Table 2.
Ultrasonic neuromodulation central nervous system (CNS) studies
| Study | Organism & target | Key findings | Safety |
|---|---|---|---|
| Legon et al. (2018b) | Human (M1) | Combined US and magnetic stimulation. US inhibits amplitude of single-pulse TMS-induced MEPs and reduces reaction times during stimulus response task. | – |
| Legon et al. (2018a) | Human (Thalamus) | Modulation of sub-cortical nuclei. Attenuation of P14 SEP amplitude. Reduction in performance of discrimination task. | – |
| Lee et al. (2016b) | Human (V1) | Phosphene perception. fMRI: activation of V1, visual pathways & cognitive processes. Modulation of VEPs. | Neurologic examination, MRI follow up (0, 2, 4 wk) and follow-up interviews (2 mo): no abnormal findings across all participants. |
| Lee et al. (2016a) | Human (S1, S2) | Elicitation of tactile sensations on hand and arm. Simultaneous S1/S2 stimulation. | No adverse changes or discomfort in mental/physical status across all individuals. |
| Ai et al. (2016) | Human (M1, S1, caudate) | fMRI responses in sensorimotor & caudate regions. | – |
| Lee et al. (2015) | Human (S1) | Elicitation of peripheral sensations on hand and arm. Modulation of SEPs. | Neurologic and neuroradiologic assessment did not show any safety concerns. |
| Mueller et al. (2014) | Human (S1) | Modulation of EEG dynamics, including phase and phase rate in beta and gamma bands. | – |
| Legon et al. (2014) | Human (S1) | Modulation of SEPs and alpha, beta and gamma frequency bands. Improvement in discrimination tasks. | – |
| Hameroff et al. (2013)* | Human (Posterior frontal cortex) | Improvement in mood scores. Small pain reduction but not significant. | One subject experienced a headache, which quickly resolved. No other side effects up to 4 mo after the study. |
| Kubanek et al. (2017) | Monkey (FEF) | US stimulation to left (right) FEF shifted animals’ choices to rightward (leftward) target. | No long term bias in animals choices after 8 d of stimulation of each region. |
| Wattiez et al. (2017) | Monkey (FEF) | Single neuron recordings in SEF: activity changes following US stimulation of FEF. ∼40% of neurons modulated. | – |
| Deffieux et al. (2013) | Monkey (FEF) | Increased latencies in antisaccade task. | Stimulation effect was transient (no significant effects observed on the following control trials). |
| Dallapiazza et al. (2018) | Pig (Thalamus) | Reversible suppression of SEPs. Selective activation of sub-nuclei within somatosensory thalamus. | Histology: no gross or microscopic tissue damage. |
| Daniels et al. (2018) | Pig (AC) | AEP suppression. | – |
| Rat (Inferior colliculus region) | AEP suppression. | Histology (H&E): no damage. No sign of inflammatory response or structural changes. AEP amplitude recovery 1 h to 1 mo. | |
| Lee et al. (2016c) | Sheep (SM1, V1) | SM1: EMG response of contralateral hind leg. V1: VEPs. | Histology: small microhemorrhage for repetitive stimulation (≥ 500 stimulations delivered at 1 s intervals). Damage not seen at longer ISIs. Post-sonication behavior normal. |
| Fisher and Gumenchuk (2018) | Mouse (Cortex) | Reduction in latency and increased Ca2+ response following electrical stimulation with US pre-treatment. | Histology: no changes in distribution of glial fibrillary acidic protein or evans blue – no neural injury or BBB opening. |
| Han et al. (2018) | Rat (Motor cortex) & Cell cultures | Response robustness increased with intensity and linked with shorter latencies. Ketamine reduced Ca2+ transients in dose-dependent manner by up to 82%. | Histology (H&E): no obvious damage, morphologic changes, tissue bleeding, or cytoplasmic swelling. |
| Guo et al. (2018) | Guinea Pig (Various including A1, S1) | US response due to indirect cochlear fluid pathway rather than direct activation. Similar activity in A1, SC1 recorded irrespective of target location. US-evoked activity eliminated by removal of cochlear fluid. | – |
| Sato et al. (2018) | Mouse (Visual cortex) | Widespread neural activation through indirect auditory mechanism. Contralateral visual cortex had similar response kinetics to targeted side, but auditory cortex showed contralateral bias. Chemical deafening greatly reduced motor outputs. | – |
| Gulick et al. (2017) | Rat (Motor cortex) | Long-term modulation of electrical stimulation: reduced hind limb responses. Direct motor response had 3 s refractory period. | No behavioral changes observed following stimulation. |
| Lee et al. (2017) | Rat | – | Histology (H&E, TUNEL assay): no cell necrosis. |
| Li et al. (2016) | Mouse (Motor cortex) | Increased specificity and decreased latencies at 5 MHz compared with 1 MHz. | Histology (H&E): no evidence of tissue bleeding or cell necrosis. |
| Kamimura et al., 2016, Kamimura et al., 2015) | Mouse (Motor & cognitive areas) | Limb movement and eyeball dilation. | Histology (H&E): no damage. |
| Darvas et al. (2016) | Rat | EEG signal at the frequency of the US PRF was induced along with demodulated activity in gamma & beta bands: potential use of US to tag deep regions for EEG-based mapping. | – |
| Yu et al. (2016) | Rat | Localization of induced brain activity using electrophysiologic source imaging. | – |
| Moore et al. (2015) | Mouse (Somatosensory cortex) | US and optogenetic responses have similar form for pyramidal neurons, but not interneurons, but amplitudes 10- to 20-fold lower for US. | – |
| Ye et al. (2015) | Mouse (Motor cortex) | Success rate decreases with frequency for given intensity. Focal spot size did not have consistent effect on success rates; most of the variance can be explained by frequency. Success strongly correlated with cavitation index and particle displacement but not ARF. | – |
| Kim et al. (2015) | Rat (Visual cortex) | VEP magnitude suppression/enhancement dependent on intensity and BD. Threshold intensity to elicit response. | – |
| King et al. (2014) | Mouse (Motor cortex) | Differences in EMG response (magnitude and latency) following rostral or caudal stimulation. | – |
| Mehić et al. (2014) | Rat (Motor cortex) | Comparison of planar, focused and modulated-focused source using 1.75 and 2.25 MHz to generate a 0.5 MHz difference frequency. Large variance in responses. Robustness of motor movement scaled with Ispta. | All histology samples showed no damage to brain tissue. |
| Younan et al. (2013) | Rat | Motor responses: tail, fore and hind limbs, eye, single whisker. Pressure threshold for response dependent on anesthesia levels. Rat skull distributes field across whole brain and introduces pressure hot spots due to reverberations. | No change in behavior or weight was observed. |
| King et al. (2013) | Mouse (Motor cortex) | EMG motor responses. Anesthesia levels important. CW as effective as pulsed US. All or nothing responses. Responses occur due to stimulus onset (within 30–100 ms). Required intensity increases with frequency. Success rate increases with PRF from 100–3000 Hz. Key variable appears to be integral of amplitude over a time interval of 50 to 150 ms. | – |
| Yang et al. (2012) | Rat (Thalamus) | Reduction in extracellular GABA for at least 2 h following sonication. No change in glutamate levels. | Histology showed no abnormal findings at either the focus or along the beam path. |
| Yoo et al. (2011a) | Rabbit (Somatomotor & visual areas) | Bimodal modulation: excitation of motor response and suppression of p30 VEP component. EEG signals confirmed by BOLD fMRI. | Histology did not reveal any tissue damage. No TUNEL positive apoptotic cells or VAF positive ischemic cells were found. No increase in gadolinium signal, suggesting no BBB disruption. |
| Yoo et al. (2011b) | Rat (Thalamus) | Reduction in anesthesia times following FUS (up to 20 min). | – |
| Min et al. (2011a) | Rat (Thalamus) | Reduction in EEG theta bursts after epileptic seizure induction. | Histology: no tissue damage (H&E) or DNA fragmentation (TUNEL). |
| Min et al. (2011b) | Rat (Thalamus) | Increase in extracellular dopamine and serotonin levels for at least 2 h post-sonication. | – |
| Tufail et al. (2010) | Mouse (Motor cortex & hippocampus) | Increased cortical spiking. TTX blocked US-evoked activity. Mean failure rate increased from 0.25–5 MHz. Lower frequencies & Isppas give more robust EMG responses. Evoked potentials in hippocampus followed by 3 s afterdischarge containing gamma, sharp wave ripple oscillations and increase in spike frequency. Increase in BDNF. | No evidence of BBB opening. No change in density of apoptotic glial cells or neurons. No differences in synapse density or cortical neuropil ultra-structure. No neurologic abnormalities during rotorod and wire-hanging tasks. |
| Koroleva et al. (1986) | Rat (Cerebral cortex & hippocampus) | Direct current potential changes and spreading depression waves. | – |
| Ballantine et al. (1960) | Cat (Edinger-Westphal nucleus) | Temporary dilation of eye. | No lesions observed. |
| Fry et al. (1958) | Cat (LGN) | Reversible suppression of VEPs. | No histologically detectable lesions. |
| Prieto et al. (2018) | Cell cultures | Patch clamp recordings: activation of Piezol but not NaV1.2 through membrane stress as a result of acoustic streaming. | – |
| Kubanek et al. (2018) | Caenorhabditis Elegans | MEC-4, a pore-forming subunit expressed in touch receptor neurons required for US-evoked behaviors. TRP-4 response due to background genetic mutation. 50% BDC and 300–1000 Hz PRF produce optimal response rates. | – |
| Menz et al. (2017) | in vitro: Isolated salamander retina | US stimulation results in micron-scale displacements. Efficacy increased with frequency, consistent with an ARF-mediated mechanism. | – |
| Kim et al. (2017) | in vitro: Hippocampal slice | MEA: region and threshold-specific increased spike activity during and after US stimulation. | – |
| Menz et al. (2013) | in vitro: Isolated salamander retina | US evoked strong response similar to visual response but with shorter latencies. US activated other cells beyond photoreceptors. PRF 15 Hz to 1 MHz had no effect on responses; only temporal-averaged power important. | – |
| Choi et al. (2013) | in vitro: Rat hippocampal neurons | MEA: increased spiking and bursting. Effect observed post exposure. Largest firing rate at 0.8 MPa, decreased at higher pressures. | – |
| Tyler et al. (2008) | in vitro: Hippocampal slices and isolated mouse brain | US-induced APs during whole-cell current clamp recordings in CA1 pyramidal neurons. Triggering of voltage-gated Na+ and Ca2+ channels, vesicle exocytosis and synaptic transmission. Addition of TTX and Cd2+ blocked Na+ and Ca2+ transients, respectively. | Repeated stimulation (36–48 h) did not alter fine membrane structure. |
| Khraiche et al. (2008) | in vitro: Hippocampal slices | MEA: US can excite neurons and increase firing rates. | – |
| Bachtold et al. (1998) | in vitro: Hippocampal slices | Enhancement and depression of electrically evoked potentials. | – |
| Rinaldi et al. (1991) | in vitro: Hippocampal slices | Depression of electrically evoked potentials. | – |
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GE LOGIQe US scanner (GE Medical Systems, China) with 12 L-RS imaging probe.
A1 = primary auditory cortex; AC = auditory cortex; AEP = auditory evoked potential; AP = action potential; ARF = acoustic radiation force; BBB = blood–brain barrier; BD = Burst duration; BDC = Burst duty cycle; BOLD = blood oxygen level dependent; CA1 = Cornu Ammonis 1 (hippocampal subregion); CW = continuous wave; EEG = electroencephalography; EMG = electromyography; FEF = frontal eye field; fMRI = functional magnetic resonance imaging; GABA = γ-aminobutyric acid; H&E = hematoxylin and eosin (staining); ISPPA = spatial-peak, pulse-averaged intensity; Ispta= spatial-peak, temporal-averaged intensity; LGN = lateral geniculate nucleus; Ml = primary motor cortex; MEA = multi electrode array; MEC-4 = Mechanosensory protein 4 (ion channel subunit); MEP = motor evoked potential; MRI = magnetic resonance imaging; PRF = pulse repetition frequency; S1 = primary somatosensory cortex; S2 = secondary somatosensory cortex; SEF = supplementary eye field; SEP = somatosensory evoked potential; SM1 = primary sensorimotor area; TMS = transcranial magnetic simulation; TRP-4 = Transient receptor potential 4 (ion channel); TTX = tetrodotoxin; TUNEL = Terminal deoxynucleotidyl transferase dUTP nick end (DNA fragmentation assay); US = ultrasound; V1 = primary visual cortex; VAF = Vanadium acid fuchsin (staining); VEP = visual evoked potential.