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StartNeuroscienceFrontiers | An Optimized Miniaturized Ultrasound Transducer for Transcranial Neuromodulation

Frontiers | An Optimized Miniaturized Ultrasound Transducer for Transcranial Neuromodulation


Introduction

Neuromodulation know-how is key to purposes such because the probe of the nervous system and treating neurological issues (Miniussi and Vallar, 2011; Kar and Sarkar, 2016). The out there neuromodulation strategies comparable to deep mind stimulation, transcranial magnetic stimulation, and the newly developed optogenetics for preclinical use are both invasive or lack satisfying spatiotemporal decision. Alternatively, transcranial ultrasound stimulation (TUS), enabling non-invasive neuromodulation with some great benefits of non-invasive (Hariz, 2013; Panczykowski et al., 2014; Baek et al., 2017; Li et al., 2018), excessive spatial decision, and excessive penetration depth, has been thought of a subsequent technology know-how for probing human mind capabilities and treating dysfunctions (Yamaoka et al., 2011; Mead et al., 2017; Guo et al., 2021). Nevertheless, since it’s nonetheless in its toddler levels, preclinical research in small animals are required to determine the elemental mechanisms and optimum parameters for treating mind dysfunction fashions.

In preclinical fashions, it has been proven that TUS can be utilized to deal with varied mind illnesses together with Parkinson’s illnesses, Alzheimer’s illnesses, and habit (Yang Y. et al., 2021). However, sonogenetics facilitates the non-invasive dissection of neural circuits in mouse brains. In small animal research, anesthesia stage is difficult to manage, which may carry further confound to the research as a number of outcomes demonstrated that the consequences of ultrasound stimulation are strongly depending on the extent of anesthesia, which may have an effect on the reliability of experimental outcomes (King et al., 2013; Lee et al., 2016). Using extra miniature transducers mounting on the cranium is a possible answer to keep away from the operation of anesthesia and immobilization. Nevertheless, a small measurement transducer (sub-MHz) is all the time accompanied by low acoustic vitality and spatial decision (Zhang et al., 2020), so acceptable stimulation circumstances and strategies for converging acoustic vitality change into the important issue of neuromodulation.

With the event of neural regulation know-how, industrial planar ultrasonic transducers regularly can not meet the exact neural regulation. Lately, some research have used targeted ultrasonic transducers to enhance accuracy (Yoo et al., 2011; Deffieux et al., 2013; Kim et al., 2014). On this examine, we proposed a transducer that each has a small wearable measurement and a half-concave construction to converge acoustic vitality, as proven in Determine 1. The half-concave construction was made by the dimple grinder. The finite component simulation software program PZFlex was used to design and analyze the only component ultrasonic transducer with completely different dimpling curvatures. Muscle exercise in mice was induced by ultrasonic transducers with completely different constructions. The outcomes point out that the half-concave ultrasonic transducer can obtain simpler convergence of sound vitality and make extra acoustic vitality transmit by the cranium when in comparison with the aircraft transducer, which ends up in the next success price.


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Determine 1. Schematic diagram of the neural regulation course of.

Strategies and Outcomes

The characterization of fabric properties is the primary and significant step within the design of units as a result of the piezoelectric dielectric properties of supplies will instantly have an effect on the ultimate efficiency of the machine, which is why students have studied it extensively over the previous years (Kuzenko, 2021; Yang L. et al., 2021). A number of sorts of literature have identified that the vitality transmission effectivity is increased when the ultrasonic stimulation frequency is decrease than 1 MHz (Hayner and Hynynen, 2001; White et al., 2006), so it’s appropriate to review the acoustic traits of ultrasonic transducers with completely different constructions at 400 kHz. Because of the impedance matching, the diameter of the piezoelectric component of a standard 400 kHz transducer is way increased than 85 mm. Inversely, the diameter of the half-concave transducer is simply 5 mm, and the piezoelectric component is 2 mm in thickness. Due to this fact, a miniaturized machine is designed by half-concave structural optimization. {The electrical} impedance and the part plots of the piezoelectric component have been measured utilizing the WK6500B 1J65120B impedance analyzer (Wayne Kerr Electronics, United Kingdom), as proven in Determine 2.


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Determine 2. Electrical impedance and part plots of pic255.

As proven in Determine 2, the measurement plot of the planar piezoelectric signifies that there are quite a lot of resonance peaks, and with the intention to additional decide the excitation frequency for subsequent experiments, the spectrum of various curvatures was simulated with the assistance of finite component simulation. Within the simulation outcomes of the piezoelectric component in Determine 3, it’s seen that there’s a resonance frequency close to 1 MHz, however with the change of curvature, the resonant peak has a sure deviation, however at 400 kHz, resonance coincidence is healthier.


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Determine 3. The impedances of various curvatures of piezoelectric component.

The finite component simulation has been proved to be an environment friendly simulation technique by many earlier research (Hou et al., 2021; Li et al., 2021b; Lin et al., 2021). On this examine, the finite component simulation mannequin was established to design the half-concave construction and simulate the efficiency of the half-concave ultrasonic transducer with the software program PZFlex and Comsol. All supplies used on this simulation are listed in Desk 1.


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Desk 1. Supplies utilized in simulation.

The simulation parameters are as follows. The thickness of the backing materials is ready to six mm in case of backpropagation. Mixed with the limitation of the particular manufacturing course of, the dimpling curvature of the half-concave ultrasonic transducer was elevated from 5 to 7.5 mm at equal intervals of 0.5 mm. In addition to, an insulating epoxy that surrounds the piezoelectric materials is 0.4 mm in width to make the situation of simulation per the experiment. Throughout the simulation, the ultrasonic transducer is happy by one cycle of sinusoidal sign with a frequency of 400 kHz and a driving voltage of 1 V peak-to-peak. Figures 4A,B present the construction diagram of the aircraft ultrasonic transducer and the half-concave ultrasonic transducer in simulation, respectively. The blue half represents the epoxy that acted because the backing layer and the insulating, and the purple half represents the piezoelectric materials, and a reflecting plate is positioned on the finish of the water physique, which is taken into account because the focal space.


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Determine 4. Simulation construction: (A) The half-concave ultrasonic transducer and (B). The aircraft ultrasonic transducer.

Underneath the above parameters, a normalized emission sound discipline is obtained by MATLAB processing, as proven in Determine 5. Because of the excitation frequency, the wavelength of the emitted sound wave is just like the scale of the transducer, so the transducer will be thought to be a degree supply, and the acoustic wavefront is just like the spherical wave (Crew et al., 1900; Simon et al., 2015). The utmost acoustic stress knowledge obtained from the emission acoustic discipline are listed in Desk 2. It may be seen that the distinction within the most acoustic stress between the transducers with completely different radii of dimpling curvature is slight, however the most acoustic stress of the half-concave ultrasonic transducer is barely bigger than that of the aircraft transducer, and the world with increased vitality within the acoustic discipline can also be bigger than that of the aircraft transducer, which demonstrates that half-concave transducer can successfully converge the sound vitality and is extra helpful to the neuromodulation of small animals.


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Determine 5. Emission acoustic discipline within the simulation.


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Desk 2. Most acoustic stress.

Primarily based on the simulation outcomes, subsequent experiments have been carried out. The manufacturing technique of the half-concave construction and the construction diagram of the dimpled ultrasonic transducer are proven in Figures 6A,B. Because the piezoelectric materials, the piezoelectric ceramic pic255 with double-side silver electrodes was ready upfront. Then one aspect of the pic255 piezoelectric ceramics was dimpled to a half-concave construction by the dimple grinder (model656, Gatan), and a 0.9 mm diameter lead was hooked up to the bottom of the dimpled utilizing conductive epoxy e-solder 3022 (VonRoll Isola, New Haven, CT). After that, the piezoelectric materials was positioned on the middle of the brass housing, after which the housing was stuffed with insulating epoxy (EPO-TEK 301) to behave as each a backing and an insulating layer. After epoxy curing, a layer of gold (∼200 μm) was sputtered on the dimpled aspect to behave because the entrance electrode, and subsequently, a skinny layer of parylene (∼1.5 μm) was vapor-deposited by a PDS 2010 Labcoator (Specialty Coating Techniques, Indianapolis, IN) to guard the ultrasonic transducer. Lastly, an SMA connector was hooked up to the ultrasonic transducer. The dimpled piezoelectric ceramic pic255 and the packaged ultrasonic transducer are proven in Figures 6C,D, respectively. In addition to, a aircraft transducer was fabricated because the management group.


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Determine 6. (A) Manufacture technique of dimpling, (B) the construction diagram of the half-concave ultrasonic transducer, (C) dimpled pic255 piezoelectric ceramic, and (D) the packaged ultrasonic transducers.

The laboratory multi-function ultrasonic testing system primarily based on LabView software program was a excessive precision check platform (Li et al., 2021a,c). Primarily based on the platform, the emission acoustic fields of ultrasonic transducers with completely different constructions have been measured at 400 kHz. In deionized water, the transducer was positioned reverse a needle hydrophone (NH0200, Precision Acoustics, Dorchester, United Kingdom). Moreover, the acoustic stress was measured within the vary of 4 mm2 × 5 mm2 within the axial aircraft of the transducer. Then it was used to get the normalized emission acoustic discipline with MATLAB software program, as proven in Determine 7. It may be seen that the emission acoustic fields of various constructions of ultrasonic transducers are comparable, and the distinction within the most acoustic stress is slight within the experiment, which is principally per the simulation outcomes.


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Determine 7. Emission acoustic discipline within the experiment.

Nevertheless, in organic purposes, it’s not complete to contemplate solely the emission acoustic discipline of ultrasonic transducers in water. To be able to additional show the flexibility of the half-concave ultrasonic transducer to hold out organic experiments, a cranium with a thickness of 0.5 mm was positioned in entrance of the transducer, and the finite component simulation software program PZFlex was additionally used to review the acoustic discipline distribution after transmitting by the cranium. All fashions have been set in water. The simulation mannequin of the cranium with a radius of curvature of 9 mm appressed to the floor of the transducer was established, and the relative place of the cranium and the transducer is proven in Determine 8D, during which the fitting inset exhibits the cranium appressed to piezoelectric materials of various transducers. MATLAB software program was used to course of the acoustic discipline knowledge after transmitting it by the cranium. The normalized acoustic discipline was obtained as proven in Figures 8A,B. The purple sprint line exhibits the –6 dB line within the acoustic stress distribution and the normalized lateral acoustic discipline distribution of various transducers at most acoustic stress level is proven in Determine 8C, which exhibits the world with increased acoustic discipline vitality can fall within the mind space that wants neuromodulation so far as potential. The utmost acoustic stress is proven in Desk 3.


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Determine 8. (A) Normalized acoustic discipline after transmitting by the cranium by simulation. (B) Normalized lateral acoustic discipline distribution of various transducers by simulation at a most acoustic stress level. (C) The normalized acoustic stress distribution of the focal space within the X-Y aircraft. (D) The relative place of the cranium and completely different transducers.


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Desk 3. The utmost acoustic stress of three transducers varieties.

It may be seen that the dimpling construction permits extra vitality to transmit by the cranium, and the utmost acoustic stress of the half-concave ultrasonic transducer is elevated by about 20% in contrast with the aircraft transducer. The dimpling depth is bigger, and the utmost acoustic stress is bigger. The larger dimpling depth achieves the larger focus impact which exhibits the upper decision and close to focus depth. So, the efficient focus and quick transmission distance can obtain increased sound vitality. In abstract, the half-concave construction can converge acoustic vitality, and the curvature of the half-concave ultrasonic transducer is extra appropriate for the pinnacle of small animals. Completely different ultrasonic transducers have been used to induce muscle exercise in mice to confirm the organic utility worth of the half-concave construction.

To additional reveal the neuromodulation results by utilizing the miniaturized transducers, we stimulated the mouse mind with these transducers and monitored the motor responses decided by electromyography (EMG). The EMG recording procedures have been just like earlier work (Qiu et al., 2021). Briefly, mice underwent anesthetic induction with 3% isoflurane in 100% oxygen and have been maintained on 0.6% isoflurane for TUS. Eye ointments have been utilized to each eyes. Two 32-gauge enamel-coated copper electrodes have been inserted into the triceps muscle tissue of each forelimbs. After the attachment of all leads, the US transducer was mounted to a three-axis positioning system. Ultrasound gel was used to couple the transducer to the pinnacle of the mouse. For all experiments, the transducer was positioned roughly 1 mm from the floor of the animal’s head, focusing on the first motor cortex as proven in Determine 9A. A warmth lamp distant from the experiment desk was used to maintain the animal heat. All of the stimulation and recordings have been completed inside 5 min. After every mouse experiment, the EMG leads have been eliminated, and the mouse was transferred to an induction chamber for restoration after which returned to its cage. The EMG indicators have been amplified with a acquire of 1,000, and the bandpass was filtered between 10 Hz and 1 kHz with a preamplifier (World Precision Devices, Sarasota, FL, United States). Information have been acquired at a 2 kHz sampling price (Lab-Jack U3, LabJack, Lakewood, CO, United States). The sonication parameters (PRF 1 kHz, 40% responsibility cycle, 200 ms) have been managed by a pc operating software program written in MATLAB (Mathworks, Natick, MA, United States). As proven in Determine 9B, The miniaturized transducers can induce EMG responses in mice experiments. The targeted transducers resulted in the next success price in comparison with the flat transducer. The EMG indicators have been post-processed and analyzed utilizing further software program written in MATLAB. For every trial, the DC drift was eliminated with a ten Hz Butterworth IIR filter, adopted by a notch filter for line frequency (60 Hz) removing. The sign was then full-wave rectified and smoothed with a 15-point shifting common filter. A sign was thought of consultant of a muscle contraction if two circumstances have been met: First, the smoothed EMG sign exceeded a contraction threshold, outlined as 6 SDs of the sign 100 ms earlier than sonication plus the imply of the sign throughout this era. Second, the smoothed EMG sign exceeded the contraction threshold inside a temporal latency of lower than 200 ms. The consultant responses was proven in Determine 9C. The response was then calculated for every set of ultrasound indicators as a hit price outlined because the variety of responses divided by the whole variety of sonications. As proven in Determine 9D, the stimulation success charges have been (32 ± 10)%, (65 ± 8)%, and (84 ± 7)%, respectively, by utilizing flat, #7, and #5 transducers. The response latencies (Determine 9E) confirmed a lowering development, however there isn’t any vital distinction. These outcomes have been anticipated as these transducers have completely different ultrasound intensities transmitted by the cranium, as proven in Determine 9.


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Determine 9. (A) Schematic diagram of in vivo mouse EMG recordings utilizing ultrasound neuromodulation to the motor cortex. (B) Instance sync pulses (orange) and EMG responses (blue) ensuing from sonication with sham, flat transducer, targeted transducer #7.5, and #5 at 1.6 MPa. (C) Consultant EMG indicators induced by a single trial, zooming from (B). (D) The success price of ultrasound evoked responses and the response latencies (E) sonicated by sham, flat, targeted transducer #7.5, and #5 (N = 6, 20 trials/animal, *p < 0.05, **p < 0.01, one-way ANOVA with post-hoc Tukey check. All statistically vital variations are proven).

Conclusion

On this examine, a brand new construction of the miniaturized ultrasonic transducer was proposed for neuromodulation, and one aspect of the piezoelectric materials was dimpled to kind the half-concave construction. Each simulated and experimental emission acoustic fields present that the half-concave construction converges the acoustic vitality in order that the upper vitality areas of the sound discipline fall in mind areas the place neuromodulation is required, which might result in simpler neuromodulation. In addition to, the scale of the half-concave ultrasonic transducer is smaller than most transducers in neuromodulation-related articles, which makes the organic experiment extra versatile. To confirm the validity of the design, completely different transducers have been used to induce muscle exercise in mice, and the consequence exhibits the half-concave ultrasonic transducer led to the next success price. Utilizing the fabricated transducer with flat, #7, and #5, the stimulation success charges have been (32 ± 10)%, (65 ± 8)%, and (84 ± 7)%, respectively. All outcomes point out the analysis on the half-concave construction may promote the event of neuromodulation.

Information Availability Assertion

The unique contributions introduced on this examine are included within the article/supplementary materials, additional inquiries will be directed to the corresponding writer/s.

Ethics Assertion

All animal experiments have been authorized by the Animal Topics Ethics 7 Sub-Committee (ASESC) of the Hong Kong Polytechnic College. Animal use and eight care have been carried out following the rules of the Division of Well being—Animals 9 (Management of Experiments) of the Hong Kong SAR authorities.

Creator Contributions

CH, YW, and XS: drafting and refining the manuscript. ZL and CZ: conducting of the experiment and simulation. CF, ZQ, and YY: important studying of the manuscript. All authors have learn and authorized the manuscript.

Funding

This examine was supported by the Nationwide Pure Science Basis of China (No. 61974110), the Key Tasks of Nationwide Protection Primary Analysis Program of Nationwide Protection Science and Trade Administration (No. JCKY2019210B003), the Shaanxi Provincial Affiliation of Science and Know-how Younger Skills Help Undertaking (No. 20190105), the Pure Science Basis of Shaanxi Province (No. 2021JM-253), and Particular Fund for Science and Know-how Innovation Technique of Guangdong Province (No. 2021B090905000).

Battle of Curiosity

The authors declare that the analysis was performed within the absence of any industrial or monetary relationships that could possibly be construed as a possible battle of curiosity.

Writer’s Word

All claims expressed on this article are solely these of the authors and don’t essentially characterize these of their affiliated organizations, or these of the writer, the editors and the reviewers. Any product which may be evaluated on this article, or declare which may be made by its producer, shouldn’t be assured or endorsed by the writer.

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