Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human

PLOS ONE RESEARCH ARTICLE Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human Hyun-Chul Kim1¤, Wonhye Lee1, Daniel S. Weisholtz2, Seung-Schik Yoo ID1* 1 Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Kim H-C, Lee W, Weisholtz DS, Yoo S-S (2023) Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human. PLoS ONE 18(7): e0288654. https://doi. org/10.1371/journal.pone.0288654 Editor: Robert Chen, University of Toronto, CANADA Received: January 9, 2023 Accepted: June 30, 2023 Published: July 21, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0288654 Copyright: © 2023 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data underlying the results presented in the study are available from the Harvard Dataverse at doi:10.7910/DVN/ 380AEI [https://dataverse.harvard.edu/dataset. xhtml?persistentId=doi:10.7910/DVN/380AEI]. ¤ Current address: Department of Artificial Intelligence, Kyungpook National University, Daegu, South Korea * Abstract The effects of transcranial focused ultrasound (FUS) stimulation of the primary somatosensory cortex and its thalamic projection (i.e., ventral posterolateral nucleus) on the generation of electroencephalographic (EEG) responses were evaluated in healthy human volunteers. Stimulation of the unilateral somatosensory circuits corresponding to the non-dominant hand generated EEG evoked potentials across all participants; however, not all perceived stimulation-mediated tactile sensations of the hand. These FUS-evoked EEG potentials (FEP) were observed from both brain hemispheres and shared similarities with somatosensory evoked potentials (SSEP) from median nerve stimulation. Use of a 0.5 ms pulse duration (PD) sonication given at 70% duty cycle, compared to the use of 1 and 2 ms PD, elicited more distinctive FEP peak features from the hemisphere ipsilateral to sonication. Although several participants reported hearing tones associated with FUS stimulation, the observed FEP were not likely to be confounded by the auditory sensation based on a separate measurement of auditory evoked potentials (AEP) to tonal stimulation (mimicking the same repetition frequency as the FUS stimulation). Off-line changes in resting-state functional connectivity (FC) associated with thalamic stimulation revealed that the FUS stimulation enhanced connectivity in a network of sensorimotor and sensory integration areas, which lasted for at least more than an hour. Clinical neurological evaluations, EEG, and neuroanatomical MRI did not reveal any adverse or unintended effects of sonication, attesting its safety. These results suggest that FUS stimulation may induce long-term neuroplasticity in humans, indicating its neurotherapeutic potential for various neurological and neuropsychiatric conditions. Introduction Transcranial focused ultrasound (FUS) techniques allow for non-invasive functional modulation of highly region-specific brain areas by locally delivering low-intensity acoustic pressure waves to the brain [1, 2]. With the ability to reach deep brain areas, which has been challenging PLOS ONE | https://doi.org/10.1371/journal.pone.0288654 July 21, 2023 1 / 28 PLOS ONE Funding: This work is supported by the Translational Research Institute for Space Health through National Aeronautics and Space Administration (NASA) Cooperative Agreement NNX16AO69A (to SSY). The funders had no role in study design, data collection, data analysis, and decision to publish or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Focused ultrasound stimulation of human sensory corticothalamic circuits in other non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), transcranial FUS has gathered momentum in the neuroscientific community as a new functional neuromodulation modality. With promising safety records gathered from animal models including non-human primate studies [3–5], the appeal of transcranial FUS brain stimulation among healthy humans is trending upward, as demonstrated in studies involving stimulation of cortical somatosensory [6–8], motor [9–11], and primary visual areas [12]. Furthermore, the ability to stimulate deep brain areas has facilitated clinical investigations that examined its effects on suppressing focal epilepsy [13] and on improving disorders of consciousness [14]. Yet, human studies examining stimulation of the thalamus, along with its safety, have been limited. To achieve neuromodulation, FUS is typically applied in packets of short-duration pulses having a specific pulse duration (PD) at a pulse repetition frequency (PRF), given at an intensity below the level that may elevate tissue temperature [5, 6, 9, 15–17]. Although the exact mechanisms of how ultrasound modulates neural tissue excitability is not yet clearly understood, stimulatory neural tissue responses have been associated with sonication given in short duration (on the order of hundreds of milliseconds) operating through a pulsed mode with a duty cycle greater than 50% (whereby the duty cycle describes the portion of active sonication per stimulation). Use of a pulsing scheme has also shown superior stimulation efficiency over continuous sonication in animal models [18–20]. Through these studies, the choice of sonication parameters has become an important component that may affect stimulation efficiency, demanding in-human evaluation of the effects of PD. Thus, we were motivated to stimulate the primary somatosensory cortex (S1, corresponding to the unilateral hand area representation) and its thalamic projection (i.e., ventral posterolateral nucleus, VPL) in healthy humans, using different PDs (0.5, 1, and 2 ms) at a constant duty cycle of 70%. The stimulatory outcome was assessed from the electroencephalographic (EEG) evoked potentials acquired simultaneously during sonication. Furthermore, to evaluate its safety among healthy individuals, clinical neurological evaluations, EEG, and neuroanatomical MRI were conducted at various time points after the FUS session (...truncated)