NeuroFUS Science & Literature

Millimeter Scale Spatial Resolutions of NeuroFUS

Neuromodulation by Focused Ultrasound (NeuroFUS) provides spatial resolutions that are higher than other noninvasive neuromodulation methods.

The left and middle images above illustrate the spatial distributions of electric fields (EFields) produced by tDCS (left) and TMS (middle). The EFields simulated using realistic finite element methods are shown normalized to the peak field strengths produced by tDCS delivered to the left dlPFC and for a TMS pulse delivered to left M1. The spatial distribution (resolution) of peak electric field strengths produced by tDCS and TMS extend up to several centimeters in some directions. Data in the right panel of images above show transcranial NeuroFUS can significantly modulate physiological EEG activity in the cortex of healthy humans (Legon et al, Nature Neuroscience, 2014). As shown above, the shape of the 0.5 MHz transcranial NeuroFUS beam is an ellipsoid with a spatial resolution of about 4.5 mm x 18 mm. As referenced in the Literature cited below, this basic method has been reproduced by others showing NeuroFUS is safe, confers high spatial resolutions, and is readily compatible with electrophysiology and imaging methods such as EEG and fMRI.

NeuroFUS for Noninvasive Deep-brain Circuit Modulation

Functional Mapping and Modulation of Thalamic Nuclei using Deep-brain NeuroFUS.

A) Using transducers operating in a phased array, Dallapiazza et al (2017) functionally mapped discrete body representations in the pig thalamus using low-intensity FUS neuromodulation. Consistent with other observations in the Literature (cited below), the authors showed that the effects of low-intensity FUS on brain activity occur in the absence of temperature changes assessed by MR thermometry. B) Low-intensity, 0.5 MHz FUS transmitted from a single element transducer can also modulate the human thalamus as assessed using EEG. The authors also showed different models for compensation of individual human skull densities measured by MRI and CT (Legon et al, 2018a). While single-element transducers provide a viable option for modulating human deep-brain regions, the use of phased arrays like the CTX and DPX Systems for low-intensity FUS neuromodulation will enable even more precise and accurate brain circuit targeting.

NeuroFUS is Compatible with Functional MRI Brain Mapping Studies.

The ability of NeuroFUS to achieve high-resolution neuromodulation integrated with EEG and fMRI provides a unique platform for conducting functional brain mapping in the study of brain diseases, identification and verification of therapeutic brain targets, as well as for investigating the role of human deep-brain regions in plasticity, learning, cognition, and others.

Functional Brain Mapping and NeuroFUS during 7T BOLD fMRI.

Several studies have shown that transcranial NeuroFUS is compatible with 1.5 and 3T MRI in animals models including humans. As illustrated above, transcranial NeuroFUS has been shown to significantly increase the area of sensory cortex activation during 7T BOLD fMRI experiments without causing artifacts or image distortions (Legon et al, 2018b).

NeuroFUS Mechanisms of Action

Acoustic microforces produced by low-intensity, pulsed ultrasound on neurons activate mechano-sensitive ion channels including voltage-gated channels.

Illustrations above show a neuronal membrane and ion channel at rest (left) and in response to NeuroFUS (middle and right). One model (middle) shows a case where the acoustic pressure of US (1) causes mechanical effects on membranes and channels (2) to change membrane conductance and channel activity (3). Another model (bottom) describes the acoustic pressure of US (1) causes the formation of a bilayer sonophore (2) that causes mechanically originated displacement currents (3) altering changes in membrane capacitance (C_m) and voltage (V_m). These actions subsequently alter neuronal membrane conductance (G_m) by affecting the voltage-mediated activity of ion channels (4). These mechanistic models (adapted from Tyler et al, Current Opinion in Neurobiology, 2018) are based on evidence in the Literature (cited below) showing the mechanical (non-thermal) bioeffects of low-intensity pulsed ultrasound (NeuroFUS) can differently modulate the activity of several voltage-gated and mechano-sensitive sodium, potassium, and calcium ion channels that are endogenously expressed in mammalian neurons and glia.

Safety of NeuroFUS

NeuroFUS has been shown to be safe for acute use in numerous animal models including humans.

Numerous studies to date have used low-intensity FUS for ultrasonic neuromodulation of brain circuits in mice, rats, rabbits, sheep, pigs, and monkeys without reporting any severe adverse side effects and with few to no adverse reactions. Many other studies have safely used low-intensity transcranial pulsed focused ultrasound for the transient modulation of human brain activity without producing significant side effects. While it is important to implement safe treatment margins and avoid tissue heating and damage, the data to date has shown that low-intensity ultrasound is acutely safe for neuromodulation.

A recent study examined acute safety in 120 human subjects across a series of seven different tFUS neuromodulation studies (Legon et al, 2018c). Data from this safety study are illustrated in the figure above. A, the schematic shows standard pulse strategies for modulating brain activity with pulsed ultrasound. B, The top panel of histograms illustrate the severity of side effect outcomes while the bottom panel shows the outcomes scored by the subjective relation to the pulsed ultrasound treatment. C, A scatter plot shows a slight but significant correlation between acoustic intensity (spatial peak pulse average) and the percentage of positive side effect responses. The types of adverse reactions or side effects that occur during tFUS neuromodulation are the same or similar that occur in response to other forms of noninvasive neuromodulation.

NeuroFUS Literature

Reviews & Opinions

Tyler, W. J., Lani, S. W., & Hwang, G. M. (2018). Ultrasonic modulation of neural circuit activity. Current Opinion in Neurobiology, 50, 222–231. https://doi.org/10.1016/j.conb.2018.04.011

Fomenko, A., Neudorfer, C., Dallapiazza, R. F., Kalia, S. K., & Lozano, A. M. (2018). Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications. Brain Stimulation, 11(6), 1209–1217. https://doi.org/10.1016/j.brs.2018.08.013

Krishna, V., Sammartino, F., & Rezai, A. (2018). A Review of the Current Therapies, Challenges, and Future Directions of Transcranial Focused Ultrasound Technology: Advances in Diagnosis and Treatment. JAMA Neurology, 75(2), 246–254. https://doi.org/10.1001/jamaneurol.2017.3129

Fini, M., & Tyler, W. J. (2017). Transcranial focused ultrasound: a new tool for non-invasive neuromodulation. International Review of Psychiatry, 29(2), 168–177. https://doi.org/10.1080/09540261.2017.1302924

Naor, O., Krupa, S., & Shoham, S. (2016). Ultrasonic neuromodulation. Journal of Neural Engineering, 13(3), 031003. https://doi.org/10.1088/1741-2560/13/3/031003

Darvas, F., Mehić, E., Caler, C. J., Ojemann, J. G., & Mourad, P. D. (2016). Toward Deep Brain Monitoring with Superficial EEG Sensors Plus Neuromodulatory Focused Ultrasound. Ultrasound in Medicine & Biology, 42(8), 1834–1847. https://doi.org/10.1016/j.ultrasmedbio.2016.02.020

Kubanek, J. (2018). Neuromodulation with transcranial focused ultrasound. Neurosurgical Focus, 44(2), E14. https://doi.org/10.3171/2017.11.FOCUS17621

Munoz, F., Aurup, C., Konofagou, E. E., & Ferrera, V. P. (2018). Modulation of Brain Function and Behavior by Focused Ultrasound. Current Behavioral Neuroscience Reports, 5(2), 153–164. https://doi.org/10.1007/s40473-018-0156-7

Tsai, S.-J. (2015). Transcranial focused ultrasound as a possible treatment for major depression. Medical Hypotheses, 84(4), 381–383. https://doi.org/10.1016/j.mehy.2015.01.030

Human & Large Animal Studies

Legon, W., Bansal, P., Ai, L., Mueller, J. K., Meekins, G., & Gillick, B. (2018c). Safety of transcranial focused ultrasound for human neuromodulation. BioRxiv, 314856. https://doi.org/10.1101/314856

Ai, L., Bansal, P., Mueller, J. K., & Legon, W. (2018). Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study. BMC Neuroscience, 19(1), 56. https://doi.org/10.1186/s12868-018-0456-6

Chaplin, V., Phipps, M. A., & Caskey, C. F. (2018). A random phased-array for MR-guided transcranial ultrasound neuromodulation in non-human primates. Physics in Medicine & Biology, 63(10), 105016. https://doi.org/10.1088/1361-6560/aabeff

Dallapiazza, R. F., Timbie, K. F., Holmberg, S., Gatesman, J., Lopes, M. B., Price, R. J., … Elias, W. J. (2018). Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound. Journal of Neurosurgery, 128(3), 875–884. https://doi.org/10.3171/2016.11.JNS16976

Deffieux, T., Younan, Y., Wattiez, N., Tanter, M., Pouget, P., & Aubry, J.-F. (2013). Low-intensity focused ultrasound modulates monkey visuomotor behavior. Current Biology: CB, 23(23), 2430–2433. https://doi.org/10.1016/j.cub.2013.10.029

Folloni, D., Verhagen, L., Mars, R. B., Fouragnan, E., Aubry, J.-F., Rushworth, M. F. S., & Sallet, J. (2018). Manipulation of deep brain activity in primates using transcranial focused ultrasound stimulation. BioRxiv, 342303. https://doi.org/10.1101/342303

Kim, H., Chiu, A., Park, S., & Yoo, S.-S. (2012). Image-guided Navigation of Single-element Focused Ultrasound Transducer. International Journal of Imaging Systems and Technology, 22(3), 177–184. https://doi.org/10.1002/ima.22020

Kim, J., & Lee, S. (2016). Development of a Wearable Robotic Positioning System for Noninvasive Transcranial Focused Ultrasound Stimulation. IEEE/ASME Transactions on Mechatronics, 21, 2284–2293. DOI: 10.1109/TMECH.2016.2580500

Lee, W., Chung, Y. A., Jung, Y., Song, I.-U., & Yoo, S.-S. (2016a). Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound. BMC Neuroscience, 17(1), 68. https://doi.org/10.1186/s12868-016-0303-6

Lee, W., Kim, H., Jung, Y., Song, I.-U., Chung, Y. A., & Yoo, S.-S. (2015). Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Scientific Reports, 5, 8743. https://doi.org/10.1038/srep08743

Lee, W., Kim, H.-C., Jung, Y., Chung, Y. A., Song, I.-U., Lee, J.-H., & Yoo, S.-S. (2016b). Transcranial focused ultrasound stimulation of human primary visual cortex. Scientific Reports, 6, 34026. https://doi.org/10.1038/srep34026

Lee, W., Kim, S., Kim, B., Lee, C., Chung, Y. A., Kim, L., & Yoo, S.-S. (2017). Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface. PloS One, 12(6), e0178476. https://doi.org/10.1371/journal.pone.0178476

Lee, W., Lee, S. D., Park, M. Y., Foley, L., Purcell-Estabrook, E., Kim, H., … Yoo, S.-S. (2016c). Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep. Ultrasound in Medicine & Biology, 42(2), 459–470. https://doi.org/10.1016/j.ultrasmedbio.2015.10.001

Legon, W., Ai, L., Bansal, P., & Mueller, J. K. (2018b). Neuromodulation with single-element transcranial focused ultrasound in human thalamus. Human Brain Mapping, 39(5), 1995–2006. https://doi.org/10.1002/hbm.23981

Legon, W., Bansal, P., Tyshynsky, R., Ai, L., & Mueller, J. K. (2018a). Transcranial focused ultrasound neuromodulation of the human primary motor cortex. Scientific Reports, 8. https://doi.org/10.1038/s41598-018-28320-1

Legon, W., Sato, T. F., Opitz, A., Mueller, J., Barbour, A., Williams, A., & Tyler, W. J. (2014). Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nature Neuroscience, 17(2), 322–329. https://doi.org/10.1038/nn.3620

Leo Ai, null, Mueller, J. K., Grant, A., Eryaman, Y., & Wynn Legon, null. (2016). Transcranial focused ultrasound for BOLD fMRI signal modulation in humans. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2016, 1758–1761. https://doi.org/10.1109/EMBC.2016.7591057

Maimbourg, G., Houdouin, A., Deffieux, T., Tanter, M., & Aubry, J.-F. (2018). 3D-printed adaptive acoustic lens as a disruptive technology for transcranial ultrasound therapy using single-element transducers. Physics in Medicine and Biology, 63(2), 025026. https://doi.org/10.1088/1361-6560/aaa037

Metwally, M. K., Han, H.-S., Jeon, H. J., Khang, G., & Kim, T.-S. (2013). Influence of the anisotropic mechanical properties of the skull in low-intensity focused ultrasound towards neuromodulation of the brain. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2013, 4565–4568. https://doi.org/10.1109/EMBC.2013.6610563

Mueller, J. K., Ai, L., Bansal, P., & Legon, W. (2017). Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound. Journal of Neural Engineering, 14(6), 066012. https://doi.org/10.1088/1741-2552/aa843e

Mueller, J., Legon, W., Opitz, A., Sato, T. F., & Tyler, W. J. (2014). Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics. Brain Stimulation, 7(6), 900–908. https://doi.org/10.1016/j.brs.2014.08.008

Wattiez, N., Constans, C., Deffieux, T., Daye, P. M., Tanter, M., Aubry, J.-F., & Pouget, P. (2017). Transcranial ultrasonic stimulation modulates single-neuron discharge in macaques performing an antisaccade task. Brain Stimulation, 10(6), 1024–1031. https://doi.org/10.1016/j.brs.2017.07.007

Qi, S., Li, Y., Zhang, W., & Chen, J. (2018). Design of A Novel Wearable LIPUS Treatment Device for Mental Health Treatment. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2018, 6052–6055. https://doi.org/10.1109/EMBC.2018.8513635

Yang, P.-F., Phipps, M. A., Newton, A. T., Chaplin, V., Gore, J. C., Caskey, C. F., & Chen, L. M. (2018). Neuromodulation of sensory networks in monkey brain by focused ultrasound with MRI guidance and detection. Scientific Reports, 8(1), 7993. https://doi.org/10.1038/s41598-018-26287-7

Mechanisms of Action

Krasovitski, B., Frenkel, V., Shoham, S., & Kimmel, E. (2011). Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proceedings of the National Academy of Sciences of the United States of America, 108(8), 3258–3263. https://doi.org/10.1073/pnas.1015771108

Kubanek, J., Shi, J., Marsh, J., Chen, D., Deng, C., & Cui, J. (2016). Ultrasound modulates ion channel currents. Scientific Reports, 6, 24170. https://doi.org/10.1038/srep24170

Kubanek, J., Shukla, P., Das, A., Baccus, S. A., & Goodman, M. B. (2018). Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 38(12), 3081–3091. https://doi.org/10.1523/JNEUROSCI.1458-17.2018

Plaksin, M., Kimmel, E., & Shoham, S. (2016). Cell-Type-Selective Effects of Intramembrane Cavitation as a Unifying Theoretical Framework for Ultrasonic Neuromodulation. ENeuro, 3(3). https://doi.org/10.1523/ENEURO.0136-15.2016

Prieto, M. L., Firouzi, K., Khuri-Yakub, B. T., & Maduke, M. (2018). Activation of Piezo1 but Not NaV1.2 Channels by Ultrasound at 43 MHz. Ultrasound in Medicine & Biology, 44(6), 1217–1232. https://doi.org/10.1016/j.ultrasmedbio.2017.12.020

Small Animal and In Vitro Models

Baek, H., Pahk, K. J., Kim, M.-J., Youn, I., & Kim, H. (2018). Modulation of Cerebellar Cortical Plasticity Using Low-Intensity Focused Ultrasound for Poststroke Sensorimotor Function Recovery. Neurorehabilitation and Neural Repair, 32(9), 777–787. https://doi.org/10.1177/1545968318790022

Baek, H., Sariev, A., Kim, M.-J., Lee, H., Kim, J., & Kim, H. (2018). A neuroprotective brain stimulation for vulnerable cerebellar Purkinje cell after ischemic stroke: a study with low-intensity focused ultrasound. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2018, 4744–4747. https://doi.org/10.1109/EMBC.2018.8513138

Casella, D. P., Dudley, A. G., Clayton, D. B., Pope, J. C., Tanaka, S. T., Thomas, J., … Caskey, C. F. (2017). Modulation of the rat micturition reflex with transcutaneous ultrasound. Neurourology and Urodynamics, 36(8), 1996–2002. https://doi.org/10.1002/nau.23241

Constans, C., Deffieux, T., Pouget, P., Tanter, M., & Aubry, J.-F. (2017). A 200-1380-kHz Quadrifrequency Focused Ultrasound Transducer for Neurostimulation in Rodents and Primates: Transcranial In Vitro Calibration and Numerical Study of the Influence of Skull Cavity. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, 64(4), 717–724. https://doi.org/10.1109/TUFFC.2017.2651648

Daniels, D., Sharabi, S., Last, D., Guez, D., Salomon, S., Zivli, Z., … Harnof, S. (2018). Focused Ultrasound-Induced Suppression of Auditory Evoked Potentials in Vivo. Ultrasound in Medicine & Biology, 44(5), 1022–1030. https://doi.org/10.1016/j.ultrasmedbio.2018.01.010

Fishman, P. S., & Frenkel, V. (2017). Focused Ultrasound: An Emerging Therapeutic Modality for Neurologic Disease. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 14(2), 393–404. https://doi.org/10.1007/s13311-017-0515-1

Fisher, J. A. N., & Gumenchuk, I. (2018). Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo. Journal of Neural Engineering, 15(3), 035004. https://doi.org/10.1088/1741-2552/aaaee1

Gulick, D. W., Li, T., Kleim, J. A., & Towe, B. C. (2017). Comparison of Electrical and Ultrasound Neurostimulation in Rat Motor Cortex. Ultrasound in Medicine & Biology, 43(12), 2824–2833. https://doi.org/10.1016/j.ultrasmedbio.2017.08.937

Guo, T., Li, H., Lv, Y., Lu, H., Niu, J., Sun, J., … Tong, S. (2015). Pulsed Transcranial Ultrasound Stimulation Immediately After The Ischemic Brain Injury is Neuroprotective. IEEE Transactions on Bio-Medical Engineering, 62(10), 2352–2357. https://doi.org/10.1109/TBME.2015.2427339

Han, S., Kim, M., Kim, H., Shin, H., & Youn, I. (2018). Ketamine Inhibits Ultrasound Stimulation-Induced Neuromodulation by Blocking Cortical Neuron Activity. Ultrasound in Medicine & Biology, 44(3), 635–646. https://doi.org/10.1016/j.ultrasmedbio.2017.11.008

Ilham, S. J., Chen, L., Guo, T., Emadi, S., Hoshino, K., & Feng, B. (2018). In vitro single-unit recordings reveal increased peripheral nerve conduction velocity by focused pulsed ultrasound. Biomedical Physics & Engineering Express, 4(4). https://doi.org/10.1088/2057-1976/aabef1

Jiang, Q., Li, G., Zhao, H., Sheng, W., Yue, L., Su, M., … Zheng, H. (2018). Temporal Neuromodulation of Retinal Ganglion Cells by Low-Frequency Focused Ultrasound Stimulation. IEEE Transactions on Neural Systems and Rehabilitation Engineering: A Publication of the IEEE Engineering in Medicine and Biology Society, 26(5), 969–976. https://doi.org/10.1109/TNSRE.2018.2821194

Kamimura, H. A. S., Wang, S., Chen, H., Wang, Q., Aurup, C., Acosta, C., … Konofagou, E. E. (2016). Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz. Medical Physics, 43(10), 5730. https://doi.org/10.1118/1.4963208

Kang-Il Song, null, Seul Lee, null, Park, S. E., Dosik Hwang, null, Hyungmin Kim, null, & Inchan Youn, null. (2017). Localization of ultrasound waveform for low intensity ultrasound-induced neuromodulation in a mouse model. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2017, 1122–1125. https://doi.org/10.1109/EMBC.2017.8037026

Kim, E., Anguluan, E., & Kim, J. G. (2017). Monitoring cerebral hemodynamic change during transcranial ultrasound stimulation using optical intrinsic signal imaging. Scientific Reports, 7(1), 13148. https://doi.org/10.1038/s41598-017-13572-0

Kim, Hyunggug, Kim, S., & Lee, H. J. (2018). Capacitive Micromachined Ultrasonic Transducer (CMUT) ring array for transcranial ultrasound neuromodulation. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2018, 2675–2678. https://doi.org/10.1109/EMBC.2018.8512731

Kim, Hyungmin, Lee, S. D., Chiu, A., Yoo, S.-S., & Park, S. (2014). Estimation of the spatial profile of neuromodulation and the temporal latency in motor responses induced by focused ultrasound brain stimulation. Neuroreport, 25(7), 475–479. https://doi.org/10.1097/WNR.0000000000000118

Kim, Hyungmin, Park, M. Y., Lee, S. D., Lee, W., Chiu, A., & Yoo, S.-S. (2015). Suppression of EEG visual-evoked potentials in rats through neuromodulatory focused ultrasound. Neuroreport, 26(4), 211–215. https://doi.org/10.1097/WNR.0000000000000330

Kim, Hyungmin, Park, M.-A., Wang, S., Chiu, A., Fischer, K., & Yoo, S.-S. (2013). PET∕CT imaging evidence of FUS-mediated (18)F-FDG uptake changes in rat brain. Medical Physics, 40(3), 033501. https://doi.org/10.1118/1.4789916

Kim, Hyungmin, Taghados, S. J., Fischer, K., Maeng, L.-S., Park, S., & Yoo, S.-S. (2012). Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound. Ultrasound in Medicine & Biology, 38(9), 1568–1575. https://doi.org/10.1016/j.ultrasmedbio.2012.04.023

Kim, H., Chiu, A., Lee, S. D., Fischer, K., & Yoo, S.-S. (2014). Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. Brain Stimulation, 7(5), 748–756. https://doi.org/10.1016/j.brs.2014.06.011

Kim, S., Kim, H., Shim, C., & Lee, H. J. (2018). Improved Target Specificity of Transcranial Focused Ultrasound Stimulation (TFUS) using Double-Crossed Ultrasound Transducers. Conference Proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2018, 2679–2682. https://doi.org/10.1109/EMBC.2018.8512812

Li, G., Qiu, W., Hong, J., Jiang, Q., Su, M., Mu, P., … Zheng, H. (2018). Imaging-Guided Dual-Target Neuromodulation of the Mouse Brain Using Array Ultrasound. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, 65(9), 1583–1589. https://doi.org/10.1109/TUFFC.2018.2847252

Li, G., Qiu, W., Zhang, Z., Jiang, Q., Su, M., Cai, R., … Zheng, H. (2018). Noninvasive Ultrasonic Neuromodulation in Freely Moving Mice. IEEE Transactions on Bio-Medical Engineering. https://doi.org/10.1109/TBME.2018.2821201

Li, G.-F., Zhao, H.-X., Zhou, H., Yan, F., Wang, J.-Y., Xu, C.-X., … Zheng, H.-R. (2016). Improved Anatomical Specificity of Non-invasive Neuro-stimulation by High Frequency (5 MHz) Ultrasound. Scientific Reports, 6, 24738. https://doi.org/10.1038/srep24738

Li, H., Sun, J., Zhang, D., Omire-Mayor, D., Lewin, P. A., & Tong, S. (2017). Low-intensity (400 mW/cm2, 500 kHz) pulsed transcranial ultrasound preconditioning may mitigate focal cerebral ischemia in rats. Brain Stimulation, 10(3), 695–702. https://doi.org/10.1016/j.brs.2017.02.008

Mehić, E., Xu, J. M., Caler, C. J., Coulson, N. K., Moritz, C. T., & Mourad, P. D. (2014). Increased anatomical specificity of neuromodulation via modulated focused ultrasound. PloS One, 9(2), e86939. https://doi.org/10.1371/journal.pone.0086939

Menz, M. D., Oralkan, O., Khuri-Yakub, P. T., & Baccus, S. A. (2013). Precise neural stimulation in the retina using focused ultrasound. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33(10), 4550–4560. https://doi.org/10.1523/JNEUROSCI.3521-12.2013

Sharabi, S., Daniels, D., Last, D., Guez, D., Zivli, Z., Castel, D., … Harnof, S. (2018). Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model. Brain Stimulation. https://doi.org/10.1016/j.brs.2018.08.014

Walling, I., Panse, D., Gee, L., Maietta, T., Kaszuba, B., Kumar, V., … Pilitsis, J. G. (2018). The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine. Brain Research, 1699, 135–141. https://doi.org/10.1016/j.brainres.2018.08.004

Wasilczuk, K. M., Bayer, K. C., Somann, J. P., Albors, G. O., Sturgis, J., Lyle, L. T., … Irazoqui, P. P. (2018). Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve. Ultrasound in Medicine & Biology. https://doi.org/10.1016/j.ultrasmedbio.2018.09.005

Weintraub, D., & Elias, W. J. (2017). The emerging role of transcranial magnetic resonance imaging-guided focused ultrasound in functional neurosurgery. Movement Disorders: Official Journal of the Movement Disorder Society, 32(1), 20–27. https://doi.org/10.1002/mds.26599

Xie, P., Zhou, S., Wang, X., Wang, Y., & Yuan, Y. (2018). Effect of pulsed transcranial ultrasound stimulation at different number of tone-burst on cortico-muscular coupling. BMC Neuroscience, 19(1), 60. https://doi.org/10.1186/s12868-018-0462-8

Yang, P. S., Kim, H., Lee, W., Bohlke, M., Park, S., Maher, T. J., & Yoo, S.-S. (2012). Transcranial focused ultrasound to the thalamus is associated with reduced extracellular GABA levels in rats. Neuropsychobiology, 65(3), 153–160. https://doi.org/10.1159/000336001

Ye, P. P., Brown, J. R., & Pauly, K. B. (2016). Frequency Dependence of Ultrasound Neurostimulation in the Mouse Brain. Ultrasound in Medicine & Biology, 42(7), 1512–1530. https://doi.org/10.1016/j.ultrasmedbio.2016.02.012

Yoo, S.-S., Kim, H., Min, B.-K., Franck, E., & Park, S. (2011). Transcranial focused ultrasound to the thalamus alters anesthesia time in rats. Neuroreport, 22(15), 783–787.

Yoo, S.-S., Yoon, K., Croce, P., Cammalleri, A., Margolin, R. W., & Lee, W. (2018). Focused ultrasound brain stimulation to anesthetized rats induces long-term changes in somatosensory evoked potentials. International Journal of Imaging Systems and Technology, 28(2), 106–112. https://doi.org/10.1002/ima.22262

Yu, K., Sohrabpour, A., & He, B. (2016). Electrophysiological Source Imaging of Brain Networks Perturbed by Low-Intensity Transcranial Focused Ultrasound. IEEE Transactions on Bio-Medical Engineering, 63(9), 1787–1794. https://doi.org/10.1109/TBME.2016.2591924

Yulug, B., Hanoglu, L., & Kilic, E. (2017). The neuroprotective effect of focused ultrasound: New perspectives on an old tool. Brain Research Bulletin, 131, 199–206. https://doi.org/10.1016/j.brainresbull.2017.04.015

https://doi.org/10.1097/WNR.0b013e32834b2957

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