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Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound

Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using... Background: Transcranial focused ultrasound (FUS) is gaining momentum as a novel non‑ invasive brain stimulation method, with promising potential for superior spatial resolution and depth penetration compared to transcranial magnetic stimulation or transcranial direct current stimulation. We examined the presence of tactile sensations elic‑ ited by FUS stimulation of two separate brain regions in humans—the primary (SI) and secondary (SII) somatosensory areas of the hand, as guided by individual‑ specific functional magnetic resonance imaging data. Results: Under image‑ guidance, acoustic stimulations were delivered to the SI and SII areas either separately or simultaneously. The SII areas were divided into sub‑ regions that are activated by four types of external tactile sensa‑ tions to the palmar side of the right hand—vibrotactile, pressure, warmth, and coolness. Across the stimulation condi‑ tions (SI only, SII only, SI and SII simultaneously), participants reported various types of tactile sensations that arose from the hand contralateral to the stimulation, such as the palm/back of the hand or as single/neighboring fingers. The type of tactile sensations did not match the sensations that are associated with specific sub ‑ regions in the SII. The neuro‑ stimulatory effects of FUS were transient and reversible, and the procedure did not cause any adverse changes or discomforts in the subject’s mental/physical status. Conclusions: The use of multiple FUS transducers allowed for simultaneous stimulation of the SI/SII in the same hemisphere and elicited various tactile sensations in the absence of any external sensory stimuli. Stimulation of the SII area alone could also induce perception of tactile sensations. The ability to stimulate multiple brain areas in a spatially restricted fashion can be used to study causal relationships between regional brain activities and their cognitive/ behavioral outcomes. Keywords: Dual transcranial focused ultrasound, Image‑ guidance, Non‑ invasive brain stimulation, Human primary and secondary somatosensory cortices, Tactile sensations neurological or neuropsychiatric diseases [2], but these Background techniques involve invasive surgical procedures. Non- Brain stimulation techniques serve as important tools for invasive techniques such as transcranial magnetic stimu- neurotherapeutics and allow for functional investigation lation (TMS) or transcranial direct current stimulation of the brain [1, 2]. Methods such as deep brain stimula- (tDCS) are available to modulate neural functions with- tion (DBS) or epidural cortical stimulation (EpCS) have out surgery [1, 3], but the stimulatory area is relatively been utilized in clinical settings for the treatment of large (on the order of centimeters) and its depth is lim- ited proximal to the cortical surface [2, 4]. Optogenetic *Correspondence: focus@cmcnu.or.kr; yoo@bwh.harvard.edu approaches offer cell-level modification of neuronal Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, Republic of Korea excitability [5, 6]; however, the required introduction of Full list of author information is available at the end of the article © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lee et al. BMC Neurosci (2016) 17:68 Page 2 of 11 genetic alterations to introduce sensitivity to light pro- also induce corresponding types of tactile sensations. The hibits immediate applications in humans. Therefore, FUS was also administered to both SI and SII simultane- the development of non-invasive and spatially-selective ously, and its effects were assessed. means of brain stimulation was sought after. Focused ultrasound (FUS) has recently shown its utility Methods in non-invasive brain stimulation [7], with greater spa- Participants and study overview tial selectivity and depth penetration compared to other This research was performed under the approval of the non-invasive techniques such as TMS or tDCS [8–10]. Institutional Review Board (IRB) of Incheon St. Mary’s The acoustic neuromodulatory effects can be tailored as Hospital, the Catholic University of Korea, in accord- either excitatory or suppressive, depending on the soni- ance with the ethical guidelines set forth by the IRB. Ten cation parameters [11, 12]. Accumulating ex  vivo [13, healthy volunteers (two females, ages 23–34, average of 14] and in  vivo [12, 15–18] evidence shows that acous- 27.8  ±  4.1  years, labeled ‘h1’ through ‘h10’ herein) with tic pressure waves delivered to localized brain struc- no clinical history of peripheral/central neurological dis- tures modulate their excitability using low-level acoustic eases participated. All participants submitted written intensity (i.e., compatible with potential human applica- consent prior to enrollment in the study. tion [19, 20]). Recently, transcranial FUS has also been Prior to the FUS procedures, functional MRI (fMRI) shown to have neuromodulatory effects on large animal was performed (on a separate day) to map the individual- models, such as the elicitation of motor and visual elec- specific SI and SII areas in the left hemisphere that are trophysiological responses in sheep [21] and the modula- functionally eloquent for four different non-painful sen - tion of saccadic movement in non-human primates [22]. sory stimuli—(1) vibrotactile, (2) pressure, (3) warmth, In humans, transcranially delivered FUS to the primary and (4) coolness [27]. Anatomical MRI and computed somatosensory cortex (SI) has been shown to modulate tomography (CT) scans of the head were also acquired the performance of tactile discrimination tasks as well on the same day. The acquired neuroimage data were as the amplitude of somatosensory evoked potentials used for neuroradiological assessments, such as, but not (SEP) [19]. More recently, we have demonstrated that limited to, existence of clinically significant intracranial FUS sonication of the SI, without giving external sensory calcifications (mainly detected by the CT), which may stimulation, evoked both sonication-specific electroen - disturb the acoustic propagation within the cranial cavity cephalographic (EEG) responses and various tactile sen- (none were found). Along with the MRI/CT procedures, sations from the hand area [20]. clinical neurological examination and the mini-mental In addition to the SI (a primary site of processing state examination (MMSE) [28] were provided to each external sensory afferent signals), the SII (located in the subject by licensed physicians. parietal operculum on the ceiling of the lateral sulcus) The FUS procedures, conducted on a separate day is an important neural substrate for processing/cogni- (gap between the MRI/CT and FUS procedures: tion of various tactile sensations, including pain or even 98.7  ±  6.0  days; mean  ±  SD, n  =  10), were divided into visceral sensations [23, 24]. To our knowledge, studies multiple sessions—(1) stimulation of the SI alone (i.e., on the stimulation of the SII areas in humans are rare. SI ), (2) stimulation of four sub-regions in the SII (i.e., FUS Spatial specificity of FUS confers the ability to simulta - SII ; in which the coordinates corresponding to the four FUS neously stimulate multiple brain regions that are close to types of tactile stimuli were identified), (3) stimulation of each other, whereas the concurrent operation of multiple both SI and SII (i.e., SI/SII ; four different SII regions FUS TMS coils in close proximity is not desirable due to the were stimulated), and (4) sham condition (i.e., Sham , FUS mutual interactions/interferences of the magnetic fields using the same FUS setup as SI/SII , but without deliv- FUS [25]. Only limited TMS studies have been reported to ery of any sonication). The sequence of these stimulation stimulate brain areas, one from each hemisphere [26], or conditions was randomized and balanced across all sub- to stimulate adjacent brain regions with temporal gaps jects. Additional neurological examination and MMSE in between [25]. Therefore, we were motivated to deliver were administered on the day of the sonication experi- neurostimulatory FUS to the SII, and to examine the out- ments both before and after FUS administration to exam- comes in terms of subjective sensations felt by the indi- ine the presence of any neurological changes. viduals. The existence of spatially-distinct sub-regions within the SII for processing different types of tactile sen - Multi‑modal imaging data and sonication planning sations [23, 27] prompted us to further explore the possi- Both CT and anatomical MRI of the participants’ head bility that FUS stimulation of sensation-specific SII areas was used for planning and image-guidance of FUS soni- (i.e., vibrotactile, pressure, warmth, and coolness) may cation [20]. Adhesive fiducial markers (PinPoint; Beekly Lee et al. BMC Neurosci (2016) 17:68 Page 3 of 11 Corp., Bristol, CT; visible in both MRI and CT) were each other; therefore, a single sonication target was attached on four locations spatially distributed over the assigned representing the SI area. On the other hand, head. Since these adhesive fiducial markers were also the locations of activation in the SII associated with dif- used for image-guidance of the sonication (that was con- ferent tactile stimuli showed a degree of spatial distribu- ducted in a separate day), their reproducible positioning tions (having a radius of 5.3 ± 2.6 mm; as identified from was crucial. To do so, we carefully identified the par - the local maximum in the activation probability) while a ticipants permanent anatomical features, such as skin degree of individual variability existed (i.e., ranged from imperfections (such as wrinkle lines and/or spots) or skin 2.1 to 10.3  mm; a group-level spatial distribution of the vein structures (such as bifurcation) to place the markers SII sub-regions was described elsewhere [27]). Thus, the (on them). These sites were photographed to be used for SII areas were divided into four different spatial locations later positioning. The spatial coordinates of these mark - to be targeted by FUS. ers in the acquired CT/MRI data were utilized as a basis for the spatial co-registration between neuroimage space The sonication setup and the physical location of the subject’s head. In order to independently deliver acoustic energy to the A clinical CT scanner (Aquilion ONE, Toshiba, SI and SII in the left hemisphere, we used two sets of Japan) was used to acquire the CT data of the head single-element FUS transducers (operating at 210  kHz [axial orientation, slice thickness  =  0.5  mm, field-of- frequency, The Ultran Group Ltd, State College, PA) view (FOV) =  24 ×  24  cm , image matrix =  512 ×  512, (Fig.  1a), which were segmented-spheres in shape, each voxel size = 0.47 × 0.47 × 0.50 mm ]. The head CT data having an outer diameter (OD) of 30  mm and a focal were used to plan for the orientation of the transcra- distance of 25  mm. Each transducer was affixed to an nial FUS, whereby we aligned the sonication pathway as articulated applicator (Zamerican, Zacuto, Chicago, IL) perpendicular as possible to the skull at the entry, while that was mounted on a helmet (named ‘FUS helmet’, avoiding thick skull segments or in-bone air-pockets Fig. 1a, modified from Giro Section Helmet, Santa Cruz, (both significantly distort the acoustic beam propa - CA) having two open spaces (8 cm in diameter) to allow gation by attenuation and diffraction/reflection). To access to the SI and SII in the left hemisphere. The posi - obtain the head MRI data, a 3-Tesla clinical MR scan- tion and orientation of the transducers could be adjusted ner (MAGNETOM Skyra, Siemens) was utilized with and locked using the applicators. The gap between the a 4-channel head coil. T1-weighted images of the ana- scalp and the transducer surface was filled with a poly - tomical MRI [3D GRAPPA sequence, acceleration fac- vinyl alcohol (PVA) hydrogel for acoustic coupling. tor  =  2, repetition time (TR)  =  1900  ms, echo time The compressible PVA hydrogel (having a thickness of (TE)  =  2.46  ms, flip angle  =  9°, FOV  =  24  ×  24  cm , ~10 mm) which was fitted around the transducer allowed image matrix  =  256  ×  256, slice thickness  =  0.94  mm, for adjustment of acoustic focal depth in the range of voxel size = 0.94 × 0.94 × 0.94 mm , sagittal orientation, 5–20  mm (detailed implementation was described else- 192 slices] were acquired from the head, covering the where [30]). The subject’s hair was parted in the middle entire telencephalic areas. Then, blood oxygenation level of each sonication entry point, and a generic ultrasound dependent (BOLD)-fMRI was conducted for each subject hydrogel (Aquasonics, Parker Laboratories, Fairfield, NJ) to map the individual-specific SI and SII areas, function - was applied onto the exposed scalp. ally eloquent for four different tactile stimulations of the For image-guided alignment of the FUS focus to the right hand—(1) vibrotactile, (2) pressure, (3) warmth, intended target, the relative location and orientation of and (4) coolness. The detailed stimulation paradigm for the transducers with respect to the helmet (i.e., subject’s the fMRI and the image processing schemes are reported head) were tracked in real-time, whereby the coordinates elsewhere [27]. of the focus can be visualized on the individual-specific The functional and anatomical MRI data, as well as the neuroanatomy (as well as the planned sonication tar- cranial information from the CT scan, were spatially co- get) via a custom-built image-guidance system as previ- registered (using the Normalized Mutual Information ously described [20, 31]. An optical tracker was attached technique [29]), and these multi-modal imaging data to the helmet and each of the two FUS transducers for were utilized for the planning and on-site individual-spe- motion tracking. Each FUS transducer was actuated by cific neuroimage-guidance for transcranial FUS sonica - a computer-controlled driving circuit (Fig.  1a). Two sets tion [20]. Individual-specific coordinates of the SI and SII of the driving circuits were used to actuate each of two in the left hemisphere were identified based on our previ - FUS transducers. Upon receiving a trigger signal from ous study on the same participants [27]. Within the SI, the control computer, the input signal (Fig.  1b) was gen- local maxima of the activations corresponding to differ - erated by a pair of function generators (33220A; Agilent ent tactile stimuli were closely clustered and overlapped technologies, Inc., Santa Clara, CA) and amplified by a Lee et al. BMC Neurosci (2016) 17:68 Page 4 of 11 Fig. 1 Experimental schematics of the dual FUS application with the sonication parameters. a Left panel a rendering of the FUS setup, and right panel its actual implementation on a mannequin head model. The two FUS foci were placed at the targeted SI and SII by image‑ guidance using optical trackers (‘tracker 1’ and ‘tracker 2’) in reference to the subject head (tracked via ‘helmet tracker’). Each tracker had four infrared‑reflective markers for real‑time motion detection. FUS transducers were actuated by the sinusoidal electrical signals with impedance matching circuits. Compressible hydrogel was used to couple the FUS transducer to the scalp. b Upper panel illustration of the acoustic parameters. SD sonication duration = 500 ms, ISI inter‑stimulation‑interval = 7 s, TBD tone ‑burst ‑ duration = 1 ms, PRF pulse‑repetition‑frequency = 500 Hz; Incident spatial‑ peak pulse‑average intensity = 35.0 W/cm I . Lower panel acoustic intensity mapping of the 210 kHz FUS transducer (longitudinal measurement sppa was taken 10 mm from the exit plane of the transducer). The red dotted lines indicate the FWHM of the intensity profile. c, d Exemplar views of the individual‑specific neuroimage ‑ guidance for targeting of ipsilateral SI or SII, respectively. The green crosshairs shown in the projection views (i.e., axial, sagittal, and coronal slices) indicates the sonication target, and the thick green line and yellow line represent the orientation of the sonica‑ tion path and planned path, respectively, connecting the target (red dot) and entry (green dot) points. In the lower right panel, the four colored dots (without the yellow bar) show the locations of anatomical markers used for the neuroimage‑registration with the subject. R and L denote right and left, respectively Class-A linear power amplifier (Electronics and Innova - [12, 16, 21] (Fig.  1b), having a sonication duration (SD) tions, Rochester, NY). An impedance-matching circuit of 500  ms, with a tone-burst-duration (TBD) of 1  ms was used to increase the power efficiency. repeated at a frequency of 500  Hz (i.e., pulse repetition frequency; PRF), yielding a 50  % duty cycle. The spatial Operating parameters and characterization of the FUS profile of the acoustic intensity field generated by the acoustic field FUS transducer was characterized (Fig.  1b) using meth- Based on our previous experiences [20, 21], 210  kHz ods described elsewhere [12]. The diameter of the FUS ultrasound was used to achieve an effective acoustic focus was measured on the acoustic intensity maps based transmission through the thick skull. We adapted similar on pressure scanning using a hydrophone (HNR500; sonication parameters that were utilized in the success- Onda, Sunnyvale, CA) over the transversal plane ful stimulation of the SI in humans [20] and in animals (31 ×  31  mm square area, 1 mm step) perpendicular to Lee et al. BMC Neurosci (2016) 17:68 Page 5 of 11 the sonication path at the acoustic focal distance using of the tactile sensation including its side). The subject’s time-of-flight information. The length of the focus was tapping response and the timing of the sonication events measured along the longitudinal plane along the beam were measured using the data acquisition system (Lab- path (31  ×  51  mm area, 1  mm step, measured 10  mm Chart 7 and PowerLab 4/35; ADInstruments). away from the exit plane of the transducer). The acoustic focus had a diameter of 6 mm and a length of 38 mm, as Post‑FUS session follow‑up defined by the full-width at half-maximum (FWHM) of After the FUS procedure, subjects were asked to remain the acoustic intensity map (Fig.  1b). The incident acous - in the study premises for 2 h, and received the post-FUS tic intensity at the FUS focus, in the absence of skull, was neurological examination and MMSE. Subsequently, 35.0 W/cm spatial-peak pulse-average acoustic intensity anatomical MRI data were acquired again for follow-up (I ), resulting in a spatial peak temporal-average acous- neuroradiological examination from all participants at sppa tic intensity (I ) of 17.5 W/cm . three different time periods—same day (n  =  3), 2  weeks spta (n  =  4), and 4  weeks (n  =  3) after the sonication ses- Image‑guided FUS to the primary and secondary sion. The physicians who conducted the neurological somatosensory cortices assessments were blinded to the nature of the study. Two On the day of the sonication experiment, the subject was months after the sonication sessions, all subjects were seated in a recliner chair. Prior to the spatial registration interviewed by telephone to check the presence of any of the subject’s physical space to the virtual space of the changes regarding mental or physical discomforts/health head MRI/CT neuroimage data, fiducial markers (stick - status concerned with the study participation. ers) were attached to the same locations that were used for the sonication planning (i.e., during the initial MRI/ Results CT session). The registration quality was assessed to Response rate of eliciting sensation by the FUS stimulation minimize target registration error (TRE) [32, 33], which FUS stimulation, via sonication of either the SI/SII was less than 4 mm (3.7 ± 1.4 mm, n = 10, mean ± SD). separately or both the SI and SII simultaneously, elic- The FUS helmet was then tightly secured on the sub - ited tactile sensations from the subjects whereby the ject’s head to maintain the location of the transducer response rate, as defined by the number of reported tac - with respect to head motion. A set of optical trackers tile responses out of 20 stimulation events, are summa- attached to the helmet (‘helmet tracker’ in Fig.  1a) and rized in Table  1. Not all of the FUS stimulation events transducers (‘tracker 1’ and ‘tracker 2’, in Fig. 1a) provided elicited sensations from the subjects. For example, one the orientation and location of the acoustic foci back to subject (‘h10’) did not report any sensation during any the experimenters, following the methods described in of the FUS conditions (noted as ‘NR’). Subject ‘h8’ also our previous work [20]. Under this image-guidance, the did not report any sensation during the SI/SII condi- FUS experimenters aligned the FUS focus to the intended tion. Furthermore, across the different FUS conditions, coordinates of the somatosensory areas (Fig.  1c, d). The we observed several sessions that a few subjects did not orientation of the sonication path was adjusted to make report any elicited sensation (Table  1, indicated as NR). the incident angle as perpendicular as possible to the Across the sonication sessions with the elicitation of tac- scalp (at an entry point), as guided by the information tile sensations, there was a degree of variability in the established during the sonication planning stage (see response rates among the subjects, ranging from 50 to “Multi-modal imaging data and sonication planning” 100 % in one subject (‘h6’) to 10–35 % in another subject section). (‘h1’). Under the sham condition, none of the participants The alignment of FUS foci was repeated prior to the reported any elicited sensations. Peripheral sensations beginning of each session (i.e., vibrotactile, pressure, from the scalp, often observed during the administration warmth, and coolness), and the sonication was adminis- of TMS [34–36], were not present. The onset of elicited tered 20 times for each session across the conditions (i.e., sensation, as measured from the response time acquisi- SI , SII , SI/SII , and Sham ). The participants tion (Additional file  1: Fig. S1), occurred with a delay of FUS FUS FUS FUS were instructed to tap a touch sensor on their left index ~2  s after the onset of sonication event (1.83  ±  1.31  s; finger (pulse transducer MLT1010/D; ADInstruments, mean ± SD, n = 784). CO) to report the timing of the tactile sensation during To qualitatively assess the degree of responses from the the sonication experiment, and also to verbally report SII and SI/SII conditions, the response rates were FUS FUS the location and type of the sensations upon the comple- averaged across only the sessions where a response was tion of each stimulation condition within the FUS ses- reported (SII and SI/SII in Table  1). Comparison Ave Ave sion. Both the subject and the operator were blinded to among the different sonication conditions showed that the nature of the sonication (i.e., the intended elicitation the response rates were not significantly different with Lee et al. BMC Neurosci (2016) 17:68 Page 6 of 11 Table 1 Response rates of elicited sensations during the FUS procedures ID SI SII SII SI/SII SI/SII Ave Ave V P W C V P W C h1 25 % 20 % 20 % 35 % 20 % 24 % 10 % 20 % 30 % 20 % 20 % h2 65 % 40 % 70 % 50 % 25 % 46 % 65 % 35 % 65 % 65 % 58 % h3 90 % 60 % 60 % 50 % 70 % 60 % 75 % 85 % 30 % 75 % 66 % h4 90 % NR 95 % NR NR 95 % 90 % 75 % NR NR 83 % h5 45 % 55 % NR 85 % 30 % 57 % 5 % 45 % 25 % 15 % 23 % h6 75 % 65 % 70 % 70 % 80 % 71 % 50 % 80 % 100 % 80 % 78 % h7 95 % 85 % NR 65 % 75 % 75 % 95 % 85 % 70 % 90 % 85 % h8 30 % 45 % 20 % NR NR 33 % NR NR NR NR – h9 95 % NR NR 70 % 70 % 70 % 50 % 80 % 75 % 90 % 74 % h10 NR NR NR NR NR – NR NR NR NR – Mean 68 % 53 % 56 % 61 % 53 % 59 % 55 % 63 % 56 % 62 % 61 % SD 28 % 21 % 30 % 17 % 26 % 22 % 34 % 26 % 29 % 32 % 26 % The response rates were derived as ‘the number of sonication events that elicited tactile sensations with respect to the number of sonication events (i.e., 20 events).’ For the FUS conditions of SII and SI/SII , the rates were tabulated for each sensation-specific session (V vibrotactile, P pressure, W warmth, C coolness), along with FUS FUS the average response rate across the sessions shown as a separate column (Ave). Mean and SD were derived without including the non-responsive cases (denoted as ‘NR’) each other (via t test; all p > 0.05). The response rate from ‘vibrotactile’ and ‘pressure’ sensations in the SI/SII FUS the SI condition was also similar to those observed condition. FUS from the previous study on the FUS stimulation of the SI Across all sonication conditions, the responsive sub- [20] (via t test, p > 0.05). It is notable, however, that about jects reported the elicited sensations mostly from the half of the subjects (n = 4) in the present study reported right hand/arm areas (i.e., sensations were felt either on high response rates, showing 90–100  % during SI . the palm or the back of the hand, contralateral to the FUS In the previous study that stimulated the SI in humans, sonicated left hemisphere) (Table  2b). The individual- none of the participants showed 90 % or higher response specific spatial distributions of sensations were illustrated rates [20]. in pseudo-color on the right hand (Fig.  2). It is interest- ing to note that the sensations felt from the fingers were Type/location of sensations elicited from FUS stimulation either from a single digit/tip or from a group of two to The types of tactile sensations reported by the respon - five adjacent fingers (Additional file  1: Table S2). The sen - sive subjects are shown in (Table  2a; Additional file  1: sation from the other locations (still all contralateral to Table S1) across the different sonication conditions (i.e., the sonication), such as the wrist, forearm, elbow, and SI , SII , and SI/SII ). Among the types of sensa- entire arm, were also reported. A few subjects (‘h1’-‘h3’) FUS FUS FUS tions reported by the subjects, a ‘tingling’ sensation was felt the sensations from the right leg (the knee or the calf ) dominant across the different FUS conditions, while sen - during the SI condition. FUS sations such as ‘feeling of weak electrical current flow’ and ‘numbness’ were also reported. Other types of sen- Post‑sonication safety profile of neurological sations, i.e., ‘heaviness/pressure’, ‘coolness’, and ‘brush- and neuroradiological assessments ing’, were also reported, although the occurrence was not The neurological examination and MMSE, along frequent. These elicited sensations were in good agree - with assessments of subject’s neuroradiological data, ment with the results from our previous investigation of revealed no abnormal findings across all subjects. In the acoustic stimulation of the SI [20], yet the ‘vibrotactile’ follow-up interviews conducted 8  weeks after the soni- and ‘warmth’ sensations were newly recognized from cation, no discomforts or changes in the mental/physi- the present study. The stimulation of different locations cal status associated with the sonication procedure were of the SII sub-regions did not elicit the corresponding/ reported. matching tactile sensations. However, two individuals (‘h2’ and ‘h5’) reported sensations that partially matched Discussion the intended type of sensations, for example, ‘warmth’ In the present study, we demonstrated that image-guided, conditions (SII or SI/SII ; Additional file  1: Table non-invasive transcranial FUS application to human FUS FUS S1). Another participant, ‘h5’, also reported matching SI and SII elicited various tactile sensations. We also Lee et al. BMC Neurosci (2016) 17:68 Page 7 of 11 Table 2 Number of subjects categorized by type and location of tactile sensations across different sonication conditions Types of sensations Sonication conditions SI SII SI/SII FUS FUS FUS (a) Tingling 7/9 78 % 7/9 78 % 6/9 67 % Heaviness/pressure 2/9 22 % 2/9 22 % 1/9 11 % Numbness 3/9 33 % 4/9 44 % 4/9 44 % Feeling of weak 4/9 44 % 5/9 56 % 6/9 67 % electrical current flow Warmth 2/9 22 % 2/9 22 % 1/9 11 % Coolness 0/9 0 % 1/9 11 % 0/9 0 % Vibrotactile 1/9 11 % 0/9 0 % 2/9 22 % Brushing 1/9 11 % 0/9 0 % 0/9 0 % Locations of sensations Sonication conditions SI SII SI/SII FUS FUS FUS (b) Hand/finger(s) 7/9 78 % 8/9 89 % 7/9 78 % Wrist 1/9 11 % 3/9 33 % 2/9 22 % Forearm 3/9 33 % 3/9 33 % 3/9 33 % Elbow 2/9 22 % 2/9 22 % 5/9 56 % Arm 1/9 11 % 1/9 11 % 1/9 11 % Leg 3/9 33 % 0/9 0 % 0/9 0 % The number of subjects categorized (a) according to the types of reported sensation descriptors and (b) the locations of sensations across three sonication conditions (SI , SII , and SI/SII ) out of 9 responsive subjects (‘h1’–‘h9’). Detailed information of the elicited sensations from each subject can be found in Additional file 1: FUS FUS FUS Tables S1–S3 showed the possibility of simultaneous acoustic stimula- achieved by FUS focus having the diameter of 6  mm tion of the SI and SII (proximal to each other), which has and the length of 38  mm at FWHM (Fig.  1b), did not not been feasible with conventional non-invasive brain have sufficient spatial selectivity to stimulate the highly- stimulation approaches such as TMS or tDCS. In terms overlapping sub-regions within the SII areas corre- of the type of sensations (Table 2; Additional file  1: Table sponding to differential tactile sensations [27, 37]. In S1), most of the elicited tactile sensations were similar to addition, convoluted gyral structure in SII sub-regions those from our previous study on acoustic stimulation of [37, 38] may obscure the selective delivery of the FUS the SI [20]. The types of tactile sensations elicited from to these regions. The use of a FUS configuration, for the SII sonication shared similarities with those elicited example, a phased-array design of ultrasound system [9, by electrical cortical stimulation of the SII [23]—cuta- 39] that has a smaller acoustic focus with wider aper- neous paresthesia (e.g., ‘tingling’, ‘light touch’, or ‘slight ture, would also be needed to provide greater spatial electric current’) or temperature sensations (e.g., ‘heat’ selectivity in acoustic stimulation. Another strategy to or ‘cold’). It may suggest that different brain stimulation increase the spatial selectivity of FUS is to use higher modalities activating the same cortical areas (in this case, acoustic frequencies [40], as the influence of the fre - the SII) may result in the cognition of the similar tactile quency on the size/shape of the focus is highlighted in perception by engaging mutual cortical-level processing. the work by Pinton et al. [41]. The use of advanced brain Elicitations of the ‘warmth’ and ‘vibrotactile’ sensations mapping techniques, such as ultra-high field/spatial- were new findings, suggesting the possibility of creating a resolution fMRI [42, 43], will also provide the ability more diverse spectrum of tactile sensations. to finely delineate sensation-specific sub-regions in the Our initial hypothesis, in which selective FUS stimu- SII. Interestingly, subjects ‘h2’ and ‘h5’ reported match- lation of the SII sub-regions (that are associated with ing types of sensations (such as ‘vibrotactile’, ‘pressure’, different types of tactile sensations, i.e., vibrotactile, and ‘warmth’), which supports the feasibility of generat- pressure, warmth, or coolness) would elicit correspond- ing intended types of sensations when the sub-regions ing tactile sensations, was rejected in the present study. of the somatosensory areas are stimulated with greater We speculate that the FUS-mediated neurostimulation, spatial selectivity. Lee et al. BMC Neurosci (2016) 17:68 Page 8 of 11 We found that the tactile sensations were reported from on-site numerical estimation of the acoustic propagation the hand/arm areas contralateral to the sonication across through/within the cranium can be utilized to estimate all FUS conditions (i.e., SI , SII , SI/SII ). In many the in situ acoustic intensity as well as its spatial accuracy FUS FUS FUS occasions (n  =  8), these sensations were localized in the of the sonication prior to the FUS application. palmar/dorsal side of the hand separately, or in a finger or In comparison of the response rates to that of our pre- in neighboring multiple fingers (Fig.  2; Additional file  1: vious investigation on the acoustic stimulation of the SI Table S2). The topological distributions of these localized [20], all three FUS conditions used in the present study responses follow the major sensory innervation patterns showed similar levels of group-averaged response rates of the radial, median, and ulnar nerves in the right upper (Table  1). However, it is notable that about half of the extremity, which suggests spatially-selective stimulation subjects who reported elicited tactile sensations showed of the relevant somatosensory areas (and nerve groups) by high levels of responsiveness (90–100 %) in the SI con- FUS FUS. The sensations were also elicited away from the hand dition (Table  1), while in the previous study [20], none area (contralateral to the sonication), such as on the wrist, achieved the high response rates of ≥90  %. Although it forearm, elbow, entire arm, and leg by a few subjects, is difficult to elucidate the exact causes for the improved which may be associated with the misaligned FUS stimu- stimulatory efficacy, we conjectured that the use of an lation (e.g., via acoustic refraction of the sonication at the increased level of incident acoustic energy (35 W/cm in skull) of the nearby somatosensory areas away from the the present study versus 3 W/cm in I previously) and sppa hand SI or SII regions, whereby similar phenomena were the use of a longer SD (500  ms versus 300  ms), coupled seen from the previous study on the acoustic stimulation with increased transcranial transmission rates due to of the SI [20]. To reduce the experimental confounders the use of lower ultrasonic frequency (210 vs. 250  kHz), induced by the acoustic attenuation/refraction at the skull, might have been contributing factors. Fig. 2 Graphical illustration of the location of tactile sensations. The distinctive locations of the elicited sensations were depicted by semi‑trans‑ parent purple color overlaid on the palmar and dorsal views of the right hand for each subject (‘h1’ through ‘h10’). The additional locations (i.e., wrist, forearm, elbow, arm, and leg) of the elicited sensations were also shown under the hand illustrations. The left column shows the locations of the responses during the SI condition. The results from the sensation‑specific sessions (i.e., ‘vibrotactile’, ‘pressure’, ‘warmth’, and ‘coolness’) FUS were merged on each column of SII (middle column) and SI/SII (right column), respectively. The number of occurrences for a set of distinctive FUS FUS locations of a sensation is represented by a color scale (1–3). NR non‑responsive cases (‘h8’ under the SI/SII condition and ‘h10’ during all FUS FUS procedures) Lee et al. BMC Neurosci (2016) 17:68 Page 9 of 11 We observed several sessions that a few subjects did other, which has not been achieved using other non-inva- not report any elicited sensations (Table  1, indicated as sive brain stimulation methods. Although simultaneous ‘NR’). Considering varying FUS target locations and inci- stimulation of the SI and SII did not show any differential dent angles of the sonication beam for each session, with effects in terms of the tactile sensations or response rates, accompanying changes of skull thickness/shape on each the ability to selectively stimulate these sensory areas sonication path, the attenuation and refraction of the FUS may be applied to future investigations of chronic pain beam during the transcranial acoustic transmission may [23, 24], whereby the interactions of the SI and SII are have reduced the level of in situ acoustic intensity at the important for perception and processing [48]. This possi - intended target. Particularly for the non-responsive sub- bility is also supported by previous studies of stimulation ject ‘h10’, the skull thickness on the sonication path to the of the SII using TMS, which modulated the pain inten- SI was 7.8 mm (Additional file  1: Table S4), which was the sity among healthy volunteers [49, 50] or patients with greatest among the subjects. The skull may have attenu - chronic drug-resistant neuropathic pain [51]. In addition, ated/refracted a significant portion of acoustic energy to FUS has been successfully delivered to the thalamic areas the level, perhaps below the threshold for excitation. in humans [8, 10], whereby stimulation of the specific We noted that the response rates from the sonication thalamic circuitries (e.g., including the ventral postero- greatly varied across the participants, ranging from 50 lateral nucleus of the thalamus) may also have potential to 100 % in one subject (‘h6’) to 10–35 % in another sub- to advance the pain-related studies. It is important to ject (‘h1’) across the sonication sessions (Table 1). Similar note, however, simultaneous sonication originating from degrees of individual variability in terms of responsive- two independent transducers may interfere with each ness to the acoustic stimulation have been reported from other within the cranial cavity, and may subsequently our previous human study [20] as well as from large [21] form additional acoustic focus (or foci) having stimula- and small animal models [17]. Although it is difficult to tory potentials. In addition, acoustic reverberation [52] be ascertained for the causes to these phenomena, we may also obscure the stimulation boundaries when mul- hypothesized that the differential stimulatory sensitivity tiple sonication beams are given proximal to each other. of the targeted neural substrates to the sonication may As these may confound stimulatory effects, caution is have contributed to the variability, which warrants fur- necessary when one aims to selectively simulate multi- ther investigations. Interestingly, the presence of inter- ple brain regions. Also, accompanying acoustic simula- subject variability in terms of responsiveness has been tions and corrective measures would help to reduce these documented in studies of other brain stimulation modali- confounders. ties such as TMS [44]. The neurostimulatory effects of FUS were transient We acknowledge that subjective measures on tactile and reversible, and the sonication procedure did not sensations may be confounded by the individual’s atten- cause any adverse changes or discomforts in the mental/ tion to certain areas of the body [45, 46]. We attempted physical status across all subjects. Considering the aver- to address the attention-related sensations by blinding age acoustic transmission rate of 20–25 % at the intended the participants on the nature of the stimulation (they targets [20] and a 50  % duty cycle, it is estimated that 2 2 were not expecting any sensations to begin with). Yet, 7.0–8.8  W/cm I , corresponding to 3.5–4.4  W/cm sppa the participants were able to identify the nature of the I , was provided to the regional brain location. This spta sensation (i.e., tactile) from the hand that was contralat- estimated intensity range is slightly higher than the eral to the sonication. Due to the subtle and often unu- international electrotechnical commission (IEC) 60601 sual sensations (such as transient tingling and numbing part 2 standard for therapeutic equipment limit of 3 W/ sensations that disappear quickly upon each stimulatory cm I [53]. Based on our past experience with sheep spta events), unbiased characterization of the tactile sensa- [21], as long as an excessive amount of stimulation is tions still poses as a challenging task [47]. More objec- avoided, the intensity up to 13.4  W/cm I (in situ) sppa tive measures that are synchronized with the sonication does not cause any microscopic damage to the brain. timing, supported by the detection and characterization However, this does not allow for the general application of the sensory evoked EEG potentials [20] in conjunc- of the given parameters to human subjects and demands tion with randomized stimulation timing, may be used to great caution when using higher acoustic intensity (and strengthen the reliability of our findings. The use of well- accompanying higher mechanical index (MI), while the designed sham/control condition will also be important current safety limit is set to 1.9 [53]). We estimated the for reducing the potential bias from the attention-related potential thermal increase (ΔT) at the sonicated region tactile illusion. of the brain by using the equation ΔT  =  2αIt/ρ C b p −1 2 Use of the FUS technique allowed for simultaneous [54]  =  2  ×  0.005  cm   ×  7.0  W/cm   ×  0.5  s/3.811  J/ stimulation of ipsilateral SI and SII that are close to each cm   °C; where α  =  absorption coefficient [55], Lee et al. BMC Neurosci (2016) 17:68 Page 10 of 11 Author details I  =  effective acoustic intensity (I ) in the focal region spta Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, considering the maximal transcranial acoustic transmis- Republic of Korea. Department of Radiology, Brigham and Women’s Hospital, sion of 40 % [20], t = sonication duration, ρ  = density of Harvard Medical School, Boston, MA, USA. the brain tissue [56], and C  = specific heat of the brain Acknowledgements tissue [56]. The estimated ΔT was 0.0092  °C, which was Authors thank Mr. Matthew Marzelli for editorial assistance and Dr. Hyungmin far below the thermal threshold that can derive either Kim for his technical help in preparing image‑ guidance software. neurostimulatory effects or tissue damage [57, 58]. Competing interests Along with promising safety data, the capability of FUS The authors declare that they have no competing interests. to selectively stimulate multiple brain regions, including Availability of data and materials those proximal to each other (such as ipsilateral SI and All datasets on which the conclusions of the manuscript rely were presented SII), would pave a new non-invasive way to study func- in the main paper and additional supplementary files. tional connectivity among neural substrates. Further Consent for publication studies employing fMRI for the assessment of network- All participants submitted written consent for publication including individual level activations in the brain during FUS neuromodu- person’s data in anonymized form. lation may help to reveal the causal relations between Ethics approval and consent to participate the region-specific brain functions of the stimulated This research was performed under the approval of the Institutional Review neural substrates and the elicited cognitive/behavioral Board (IRB) of Incheon St. Mary’s Hospital, the Catholic University of Korea, in responses. The potential impact of FUS as a functional accordance with the ethical guidelines set forth by the IRB. All participants submitted written consent prior to enrollment in the study. neuromodulation method awaits further evaluation across various disciplines from basic scientific studies to Funding clinical applications. 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Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound

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Springer Journals
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Copyright © 2016 by The Author(s)
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Biomedicine; Neurosciences; Neurobiology; Animal Models
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Abstract

Background: Transcranial focused ultrasound (FUS) is gaining momentum as a novel non‑ invasive brain stimulation method, with promising potential for superior spatial resolution and depth penetration compared to transcranial magnetic stimulation or transcranial direct current stimulation. We examined the presence of tactile sensations elic‑ ited by FUS stimulation of two separate brain regions in humans—the primary (SI) and secondary (SII) somatosensory areas of the hand, as guided by individual‑ specific functional magnetic resonance imaging data. Results: Under image‑ guidance, acoustic stimulations were delivered to the SI and SII areas either separately or simultaneously. The SII areas were divided into sub‑ regions that are activated by four types of external tactile sensa‑ tions to the palmar side of the right hand—vibrotactile, pressure, warmth, and coolness. Across the stimulation condi‑ tions (SI only, SII only, SI and SII simultaneously), participants reported various types of tactile sensations that arose from the hand contralateral to the stimulation, such as the palm/back of the hand or as single/neighboring fingers. The type of tactile sensations did not match the sensations that are associated with specific sub ‑ regions in the SII. The neuro‑ stimulatory effects of FUS were transient and reversible, and the procedure did not cause any adverse changes or discomforts in the subject’s mental/physical status. Conclusions: The use of multiple FUS transducers allowed for simultaneous stimulation of the SI/SII in the same hemisphere and elicited various tactile sensations in the absence of any external sensory stimuli. Stimulation of the SII area alone could also induce perception of tactile sensations. The ability to stimulate multiple brain areas in a spatially restricted fashion can be used to study causal relationships between regional brain activities and their cognitive/ behavioral outcomes. Keywords: Dual transcranial focused ultrasound, Image‑ guidance, Non‑ invasive brain stimulation, Human primary and secondary somatosensory cortices, Tactile sensations neurological or neuropsychiatric diseases [2], but these Background techniques involve invasive surgical procedures. Non- Brain stimulation techniques serve as important tools for invasive techniques such as transcranial magnetic stimu- neurotherapeutics and allow for functional investigation lation (TMS) or transcranial direct current stimulation of the brain [1, 2]. Methods such as deep brain stimula- (tDCS) are available to modulate neural functions with- tion (DBS) or epidural cortical stimulation (EpCS) have out surgery [1, 3], but the stimulatory area is relatively been utilized in clinical settings for the treatment of large (on the order of centimeters) and its depth is lim- ited proximal to the cortical surface [2, 4]. Optogenetic *Correspondence: focus@cmcnu.or.kr; yoo@bwh.harvard.edu approaches offer cell-level modification of neuronal Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, Republic of Korea excitability [5, 6]; however, the required introduction of Full list of author information is available at the end of the article © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lee et al. BMC Neurosci (2016) 17:68 Page 2 of 11 genetic alterations to introduce sensitivity to light pro- also induce corresponding types of tactile sensations. The hibits immediate applications in humans. Therefore, FUS was also administered to both SI and SII simultane- the development of non-invasive and spatially-selective ously, and its effects were assessed. means of brain stimulation was sought after. Focused ultrasound (FUS) has recently shown its utility Methods in non-invasive brain stimulation [7], with greater spa- Participants and study overview tial selectivity and depth penetration compared to other This research was performed under the approval of the non-invasive techniques such as TMS or tDCS [8–10]. Institutional Review Board (IRB) of Incheon St. Mary’s The acoustic neuromodulatory effects can be tailored as Hospital, the Catholic University of Korea, in accord- either excitatory or suppressive, depending on the soni- ance with the ethical guidelines set forth by the IRB. Ten cation parameters [11, 12]. Accumulating ex  vivo [13, healthy volunteers (two females, ages 23–34, average of 14] and in  vivo [12, 15–18] evidence shows that acous- 27.8  ±  4.1  years, labeled ‘h1’ through ‘h10’ herein) with tic pressure waves delivered to localized brain struc- no clinical history of peripheral/central neurological dis- tures modulate their excitability using low-level acoustic eases participated. All participants submitted written intensity (i.e., compatible with potential human applica- consent prior to enrollment in the study. tion [19, 20]). Recently, transcranial FUS has also been Prior to the FUS procedures, functional MRI (fMRI) shown to have neuromodulatory effects on large animal was performed (on a separate day) to map the individual- models, such as the elicitation of motor and visual elec- specific SI and SII areas in the left hemisphere that are trophysiological responses in sheep [21] and the modula- functionally eloquent for four different non-painful sen - tion of saccadic movement in non-human primates [22]. sory stimuli—(1) vibrotactile, (2) pressure, (3) warmth, In humans, transcranially delivered FUS to the primary and (4) coolness [27]. Anatomical MRI and computed somatosensory cortex (SI) has been shown to modulate tomography (CT) scans of the head were also acquired the performance of tactile discrimination tasks as well on the same day. The acquired neuroimage data were as the amplitude of somatosensory evoked potentials used for neuroradiological assessments, such as, but not (SEP) [19]. More recently, we have demonstrated that limited to, existence of clinically significant intracranial FUS sonication of the SI, without giving external sensory calcifications (mainly detected by the CT), which may stimulation, evoked both sonication-specific electroen - disturb the acoustic propagation within the cranial cavity cephalographic (EEG) responses and various tactile sen- (none were found). Along with the MRI/CT procedures, sations from the hand area [20]. clinical neurological examination and the mini-mental In addition to the SI (a primary site of processing state examination (MMSE) [28] were provided to each external sensory afferent signals), the SII (located in the subject by licensed physicians. parietal operculum on the ceiling of the lateral sulcus) The FUS procedures, conducted on a separate day is an important neural substrate for processing/cogni- (gap between the MRI/CT and FUS procedures: tion of various tactile sensations, including pain or even 98.7  ±  6.0  days; mean  ±  SD, n  =  10), were divided into visceral sensations [23, 24]. To our knowledge, studies multiple sessions—(1) stimulation of the SI alone (i.e., on the stimulation of the SII areas in humans are rare. SI ), (2) stimulation of four sub-regions in the SII (i.e., FUS Spatial specificity of FUS confers the ability to simulta - SII ; in which the coordinates corresponding to the four FUS neously stimulate multiple brain regions that are close to types of tactile stimuli were identified), (3) stimulation of each other, whereas the concurrent operation of multiple both SI and SII (i.e., SI/SII ; four different SII regions FUS TMS coils in close proximity is not desirable due to the were stimulated), and (4) sham condition (i.e., Sham , FUS mutual interactions/interferences of the magnetic fields using the same FUS setup as SI/SII , but without deliv- FUS [25]. Only limited TMS studies have been reported to ery of any sonication). The sequence of these stimulation stimulate brain areas, one from each hemisphere [26], or conditions was randomized and balanced across all sub- to stimulate adjacent brain regions with temporal gaps jects. Additional neurological examination and MMSE in between [25]. Therefore, we were motivated to deliver were administered on the day of the sonication experi- neurostimulatory FUS to the SII, and to examine the out- ments both before and after FUS administration to exam- comes in terms of subjective sensations felt by the indi- ine the presence of any neurological changes. viduals. The existence of spatially-distinct sub-regions within the SII for processing different types of tactile sen - Multi‑modal imaging data and sonication planning sations [23, 27] prompted us to further explore the possi- Both CT and anatomical MRI of the participants’ head bility that FUS stimulation of sensation-specific SII areas was used for planning and image-guidance of FUS soni- (i.e., vibrotactile, pressure, warmth, and coolness) may cation [20]. Adhesive fiducial markers (PinPoint; Beekly Lee et al. BMC Neurosci (2016) 17:68 Page 3 of 11 Corp., Bristol, CT; visible in both MRI and CT) were each other; therefore, a single sonication target was attached on four locations spatially distributed over the assigned representing the SI area. On the other hand, head. Since these adhesive fiducial markers were also the locations of activation in the SII associated with dif- used for image-guidance of the sonication (that was con- ferent tactile stimuli showed a degree of spatial distribu- ducted in a separate day), their reproducible positioning tions (having a radius of 5.3 ± 2.6 mm; as identified from was crucial. To do so, we carefully identified the par - the local maximum in the activation probability) while a ticipants permanent anatomical features, such as skin degree of individual variability existed (i.e., ranged from imperfections (such as wrinkle lines and/or spots) or skin 2.1 to 10.3  mm; a group-level spatial distribution of the vein structures (such as bifurcation) to place the markers SII sub-regions was described elsewhere [27]). Thus, the (on them). These sites were photographed to be used for SII areas were divided into four different spatial locations later positioning. The spatial coordinates of these mark - to be targeted by FUS. ers in the acquired CT/MRI data were utilized as a basis for the spatial co-registration between neuroimage space The sonication setup and the physical location of the subject’s head. In order to independently deliver acoustic energy to the A clinical CT scanner (Aquilion ONE, Toshiba, SI and SII in the left hemisphere, we used two sets of Japan) was used to acquire the CT data of the head single-element FUS transducers (operating at 210  kHz [axial orientation, slice thickness  =  0.5  mm, field-of- frequency, The Ultran Group Ltd, State College, PA) view (FOV) =  24 ×  24  cm , image matrix =  512 ×  512, (Fig.  1a), which were segmented-spheres in shape, each voxel size = 0.47 × 0.47 × 0.50 mm ]. The head CT data having an outer diameter (OD) of 30  mm and a focal were used to plan for the orientation of the transcra- distance of 25  mm. Each transducer was affixed to an nial FUS, whereby we aligned the sonication pathway as articulated applicator (Zamerican, Zacuto, Chicago, IL) perpendicular as possible to the skull at the entry, while that was mounted on a helmet (named ‘FUS helmet’, avoiding thick skull segments or in-bone air-pockets Fig. 1a, modified from Giro Section Helmet, Santa Cruz, (both significantly distort the acoustic beam propa - CA) having two open spaces (8 cm in diameter) to allow gation by attenuation and diffraction/reflection). To access to the SI and SII in the left hemisphere. The posi - obtain the head MRI data, a 3-Tesla clinical MR scan- tion and orientation of the transducers could be adjusted ner (MAGNETOM Skyra, Siemens) was utilized with and locked using the applicators. The gap between the a 4-channel head coil. T1-weighted images of the ana- scalp and the transducer surface was filled with a poly - tomical MRI [3D GRAPPA sequence, acceleration fac- vinyl alcohol (PVA) hydrogel for acoustic coupling. tor  =  2, repetition time (TR)  =  1900  ms, echo time The compressible PVA hydrogel (having a thickness of (TE)  =  2.46  ms, flip angle  =  9°, FOV  =  24  ×  24  cm , ~10 mm) which was fitted around the transducer allowed image matrix  =  256  ×  256, slice thickness  =  0.94  mm, for adjustment of acoustic focal depth in the range of voxel size = 0.94 × 0.94 × 0.94 mm , sagittal orientation, 5–20  mm (detailed implementation was described else- 192 slices] were acquired from the head, covering the where [30]). The subject’s hair was parted in the middle entire telencephalic areas. Then, blood oxygenation level of each sonication entry point, and a generic ultrasound dependent (BOLD)-fMRI was conducted for each subject hydrogel (Aquasonics, Parker Laboratories, Fairfield, NJ) to map the individual-specific SI and SII areas, function - was applied onto the exposed scalp. ally eloquent for four different tactile stimulations of the For image-guided alignment of the FUS focus to the right hand—(1) vibrotactile, (2) pressure, (3) warmth, intended target, the relative location and orientation of and (4) coolness. The detailed stimulation paradigm for the transducers with respect to the helmet (i.e., subject’s the fMRI and the image processing schemes are reported head) were tracked in real-time, whereby the coordinates elsewhere [27]. of the focus can be visualized on the individual-specific The functional and anatomical MRI data, as well as the neuroanatomy (as well as the planned sonication tar- cranial information from the CT scan, were spatially co- get) via a custom-built image-guidance system as previ- registered (using the Normalized Mutual Information ously described [20, 31]. An optical tracker was attached technique [29]), and these multi-modal imaging data to the helmet and each of the two FUS transducers for were utilized for the planning and on-site individual-spe- motion tracking. Each FUS transducer was actuated by cific neuroimage-guidance for transcranial FUS sonica - a computer-controlled driving circuit (Fig.  1a). Two sets tion [20]. Individual-specific coordinates of the SI and SII of the driving circuits were used to actuate each of two in the left hemisphere were identified based on our previ - FUS transducers. Upon receiving a trigger signal from ous study on the same participants [27]. Within the SI, the control computer, the input signal (Fig.  1b) was gen- local maxima of the activations corresponding to differ - erated by a pair of function generators (33220A; Agilent ent tactile stimuli were closely clustered and overlapped technologies, Inc., Santa Clara, CA) and amplified by a Lee et al. BMC Neurosci (2016) 17:68 Page 4 of 11 Fig. 1 Experimental schematics of the dual FUS application with the sonication parameters. a Left panel a rendering of the FUS setup, and right panel its actual implementation on a mannequin head model. The two FUS foci were placed at the targeted SI and SII by image‑ guidance using optical trackers (‘tracker 1’ and ‘tracker 2’) in reference to the subject head (tracked via ‘helmet tracker’). Each tracker had four infrared‑reflective markers for real‑time motion detection. FUS transducers were actuated by the sinusoidal electrical signals with impedance matching circuits. Compressible hydrogel was used to couple the FUS transducer to the scalp. b Upper panel illustration of the acoustic parameters. SD sonication duration = 500 ms, ISI inter‑stimulation‑interval = 7 s, TBD tone ‑burst ‑ duration = 1 ms, PRF pulse‑repetition‑frequency = 500 Hz; Incident spatial‑ peak pulse‑average intensity = 35.0 W/cm I . Lower panel acoustic intensity mapping of the 210 kHz FUS transducer (longitudinal measurement sppa was taken 10 mm from the exit plane of the transducer). The red dotted lines indicate the FWHM of the intensity profile. c, d Exemplar views of the individual‑specific neuroimage ‑ guidance for targeting of ipsilateral SI or SII, respectively. The green crosshairs shown in the projection views (i.e., axial, sagittal, and coronal slices) indicates the sonication target, and the thick green line and yellow line represent the orientation of the sonica‑ tion path and planned path, respectively, connecting the target (red dot) and entry (green dot) points. In the lower right panel, the four colored dots (without the yellow bar) show the locations of anatomical markers used for the neuroimage‑registration with the subject. R and L denote right and left, respectively Class-A linear power amplifier (Electronics and Innova - [12, 16, 21] (Fig.  1b), having a sonication duration (SD) tions, Rochester, NY). An impedance-matching circuit of 500  ms, with a tone-burst-duration (TBD) of 1  ms was used to increase the power efficiency. repeated at a frequency of 500  Hz (i.e., pulse repetition frequency; PRF), yielding a 50  % duty cycle. The spatial Operating parameters and characterization of the FUS profile of the acoustic intensity field generated by the acoustic field FUS transducer was characterized (Fig.  1b) using meth- Based on our previous experiences [20, 21], 210  kHz ods described elsewhere [12]. The diameter of the FUS ultrasound was used to achieve an effective acoustic focus was measured on the acoustic intensity maps based transmission through the thick skull. We adapted similar on pressure scanning using a hydrophone (HNR500; sonication parameters that were utilized in the success- Onda, Sunnyvale, CA) over the transversal plane ful stimulation of the SI in humans [20] and in animals (31 ×  31  mm square area, 1 mm step) perpendicular to Lee et al. BMC Neurosci (2016) 17:68 Page 5 of 11 the sonication path at the acoustic focal distance using of the tactile sensation including its side). The subject’s time-of-flight information. The length of the focus was tapping response and the timing of the sonication events measured along the longitudinal plane along the beam were measured using the data acquisition system (Lab- path (31  ×  51  mm area, 1  mm step, measured 10  mm Chart 7 and PowerLab 4/35; ADInstruments). away from the exit plane of the transducer). The acoustic focus had a diameter of 6 mm and a length of 38 mm, as Post‑FUS session follow‑up defined by the full-width at half-maximum (FWHM) of After the FUS procedure, subjects were asked to remain the acoustic intensity map (Fig.  1b). The incident acous - in the study premises for 2 h, and received the post-FUS tic intensity at the FUS focus, in the absence of skull, was neurological examination and MMSE. Subsequently, 35.0 W/cm spatial-peak pulse-average acoustic intensity anatomical MRI data were acquired again for follow-up (I ), resulting in a spatial peak temporal-average acous- neuroradiological examination from all participants at sppa tic intensity (I ) of 17.5 W/cm . three different time periods—same day (n  =  3), 2  weeks spta (n  =  4), and 4  weeks (n  =  3) after the sonication ses- Image‑guided FUS to the primary and secondary sion. The physicians who conducted the neurological somatosensory cortices assessments were blinded to the nature of the study. Two On the day of the sonication experiment, the subject was months after the sonication sessions, all subjects were seated in a recliner chair. Prior to the spatial registration interviewed by telephone to check the presence of any of the subject’s physical space to the virtual space of the changes regarding mental or physical discomforts/health head MRI/CT neuroimage data, fiducial markers (stick - status concerned with the study participation. ers) were attached to the same locations that were used for the sonication planning (i.e., during the initial MRI/ Results CT session). The registration quality was assessed to Response rate of eliciting sensation by the FUS stimulation minimize target registration error (TRE) [32, 33], which FUS stimulation, via sonication of either the SI/SII was less than 4 mm (3.7 ± 1.4 mm, n = 10, mean ± SD). separately or both the SI and SII simultaneously, elic- The FUS helmet was then tightly secured on the sub - ited tactile sensations from the subjects whereby the ject’s head to maintain the location of the transducer response rate, as defined by the number of reported tac - with respect to head motion. A set of optical trackers tile responses out of 20 stimulation events, are summa- attached to the helmet (‘helmet tracker’ in Fig.  1a) and rized in Table  1. Not all of the FUS stimulation events transducers (‘tracker 1’ and ‘tracker 2’, in Fig. 1a) provided elicited sensations from the subjects. For example, one the orientation and location of the acoustic foci back to subject (‘h10’) did not report any sensation during any the experimenters, following the methods described in of the FUS conditions (noted as ‘NR’). Subject ‘h8’ also our previous work [20]. Under this image-guidance, the did not report any sensation during the SI/SII condi- FUS experimenters aligned the FUS focus to the intended tion. Furthermore, across the different FUS conditions, coordinates of the somatosensory areas (Fig.  1c, d). The we observed several sessions that a few subjects did not orientation of the sonication path was adjusted to make report any elicited sensation (Table  1, indicated as NR). the incident angle as perpendicular as possible to the Across the sonication sessions with the elicitation of tac- scalp (at an entry point), as guided by the information tile sensations, there was a degree of variability in the established during the sonication planning stage (see response rates among the subjects, ranging from 50 to “Multi-modal imaging data and sonication planning” 100 % in one subject (‘h6’) to 10–35 % in another subject section). (‘h1’). Under the sham condition, none of the participants The alignment of FUS foci was repeated prior to the reported any elicited sensations. Peripheral sensations beginning of each session (i.e., vibrotactile, pressure, from the scalp, often observed during the administration warmth, and coolness), and the sonication was adminis- of TMS [34–36], were not present. The onset of elicited tered 20 times for each session across the conditions (i.e., sensation, as measured from the response time acquisi- SI , SII , SI/SII , and Sham ). The participants tion (Additional file  1: Fig. S1), occurred with a delay of FUS FUS FUS FUS were instructed to tap a touch sensor on their left index ~2  s after the onset of sonication event (1.83  ±  1.31  s; finger (pulse transducer MLT1010/D; ADInstruments, mean ± SD, n = 784). CO) to report the timing of the tactile sensation during To qualitatively assess the degree of responses from the the sonication experiment, and also to verbally report SII and SI/SII conditions, the response rates were FUS FUS the location and type of the sensations upon the comple- averaged across only the sessions where a response was tion of each stimulation condition within the FUS ses- reported (SII and SI/SII in Table  1). Comparison Ave Ave sion. Both the subject and the operator were blinded to among the different sonication conditions showed that the nature of the sonication (i.e., the intended elicitation the response rates were not significantly different with Lee et al. BMC Neurosci (2016) 17:68 Page 6 of 11 Table 1 Response rates of elicited sensations during the FUS procedures ID SI SII SII SI/SII SI/SII Ave Ave V P W C V P W C h1 25 % 20 % 20 % 35 % 20 % 24 % 10 % 20 % 30 % 20 % 20 % h2 65 % 40 % 70 % 50 % 25 % 46 % 65 % 35 % 65 % 65 % 58 % h3 90 % 60 % 60 % 50 % 70 % 60 % 75 % 85 % 30 % 75 % 66 % h4 90 % NR 95 % NR NR 95 % 90 % 75 % NR NR 83 % h5 45 % 55 % NR 85 % 30 % 57 % 5 % 45 % 25 % 15 % 23 % h6 75 % 65 % 70 % 70 % 80 % 71 % 50 % 80 % 100 % 80 % 78 % h7 95 % 85 % NR 65 % 75 % 75 % 95 % 85 % 70 % 90 % 85 % h8 30 % 45 % 20 % NR NR 33 % NR NR NR NR – h9 95 % NR NR 70 % 70 % 70 % 50 % 80 % 75 % 90 % 74 % h10 NR NR NR NR NR – NR NR NR NR – Mean 68 % 53 % 56 % 61 % 53 % 59 % 55 % 63 % 56 % 62 % 61 % SD 28 % 21 % 30 % 17 % 26 % 22 % 34 % 26 % 29 % 32 % 26 % The response rates were derived as ‘the number of sonication events that elicited tactile sensations with respect to the number of sonication events (i.e., 20 events).’ For the FUS conditions of SII and SI/SII , the rates were tabulated for each sensation-specific session (V vibrotactile, P pressure, W warmth, C coolness), along with FUS FUS the average response rate across the sessions shown as a separate column (Ave). Mean and SD were derived without including the non-responsive cases (denoted as ‘NR’) each other (via t test; all p > 0.05). The response rate from ‘vibrotactile’ and ‘pressure’ sensations in the SI/SII FUS the SI condition was also similar to those observed condition. FUS from the previous study on the FUS stimulation of the SI Across all sonication conditions, the responsive sub- [20] (via t test, p > 0.05). It is notable, however, that about jects reported the elicited sensations mostly from the half of the subjects (n = 4) in the present study reported right hand/arm areas (i.e., sensations were felt either on high response rates, showing 90–100  % during SI . the palm or the back of the hand, contralateral to the FUS In the previous study that stimulated the SI in humans, sonicated left hemisphere) (Table  2b). The individual- none of the participants showed 90 % or higher response specific spatial distributions of sensations were illustrated rates [20]. in pseudo-color on the right hand (Fig.  2). It is interest- ing to note that the sensations felt from the fingers were Type/location of sensations elicited from FUS stimulation either from a single digit/tip or from a group of two to The types of tactile sensations reported by the respon - five adjacent fingers (Additional file  1: Table S2). The sen - sive subjects are shown in (Table  2a; Additional file  1: sation from the other locations (still all contralateral to Table S1) across the different sonication conditions (i.e., the sonication), such as the wrist, forearm, elbow, and SI , SII , and SI/SII ). Among the types of sensa- entire arm, were also reported. A few subjects (‘h1’-‘h3’) FUS FUS FUS tions reported by the subjects, a ‘tingling’ sensation was felt the sensations from the right leg (the knee or the calf ) dominant across the different FUS conditions, while sen - during the SI condition. FUS sations such as ‘feeling of weak electrical current flow’ and ‘numbness’ were also reported. Other types of sen- Post‑sonication safety profile of neurological sations, i.e., ‘heaviness/pressure’, ‘coolness’, and ‘brush- and neuroradiological assessments ing’, were also reported, although the occurrence was not The neurological examination and MMSE, along frequent. These elicited sensations were in good agree - with assessments of subject’s neuroradiological data, ment with the results from our previous investigation of revealed no abnormal findings across all subjects. In the acoustic stimulation of the SI [20], yet the ‘vibrotactile’ follow-up interviews conducted 8  weeks after the soni- and ‘warmth’ sensations were newly recognized from cation, no discomforts or changes in the mental/physi- the present study. The stimulation of different locations cal status associated with the sonication procedure were of the SII sub-regions did not elicit the corresponding/ reported. matching tactile sensations. However, two individuals (‘h2’ and ‘h5’) reported sensations that partially matched Discussion the intended type of sensations, for example, ‘warmth’ In the present study, we demonstrated that image-guided, conditions (SII or SI/SII ; Additional file  1: Table non-invasive transcranial FUS application to human FUS FUS S1). Another participant, ‘h5’, also reported matching SI and SII elicited various tactile sensations. We also Lee et al. BMC Neurosci (2016) 17:68 Page 7 of 11 Table 2 Number of subjects categorized by type and location of tactile sensations across different sonication conditions Types of sensations Sonication conditions SI SII SI/SII FUS FUS FUS (a) Tingling 7/9 78 % 7/9 78 % 6/9 67 % Heaviness/pressure 2/9 22 % 2/9 22 % 1/9 11 % Numbness 3/9 33 % 4/9 44 % 4/9 44 % Feeling of weak 4/9 44 % 5/9 56 % 6/9 67 % electrical current flow Warmth 2/9 22 % 2/9 22 % 1/9 11 % Coolness 0/9 0 % 1/9 11 % 0/9 0 % Vibrotactile 1/9 11 % 0/9 0 % 2/9 22 % Brushing 1/9 11 % 0/9 0 % 0/9 0 % Locations of sensations Sonication conditions SI SII SI/SII FUS FUS FUS (b) Hand/finger(s) 7/9 78 % 8/9 89 % 7/9 78 % Wrist 1/9 11 % 3/9 33 % 2/9 22 % Forearm 3/9 33 % 3/9 33 % 3/9 33 % Elbow 2/9 22 % 2/9 22 % 5/9 56 % Arm 1/9 11 % 1/9 11 % 1/9 11 % Leg 3/9 33 % 0/9 0 % 0/9 0 % The number of subjects categorized (a) according to the types of reported sensation descriptors and (b) the locations of sensations across three sonication conditions (SI , SII , and SI/SII ) out of 9 responsive subjects (‘h1’–‘h9’). Detailed information of the elicited sensations from each subject can be found in Additional file 1: FUS FUS FUS Tables S1–S3 showed the possibility of simultaneous acoustic stimula- achieved by FUS focus having the diameter of 6  mm tion of the SI and SII (proximal to each other), which has and the length of 38  mm at FWHM (Fig.  1b), did not not been feasible with conventional non-invasive brain have sufficient spatial selectivity to stimulate the highly- stimulation approaches such as TMS or tDCS. In terms overlapping sub-regions within the SII areas corre- of the type of sensations (Table 2; Additional file  1: Table sponding to differential tactile sensations [27, 37]. In S1), most of the elicited tactile sensations were similar to addition, convoluted gyral structure in SII sub-regions those from our previous study on acoustic stimulation of [37, 38] may obscure the selective delivery of the FUS the SI [20]. The types of tactile sensations elicited from to these regions. The use of a FUS configuration, for the SII sonication shared similarities with those elicited example, a phased-array design of ultrasound system [9, by electrical cortical stimulation of the SII [23]—cuta- 39] that has a smaller acoustic focus with wider aper- neous paresthesia (e.g., ‘tingling’, ‘light touch’, or ‘slight ture, would also be needed to provide greater spatial electric current’) or temperature sensations (e.g., ‘heat’ selectivity in acoustic stimulation. Another strategy to or ‘cold’). It may suggest that different brain stimulation increase the spatial selectivity of FUS is to use higher modalities activating the same cortical areas (in this case, acoustic frequencies [40], as the influence of the fre - the SII) may result in the cognition of the similar tactile quency on the size/shape of the focus is highlighted in perception by engaging mutual cortical-level processing. the work by Pinton et al. [41]. The use of advanced brain Elicitations of the ‘warmth’ and ‘vibrotactile’ sensations mapping techniques, such as ultra-high field/spatial- were new findings, suggesting the possibility of creating a resolution fMRI [42, 43], will also provide the ability more diverse spectrum of tactile sensations. to finely delineate sensation-specific sub-regions in the Our initial hypothesis, in which selective FUS stimu- SII. Interestingly, subjects ‘h2’ and ‘h5’ reported match- lation of the SII sub-regions (that are associated with ing types of sensations (such as ‘vibrotactile’, ‘pressure’, different types of tactile sensations, i.e., vibrotactile, and ‘warmth’), which supports the feasibility of generat- pressure, warmth, or coolness) would elicit correspond- ing intended types of sensations when the sub-regions ing tactile sensations, was rejected in the present study. of the somatosensory areas are stimulated with greater We speculate that the FUS-mediated neurostimulation, spatial selectivity. Lee et al. BMC Neurosci (2016) 17:68 Page 8 of 11 We found that the tactile sensations were reported from on-site numerical estimation of the acoustic propagation the hand/arm areas contralateral to the sonication across through/within the cranium can be utilized to estimate all FUS conditions (i.e., SI , SII , SI/SII ). In many the in situ acoustic intensity as well as its spatial accuracy FUS FUS FUS occasions (n  =  8), these sensations were localized in the of the sonication prior to the FUS application. palmar/dorsal side of the hand separately, or in a finger or In comparison of the response rates to that of our pre- in neighboring multiple fingers (Fig.  2; Additional file  1: vious investigation on the acoustic stimulation of the SI Table S2). The topological distributions of these localized [20], all three FUS conditions used in the present study responses follow the major sensory innervation patterns showed similar levels of group-averaged response rates of the radial, median, and ulnar nerves in the right upper (Table  1). However, it is notable that about half of the extremity, which suggests spatially-selective stimulation subjects who reported elicited tactile sensations showed of the relevant somatosensory areas (and nerve groups) by high levels of responsiveness (90–100 %) in the SI con- FUS FUS. The sensations were also elicited away from the hand dition (Table  1), while in the previous study [20], none area (contralateral to the sonication), such as on the wrist, achieved the high response rates of ≥90  %. Although it forearm, elbow, entire arm, and leg by a few subjects, is difficult to elucidate the exact causes for the improved which may be associated with the misaligned FUS stimu- stimulatory efficacy, we conjectured that the use of an lation (e.g., via acoustic refraction of the sonication at the increased level of incident acoustic energy (35 W/cm in skull) of the nearby somatosensory areas away from the the present study versus 3 W/cm in I previously) and sppa hand SI or SII regions, whereby similar phenomena were the use of a longer SD (500  ms versus 300  ms), coupled seen from the previous study on the acoustic stimulation with increased transcranial transmission rates due to of the SI [20]. To reduce the experimental confounders the use of lower ultrasonic frequency (210 vs. 250  kHz), induced by the acoustic attenuation/refraction at the skull, might have been contributing factors. Fig. 2 Graphical illustration of the location of tactile sensations. The distinctive locations of the elicited sensations were depicted by semi‑trans‑ parent purple color overlaid on the palmar and dorsal views of the right hand for each subject (‘h1’ through ‘h10’). The additional locations (i.e., wrist, forearm, elbow, arm, and leg) of the elicited sensations were also shown under the hand illustrations. The left column shows the locations of the responses during the SI condition. The results from the sensation‑specific sessions (i.e., ‘vibrotactile’, ‘pressure’, ‘warmth’, and ‘coolness’) FUS were merged on each column of SII (middle column) and SI/SII (right column), respectively. The number of occurrences for a set of distinctive FUS FUS locations of a sensation is represented by a color scale (1–3). NR non‑responsive cases (‘h8’ under the SI/SII condition and ‘h10’ during all FUS FUS procedures) Lee et al. BMC Neurosci (2016) 17:68 Page 9 of 11 We observed several sessions that a few subjects did other, which has not been achieved using other non-inva- not report any elicited sensations (Table  1, indicated as sive brain stimulation methods. Although simultaneous ‘NR’). Considering varying FUS target locations and inci- stimulation of the SI and SII did not show any differential dent angles of the sonication beam for each session, with effects in terms of the tactile sensations or response rates, accompanying changes of skull thickness/shape on each the ability to selectively stimulate these sensory areas sonication path, the attenuation and refraction of the FUS may be applied to future investigations of chronic pain beam during the transcranial acoustic transmission may [23, 24], whereby the interactions of the SI and SII are have reduced the level of in situ acoustic intensity at the important for perception and processing [48]. This possi - intended target. Particularly for the non-responsive sub- bility is also supported by previous studies of stimulation ject ‘h10’, the skull thickness on the sonication path to the of the SII using TMS, which modulated the pain inten- SI was 7.8 mm (Additional file  1: Table S4), which was the sity among healthy volunteers [49, 50] or patients with greatest among the subjects. The skull may have attenu - chronic drug-resistant neuropathic pain [51]. In addition, ated/refracted a significant portion of acoustic energy to FUS has been successfully delivered to the thalamic areas the level, perhaps below the threshold for excitation. in humans [8, 10], whereby stimulation of the specific We noted that the response rates from the sonication thalamic circuitries (e.g., including the ventral postero- greatly varied across the participants, ranging from 50 lateral nucleus of the thalamus) may also have potential to 100 % in one subject (‘h6’) to 10–35 % in another sub- to advance the pain-related studies. It is important to ject (‘h1’) across the sonication sessions (Table 1). Similar note, however, simultaneous sonication originating from degrees of individual variability in terms of responsive- two independent transducers may interfere with each ness to the acoustic stimulation have been reported from other within the cranial cavity, and may subsequently our previous human study [20] as well as from large [21] form additional acoustic focus (or foci) having stimula- and small animal models [17]. Although it is difficult to tory potentials. In addition, acoustic reverberation [52] be ascertained for the causes to these phenomena, we may also obscure the stimulation boundaries when mul- hypothesized that the differential stimulatory sensitivity tiple sonication beams are given proximal to each other. of the targeted neural substrates to the sonication may As these may confound stimulatory effects, caution is have contributed to the variability, which warrants fur- necessary when one aims to selectively simulate multi- ther investigations. Interestingly, the presence of inter- ple brain regions. Also, accompanying acoustic simula- subject variability in terms of responsiveness has been tions and corrective measures would help to reduce these documented in studies of other brain stimulation modali- confounders. ties such as TMS [44]. The neurostimulatory effects of FUS were transient We acknowledge that subjective measures on tactile and reversible, and the sonication procedure did not sensations may be confounded by the individual’s atten- cause any adverse changes or discomforts in the mental/ tion to certain areas of the body [45, 46]. We attempted physical status across all subjects. Considering the aver- to address the attention-related sensations by blinding age acoustic transmission rate of 20–25 % at the intended the participants on the nature of the stimulation (they targets [20] and a 50  % duty cycle, it is estimated that 2 2 were not expecting any sensations to begin with). Yet, 7.0–8.8  W/cm I , corresponding to 3.5–4.4  W/cm sppa the participants were able to identify the nature of the I , was provided to the regional brain location. This spta sensation (i.e., tactile) from the hand that was contralat- estimated intensity range is slightly higher than the eral to the sonication. Due to the subtle and often unu- international electrotechnical commission (IEC) 60601 sual sensations (such as transient tingling and numbing part 2 standard for therapeutic equipment limit of 3 W/ sensations that disappear quickly upon each stimulatory cm I [53]. Based on our past experience with sheep spta events), unbiased characterization of the tactile sensa- [21], as long as an excessive amount of stimulation is tions still poses as a challenging task [47]. More objec- avoided, the intensity up to 13.4  W/cm I (in situ) sppa tive measures that are synchronized with the sonication does not cause any microscopic damage to the brain. timing, supported by the detection and characterization However, this does not allow for the general application of the sensory evoked EEG potentials [20] in conjunc- of the given parameters to human subjects and demands tion with randomized stimulation timing, may be used to great caution when using higher acoustic intensity (and strengthen the reliability of our findings. The use of well- accompanying higher mechanical index (MI), while the designed sham/control condition will also be important current safety limit is set to 1.9 [53]). We estimated the for reducing the potential bias from the attention-related potential thermal increase (ΔT) at the sonicated region tactile illusion. of the brain by using the equation ΔT  =  2αIt/ρ C b p −1 2 Use of the FUS technique allowed for simultaneous [54]  =  2  ×  0.005  cm   ×  7.0  W/cm   ×  0.5  s/3.811  J/ stimulation of ipsilateral SI and SII that are close to each cm   °C; where α  =  absorption coefficient [55], Lee et al. BMC Neurosci (2016) 17:68 Page 10 of 11 Author details I  =  effective acoustic intensity (I ) in the focal region spta Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, considering the maximal transcranial acoustic transmis- Republic of Korea. Department of Radiology, Brigham and Women’s Hospital, sion of 40 % [20], t = sonication duration, ρ  = density of Harvard Medical School, Boston, MA, USA. the brain tissue [56], and C  = specific heat of the brain Acknowledgements tissue [56]. The estimated ΔT was 0.0092  °C, which was Authors thank Mr. Matthew Marzelli for editorial assistance and Dr. Hyungmin far below the thermal threshold that can derive either Kim for his technical help in preparing image‑ guidance software. neurostimulatory effects or tissue damage [57, 58]. Competing interests Along with promising safety data, the capability of FUS The authors declare that they have no competing interests. to selectively stimulate multiple brain regions, including Availability of data and materials those proximal to each other (such as ipsilateral SI and All datasets on which the conclusions of the manuscript rely were presented SII), would pave a new non-invasive way to study func- in the main paper and additional supplementary files. tional connectivity among neural substrates. Further Consent for publication studies employing fMRI for the assessment of network- All participants submitted written consent for publication including individual level activations in the brain during FUS neuromodu- person’s data in anonymized form. lation may help to reveal the causal relations between Ethics approval and consent to participate the region-specific brain functions of the stimulated This research was performed under the approval of the Institutional Review neural substrates and the elicited cognitive/behavioral Board (IRB) of Incheon St. Mary’s Hospital, the Catholic University of Korea, in responses. The potential impact of FUS as a functional accordance with the ethical guidelines set forth by the IRB. All participants submitted written consent prior to enrollment in the study. neuromodulation method awaits further evaluation across various disciplines from basic scientific studies to Funding clinical applications. 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Published: Oct 26, 2016

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