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Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS) Neuromodulation: From Theoretical Principles to Stimulation Practices

Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS)... REVIEW published: 11 June 2019 doi: 10.3389/fneur.2019.00549 Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS) Neuromodulation: From Theoretical Principles to Stimulation Practices 1,2 1,2 1 Lazzaro di Biase *, Emma Falato and Vincenzo Di Lazzaro Neurology, Neurophysiology, and Neurobiology Unit, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy, Unit of Neurophysiology and Neuroengineering of Human-Technology Interaction, School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy Transcranial focused ultrasound is an emerging technique for non-invasive neurostimulation. Compared to magnetic or electric non-invasive brain stimulation, this technique has a higher spatial resolution and can reach deep structures. In addition, both animal and human studies suggest that, potentially, different sites of the central and peripheral nervous system can be targeted by this technique. Depending on stimulation Edited by: parameters, transcranial focused ultrasound is able to determine a wide spectrum Matteo Bologna, of effects, ranging from suppression or facilitation of neural activity to tissue ablation. Sapienza University of Rome, Italy The aim is to review the state of the art of the human transcranial focused ultrasound Reviewed by: Hyungmin Kim, neuromodulation literature, including the theoretical principles which underlie the Korea Institute of Science and explanation of the bioeffects on neural tissues, and showing the stimulation techniques Technology (KIST), South Korea Jérôme Sallet, and parameters used and their outcomes in terms of clinical, neurophysiological or University of Oxford, United Kingdom neuroimaging results and safety. *Correspondence: Keywords: focused ultrasound, transcranial stimulation, non-invasive brain stimulation (NIBS), transcranial Lazzaro di Biase focused ultrasound (tFUS), transcranial ultrasound (tUS) lazzaro.dibiase@gmail.com; l.dibiase@unicampus.it INTRODUCTION Specialty section: This article was submitted to Preliminary animal studies suggest that, potentially, different sites in the peripheral nervous system, Movement Disorders, a section of the journal from nerves (1) to spinal roots (2), and in the central nervous system, from superficial regions Frontiers in Neurology like primary motor cortex (3) or frontal eye field (4), to more deep areas like hippocampus (3), amygdala (5), or thalamus (6) can be targeted by focused ultrasound stimulation technique. In Received: 18 February 2019 Accepted: 07 May 2019 addition, animal studies showed that this technique has a high spatial resolution, useful also for Published: 11 June 2019 mapping small brain areas, as shown by Fry (7) for the mapping of lateral geniculate nucleus, or by Ballantine et al. (2) for the stimulation of Edinger-Westphal nucleus. Citation: di Biase L, Falato E and Di Lazzaro V Furthermore, a recent fMRI resting-state functional connectivity animal study (8), showed that (2019) Transcranial Focused the effect of tFUS neuromodulation can last for up to 2 h after stimulation, opening a new way Ultrasound (tFUS) and Transcranial to explore not only the online effect but also the long lasting effect of neuromodulation. The first Unfocused Ultrasound (tUS) human transcranial application of ultrasounds for neuromodulation was described by Hameroff Neuromodulation: From Theoretical et al. (9), with an unfocused transcranial ultrasound (tUS) continuous stimulation of posterior Principles to Stimulation Practices. frontal cortex, applied on 31 patients affected by chronic pain. The first human application of Front. Neurol. 10:549. doi: 10.3389/fneur.2019.00549 focused transcranial ultrasound (tFUS) technique was described by Legon et al. (10). They targeted Frontiers in Neurology | www.frontiersin.org 1 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation the primary somatosensory cortex of healthy volunteers, in with an increase of intensity, there is a pore formation and a within-subjects, sham-controlled study. One of the most with the maximum stretch that can be achieved with the interesting results of tFUS applications was a case report of technique a membrane rupture and irreversible lesion is obtained emergence from minimally conscious state, after low intensity (28) (Figure 1). non-invasive ultrasonic thalamic stimulation in a patient after Considering the electrical properties of the cell membrane acute brain injury (11). Following this first single evidence, a at rest, which can be approximated with a parallel plate clinical trial is ongoing to explore the effect of thalamic low capacitor, a hypothesis is that the dynamic fluctuation of intensity focused ultrasound in acute brain injury patients (12). the membrane bilayer changes the instantaneous membrane Regarding peripheral nervous system neuromodulation, capacitance and leads to a capacitive current, which can Bailey et al. (13) explored the ability of continuous US at 1.5 potentially activate voltage-dependent sodium and potassium MHz in modulating the ulnar nerve stimulation response to channels (27) (Figure 2). The neuronal bilayer sonophore model magnetic stimulation (MS). This study showed no significant (27) combines, in a complementary way, all the biomechanical change in electromyographic response during magnetic plus US and bioelectrical proprieties of the cell membrane described, and ulnar nerve stimulation. However, further studies are needed in predicts the stimulation parameter needed to reach a successful order to explore different parameter of stimulation. motor cortex stimulation. It explains, for example, the higher In recent years, the scientific community showed a progressive efficacy of long US stimulation pulses (3, 29, 30), and how increasing interest on FUS neuromodulation, and some reviews the action potential can be elicited after the end of the US have been published in order to summarize the state of the art on stimulus (27, 31), with a good overlap with the experimental this topic (14–18). results obtained using real stimulation on the mouse motor cortex (30). Mechanisms of Actions of US Stimulation Parameters Neuromodulation An acoustic wave can be defined by two fundamental parameters: Focused ultrasound is a non-invasive, non-ionizing technique. the intensity, defined as the amplitude of the wave, and the In order to target a brain region, the first challenge is instantaneous period (T), defined as the time needed to complete to let ultrasounds single waves to reach the target at the same time, without different acoustic reflection, refraction, and distortion due to the inhomogeneity of skull bone. This problem can be solved by time shifting each single ultrasound wave, according to the related skull bone acoustical properties, in order to let all the waves to reach the target at the same time (19–22). The mechanical interaction between US and neuronal membranes can modify the membrane gating kinetics through the action on mechanosensitive voltage-gated ion channels or neurotransmitter receptors (23–25). The study of Tyler et al. (25) supports this hypothesis. Their study showed, on ex vivo mouse brains and hippocampal slice cultures, that low-intensity, low- frequency ultrasound (LILFU) is able to activate voltage-gated sodium and calcium channels. However, this can’t be the only mechanism of action, explaining the action potential induction, since in simulations, considering the role of membrane tension on activation of mechanically sensitive voltage gated channels, the resulting effect was too low to induce an excitation (26, 27). In addition, the mechanical action of US is able to induce cavitation into the cellular membrane, by means of membrane pore formation, which changes the membrane permeability. The bilayer sonophore model (28) was introduced to better explain the bioeffects of US, taking into consideration the biomechanical proprieties of US and of cell membranes. According to this model (28), the mechanical energy of US leads to periodic expansions and contractions of the membrane. In this FIGURE 1 | Ultrasound gradually increases tension in the membrane. From the reference stage (S0), the stretch first activates mechanosensitive proteins model, the US bioeffect is dependent on the tension applied to (S1); growing tension might damage membrane proteins (S2) and then might the membrane. With a progressive increase in membrane stretch induce pore formation (S3a, S3b) or cause membrane rupture [modified, with intensity, the bioeffect is mediated by different mechanisms. permission, from Krasovitski et al. (28)]. First by the activation of mechanosensitive proteins. Then, Frontiers in Neurology | www.frontiersin.org 2 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation FIGURE 2 | (A) Under US effect the membrane starts fluctuating around a steady state. (B) Mechano-electrical dynamics of the model membrane to US (pressure amplitude 500 kPa and frequency 0.5 MHz): The increase in Acoustic pressure induces an increase in attraction/repulsion force, which increases the capacitance leading finally to a capacitive current. Acoustic pressure (kPa), tension (mN/m), combined attraction/repulsion force per area between the leaflets (sum of molecular 2 2 and electrostatic forces, kPa), membrane capacitance (μF/cm ), and capacitive displacement current (A/cm ) [modified, under the terms of the Creative Commons Attribution 3.0 License, from Plaksin et al. (27)]. one single oscillation cycle, which is used to calculate the Acoustic For safety reasons the indexes that describe the thermal frequency (Af) (Figure 3, Equation 1). In addition to these two and biomechanical effects of the sonication need to be defined. parameters, the stimulus duration (StimD) is the total duration These parameters are related to the instantaneous intensity of one single sonication. of stimulation and its instantaneous acoustic pressure. The During the stimulus duration two paradigms of sonication are two main mechanisms that can induce tissue damage are: used: continuous or pulsed. Some of these protocols resemble local heating, which through proteins denaturation leads to those used for non-invasive brain stimulation based on repetitive cell death, and inertial cavitation. The latter is thought to transcranial magnetic stimulation [see Di Lazzaro and Rothwell be mediated by the collapse of gas bubbles due to the (32) for a review]. The most used one for neuromodulation is the pressure exerted by ultrasonic field sufficiently strong to allow pulsed paradigm. tissue damage. For the pulsed paradigm, two additional periods need to Both, animal histological studies (8, 41, 42) and human be defined: the pulse duration (PD), which is the period of neuroimaging studies (37, 38), showed that it is possible to acoustic sonication from the starting point of oscillation to the neuromodulate brain circuits without inducing tissue damage. ending point, before the pause and the pulse repetition period The thermal index (TI) is the ratio of total acoustic power (PRP), which is the period between the starting point of two to the acoustic power required to raise tissue temperature consecutive sonications, or, in other terms, the sum of the by 1 C under defined assumptions. Finally, the non-thermal, pulse duration (PD) and the pause between two consecutive mechanical bioeffect is described by the mechanical index (MI), sonications. This period is used to calculate the pulse repetition which is directly proportional to the ultrasound beam’s peak frequency (PRF) (Figure 3, Equation 2). For the pulsed paradigm, negative pressure and inversely proportional to the frequency of the duty cycle (DC) (Figure 3, Equation 3) is the fraction of the the beam. pulsed repetition period (PRP) covered by the pulse duration The intensity, spatial-peak pulse-average (I ) is the value SPPA (PD). The cycles per pulse (c/p) are the number of cycles during a of the pulse-average intensity at the point in the acoustic field single pulse (Figure 3, Equation 4); instead, the number of pulses where the pulse-average intensity is a maximum or is a local (Np) is the number of pulses throughout the stimulus duration maximum within a specified region. The intensity, spatial-peak (Figure 3, Equation 5). temporal-average (I ) is the value of the temporal-average SPTA The sonication delivered during the stimulus duration period intensity at the point in the acoustic field where the temporal- can be repeated, without pauses, for the continuous stimulation average intensity is a maximum, or is a local maximum within a protocol. Instead, intermittent protocols are characterized by specified region. pauses between the sonications, defined as inter stimulation The FDA guidelines defined the safety threshold for diagnostic intervals (ISIs). The intermittent protocol is the most used for usage of US for adult cephalic ultrasound, which can be applied FUS neurostimulation, instead the continuous one is the most to neuromodulation. These parameters are Isspa ≤ 190 W/cm , used for the unfocused stimulation (Table 1). Ispta ≤ 94 mW/cm and a mechanical index ≤ 1.9 (43). Frontiers in Neurology | www.frontiersin.org 3 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation FIGURE 3 | (A) Intermittent protocol stimulation. The single sonications are followed by pauses, defined inter stimulation interval (ISI). (B) Pulsed paradigm of stimulation, defined by the following parameters: Intensity of stimulation, instantaneous period (T), pulse duration (PD), pulse repetition period (PRP), stimulus duration (StimD). (C) Fundamental equations for the stimulation protocol description: Equation (1) = Acoustic frequency (Af), Equation (2) = pulse repetition frequency (PRF), Equation (3) = duty cycle (DC), Equation (4) = cycles per pulse (c/p), Equation (5) = number of pulses (Np). Focused Ultrasound for Targeted Drug studies which described focused ultrasound neuromodulation approaches were included in the present review. In addition Delivery to the search protocol described, further articles suggested by Focused ultrasound technique can be used also to facilitate drugs experts in the field where read and screened (Table 1). delivery in a specific brain area. Until now the most explored application is chemotherapy delivering. However, this versatile technique could be applied for neuromodulation purposes, with RESULTS different mechanisms. The first mechanism is a focal blood–brain barrier (BBB) Physiological Effects in Normal Subjects opening, through a transient opening of endothelial tight Legon et al. (10) used tFUS to target the human primary junctions. Indeed, both animal (44, 45) and human (46) somatosensory cortex (S1), showing that tFUS significantly studies showed that FUS in combination with microbubbles decreased the amplitudes of somatosensory evoked potentials administered intravenously can open the BBB, in a targeted, non- elicited by median nerve stimulation. Furthermore, tFUS invasive, safe, and reversible manner. This technique could be significantly modulated the spectral content of sensory-evoked used for targeted neuromodulation, with therapy which doesn’t brain oscillations and enhanced the performance on sensory cross the BBB. For example Wang et al. (47) showed that it discrimination tasks. The neurophysiologic effects had a spatial is possible to facilitate gene therapy delivery with recombinant resolution of about 1 cm or less. adeno-associated virus, in a non-invasive way, through focused In another study, tFUS altered EEG intrinsic oscillatory ultrasound targeted BBB opening, with potential applications for dynamics, preferentially affecting the phase distribution of beta optogenetics (48) neuromodulation. band and modulated the phase rate across beta and gamma The second system is the local release of drugs, minimizing frequencies. Furthermore, tFUS affected the phase distributions the effect on other brain areas. Indeed, focused ultrasound can in the beta band of the early but not of the late components of be used to locally release drugs which are administered into somatosensory evoked potentials, suggesting a spatial specificity. the bloodstream through a vehicle (e.g., microbubble, liposome) This hypothesis was supported by the loss of neuromodulatory sensitive to local temperature or pressure changes (49). effects after the displacement of the transducer 1 cm laterally from the original cortical target (39). Primary (SI) and secondary (SII) somatosensory cortical areas of the hand were targeted in a study by Lee et al. (50), in METHODS which two transducers were used. The areas were stimulated The literature search methods included the PubMed/MEDLINE separately or simultaneously, under neuronavigation guide. tFUS databases with the following research string, in Nov 2018: elicited various types of tactile sensations in the contralateral (“Neuromodulation” OR “Brain Stimulation”) AND (“focused hand/arm regions. The effects were transient and reversible, and ultrasound” OR HIFU OR LIFU OR Low-intensity focused the stimulation resulted safe, as assessed by repeated clinical and ultrasound). After abstract reading and screening, only human neuroradiological evaluations. In addition this study showed, the Frontiers in Neurology | www.frontiersin.org 4 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 5 June 2019 | Volume 10 | Article 549 TABLE 1 | tFUS and tUS neuromodulation studies. References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Ai et al. (33) Custom-made, 5 Healthy Within- Primary 54 stimuli, ISI 5.5 s A : 0.50 MHz; I : 16.95 tFUS increased No auditory or f SPPA single-element FUS volunteers subjects, motor cortex PD: 0.36 ms; W/cm ; BOLD activation tactile sensation transducer; sham- (tFUS paired with PRF: 1 kHz; MI: 0.97 volumes A : 0.50 MHz Diameter controlled high field 7T fMRI Np: 500; DC: generated during a 30 mm, focal length 30 mm, study targeted on the 36%; cued tapping task. 7T MRI compatible dominant thumb c/p: 180; StimD: The effect was Focused, Pulsed BOLD representation) 500 ms spatially confined to the sonicated area. No detectable effects on SMA and PMd. Legon et al. Custom- designed, 12 (exp. 1) Healthy Within- Primary Exp1: 10 A : 0.50 MHz; I : 17.12 Concentric and Mild and moderate SPPA (34) single-element FUS 10 (exp. 2) volunteers subjects, motor cortex tFUS/TMS stimuli PD: 0.36 ms; W/cm ; concurrent symptoms such as transducer; 28 (exp. 3) sham- (Exp 1–2: from RMT-20% to PRF: 1 kHz; I : 6.16 tFUS/TMS on M1 neck pain, SPTA A : 0.50 MHz controlled dominant FDI 100% stimulator Np: 500; DC: W/cm ; inhibited the sleepiness, muscle Height 1.25 cm, aperture study hotspot; Exp 3: output, in 36%; MI: 0.9 amplitude of twitches, itchiness 30 mm, focal length 22 mm, dominant increments of 5%, c/p: 180; single-pulse and headache Attached at the center of a APB hotspot) ISI of 10 seconds) StimD: 500 ms MEPs, attenuated (assessed by TMS 8-coil (Magstim Inc., Exp2: 10 tFUS 100 ms prior intracortical questionnaire). No UK) for concurrent and tFUS/TMS to: the TMS pulse facilitation, did not severe symptoms concentric stimulations every (exp. 1), to the CS affect intracortical reported. tFUS/TMS delivery 10 s for each TMS (exp. 2) and to the inhibition and Focused, Pulsed paired-pulse ISI visual stimulus significantly from 1 to 15 ms. (exp. 3) reduced reaction Exp3: 100 stimuli time in a motor at random time task. intervals between 3 and 6 s Legon et al. Custom-designed, 20 (exp. 1) Healthy Within- Unilateral Exp1: 300 stimuli, A : 0.50 MHz; I : 14.56 tFUS decreased Not available f SPPA (35) single-element FUS 20 (exp. 2) volunteers subjects, sensory thalamus ISI 4 s PD: 0.36 ms; W/cm ; P14 SEP transducer (Ultran Group, sham- targeted through a Exp2: 90 stimuli PRF: 1 kHz; MI: 0.89 amplitude. Inc., State College, PA); controlled neuronavigation Np: 500; DC: After bone Decrease in ability A : 0.50 MHz study system from the 36%; transmission: in a tactile Aperture 63 mm, focal individual MRI c/p: 180; I : 7.03; judgement task. SPPA length 70.92 mm (55 mm StimD: 500 ms W/cm ; Effect upon from exit plane), f# 1.13 Median nerve MI: 0.56 cortical oscillatory Focused, Pulsed stimuli time-locked dynamics to occur 100 ms after the onset of tFUS waveforms (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 6 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Leo et al. 2 transducers: 6 (3T exp.) Healthy Pre-post 3T experiment: 3T experiment: 3T experiment: A : I : 6W/cm tFUS induced Not available f SPPA (36) 1) 3T experiment: 1 (7T exp.) volunteers interventional Primary motor 90 stimuli, ISI 0.50 MHz; (after bone BOLD fMRI signals A : 0.50 MHz Active study cortex hand knob 12-14 s PRF: 1 kHz; transmission) in the targeted diameter 60 mm, focal of the dominant 7T experiment: Np: 500; DC: cortical regions (in length 55 mm, focal FWHM hemisphere 7T 5 off/on cycles, 36%; 3 of 6 subjects) intensity volume 48.64 mm experiment: Left stimulation c/p: 180; and in the targeted head of delivered at ISI StimD: 500 ms 7T subcortical region 2) 7T experiment: the caudate 12 s during on experiment: A : 0.86 MHz Active cycles A : 0.86 MHz; f f diameter 64 mm, focal PRF: 1 kHz; length 54 mm, focal FWHM DC: 50%; c/p: intensity volume 35.77 mm 420; Both: Focused, Pulsed StimD: 500 ms Lee et al. MRI-compatible 19 (exp. 1) Healthy Within- Primary visual Exp.1: Af: 0.27 MHz; I : 16.6 tFUS induced No adverse SPPA (37) FUS transducer 10 (exp. 2) volunteers subjects, cortex, under 3T 50 stimuli, ISI 13 s PRF: 500 Hz; PD: W/cm2 BOLD fMRI signals effects, as Af: 0.27 MHz single- MRI guidance Exp.2: 1 ms; Estimates at the in V1 and other assessed by Focal length 3 cm, acoustic blind, 50 stimuli, ISI 2.5 s DC: 50%; StimD: target location: visual areas, neurological focus 3 mm (diameter) and sham- 300 ms I : mean 3 elicited examination, SPPA 17 mm (length) Focused, controlled W/cm2; phosphenes and anatomical MRI (at Pulsed study MI: mean 0.6 elicited cortical 3 time points) and evoked EEG follow-up potentials similar telephone to the classical interviews (after 2 VEP generated by months) photic stimulation Lee et al. Two sets of single-element 10 Healthy Within- Left primary and 20 stimuli for each Af: 0.21 MHz; I : 35.0 tFUS of either No abnormal SPPA (37) FUS transducers (Ultran volunteers subjects, secondary session (4 PRF: 500 Hz; W/cm ; primary and findings post-tFUS Group Ltd, State double somatosensory sessions) PD: 1 ms; I : 17.5 secondary (assessed by SPTA College, PA) blind,sham- cortex (areas of DC: 50%; StimD: W/cm somatosensory neurological Af: 0.21 MHz Shape: controlled the hand, 500 ms Estimates at the cortex, stimulated examination, segmented-spheres Outer study separately or target location: separately or MMSE, anatomical diameter (OD):30 mm Focal simultaneously I : 7.0–8.8 simultaneously, MRI on the same SPPA distance: 25 mm. Each stimulated under W/cm eliciited tactile day, at 2 weeks transducer was affixed to an multi-modal I : 3.5–4.4 sensations from and 4 weeks, and SPTA applicator (Zamerican, neuroimage- W/cm the contralateral by telephone Zacuto, Chicago, IL) guidance) hand/arm areas interview at 2 mounted on a helmet months after the (modified from Giro Section sonications) Helmet, Santa Cruz, CA) Focused, Pulsed (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 7 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Monti et al. BXPulsar 1001, 1 Post- Case Thalamus 10 sonications, A : 0.65 MHz; I : 720 Emergence from Clinical f SPTA (11) Brainsonix Inc. traumatic report, part (MRI-guided by a 30 s each, PD: 0.5 ms; mW/cm minimally improvement Single-element spherical disorder of of an 3 Tesla Magnetom separated by 30 s PRF: 100 Hz conscious state suggested that the transducer; consciousness ongoing Tim Trio pause intervals procedure was A : 0.65 MHz Diameter and (minimally clinical trial MR scanner) safe and radius of curvature 71.5 mm conscious (12) well-tolerated Focused, Pulsed state) 19 days post-injury Lee et al. Ceramic piezoelectric FUS 12 (exp. 1) Healthy Within- Primary (Exp. 1): A : 0.25 MHz; I : 3W/cm tFUS elicited No adverse f SPPA (38) transducer (Channel 6 (exp. 2) volunteers subjects, somatosensory 200 stimuli, ISI 3 s PRF: 500 Hz; Estimated I at transient tactile effects, as SPPA Industries, Santa sham- cortex (hand area) (Exp. 2): Tone-burst- the target: sensations on the assessed by Barbara, CA) controlled under subject- 100 stimuli, ISI duration: 1 ms; 0.7 ± 0.5 W/cm hand and arm area neurological Outer diameter 6 cm, study specific image- 2 s DC: 50%; contralateral to the examination, radius-of- curvature 7 cm guidance StimD: 300 ms sonicated anatomical MRI (at A : 0.25 MHz Low Intensity hemisphere, with 3 time points) and Focused anatomical follow-up Ultrasound Pulsation specificity of up to telephone a finger. EEG interviews (after 2 showed months) sonication-specific evoked potentials. Mueller Two-channel, 2 MHz 18 (exp. 1) Healthy Within- Exp.1 120 stimuli, ISI 6 s A : 0.50 MHz; I : 23.87 tFUS altered EEG Not available f SPPA et al. (39) function generator (BK 7 volunteers subjects, Somatosensory PD: 0.36 ms; W/cm ; beta phase and Precision Instruments) (exp. 2) sham- cortex (CP3) PRF: 1 kHz; MI: 1.13 modulated the delivered at 0.5 MHz controlled Exp.2 1cm laterally Np: 500; c/p: 180; phase rate across Focused, pulsed study StimD: 500 ms beta and gamma frequencies. tFUS affected phase distributions in the beta band of early SEP components. Neuromodulatory effects were lost when the transducer was displaced 1 cm laterally from the original cortical target. (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 8 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Legon et al. Custom-made, 10 (exp. 1) Healthy Within- Primary Exp 1 and 2: 120 A : 0.50 MHz; I : 23.87 Exp1. A: tFUS No thermal or f SPPA (10) single-element FUS 8 (exp. 2) volunteers subjects, somatosensory stimuli, ISI 6 s PD: 0.36 ms; W/cm significantly mechanical transducer; 12 (exp. 3) sham- cortex (crown of Exp 3: 90 stimuli PRF: 1 kHz; (=4-fold lower attenuated the sensation A : 0.50 MHz Diameter 12 (exp. 4) controlled the postcentral 100 ms before Np: 500; DC: through the skull); amplitudes of 30 mm, focal length 30 mm study gyrus and each task 36%; MI: 1.13 somatosensory Focused, Pulsed posterior wall of Exp4: 120, ISI 6 s c/p: 180; Peak rarefactional evoked potentials the central sulcus, StimD: 500 ms pressure: 0.80 B: tFUS encephalographic Median nerve MPa significantly electrode CP3) stimuli time-locked modulated the to occur 100 ms spectral content of after the onset of sensory-evoked tFUS waveforms brain oscillations Exp2. tFUS modulation of brain activity is spatially restricted ( 1 cm or less) Exp3 and 4. tFUS significantly enhanced performance on sensory discrimination tasks without affecting task attention or response bias. tUS: Phillips CX50 21 (active Healthy Between- Primary 2 min Af: 2.32 MHz; Isppa: 34.96 tUS increased No significant Gibson Diagnostic System, with a stim) volunteers subjects, motor cortex HGen, B-mode; W/cm ; Ispta: cortical excitability differences in et al. (40) Phillips S5-1 broadband 22 (sham single- (abductor pollicis Harmonics: on; 132.85 mW/cm ; (average increase sensations linked plane sector transducer stim) blind, brevis DC: <1%; Focal MI: 0.67 in MEPs amplitude tingling, itching array; aperture 20.3cm, sham- motor hotspot) depth: 10 cm Peak negative of 33.7% at 1 min etc. (assessed by frequency range 1–5 MHz. controlled pressure: 1.02 and of 32.2% at questionnaires) TMS: study MPa (in degassed 6 min post between active neuronavigation-assisted water) stimulation. and sham group eXemia TMS system No significant (Nextstim Ltd., Helsinki, differences at 11 Finland) with a 70 and 16 min mm 8-coil. post stimulation). Unfocused, Continuous No differences in mood (assessed by a brief questionnaire on subject well-being) (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation feasibility of the simultaneous stimulation of different human brain areas. In Lee et al. (38), tFUS stimulation of the human somatosensory cortex elicited somatosensory sensations with anatomical specificity up to a finger, and evoked EEG potentials. fMRI studies showed the effects of tFUS on cortical and subcortical brain areas, with the ability of high-resolution non- invasive functional brain mapping (33, 36, 37). Indeed, Leo et al. (36), demonstrated that tFUS stimulation of cortical (primary motor cortex) and subcortical (head of the caudate) areas can induce blood oxygen level dependent (BOLD) signals in 3T and 7T fMRI, respectively. More recently, pairing tFUS on human primary motor cortex (M1) with 7T BOLD fMRI signals in a cued finger tapping task study, Ai et al. (33) showed that tFUS selectively increases BOLD activation volumes of the target finger representation. These effects did not spatially overcome the sonicated area, and therefore did not involve other motor regions, such as supplementary motor area (SMA) and dorsal premotor cortex (PMd). tFUS has been used also to target the human primary visual cortex (V1) Lee et al. (37) showed, on BOLD fMRI signals, that tFUS stimulation elicited the activation of a network of brain regions, including V1 and other areas involved in visual and higher-order cognitive processes. Furthermore, stimulation elicited perception of phosphenes and EEG evoked responses. The effects of tFUS on corticospinal excitability have also been studied through transcranial magnetic stimulation (TMS). Combining a custom-made FUS transducer and a 8-shaped TMS coil, Legon et al. (34) assessed for the first time in humans the effect of concentric and concurrent tFUS/TMS stimulation on M1. The stimulation had an inhibitory effect on single-pulse MEPs and intracortical facilitation, and significantly decreased the reaction time in a motor task. Legon et al. (35) tested the effects tFUS stimulation on sensory thalamus, that was targeted by a single-element focused ultrasound through a neuronavigation system based on the individual subject anatomical MRI. tFUS stimulation inhibited the P14 SEP, and was associated with a change in EEG oscillatory dynamics and to a reduced ability in a tactile judgement task. In addition, this study outlined the value of taking into account the individual skull morphology to produce safe and accurate stimulations. In a recent single-blind, sham-controlled study (40), tUS was targeted to the motor cortex through a diagnostic imaging ultrasound system. The unfocused stimulation increased MEPs amplitude by 34% compared to baseline, and the increase was recorded up to 6 min after the stimulation. This short-term increase of motor cortex excitability contrasts with a previous findings of MEP inhibition during concurrent tFUS/TMS (34). As discussed by the authors, stimulation parameters and other methodological factors might explain the different findings. Therapeutic Application Despite several studies showed the neurological therapeutic applications of lesional FUS and FUS mediated BBB opening in different diseases like essential tremor (51–54), Parkinson’s disease (55–57), depression (58, 59), obsessive-compulsive Frontiers in Neurology | www.frontiersin.org 9 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects General Electric LOGIQe, 31 Chronic pain Double Posterior frontal 15 s stimulation A : 8 MHz; MI = 0.7 tUS significantly Transient Hameroff 12L-RS probe blind, cortex, B Mode; Max Intensity = improved headache et al. (9) A : 8 MHz Unfocused, sham- contralateral to the Power: 100%; 152 mW/cm measures of global exacerbation Continuous controlled, maximal pain Depth: 3.5 cm; TIs = 0.5 affect derived from following crossover Harmonics: on; TIc = 0.2 (values subjective reports, stimulation (1 subj) study Cross- Xbeam: on at the posterior at 10 and 40 min frontal scalp) following stimulation. In gray background: unfocused stimulation protocols, in white background: focused stimulation protocols. Af, acoustic frequency; c/p, cycles per pulse; DC, duty cycle; Exp, experiment; ISI, inter stimulus interval; ISPPA, Intensity Spatial Peak Pulse Average; ISPTA, Intensity spatial peak temporal average; MEPs, motor evoked potentials; MI, mechanical index; Na, not available; Np, number of pulses; PD, pulse duration (width); PMd, dorsal premotor cortex; PRF, pulse repetition frequency; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; SD, Sonication Duration; SMA, supplementary motor area; StimD, stimulus duration; TI, Thermal Index; Tib, Thermal Index of bone; Tic, Thermal Index of Skull/Cranium; Tis, Thermal Index of soft tissue; TMS, transcranial magnetic stimulation. Note: where not specified, I is the incident acoustic intensity estimated before transcutaneous and transcranial transmission, SPPA e.g., In free water. di Biase et al. Transcranial Ultrasound Neuromodulation disorder (60, 61), neuropatic pain (62, 63), Alzheimer disease Compared to magnetic or electric non-invasive brain (46, 64), only two studies explored in humans the therapeutic stimulation, this technique has a higher spatial resolution and can efficacy of tUS (9) and tFUS (11) bioelectrical neuromodulation reach deep structures. In addition, animal studies suggest that, (Table 1). potentially, different sites of the central and peripheral nervous Hameroff et al. (9) used a 8 MHz unfocused transducer to system can be targeted by this technique. study the effects of transcranial ultrasound stimulation (tUS) on Even if still in a small number, the increasing interest in this mood, and global affect in 31 patients with chronic pain, in a technique, led to encouraging results in human studies. These double-blind, sham-controlled crossover study. Stimulation was preliminary human studies focused their attention on classic targeted to the posterior frontal cortex, contralateral to the most non-invasive neurostimulation targets, like the primary motor severe pain. After the stimulation, a significant improvement in cortex, somatosensory area or primary visual cortex, with some subjective parameters of global affect derived from the Visual studies that explored deep structures like thalamus (11, 35) or Analog Mood Scale was found. basal ganglia (36). All showed neurostimulation efficacy in terms As part of an ongoing clinical trial on low intensity of clinical, neurophysiological or functional neuroradiological focused ultrasound in acute brain injury (12), Monti outcomes (Table 1). et al. (11) reported a case of emergence from minimally The data collected since now shows that this technique is conscious state after low intensity non-invasive ultrasonic safe and well-tolerated, when the stimulation parameters and thalamic stimulation. protocol follow the available guidelines. In addition, tFUS can be also conducted without hair shaving (65). The majority Transcranial Focused vs. Unfocused of the studies reported no severe adverse effects. Mild and moderate symptoms are reported such as neck pain, sleepiness, Ultrasound Neuromodulation muscle twitches, itchiness, and headache (9, 34) (Table 1). In Despite transcranial focused ultrasound (tFUS) and transcranial future studies, proper assessments, aimed to define the safety unfocused ultrasound (tUS) neuromodulation techniques share parameters for tUS and tFUS, are needed. Finally, every tUS or the same basic mechanisms of action, when applied on the same tFUS protocol should explore the role of auditory confounding target they can lead to quite different results. factors on the neural responses, in order to show that the These results are related to the intrinsic differences between effect of stimulation is the consequence only of the targeted the two techniques. The most important, one is the volume of area neuromodulation, and not due to an indirect auditory the brain involved in the ultrasound field. It is intuitive that impact (66, 67). the volume of the brain involved in the focused or unfocused neuromodulation, and the underlying neural circuits, are crucial Overall, the results up to now encourage the study of tUS and tFUS as non-invasive neuromodulatory techniques to determine the output of the tFUS or tUS neuromodulation. in humans. The high spatial resolution of tFUS and the This has been supported also by experimental results, where tFUS possibility of stimulating cortical and deep brain regions and tUS were applied on the same target, the primary motor suggest many potential applications, such as cortical and cortex: tUS increased MEPs amplitude (40) instead tFUS induced subcortical mapping, the study of functional connectivity, the a MEP inhibition (34). In addition, the sonication delivered modulation of neurotransmission. Regarding tUS as a potential during the stimulus duration period, is generally continuous, neuromodulatory tool, noteworthy is the high accessibility of without pauses, for tUS, and pulsed, characterized by pauses the devices, which are routinely used in health care settings. between the sonications, for tFUS. Low-intensity pulsed FUS is Further research is needed to clarify tUS and tFUS efficacy and the most effective FUS technique for neuromodulation in both underlying mechanisms, and to optimize stimulation parameters animal model (5, 6) and humans (Table 1). Instead, high intensity continuous FUS is widely used for therapeutic irreversible and targeting accuracy. The initial safety profiles seem promising. A rigorous approach must be maintained in order to ensure lesioning (51, 55, 58, 60). safe sonications. DISCUSSION AUTHOR CONTRIBUTIONS Transcranial focused ultrasound is an emerging technique for LB: conception, organization, execution, and writing of the first non-invasive neurostimulation, with direct action on bioelettrical draft. EF: execution, writing of the first draft, and review and neural activity, and in addition could be used for targeted drug delivery. critique. VD: conception, organization, and review and critique. REFERENCES 2. Ballantine H Jr., Bell E, Manlapaz J. 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Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS) Neuromodulation: From Theoretical Principles to Stimulation Practices

Frontiers in Neurology , Volume 10 – Jun 11, 2019

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Abstract

REVIEW published: 11 June 2019 doi: 10.3389/fneur.2019.00549 Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS) Neuromodulation: From Theoretical Principles to Stimulation Practices 1,2 1,2 1 Lazzaro di Biase *, Emma Falato and Vincenzo Di Lazzaro Neurology, Neurophysiology, and Neurobiology Unit, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy, Unit of Neurophysiology and Neuroengineering of Human-Technology Interaction, School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy Transcranial focused ultrasound is an emerging technique for non-invasive neurostimulation. Compared to magnetic or electric non-invasive brain stimulation, this technique has a higher spatial resolution and can reach deep structures. In addition, both animal and human studies suggest that, potentially, different sites of the central and peripheral nervous system can be targeted by this technique. Depending on stimulation Edited by: parameters, transcranial focused ultrasound is able to determine a wide spectrum Matteo Bologna, of effects, ranging from suppression or facilitation of neural activity to tissue ablation. Sapienza University of Rome, Italy The aim is to review the state of the art of the human transcranial focused ultrasound Reviewed by: Hyungmin Kim, neuromodulation literature, including the theoretical principles which underlie the Korea Institute of Science and explanation of the bioeffects on neural tissues, and showing the stimulation techniques Technology (KIST), South Korea Jérôme Sallet, and parameters used and their outcomes in terms of clinical, neurophysiological or University of Oxford, United Kingdom neuroimaging results and safety. *Correspondence: Keywords: focused ultrasound, transcranial stimulation, non-invasive brain stimulation (NIBS), transcranial Lazzaro di Biase focused ultrasound (tFUS), transcranial ultrasound (tUS) lazzaro.dibiase@gmail.com; l.dibiase@unicampus.it INTRODUCTION Specialty section: This article was submitted to Preliminary animal studies suggest that, potentially, different sites in the peripheral nervous system, Movement Disorders, a section of the journal from nerves (1) to spinal roots (2), and in the central nervous system, from superficial regions Frontiers in Neurology like primary motor cortex (3) or frontal eye field (4), to more deep areas like hippocampus (3), amygdala (5), or thalamus (6) can be targeted by focused ultrasound stimulation technique. In Received: 18 February 2019 Accepted: 07 May 2019 addition, animal studies showed that this technique has a high spatial resolution, useful also for Published: 11 June 2019 mapping small brain areas, as shown by Fry (7) for the mapping of lateral geniculate nucleus, or by Ballantine et al. (2) for the stimulation of Edinger-Westphal nucleus. Citation: di Biase L, Falato E and Di Lazzaro V Furthermore, a recent fMRI resting-state functional connectivity animal study (8), showed that (2019) Transcranial Focused the effect of tFUS neuromodulation can last for up to 2 h after stimulation, opening a new way Ultrasound (tFUS) and Transcranial to explore not only the online effect but also the long lasting effect of neuromodulation. The first Unfocused Ultrasound (tUS) human transcranial application of ultrasounds for neuromodulation was described by Hameroff Neuromodulation: From Theoretical et al. (9), with an unfocused transcranial ultrasound (tUS) continuous stimulation of posterior Principles to Stimulation Practices. frontal cortex, applied on 31 patients affected by chronic pain. The first human application of Front. Neurol. 10:549. doi: 10.3389/fneur.2019.00549 focused transcranial ultrasound (tFUS) technique was described by Legon et al. (10). They targeted Frontiers in Neurology | www.frontiersin.org 1 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation the primary somatosensory cortex of healthy volunteers, in with an increase of intensity, there is a pore formation and a within-subjects, sham-controlled study. One of the most with the maximum stretch that can be achieved with the interesting results of tFUS applications was a case report of technique a membrane rupture and irreversible lesion is obtained emergence from minimally conscious state, after low intensity (28) (Figure 1). non-invasive ultrasonic thalamic stimulation in a patient after Considering the electrical properties of the cell membrane acute brain injury (11). Following this first single evidence, a at rest, which can be approximated with a parallel plate clinical trial is ongoing to explore the effect of thalamic low capacitor, a hypothesis is that the dynamic fluctuation of intensity focused ultrasound in acute brain injury patients (12). the membrane bilayer changes the instantaneous membrane Regarding peripheral nervous system neuromodulation, capacitance and leads to a capacitive current, which can Bailey et al. (13) explored the ability of continuous US at 1.5 potentially activate voltage-dependent sodium and potassium MHz in modulating the ulnar nerve stimulation response to channels (27) (Figure 2). The neuronal bilayer sonophore model magnetic stimulation (MS). This study showed no significant (27) combines, in a complementary way, all the biomechanical change in electromyographic response during magnetic plus US and bioelectrical proprieties of the cell membrane described, and ulnar nerve stimulation. However, further studies are needed in predicts the stimulation parameter needed to reach a successful order to explore different parameter of stimulation. motor cortex stimulation. It explains, for example, the higher In recent years, the scientific community showed a progressive efficacy of long US stimulation pulses (3, 29, 30), and how increasing interest on FUS neuromodulation, and some reviews the action potential can be elicited after the end of the US have been published in order to summarize the state of the art on stimulus (27, 31), with a good overlap with the experimental this topic (14–18). results obtained using real stimulation on the mouse motor cortex (30). Mechanisms of Actions of US Stimulation Parameters Neuromodulation An acoustic wave can be defined by two fundamental parameters: Focused ultrasound is a non-invasive, non-ionizing technique. the intensity, defined as the amplitude of the wave, and the In order to target a brain region, the first challenge is instantaneous period (T), defined as the time needed to complete to let ultrasounds single waves to reach the target at the same time, without different acoustic reflection, refraction, and distortion due to the inhomogeneity of skull bone. This problem can be solved by time shifting each single ultrasound wave, according to the related skull bone acoustical properties, in order to let all the waves to reach the target at the same time (19–22). The mechanical interaction between US and neuronal membranes can modify the membrane gating kinetics through the action on mechanosensitive voltage-gated ion channels or neurotransmitter receptors (23–25). The study of Tyler et al. (25) supports this hypothesis. Their study showed, on ex vivo mouse brains and hippocampal slice cultures, that low-intensity, low- frequency ultrasound (LILFU) is able to activate voltage-gated sodium and calcium channels. However, this can’t be the only mechanism of action, explaining the action potential induction, since in simulations, considering the role of membrane tension on activation of mechanically sensitive voltage gated channels, the resulting effect was too low to induce an excitation (26, 27). In addition, the mechanical action of US is able to induce cavitation into the cellular membrane, by means of membrane pore formation, which changes the membrane permeability. The bilayer sonophore model (28) was introduced to better explain the bioeffects of US, taking into consideration the biomechanical proprieties of US and of cell membranes. According to this model (28), the mechanical energy of US leads to periodic expansions and contractions of the membrane. In this FIGURE 1 | Ultrasound gradually increases tension in the membrane. From the reference stage (S0), the stretch first activates mechanosensitive proteins model, the US bioeffect is dependent on the tension applied to (S1); growing tension might damage membrane proteins (S2) and then might the membrane. With a progressive increase in membrane stretch induce pore formation (S3a, S3b) or cause membrane rupture [modified, with intensity, the bioeffect is mediated by different mechanisms. permission, from Krasovitski et al. (28)]. First by the activation of mechanosensitive proteins. Then, Frontiers in Neurology | www.frontiersin.org 2 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation FIGURE 2 | (A) Under US effect the membrane starts fluctuating around a steady state. (B) Mechano-electrical dynamics of the model membrane to US (pressure amplitude 500 kPa and frequency 0.5 MHz): The increase in Acoustic pressure induces an increase in attraction/repulsion force, which increases the capacitance leading finally to a capacitive current. Acoustic pressure (kPa), tension (mN/m), combined attraction/repulsion force per area between the leaflets (sum of molecular 2 2 and electrostatic forces, kPa), membrane capacitance (μF/cm ), and capacitive displacement current (A/cm ) [modified, under the terms of the Creative Commons Attribution 3.0 License, from Plaksin et al. (27)]. one single oscillation cycle, which is used to calculate the Acoustic For safety reasons the indexes that describe the thermal frequency (Af) (Figure 3, Equation 1). In addition to these two and biomechanical effects of the sonication need to be defined. parameters, the stimulus duration (StimD) is the total duration These parameters are related to the instantaneous intensity of one single sonication. of stimulation and its instantaneous acoustic pressure. The During the stimulus duration two paradigms of sonication are two main mechanisms that can induce tissue damage are: used: continuous or pulsed. Some of these protocols resemble local heating, which through proteins denaturation leads to those used for non-invasive brain stimulation based on repetitive cell death, and inertial cavitation. The latter is thought to transcranial magnetic stimulation [see Di Lazzaro and Rothwell be mediated by the collapse of gas bubbles due to the (32) for a review]. The most used one for neuromodulation is the pressure exerted by ultrasonic field sufficiently strong to allow pulsed paradigm. tissue damage. For the pulsed paradigm, two additional periods need to Both, animal histological studies (8, 41, 42) and human be defined: the pulse duration (PD), which is the period of neuroimaging studies (37, 38), showed that it is possible to acoustic sonication from the starting point of oscillation to the neuromodulate brain circuits without inducing tissue damage. ending point, before the pause and the pulse repetition period The thermal index (TI) is the ratio of total acoustic power (PRP), which is the period between the starting point of two to the acoustic power required to raise tissue temperature consecutive sonications, or, in other terms, the sum of the by 1 C under defined assumptions. Finally, the non-thermal, pulse duration (PD) and the pause between two consecutive mechanical bioeffect is described by the mechanical index (MI), sonications. This period is used to calculate the pulse repetition which is directly proportional to the ultrasound beam’s peak frequency (PRF) (Figure 3, Equation 2). For the pulsed paradigm, negative pressure and inversely proportional to the frequency of the duty cycle (DC) (Figure 3, Equation 3) is the fraction of the the beam. pulsed repetition period (PRP) covered by the pulse duration The intensity, spatial-peak pulse-average (I ) is the value SPPA (PD). The cycles per pulse (c/p) are the number of cycles during a of the pulse-average intensity at the point in the acoustic field single pulse (Figure 3, Equation 4); instead, the number of pulses where the pulse-average intensity is a maximum or is a local (Np) is the number of pulses throughout the stimulus duration maximum within a specified region. The intensity, spatial-peak (Figure 3, Equation 5). temporal-average (I ) is the value of the temporal-average SPTA The sonication delivered during the stimulus duration period intensity at the point in the acoustic field where the temporal- can be repeated, without pauses, for the continuous stimulation average intensity is a maximum, or is a local maximum within a protocol. Instead, intermittent protocols are characterized by specified region. pauses between the sonications, defined as inter stimulation The FDA guidelines defined the safety threshold for diagnostic intervals (ISIs). The intermittent protocol is the most used for usage of US for adult cephalic ultrasound, which can be applied FUS neurostimulation, instead the continuous one is the most to neuromodulation. These parameters are Isspa ≤ 190 W/cm , used for the unfocused stimulation (Table 1). Ispta ≤ 94 mW/cm and a mechanical index ≤ 1.9 (43). Frontiers in Neurology | www.frontiersin.org 3 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation FIGURE 3 | (A) Intermittent protocol stimulation. The single sonications are followed by pauses, defined inter stimulation interval (ISI). (B) Pulsed paradigm of stimulation, defined by the following parameters: Intensity of stimulation, instantaneous period (T), pulse duration (PD), pulse repetition period (PRP), stimulus duration (StimD). (C) Fundamental equations for the stimulation protocol description: Equation (1) = Acoustic frequency (Af), Equation (2) = pulse repetition frequency (PRF), Equation (3) = duty cycle (DC), Equation (4) = cycles per pulse (c/p), Equation (5) = number of pulses (Np). Focused Ultrasound for Targeted Drug studies which described focused ultrasound neuromodulation approaches were included in the present review. In addition Delivery to the search protocol described, further articles suggested by Focused ultrasound technique can be used also to facilitate drugs experts in the field where read and screened (Table 1). delivery in a specific brain area. Until now the most explored application is chemotherapy delivering. However, this versatile technique could be applied for neuromodulation purposes, with RESULTS different mechanisms. The first mechanism is a focal blood–brain barrier (BBB) Physiological Effects in Normal Subjects opening, through a transient opening of endothelial tight Legon et al. (10) used tFUS to target the human primary junctions. Indeed, both animal (44, 45) and human (46) somatosensory cortex (S1), showing that tFUS significantly studies showed that FUS in combination with microbubbles decreased the amplitudes of somatosensory evoked potentials administered intravenously can open the BBB, in a targeted, non- elicited by median nerve stimulation. Furthermore, tFUS invasive, safe, and reversible manner. This technique could be significantly modulated the spectral content of sensory-evoked used for targeted neuromodulation, with therapy which doesn’t brain oscillations and enhanced the performance on sensory cross the BBB. For example Wang et al. (47) showed that it discrimination tasks. The neurophysiologic effects had a spatial is possible to facilitate gene therapy delivery with recombinant resolution of about 1 cm or less. adeno-associated virus, in a non-invasive way, through focused In another study, tFUS altered EEG intrinsic oscillatory ultrasound targeted BBB opening, with potential applications for dynamics, preferentially affecting the phase distribution of beta optogenetics (48) neuromodulation. band and modulated the phase rate across beta and gamma The second system is the local release of drugs, minimizing frequencies. Furthermore, tFUS affected the phase distributions the effect on other brain areas. Indeed, focused ultrasound can in the beta band of the early but not of the late components of be used to locally release drugs which are administered into somatosensory evoked potentials, suggesting a spatial specificity. the bloodstream through a vehicle (e.g., microbubble, liposome) This hypothesis was supported by the loss of neuromodulatory sensitive to local temperature or pressure changes (49). effects after the displacement of the transducer 1 cm laterally from the original cortical target (39). Primary (SI) and secondary (SII) somatosensory cortical areas of the hand were targeted in a study by Lee et al. (50), in METHODS which two transducers were used. The areas were stimulated The literature search methods included the PubMed/MEDLINE separately or simultaneously, under neuronavigation guide. tFUS databases with the following research string, in Nov 2018: elicited various types of tactile sensations in the contralateral (“Neuromodulation” OR “Brain Stimulation”) AND (“focused hand/arm regions. The effects were transient and reversible, and ultrasound” OR HIFU OR LIFU OR Low-intensity focused the stimulation resulted safe, as assessed by repeated clinical and ultrasound). After abstract reading and screening, only human neuroradiological evaluations. In addition this study showed, the Frontiers in Neurology | www.frontiersin.org 4 June 2019 | Volume 10 | Article 549 di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 5 June 2019 | Volume 10 | Article 549 TABLE 1 | tFUS and tUS neuromodulation studies. References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Ai et al. (33) Custom-made, 5 Healthy Within- Primary 54 stimuli, ISI 5.5 s A : 0.50 MHz; I : 16.95 tFUS increased No auditory or f SPPA single-element FUS volunteers subjects, motor cortex PD: 0.36 ms; W/cm ; BOLD activation tactile sensation transducer; sham- (tFUS paired with PRF: 1 kHz; MI: 0.97 volumes A : 0.50 MHz Diameter controlled high field 7T fMRI Np: 500; DC: generated during a 30 mm, focal length 30 mm, study targeted on the 36%; cued tapping task. 7T MRI compatible dominant thumb c/p: 180; StimD: The effect was Focused, Pulsed BOLD representation) 500 ms spatially confined to the sonicated area. No detectable effects on SMA and PMd. Legon et al. Custom- designed, 12 (exp. 1) Healthy Within- Primary Exp1: 10 A : 0.50 MHz; I : 17.12 Concentric and Mild and moderate SPPA (34) single-element FUS 10 (exp. 2) volunteers subjects, motor cortex tFUS/TMS stimuli PD: 0.36 ms; W/cm ; concurrent symptoms such as transducer; 28 (exp. 3) sham- (Exp 1–2: from RMT-20% to PRF: 1 kHz; I : 6.16 tFUS/TMS on M1 neck pain, SPTA A : 0.50 MHz controlled dominant FDI 100% stimulator Np: 500; DC: W/cm ; inhibited the sleepiness, muscle Height 1.25 cm, aperture study hotspot; Exp 3: output, in 36%; MI: 0.9 amplitude of twitches, itchiness 30 mm, focal length 22 mm, dominant increments of 5%, c/p: 180; single-pulse and headache Attached at the center of a APB hotspot) ISI of 10 seconds) StimD: 500 ms MEPs, attenuated (assessed by TMS 8-coil (Magstim Inc., Exp2: 10 tFUS 100 ms prior intracortical questionnaire). No UK) for concurrent and tFUS/TMS to: the TMS pulse facilitation, did not severe symptoms concentric stimulations every (exp. 1), to the CS affect intracortical reported. tFUS/TMS delivery 10 s for each TMS (exp. 2) and to the inhibition and Focused, Pulsed paired-pulse ISI visual stimulus significantly from 1 to 15 ms. (exp. 3) reduced reaction Exp3: 100 stimuli time in a motor at random time task. intervals between 3 and 6 s Legon et al. Custom-designed, 20 (exp. 1) Healthy Within- Unilateral Exp1: 300 stimuli, A : 0.50 MHz; I : 14.56 tFUS decreased Not available f SPPA (35) single-element FUS 20 (exp. 2) volunteers subjects, sensory thalamus ISI 4 s PD: 0.36 ms; W/cm ; P14 SEP transducer (Ultran Group, sham- targeted through a Exp2: 90 stimuli PRF: 1 kHz; MI: 0.89 amplitude. Inc., State College, PA); controlled neuronavigation Np: 500; DC: After bone Decrease in ability A : 0.50 MHz study system from the 36%; transmission: in a tactile Aperture 63 mm, focal individual MRI c/p: 180; I : 7.03; judgement task. SPPA length 70.92 mm (55 mm StimD: 500 ms W/cm ; Effect upon from exit plane), f# 1.13 Median nerve MI: 0.56 cortical oscillatory Focused, Pulsed stimuli time-locked dynamics to occur 100 ms after the onset of tFUS waveforms (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 6 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Leo et al. 2 transducers: 6 (3T exp.) Healthy Pre-post 3T experiment: 3T experiment: 3T experiment: A : I : 6W/cm tFUS induced Not available f SPPA (36) 1) 3T experiment: 1 (7T exp.) volunteers interventional Primary motor 90 stimuli, ISI 0.50 MHz; (after bone BOLD fMRI signals A : 0.50 MHz Active study cortex hand knob 12-14 s PRF: 1 kHz; transmission) in the targeted diameter 60 mm, focal of the dominant 7T experiment: Np: 500; DC: cortical regions (in length 55 mm, focal FWHM hemisphere 7T 5 off/on cycles, 36%; 3 of 6 subjects) intensity volume 48.64 mm experiment: Left stimulation c/p: 180; and in the targeted head of delivered at ISI StimD: 500 ms 7T subcortical region 2) 7T experiment: the caudate 12 s during on experiment: A : 0.86 MHz Active cycles A : 0.86 MHz; f f diameter 64 mm, focal PRF: 1 kHz; length 54 mm, focal FWHM DC: 50%; c/p: intensity volume 35.77 mm 420; Both: Focused, Pulsed StimD: 500 ms Lee et al. MRI-compatible 19 (exp. 1) Healthy Within- Primary visual Exp.1: Af: 0.27 MHz; I : 16.6 tFUS induced No adverse SPPA (37) FUS transducer 10 (exp. 2) volunteers subjects, cortex, under 3T 50 stimuli, ISI 13 s PRF: 500 Hz; PD: W/cm2 BOLD fMRI signals effects, as Af: 0.27 MHz single- MRI guidance Exp.2: 1 ms; Estimates at the in V1 and other assessed by Focal length 3 cm, acoustic blind, 50 stimuli, ISI 2.5 s DC: 50%; StimD: target location: visual areas, neurological focus 3 mm (diameter) and sham- 300 ms I : mean 3 elicited examination, SPPA 17 mm (length) Focused, controlled W/cm2; phosphenes and anatomical MRI (at Pulsed study MI: mean 0.6 elicited cortical 3 time points) and evoked EEG follow-up potentials similar telephone to the classical interviews (after 2 VEP generated by months) photic stimulation Lee et al. Two sets of single-element 10 Healthy Within- Left primary and 20 stimuli for each Af: 0.21 MHz; I : 35.0 tFUS of either No abnormal SPPA (37) FUS transducers (Ultran volunteers subjects, secondary session (4 PRF: 500 Hz; W/cm ; primary and findings post-tFUS Group Ltd, State double somatosensory sessions) PD: 1 ms; I : 17.5 secondary (assessed by SPTA College, PA) blind,sham- cortex (areas of DC: 50%; StimD: W/cm somatosensory neurological Af: 0.21 MHz Shape: controlled the hand, 500 ms Estimates at the cortex, stimulated examination, segmented-spheres Outer study separately or target location: separately or MMSE, anatomical diameter (OD):30 mm Focal simultaneously I : 7.0–8.8 simultaneously, MRI on the same SPPA distance: 25 mm. Each stimulated under W/cm eliciited tactile day, at 2 weeks transducer was affixed to an multi-modal I : 3.5–4.4 sensations from and 4 weeks, and SPTA applicator (Zamerican, neuroimage- W/cm the contralateral by telephone Zacuto, Chicago, IL) guidance) hand/arm areas interview at 2 mounted on a helmet months after the (modified from Giro Section sonications) Helmet, Santa Cruz, CA) Focused, Pulsed (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 7 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Monti et al. BXPulsar 1001, 1 Post- Case Thalamus 10 sonications, A : 0.65 MHz; I : 720 Emergence from Clinical f SPTA (11) Brainsonix Inc. traumatic report, part (MRI-guided by a 30 s each, PD: 0.5 ms; mW/cm minimally improvement Single-element spherical disorder of of an 3 Tesla Magnetom separated by 30 s PRF: 100 Hz conscious state suggested that the transducer; consciousness ongoing Tim Trio pause intervals procedure was A : 0.65 MHz Diameter and (minimally clinical trial MR scanner) safe and radius of curvature 71.5 mm conscious (12) well-tolerated Focused, Pulsed state) 19 days post-injury Lee et al. Ceramic piezoelectric FUS 12 (exp. 1) Healthy Within- Primary (Exp. 1): A : 0.25 MHz; I : 3W/cm tFUS elicited No adverse f SPPA (38) transducer (Channel 6 (exp. 2) volunteers subjects, somatosensory 200 stimuli, ISI 3 s PRF: 500 Hz; Estimated I at transient tactile effects, as SPPA Industries, Santa sham- cortex (hand area) (Exp. 2): Tone-burst- the target: sensations on the assessed by Barbara, CA) controlled under subject- 100 stimuli, ISI duration: 1 ms; 0.7 ± 0.5 W/cm hand and arm area neurological Outer diameter 6 cm, study specific image- 2 s DC: 50%; contralateral to the examination, radius-of- curvature 7 cm guidance StimD: 300 ms sonicated anatomical MRI (at A : 0.25 MHz Low Intensity hemisphere, with 3 time points) and Focused anatomical follow-up Ultrasound Pulsation specificity of up to telephone a finger. EEG interviews (after 2 showed months) sonication-specific evoked potentials. Mueller Two-channel, 2 MHz 18 (exp. 1) Healthy Within- Exp.1 120 stimuli, ISI 6 s A : 0.50 MHz; I : 23.87 tFUS altered EEG Not available f SPPA et al. (39) function generator (BK 7 volunteers subjects, Somatosensory PD: 0.36 ms; W/cm ; beta phase and Precision Instruments) (exp. 2) sham- cortex (CP3) PRF: 1 kHz; MI: 1.13 modulated the delivered at 0.5 MHz controlled Exp.2 1cm laterally Np: 500; c/p: 180; phase rate across Focused, pulsed study StimD: 500 ms beta and gamma frequencies. tFUS affected phase distributions in the beta band of early SEP components. Neuromodulatory effects were lost when the transducer was displaced 1 cm laterally from the original cortical target. (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation Frontiers in Neurology | www.frontiersin.org 8 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects Legon et al. Custom-made, 10 (exp. 1) Healthy Within- Primary Exp 1 and 2: 120 A : 0.50 MHz; I : 23.87 Exp1. A: tFUS No thermal or f SPPA (10) single-element FUS 8 (exp. 2) volunteers subjects, somatosensory stimuli, ISI 6 s PD: 0.36 ms; W/cm significantly mechanical transducer; 12 (exp. 3) sham- cortex (crown of Exp 3: 90 stimuli PRF: 1 kHz; (=4-fold lower attenuated the sensation A : 0.50 MHz Diameter 12 (exp. 4) controlled the postcentral 100 ms before Np: 500; DC: through the skull); amplitudes of 30 mm, focal length 30 mm study gyrus and each task 36%; MI: 1.13 somatosensory Focused, Pulsed posterior wall of Exp4: 120, ISI 6 s c/p: 180; Peak rarefactional evoked potentials the central sulcus, StimD: 500 ms pressure: 0.80 B: tFUS encephalographic Median nerve MPa significantly electrode CP3) stimuli time-locked modulated the to occur 100 ms spectral content of after the onset of sensory-evoked tFUS waveforms brain oscillations Exp2. tFUS modulation of brain activity is spatially restricted ( 1 cm or less) Exp3 and 4. tFUS significantly enhanced performance on sensory discrimination tasks without affecting task attention or response bias. tUS: Phillips CX50 21 (active Healthy Between- Primary 2 min Af: 2.32 MHz; Isppa: 34.96 tUS increased No significant Gibson Diagnostic System, with a stim) volunteers subjects, motor cortex HGen, B-mode; W/cm ; Ispta: cortical excitability differences in et al. (40) Phillips S5-1 broadband 22 (sham single- (abductor pollicis Harmonics: on; 132.85 mW/cm ; (average increase sensations linked plane sector transducer stim) blind, brevis DC: <1%; Focal MI: 0.67 in MEPs amplitude tingling, itching array; aperture 20.3cm, sham- motor hotspot) depth: 10 cm Peak negative of 33.7% at 1 min etc. (assessed by frequency range 1–5 MHz. controlled pressure: 1.02 and of 32.2% at questionnaires) TMS: study MPa (in degassed 6 min post between active neuronavigation-assisted water) stimulation. and sham group eXemia TMS system No significant (Nextstim Ltd., Helsinki, differences at 11 Finland) with a 70 and 16 min mm 8-coil. post stimulation). Unfocused, Continuous No differences in mood (assessed by a brief questionnaire on subject well-being) (Continued) di Biase et al. Transcranial Ultrasound Neuromodulation feasibility of the simultaneous stimulation of different human brain areas. In Lee et al. (38), tFUS stimulation of the human somatosensory cortex elicited somatosensory sensations with anatomical specificity up to a finger, and evoked EEG potentials. fMRI studies showed the effects of tFUS on cortical and subcortical brain areas, with the ability of high-resolution non- invasive functional brain mapping (33, 36, 37). Indeed, Leo et al. (36), demonstrated that tFUS stimulation of cortical (primary motor cortex) and subcortical (head of the caudate) areas can induce blood oxygen level dependent (BOLD) signals in 3T and 7T fMRI, respectively. More recently, pairing tFUS on human primary motor cortex (M1) with 7T BOLD fMRI signals in a cued finger tapping task study, Ai et al. (33) showed that tFUS selectively increases BOLD activation volumes of the target finger representation. These effects did not spatially overcome the sonicated area, and therefore did not involve other motor regions, such as supplementary motor area (SMA) and dorsal premotor cortex (PMd). tFUS has been used also to target the human primary visual cortex (V1) Lee et al. (37) showed, on BOLD fMRI signals, that tFUS stimulation elicited the activation of a network of brain regions, including V1 and other areas involved in visual and higher-order cognitive processes. Furthermore, stimulation elicited perception of phosphenes and EEG evoked responses. The effects of tFUS on corticospinal excitability have also been studied through transcranial magnetic stimulation (TMS). Combining a custom-made FUS transducer and a 8-shaped TMS coil, Legon et al. (34) assessed for the first time in humans the effect of concentric and concurrent tFUS/TMS stimulation on M1. The stimulation had an inhibitory effect on single-pulse MEPs and intracortical facilitation, and significantly decreased the reaction time in a motor task. Legon et al. (35) tested the effects tFUS stimulation on sensory thalamus, that was targeted by a single-element focused ultrasound through a neuronavigation system based on the individual subject anatomical MRI. tFUS stimulation inhibited the P14 SEP, and was associated with a change in EEG oscillatory dynamics and to a reduced ability in a tactile judgement task. In addition, this study outlined the value of taking into account the individual skull morphology to produce safe and accurate stimulations. In a recent single-blind, sham-controlled study (40), tUS was targeted to the motor cortex through a diagnostic imaging ultrasound system. The unfocused stimulation increased MEPs amplitude by 34% compared to baseline, and the increase was recorded up to 6 min after the stimulation. This short-term increase of motor cortex excitability contrasts with a previous findings of MEP inhibition during concurrent tFUS/TMS (34). As discussed by the authors, stimulation parameters and other methodological factors might explain the different findings. Therapeutic Application Despite several studies showed the neurological therapeutic applications of lesional FUS and FUS mediated BBB opening in different diseases like essential tremor (51–54), Parkinson’s disease (55–57), depression (58, 59), obsessive-compulsive Frontiers in Neurology | www.frontiersin.org 9 June 2019 | Volume 10 | Article 549 TABLE 1 | Continued References Device N. of Disease Study Stimulation Protocol Ultrasound Energy Results Adverse events subjects type/healthy design target duration parameters subjects General Electric LOGIQe, 31 Chronic pain Double Posterior frontal 15 s stimulation A : 8 MHz; MI = 0.7 tUS significantly Transient Hameroff 12L-RS probe blind, cortex, B Mode; Max Intensity = improved headache et al. (9) A : 8 MHz Unfocused, sham- contralateral to the Power: 100%; 152 mW/cm measures of global exacerbation Continuous controlled, maximal pain Depth: 3.5 cm; TIs = 0.5 affect derived from following crossover Harmonics: on; TIc = 0.2 (values subjective reports, stimulation (1 subj) study Cross- Xbeam: on at the posterior at 10 and 40 min frontal scalp) following stimulation. In gray background: unfocused stimulation protocols, in white background: focused stimulation protocols. Af, acoustic frequency; c/p, cycles per pulse; DC, duty cycle; Exp, experiment; ISI, inter stimulus interval; ISPPA, Intensity Spatial Peak Pulse Average; ISPTA, Intensity spatial peak temporal average; MEPs, motor evoked potentials; MI, mechanical index; Na, not available; Np, number of pulses; PD, pulse duration (width); PMd, dorsal premotor cortex; PRF, pulse repetition frequency; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; SD, Sonication Duration; SMA, supplementary motor area; StimD, stimulus duration; TI, Thermal Index; Tib, Thermal Index of bone; Tic, Thermal Index of Skull/Cranium; Tis, Thermal Index of soft tissue; TMS, transcranial magnetic stimulation. Note: where not specified, I is the incident acoustic intensity estimated before transcutaneous and transcranial transmission, SPPA e.g., In free water. di Biase et al. Transcranial Ultrasound Neuromodulation disorder (60, 61), neuropatic pain (62, 63), Alzheimer disease Compared to magnetic or electric non-invasive brain (46, 64), only two studies explored in humans the therapeutic stimulation, this technique has a higher spatial resolution and can efficacy of tUS (9) and tFUS (11) bioelectrical neuromodulation reach deep structures. In addition, animal studies suggest that, (Table 1). potentially, different sites of the central and peripheral nervous Hameroff et al. (9) used a 8 MHz unfocused transducer to system can be targeted by this technique. study the effects of transcranial ultrasound stimulation (tUS) on Even if still in a small number, the increasing interest in this mood, and global affect in 31 patients with chronic pain, in a technique, led to encouraging results in human studies. These double-blind, sham-controlled crossover study. Stimulation was preliminary human studies focused their attention on classic targeted to the posterior frontal cortex, contralateral to the most non-invasive neurostimulation targets, like the primary motor severe pain. After the stimulation, a significant improvement in cortex, somatosensory area or primary visual cortex, with some subjective parameters of global affect derived from the Visual studies that explored deep structures like thalamus (11, 35) or Analog Mood Scale was found. basal ganglia (36). All showed neurostimulation efficacy in terms As part of an ongoing clinical trial on low intensity of clinical, neurophysiological or functional neuroradiological focused ultrasound in acute brain injury (12), Monti outcomes (Table 1). et al. (11) reported a case of emergence from minimally The data collected since now shows that this technique is conscious state after low intensity non-invasive ultrasonic safe and well-tolerated, when the stimulation parameters and thalamic stimulation. protocol follow the available guidelines. In addition, tFUS can be also conducted without hair shaving (65). The majority Transcranial Focused vs. Unfocused of the studies reported no severe adverse effects. Mild and moderate symptoms are reported such as neck pain, sleepiness, Ultrasound Neuromodulation muscle twitches, itchiness, and headache (9, 34) (Table 1). In Despite transcranial focused ultrasound (tFUS) and transcranial future studies, proper assessments, aimed to define the safety unfocused ultrasound (tUS) neuromodulation techniques share parameters for tUS and tFUS, are needed. Finally, every tUS or the same basic mechanisms of action, when applied on the same tFUS protocol should explore the role of auditory confounding target they can lead to quite different results. factors on the neural responses, in order to show that the These results are related to the intrinsic differences between effect of stimulation is the consequence only of the targeted the two techniques. The most important, one is the volume of area neuromodulation, and not due to an indirect auditory the brain involved in the ultrasound field. It is intuitive that impact (66, 67). the volume of the brain involved in the focused or unfocused neuromodulation, and the underlying neural circuits, are crucial Overall, the results up to now encourage the study of tUS and tFUS as non-invasive neuromodulatory techniques to determine the output of the tFUS or tUS neuromodulation. in humans. The high spatial resolution of tFUS and the This has been supported also by experimental results, where tFUS possibility of stimulating cortical and deep brain regions and tUS were applied on the same target, the primary motor suggest many potential applications, such as cortical and cortex: tUS increased MEPs amplitude (40) instead tFUS induced subcortical mapping, the study of functional connectivity, the a MEP inhibition (34). In addition, the sonication delivered modulation of neurotransmission. Regarding tUS as a potential during the stimulus duration period, is generally continuous, neuromodulatory tool, noteworthy is the high accessibility of without pauses, for tUS, and pulsed, characterized by pauses the devices, which are routinely used in health care settings. between the sonications, for tFUS. Low-intensity pulsed FUS is Further research is needed to clarify tUS and tFUS efficacy and the most effective FUS technique for neuromodulation in both underlying mechanisms, and to optimize stimulation parameters animal model (5, 6) and humans (Table 1). Instead, high intensity continuous FUS is widely used for therapeutic irreversible and targeting accuracy. The initial safety profiles seem promising. A rigorous approach must be maintained in order to ensure lesioning (51, 55, 58, 60). safe sonications. DISCUSSION AUTHOR CONTRIBUTIONS Transcranial focused ultrasound is an emerging technique for LB: conception, organization, execution, and writing of the first non-invasive neurostimulation, with direct action on bioelettrical draft. EF: execution, writing of the first draft, and review and neural activity, and in addition could be used for targeted drug delivery. critique. VD: conception, organization, and review and critique. REFERENCES 2. Ballantine H Jr., Bell E, Manlapaz J. 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Meng Y, Voisin MR, Suppiah S, Kalia SK, Kalia LV, Hamani C, et al. Is there The use, distribution or reproduction in other forums is permitted, provided the a role for MR-guided focused ultrasound in Parkinson’s disease? Mov Disord. original author(s) and the copyright owner(s) are credited and that the original (2018) 33:575–9. doi: 10.1002/mds.27308 publication in this journal is cited, in accordance with accepted academic practice. 58. Kim M, Kim C-H, Jung HH, Kim SJ, Chang JW. Treatment of No use, distribution or reproduction is permitted which does not comply with these major depressive disorder via magnetic resonance-guidedfocused ultrasound terms. Frontiers in Neurology | www.frontiersin.org 12 June 2019 | Volume 10 | Article 549

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