Philipp Ziebell, Johannes Rodrigues, André Forster, Joseph L. Sanguinetti, John JB. Allen, Johannes Hewig

• Highlights • Transcranial ultrasound neuromodulation/stimulation (TUS) is a growing field. • We conducted a double-blind sham-controlled within-subjects large sample TUS study. • Right prefrontal cortex TUS inhibits midfrontal theta electroencephalography (MFT). • TUS MFT inhibition explains greater approach versus withdrawal in a virtual T-maze. • This distinct TUS-MFT-behavior link merits future basic and applied research. Abstract Recent reviews highlighted low-intensity transcranial focused ultrasound (TUS) as a promising new toolHighlights • Transcranial ultrasound neuromodulation/stimulation (TUS) is a growing field. • We conducted a double-blind sham-controlled within-subjects large sample TUS study. • Right prefrontal cortex TUS inhibits midfrontal theta electroencephalography (MFT). • TUS MFT inhibition explains greater approach versus withdrawal in a virtual T-maze. • This distinct TUS-MFT-behavior link merits future basic and applied research. Abstract Recent reviews highlighted low-intensity transcranial focused ultrasound (TUS) as a promising new tool for non-invasive neuromodulation in basic and applied sciences. Our preregistered double-blind within-subjects study (N = 152) utilized TUS targeting the right prefrontal cortex, which, in earlier work, was found to positively enhance self-reported global mood, decrease negative states of self-reported emotional conflict (anxiety/worrying), and modulate related midfrontal functional magnetic resonance imaging activity in affect regulation brain networks. To further explore TUS effects on objective physiological and behavioral variables, we used a virtual T-maze task that has been established in prior studies to measure motivational conflicts regarding whether participants execute approach versus withdrawal behavior (with free-choice responses via continuous joystick movements) while allowing to record related electroencephalographic data such as midfrontal theta activity (MFT). MFT, a reliable marker of conflict representation on a neuronal level, was of particular interest to us since it has repeatedly been shown to explain related behavior, with relatively low MFT typically preceding approach-like risky behavior and relatively high MFT typically preceding withdrawal-like risk aversion. Our central hypothesis is that TUS decreases MFT in T-maze conflict situations and thereby increases approach and reduces withdrawal. Results indicate that TUS led to significant MFT decreases, which significantly explained increases in approach behavior and decreases in withdrawal behavior. This study expands TUS evidence on a physiological and behavioral level with a large sample size of human subjects, suggesting the promise of further research based on this distinct TUS-MFT-behavior link to influence conflict monitoring and its behavioral consequences. Ultimately, this can serve as a foundation for future clinical work to establish TUS interventions for emotional and motivational mental health.…