Developing a Head-Attached Interface Device for Closed-Loop

Transcranial Ultrasound Stimulation in the Mouse Brain

Ryo Furukawa

, Shuichi Murakami

and Takashi Tateno

Bioengineering and Bioinformatics, Graduate School of Information Science and Technology, Hokkaido University,

Kita 14, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0814, Japan

Osaka Research Institute of Industrial Science and Technology, 2-7-1, Ayumino, Izumi, Osaka, 594-1157, Japan

Bioengineering and Bioinformatics, Faculty of Information Science and Technology, Hokkaido University, Kita 14,

Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0814, Japan

Keywords: Closed-Loop System, Event-Related Potential, Micromachined Transducer, Transcranial Ultrasound Stimulation,

Wearable Device.

Abstract: Transcranial ultrasound stimulation (TUS), which can be used to noninvasively stimulate local and deep brain

areas, holds significant promise for clinical applications. However, TUS apparatus is typically constructed

with several components, including a relatively large single-element ultrasound (US) transducer, a waveguide,

and a driving source. These components pose challenges when conducting experiments with freely moving

small animals, especially in the context of wearable devices. Additionally, conventional open-loop stimulation

systems do not allow for the simultaneous monitoring of neural activity, which can sometimes result in the

overactivation of neural responses. In this study, we developed a head-mounted piezoelectric micromachined

ultrasound transducer (PMUT) array with integrated monitoring electrodes to serve as a TUS interface for

mice. To determine effective array patterns for optimal US beam profiles, we first conducted beamforming

simulations. We then microfabricated the PMUT arrays according to the results of these simulations.

Subsequently, we performed electroencephalographic (EEG) recordings to evaluate the potential of TUS in

mice while simultaneously monitoring neural activities. Finally, we discuss future applications of a closed-

loop TUS system in the treatment of brain diseases.

1 INTRODUCTION

Neuromodulation has been utilized as a clinical tool

for treating brain disorders (Davidson et al., 2024;

Mattioli et al., 2024). However, conventional

neuromodulation techniques, including

electromagnetic stimulation, face challenges related

to spatial resolution, invasiveness, and effective

transmission to deep brain regions (Rezayat &

Toostani, 2016).

Transcranial ultrasound stimulation holds

promise for clinical applications owing to its low or

non-invasive nature, high spatial resolution, and

ability to transmit mechanical vibrations into the

brain to induce neuromodulation (Tufail et al., 2010).

Recently, miniaturized devices based on

https://orcid.org/0000-0001-8920-1025

https://orcid.org/0000-0002-8862-8446

https://orcid.org/0000-0001-9429-9880

microelectromechanical system (MEMS) technology

have been reported for the purpose of ultrasound (US)

neuromodulation (Jo et al., 2019). However, because

the conventional transcranial ultrasound stimulation

(TUS) devices used in animals are specialized for

brain stimulation itself, simultaneously monitoring

neural activity driven by these devices requires

separate recording systems from the stimulation

devices (H. Kim et al., 2019; Zhou et al., 2019).

Therefore, the integration of stimulation and

recording devices is beneficial for realizing an on-

demand stimulation paradigm, which would enable

brain stimulation as needed for short periods without

causing overstimulation. More specifically, deep

brain stimulation (DBS) is utilized as one of the

symptomatic treatments for Parkinson’s disease and

Furukawa, R., Murakami, S. and Tateno, T.

Developing a Head-Attached Interface Device for Closed-Loop Transcranial Ultrasound Stimulation in the Mouse Brain.

DOI: 10.5220/0013082900003911

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 18th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2025) - Volume 1, pages 17-25

ISBN: 978-989-758-731-3; ISSN: 2184-4305

has demonstrated clinical efficacy in alleviating

symptoms (Okun, 2012). Currently, DBS systems are

commonly implemented using an open-loop

configuration; however, this approach has associated

with side effects, including the induction of neural

hyperactivity. To address these challenges, a closed-

loop DBS system that monitors neural activity and

adaptively delivers stimulation as needed is being

explored as a promising solution (Little et al., 2016).

Conventional TUS devices are open-loop

stimulators, which can sometimes induce excessive

neural activity, whereas the on-demand stimulation

paradigm requires a closed-loop stimulation system

(Takeuchi & Berényi, 2020). Although several

studies have reported methods for closed-loop TUS

systems (Jo et al., 2022; Xie et al., 2022), in these

studies, the stimulator and monitoring electrodes

were not packaged together as one device. For future

applications for chronic conditions in small animal

models such as rodents, small-sized systems using an

integrated device are desired.

Here, we describe our development of a head-

attached interface device for TUS applied to mice in

a closed-loop manner. This paper primarily describes:

(i) the design of a closed-loop TUS device, (ii) a

fabrication method to realize this design, and (iii) a

demonstration of the device’s usefulness by

analyzing electroencephalographic (EEG) data

recorded from a mouse head through the incorporated

monitoring electrodes. First, we describe the design

of a piezoelectric micromachined ultrasound

transducer (PMUT) combined with monitoring

electrodes. Second, we explain our detailed

microfabrication method. Third, we present EEG

recordings to examine whether the head-attached

device could be used for monitoring neural activities.

Finally, we discuss future applications of a wearable

closed-loop TUS system for the treatment of human

brain diseases.

2 METHODS

2.1 Design

To achieve TUS in a mouse brain, we aimed to

develop a PMUT with several diaphragms, the design

and structure of which were based on a previous study

(Furukawa et al., 2024). The PMUT is designed to

meet the following three conditions: (i) a resonant

frequency of 500 kHz for each diaphragm, (ii)

ultrasound pressure generated by mechanical

oscillations greater than 100 kPa, and (iii) a focal

length of over 5 mm (Yuan et al., 2021). Additionally,

microelectrodes (200 × 200 μm) were designed on the

back side of the PMUT to monitor EEG signals from

a mouse. The size of the microelectrodes was

determined on the basis of a previous report that

demonstrated low electrode impedance with the same

size and materials (Furukawa et al., 2024).

The structure of the PMUT is similar to that of a

previously reported device (Furukawa et al., 2024),

and consists of the following five components: (1) a

lead zirconate titanate (PZT) plate, (2) a silicon (Si)

layer, (3) an SiO₂ membrane, (4) top and bottom Pt/Ti

electrodes, and (5) an Si supporting layer. To operate

the diaphragm as a transducer and generate acoustic

pressure, a thin film of piezoelectric material was

used to convert electrical (voltage) signals into

ultrasound pressure changes. To obtain a thin

diaphragm that could function as a vibrating plate,

circular openings were designed from the rear side of

the supportive Si substrate.

Before fabricating the device, we numerically

simulated the vibrations of diaphragms in the PMUT

using general-purpose physics simulation software

(COMSOL Multiphysics, Ver. 6.2, COMSOL AB,

Sweden) on a supercomputer system (PRIMERGY

CX400/CX2550, FUJITSU, Japan) at the Hokkaido

University Computer Centre. Using the finite element

method (FEM) in this simulation software, we

calculated the primary resonant frequency, targeting

500 kHz, and determined the required sizes for the

PMUT.

Next, to explore the effective design of a US array

for TUS within a restricted area (10 × 10 mm), we

conducted a beamforming simulation with two

variable parameters with the aim of achieving target

acoustic pressures and focal length: (i) the distance

between the centers of diaphragms (d) ranging from

1 to 2 mm in 0.5-mm steps; and (ii) the excitation time

delay (Δt) ranging from 0 to 1.8 μs in 0.2-μs steps

(Fig. 1A) when used as a phased array system. The

excitation time delay was used to steer the US beam.

For this numerical simulation, the combinations of

the distance d and the total number of diaphragms

(cells) in individual PMUTs for our explored design

are summarized in Table 1.

Table 1: Design of the PMUT phased array used in the

beamforming simulation.

d (mm) Total cell numbe

1.0 25

1.5 17

2.0 17

In our simulation, for the acoustic pressure p

, the

wave equation is described as:

BIODEVICES 2025 - 18th International Conference on Biomedical Electronics and Devices

Figure 1: The design of a wearable PMUT phased array for closed-loop TUS. (A) Overall patterns of the PMUT design (left

view) and an enlarged view of the centre part (right panel). Gold lines, squares, and circles represent the upper electrodes and

their pads used to drive the transducer. Green squares are contact holes of the bottom electrode. Blue small and large squares

are microelectrodes and their pads used to acquire EEG signals from mice. (B) (a) Schematic of the head-attached type PMUT.

A surgically fixed bottom frame and removable top frame hold the PMUT. (b) Image of the fully packaged PMUT device.

∇∙

𝜌



∇𝑝



𝐪







𝑘



𝑝



𝜌

𝑄



(1)

𝑘







2𝜋𝑓

𝑐





(2)

where 𝜌 is the density of the medium, c is the speed

of sound, f is the driving US frequency, parameter q

is the dipole domain source (which represents a

domain volumetric force), and Q

is the monopole

domain source for a uniform strength in all directions.

Several PMUTs have recently been reported

for neuromodulation in rodents. A 1D-array PMUT

with a 275-μm radius for each diaphragm was

reported, with a single transducer generating 67.3 kPa

with an applied voltage of 66 V (Lee et al., 2019; Oh

et al., 2019). A 2D-array PMUT with a 580-μm radius

for each diaphragm was also reported, for which a

single transducer generated 65.6 ± 1.8 kPa with an

applied voltage of 70 V (Furukawa et al., 2024). In

these previous reports, the acoustic pressures were all

measured at a distance of approximately 1 mm away

from the devices. Therefore, in the structural model

of our simulation, we determined 60 kPa at 1 mm

from each diaphragm to be the desired acoustic

pressure value generated (i.e., 1.25 MPa).

2.2 Microfabrication and Packaging

Our microfabrication process was based on a previous

report on the standard MEMS technology (Kuwano et

al., 2020). The initial substrate was a silicon-on-

insulator (SOI) wafer consisting of the following

three layers: a device layer (Si, 15 μm), an insulating

Developing a Head-Attached Interface Device for Closed-Loop Transcranial Ultrasound Stimulation in the Mouse Brain

membrane (SiO

, 1 μm), and a handle layer (Si, 500

μm) with a 1-μm thermal-oxidized SiO

layer.

Briefly, our microfabrication process was as follows:

1. To form the microelectrode, a layer

consisting of a 100-nm-thick Pt coating and

a 10-nm-thick Ti coating was deposited on

the back side of the substrate using a

sputtering system (RSC-3ERD, Riken-sha

Co., Japan).

2. Subsequently, the recording electrodes and

their wires were patterned on the back side

by photolithography using an inductively

coupled plasma reactive ion etching (ICP-

RIE) system (RIE-101HU, SUMCO Co.,

Japan).

3. Next, the protective film (TMMR 2000SV,

TOKYO OHKA KOGYO CO., LTD.) for

the wires was formed on the bottom side.

4. A contact hole to expose the bottom

electrode of the PMUT was formed on the

front side of the substrate using a Deep-RIE

instrument (MUC-21 ASE-SRE, SPP

Technologies Co., Japan).

5. A PZT plate with a thickness of 100 μm (PI

Japan) was attached to the front side of the

SOI substrate with an epoxy adhesive (E205,

Konishi Co., Ltd.).

6. The thickness of the PZT plate was reduced

to 40 μm by using a griding machine

(Mechatec300 SPC, Kitagawa GRESTECH

Co., Ltd.).

7. In order to form the top electrodes of the

PZT and their lead wires, a layer consisting

of a 100-nm-thick Pt coating and a 10-nm-

thick Ti coating was deposited using a

sputtering system, and was patterned using a

lift-off technique.

8. To create the diaphragm shape, the Si handle

layer was removed from the back side using

a Deep-RIE instrument (MUC-21 ASE-

SRE, SPP Technologies Co., Japan).

After the process, the fabricated PMUT device

was packaged with the flexible printed circuit board

(Fig. 1B).

2.3 Measuring Event-Related

Potentials

2.3.1 Surgical Procedure

In this study, all animal experiments were carried out

in accordance with the NIH Guide for the Care and

Use of Laboratory Animals and with approval from

the International Animal Care and Use Committee of

Hokkaido University. For the animal experiments,

two female and one male C57BL/6J mice (Japan

SLC, Japan; 7 to 8 weeks old) were used.

Intraperitoneal injections of a mixture of

medetomidine (0.3 mg/kg), midazolam (4.0 mg/kg),

and butorphanol (5.0 mg/kg) were used to initiate

anesthesia, and anesthesia levels were confirmed by

the level of response when pinching the leg

(Yoshikawa et al., 2023).

The fur on top of the skull was gently removed,

then the scalp was carefully excised to expose the

skull. The custom-made 3D-printed bottom frame (20

× 40 mm; the center was positioned at the lambda)

was attached to hold the packaged PMUT by

sandwiching it with the top frame (Fig. 1B). The gap

between the PMUT and skull was filled with US gel.

2.3.2 Signal Recording and Sound Stimuli

The sensing microelectrodes were examined to detect

neural activities in extracellular field potentials

through EEG recordings. Pure-tone burst sounds

(frequencies: 2, 4, 8, 16, and 32 kHz; sound intensity:

80 dB sound pressure level [SPL]; duration: 100 ms)

were used to record the sound event-related potentials

(ERPs) in response to the acoustic stimulation. We

used linearly increasing onset and decreasing offset

stimulus envelopes set at 10% of the total duration of

each stimulus. Sound stimuli were presented via a

speaker (MF1; Tucker-Davis Technologies). The

EEG signals were recorded at a sampling rate of 1

kHz. Fifty trials were conducted under the same

conditions.

2.4 Data Analysis

All statistical analyses were performed using order

statistics without assuming a specific distribution,

employing non-parametric statistical methods. EEG

data were compared using the Wilcoxon signed-rank

test with Python (Ver. 3.12.1). The statistical analyses

were conducted for data acquired at two channels

(Chs 4 and 6) located at the inferior colliculus (IC).

We defined the baseline amplitude as the averaged

pre-stimulus peak amplitude before the stimulation

onset. In contrast, an ERP amplitude for 0.5 s after the

onset of a stimulus was defined as the post-stimulus

peak amplitude.

BIODEVICES 2025 - 18th International Conference on Biomedical Electronics and Devices

Figure 2: Simulated US beam profiles of the PMUT phased array. The distance (d) is represented in the right panel of Fig.

1A.

3 RESULTS

3.1 Ultrasound Beamforming

On the basis of the results of the numerical

calculations for our PMUT structural model with a

resonant frequency of 500 kHz, we selected the

following size parameters: a diaphragm radius of 235

μm, a PZT layer thickness of 40 μm, and a Si layer

thickness of 15 μm. Subsequently, using these

determined diaphragm sizes, we conducted a

beamforming simulation of the designed PMUT (Fig.

1A), in which each diaphragm array had different

nearest distances (d) between diaphragms (d = 1.0,

1.5, and 2.0 mm) and/or different total numbers of

diaphragms (17 or 25 cells, see Table 1). For example,

for the array pattern of d = 1.0 mm and 27 diaphragms,

Fig. 2A illustrates the two-dimensional (2D; x-z field)

acoustic pressure distributions at y = 0 mm in the 3D

acoustic field, resulting in a far-field peak at over 5

mm with a peak pressure exceeding hundreds of kPa.

Moreover, with the array pattern of d = 1.5 mm (or

Developing a Head-Attached Interface Device for Closed-Loop Transcranial Ultrasound Stimulation in the Mouse Brain

Figure 3: US beam profile for the axial distance in Fig. 2.

(A) Acoustic pressure distribution with different delay

times in the array pattern of d = 1.0 mm (Fig. 2A). Each

inverted triangle marker represents a local peak under the

delay time. (B) Focal length and delay times for primary

and secondary peaks indicated in panel (A). For some delay

time conditions, no secondary peaks were detected.

2.0 mm) and 17 diaphragms, although a far-field peak

exists at approximately 5 mm in the 2D field with the

axial direction (perpendicular to the PMUT array

surface), the simulated acoustic pressures were

smaller (in the tens of kPa) compared with the array

pattern of d = 1.0 mm (Figs. 2B, C). The acoustic field

in the axial direction (i.e., z direction) for the array

pattern of d = 1.0 mm is shown in Fig. 3A. The

inverted triangle markers represent the primary or

secondary peaks (local maxima). The focal lengths

depending on the delay times (Δt) of the phased array

are summarized in Fig. 3B. We found that using a

delay time Δt of 1.0 μs, a primary peak in the acoustic

field showed a local maximum at the farthest-most

field. This result suggests that using the delay time

(e.g., Δt = 0.6 μs for the surface or Δt = 1.4 μs for the

center) and a 70-V input voltage to the PMUT, the US

beam generated by the array of d = 1.0 mm can reach

a brain target within a range from the surface to the

center of a mouse brain.

3.2 Packaging of the Wearable PMUT

We successfully microfabricated the PMUT phased

array and integrated it with a custom-made flexible

printed circuit (FPC). The total weight of the

packaged device, including the head frames, PMUT,

FPC, and any other components, was 1.40 g.

3.3 Event-Related Potentials

To examine the device’s ability to detect neural

activity from EEG signals, we conducted ERP

recordings in response to sound stimulation. The

schematic for the EEG recordings with six monitoring

electrodes (Chs 1 to 6) is illustrated in Fig. 4A.

Additionally, a typical example of averaged

waveforms evoked by sound stimuli (4-kHz pure-

tone burst, 80 dB SPL) is shown in Fig. 4B. The

waveforms obtained from two channels (e.g., Chs 4

and 6 in Fig. 4B) located around the IC showed

negative and positive peaks after sound stimulation

onset (−4.9 μV and 6.6 μV at Ch 4 in Fig. 4B).

Furthermore, averaged waveforms obtained from Ch

4 in response to sound stimulation with different

frequencies are illustrated in Fig. 4Ca. Negative or

positive peaks after the onset of the stimulation were

observed in response to the pure-tone bursts

examined (Fig. 4Ca). In particular, ERP peaks (post-

amplitudes) larger than the corresponding baseline

amplitudes (pre-amplitudes) were detected in

response to 4- and 8-kHz pure-tone burst stimuli (*p

< 0.05, n = 6 from three animals). In contrast, no

significant differences were found between pre and

post peak amplitudes in responses to the stimuli with

2, 16, and 32 kHz.

4 DISCUSSION

The total weights of previously reported wearable

transducers for rodents were 0.765 and 20 g for rats

(E. Kim et al., 2021; H. Kim et al., 2019), and 2 g for

mice (Zhou et al., 2019). Since our developed device

has a total weight of 1.4 g, we suggest that it is

suitable for application in experiments with freely

moving mice. However, the signal generator and

driving voltage source are not included in our weight

measurement.

BIODEVICES 2025 - 18th International Conference on Biomedical Electronics and Devices

In this study, we describe the development of

a MEMS-based PMUT phased array as a wearable

TUS interface device for closed-loop stimulation. The

resonant frequency of a single element transducer was

first calculated, followed by determination of the

sizes and the structure. Subsequently, US

beamforming was simulated with 25 or 17 cells with

a variable delay time for the driving signals of the

phased array. Guided by the numerical findings, we

proceeded to design and microfabricate wearable

PMUTs featuring 25 circular diaphragms, and

incorporating six square monitoring electrodes. To

our knowledge, this is the first report of the packaging

of monitoring electrodes onto a wearable PMUT.

With regard to the results of the beamforming

simulation, we expect to be able to modulate neural

activity with the output US beam. In addition, we

suggest that the focal length can be manipulated

across a wide range of regions in the mouse brain by

adjusting the excitation delay time (Figs. 3A, B). To

experimentally confirm the simulated beam profiles,

we will measure the acoustic pressure distribution

with a needle hydrophone (Furukawa et al., 2022).

Next, we demonstrated sound-driven EEG

recordings as a step towards the future application of

a wearable closed-loop TUS system. We successfully

detected the sound ERPs with the incorporated

electrodes, and since the IC is located 2–3 mm caudal

to the lambda and 2 mm lateral to the midline, the

observed ERPs could possibly be attributed to

Figure 4: Sound ERP waveforms at six sites on the mouse skull. (A) The six recording sites on the mouse skull are illustrated

with channel numbers (Chs 1 to 6). (B) Averaged ERP waveforms in response to sound stimulation (pure-tone burst, 4 kHz,

80 dB SPL). (C) ERP waveforms recorded at (a) Ch 4 and (b) comparison between pre- and post-maximum amplitudes of the

pure-tone burst with different frequencies (*p < 0.05, n = 6 from three animals). The timings of the sound onset are represented

by vertical blue bars.

Developing a Head-Attached Interface Device for Closed-Loop Transcranial Ultrasound Stimulation in the Mouse Brain

neural activity in the IC. Lower frequencies (e.g., 4

kHz) tend to evoke neural activity in shallow laminae

in the mouse IC (Sato et al., 2024), which is consistent

with the frequency characteristic of our observed

ERPs (Figs. 4Ca, 4b).

In future applications, we plan to test this device

in closed-loop TUS as a treatment method for brain

diseases. In line with this purpose, the oscillatory

power of specific frequencies is utilized as a reliable

EEG biomarker. Further, EEG biomarkers play a

pivotal role in diagnosing and understanding

neurological disorders, including epilepsy

(Buchhalter et al., 2022; Saeedinia et al., 2024),

Alzheimer’s disease (Chetty et al., 2024; Meghdadi et

al., 2021), and psychiatric disorders (Abi-Dargham &

Horga, 2016). In future applications of our device,

EEG biomarkers could provide PMUT device uses

with invaluable data for early detection and

intervention by capturing aberrations in brain activity

characteristics.

ACKNOWLEDGEMENTS

R.F. was supported by Grant-in-Aid for JSPS Fellows

[grant number JP23KJ0047]. T.T. was supported by

supported by the Murata Science Foundation, the

Suzuken Memorial Foundation, the Nakatani

Foundation for Advancement of Measuring

Technologies in Biomedical Engineering, a Grant-in-

Aid for Exploratory Research [grant number

21K19755], and a Grant-in-Aid for Scientific

Research (B) [grant number 23H03416] (Japan). The

authors appreciate Mr. Kawakatsu for his kind advice

and support.

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