# Strengths and weaknesses of transcranial ultrasound stimulation and its promise in psychiatry: an overview of the technology and a systematic review of the clinical applications

David Attali, Maxime Daniel, Marion Plaze, Jean-François Aubry

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David Attali, Maxime Daniel, Marion Plaze, Jean-François Aubry. Strengths and weaknesses of transcranial ultrasound stimulation and its promise in psychiatry: an overview of the technology and a systematic review of the clinical applications. International Journal of Hyperthermia, 2025, 42 (1), pp.2539986. 10.1080/02656736.2025.2539986. hal-05335770

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# Strengths and weaknesses of transcranial ultrasound stimulation and its promise in psychiatry: an overview of the technology and a systematic review of the clinical applications

David Attali, Maxime Daniel, Marion Plaze & Jean-François Aubry

**To cite this article:** David Attali, Maxime Daniel, Marion Plaze & Jean-François Aubry (2025) Strengths and weaknesses of transcranial ultrasound stimulation and its promise in psychiatry: an overview of the technology and a systematic review of the clinical applications, *International Journal of Hyperthermia*, 42:1, 2539986, DOI: 10.1080/02656736.2025.2539986

**To link to this article:** https://doi.org/10.1080/02656736.2025.2539986

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# Strengths and weaknesses of transcranial ultrasound stimulation and its promise in psychiatry: an overview of the technology and a systematic review of the clinical applications

David Attali<sup>a,b#</sup>, Maxime Daniel<sup>a#</sup>, Marion Plaze<sup>b,c</sup> and Jean-François Aubry<sup>a</sup>

<sup>a</sup>Institute Physics for Medicine Paris, Inserm U1273, ESPCI Paris, PSL University, CNRS UMR 8063, Paris, France; <sup>b</sup>GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte-Anne, Paris, France; <sup>c</sup>Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, IMA-brain team, Paris, France

## ABSTRACT

This article reviews early studies that have demonstrated the ability of low intensity ultrasound waves to modulate brain activity. It also reviews the technological developments that have enabled transcranial ultrasound stimulation (TUS) to achieve millimetric spatial accuracy. This allows precise, noninvasive and reversible brain stimulation, a unique capability when compared to existing techniques such as transcranial magnetic stimulation, transcranial direct-current stimulation, and deep brain stimulation with implanted electrodes. TUS is now technologically ready for clinical translation. As psychiatric disorders have a high prevalence in the general population, and suffer from unmet noninvasive deep brain stimulation clinical needs, this article focuses on the potential application of TUS in psychiatry and reviews recently published clinical proofs of concept that have addressed depression, anxiety, schizophrenia and substance use disorders. Finally, the strengths and weaknesses of TUS technology are discussed, with reference to its clinical translation.

## ARTICLE HISTORY

Received 16 January 2025
Revised 24 June 2025
Accepted 22 July 2025

## KEYWORDS

Neuromodulation;
transcranial ultrasound
stimulation; numerical
modeling; psychiatry;
depression; addiction

## Introduction

Psychiatric disorders present a significant global health challenge, with an estimated prevalence of nearly one in five people being affected annually [1]. Major depressive disorder, bipolar disorder, anxiety disorders, substance use disorders and schizophrenia are the leading causes of disability worldwide, contributing to a substantial personal, societal and economic burden [2]. Despite advances in psychopharmacology, 20–60% of patients with psychiatric disorders are drug resistant [3]. Pharmacoresistance not only exacerbates the individual burden of illness but also leads to a substantial increase in morbidity and healthcare burden and costs, up to 10 times higher than in nonresistant patients [4,5]. These limitations of psychopharmacology highlight the urgent need for novel therapeutic approaches that can effectively address pharmacoresistance.

The treatment of these drug-resistant disorders is therefore based on non-pharmacological approaches, such as neurostimulation techniques. However, none of these are currently optimal. Electroconvulsive therapy (ECT) involves non-targeted neuromodulation. ECT is associated with remission rates of up to 80% in depression [6], but its use is partly limited by its cognitive side effects, (such as retrograde amnesia [7]), and the need for anesthesia. Repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are targeted, better tolerated, noninvasive techniques. However, these have poor spatial resolution and limited ability to stimulate deep brain regions. Deep brain stimulation with implanted electrodes (DBS) is able to precisely neuromodulate deep-seated brain areas [8–14] but

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requires invasive neurosurgery with the risk of bleeding or infection [15]. As a result, DBS is limited to a small number of patients with the most resistant and severe forms of mental disorders. This latter limitation contrasts with the incidence of drug resistance and the increasing interest in neuromodulation of the deep brain networks which are widely involved in psychiatric disorders [16,17].

Transcranial ultrasound stimulation (TUS) is an innovative treatment that allows noninvasive, precise, and focal neuromodulation of deep brain regions for the first time. This review aims to provide a comprehensive overview of the current state of ultrasound neuromodulation in psychiatry, introducing the technology, discussing its mechanisms, clinical applications, challenges, and limitations.

# Transcranial ultrasound stimulation

## Preclinical evidence

Although altering brain activity with ultrasound waves may seem futuristic, there was evidence of ultrasonic neuromodulation as early as 1950s from the Fry brothers at the University of Illinois, Urbana. They demonstrated that the transmission of ultrasound waves to the lateral geniculate nucleus could transiently suppress the induced response in the primary visual cortex in cats [18]. Nevertheless, the statement from the authors that 'the intervening skull bone must be removed' due to the defocusing effect of the skull" [19] led to Gavrilov and his colleagues from the Russian Academy of Science further investigating the effect of ultrasound stimulation in the central nervous structures of invertebrates [20]. These two pioneering teams paved the way to noninvasive ultrasound stimulation of the central nervous system. Further work aimed at reproducing the neuromodulatory effect of ultrasound in mice [21–24], rats [25–30], rabbits [31], pigs [32] or non-human primates [33–36].

In line with these studies, preclinical transcranial low intensity focused ultrasound has shown promising results in rodent models of anxiety [37] and depression [38–40].

## Mechanism of action

Many hypotheses have been put forward about the mechanisms behind ultrasound neuromodulation [41,42] and these are still being debated. The existence of an acoustic lower bound threshold for inducing the effect has even been questioned as, surprisingly, early work reported higher electromyography (EMG) responses when lower acoustic intensities were used [43]. In contrast, and shortly after this pioneering work, Younan et al. [25], Yoo et al. [31], King et al. [22], from three different international institutions, reported an acoustic intensity threshold of approximately 500mW/cm², below which no effect was observed during ultrasonic neuromodulation studies in rats. The presence of an intensity threshold is no longer in doubt; however, the specific value of this threshold for each species remains under investigation.

Thermal and mechanical effects are both prone to impacting neuronal activity. An increase in temperature raises the firing rate of temperature-sensitive neurons by a factor of 1.1 impulses per second per degree Celsius [44]. Although it is possible to take advantage of the energy deposition of ultrasound beams to increase the temperature in the brain [45], the vast majority of pre-clinical TUS studies adjust the acoustic parameters to minimize the temperature elevation to less than 0.1 °C [46], for example by decreasing the pulse repetition frequency, and/or decreasing the pulse duration. The International Transcranial Ultrasonic Stimulation Safety and Standards (ITRUSST) consortium have summarized the definitions of all the acoustic parameters, together with a checklist for reporting the methods that have been used in neuromodulation studies [47].

It has been shown that focused ultrasound can excite neurons through a primarily mechanical mechanism [48] mediated by the ultrasound-induced opening of mechano-sensitive channels on the cellular membrane [48,49] that trigger action potentials [24,48,49], without the need for cavitation, temperature changes, large-scale deformation, or synaptic transmission [48]. One last, but not least, question remains: how do mechanical ultrasound waves trigger the opening of a mechano-sensitive channel? Further understanding of the precise mechanism would facilitate further optimization of the ultrasound parameters (carrying frequency, pulse repetition frequency, amplitude, pulse duration... [47]).
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# Transcranial focusing

## Effect of the skull

For a long time, the skull has been the major obstacle to the development of ultrasonic brain therapies. Pioneering clinical studies thus resorted to a craniotomy prior to any ultrasound intervention [50]. In some cases, the scalp was sutured after the removal of skull bone to allow repeated ultrasonic interventions [51]. Such procedures were deemed necessary because of (1) the high absorption of the skull bone which induced an overheating of the skull and surrounding tissues, (2) the impedance mismatch between the skull and surrounding tissues which limits the transmission of acoustic energy inside the braincase and (3) the phase shifts induced by the skull which distort the ultrasound beam and shifts the focal spot away from the intended target [50].

Further work allowed better characterization of the acoustic properties of the skull [19,52–54]. Although the literature agrees on a linear increase in sound speed within the skull as Hounsfield Unit (HU) values from computed tomography (CT) images rise [55,56], there is little consensus regarding acoustic attenuation models [57].

The influence of the skull on ultrasonic wave propagation, including its effects on the pressure field shape and on pressure transmission, has been extensively studied and characterized [58–60]. Figure 1(a) illustrates a typical transcranial pressure field obtained with a hemispherical transducer in the absence of aberration correction. The acoustic pressure at the scalp surface is notable when compared to the pressure at the focus. This is due to two factors: the low acoustic transmission through the skull and the spread of the acoustic energy in the vicinity of the focus due to a loss of coherence of the wave front induced by the skull. Additionally, skull-induced refraction shifts the maximum of the pressure field out of the geometrical focus of the transducer. This phenomenon has been reported in various studies: a 9.3 mm shift by Cain et al. [61], up to 28 mm axially and 3.8 mm laterally by Deffieux and Konofagou [62], up to 10.1 mm by Gimeno et al. [63] and up to 9.7 mm by Mueller et al. [64], making it difficult to precisely target deep seated regions of the brain.

## Skull aberration correction

The defocusing effect of the skull discussed in the previous section can be mitigated by the use of aberration correction methods. Transcranial time-reversal, introduced in 1996 [66], leverages the time-invariance property of the wave equation through a three-step process: (1) generation of an ultrasonic wave from a source positioned at the desired brain target, (2) recording of the wave received

<figure><img src="image_18.png" /><figcaption>**Figure 1.** 3D simulation of a wave emitted from a hemispherical transducer (Insightec Exablate Neuro) through a head model. For visualization purposes the purple volumes correspond to the pressure thresholded at –12 dB. In addition, the pressure field thresholded at –3 dB was superimposed and displayed with an orange-yellow color to highlight the location of the pressure maximum. (a) With no aberration correction – all elements were driven in phase. Note that the tiny purple volumes located slightly above the focus are not inside the cranium but on the exterior of the skull and to each side. (b) With aberration correction – phases were computed using a numerical model of the head and a time-reversal simulation from a point source located at the geometric focus of the transducer [65].</figcaption></figure>
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outside the head with an array of transducer, and (3) transmission of the time-reversed wave backwards. This process enables the wave to refocus precisely at the original source location. The time-reversal operation can be replaced by time-shifting a reference signal, as demonstrated in [67]. Refinements of this technique include an amplitude compensation step to compensate not only for the phase distortion caused by the skull, but also for its attenuation [68]. Additionally, inverse filtering using a matrix-based approach has been developed to optimize the focal spot shape in the brain [69,70]. However, all the methods presented in the aforementioned papers are invasive, as they require the insertion of a single-element transducer into the brain.

Consequently, the remainder of this section will focus on minimally invasive and noninvasive techniques developed to correct skull-induced aberrations. These techniques can be categorized into two distinct approaches: (1) methods that use numerical models of the skull and simulations to estimate numerically skull aberrations, and (2) experimental methods, based on direct measurements performed with emitters and/or receivers located exclusively outside the head.

Simulations-based aberration correction techniques have first been validated experimentally using magnetic resonance images (MRI) of the skull, which only provide thickness information [71,72]. Later, these techniques were applied using computed tomography (CT) images, which allow the estimation not only of the geometry, but also of the intrinsic acoustic properties of the skull [73,74]. CT-based approaches have been implemented in clinical devices [75]. Figure 1(b) depicts the result of a 3D simulation in which phases were adjusted using a CT-based model of a head and a simulation to correct for skull aberrations. To avoid the ionizing radiations of CT, more recent studies focused on modeling the internal structure of the skull with MRI, by either innovative ultra-short time echo (UTE) sequences [76–79], or T1 sequences which are part of the clinical routine [80], some of which taking advantage of machine learning to create synthetic CT images from MR images [81–83]. From a computational point of view, skull-induced aberrations can be computed either by solving the wave equation in a heterogeneous medium using e.g., the MATLAB k-Wave toolbox [84] or BabelBrain [85], or even a ray-tracing software, which is less computationally expensive [82,86,87]. Benchmarking of different computational models is available [88].

In parallel to this modeling work, ultrasonic phased arrays have been designed to put these approaches into practice with an ever-increasing number of elements: from arrays made of 64 elements in 2000 [72], to 200 [60], 512 [89], 1024 [75] and ultimately 4096 elements in 2021 [90]. As the number of elements has increased, so has the complexity and cost of the devices. To address this, acoustic lenses were introduced as a disruptive method of correcting skull aberrations using single-element transducers [91]. Acoustic lenses were originally developed in the 1990s for simultaneous multiple hyperthermia treatments in homogeneous media [92,93]. However, these ideas were largely abandoned for nearly 20 years, until the advent of 3D printing enabled the creation of complex lenses capable of focusing complex patterns of ultrasonic waves in water [94,95], and correcting skull aberrations [91,96,97]. Recent studies aim to extend transcranial holographic techniques to target broader brain areas that cannot be targeted with a single focus [98–102] or to achieve broadband focusing for multifrequency neurostimulation [103].

Experimental methods, in contrast, do not depend on numerical models and simulations but rely solely on measurements. A proof of concept for this approach was presented by Aarnio et al. [104], who use the resonance frequencies of the skull and the wave that is reflected at each interface of the skull to estimate the phase shift induced by the skull. Another intrinsic approach, proposed for imaging applications, involves using two arrays of 128 transducers placed on each side of the skull [105]. This method involves recording the signals emitted by one of the arrays that pass through both temporal windows. A matrix-based formalism is then used to differentiate the phase shifts and attenuation caused by each temporal window, allowing for the correction of skull-induced aberrations. A similar approach was recently implemented in a transcranial neuromodulation device, where phase shifts are estimated by comparing measurements taken in water to those taken through the subject, enabling the refocusing of the wave within the brain [106]. It has also been proposed to create a cavitation bubble at the intended target to serve as a beacon. A first proof-of-concept demonstration through an aberrating medium was published by Pernot et al. [107] in which a high-power low-frequency transducer generated a cavitation bubble at the target, and the signal emitted by the bubble was recorded after propagation through the aberrating medium using a higher frequency transducer to determine the time delays needed to refocus the wave through the medium. The translation of this technique to transcranial focusing is challenging
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due to the skull's strong aberrating and attenuating effects, which makes it difficult to generate a cavitation bubble at the desired location. To address this, an initial step involving simulation-based aberration correction has been proposed to ensure that the bubble is generated at the correct location. Only after this step, can the cavitation bubble be created, its signal recorded, and used to achieve a high-quality focus [108,109]. Nevertheless, producing a bubble in situ for refocusing purposes is likely to imply sonication regimes above a mechanical index of 1.9 which does not correspond to the latest safety consensus for transcranial ultrasound stimulation [110]. The next section specifically addresses transcranial focusing for neuromodulation purposes.

## Consideration of the skull in human neuromodulation studies

In human neuromodulation studies, the impact of the skull on acoustic propagation is often downplayed and rarely corrected. To date, only four devices capable of correcting skull aberrations have been used in patients or in healthy volunteers. The first is the Insightec Exablate 4000 (Figure 2(C)), which employs a CT image of the skull and a proprietary ray-tracing algorithm for aberration correction [111,112]. The second is the Diadem (Figure 2(E)), which utilizes two ultrasonic arrays positioned on either side of the skull for this purpose [106,113–116]. The third, presented in Martin et al. [117] is based on a hemi-ellipsoid array composed of 256 transducers, and planning steps, including phase aberration correction, were performed with k-Plan based on low-dose head CT scans and MR images. The fourth is a custom

<figure><img src="image_21.png" /><figcaption>**Figure 2.** (a-c): Evolution of the number of transducer elements on clinical ultrasound devices used for transcranial therapies. (a): a proof-of-concept made of a 64 elements transducer, reproduced and adapted with permission from [72]. (b): a proof-of-concept of ultrasound transducer with 200 elements and a quasi-random arrangement, reproduced and adapted with permission from [60]. (c): the Insightec Exablate 4000, a 1024 elements FDA-approved and CE-marked clinical device, figure reproduced and adapted with permission from [167]. (d): a twin-transducers array presented in 2006 for transcranial ultrasound imaging, reproduced and adapted with permission from [105]. (e): a twin-transducers array used for clinical ultrasound neuromodulation which does not require online MR-guidance nor simulations to correct for skull aberrations, reproduced and adapted from [116].</figcaption></figure>
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single-element device presented in Attali et al. [118], which is coupled with a patient-specific acoustic metalens whose aim is to correct for skull aberrations. It is to be noted that for these devices, the head is held in position using either a stereotactic frame (Insightec device), a face mask (Diadem and Martin et al. device) or a head support (Attali et al. device). These studies represent only a small fraction of all human ultrasonic neuromodulation research. In the majority of studies that do not correct for skull aberrations, varying levels of attention are given to the skull and its effects on acoustic propagation. A few studies have adopted a subject-specific approach. This includes simulating pressure fields prior to stimulation to identify the optimal entry point [119] and evaluate stimulation safety [85,120,121], or performing simulations to estimate the acoustic transmission and consequently adjust the driving power to apply the same in-situ pressure levels across all subjects [122,123]. A semi-real time simulation tool has been proposed to assist the positioning of the transducer [124]. Some studies have included simulations to determine retrospectively the pressure field inside heads of the subjects, therefore taking into account individual variabilities, but these did not exploit these simulations during the procedure [125-131]. Other studies have used available medical images from databases to estimate the transcranial pressure field [61,132-138] or performed measurements through an ex-vivo skull [139-142]. These measurements were subsequently used as references for calculating the transmission coefficient and/or evaluating the skull's impact. However, these approaches did not account for individual variability between the subjects enrolled in the study. A notable set of studies do not mention having performed simulations [143-162]. This is of concern as skull aberrations are likely to impact the efficacy of the stimulation by increasing the variability in target engagement. As detailed in Section "Effect of the skull," several studies have reported a shift in the maximum pressure greater than 9 mm [61-64] which is greater than most anatomical targets, especially when targeting white matter bundles [118]. Based on the review of the shifts induced by the human skull, we recommend implementing personalized skull aberration correction for clinical translation in general, and for psychiatric disorders in particular. The defocusing effect of the skull might indeed impact the efficacy of the intervention at both the subject and the group level, e.g., if the uncorrected acoustic focus is off-target or if the uncorrected acoustic transmission is too low to reach the neuromodulation threshold [22,25,31]. Phase aberration correction is currently the gold standard. Whenever the hardware does not include phase-aberration correction, an assessment of the effect of the skull should be performed to take it into account prospectively during the planning of the intervention, as was done in a growing subset of papers which propose tools to find the optimum position of the transducer on the skin surface to mitigate the effect of the skull [124,163-166].

It is to be noted that methods of estimating the intensity vary considerably among the aforementioned studies, with some studies reporting only the free field intensity, others reporting the intensity derated by 0.3dB/cm/MHz, and with others using simulations or ex-vivo measurements to estimate the in-situ pressure.

## Review of trials for psychiatric disorders

There is a growing body of scientific literature on the clinical applications of TUS, particularly in psychiatry and addiction. Different stimulation protocols were published, even for a given indication, in terms of the devices used, the ultrasound emission parameters, and the targeting methods. A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria [168].

The aim of this review is to list all TUS clinical studies on psychiatric or addiction-related indications, and to detail and discuss the methodologies used and the associated clinical results in terms of clinical efficacy and patient safety. The methodology of this systematic review is detailed in the supplementary materials, including search strategy, study selection and data collection.

## Depression

Depression is the most commonly studied psychiatric disorder in the context of ultrasound neuromodulation. Some studies targeted deep brain areas in a DBS-like manner, such as the thalamus [131], the subcallosal cingulate area (SCC) [106,113,114,118], the pregenual cingulate cortex (pgCC) [114], the ventral capsule/ventral striatum (VC/VS) [131], the bed nucleus of stria terminalis (BNST) [131], and the
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amygdala [162], while others used a TMS-like approach, focusing the ultrasound beam on superficial cortical brain areas such as the dorsolateral prefrontal cortex (DLPFC) [130]. Moreover, as detailed below, there is significant variability in all ultrasound parameters. Indeed, the estimated in-situ $I_{SPPA}$ ranged from 600mW/cm² in Oh et al. [130] to 50W/cm² in Fan et al. [131]. The acoustic pressure at the target ranged from 0.135MPa in Oh et al. [130] to 1.2MPa in Fan et al. [131]. Finally, the pulse duration ranged from 1ms in Oh et al. [130] to 30ms in Riis et al. [106,114]. Table 1 lists the study design, main outcomes, and tolerance data for each trial reviewed. Table 2 shows the device and ultrasound parameters used for each trial.

## Deep-TUS in depression

A series of three consecutive clinical applications of deep TUS in treatment-resistant depression (TRD) using the Diadem device have been published [106,113,114]. The first published Diadem experiment [106] presents the development of the device comprising two multi-element transmitters and receivers, for skull-aberrations correction and for estimation and personalization of the acoustic power delivered to the brain target. Then, the results of a proof-of-concept application in two patients with severe TRD are presented. Two deep brain regions were targeted for each participant, the SCC and the VS. The laterality of these targets is not mentioned as the centroid of the focal beam may have been set to the midline so that both SCC were targeted simultaneously. Active stimulation was defined as a 650kHz continuous wave for 30ms followed by a 4s off period (corresponding to a DC of 0.75% and a PRF of 0.23Hz), repeated for a total duration of 60 to 180s. Sham stimulation was also performed. The device adjusted the emitted power to deliver a pressure at target of 1MPa, corresponding to an MI of 1.2 and an $I_{SPTA}$ of 31W/cm2. The two deep targets were randomly sonicated, in a single-blinded fashion. Efficacy on depression severity was assessed in a non-consensus approach using a 7-point visual analogue scale (VAS) ranging from -3 ('much less depressed'), to +3, ('much more depressed'), with 0 indicating no change. In both participants, SCC-TUS was associated with an improvement in depression severity, whereas VS-TUS and sham stimulation were not. No adverse effects were observed, and no changes were seen visible on T1-w and T2-w brain MRIs after TUS.

The second article by this team is a case report of a patient with severe TRD who underwent a closely similar TUS protocol [114]. Three targets were selected, the posterior and anterior SCC and the pgCC. The targets were stimulated ten times for 20 to 180s each (with an average of 2min) with the same parameters as described above, and with the order between the three targets randomized. The total TUS duration was 64min, delivered during a single day. Efficacy was assessed using the 6-item Hamilton Depressive Rating Scale (HDRS-6), with a pretreatment score of 16 (i.e., severe depression) falling to 0 the day after treatment (i.e., remission). The authors report that the patient remained in remission with an HDRS-6 score of 0 for at least 44days after the single day treatment, as a recurrence of depression occurred about 5months after treatment. No adverse effects were noted, and no changes were seen on post-TUS T1-w and T2-w MRI of the brain.

The third is a report of the results of a double-blind, randomized, sham-controlled, crossover trial [113]. Twenty-nine patients with moderate to severe major depressive disorder or bipolar depressive disorder without psychotic features were enrolled. The inclusion criteria did not specify drug-resistance but all participants had a clinical history of treatment resistance. Clinically significant suicidal ideation in the past month and a lifetime history of a serious suicide attempt were among exclusion criteria. Three regions of SCC (anterior, central, posterior) were targeted sequentially. The ultrasound parameters differed from the two previous articles. Instead of a continuous wave for 30ms followed by a 4s off period (corresponding to a DC of 0.75%), low-intensity ultrasound was delivered in 30ms bursts with pulses of 5ms on and 5ms off, separated by a 1.4s or 0.7s burst interval and repeated for 1 or 3min. A total of 41min of TUS was applied in a single day session, and depression severity was assessed the day after and one week later using the HDRS-6. Each subject underwent one active session and one sham session in a crossover design. No significant differences were found in the crossover statistical analyses. The authors report that when comparing the active and the sham treatment before crossover (as in a parallel group design), and only in a per-protocol sample (n=19 instead of 29), depression scores improved significantly more with TUS (-55% in severity) than with sham stimulation (-22% in severity) the day after treatment. At follow-up, the most commonly reported side effects were depressed mood, headache and
<table><caption>Table 1. Study design and main results of TUS trials for psychiatric disorders.</caption><thead><tr><th>Indication</th><th>Authors, year</th><th>Study design</th><th>Inclusion criteria</th><th>Subjects</th><th>Target</th><th>Target definition</th><th>Main evaluation scale</th><th>Main results</th><th>Tolerance</th></tr></thead><tbody><tr><td>Depression<br>Deep-TUS</td><td>Riis et al. 2023a<br>[106]</td><td>Single-blind case report</td><td>Moderate to severe MDD or BDD</td><td>n=2 with severe TRD</td><td>2 deep brain regions targeted sequentially: bilateral SCC and VS</td><td>Structural MRI</td><td>7-point VAS</td><td>Improvement in depression severity with SCC-TUS only (not with VS-TUS and sham-TUS)</td><td>No adverse events were observed; no changes were seen visible on T1-w and T2-w brain MRIs after TUS.</td></tr><tr><td></td><td>Riis et al. 2023b<br>[114]</td><td>Case report</td><td>NC</td><td>n=1 with severe TRD</td><td>3 deep brain regions targeted sequentially: bilateral posterior SCC, anterior SCC, and pgCC</td><td>Structural MRI; MNI coordinates of posterior SCC [0, 26, -8]; anterior SCC [0, 34, -6]; pgCC [0, 34, 3]</td><td>HDRS-6</td><td>Remission the day after treatment, lasting at least 44 days</td><td>No adverse events were observed; no changes were seen visible on T1-w and T2-w brain MRIs after TUS.</td></tr><tr><td></td><td>Riis et al. 2024<br>[113]</td><td>Double-blind, randomized, sham-controlled, crossover trial</td><td>Moderate to severe MDD or BDD without psychotic features</td><td>n=29 enrolled n=22 randomized n=14 or 20 analyzed</td><td>3 deep brain regions targeted sequentially: bilateral SCC, anterior target (-4mm), posterior target (+4mm)</td><td>Structural MRI</td><td>HDRS-6</td><td>No significant differences were found in the crossover statistical analyses; before crossover, in the per-protocol sample (n=19), depression scores improved more with active-TUS (-55%) vs sham-TUS (-22%) the day after TUS</td><td>Most commonly reported side effects were depressed mood, headache and anxiety; 2 participants experienced serious psychiatric adverse events following active-TUS</td></tr><tr><td></td><td>Fan et al. 2024<br>[131]</td><td>3-phase case study: an exploratory phase 1, a candidate brain region testing phase 2, and a top-candidate testing with neuroimaging phase 3 (double-blind, versus sham)</td><td>NC</td><td>n=1 with TRD</td><td>3 deep brain regions targeted sequentially in phase 2: VC, BNST and ANT; left and right, sequentially</td><td>NC</td><td>VAS and HDRS-6</td><td>Reduction in VAS and HDRS-6 was observed across all stimulation conditions, included the sham; ANT-TUS significantly reduced VAS scores over time compared to sham</td><td>No adverse events were reported; no structural changes on post-stimulation MRI scan</td></tr><tr><td></td><td>Barksdale et al. 2025<br>[162]</td><td>2-phase: double-blind sham-controlled fMRI target engagement study and open-label single-arm trial</td><td>'Mood, anxiety, and trauma-related disorders (MATRDS); i.e., a wide range of mood, anxiety and post-traumatic stress disorders</td><td>n=29 enrolled n=24 initiated TUS course n=21 received all sessions</td><td></td><td>Deep target: left amygdala</td><td>Structural MRI</td><td>Significant decrease of MASQ (-21.2% decrease) after the 3-week TUS course</td><td>No serious adverse events were reported</td></tr><tr><td></td><td>Attali et al. 2025<br>[118]</td><td>Open-label pilot study</td><td>Severe and drug-resistant MDD</td><td>n=5 enrolled n=5 received all sessions</td><td></td><td>Deep target: crossing of three white matter tracts of the SCC</td><td>Diffusion tensor MRI and tractography</td><td>Significant reduction in depression severity at day 5 of treatment (-61% in MADRS), i.e., after 25 sessions (5 sessions a day for 5 days)</td><td>No serious adverse events were reported; most commonly reported side effects was sleepiness; no structural changes on the MRI following TUS course</td></tr><tr><td>Superficial-TUS</td><td>Oh et al. 2024<br>[130]</td><td>Double-blind, randomized, sham-controlled trial</td><td>Mild to severe, drug-resistant or drug-naive, non-psychotic MDD</td><td>n=26 randomized n=24 completed the TUS course n=23 analyzed</td><td></td><td>Superficial target: left DLPFC</td><td>Structural MRI; MNI coordinates [-42, 44, 30]</td><td>Significant effect of TUS on depression severity at end of treatment (-41%) and at follow-up (-48%) compared to sham (-12% and -15%, respectively)</td><td>No adverse events were reported</td></tr></tbody></table>

(Continued)

<figure><img src="image_24.png" /></figure>
<figure><img src="image_25.png" /><figcaption>Table 1. Continued.</figcaption></figure>

<table><thead><tr><th>Indication</th><th>Authors, year</th><th>Study design</th><th>Inclusion criteria</th><th>Subjects</th><th>Target</th><th>Target definition</th><th>Main evaluation scale</th><th>Main results</th><th>Tolerance</th></tr></thead><tbody><tr><td>Anxiety</td><td>Mahdavi et al. 2023 [159]</td><td>Open label pilot study</td><td>Severe treatment-resistant GAD</td><td>n=25</td><td>Deep target: right amygdala</td><td>Functional and structural MRI</td><td>HAM-A</td><td>Significant decrease in anxiety following TUS (-38%): 8 out of 25 patients in remission</td><td>No adverse events were reported</td></tr><tr><td>Schizophrenia</td><td>Zhai et al. 2023 [170]</td><td>Double-blind, randomized, sham-controlled trial</td><td>Schizophrenia with predominantly negative syndrome</td><td>n=32 randomized n=26 completed the TUS course and analyzed</td><td>Superficial target: left DLPFC</td><td>NC</td><td>SANS</td><td>Significant reduction in SANS scores in the TUS group, whereas no significant changes were observed in the sham group</td><td>No adverse events were reported; 2 patients in the TUS group reported difficulty falling asleep; 2 patients were excluded for aggravated symptoms in the TUS group, and 1 in the sham group</td></tr><tr><td>Addiction</td><td>Rezai et al. 2025 [112]</td><td>Single-blind case series</td><td>Opioid-use disorder</td><td>n=17 enrolled n=16 completed the TUS procedure n=8 analyzed</td><td>Deep target: bilateral NAc and white matter tracts</td><td>Structural MRI and tractography</td><td>Cue-induced craving in opioids using a VAS</td><td>Significant acute and sustained (90-day, follow-up) decrease of cue-induced opioid craving at the group level. Similar craving reductions observed for co-occurring substances</td><td>One serious adverse event is reported, a drug overdose, considered not to be related to TUS; other mild-to-moderate adverse events are reported, such as headache and anxiety; no structural changes on post-stimulation MRI scan</td></tr></tbody></table>

Abbreviations: MDD: major depressive disorder; BDD: bipolar depressive disorder; TRD: treatment-resistant depression; GAD: generalized anxiety disorder; SCC: subcallosal cingulate cortex; pgCC: pregenual cingulate cortex; VS: ventral striatum; VC: ventral capsule; BNST: bed nucleus of stria terminalis; ANT: anterior nucleus of the thalamus; DLPFC: dorsolateral prefrontal cortex; NAc: nucleus accumbens; VAS: visual analogue scale; HDRS-6: 6-item Hamilton Depressive Rating Scale; HDRS-17: 17-item Hamilton Depressive Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; MASQ-GD: Mood and Anxiety Symptom Questionnaire; HAM-A: Hamilton Anxiety Rating Scale; SANS: Scale for the Assessment of Negative Symptoms; NC: not communicated.
<table><caption>Table 2. Device and ultrasound parameters used in TUS trials for psychiatric disorders.</caption><thead><tr><th>Indication</th><th>Authors, year</th><th>Device</th><th>Skill<br>aberration<br>correction</th><th>Neuronavigation</th><th>Pulse timing parameters</th><th>In situ estimates of exposure</th><th>Transducer placement</th></tr></thead><tbody><tr><td><strong>Depression</strong><br>Deep-TUS</td><td>Rilis et al. 2023a<br>[106]</td><td>Diadem, with 252 elements</td><td>Yes</td><td>No</td><td>Operating frequency: 650kHz<br>Pulse duration: 30ms<br>Pulse repetition interval: 4s<br>Pulse train duty cycle: 0.75%<br>Pulse train duration: 60 to 180s<br>Pulse train repetition interval: NC<br>Pulse train repeat duration: ~1.5h (active+sham)<br>Number of sessions: 1, single day</td><td>Brain target PNP: 1 MPa<br>(estimated in situ)<br>MI: 1.2<br>l<sub>5PPK</sub>: 31W/cm<sup>2</sup><br>l<sub>5PRA</sub>: 0.233W/cm<sup>2</sup><br>Thermal estimates: NC</td><td>Transducer position is defined during a<br>planning session, using structural MRI; then<br>a thermoplastic mask is used for identical<br>transducer positioning outside of MRI bore</td></tr><tr><td>Rilis et al. 2023b<br>[114]</td><td>Diadem, with 252 elements</td><td>Yes</td><td>No</td><td>Operating frequency: 650kHz<br>Pulse duration: 30ms<br>Pulse repetition interval: 4s<br>Pulse train duty cycle: 0.75%<br>Pulse train duration: 20 to 180s<br>Pulse train repetition interval: NC<br>Pulse train repeat duration: NC; a total of 64 min of<br>TUS was applied</td><td>Brain target PNP: 1 MPa<br>(estimated in situ)<br>MI: 1.2<br>l<sub>5PPK</sub>: 31W/cm<sup>2</sup><br>l<sub>5PRA</sub>: 0.233W/cm<sup>2</sup><br>Thermal estimates: NC</td><td>Same</td></tr><tr><td>Rilis et al. 2024<br>[113]</td><td>Diadem, with 252 elements</td><td>Yes</td><td>No</td><td>Number of sessions: 1, single day<br>Operating frequency: 650kHz<br>Pulse duration: 5ms<br>Pulse repetition interval: 10 ms<br>Pulse train duty cycle: 50%<br>Pulse train duration: 30 ms<br>Pulse train repetition interval: 0.7 or 1.4s<br>Pulse train repeat duty cycle: 4.3% or 2.1%<br>Pulse train repeat duration: 1 or 3 min<br>Pulse train repetition 2 interval: NC<br>Pulse train repetition 2 duty cycle: NC<br>Pulse train repetition 2 duration: NC; a total of<br>41 min of TUS was applied</td><td>Brain target PNP: 1 MPa<br>(estimated in situ)<br>MI: 1.2<br>l<sub>5PPK</sub>: 31W/cm<sup>2</sup><br>l<sub>5PRA</sub>: NC<br>Thermal estimates: NC</td><td>Same</td></tr><tr><td>Fan et al. 2024<br>[131]</td><td>ATTN201 (Attune<br>Neurosciences, Inc.), a<br>wearable device with<br>128 elements</td><td>No, but<br>dynamic<br>steering</td><td>No</td><td>Operating frequency: 500 kHz<br>Pulse duration: 5.2 ms<br>Pulse repetition interval: 40 ms (phase 2 and 3)<br>Pulse train duty cycle: 13%<br>Pulse train duration: 5 min<br>Pulse train repetition interval: 10 min<br>Pulse train repeat duty cycle: 33%<br>Overall duty cycle: 4.3%<br>Pulse train repeat duration: 120 min/target<br>Number of sessions: 1, single day</td><td>Brain target PNP: 1.2 MPa<br>(estimated with simulations)<br>MI: 1.7<br>l<sub>5PPK</sub>: 45W/cm<sup>2</sup><br>l<sub>5PRA</sub>: NC<br>TR: 1.6°C in the brain</td><td>The device is head-worn, custom fitted and<br>positioned over both temporal windows of<br>the skull; reproducible placement is<br>ensured through a removable nose piece<br>anchored to the nasion and training of the<br>patient</td></tr><tr><td>Barksdale et al.<br>2025<br>[162]</td><td>Brainsonix Pulsar 1002</td><td>No</td><td>Yes</td><td>Operating frequency: 650kHz<br>Pulse duration: 5 ms<br>Pulse repetition interval: 100 ms<br>Pulse train duty cycle: 3%<br>Pulse train duration: 30s<br>Pulse train repetition interval: 60s<br>Pulse train repeat duty cycle: 50%<br>Overall duty cycle: 2.5%<br>Pulse train repeat duration: 10 min<br>Number of sessions: 5 sessions per week for 3 weeks</td><td>Brain target PNP: 0.64 MPa<br>(deated by 0.3 dB/cm/MHz)<br>MI: 0.81<br>l<sub>5PPK</sub>: 14W/cm<sup>2</sup><br>l<sub>5PRA</sub>: 0.72W/cm<sup>2</sup><br>Thermal estimates: NC</td><td>Initial positioning is defined via an iterative<br>procedure based on MR structural images<br>on which the transducer is visible, for the<br>focus to end up on the defined target;<br>then an optical neuronavigator is used to<br>record and store the position of the<br>transducer, for reproducible placement<br>during following TUS sessions</td></tr></tbody></table>

(Continued)

<figure><img src="image_26.png" /></figure>
<figure><img src="image_27.png" /><figcaption>Table 2. Continued.</figcaption></figure>

<table><thead><tr><th>Indication</th><th>Authors, year</th><th>Device</th><th>Skull<br>aberration<br>correction</th><th>Neuronavigation</th><th>Pulse timing parameters</th><th>In situ estimates of exposure</th><th>Transducer placement</th></tr></thead><tbody><tr><td>Attali et al. 2025<br>[118]</td><td>Custom single-element<br>device coupled with<br>personalized acoustic<br>metalenses to correct for<br>skull aberrations</td><td></td><td>Yes</td><td>Yes</td><td>Operating frequency: 500kHz<br>Pulse duration: 4.5ms<br>Pulse repetition interval: 71ms<br>Pulse train duty cycle: 5%<br>Pulse train duration: 5s<br>Pulse train repetition interval: 15s<br>Pulse train repeat duty cycle: 33%<br>Overall duty cycle: 1.8%<br>Pulse train repeat duration: 5min<br>Number of sessions: 5 sessions per day for 5days<br>Operating frequency: 500kHz<br>Pulse duration: 1ms<br>Pulse repetition interval: 2ms<br>Pulse train duty cycle: 50%<br>Pulse train duration: 0.3s<br>Pulse train repetition interval: 6s<br>Pulse train repeat duty cycle: 5%<br>Overall duty cycle: 2.5%<br>Pulse train repeat duration: 20min<br>Number of sessions: 3 sessions per week for 2 weeks</td><td>Brain target PNP: mean of 563 kPa (numerical simulations)<br>MI: 1.6<br>l<sub>SPPA.3</sub>: mean of 11W/cm<sup>2</sup><br>l<sub>SPTA.3</sub>: mean of 184 mW/cm<sup>2</sup><br>Thermal estimates: TIC of 1.18; thermal rise in skin, skull and brain &lt;2 °C</td><td>Transducer position, on the forehead while avoiding sensitive structures, is defined during planning, prior to metalens fabrication; transducer placement is then ensured by neuronavigation</td></tr><tr><td>Superficial TUS<br>[130]</td><td>Oh et al. 2024<br>N5-US100 (Neurosona Co.)<br>Ltd</td><td>No</td><td>No</td><td>Yes</td><td>Operating frequency: 500kHz<br>Pulse duration: 1ms<br>Pulse repetition interval: 2ms<br>Pulse train duty cycle: 50%<br>Pulse train duration: 0.3s<br>Pulse train repetition interval: 6s<br>Pulse train repeat duty cycle: 5%<br>Overall duty cycle: 2.5%<br>Pulse train repeat duration: 20min<br>Number of sessions: 3 sessions per week for 2 weeks</td><td>Brain target PNP: 0.135 MPa (derating factor of 55%)<br>MI: 0.27<br>l<sub>SPPA.3</sub>: 0.6W/cm<sup>2</sup><br>l<sub>SPTA.3</sub>: 0.3W/cm<sup>2</sup><br>Thermal estimates: NC</td><td>Prior to stimulation, CT and MRI are performed with fiducial markers positioned on the patient head; during TUS sessions, fiducial markers are positioned the same way and used for neuronavigation; transducer is positioned perpendicular to the entry point</td></tr><tr><td>Anxiety<br>[159]</td><td>Mahdavi et al.<br>2023<br>[170]</td><td>Brainsonix Pulsar 1002</td><td>No</td><td>No</td><td>Operating frequency: 650 kHz<br>Pulse duration: 5ms<br>Pulse repetition interval: 100ms<br>Pulse train duty cycle: 5%<br>Pulse train duration: 30s<br>Pulse train repetition interval: 60s<br>Pulse train repeat duty cycle: 50%<br>Overall duty cycle: 2.5%<br>Pulse train repeat duration: 10min<br>Number of sessions: 1 per week for 8 weeks<br>Operating frequency: 500 kHz<br>Pulse duration: 0.5ms<br>Pulse repetition interval: 10ms<br>Pulse train duty cycle: 5%<br>Pulse train duration: 0.5s<br>Pulse train repetition interval: 8.5s<br>Pulse train repeat duty cycle: 5.8%<br>Overall duty cycle: 0.3%<br>Pulse train repeat duration: 15min<br>Number of sessions: 5 per week for 3 weeks<br>Operating frequency: 220 kHz<br>Pulse duration: 0.1s<br>Pulse repetition interval: 3s<br>Pulse train duty cycle: 3.3%<br>Pulse train duration: N/A<br>Pulse train repetition interval: N/A<br>Pulse train repeat duty cycle: N/A<br>Overall duty cycle: 3.3%<br>Pulse train repeat duration: 5min<br>Number of sessions: 4 sessions the same day</td><td>Brain target PNP: 0.61 MPa (derated by 0.3dB/cm/MHz)<br>MI: 0.75<br>l<sub>SPPA.3</sub>: 14W/cm<sup>2</sup><br>l<sub>SPTA.3</sub>: 0.72W/cm<sup>2</sup><br>Thermal estimates: NC</td><td>Transducer was positioned on the squama of the temporal bone and using neuronavigation; positioning was secured using a 3D printed head-holder</td></tr><tr><td>Schizophrenia<br>[170]</td><td>Zhai et al. 2023<br>V391-SU (Olympus NDT)</td><td>No</td><td>No</td><td>No</td><td>Operating frequency: 500 kHz<br>Pulse duration: 0.5ms<br>Pulse repetition interval: 10ms<br>Pulse train duty cycle: 5%<br>Pulse train duration: 0.5s<br>Pulse train repetition interval: 8.5s<br>Pulse train repeat duty cycle: 5.8%<br>Overall duty cycle: 0.3%<br>Pulse train repeat duration: 15min<br>Number of sessions: 5 per week for 3 weeks<br>Operating frequency: 220 kHz<br>Pulse duration: 0.1s<br>Pulse repetition interval: 3s<br>Pulse train duty cycle: 3.3%<br>Pulse train duration: N/A<br>Pulse train repetition interval: N/A<br>Pulse train repeat duty cycle: N/A<br>Overall duty cycle: 3.3%<br>Pulse train repeat duration: 5min<br>Number of sessions: 4 sessions the same day</td><td>Brain target PNP: NC<br>MI: NC<br>l<sub>SPPA.3</sub>: 8 W/cm<sup>2</sup> (unclear if in situ or not)<br>l<sub>SPTA.3</sub>: 0.4W/cm<sup>2</sup> (unclear if in situ or not)<br>Thermal estimates: NC</td><td>No information</td></tr><tr><td>Addiction<br>[112]</td><td>Rezai et al. 2025<br>V391-SU (Olympus NDT)<br>(Insightec)</td><td>Exablate Neuro Type 2<br>(Insightec)</td><td>Yes</td><td>No</td><td>Operating frequency: 500 kHz<br>Pulse duration: 0.5ms<br>Pulse repetition interval: 10ms<br>Pulse train duty cycle: 5%<br>Pulse train duration: 0.5s<br>Pulse train repetition interval: 8.5s<br>Pulse train repeat duty cycle: 5.8%<br>Overall duty cycle: 0.3%<br>Pulse train repeat duration: 15min<br>Number of sessions: 5 per week for 3 weeks<br>Operating frequency: 220 kHz<br>Pulse duration: 0.1s<br>Pulse repetition interval: 3s<br>Pulse train duty cycle: 3.3%<br>Pulse train duration: N/A<br>Pulse train repetition interval: N/A<br>Pulse train repeat duty cycle: N/A<br>Overall duty cycle: 3.3%<br>Pulse train repeat duration: 5min<br>Number of sessions: 4 sessions the same day</td><td>Brain target PNP: NC<br>MI: NC<br>l<sub>SPPA.3</sub>: 8 W/cm<sup>2</sup> (unclear if in situ or not)<br>l<sub>SPTA.3</sub>: 0.4W/cm<sup>2</sup> (unclear if in situ or not)<br>Thermal estimates: NC</td><td>Patients were head-fixed and transducer position was defined using a stereotactic frame (n=4) or a frameless dental mold assembly (n=4)</td></tr></tbody></table>

Abbreviations: PNP, peak negative pressure; MI, mechanical index; ISPPA, intensity spatial peak pulse average; SPPTA, intensity spatial peak temporal average; TR, thermal rise; TI, thermal index; NC, not communicated.

Pulse timing parameters are reported according to the ITRUSST consensus on standardized reporting for TUS [47].
<figure><img src="image_28.png" /></figure>

anxiety. The authors outline that two participants experienced serious psychiatric adverse events following real stimulation: a worsening of depression and a suicide attempt by drug ingestion 3 days after active stimulation in one participant; and a rapid worsening of depression with suicidal ideation the day after active treatment in another participant. Of note, online fMRI showed a decrease in SCC activity during stimulation at an individual level.

Another deep TUS experiment in TRD is a case report using a different ultrasound device, a wearable device with dynamic steering, but without taking into account the defocusing of the skull [131]. A patient underwent a 3-phase protocol. Phase 1 was an initial exploratory step in which several deep brain regions (such as SCC, VC/VS and thalamus) were targeted to qualitatively assess whether TUS induces an acute offline effect on depression. In addition, two stimulation patterns were evaluated, differing in PRF (1 Hz or 25 Hz). Other parameters were common between the two patterns, and consisting of 500 kHz fundamental frequency, 13% DC and 300s burst duration. The 25 Hz PRF was used in the next steps. Based on conservative estimations, the authors report a maximum pressure at target of approximately 1.2 MPa, corresponding to an $I_{SPPA}$ of 45 W/cm$^2$, a MI of 1.7 and an estimated thermal rise of 1.6 °C in the brain. Phase 2 assessed the efficacy of TUS on the ventral capsule (VC), the BNST and the anterior nucleus of the thalamus (ANT). Both left and right lateralized regions were sonicated sequentially with a 10 min interval, for a total sonication time of 40 min per region. Sham stimulations were also performed. Efficacy was assessed using a VAS and the HDRS-6. In phase 2, all conditions including sham stimulation reduced depression intensity, but only ANT-TUS induced a significant decrease in VAS compared to sham. A similar trend was observed for HDRS-6, but without significance. No adverse events were reported, and post-treatment MRIs showed no structural changes. Phase 3 was a double-blinded assessment of ANT-TUS (considered the lead candidate) versus sham-TUS, with resting-state fMRI performed post-stimulation for each condition. The efficacy and tolerance of ANT-TUS during this last step is not reported. Functional imaging analysis showed a decrease in default mode network (DMN) connectivity following ANT-TUS.

Attali et al. [118] reported results from an open-label study in treatment-resistant depression (TRD), using personalized metamaterials ('metalens') to correct for skull-induced aberrations. Metalens enabled millimeter-level precision in deep targeting using a portable device. Five patients with severe TRD were enrolled in this open-label study. TUS was delivered 5 times a day for 5 days, for a total of 25 sessions, with a 500 kHz central frequency, a 10 Hz PRF and a 1.7% DC delivered over 5 min, and an estimated mean pressure at target of 563 kPa. The deep-seated target was personalized using tractography from diffusion tensor MRI and defined as the intersection of white matter tracts involved in depression (the forceps minor, the uncinate fasciculus and the cingulum bundle) located in the subcallosal cingulate region. No serious adverse events occurred during this study, with a total of 125 TUS sessions. Post-treatment MRI scans showed no lesion in the brain, and none of the patients reported sensation or pain on the scalp during or after the sessions. Regarding efficacy, the primary outcome of the open-label trial was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to the endpoint at day 5. By day 5 of treatment, depression severity was reduced by an average of 60.9% (range: [30–83.9%]), and four out of five patients qualified as responders (≥50% decrease in the MADRS), with two of these responders in full remission (MADRS ≤10).

Finally, Barksdale et al. [162] conducted a deep TUS study targeting the left amygdala in patients suffering from 'Mood, anxiety, and trauma-related disorders (MATRDs)', corresponding to a wide range of mood disorders (depression, bipolar disorder), anxiety disorders and post-traumatic stress disorders. They report results of a double-blind, sham-controlled, within-subject fMRI target-engagement study in patients with MATRDs and healthy controls, and results of a single-arm open pilot trial on a total of 29 MATRD patients. Exclusion criteria included current suicidal ideation, recent suicide attempt and current or recent psychotic symptoms. The device used (Brainsonix Pulsar 1002) does not allow for correction of skull-induced aberrations. Active TUS consisted in 10 Hz PRF and 5% DC delivered over 10 min in 10 sets of 30 s on/off blocks, and an estimated pressure at target of 0.64 MPa. The target engagement study relied on fMRI results, which demonstrated a significant attenuation of left amygdala BOLD signal after active TUS versus sham TUS. For the open label study, 15 active TUS sessions were delivered once daily, 5 times a week, for 3 weeks. The primary outcomes were related to safety (rates and severity of adverse events), acceptability (treatment completion) and efficacy (changes in Mood and Anxiety Symptom Questionnaire, MASQ). The authors report no serious adverse events and a procedure acceptability
<figure><img src="image_29.png" /></figure>

reflected by an 88% completion rate of the 15-session TUS course. Regarding efficacy, a significant
decrease of MASQ scores was observed after the 15-session TUS course, from 26.8±6.4 at baseline to
21.1±7.0 at post-treatment (i.e., a 21.2% decrease).

Superficial-TUS in depression

One study has investigated the effect of TUS on superficial brain regions in a TMS-like approach. Oh et al. conducted a randomized, double-blind, sham-controlled clinical trial of TUS targeting the left DLPFC in patients with mild to severe, drug-resistant or drug-naive, non-psychotic major depressive disorder [130]. Using a lower pressure at target than other protocols, 135 kPa (estimated considering a 55% transmission loss), associated with an MI of 0.27 and an $I_{SPPA}$ of 0.6W/cm$^2$, ultrasound was delivered for 1 ms every 2 ms (50% DC), 300 ms every 6s (2.5% overall DC), during 20 min sessions three time a week for 2 consecutive weeks. The primary outcome measure was change in depressive symptoms as assessed by the MADRS. Forty participants were recruited, 26 were randomized and 23 completed the protocol. There was a significant effect of TUS on depression severity at end of treatment and at follow-up, with a mean reduction of 41% and 48%, respectively, compared to sham which was associated with a reduction of depressive intensity of -12% and -15%, respectively. No adverse effects were reported. In addition, resting-state functional connectivity analysis revealed an effect of left DLPFC TUS on connectivity between the SCC and the medial prefrontal cortex, cerebellum, and right middle frontal gyrus.

Generalized anxiety disorder

To date, the only TUS study on anxiety has been conducted by Mahdavi et al. [159], targeting the right amygdala. Twenty-five patients were enrolled in an open label pilot study of ultrasonic neuromodulation on severe treatment-resistant generalized anxiety disorder. The Brainsonix Pulsar 1002 [169] device was driven at 650 kHz with an $I_{SPPA,3}$ of 14W/cm$^2$ and an $I_{SPTA,3}$ of 720 mW/cm$^2$, which falls within the FDA exposure limits. The estimated mechanical index was 0.75, with a pressure at target of 0.61 MPa. The pulse duty cycle was 5% with a pulse duration of 5 ms. Each burst lasted for 30s, followed by a 30s pause, yielding an overall duty cycle of 2.5%. The right amygdala was targeted for ten minutes once a week for eight weeks. The primary outcome of this study was the changes on the Hamilton Anxiety Rating Scale (HAM-A). The study reports a significant decrease in anxiety (-38%) as measured by the HAM-A, following TUS, with 8 out of 25 patients had a final HAM-A score below 14, which is indicative of symptom remission. No adverse events were reported.

Schizophrenia

A double-blind, randomized, sham-controlled trial of ultrasonic neuromodulation for the negative symptoms of schizophrenia was conducted [170]. Participants were randomized to receive either active or sham TUS in a regimen consisting of fifteen 15-min sessions over three weeks. The left DLPFC was targeted using an Olympus NDT V391-SU transducer operating at 500 kHz but no information related to acoustic intensities or pressure at target is reported. The pulse duty cycle was 5%, with each pulse lasting 0.5 ms. Each burst lasted 500 ms, followed by 8 s pauses, resulting in an overall duty cycle of 0.29%. The acoustic output of the transducer is not reported in the paper but we found another article from the same authors using the same transducer and reporting in water 8W/cm² $I_{SPPA}$ and 0.4W/cm² $I_{SPTA}$ [133]. A total of 32 patients were randomized, with 26 completing the study. The primary outcome was the change in negative symptoms, assessed using the Scale for the Assessment of Negative Symptoms (SANS). The study reported a significant reduction in SANS scores in the TUS group, whereas no significant changes were observed in the sham group. No serious adverse events were reported, although two patients were excluded for aggravated symptoms in the TUS group, and one in the sham group, and two patients in the TUS group reported difficulty falling asleep.

Substance use disorder

Rezai et al. [112] investigated the effects of simultaneous bilateral stimulation of NAc on opioid use disorder. In this open-label study, 17 patients were enrolled, 16 completed the procedure and 8 were
analyzed in the report. Targeting was based on structural MR images combined with tractography in order to identify the position of relevant neural pathways (medial forebrain bundle, anterior thalamic radiation and corticostriatal connections) and the actual target was chosen such that it would overlap both the NAc and white matter. The study used the MR-guided Insightec low-frequency Exablate Neuro system, which includes a proprietary skull aberrations correction algorithm. However, the manufacturer modified the initiation files to enable custom pulse sequences for neuromodulation. The device was operated at 220 kHz. Following a 5-min sham sequence, the study reports that TUS was performed on 8 subspots with a DC of 3.3%, corresponding to 100 ms of stimulation every 3s, for 5 min, repeated 4 times. No information related to acoustic intensities or pressure at target is reported. After this single TUS session, subjects were followed up for a period of 90 days. There was one serious adverse event, a drug overdose, considered not to be related to the procedure. Other mild-to-moderate adverse events are reported, such as headache and anxiety. Efficacy was assessed through cue-induced craving in opioids using a visual analogue scale (from 0 to 10), with a significant decrease from pre-TUS (median of 6.9) to day 1 post-TUS (median of 0.7) and day 90 (median of 0.6). Similar decrease in craving was observed for co-occurring substances, and efficacy was further assessed by urine toxicology. Seven of 8 participants remained abstinent at day 30 post-TUS, and 5 of 8 remained abstinent at day 90 post-TUS. Finally, fMRI analysis revealed a decreased connectivity between NAC and prefrontal and cingulated cortex regions.

# Conclusion: strengths and weaknesses of transcranial ultrasound stimulation for successful clinical translation

## Strengths

The primary strength of TUS lies in its unique ability to modulate the activity of deep-seated brain areas without incision and with a millimetric precision. Numerous studies support the safety of TUS when delivered within a mechanical and thermal index limit established by diagnostic ultrasound guidelines [171,172]. Additionally, the apparent simplicity of the setups used in preclinical studies—often consisting in a single element transducers connected to an amplified off-the-shelf function generator below diagnostic ultrasound guidelines [21]—has generated considerable interest in the brain stimulation community [173].

The studies reviewed in this article demonstrate the potential of TUS in various psychiatric conditions. In the treatment of negative symptoms in schizophrenia, severe generalized anxiety disorder, and opioid use disorder, the authors report positive and significant results, with good tolerability. In depression, studies reported significant improvements with two markedly different approaches: three teams reported efficacy data of deep TUS [113,118,162], while Oh et al. achieved positive results with left DLPFC-TUS, similar to rTMS protocols [130]. Of note, since all clinical applications in psychiatry and addictology targeted brain regions that needed to be inhibited, low duty cycles of maximum 5% were used, in accordance with data suggesting an activating or inhibiting effect of TUS linked to high or low duty cycles, respectively [174]. Targeting methods in TUS may prove pivotal for its future medical applications, as suggested by recent advancements in rTMS [175]. Indeed, brain MRI offers several hypothesis-driven strategies for identifying the targets: pinpointing a reproducible anatomical target using structural brain imaging; enhancing or counteracting a functional connectivity pattern between two or more regions or within a broad network such as the default mode network using functional MRI; or leveraging diffusion MRI and tractography to target a structural connectivity network. In the light of these target selection strategies, the precision of TUS is an advantage and aberration correction is a must.

TUS holds promise for investigating drug-resistant neuropsychiatric disorders where invasive deep brain stimulation has proven effective, such as obsessive-compulsive disorder, addiction, eating disorders and Tourette's syndrome. Its potential for broad application is compelling. However, as with any emerging treatment, its effectiveness can only be confirmed through well-powered, randomized, placebo-controlled trials. Furthermore, the potential of TUS extends well beyond psychiatric or even medical applications. In neuroscience, the role of deep brain regions could only be studied by correlation using functional MRI, electroencephalography or magnetoencephalography. Focused ultrasound can now be
<figure><img src="image_30.png" /></figure>

used to explore the functional causality of these deep brain networks in neurocognition through tran-
sient neuromodulation, similar to how TMS has been done to target superficial cortical structures, thus
expanding the scope of possibilities.

Weaknesses

As TUS is an emerging technology, there is unfortunately a lack of standardize reporting. As highlighted in the review, data were missing in some studies to fully extract the acoustic pressure parameters. A consensus on standardized reporting for transcranial ultrasound stimulation was recently published. As the field is transitioning to human applications it is crucial that the community adopts standard reporting to be able to reproduce the studies and to retrospectively investigate the mechanical and thermal effects of ultrasound for safety reasons.

Currently, no established guidelines exist for the safe use of TUS in humans, unlike diagnostic ultra-
sound [176] or high intensity ultrasound [177]. This lack of standards poses challenges for companies
designing clinical devices. However, international consensus on the biophysical safety of TUS is beginning
to emerge [110], largely based on diagnostic ultrasound guidelines. These efforts may pave the way for
official standards to be developed by international commissions in the near future.

The relative ease of assembling a TUS system [21] is also a potential threat to the technology as it
may give the false impression that clinical transfer is easy to achieve. Proof-of-concept setups designed
for use in rodents and primates cannot be applied to humans without comprehensive risk analyses and
without thorough consideration of regulatory requirements. These analyses must encompass not only
ultrasound biophysical safety, but also electrical safety and all other assessments required for human use.
The high absorption of ultrasound in the skull puts the skin and cortical brain at risk [46] leaving little
margin for error in the electronics driving the transducer. For example, continuous sonication can pro-
duce a lesion in the brain in under 10s, as intentionally demonstrated by Dervishi et al. to treat brain
tumors [178], a scenario that must be avoided during TUS. A large consortium recently established con-
sensus on considerations about the biophysical safety of ultrasound [110]. They provide a comprehensive
set of ultrasonic parameters and levels that they consider biophysically safe. In the light of the review of
clinical trials for psychiatric disorders, we believe that effective transcranial ultrasound stimulation can be
achieved within the recommendations of the international consortium [110], provided the emission of
the ultrasound waves is under control with the ultrasound device used.

Preclinical studies on rodents and non-human primates benefited from the limited skull thickness in
these animals [31,33–35], resulting in a reduced impact of the skull on ultrasound propagation into the
brain [179]. In contrast, the defocusing effect of the human skull [58] has been overlooked in numerous
TUS studies in humans [143–162] despite evidence showing that the human skull can shift the focal spot
9mm to 28mm away from the intended target [61–64]. As reviewed in this paper, several techniques
have been developed to mitigate the effect of the skull. These include adjusting time delays on multiele-
ment arrays [75] or tailoring the thickness of an acoustic lens placed in front of a single element trans-
ducer [91]. While these methods are not yet widely adopted, they have shown promising results in
stimulating deep brain structures in humans, such as the thalamus [111] and the nucleus accumbens
[112] or the subcallosal cingulate [118]. The field of TUS in still in its infancy, and the optimization of
ultrasound parameters remains a critical challenge, likely requiring different parameters for different brain
regions. Eliminating the uncertainty caused by skull-induced shifts is an essential first step, yet it is one
that is too frequently neglected. Phase aberration correction are efficient and available techniques that
we recommend to implement in clinical applications of TUS, especially for psychiatric applications were
targets of interest as small as the intersection of fiber bundles can be suggested [113]. Such targets have
been stimulated with ultrasound with metalens correction [118]. The metalens enabled to reduce the
maximum targeting error from 12.3mm (without correction) to 1.8mm (with the metalens), which con-
tributes not only to increase the efficacy of the treatment by stimulating the desired target but also to
decrease the variability amongst patients. Whenever the hardware does not include phase-aberration
correction, we recommend to at least assess the effect of the skull and to take it into account prospec-
tively during the planning of the intervention.
<figure><img src="image_31.png" /></figure>

## Acknowledgements

The authors thank Prof Gail ter Haar for proofreading the manuscript.

## Disclosure statement

JFA holds 5 patents on transcranial ultrasound and is a co-founder of Sonomind (Paris, France). MP has been invited to scientific meetings, consulted and served as a speaker, and received compensation from Janssen.

## Generative artificial intelligence

Once the article was drafted, Chat GPT was used to improve the wording for selected sentences. In addition, the final article was proofread by a native English speaker.

## Funding

The authors thank the Focused Ultrasound Foundation for their support within the Center of Excellence program.

## Data availability statement

The results presented in this paper come from published literature. The data used to illustrate Figure 1 can be made available upon request directed to the corresponding author.

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