Transcranial focused ultrasound (FUS) is making progress as a new non-invasive mode of regional brain stimulation. Current evidence of FUS-mediated neurostimulation for humans has been limited to the observation of subjective sensory manifestations and electrophysiological responses, thus warranting the identification of stimulated brain regions. Here, we report FUS sonication of the primary visual cortex (V1) in humans, resulting in elicited activation not only from the sonicated brain area, but also from the network of regions involved in visual and higher-order cognitive processes (as revealed by simultaneous acquisition of blood-oxygenation-level-dependent functional magnetic resonance imaging). Accompanying phosphene perception was also reported. The electroencephalo graphic (EEG) responses showed distinct peaks associated with the stimulation. None of the participants showed any adverse effects from the sonication based on neuroimaging and neurological examinations. Retrospective numerical simulation of the acoustic profile showed the presence of individual variability in terms of the location and intensity of the acoustic focus. With exquisite spatial selectivity and capability for depth penetration, FUS may confer a unique utility in providing non-invasive stimulation of region-specific brain circuits for neuroscientific and therapeutic applications.

Background: Using mobile communication technology as new personalized approach to treat mental disorders or to more generally improve quality of life is highly promising. Knowledge about intervention components that target key psychopathological processes in terms of transdiagnostic psychotherapy approaches is urgently needed. We explored the use of smartphone-based micro-interventions based on psychotherapeutic techniques, guided by short video-clips, to elicit mood changes.Method: As part of a larger neurofeedback study, all subjects—after being randomly assigned to an experimental or control neurofeedback condition—underwent daily smartphone-based micro-interventions for 13 consecutive days. They were free to choose out of provided techniques, including viscerosensory attention, emotional imagery, facial expression, and contemplative repetition. Changes in mood were assessed in real world using the Multidimensional Mood State Questionnaire (scales: good–bad, GB; awake–tired, AT; and calm–nervous, CN).Results: Twenty-seven men participated on at least 11 days and were thus included in the analyses. Altogether, they underwent 335, generally well-tolerated, micro-intervention sessions, with viscerosensory attention (178 sessions, 53.13%) and contemplative repetition (68 sessions, 20.30%) being the most frequently applied techniques. Mixed models indicated that subjects showed better mood [GB: b = 0.464, 95%confidence interval (CI) [0.068, 0.860], t(613.3) = 2.298, p = 0.022] and became more awake [AT: b = 0.514, 95%CI [0.103, 0.925], t(612.4) = 2.456, p = 0.014] and calmer [CN: b = 0.685, 95%CI [0.360, 1.010], t(612.3) = 4.137, p < 0.001] from pre- to post-micro-intervention. These mood improvements from pre- to post-micro-intervention were associated with changes in mood from the 1st day until the last day with regard to GB mood (r = 0.614, 95%CI [0.297, 0.809], p < 0.001), but not AT mood (r = 0.279, 95%CI [−0.122, 0.602], p = 0.167) and CN mood (r = 0.277, 95%CI [0.124, 0.601], p = 0.170).Discussion: Our findings provide evidence for the applicability of smartphone-based micro-interventions eliciting short-term mood changes, based on techniques used in psychotherapeutic approaches, such as mindfulness-based psychotherapy, transcendental meditation, and other contemplative therapies. The results encourage exploring these techniques' capability to improve mood in randomized controlled studies and patients. Smartphone-based micro-interventions are promising to modify mood in real-world settings, complementing other psychotherapeutic interventions, in line with the precision medicine approach. The here presented data were collected within a randomized trial, registered at ClinicalTrials.gov (Identifier: NCT01921088) https://clinicaltrials.gov/ct2/show/NCT01921088.

Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. We examined the neuromodulatory effects of FUS in unanesthetized sheep by developing a custom-fit headgear capable of reproducibly placing an acoustic focus on the unilateral motor cortex (M1) and corresponding thalamic area. The efferent responses to sonication, based on the acoustic parameters previously identified in anesthetized sheep, were measured using electromyography (EMG) from both hind limbs across three experimental conditions: on-target sonication, off-target sonication, and without sonication. Excitatory sonication yielded greater amplitude of EMG signals obtained from the hind limb contralateral to sonication than that from the ipsilateral limb. Spurious appearance of motion-related EMG signals limited the amount of analyzed data (~ 10% selection of acquired data) during excitatory sonication, and the averaged EMG response rates elicited by the M1 and thalamic stimulations were 7.5 ± 1.4% and 6.7 ± 1.5%, respectively. Suppressive sonication, while sheep walked on the treadmill, temporarily reduced the EMG amplitude from the limb contralateral to sonication. No significant change was found in the EMG amplitudes during the off-target sonication. Behavioral observation throughout the study and histological analysis showed no sign of brain tissue damage caused by the acoustic stimulation. Marginal response rates observed during excitatory sonication call for technical refinement to reduce motion artifacts during EMG acquisitions as well as acoustic aberration correction schemes to improve spatial accuracy of sonication. Yet, our results indicate that low-intensity FUS modulated the excitability of regional brain tissues reversibly and safely in awake sheep, supporting its potential in theragnostic applications.

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