Table 1.
Characteristics of included animal studies.
| References | Experimental subjects | Protocol of TUS | Brain targets | Outcomes of interest | Major findings |
|---|---|---|---|---|---|
| Tufail et al. (2010) | Normal mice (n = 11) | Frequency: 0.25 to 0.5 MHZ; Intensity: 0.075 to 0.229 W/cm2 (ISPPA); Pulse repetition frequency: 1.2 to 3 kHZ; Duty cycle: 19 to 86%; Sonication duration: 26 to 333 ms; |
Motor cortex | Behavior: EMG, Rotorod task and wire-hanging task; |
(1) Ultrasonic stimulation of the motor cortex evoked motor behaviors; (2) No significant effects on Rotorod task and wire-hanging task. |
| Yoo et al. (2011a) | Normal rabbits (n = 19) | Motor paradigm: Frequency: 0.69 MHz; Intensity: 3.3, 6.4, 9.5, and 12.6 W/cm2 (ISPPA); Pulse repetition frequency: 0.01 kHZ; Duty cycle: 50%; Sonication duration: 500, 1,000, 1,500, and 2,000 ms; Suppression paradigm: Frequency: 0.69 MHz; Intensity: 3.3 and 6.4 W/cm2 (ISPPA); Pulse repetition frequency: 0.1 kHZ; Duty cycle: 5%; Sonication duration: > 7,000 to 8,000 ms; |
Motor cortex and visual areas | Neuroimaging: fMRI; |
TUS had bimodal modulatory effects: (1) Motor paradigm: ultrasound induced the motor cortex activation and detectable motor activity (ISPPA = 12.6 W/cm2); (2) Suppression paradigm: ultrasound reduced the magnitude of P30 VEP component (ISPPA = 3.3 W/cm2). |
| Yoo et al. (2011b) | Normal rats (n = 17) | Frequency: 0.65 MHZ Intensity: 3.3 W/cm2 or 6 W/cm2 (ISPPA); Pulse repetition frequency: 0.1 kHZ; Tone burst duration: 0.5 ms; |
Thalamus | Behavior: Time to voluntary movement from anesthesia; anesthetic duration; |
(1) Ultrasonic stimulation significantly reduced the time to show pinch response and voluntary movement; (2) A higher intensity of 6 W/cm2 (ISPPA) significantly decreased anesthetic duration. |
| Deffieux et al. (2013) | Normal macaque monkey (n = 2) | Frequency: 0.32 MHZ; Intensity: 4 ± 1.1 W/cm2 (ISPPA); Duty cycle: 100%; Sonication duration: 100 ms; |
Left FEF and Premotor cortex; | Behavior: Antisaccade task; | Ultrasonic stimulation significantly modulated antisaccade task latencies. |
| Kim et al. (2013) | Normal rats (n = 17) | Frequency: 0.35 MHZ Intensity: 3 W/cm2 (ISPTA); Pulse repetition frequency: 1 kHZ; Tone burst duration: 0.5 ms; Sonication duration: 300 ms; |
Unilateral hemisphere | Neuroimaging: PET (F-FDG uptake); | Spatially distinct increases of the glucose metabolic activity was present only at the center of stimulation focus. |
| Kim et al. (2014a) | Normal rats (n = 7) | Frequency: 0.35 MHZ Intensity: 3 W/cm2 (ISPTA); Pulse repetition frequency: 1 kHZ; Duty cycle: 50%; Sonication duration: 300 ms; |
Motor cortex | Behavior: Tail movement; Neuroimaging: PET (F-FDG uptake); |
(1) The size of the neuromodulatory area was found to be much smaller than the size of the acoustic focus; (2) The average delay in motor response was measured to be 171 ± 63 ms from the onset of sonication. |
| Kim et al. (2014b) | Normal rats (n = 37) | Frequency: 0.35 and 0.65 MHZ Intensity: 4.9-22.4 W/cm2 (ISPTA); Pulse repetition frequency: 0.06 to 2.8 kHZ; Duty cycle: 30 to 100% Sonication duration: 150-400 ms; |
Motor cortex | Behavior: Tail movement; |
Movement was elicited at minimum threshold intensities of 4.9–5.6 W/cm2 (ISPPA) in 50% of duty cycle, and 300 ms of sonication duration, at 0.35 kHz. |
| Kim et al. (2015) | Normal rats (n = 24) | Frequency: 0.35 MHZ Intensity: 1, 3, and 5 W/cm2 (ISPPA); Pulse repetition frequency: 0.1 kHZ; Duty cycle: 1, 3, 5, and 8.3% Tone-burst duration: 0.5 ms; Sonication exposure: 150 s; |
Visual area | Neuro-oscillation: EEG (VEP); |
(1) The magnitude of VEP was suppressed during the sonication using a 5% duty cycle and an intensity of 3 W/cm2 (ISPPA); however, this suppressive effect was not present when using a lower intensity and duty cycle; (2) A higher intensity and duty cycle resulted in a slight elevation in VEP magnitude. |
| Chu et al. (2015) | Normal rats (n = 118) | Frequency: 0.4 MHZ; Intensity: 0.3, 0.55 and 0.8 (MI); Pulse repetition frequency: 0.01 kHZ; Duty cycle: 1%; Sonication duration: 10 ms; Sonication exposure: 120 s; |
left primary somatosensory cortex | Neuro-oscillation: EEG (SSEP); Neuroimaging: fMRI (BOLD); |
(1) 0.8-MI TUS profoundly suppressed SSEP amplitude and prolonged latency for 7 days; 0.55-MI TUS resulted in short-term suppression of SSEP for < 60 min and did not affect latency. No significant change was observed for the 0.3-MI and control groups. (2) BOLD responses were reduced for 2 days for the 0.8-MI group; transiently reduced for the 0.55-MI group and was not observed for the 0.3- MI and control groups. |
| Guo et al. (2015) | Ischemic stroke rats (n = 38) | Frequency: 0.5 MHZ; Intensity: 0.57 and 0.86 W/cm2 (ISPTA); Pulse repetition frequency: 1.5 kHZ; Number of acoustic cycles per pulse: 200; Sonication duration: 400 ms per trial; Sonication exposure: 144 s (totally 360 trials); |
Ischemic core | Structure: Lesion volume; Behavior: NSS; |
(1) Ischemic lesion was significantly reduced after receiving TUS; (2) The cortical infarct volume of animals in the control group was more than 3 fold of that in the TUS group; (3) Animals in the TUS group showed significantly lower NSS than that in the control group. |
| Lee et al. (2014) | Normal sheep (n = 8) | Frequency: 0.25 MHZ; Intensity: 1.4 to 15.5 W/cm2 (ISPPA); Pulse repetition frequency: 0.5 kHZ; Duty cycle: 50%; Sonication duration: 50 to 150 ms; |
Sensorimotor cortex | Neuropsychological index: MEPs; |
(1) A MEP from the hind leg muscle contralateral to the sonicated hemisphere was detected when using an intensity of 6.9 W/cm2 (ISPPA). |
| Lee et al. (2016c) | Normal sheep (n = 8) | Frequency: 0.25 MHZ; Intensity: 1.7 to 14.3 W/cm2 (ISPPA); Pulse repetition frequency: 0.5 kHZ; Duty cycle: 50%; Sonication duration: 300 ms; |
Primary sensorimotor and visual areas | Neuropsychological index: MEPs; Neuro-oscillation: EEG (VEP); |
(1) Sonication over the primary sensorimotor areas elicited electromyographic responses from the contralateral hind leg at different intensity thresholds in different sheep; (2) Sonication over the visual areas generated VEPs at different intensity thresholds in different sheep. |
| Yu et al. (2016) | Normal rats (n = 3) | Frequency: 0.5 MHZ; Intensity: 0.01 W/cm2 (ISPTA); Pulse repetition frequency: 2 kHZ; Sonication duration: 5 and 200 ms; |
Multiple-site (16 scalp EEG electrodes) | Neuro-oscillation: EEG (ESI); |
TUS activated the stimulation site and the activation propagating to surrounding areas over time, denoted by ESI. |
| Wattiez et al. (2017) | Normal macaque monkey (n = 2) | Frequency: 0.32 MHZ; Intensity: 1.9 and 5.6 W/cm2 (ISPPA); Duty cycle: 100%; Sonication duration: 100 ms; |
FEF | Neuronal activity: Single-neuron recording (during an antisaccade task); | Supplementary eye field activity was significantly increased shortly after TUS. |
| Dallapiazza et al. (2018) | Normal Yorkshire swine (n = 10) |
Frequency: 1.14 MHZ; Intensity: 25–30 W/cm2 (ISPPA); Pulse repetition frequency: 0.01 kHZ; Duty cycle: 43.7%; Sonication duration: 43.7 ms; Sonication exposure: 40 s; |
Sensory thalamus; ventroposterolateral thalamic nucleus | Neuro-oscillation: EEG (SSEP); |
Ultrasonic stimulation suppressed the SSEP (trigeminal-evoked or tibial-evoked). |
| Guo et al. (2018) | Normal guinea pigs (n = 2) | Frequency: 0.22 MHZ; Intensity: 0.02 W/cm2 (ISPPA); Pulse repetition frequency: 1 kHZ; Sonication duration: 500 ms; |
Primary somatosensory cortex, primary auditory cortex and visual cortex; | Neuronal activity: Neural recording; |
(1) Ultrasonic stimulation elicited extensive activation across cortical and subcortical brain regions. (2) Transection of the auditory nerves or removal of cochlear fluids eliminated the US-induced activation. |
| Sato et al. (2018) | Transgenic Thy1-GCaMP6s mice (intact and deafened) (n = 20) | Frequency: 0.5 MHZ; Intensity: 0.034 to 4.2 W/cm2 (ISPTA); Pulse repetition frequency: 1.5 kHZ; Sonication duration: 80 ms; |
Primary somatosensory cortex, primary auditory cortex and visual cortex; | Neuronal activity: Neural recording; Behavior: EMG; |
Both ultrasound and audible sound elicited motor responses, with both responses reduced by chemical deafening. |
| Yang et al. (2018) | Normal macaque monkey (n = 2) | Frequency: 0.25 MHZ; Intensity: 29.5 W/cm2 (ISPPA); Pulse repetition frequency: 2 kHZ; Duty cycle: 50%; Sonication duration: 300 ms Sonication exposure: 3 s (10 sonications); |
Primary somatosensory cortex | Neuroimaging: fMRI; | (1) Tactile stimulation-and TUS evoked similar fMRI activation patterns; (2) FUS conditions also indicated that TUS modulated the tactile network differently; |
| Yoo et al. (2018) | Normal rats (n = 11) | Frequency: 0.65 MHZ; Intensity: 4.2 W/cm2 (ISPPA); Pulse repetition frequency: 0.1 kHZ; Duty cycle: 5% Sonication exposure: 30-min; |
Somatosensory areas | Neuro-oscillation: EEG (SEP); |
SEP changes were found beyond 35-min after TUS; |
| Zhang et al. (2018) | Depressed rats (n = 76) | Frequency: 0.5 MHZ; Intensity: 7.59 W/cm2 (ISPPA); Pulse repetition frequency: 1.5 kHZ; Duty cycle: 60%; Sonication duration: 400 ms; Sonication exposure: 15-min per day for 2 weeks; |
Prefrontal cortex | Behavior: Sucrose Preference Test, Open-field Test and Forced Swimming Test; | Recovery of depression-like phenotypes, i.e., anhedonia and reduced exploratory behaviors was found after TUS |
| Li et al. (2019) | Normal mice (n = 17) | Frequency: 2 MHZ; Intensity: 46 W/cm2 (ISPPA); 0.70 W/cm2 (ISPTA) Pulse repetition frequency: 1 kHZ; Duty cycle: 30%; Sonication duration: 300 ms; Sonication exposure: 360 s; |
Primary somatosensory cortex | Neuronal activity: Neural recording; Behavior: Head-turning behaviors; |
TUS induced action potentials and evoked head-turning behaviors. |
| Xie et al. (2018) | Normal mice (n = 9) | Frequency: 0.5 MHZ; Intensity: 1.10 W/cm2 (AI); Pulse repetition frequency: 1 kHZ; Number of acoustic cycles per pulse: 250; Number of tone bursts: 100, 150, 200, 250 and 300; |
Primary motor cortex | Neuronal activity: Local filed potential; Cortico-muscular coupling assessed by mutual information and transfer entropy; Behavior: EMG; |
TUS altered the cortico-muscular coupling which was significantly enhanced with the increase of NTB. |
| Daniels et al. (2018) | Normal rats (n = 22) and pig (n = 5) | Frequency: 0.23 MHZ; Intensity: 2.3 W/cm2 and 4.6 W/cm2 (ISPPA) Pulse repetition frequency: 1 kHZ; Duty cycle: 3%; Sonication duration: 100 ms; Sonication exposure: 52 s; |
Inferior colliculus (rats) Auditory cortex region (pigs) |
Neuro-oscillation: AEPs; |
(1) TUS suppressed the AEPs in all animals; (2) The suppressive effect was weaker for rats treated at 2.3 W/cm2 than that treated at 4.6 W/cm2. |
| Sharabi et al. (2019) | Harmaline-induced rats TUS, n = 5 and sham, n = 8) and normal rats (TUS, n = 5, and sham, n = 3) | Frequency: 0.23 MHZ; Intensity: 27.2 W/cm2 (ISPPA); Pulse repetition frequency: 1 kHZ; Duty cycle: 100%; Sonication duration: 100 ms; Sonication exposure: 52 s; |
Medulla oblongata region | Behavior: EMG; |
(1) TUS induced tremor suppression in 12 out of 13 Harmaline-induced rats; (2) TUS induced motor response which was synchronized with the sonication in both Harmaline-induced rats and normal rats. |
ISPPA, Intensity spatial peak pulse average; EMG, Electromyography; fMRI, Functional magnetic resonance imaging; ISPTA, Intensity spatial peak time average; FEF, Frontal eye field; PET, Positron emission tomography; FDG, 18-fludeoxyglucose; VEP, Visual evoked potential; SSEPs, Somatosensory evoked potentials; BOLD, Blood-oxygen-level dependent; NSS, Neurological severity score; MEP, Motor evoked potential; ESI, Electrophysiological source imaging; SEP, Somatosensory evoked potential; AI, Auditory intensity; AEP, Auditory evoked potential; NTB, Number of tone burst.