Table 1.
tFUS and tUS neuromodulation studies.
| References | Device | N. of subjects | Disease type/healthy subjects | Study design | Stimulation target | Protocol duration | Ultrasound parameters | Energy | Results | Adverse events |
|---|---|---|---|---|---|---|---|---|---|---|
| Ai et al. (33) | Custom-made, single-element FUS transducer; Af: 0.50 MHz Diameter 30 mm, focal length 30 mm, 7T MRI compatible Focused, Pulsed | 5 | Healthy volunteers | Within-subjects, sham-controlled study | Primary motor cortex (tFUS paired with high field 7T fMRI targeted on the dominant thumb BOLD representation) | 54 stimuli, ISI 5.5 s | Af: 0.50 MHz; PD: 0.36 ms; PRF: 1 kHz; Np: 500; DC: 36%; c/p: 180; StimD: 500 ms | ISPPA: 16.95 W/cm2; MI: 0.97 | tFUS increased BOLD activation volumes generated during a cued tapping task. The effect was spatially confined to the sonicated area. No detectable effects on SMA and PMd. | No auditory or tactile sensation |
| Legon et al. (34) | Custom- designed, single-element FUS transducer; Af: 0.50 MHz Height 1.25 cm, aperture 30 mm, focal length 22 mm, Attached at the center of a TMS 8-coil (Magstim Inc., UK) for concurrent and concentric tFUS/TMS delivery Focused, Pulsed | 12 (exp. 1) 10 (exp. 2) 28 (exp. 3) | Healthy volunteers | Within-subjects, sham-controlled study | Primary motor cortex (Exp 1–2: dominant FDI hotspot; Exp 3: dominant APB hotspot) | Exp1: 10 tFUS/TMS stimuli from RMT-20% to 100% stimulator output, in increments of 5%, ISI of 10 seconds) Exp2: 10 tFUS/TMS stimulations every 10 s for each TMS paired-pulse ISI from 1 to 15 ms. Exp3: 100 stimuli at random time intervals between 3 and 6 s | Af: 0.50 MHz; PD: 0.36 ms; PRF: 1 kHz; Np: 500; DC: 36%; c/p: 180; StimD: 500 ms tFUS 100 ms prior to: the TMS pulse (exp. 1), to the CS (exp. 2) and to the visual stimulus (exp. 3) | ISPPA: 17.12 W/cm2; ISPTA: 6.16 W/cm2; MI: 0.9 | Concentric and concurrent tFUS/TMS on M1 inhibited the amplitude of single-pulse MEPs, attenuated intracortical facilitation, did not affect intracortical inhibition and significantly reduced reaction time in a motor task. | Mild and moderate symptoms such as neck pain, sleepiness, muscle twitches, itchiness and headache (assessed by questionnaire). No severe symptoms reported. |
| Legon et al. (35) | Custom-designed, single-element FUS transducer (Ultran Group, Inc., State College, PA); Af: 0.50 MHz Aperture 63 mm, focal length 70.92 mm (55 mm from exit plane), f# 1.13 Focused, Pulsed | 20 (exp. 1) 20 (exp. 2) | Healthy volunteers | Within-subjects, sham-controlled study | Unilateral sensory thalamus targeted through a neuronavigation system from the individual MRI | Exp1: 300 stimuli, ISI 4 s Exp2: 90 stimuli | Af: 0.50 MHz; PD: 0.36 ms; PRF: 1 kHz; Np: 500; DC: 36%; c/p: 180; StimD: 500 ms Median nerve stimuli time-locked to occur 100 ms after the onset of tFUS waveforms | ISPPA: 14.56 W/cm2; MI: 0.89 After bone transmission: ISPPA: 7.03; W/cm2; MI: 0.56 | tFUS decreased P14 SEP amplitude. Decrease in ability in a tactile judgement task. Effect upon cortical oscillatory dynamics | Not available |
| Leo et al. (36) | 2 transducers: 1) 3T experiment: Af: 0.50 MHz Active diameter 60 mm, focal length 55 mm, focal FWHM intensity volume 48.64 mm3 2) 7T experiment: Af: 0.86 MHz Active diameter 64 mm, focal length 54 mm, focal FWHM intensity volume 35.77 mm3 Both: Focused, Pulsed | 6 (3T exp.) 1 (7T exp.) | Healthy volunteers | Pre-post interventional study | 3T experiment: Primary motor cortex hand knob of the dominant hemisphere 7T experiment: Left head of the caudate | 3T experiment: 90 stimuli, ISI 12-14 s 7T experiment: 5 off/on cycles, stimulation delivered at ISI ≅ 12 s during on cycles | 3T experiment: Af: 0.50 MHz; PRF: 1 kHz; Np: 500; DC: 36%; c/p: 180; StimD: 500 ms 7T experiment: Af: 0.86 MHz; PRF: 1 kHz; DC: 50%; c/p: 420; StimD: 500 ms | ISPPA: 6W/cm2 (after bone transmission) | tFUS induced BOLD fMRI signals in the targeted cortical regions (in 3 of 6 subjects) and in the targeted subcortical region | Not available |
| Lee et al. (37) | MRI-compatible FUS transducer Af: 0.27 MHz Focal length 3 cm, acoustic focus 3 mm (diameter) and 17 mm (length) Focused, Pulsed | 19 (exp. 1) 10 (exp. 2) | Healthy volunteers | Within-subjects, single-blind, sham-controlled study | Primary visual cortex, under 3T MRI guidance | Exp.1: 50 stimuli, ISI 13 s Exp.2: 50 stimuli, ISI 2.5 s | Af: 0.27 MHz; PRF: 500 Hz; PD: 1 ms; DC: 50%; StimD: 300 ms | ISPPA: 16.6 W/cm2 Estimates at the target location: ISPPA: mean 3 W/cm2; MI: mean 0.6 | tFUS induced BOLD fMRI signals in V1 and other visual areas, elicited phosphenes and elicited cortical evoked EEG potentials similar to the classical VEP generated by photic stimulation | No adverse effects, as assessed by neurological examination, anatomical MRI (at 3 time points) and follow-up telephone interviews (after 2 months) |
| Lee et al. (37) | Two sets of single-element FUS transducers (Ultran Group Ltd, State College, PA) Af: 0.21 MHz Shape: segmented-spheres Outer diameter (OD):30 mm Focal distance: 25 mm. Each transducer was affixed to an applicator (Zamerican, Zacuto, Chicago, IL) mounted on a helmet (modified from Giro Section Helmet, Santa Cruz, CA) Focused, Pulsed | 10 | Healthy volunteers | Within-subjects, double blind,sham-controlled study | Left primary and secondary somatosensory cortex (areas of the hand, separately or simultaneously stimulated under multi-modal neuroimage-guidance) | 20 stimuli for each session (4 sessions) | Af: 0.21 MHz; PRF: 500 Hz; PD: 1 ms; DC: 50%; StimD: 500 ms | ISPPA: 35.0 W/cm2; ISPTA: 17.5 W/cm2 Estimates at the target location: ISPPA: 7.0–8.8 W/cm2 ISPTA: 3.5–4.4 W/cm2 | tFUS of either primary and secondary somatosensory cortex, stimulated separately or simultaneously, eliciited tactile sensations from the contralateral hand/arm areas | No abnormal findings post-tFUS (assessed by neurological examination, MMSE, anatomical MRI on the same day, at 2 weeks and 4 weeks, and by telephone interview at 2 months after the sonications) |
| Monti et al. (11) | BXPulsar 1001, Brainsonix Inc. Single-element spherical transducer; Af: 0.65 MHz Diameter and radius of curvature 71.5 mm Focused, Pulsed | 1 | Post-traumatic disorder of consciousness (minimally conscious state) 19 days post-injury | Case report, part of an ongoing clinical trial (12) | Thalamus (MRI-guided by a 3 Tesla Magnetom Tim Trio MR scanner) | 10 sonications, 30 s each, separated by 30 s pause intervals | Af: 0.65 MHz; PD: 0.5 ms; PRF: 100 Hz | ISPTA: 720 mW/cm2 | Emergence from minimally conscious state | Clinical improvement suggested that the procedure was safe and well-tolerated |
| Lee et al. (38) | Ceramic piezoelectric FUS transducer (Channel Industries, Santa Barbara, CA) Outer diameter 6 cm, radius-of- curvature 7 cm Af: 0.25 MHz Low Intensity Focused Ultrasound Pulsation | 12 (exp. 1) 6 (exp. 2) | Healthy volunteers | Within-subjects, sham-controlled study | Primary somatosensory cortex (hand area) under subject- specific image-guidance | (Exp. 1): 200 stimuli, ISI 3 s (Exp. 2): 100 stimuli, ISI ≅2 s | Af: 0.25 MHz; PRF: 500 Hz; Tone-burst-duration: 1 ms; DC: 50%; StimD: 300 ms | ISPPA: 3W/cm2 Estimated ISPPA at the target: 0.7 ± 0.5 W/cm2 | tFUS elicited transient tactile sensations on the hand and arm area contralateral to the sonicated hemisphere, with anatomical specificity of up to a finger. EEG showed sonication-specific evoked potentials. | No adverse effects, as assessed by neurological examination, anatomical MRI (at 3 time points) and follow-up telephone interviews (after 2 months) |
| Mueller et al. (39) | Two-channel, 2 MHz function generator (BK Precision Instruments) delivered at 0.5 MHz Focused, pulsed | 18 (exp. 1) 7 (exp. 2) | Healthy volunteers | Within-subjects, sham-controlled study | Exp.1 Somatosensory cortex (CP3) Exp.2 1cm laterally | 120 stimuli, ISI 6 s | Af: 0.50 MHz; PD: 0.36 ms; PRF: 1 kHz; Np: 500; c/p: 180; StimD: 500 ms | ISPPA: 23.87 W/cm2; MI: 1.13 | tFUS altered EEG beta phase and modulated the phase rate across beta and gamma frequencies. tFUS affected phase distributions in the beta band of early SEP components. Neuromodulatory effects were lost when the transducer was displaced 1 cm laterally from the original cortical target. | Not available |
| Legon et al. (10) | Custom-made, single-element FUS transducer; Af: 0.50 MHz Diameter 30 mm, focal length 30 mm Focused, Pulsed | 10 (exp. 1) 8 (exp. 2) 12 (exp. 3) 12 (exp. 4) | Healthy volunteers | Within-subjects, sham-controlled study | Primary somatosensory cortex (crown of the postcentral gyrus and posterior wall of the central sulcus, encephalographic electrode CP3) | Exp 1 and 2: 120 stimuli, ISI 6 s Exp 3: 90 stimuli 100 ms before each task Exp4: 120, ISI 6 s | Af: 0.50 MHz; PD: 0.36 ms; PRF: 1 kHz; Np: 500; DC: 36%; c/p: 180; StimD: 500 ms Median nerve stimuli time-locked to occur 100 ms after the onset of tFUS waveforms | ISPPA: 23.87 W/cm2 (≅4-fold lower through the skull); MI: 1.13 Peak rarefactional pressure: 0.80 MPa | Exp1. A: tFUS significantly attenuated the amplitudes of somatosensory evoked potentials B: tFUS significantly modulated the spectral content of sensory-evoked brain oscillations Exp2. tFUS modulation of brain activity is spatially restricted (≅1 cm or less) Exp3 and 4. tFUS significantly enhanced performance on sensory discrimination tasks without affecting task attention or response bias. | No thermal or mechanical sensation |
| Gibson et al. (40) | tUS: Phillips CX50 Diagnostic System, with a Phillips S5-1 broadband plane sector transducer array; aperture 20.3cm, frequency range 1–5 MHz. TMS: neuronavigation-assisted eXemia TMS system (Nextstim Ltd., Helsinki, Finland) with a 70 mm 8-coil. Unfocused, Continuous | 21 (active stim) 22 (sham stim) | Healthy volunteers | Between-subjects, single-blind, sham-controlled study | Primary motor cortex (abductor pollicis brevis motor hotspot) | 2 min | Af: 2.32 MHz; HGen, B-mode; Harmonics: on; DC: < 1%; Focal depth: 10 cm | Isppa: 34.96 W/cm2; Ispta: 132.85 mW/cm2; MI: 0.67 Peak negative pressure: 1.02 MPa (in degassed water) | tUS increased cortical excitability (average increase in MEPs amplitude of 33.7% at 1 min and of 32.2% at 6 min post stimulation. No significant differences at 11 and 16 min post stimulation). No differences in mood (assessed by a brief questionnaire on subject well-being) | No significant differences in sensations linked tingling, itching etc. (assessed by questionnaires) between active and sham group |
| Hameroff et al. (9) | General Electric LOGIQe, 12L-RS probe Af: 8 MHz Unfocused, Continuous | 31 | Chronic pain | Double blind, sham-controlled, crossover study | Posterior frontal cortex, contralateral to the maximal pain | 15 s stimulation | Af: 8 MHz; B Mode; Power: 100%; Depth: 3.5 cm; Harmonics: on; Cross- Xbeam: on | MI = 0.7 Max Intensity = 152 mW/cm2 TIs = 0.5 TIc = 0.2 (values at the posterior frontal scalp) | tUS significantly improved measures of global affect derived from subjective reports, at 10 and 40 min following stimulation. | Transient headache exacerbation following stimulation (1 subj) |
In gray background: unfocused stimulation protocols, in white background: focused stimulation protocols. Af, acoustic frequency; c/p, cycles per pulse; DC, duty cycle; Exp, experiment; ISI, inter stimulus interval; ISPPA, Intensity Spatial Peak Pulse Average; ISPTA, Intensity spatial peak temporal average; MEPs, motor evoked potentials; MI, mechanical index; Na, not available; Np, number of pulses; PD, pulse duration (width); PMd, dorsal premotor cortex; PRF, pulse repetition frequency; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; SD, Sonication Duration; SMA, supplementary motor area; StimD, stimulus duration; TI, Thermal Index; Tib, Thermal Index of bone; Tic, Thermal Index of Skull/Cranium; Tis, Thermal Index of soft tissue; TMS, transcranial magnetic stimulation. Note: where not specified, ISPPA is the incident acoustic intensity estimated before transcutaneous and transcranial transmission, e.g., In free water.