Biomedical applications of ultrasound have taken great strides into a new arena of noninvasive brain stimulation (NIBS). The journey can be traced back to the work by E. Newton Harvey (an early 20th-century zoologist, also one of the early pioneers in bioluminescence research), who discovered that ultrasound modifies the function of electrically excitable biological tissues. Subsequent investigations by William and Francis Fry as well as Leonid Gavrilov during the 1950s have demonstrated that ultrasound can temporarily alter the function of the brain and the peripheral nerves.
Ultrasound technology has since evolved, enabling the delivery of highly focused acoustic energy not only to the cortical surface, but also to deep regions of the brain through the intact skull, with a focal size measuring only a few millimeters. The advent of this transcranial focused ultrasound (tFUS) technique is owed to the development of multi-array ultrasound transducer/control systems as well as advances in image-guidance methods through which the location and intensity of the invisible acoustic focus can be accurately controlled after being transmitted through the skull.
Armed with technological advances, together with the wisdom of the past, a series of studies through the last decade have revealed that FUS, given in a batch of pulses at a low intensity (below the threshold for heat generation or mechanical damage), can reversibly modulate (increase or decrease) the excitability of brain tissue.1–3 This revelation has opened new possibilities for tuning up/down regional brain function due to the exquisite spatial selectivity and depth control of tFUS.
Existing NIBS techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct/alternating current stimulation (tDCS/tACS), offer non-pharmacological alternatives for modifying brain function; however, they cannot reach deep brain areas with sufficient spatial selectivity. In addition, emerging evidence indicates that the modulatory effects of tFUS outlast the duration of sonication, which is critical for its therapeutic effects to occur.4,5 Together, noninvasive neuromodulation by ultrasound may present a unique opportunity to treat various brain-related conditions, ranging from neurological to psychiatric.
Although the precise mechanisms that underlie the neuromodulatory effects of ultrasound remain unclear, several candidate mechanisms have been proposed, including transient changes in transmembrane capacitance and subsequent effects on action potential generation, functional modulation of mechanosensitive ion channels, and the modification of glial cell excitability.6 It is quite exciting to witness a rising number of publications interrogating the mechanisms surrounding ultrasound-mediated neuromodulation.
Along with a promising safety record in small/large animals, non-human primates, and studies involving healthy individuals7, various clinical trials are being conducted or completed. Some examples include the treatment of major depressive disorder, epilepsy, Alzheimer’s disease, disorders of consciousness, and substance use disorder. The applications of ultrasound-mediated neuromodulation also extend to treating peripheral nerve diseases or noninvasive evaluation of regional brain function. The scope of clinical application is expected to expand since there are virtually no other known (noninvasive) means to selectively modulate local brain function across the brain volume.
So far, only a very limited number of incidents of minor discomfort (at the scalp) or temporary neurological symptoms (including ones that may not be directly related to the sonication) have been reported, which attest to the encouraging safety profile of this new technique. Notwithstanding, the absence of concrete information on the operational envelope and device characteristics impedes its rapid translation into clinical practice. Fortunately, a group of scientists, doctors, and engineers around the world have formed a consortium called the International Transcranial Ultrasonic Stimulation Safety and Standards (iTRUSST) and started to establish expert opinions and consensus on regulatory guidelines and standardization of the technique.8
With immense potential in introducing new treatment options, it will be interesting and exhilarating to see how ultrasound neuromodulation will become one of the mainstream neurotherapeutic modalities of the future.
1. Bystritsky A, Korb AS, Douglas PK, et al. A review of low-intensity focused ultrasound pulsation. Brain Stimul 2011; 4:125–136. doi:10.1016/j.brs.2011.03.007.
2. Darmani G, Bergmann TO, Butts Pauly K, et al. Non-invasive transcranial ultrasound stimulation for neuromodulation. Clin Neurophysiol 2022; 135:51–73. doi:10.1016/j.clinph.2021.12.010.
3. Arulpragasam AR, van ‘t Wout-Frank M, Barredo J, Faucher CR, Greenberg BD, Philip NS. Low intensity focused ultrasound for non-invasive and reversible deep brain neuromodulation-A paradigm shift in psychiatric research. Front Psychiatry 2022; 13:825802. doi:10.3389/fpsyt.2022.825802.
4. Verhagen L, Gallea C, Folloni D, et al. Offline impact of transcranial focused ultrasound on cortical activation in primates. Elife 2019; 8: e40541. doi:10.7554/eLife.40541.
5. Kim HC, Lee W, Weisholtz DS, Yoo SS. Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human. PLoS ONE 2023; 18:e0288654. doi:10.1371/journal.pone.0288654.
6. Fomenko A, Neudorfer C, Dallapiazza RF, Kalia SK, Lozano AM. Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications. Brain Stimul 2018; 11:1209–1217. doi:10.1016/j.brs.2018.08.013.
7. Lee W, Weisholtz DS, Strangman GE, Yoo SS. Safety review and perspectives of transcranial focused ultrasound brain stimulation. Brain Neurorehabil 2021; 14:e4. doi:10.12786/bn.2021.14.e4.
8. Attali D, Tiennot T, Schafer M, et al. Three-layer model with absorption for conservative estimation of the maximum acoustic transmission coefficient through the human skull for transcranial ultrasound stimulation. Brain Stimul 2023; 16:48–55. doi:10.1016/j.brs.2022.12.005.
About the Author
Seung Schik Yoo, PhD, MBA, is an Associate Professor of Radiology at Harvard Medical School, a Director of the Neuromodulation and Tissue Engineering Laboratory (NTEL) at Brigham and Women’s Hospital, and a faculty of Harvard’s Mind Brain Behavior Interfaculty Initiative.
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