TABLE 2.
tFUS neuromodulation studies in human.
| References | Subjects/study design | Targets | Sonication parameters | indexes | Key findings | Modulate effects | Adverse effects |
| Lee et al. (2015) | Healthy volunteers (n = 1)/within- subjects, sham- controlled study | S1 (hand) | Focused, frequency = 250 kHz, PRF = 500 Hz, TBD = 1 ms, DC = 50%, SD = 300 ms, Isppa = 3 W/cm2 | EEG, fMRI, tactile sensations task | tFUS elicited transient tactile sensations accurately to one finger, evoked cortical potentials similar to the SEPs generated by MN stimulation. | Excitatory | No |
| Lee et al. (2016b) | Healthy volunteers (n = 29)/within- subjects, single- blind, sham- controlled study | V1 | Focused, frequency = 270 kHz, PRF = 500 Hz, PD = 1 ms, DC = 50%, SD = 300 ms, Isppa = 3 W/cm2 | fMRI, EEG, phosphene perception task | tFUS elicited activation of V1 and other visual areas, elicited cortical evoked EEG potentials similar to classical VEPs | Excitatory | No |
| Lee et al. (2016a) | Healthy volunteers (n = 10)/within- subjects, double- blind, sham- controlled study | S1 and S2 | Focused, frequency = 210 kHz, PRF = 500 Hz, PD = 1 ms, DC = 50%, SD = 500 ms, Isppa = 7.0–8.8 W/cm2 | fMRI, EEG, tactile sensory task | tFUS targeting at S1 and S2 separately or simultaneously, elicited tactile sensations from the contralateral hand/arm areas | Excitatory | No |
| Liu et al. (2021) | Healthy subjects (n = 9)/sham-controlled, crossover study | S1 | Focused, frequency = 500 kHz, SD = 500 ms, PRF = 300 Hz | 64-channel EEG and ESI, sensory task | tFUS improved the subjects’ discrimination ability through excitatory effects | Excitatory | Not available |
| Gibson et al. (2018) | Healthy volunteers (n = 40)/between- subjects, single- blind, sham- controlled study | M1 | Unfocused, Continuous, frequency = 2.32 MHz, Isppa = 34.96 W/cm2 | TMS-induced MEPs | Ultrasound increased MEPs amplitude: 33.7% at 1 min, 32.2% at 6 min post stimulation) | Excitatory | No |
| Ai et al. (2018) | Healthy volunteers (n = 6)/Pre-post interventional study | Primary sensorimotor cortex (caudate area) | Focused, frequency = 500 kHz, PRF = 1 kHz, DC = 36% in 3T MRI experiment; frequency = 860 kHz, PRF = 0.5 kHz, DC = 50% in 7T MRI experiment; SD = 500 ms, Isppa: 6 W/cm2 | fMRI scan (cortical BOLD at 3T and sub-cortical BOLD at 7T) | BOLD response was detected in the S1 in the 3T studies and in the caudate in the 7T study | Excitatory | Not available |
| Leo et al. (2016) | Healthy volunteers (n = 5)/within- subjects, sham- controlled study | M1 | Focused, frequency = 500 kHz, PD = 0.36 ms; PRF = 1 kHz; DC = 36%; SD = 500 ms. Isppa: 16.95 W/cm2 | fMRI scan during finger tapping task | tFUS induced BOLD response in the targeted cortical regions (in 3 of 6 subjects) | Excitatory | No |
| Yu et al. (2020) | Healthy subjects (n = 15)/within- subjects, sham- controlled study | S1 (leg area) | Focused, frequency = 500 kHz, SD = 500 ms, PRF = 300 and 3,000 Hz, Isppa = 5.90 W/cm2 | 64-channel EEG and ESI, EMP, voluntary foot tapping task | tFUS modulated MRCP source dynamics with high spatiotemporal resolutions; tFUS increased the MSPA; high ultrasound PRF enhances the MSPA outperforms low PRF. | Excitatory | Not available |
| Legon et al. (2014) | Healthy volunteers (n = 30 totally in 3 exp)/within- subjects, sham- controlled study | CP3 | Focused, frequency = 500 kHz, SD = 500 ms; PRF = 1 kHz; DC = 36%, Isppa = 23.87 W/cm2 | EEG activity recorded from four electrodes surrounding CP3 (C3, CP1, CP5 and P3); SEPs induced by MN stimulation; two-point discrimination tasks | tFUS spatially attenuated the amplitudes of SEPs, modulated the spectral content of sensory-evoked brain oscillations, enhanced the somatosensory discrimination abilities. | Inhibitory | No thermal or mechanical sensations |
| Mueller et al. (2014) | Healthy volunteers (n = 25)/within- subjects, sham- controlled study | CP3 and 1 cm laterally | Focused, frequency = 500 kHz, PD = 0.36 ms; PRF = 1 kHz, DC = 36%; SD = 500 ms, Isppa = 23.87 W/cm2 | EEG data were acquired at sites C3, CP1, CP5, and P3; SEPs induced by MN stimulation | tFUS altered the phase distribution of intrinsic brain activity for beta frequencies, changed the phase rate of beta and gamma frequencies, affected phase distributions in the beta band of early SEPs | Inhibitory | Not available |
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| Legon et al. (2018a) | Healthy volunteers (n = 40)/within- subjects, sham- controlled study | Unilateral sensory nuclei of thalamus | Focused, frequency = 500 kHz; PD = 0.36 ms; PRF = 1 kHz; DC = 36%; Isppa: 7.03 W/cm2 | EEG, SEPs induced by MN stimulation, two-point discrimination tasks | FUS inhibited the amplitude of the P14 SEPs, attenuated alpha and beta power, inhibited the locked gamma power, decreased the performance in tactile judgment task | Inhibitory | Not available |
| Legon et al. (2018b) | Healthy volunteers (n = 50)/within- subjects, sham- controlled study | M1 | Focused, frequency = 500 kHz, PD = 0.36 ms; PRF = 1 kHz; DC = 36%; SD = 500 ms, Isppa = 17.12 W/cm2 | Recruitment curves, MEPs, SICI, ICF, stimulus response reaction time task | tFUS inhibited the amplitude of MEPs, attenuated ICF, reduced reaction time in a motor task. | Inhibitory | Mild and moderate neck pain, sleepiness, muscle twitches, itchiness and headache. |
| Fomenko et al. (2020) | Healthy subjects (n = 16)/double-blinded study | M1 | Annular ultrasound, frequency = 500 kHz, PRF = 1,000 Hz, SD = 0.1–0.5 s, DC = 10/30/50%, Isp ta = 0.93/2.78/4.63 W/cm2 | TMS-induced resting peak-to-peak MEPs, visuomotor task | Ultrasound dose dependently suppressed TMS-elicited MEPs, increased GABAA- mediated SICI and decreased reaction time on visuomotor task | Inhibitory | No |
| Sanguinetti et al. (2020) | Healthy subjects (n = 50)/randomized, placebo-controlled, double-blind study | rIFG | Focused, frequency = 500 kHz, PD = 65 μs, PRF = 40 Hz, DC = 0.26%, SD = 30 s, Ispta = 130 mW/cm2 | Mood questionnaires and EEG, fMRI and resting-state functional connectivity | 30-s tFUS induced positive mood effects for up to 30 min, 2 min of tFUS modulated functional connectivity related to the rIFG and DMN | Unknown | Not available |
| Hameroff et al. (2013) | Chronic pain (n = 31)/double blind, sham- controlled, crossover study | Posterior frontal cortex, contralateral to the maximal pain | Unfocused, Continuous, frequency = 8 MHz, MI = 0.7, max Intensity = 152 mW/cm2 | Heart rate, systolic and diastolic blood pressure, oxygen saturation, numerical rating scale for pain, Visual Analog Mood Scale | 15 s ultrasound significantly improved mood at 10 and 40 min following stimulation | Excitatory | Transient headache exacerbation following stimulation (1 subj) |
| Monti et al. (2016) | Post-traumatic disorder of consciousness 19 days post-injury (n = 1)/Case report, part of an ongoing clinical trial | Thalamus | Focused frequency = 650 kHz, PD = 0.5 ms; DC = 5%, PRF = 100 Hz. Ispta = 720 mW/cm2. | Chart review, response to command, and reliable communication (by yes/no head gesturing) | 3 days of ultrasound treatment the patient demonstrated emergence from minimally conscious state. 5 days after treatment, the patient attempted to walk. | Excitatory | No |
| Beisteiner et al. (2020) | AD patients (n = 35)/multicenter pre-post study | AD relevant brain areas and the global brain | Single ultrashort (3 μs) ultrasound pulses, typical energy levels = 0.2–0.3 mJ/mm2, PRF = 1–5 Hz, maximum energy flux density = 0.25 Mj/mm2 at 4 Hz, maximum Ispta = 0.1 W/cm2, maximum number of pulses per treatment = 6,000 | EEG data recorded at CP3, SEPs, neuropsychological tests, MRI | TPS treatment significantly improved neuropsychological scores, the effects last up to 3 months and correlates with an upregulation of the memory network | Excitatory | No |
| Badran et al. (2020) | Healthy subjects (n = 19)/double-blind, sham-controlled, crossover study | Right anterior thalamus | Focused, frequency = 650 kHz, PD = 5 ms, PRF = 10 Hz, DC = 5%, SD = 30 s, Ispta = 719 and 995 W/cm2 | Sensory threshold, sensory, pain, and tolerance thresholds to a thermal stimulus | Thermal pain sensitivity was significantly attenuated after tFUS treatment | Inhibitory | No |
AD, Alzheimer’s disease; BOLD, blood oxygenation level dependent; DC, duty cycle; DMN, default mode network; EMG, electromyography; ESI, electrophysiological source imaging; Ispta, the intensity of spatial-peak temporal average; M1, primary motor cortex; MEPs, motor-evoked potential; MRCP, movement-related cortical potential; MSPA, MRCP source profile amplitude; MN, median nerve; PRF, pulse repetition frequency; rIFG, right inferior frontal gyrus; S1, left primary and secondary somatosensory cortex; S2, left secondary somatosensory cortex; SEPs, somatosensory evoked potentials; SD, sonication duration; TBD, tone-burst duration; TPS, transcranial pulse stimulation; SICI, short interval intracortical inhibition; TMS, transcranial magnetic stimulation; V1, primary visual cortex; VEPs, visual evoked potentials.