Neuromodulation by Focused Ultrasound

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Neuromodulation by Focused Ultrasound (NeuroFUS) provides the highest spatial resolution of all the noninvasive neuromodulation methods. It is safe, effective, and works by mechanically modulating the activity of ion channels. In collaboration with strategic partners, we are developing brain applications for the treatment of mental health disorders and peripheral applications for the treatment of neurogenic pain.

The Spatial Resolution of Neuromodulation. Transcranial focused ultrasound (tFUS) for neuromodulation can achieve a spatial resolution equivalent to the spatial dimensions of electric fields generated by deep-brain stimulating electrodes as shown below. In the periphery, higher frequency FUS (i.e. 2.5 MHz) can achieve a spatial resolution for neuromodulation that exceeds that of surgically-implanted electrodes used to treat various types of pain and other neuro-inflammatory or auto-immune disorders.

The top panel of images shows a 0.5 MHz transcranial focused ultrasound (tFUS) beam used to noninvasively modulate the human thalamus (left). The two X-Z beam profiles shown on the right for 0.5 and 2.5 MHz are produced by NeuroFUS CTX-500 and mTX-2500 transducers. The right panel of images show the electric field produced by tDCS (top) and TMS (bottom). The bottom panel shows a pair of SCS electrodes (left). A common Medtronic DBS electrode is shown next to a DBS electric field model (right). The full width at half maximum (FWHM) at active electrode leads shown is ~ 4 mm, which is similar to the 5 mm FWHM for the 0.5 MHz tFUS beams shown in the top panel. As further illustrated, the 2.5 MHz neuromodulation FUS beam is geometrically smaller than the DBS electrode. tFUS image from Legon et al, 2018 and DBS field model modified from Buston and McIntyre, 2008.

Mechanisms of Action. Pulsed ultrasound can safely stimulate and suppress neuronal cellular activity. The core mechanisms responsible involve actions exerted by micro-mechanical pressure waves induced by low-intensity, pulsed ultrasound on ion channels. It has been shown that low-intensity, pulsed ultrasound modulates the activity of many voltage-gated channels (i.e. sodium and calcium), as well as mechano-sensitive channels (i.e. TRP, Piezo, and TREK) using our patented methods.

Next Steps. We are working with strategic partners to finalize the development of transcranial focused ultrasound (tFUS) for the treatment of depression and anxiety. As shown below, neuromodulation by tFUS confers numerous advantages over transcranial magnetic stimulation (TMS) that is already FDA-cleared for the treatment of depression with other billable indications emerging.

Ultrasonic Neuromodulation Bibliography

Abbreviated list of cited Works incorporating patented ultrasonic neuromodulation methods licensed to IST, LLC.

Basic CNS & PNS Neuromodulation Studies in Animal and Cellular Models

W. J. Tyler, Y. Tufail, M. Finsterwald, M. L. Tauchmann, E. J. Olson, and C. Majestic, "Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound," (in eng), PLoS ONE, vol. 3, no. 10, p. e3511, 2008 2008, doi: 10.1371/journal.pone.0003511.

Y. Tufail et al., "Transcranial pulsed ultrasound stimulates intact brain circuits," (in eng), Neuron, vol. 66, no. 5, pp. 681-694, 2010/06/10/ 2010, doi: 10.1016/j.neuron.2010.05.008.

H. Kim, S. J. Taghados, K. Fischer, L.-S. Maeng, S. Park, and S.-S. Yoo, "Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound," (in eng), Ultrasound Med Biol, vol. 38, no. 9, pp. 1568-1575, 2012/09// 2012, doi: 10.1016/j.ultrasmedbio.2012.04.023.

P. S. Yang et al., "Transcranial focused ultrasound to the thalamus is associated with reduced extracellular GABA levels in rats," (in eng), Neuropsychobiology, vol. 65, no. 3, pp. 153-160, 2012 2012, doi: 10.1159/000336001.

M. D. Menz, O. Oralkan, P. T. Khuri-Yakub, and S. A. Baccus, "Precise neural stimulation in the retina using focused ultrasound," (in eng), J. Neurosci., vol. 33, no. 10, pp. 4550-4560, 2013/03/06/ 2013, doi: 10.1523/JNEUROSCI.3521-12.2013.

T. Deffieux, Y. Younan, N. Wattiez, M. Tanter, P. Pouget, and J.-F. Aubry, "Low-intensity focused ultrasound modulates monkey visuomotor behavior," (in eng), Curr. Biol., vol. 23, no. 23, pp. 2430-2433, 2013/12/02/ 2013, doi: 10.1016/j.cub.2013.10.029.

H. Kim, M.-A. Park, S. Wang, A. Chiu, K. Fischer, and S.-S. Yoo, "PET∕CT imaging evidence of FUS-mediated (18)F-FDG uptake changes in rat brain," (in eng), Med Phys, vol. 40, no. 3, p. 033501, 2013/03// 2013, doi: 10.1118/1.4789916.

E. J. Juan, R. González, G. Albors, M. P. Ward, and P. Irazoqui, "Vagus Nerve Modulation Using Focused Pulsed Ultrasound: Potential Applications and Preliminary Observations in a Rat," (in eng), Int J Imaging Syst Technol, vol. 24, no. 1, pp. 67-71, 2014/03/01/ 2014, doi: 10.1002/ima.22080.

C. J. Wright, J. Rothwell, and N. Saffari, "Ultrasonic stimulation of peripheral nervous tissue: an investigation into mechanisms," Journal of Physics: Conference Series, vol. 581, p. 012003, 2015/01/29 2015, doi: 10.1088/1742-6596/581/1/012003.

H. Kim, M. Y. Park, S. D. Lee, W. Lee, A. Chiu, and S.-S. Yoo, "Suppression of EEG visual-evoked potentials in rats through neuromodulatory focused ultrasound," (in eng), Neuroreport, vol. 26, no. 4, pp. 211-215, 2015/03/04/ 2015, doi: 10.1097/WNR.0000000000000330.

A. Leo, J. K. Mueller, A. Grant, Y. Eryaman, and L. Wynn, "Transcranial focused ultrasound for BOLD fMRI signal modulation in humans," (in eng), Conf Proc IEEE Eng Med Biol Soc, vol. 2016, pp. 1758-1761, Aug 2016, doi: 10.1109/embc.2016.7591057.

H. A. S. Kamimura et al., "Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz," (in eng), Med Phys, vol. 43, no. 10, p. 5730, 2016/10// 2016, doi: 10.1118/1.4963208.

G.-F. Li et al., "Improved Anatomical Specificity of Non-invasive Neuro-stimulation by High Frequency (5 MHz) Ultrasound," (in eng), Sci Rep, vol. 6, p. 24738, 2016/04/20/ 2016, doi: 10.1038/srep24738.

R. F. Dallapiazza et al., "Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound," (in eng), J. Neurosurg., vol. 128, no. 3, pp. 875-884, 2018/03// 2018, doi: 10.3171/2016.11.JNS16976.

L. Zhao, Y. Feng, H. Hu, A. Shi, L. Zhang, and M. Wan, "Low-Intensity Pulsed Ultrasound Enhances Nerve Growth Factor-Induced Neurite Outgrowth through Mechanotransduction-Mediated ERK1/2-CREB-Trx-1 Signaling," (in eng), Ultrasound Med Biol, vol. 42, no. 12, pp. 2914-2925, 2016//12/ 2016, doi: 10.1016/j.ultrasmedbio.2016.07.017.

D. P. Casella et al., "Modulation of the rat micturition reflex with transcutaneous ultrasound," (in eng), Neurourol Urodyn, vol. 36, no. 8, pp. 1996-2002, Nov 2017, doi: 10.1002/nau.23241.

N. Wattiez et al., "Transcranial ultrasonic stimulation modulates single-neuron discharge in macaques performing an antisaccade task," (in eng), Brain Stimul, vol. 10, no. 6, pp. 1024-1031, 2017/12//Nov - undefined 2017, doi: 10.1016/j.brs.2017.07.007.

S. J. Ilham, L. Chen, T. Guo, S. Emadi, K. Hoshino, and B. Feng, "In vitro single-unit recordings reveal increased peripheral nerve conduction velocity by focused pulsed ultrasound," (in eng), Biomed Phys Eng Express, vol. 4, no. 4, 2018 2018, doi: 10.1088/2057-1976/aabef1.

M. E. Downs, S. A. Lee, G. Yang, S. Kim, Q. Wang, and E. E. Konofagou, "Non-invasive peripheral nerve stimulation via focused ultrasound in vivo," (in eng), Phys Med Biol, vol. 63, no. 3, p. 035011, Jan 26 2018, doi: 10.1088/1361-6560/aa9fc2.

W. Lee, P. Croce, R. W. Margolin, A. Cammalleri, K. Yoon, and S.-S. Yoo, "Transcranial focused ultrasound stimulation of motor cortical areas in freely-moving awake rats," (in eng), BMC Neuroscience, vol. 19, no. 1, p. 57, 2018/09/19/ 2018, doi: 10.1186/s12868-018-0459-3.

G. Li et al., "Noninvasive Ultrasonic Neuromodulation in Freely Moving Mice," (in eng), IEEE Trans Biomed Eng, 2018/04/02/ 2018, doi: 10.1109/TBME.2018.2821201.

P.-F. Yang et al., "Neuromodulation of sensory networks in monkey brain by focused ultrasound with MRI guidance and detection," (in eng), Sci Rep, vol. 8, no. 1, p. 7993, 2018/05/22/ 2018, doi: 10.1038/s41598-018-26287-7.

D. Daniels et al., "Focused Ultrasound-Induced Suppression of Auditory Evoked Potentials in Vivo," (in eng), Ultrasound Med Biol, vol. 44, no. 5, pp. 1022-1030, 2018//05/ 2018, doi: 10.1016/j.ultrasmedbio.2018.01.010.

M. Mohammadjavadi, P. P. Ye, A. Xia, J. Brown, G. Popelka, and K. B. Pauly, "Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation," (in eng), Brain Stimul, vol. 12, no. 4, pp. 901-910, Jul - Aug 2019, doi: 10.1016/j.brs.2019.03.005.

D. Folloni et al., "Manipulation of Subcortical and Deep Cortical Activity in the Primate Brain Using Transcranial Focused Ultrasound Stimulation," (in eng), Neuron, vol. 101, no. 6, pp. 1109-1116.e5, Mar 20 2019, doi: 10.1016/j.neuron.2019.01.019.

L. Verhagen et al., "Offline impact of transcranial focused ultrasound on cortical activation in primates," (in eng), Elife, vol. 8, Feb 12 2019, doi: 10.7554/eLife.40541.

X. Huang et al., "Transcranial Low-Intensity Pulsed Ultrasound Modulates Structural and Functional Synaptic Plasticity in Rat Hippocampus," (in eng), IEEE Trans Ultrason Ferroelectr Freq Control, vol. 66, no. 5, pp. 930-938, May 2019, doi: 10.1109/tuffc.2019.2903896.

M. G. Bianco et al., "Neural Modulation of the Primary Auditory Cortex by Intracortical Microstimulation with a Bio-Inspired Electronic System," (in eng), Bioengineering (Basel), vol. 7, no. 1, Mar 2 2020, doi: 10.3390/bioengineering7010023.

N. Pang et al., "Transcranial Ultrasound Stimulation of Hypothalamus in Aging Mice," (in eng), IEEE Trans Ultrason Ferroelectr Freq Control, 2020/01/21/ 2020, doi: 10.1109/TUFFC.2020.2968479.

Y. Yuan, Z. Wang, M. Liu, and S. Shoham, "Cortical hemodynamic responses induced by low-intensity transcranial ultrasound stimulation of mouse cortex," (in eng), Neuroimage, vol. 211, p. 116597, 2020/05/01/ 2020, doi: 10.1016/j.neuroimage.2020.116597.

K. M. Wasilczuk et al., "Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve," (in eng), Ultrasound Med Biol, 2018/11/02/ 2018, doi: 10.1016/j.ultrasmedbio.2018.09.005.

I. Walling et al., "The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine," (in eng), Brain Res., vol. 1699, pp. 135-141, 2018/11/15/ 2018, doi: 10.1016/j.brainres.2018.08.004.

D. P. Zachs et al., "Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis," (in eng), Nat Commun, vol. 10, no. 1, p. 951, 2019//03/12 2019, doi: 10.1038/s41467-019-08721-0.

V. Cotero et al., "Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation," (in eng), Nat Commun, vol. 10, no. 1, p. 952, 2019//03/12 2019, doi: 10.1038/s41467-019-08750-9.

Y. Zhang et al., "Ultrasound improves the outcomes of cardiopulmonary resuscitation in rats by stimulating the cholinergic antiinflammatory pathway," (in eng), Mol Med Rep, vol. 20, no. 3, pp. 2675-2684, Sep 2019, doi: 10.3892/mmr.2019.10527.

A. Hellman et al., "Low Intensity Focused Ultrasound Modulation of Vincristine Induced Neuropathy," (in eng), Neuroscience, vol. 430, pp. 82-93, 2020/03/15/ 2020, doi: 10.1016/j.neuroscience.2020.01.021.

A. Hellman et al., "Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury," (in eng), Neuroscience, vol. 429, pp. 264-272, 2020/03/01/ 2020, doi: 10.1016/j.neuroscience.2020.01.016.

D. Liang, J. Chen, W. Zhou, J. Chen, W. Chen, and Y. Wang, "Alleviation Effects and Mechanisms of Low-intensity Focused Ultrasound on Pain Triggered by Soft Tissue Injury," (in eng), J Ultrasound Med, vol. 39, no. 5, pp. 997-1005, May 2020, doi: 10.1002/jum.15185.

K. Cullion et al., "Local anesthesia enhanced with increasing high-frequency ultrasound intensity," (in eng), Drug Deliv Transl Res, Apr 19 2020, doi: 10.1007/s13346-020-00760-1.

Human Studies

W. Legon, A. Rowlands, A. Opitz, T. F. Sato, and W. J. Tyler, "Pulsed ultrasound differentially stimulates somatosensory circuits in humans as indicated by EEG and FMRI," (in eng), PLoS ONE, vol. 7, no. 12, p. e51177, 2012 2012, doi: 10.1371/journal.pone.0051177.

W. Legon et al., "Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans," (in eng), Nat. Neurosci., vol. 17, no. 2, pp. 322-329, 2014/02// 2014, doi: 10.1038/nn.3620.

W. Lee, H. Kim, S. Lee, S.-S. Yoo, and Y. A. Chung, "Creation of various skin sensations using pulsed focused ultrasound: Evidence for functional neuromodulation," Int J Imaging Syst Technol, vol. 24, no. 2, pp. 167-174, 2014/06/01 2014, doi: 10.1002/ima.22091.

W. Lee, Y. A. Chung, Y. Jung, I.-U. Song, and S.-S. Yoo, "Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound," (in eng), BMC Neuroscience, vol. 17, no. 1, p. 68, 2016//10/26 2016, doi: 10.1186/s12868-016-0303-6.

W. Lee et al., "Transcranial focused ultrasound stimulation of human primary visual cortex," (in eng), Sci Rep, vol. 6, p. 34026, 2016/09/23/ 2016, doi: 10.1038/srep34026.

W. Lee et al., "Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface," (in eng), PLoS ONE, vol. 12, no. 6, p. e0178476, 2017 2017, doi: 10.1371/journal.pone.0178476.

W. Legon, P. Bansal, R. Tyshynsky, L. Ai, and J. K. Mueller, "Transcranial focused ultrasound neuromodulation of the human primary motor cortex," Sci Rep, vol. 8, 2018/07/03/ 2018, doi: 10.1038/s41598-018-28320-1.

L. Ai, P. Bansal, J. K. Mueller, and W. Legon, "Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study," BMC Neuroscience, vol. 19, no. 1, p. 56, 2018/09/14/ 2018, doi: 10.1186/s12868-018-0456-6.

S. T. Brinker, F. Preiswerk, P. J. White, T. Y. Mariano, N. J. McDannold, and E. J. Bubrick, "Focused Ultrasound Platform for Investigating Therapeutic Neuromodulation Across the Human Hippocampus," (in eng), Ultrasound Med Biol, vol. 46, no. 5, pp. 1270-1274, 2020/05// 2020, doi: 10.1016/j.ultrasmedbio.2020.01.007.

Ultrasonic Neuromodulation in Models of Epilepsy

Y. Tufail, A. Yoshihiro, S. Pati, M. M. Li, and W. J. Tyler, "Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound," (in eng), Nat Protoc, vol. 6, no. 9, pp. 1453-1470, 2011/09/01/ 2011, doi: 10.1038/nprot.2011.371.

B. K. Min et al., "Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity," (in eng), BMC Neurosci, vol. 12, p. 23, Mar 6 2011, doi: 10.1186/1471-2202-12-23.

S.-G. Chen et al., "Transcranial focused ultrasound pulsation suppresses pentylenetetrazol induced epilepsy in vivo," (in eng), Brain Stimul, vol. 13, no. 1, pp. 35-46, 2020/02//Jan - undefined 2020, doi: 10.1016/j.brs.2019.09.011.

J. Zou et al., "Ultrasound Neuromodulation Inhibits Seizures in Acute Epileptic Monkeys," (in eng), iScience, vol. 23, no. 5, p. 101066, 2020/04/18/ 2020, doi: 10.1016/j.isci.2020.101066.

Ultrasonic Neuromodulation in Models of Multiple Sclerosis

T. A. Olmstead, P. A. Chiarelli, D. J. Griggs, A. M. McClintic, A. N. Myroniv, and P. D. Mourad, "Transcranial and pulsed focused ultrasound that activates brain can accelerate remyelination in a mouse model of multiple sclerosis," (in eng), J Ther Ultrasound, vol. 6, p. 11, 2018, doi: 10.1186/s40349-018-0119-1.

Ultrasonic Neuromodulation in Models of Depression

S.-J. Tsai, "Transcranial focused ultrasound as a possible treatment for major depression," (in eng), Med. Hypotheses, vol. 84, no. 4, pp. 381-383, 2015/04// 2015, doi: 10.1016/j.mehy.2015.01.030.

D. Zhang et al., "Antidepressant-like Effect of Low-intensity Transcranial Ultrasound Stimulation," (in eng), IEEE Trans Biomed Eng, 2018/06/08/ 2018, doi: 10.1109/TBME.2018.2845689.

J. L. Sanguinetti et al., "Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans," (in eng), Front Hum Neurosci, vol. 14, p. 52, 2020 2020, doi: 10.3389/fnhum.2020.00052.

Ultrasonic Neuromodulation in Models of Alzheimer's Disease

B. Yulug, L. Hanoglu, and E. Kilic, "The neuroprotective effect of focused ultrasound: New perspectives on an old tool," (in eng), Brain Res. Bull., vol. 131, pp. 199-206, 2017/05// 2017, doi: 10.1016/j.brainresbull.2017.04.015.

R. Beisteiner et al., "Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy," (in eng), Adv Sci (Weinh), vol. 7, no. 3, p. 1902583, Feb 2020, doi: 10.1002/advs.201902583.

Ultrasonic Neuromodulation Mechanisms of Action Studies

J. Kubanek, J. Shi, J. Marsh, D. Chen, C. Deng, and J. Cui, "Ultrasound modulates ion channel currents," (in eng), Sci Rep, vol. 6, p. 24170, 2016//04/26 2016, doi: 10.1038/srep24170.

S. H. Yoo, P. Croce, R. W. Margolin, S. D. Lee, and W. Lee, "Pulsed focused ultrasound changes nerve conduction of earthworm giant axonal fibers," Neuroreport, vol. 28, no. 4, 2017.

M. L. Prieto, K. Firouzi, B. T. Khuri-Yakub, and M. Maduke, "Activation of Piezo1 but Not NaV1.2 Channels by Ultrasound at 43 MHz," (in eng), Ultrasound Med Biol, vol. 44, no. 6, pp. 1217-1232, 2018//06/ 2018, doi: 10.1016/j.ultrasmedbio.2017.12.020.

J. Kubanek, P. Shukla, A. Das, S. A. Baccus, and M. B. Goodman, "Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System," (in eng), J. Neurosci., vol. 38, no. 12, pp. 3081-3091, 2018/03/21/ 2018, doi: 10.1523/JNEUROSCI.1458-17.2018.

J. W. Lin, F. Yu, W. S. Muller, G. Ehnholm, and Y. Okada, "Focused ultrasound transiently increases membrane conductance in isolated crayfish axon," (in eng), J Neurophysiol, vol. 121, no. 2, pp. 480-489, Feb 1 2019, doi: 10.1152/jn.00541.2018.

K. Cui, S. Zhang, J. Sun, X. Zhang, C. Ding, and G. Xu, "Inhibitory effect of ultrasonic stimulation on the voltage-dependent potassium currents in rat hippocampal CA1 neurons," (in eng), BMC Neurosci, vol. 20, no. 1, p. 3, Jan 5 2019, doi: 10.1186/s12868-018-0485-1.

Z. Qiu et al., "The Mechanosensitive Ion Channel Piezo1 Significantly Mediates In Vitro Ultrasonic Stimulation of Neurons," (in eng), iScience, vol. 21, pp. 448-457, Nov 22 2019, doi: 10.1016/j.isci.2019.10.037.