words: transcranial ultrasound stimulation; TUS; threat learning; amygdala