Technical Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation for Neurorehabilitation

전체 글



• Focused ultrasound (FUS) potentially offers non-invasive, non-pharmacological options for neuromodulation.

• FUS provides exquisite depth penetration and spatial selectivity.

• FUS can also be used to temporarily disrupt the blood-brain barrier.

• The neuromodulation may ramify into long-term neuroplasticity for neurorehabilitation.

• Further investigations are needed to reveal its basic mechanism, long-term safety, and efficacy.


Received: Jun 11, 2018 Accepted: Sep 10, 2018 Correspondence to Seung-Schik Yoo

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.


Seung-Schik Yoo

Technical Review and Perspectives of

Transcranial Focused Ultrasound Brain

Stimulation for Neurorehabilitation




Lack of a region-specific brain stimulation modality having both spatial specificity and depth penetration has limited clinicians to explore novel non-pharmacological treatment options in neurorehabilitation. Focused ultrasound (FUS) has shown excitatory and suppressive modulatory effects on neural tissues in both central and peripheral nervous systems by transcranially delivering low-intensity highly focused acoustic pressure waves to region- specific neural structures in a completely non-invasive fashion. This emerging technique, with exquisite spatial selectively and depth penetration, is considered as a new mode of brain stimulation that may significantly improve existing brain stimulation modalities. This review aims to provide the perspectives of FUS-mediated brain stimulation in neurorehabilitation, along with potential pitfalls and cautions that need to be taken into consideration. When combined with the intravascular introduction of microbubble-based ultrasound contrast agents, the technique adds therapeutic potentials in delivering drug/genes/cells across the blood-brain barrier, which may open new opportunities for neurorehabilitation. Efforts are being made to construct FUS devices appropriate for routine clinical use, to investigate its fundamental mechanisms, and to optimize the sonication parameters. Repeated administration of the technique for inducing neuroplasticity, including the assessment of long-term safety, is warranted to reveal its utility in neurorehabilitation.

Keywords: Focused Ultrasound; Neuronal Plasticity; Excitation; Suppression; Acoustics


The dawn of the therapeutic ultrasound

The use of ultrasound in modern medicine can be first traced to the discovery of piezoelectric phenomena and corresponding piezocrystals by the Curie bothers (Jacques and Pierre) in 1880 [1,2]. Electrical currents cause physical deformation of these piezo-materials (i.e., transducers), subsequently emitting sound pressure waves in an ultrasound frequency range by tuning the vibration frequency greater than human hearing (> 20 kHz). The utility of ultrasound in biology was explored first in early 1900s for the therapeutic purposes, for example, alleviating muscle/joint pain or indigestion. The ultrasound technology was drastically evolved over the Second World War period [3], in detecting submarines while many of these technologies were later translated to the advent of diagnostic ultrasound Brain Neurorehabil. 2018 Sep;11(2):e16 pISSN 1976-8753·eISSN 2383-9910


Received: Jun 11, 2018 Accepted: Sep 10, 2018 Correspondence to Seung-Schik Yoo

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

E-mail: Copyright © 2018. Korea Society for Neurorehabilitation

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https:// which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ORCID iDs Seung-Schik Yoo Conflict of Interest

The author has no potential conflicts of interest to disclose.

Seung-Schik Yoo

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Technical Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation for Neurorehabilitation

Brain & NeuroRehabilitation


imagers and its subsequent and prevailing use in modern medicine. Therapeutic ultrasound had been limited to a few applications [4], such as thermal ablation of the soft tissues, physiotherapies of the muscular conditions, and lithotripsy of the kidney stones. Most of these limitations have been attributed to technical challenges in delivering acoustic pressure waves through bone, whereby the bone introduces significant distortion/scattering/

absorption in sound wave propagation [5].

Basic review of acoustics

Propagation of the sound waves through any media is complex phenomenon involving linear and non-linear interactions, which go beyond the scope of this review. Therefore, only the basic element of the acoustic physics is introduced. Transmission of the acoustic waves through the media is heavily dependent on their wavelength and corresponding frequencies. Acoustic pressure waves travel in a speed of up to 340 m/s in the air and up to 1,500 m/s in the water-based media while the speed drastically increases in solid media such as bones. The wavelength, as determined by its frequency (Hz) and the speed of the sound waves, is represented by the speed of the sound divided by its frequency. For example, the ultrasound having frequency of 250 kHz in water has a wavelength about 6 mm (i.e., 1,500 m/s ÷ 250,000 Hz). On the other hand, ultrasound used in typical imaging applications, on the order of 2.5 MHz, has therefore, much shorter wavelength of 0.6 mm. Ultrasound typically interacts (through reflection/scattering/absorption) with the objects that are greater than its wavelength, and the ultrasound with a short wavelength (thus high frequency) is therefore used to detect small objects in the body (by detecting the reflective ultrasound

‘echo’ bouncing from the object). On the other hand, to penetrate the bone, for example, skull having nominal 6 mm in thickness, a much longer wavelength (thus lower frequency) ultrasound is needed. For these reasons, a frequency range of 200–700 kHz is used for the transcranial application of therapeutic transcranial ultrasound [6].

Advent of transcranial focused ultrasound (FUS)

FUS technique enables the delivery of highly-focused (with a diameter and length of the focal size measuring less than 10 millimeters) acoustic energy to biological tissue by using an acoustic lens [7], the transducer geometry [8], or the phased actuation of multiple FUS transducer elements [9]. When operating in high-intensity range (typically ranging from a few 100 to 1,000 W), the mechanical energy of the sound waves is transposed to heat which subsequently raises the tissue temperature and causes hyperthermic destruction of the tissue-of-interest. Technical breakthroughs have been made for past decade in transcranial high-intensity FUS methods, whereby phased-array ultrasound configuration (consists of > 500–1,000 small transducer elements surrounding the head) and the independent actuation of transducers are used to correct the acoustic aberration caused by the skull [9,10].

The technique has been clinically deployed for the thermal ablation of brain tumors and functional neurosurgery in humans [11,12]. A single-element FUS configuration, utilizing a segmented spherical shape of the transducer having variable or fixed focal depths, can also deliver focused acoustic energy to the brain transcranially [13,14]. In high-intensity ranges, the skull is the major source of acoustic energy absorption; therefore, heating should be carefully monitored. In addition, image-guidance, such as intra-operative magnetic resonance imaging (MRI) and separate magnetic resonance-based navigation systems are used to locate/steer the invisible acoustic focus.



Background information

A non-invasive brain stimulation method that enables the controlled modulation of brain activity in a spatially-restricted fashion is sought after as it would offer a new mode of neurotherapeutics. Invasive techniques, such as deep brain stimulation, vagus nerve stimulation, and electrocorticography, are used to modify region-specific cortical function of the brain; however, they carry risks associated with surgery. As a potential alternative to these invasive procedures, transcranial magnetic stimulation (TMS) has been used to modulate cortical activities through the induction of electrical currents on the cortical surfaces by applying strong magnetic fields over the skull [15,16]. Transcranial direct current stimulation also allows for non-invasive modulation of brain function by applying weak electrical currents to the scalp and underlying cortical tissues [17]. These modulatory effects have been considered in the context of various clinical applications, including neurorehabilitation and the treatment of major depression [18-21].

Despite the ability to non-invasively modulate brain function, the lack of spatial specificity and penetration depth due to the inductive nature of magnetic stimulation or electrical current conduction severely limits their scope of applications [15]. Optogenetic approaches for brain stimulation [22,23], with the ability to control the activity of an individual/group of neural cells, require the genetic modification of neural cells for gaining light-sensitivity, and therefore, are not applicable for immediate translations to humans.

Since a seminal investigation by Fry et al. [24] showing the neuromodulatory potential of FUS in temporarily inhibiting visual evoked potentials by sonicating lateral geniculate nucleus in cats, a series of subsequent studies have found that the administration of FUS, given in a batch of pulses at a low intensity (below the threshold for heat generation or mechanical damage), can reversibly modulate the excitability of regional brain tissue [25,26] (detailed review can be found in Bystritsky et al.[27]). We have demonstrated the feasibility of brain stimulation using low-intensity transcranial focused ultrasound (tFUS) through various animal models [28-30], and more recently, in humans [14,31-33]. In addition, tFUS is less prone to generate audible sounds or to create scalp sensations (such as TMS) in humans. Thus, it will be better-suited to provide sham or control conditions during the stimulation, without creating significant cognitive confounders compared to TMS [13,14]. As being augmented by the past decade of research around the world, tFUS has gained momentum in showing unprecedented flexibility in depth control as well as spatial resolution of brain stimulation.


The phased-array FUS transducer configuration, typically taking the form of a hemispheric helmet that surrounds the head, is efficient in reaching deep brain areas, as the ‘angle of attack’ of the acoustic wavefront originating from each transducer element is large relative to the skull surface [12,34]. However, when the focus is placed near the surface of the brain (for example, cortical areas), the incident angles of acoustic wave front with respect to the skull surface become smaller for a large portion of the transducer arrays, and subsequently increase the level of refraction/reflection at the skull surface beyond control. To remedy this shortcoming, a smaller, single-element FUS transducer can be maneuvered around the skull to deliver FUS to the desired brain location while maintaining the large incident angle to the skull surface (illustrated in Fig. 1). Instead of a helmet-like tFUS device that are filled with degassed water to couple the sound wave between the transducers and the scalp (in the case


tFUS Brain Stimulation for Neurorehabilitation Brain & NeuroRehabilitation


of a phased-array device), a compressible polyvinyl alcohol hydrogel [35] is provided as a simple form of acoustic coupling media [14,31-33]. The single-element tFUS configuration does not require surgical-grade preparations for patients (phased-array tFUS typically requires a shaving of the hair and implantation of the neurosurgical stereotactic frame to the skull to fixate the head with respect to the transducer array), which is applicable for practical routine-use in an out-patient setting.

Image-guidance is crucial in applying the small acoustic focus of the sonication to specific anatomies-of-interest, which differ among individuals, both anatomically and functionally.

Since the skull may introduce significant distortions in the acoustic propagation, a simple geometric derivation of the acoustic focal location within the cranial cavity is often

inaccurate [14]. Thus, the image-guidance also demands an integrated numerical simulation environment, which can estimate the acoustic propagation/focusing within the cranial cavity. The simulation favors the implementation of an expedited processing scheme, e.g., multi-resolution, the finite-difference time-domain formulation to model the transcranial propagation of acoustic waves and the concurrent feedback to the operator [5]. This capability is important since there is no currently-available, non-thermal method to image/

track the acoustic focal location in vivo. The neuromodulatory effects take place at a much lower intensity than that can be detected by an MRI technique [36]. The simulation-assisted guidance helps to increase the spatial accuracy of sonication, and may inform the operator of the potential safety risks, such as formation of standing waves [6,37].

On-site numerical simulation of acoustic propagation transducerFUS



Coupling hydrogel Head motion


Motion-detection infrared camera

Motion-detection Registration


Pressure peak ratio


Acoustic simulation Physical space

Virtual space

Fig. 1. Schematics of a single-element transducer-based tFUS setup. Acquisition of neuroanatomical information in the form of volumetric MR/fMRI/CT and their co-registration with the corresponding physical space, all under the acoustic simulation that estimates the location and intensity of the acoustic focus. A motion-detection camera will be used to co-register the physical and virtual space, and to provide the operator with real-time updates on the position and orientation of the tFUS transducer.

tFUS, transcranial focused ultrasound; MR, magnetic resonance; fMRI, functional magnetic resonance imaging;

CT, computed tomography; FUS, focused ultrasound; MRI, magnetic resonance imaging.


The schematics for single-element FUS transducer configuration is shown in Fig. 1. Typically, 3-dimensional optical registration/tracking system [38], is provided for image-guidance and navigation, whereby the detailed method is described in neuromodulatory studies involving humans [14] and sheep [29]. A structural and functional magnetic resonance imaging (fMRI) are performed to obtain information about the individual's neuroanatomy and to map the relevant brain area. MRI/computed tomography (CT)-visible fiducial markers (e.g., Pinpoint, Beekley Medical, Bristol, CT, USA) are applied to the skin (on skin blemishes, wrinkle lines, and cutaneous veins which offer reliable landmarks spanning over 5 years), serving as reference coordinates for the spatial registration between the image data ‘virtual space’ and the head ‘physical space’ (Fig. 1). An MRI is used to acquire high-resolution T1/ T2-weighted images from the brain. With the fiducial markers in the same place as the MRI, structural information of the skull is obtained using high-resolution CT, and subsequently spatially co-registered with the fMRI data, to provide the information for sonication planning and real-time guidance, along with on-site simulation-assisted estimation of the location and intensity of the acoustic focus (detailed method is described in Lee et al. [14]). A CT scan also provides information of the calcification that may interfere or absorb the acoustic energy which may impose safety risks, and serves as a screening tool. The image-guidance acquisition process includes the determination of the desired entry/target point, sonication angular orientation, and real-time display of spatial error between the tracked acoustic focus from the target [14,38] (Fig. 1).

Sonication parameters

Sinusoidal ultrasound waves are widely used, and given in a pulsed fashion. The acoustic intensity, i.e., the acoustic power per given area (i.e., W/cm2), is conventionally expressed in spatial-peak pulse-average intensity (Isppa) while spatial-peak temporal-average intensity (Ispta) represents its time-averaged value per each stimulus. FUS is given in a batch of pulsed sinusoidal pressure waves at a fundamental frequency of 250 kHz, typically within 200–700 kHz range for transcranial application [6]. The individual pulses, each having a specific tone- burst-duration (TBD), are administered repeatedly at a certain pulse repetition frequency (PRF) (Fig. 2 for the schematics), whereby TBD and PRF together determine the duty cycle of sonication (expressed in %, indicating the fraction of active sonication time per given quanta). The overall duration of pulsed sonication is described as the sonication duration (SD). We have found that stimulatory effects are elicited in high duty cycles (50%–70% range) at short SD, whereas suppressive effects are seen at lower duty cycles (5% or less) and longer SD (few tens of seconds) [28,30,39]. The jury is still out about exact parameters and whether the effects are occurring at single cell-level, and further study is necessary to reveal the exact parameters and underlying mechanisms (Fig. 2).

Recent reviews and potential mechanism

Although the detailed mechanism behind this ultrasound-mediated neuromodulation has yet to be ascertained, transient deformation of the neuronal cell membrane, and associated changes in trans-membrane capacitance/subsequent modulation of action potentials [40-42], or the manipulation of cellular excitability of glial cells mediated via mechanoreceptors [43], have been suggested as a few of the likely candidates. Recent investigations on rodent models have also suggested the potential involvement of auditory areas in mediating physical response to FUS [44], in forms of auditory startle responses. Although these seemingly confounding effects have yet to be seen in humans and non-human primates, one should be careful in designing experiments with consideration of potential involvement of the neural substrates other than the ones that are directly stimulated by FUS.


tFUS Brain Stimulation for Neurorehabilitation Brain & NeuroRehabilitation


Long-term plasticity

One of important questions in evaluating the utility of tFUS in neurorehabilitation is whether the effects of sonication can actually outlast the SD itself. In order to have therapeutic effects to take place, one should examine the presence of long-term effects of sonication, enough for inducing the neural plasticity. We transcranially applied FUS to the somatosensory areas of the anesthetized rats for 10 minutes at a low duty cycle (5%) and intensity, and measured the time-progression of somatosensory evoked potentials (SEPs) induced by the unilateral electrical stimulation of the hind limb [45]. Compared to the control sham condition (which did not involve any sonication), differential SEP features were observed and found to persist beyond 35 minutes after stopping the administration of FUS. Although there are possible confounders due to the use of anesthesia (ketamine and xylazine) in this rodent study, the presence of this non-transient neuromodulatory effect provides early evidence that FUS- mediated brain stimulation has the potential to induce neuroplasticity. The utility of long- term, repeated administrations of the technique and its clinical efficacy in setting in more permanent neuroplasticity, especially for the context of neurorehabilitation, calls for further investigation.

Safety concerns

One should pay close attention to sonication parameters so that they will not exceed major safety-guidelines, i.e., Mechanical Index < 1.9, Isppa < 12 W/cm2, and Ispta ≤ 3 W/cm2 (European standard for ultrasound stimulation device [46]) to maximize the safety [47]. Particularly relevant for the transcranial application, potential pressure reverberation [48] (resulting in inhomogeneous intensity profile near the focus) and the formation of standing waves (pressure waves outside of the intended focus, caused by the undesired positive interferences within the cranium cavity) [49], should be avoided. It is also important to monitor the presence of potential skull heating in the ultrasound beam path if the FUS is given relatively close to the skull base (the thalamus is one of the examples). Also, since a stroke or cerebral hemorrhaging may impact the mechanical integrity of the affected brain regions, making them particularly vulnerable to any external mechanical agitation (which is caused by the FUS), additional restrictions and cautions in performing tFUS are advised. Due to these unknown risks involving the patient population, tFUS has been conceived and applied to only a few clinical arenas (e.g., Alzheimer's disease, epilepsy, and modulation of consciousness in coma/vegetative state/minimally-consciousness state).



1/PRF Sinusoidal

ultrasound waves Acoustic intensity


Inter sonication interval

Fig. 2. Illustration for the definition of sonication parameters used in the experiment.

TBD, tone-burst-duration; PRF, pulse repetition frequency; SD, sonication duration.


Other potential utilities of tFUS

The past decade of research has shown that the pulsed application of FUS, when combined with the intravenous injection of microbubbles (clinically used in ultrasound imaging), can temporarily and reversibly disrupt the regional blood-brain barrier (BBB) detailed review is provided in Cammalleri et al. [50]. This technique has shown new possibility for transferring exogenous pharmaceutical/biological agents, including genetic materials and even cells across the BBB. These new possibilities will provide a niche for delivering therapeutic agents for neurorehabilitation.

Other than applications in neurorehabilitation, tFUS brain stimulation may open new non- invasive therapeutic avenues for the treatment of neurological/psychiatric conditions. For example, tFUS may be applied to modify aberrant prefrontal cortex function associated with drug-resistant depression [51]. Also, modulation of the reward neural substrates, such as ventral striatum [52,53], may someday help to treat substance abuse. The ability to modulate the function of spatially-selective brain areas may also provide the technical foundations for non-invasive assessment/mapping of brain dysfunction, for example, an interrogation of normal or aberrant neural activity. We also note that identical tFUS techniques can be used to effect the neural conduction through myelinated nerves and to elicit tactile sensations by directly stimulating the nerve endings [54,55], suggesting its further applicability in the peripheral nervous system, with potential utility in modulating white matter tracts in the brain.


In summary, beyond the utility in transcranial modulation of brain function for neurorehabilitation, tFUS is anticipated to promote a wide spectrum of applications, providing a broad range of non-pharmacological therapeutic opportunities, yet the technique has many challenges ahead for its effective and safe use, especially regarding its long-term and repeated application. Multi-faceted and multi-disciplinary approaches in research would overcome those challenges.


The author acknowledges the editorial review by Dr. Wonhye Lee, Mr. Phillip Croce, and Mr.

Stanley Tran.


1. Curie J, Curie P. Dilatation électrique du quartz. J Phys Theor Appl 1889;8:149-168.


2. Duck F. ‘The electrical expansion of quartz’ by Jacques and Pierre Curie. Ultrasound 2009;17:197-203.


3. Fyfe MC, Bullock MI. Therapeutic ultrasound: some historical background and development in knowledge of its effect on healing. Aust J Physiother 1985;31:220-224.


4. Miller DL, Smith NB, Bailey MR, Czarnota GJ, Hynynen K, Makin IR. Bioeffects Committee of the American Institute of Ultrasound in Medicine. Overview of therapeutic ultrasound applications and safety considerations. J Ultrasound Med 2012;31:623-634.



tFUS Brain Stimulation for Neurorehabilitation Brain & NeuroRehabilitation


5. Yoon K, Lee W, Croce P, Cammalleri A, Yoo SS. Multi-resolution simulation of focused ultrasound propagation through ovine skull from a single-element transducer. Phys Med Biol 2018;63:105001.


6. White PJ, Clement GT, Hynynen K. Longitudinal and shear mode ultrasound propagation in human skull bone. Ultrasound Med Biol 2006;32:1085-1096.


7. Lele PP. A simple method for production of trackless focal lesions with focused ultrasound: physical factors. J Physiol 1962;160:494-512.


8. Khokhlova TD, Hwang JH. HIFU for palliative treatment of pancreatic cancer. J Gastrointest Oncol 2011;2:175-184.


9. Hynynen K, Clement GT, McDannold N, Vykhodtseva N, King R, White PJ, Vitek S, Jolesz FA. 500-element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls. Magn Reson Med 2004;52:100-107.


10. Song J, Hynynen K. Feasibility of using lateral mode coupling method for a large scale ultrasound phased array for noninvasive transcranial therapy. IEEE Trans Biomed Eng 2010;57:124-133.


11. Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann Neurol 2009;66:858-861.


12. McDannold N, Clement GT, Black P, Jolesz F, Hynynen K. Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 2010;66:323-332.


13. Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A, Tyler WJ. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci 2014;17:322-329.


14. Lee W, Kim H, Jung Y, Song IU, Chung YA, Yoo SS. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci Rep 2015;5:8743.


15. Fregni F, Pascual-Leone A. Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat Clin Pract Neurol 2007;3:383-393.


16. Loo CK, Mitchell PB. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J Affect Disord 2005;88:255-267.


17. Picht T, Schmidt S, Brandt S, Frey D, Hannula H, Neuvonen T, Karhu J, Vajkoczy P, Suess O. Preoperative functional mapping for rolandic brain tumor surgery: comparison of navigated transcranial magnetic stimulation to direct cortical stimulation. Neurosurgery 2011;69:581-588.


18. Segrave RA, Arnold S, Hoy K, Fitzgerald PB. Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study. Brain Stimul 2014;7:325-331.


19. Viana RT, Laurentino GE, Souza RJ, Fonseca JB, Silva Filho EM, Dias SN, Teixeira-Salmela LF, Monte-Silva KK. Effects of the addition of transcranial direct current stimulation to virtual reality therapy after stroke:

a pilot randomized controlled trial. NeuroRehabilitation 2014;34:437-446.


20. Helmich RC, Siebner HR, Bakker M, Münchau A, Bloem BR. Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease. J Neurol Sci 2006;248:84-96.


21. Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, Yoo WK, Hallett M. Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke.

Stroke 2006;37:1471-1476.


22. Deisseroth K. Optogenetics. Nat Methods 2011;8:26-29.


23. Miesenböck G. The optogenetic catechism. Science 2009;326:395-399.



24. Fry FJ, Ades HW, Fry WJ. Production of reversible changes in the central nervous system by ultrasound.

Science 1958;127:83-84.


25. Gavrilov LR, Tsirulnikov EM, Davies IA. Application of focused ultrasound for the stimulation of neural structures. Ultrasound Med Biol 1996;22:179-192.


26. Bachtold MR, Rinaldi PC, Jones JP, Reines F, Price LR. Focused ultrasound modifications of neural circuit activity in a mammalian brain. Ultrasound Med Biol 1998;24:557-565.


27. Bystritsky A, Korb AS, Douglas PK, Cohen MS, Melega WP, Mulgaonkar AP, DeSalles A, Min BK, Yoo SS.

A review of low-intensity focused ultrasound pulsation. Brain Stimul 2011;4:125-136.


28. Kim H, Chiu A, Lee SD, Fischer K, Yoo SS. Focused ultrasound-mediated non-invasive brain stimulation:

examination of sonication parameters. Brain Stimul 2014;7:748-756.


29. Lee W, Lee SD, Park MY, Foley L, Purcell-Estabrook E, Kim H, Fischer K, Maeng LS, Yoo SS. Image-guided focused ultrasound-mediated regional brain stimulation in sheep. Ultrasound Med Biol 2016;42:459-470.


30. Yoo SS, Bystritsky A, Lee JH, Zhang Y, Fischer K, Min BK, McDannold NJ, Pascual-Leone A, Jolesz FA.

Focused ultrasound modulates region-specific brain activity. Neuroimage 2011;56:1267-1275.


31. Lee W, Chung YA, Jung Y, Song IU, Yoo SS. Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound. BMC Neurosci 2016;17:68.


32. Lee W, Kim HC, Jung Y, Chung YA, Song IU, Lee JH, Yoo SS. Transcranial focused ultrasound stimulation of human primary visual cortex. Sci Rep 2016;6:34026.


33. Lee W, Kim S, Kim B, Lee C, Chung YA, Kim L, Yoo SS. Non-invasive transmission of sensorimotor information in humans using an EEG/focused ultrasound brain-to-brain interface. PLoS One 2017;12:e0178476.


34. Yoon K, Lee W, Croce P, Cammalleri A, Yoo SS. Multi-resolution simulation of focused ultrasound propagation through ovine skull from a single-element transducer. Phys Med Biol 2018;63:105001.


35. Lee W, Lee S, Park M, Yang J, Yoo SS. Evaluation of polyvinyl alcohol cryogel as an acoustic coupling medium for low-intensity transcranial focused ultrasound. Int J Imaging Syst Technol 2014;24:332-338.


36. Kaye EA, Chen J, Pauly KB. Rapid MR-ARFI method for focal spot localization during focused ultrasound therapy. Magn Reson Med 2011;65:738-743.


37. Schwenke M, Strehlow J, Haase S, Jenne J, Tanner C, Langø T, Loeve AJ, Karakitsios I, Xiao X, Levy Y, Sat G, Bezzi M, Braunewell S, Guenther M, Melzer A, Preusser T. An integrated model-based software for FUS in moving abdominal organs. Int J Hyperthermia 2015;31:240-250.


38. Kim H, Chiu A, Park S, Yoo SS. Image-guided navigation of single-element focused ultrasound transducer. Int J Imaging Syst Technol 2012;22:177-184.


39. Min BK, Bystritsky A, Jung KI, Fischer K, Zhang Y, Maeng LS, Park SI, Chung YA, Jolesz FA, Yoo SS.

Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. BMC Neurosci 2011;12:23.


40. Krasovitski B, Frenkel V, Shoham S, Kimmel E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc Natl Acad Sci U S A 2011;108:3258-3263.


41. Plaksin M, Shoham S, Kimmel E. Intramembrane cavitation as a predictive bio-piezoelectric mechanism for ultrasonic brain stimulation. Phys Rev X 2014;4:011004.


42. Prieto ML, Ömer O, Khuri-Yakub BT, Maduke MC. Dynamic response of model lipid membranes to ultrasonic radiation force. PLoS One 2013;8:e77115.



tFUS Brain Stimulation for Neurorehabilitation Brain & NeuroRehabilitation


43. Ostrow LW, Suchyna TM, Sachs F. Stretch induced endothelin-1 secretion by adult rat astrocytes involves calcium influx via stretch-activated ion channels (SACs). Biochem Biophys Res Commun 2011;410:81-86.


44. Sato T, Shapiro MG, Tsao DY. Ultrasonic neuromodulation causes widespread cortical activation via an indirect auditory mechanism. Neuron 2018;98:1031-1041.e5.


45. Yoo SS, Yoon K, Croce P, Cammalleri A, Margolin RW, Lee W. Focused ultrasound brain stimulation to anesthetized rats induces long-term changes in somatosensory evoked potentials. Int J Imaging Syst Technol 2018;28:106-112.


46. Hekkenberg RT, Beissner K, Zeqiri B, Bezemer RA, Hodnett M. Validated ultrasonic power measurements up to 20 W. Ultrasound Med Biol 2001;27:427-438.


47. Duck FA. Medical and non-medical protection standards for ultrasound and infrasound. Prog Biophys Mol Biol 2007;93:176-191.


48. Younan Y, Deffieux T, Larrat B, Fink M, Tanter M, Aubry JF. Influence of the pressure field distribution in transcranial ultrasonic neurostimulation. Med Phys 2013;40:082902.


49. Furuhata H, Saito O. Comparative study of standing wave reduction methods using random modulation for transcranial ultrasonication. Ultrasound Med Biol 2013;39:1440-1450.


50. Cammalleri A, Croce P, Lee W, Yoon K, Yoo SS. Therapeutic potentials of localized blood-brain barrier disruption by non-invasive transcranial focused ultrasound: a technical review. J Clin Neurophysiol.

Forthcoming 2018.

51. Cohen CI, Amassian VE, Akande B, Maccabee PJ. The efficacy and safety of bilateral rTMS in medication- resistant depression. J Clin Psychiatry 2003;64:613-614.


52. Wang Z, Faith M, Patterson F, Tang K, Kerrin K, Wileyto EP, Detre JA, Lerman C. Neural substrates of abstinence-induced cigarette cravings in chronic smokers. J Neurosci 2007;27:14035-14040.


53. Stein EA, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, Hoffmann RG, Hawkins M, Rao SM, Bandettini PA, Bloom AS. Nicotine-induced limbic cortical activation in the human brain: a functional MRI study.

Am J Psychiatry 1998;155:1009-1015.


54. Lee W, Kim H, Lee S, Yoo SS, Chung YA. Creation of various skin sensations using pulsed focused ultrasound: evidence for functional neuromodulation. Int J Imaging Syst Technol 2014;24:167-174.


55. Yoo SS, Lee W, Kim H. Pulsed application of focused ultrasound to the LI4 elicits deqi sensations: pilot study. Complement Ther Med 2014;22:592-600.




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