Donders Institute for Brain, Cognition, and Behaviour; Radboud University Nijmegen, Nijmegen, Netherlands
Yazan Shamli Oghli
Krembil Research Institute, University Health Network; University of Toronto, Toronto, Canada
Talyta C Grippe
Krembil Research Institute, University Health Network; University of Toronto, Toronto, Canada
Tulika Nandi
Neuroimaging Center; Johannes-Gutenberg University Medical Center Mainz, Mainz, Germany
Judith Lefkes
Donders Institute for Brain, Cognition, and Behaviour; Radboud University Nijmegen, Nijmegen, Netherlands
Sjoerd W Meijer
Donders Institute for Brain, Cognition, and Behaviour; Radboud University Nijmegen, Nijmegen, Netherlands
Soha Farboud
Donders Institute for Brain, Cognition, and Behaviour; Radboud University Nijmegen, Nijmegen, Netherlands
Marwan Engels
Donders Institute for Brain, Cognition, and Behaviour; Radboud University Nijmegen, Nijmegen, Netherlands
Michelle Hamani
Krembil Research Institute, University Health Network; University of Toronto, Toronto, Canada
Melissa Null
Neuroimaging Center; Johannes-Gutenberg University Medical Center Mainz, Mainz, Germany
Angela Radetz
Neuroimaging Center; Johannes-Gutenberg University Medical Center Mainz, Mainz, Germany
Umair Hassan
Neuroimaging Center; Johannes-Gutenberg University Medical Center Mainz, Mainz, Germany
Ghazaleh Darmani
Krembil Research Institute, University Health Network; University of Toronto, Toronto, Canada
Andrey Chetverikov
Donders Institute for Brain, Cognition, and Behaviour; Radboud University Nijmegen, Nijmegen, Netherlands; Department of Psychosocial Science, Faculty of Psychology, University of Bergen, Bergen, Norway
Department of Psychosocial Science, Faculty of Psychology, University of Bergen, Bergen, Norway
Til Ole Bergmann
Neuroimaging Center; Johannes-Gutenberg University Medical Center Mainz, Mainz, Germany; Leibniz Institute for Resilience Research Mainz, Mainz, Germany
Robert Chen
Krembil Research Institute, University Health Network; University of Toronto, Toronto, Canada
Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Furthermore, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Furthermore, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.
