BACKGROUND:Transcranial ultrasound stimulation (TUS) enables non-invasive neuromodulation of cortical and subcortical brain regions. Technological advances have facilitated rapid expansion of the field in recent years. However, the overall scope, methodological trends, and reporting practices of human TUS research remain unclear. OBJECTIVE:To characterize the global landscape of registered clinical trials using TUS for neuromodulation, including their design features, indications, targets, device platforms, and dissemination. METHODS:A systematic search of major international registries (ClinicalTrials.gov, WHO ICTRP, EUCTR, ChiCTR, CRiS, ANZCTR, JPRN, ISRCTN, and CTRI) was performed through September 2025. Interventional studies using low-intensity ultrasound for brain neuromodulation were included. Data were extracted on indication, target, device, design, enrollment, sponsorship, and publication linkage. RESULTS:A total of 177 unique clinical trials were identified. Registrations have increased sharply over time, with 27 trials registered between 2014 and 2019, and 150 trials registered in the last 5 years. The United States (52%) and China (18%) lead activity. Psychiatric disorders were the most common indication (32%), followed by healthy volunteer studies (16%), pain (11%), cognitive (11%), and movement disorder (9%) studies. Among trials specifying a target, over half (51%) targeted subcortical regions. A considerable proportion of studies were randomized, multi-arm, and double-blinded (40%). Device information was reported in 32% of trials, identifying 11 distinct commercial and prototype systems. Of completed trials, 37% were linked to a peer-reviewed publication. CONCLUSIONS:TUS clinical research is expanding rapidly but remains heterogeneous in design, targets, and device reporting. Enhanced transparency in trial registration and parameter documentation will facilitate the development of stronger study designs and encourage the field to direct its efforts toward understudied areas.

BACKGROUND AND OBJECTIVES:Motivated by growing literature suggesting that skull density ratio (SDR) has limitations in patient selection and outcome prediction for magnetic resonance‑guided focused ultrasound treatments, this study sought to systematically review imaging-based alternatives to SDR that have been explored in relation to clinical and technical outcomes. METHODS:This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and was registered in the International Prospective Register of Systematic Reviews (CRD420251081059). We searched MEDLINE, Embase, and Scopus from inception to February 2025 for studies evaluating imaging-derived alternatives to SDR in human magnetic resonance‑guided focused ultrasound procedures. Data were extracted independently by 2 reviewers and studies were grouped into 4 categories: skull geometric factors, histogram-based SDR analysis, patient-specific multivariate modeling, and advanced imaging processing. Each category was also assessed for clinical implementation feasibility based on imaging processing complexity, required expertise, and scalability. RESULTS:Of 1684 screened studies, 23 met the inclusion criteria. Skull geometric factors (n = 9), particularly skull thickness and volume, were the most commonly studied and showed consistent associations with both thermal and clinical outcomes. Histogram-based SDR metrics (eg, skewness) occasionally had stronger correlations with outcomes than mean SDR. Multivariate models and advanced imaging showed strong technical correlations but comparatively lower clinical feasibility due to complexity and computing demands. CONCLUSION:Although SDR remains the approved screening metric, our review suggests potential imaging-based alternatives to SDR. Specifically, readily available and implementable metrics such as skull geometric features show promising correlations with clinical and technical outcomes. Other methods, such as multivariate modeling, show promise but will need more time to become validated, accessible, and widely implemented.

Chronic craniofacial pain can lead to significant morbidity and reduced quality-of-life. Refractory pain subsequently leads to maladaptive changes within the central nervous system (CNS). It is logical to consider modulation of implicated neural networks to mitigate or reverse these changes in order to alleviate suffering. In this report, we reviewed the current literature in neuromodulation of CNS in facial pain treatment. We conducted PRISMA-compliant systematic review using MEDLINE and EMBASE databases. We included studies applying stimulation to the CNS to treat facial pain. Demographic data, design, duration, participants, clinical details, outcomes, adverse effects were extracted. Out of 1005 unique publications, 57 were included for analysis. Main techniques included were transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), motor cortex stimulation (MCS), deep brain stimulation (DBS), and spinal cord stimulation (SCS). For tDCS, rTMS, and MCS, the main stimulation target was primary motor cortex; while several different DBS targets (e.g., thalamic nuclei, anterior cingulate cortex, periaqueductal grey matter) were studied. While most studies showed improvement in Numeric Rating Scale for pain, values range widely from 11.1% in one MCS study to 90% in one rTMS study, with majority within 20-60%. There is heterogeneity across research designs, including patient selection, outcome measures, and follow-up. Standardized reporting framework is required to allow direct comparison between different modalities within subgroups of facial pain patients.

Transcranial ultrasound stimulation (TUS) is a promising noninvasive technique for modulating deep brain targets and circuits with high spatial precision. For its successful clinical translation, confirmation of target engagement, together with a deeper understanding of the effects of TUS, is essential. To advance these goals, we obtained direct measures of neural activity using electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) during TUS of deep and superficial targets, guided by magnetic resonance imaging-based acoustic modeling and real-time neuronavigation. Seventeen patients were studied in the on-medication and off-deep brain stimulation states. Each patient received one active and one sham session in a randomized order, and 13 of 17 patients (76%) completed a third session, which was always active. Each active condition targeted a single site-either the primary motor cortex (M1), the globus pallidus internus (GPi), or the occipital cortex (control site)-with 10 patients per active target. TUS effects on the STN were found to be target specific. Stimulation of the M1 reduced STN beta oscillation activity compared with sham stimulation and was associated with improvements in motor signs. These effects were brain state specific, showing distinct modulation patterns at rest versus during movement. In contrast, TUS targeting the GPi increased beta activity relative to control conditions and did not improve motor signs. Our results provide mechanistic evidence that TUS can safely and selectively modulate pathological brain rhythms in the STN in PD, supporting its potential as a targeted, noninvasive therapeutic modality.

Ultrasound offers a powerful means of modulating human cognition by noninvasively targeting subcortical structures previously accessible only via invasive procedures. While decades of research have mapped cortical circuits of attention, deep hubs such as the basal ganglia and thalamus are increasingly recognized as key nodes in attention networks. We tested whether low-intensity transcranial ultrasound stimulation (TUS) of the globus pallidus internus (GPi) and pulvinar modulates visual search, an attention-dependent task, predicting site-specific effects that reflect distinct basal ganglia-thalamic circuit functions. Focal TUS reduced reaction times, suggesting a facilitation of attention-related task performance. A dissociation emerged across sites: stimulation of both GPi and pulvinar reduced reaction times, but pulvinar yielded more robust benefits for target-present trials at peripheral eccentricities, and improved search efficiency in the same trials. These results support distinct contributions of basal ganglia and thalamic nodes to attention-related behavior and show that TUS can be used to probe circuit-level mechanisms of cognition in humans.

The translation of experimental brain stimulation procedures to clinical practice remains a significant challenge. In the present book chapter we review emergent innovations that have recently surfaced or are imminent to make the leap, improving the treatment of patients with brain disorders. We focus on two domains of accelerated innovative potential in both invasive and non-invasive brain stimulation domains. First, current advances in deep brain stimulation (DBS) methodology are introduced. DBS is an established treatment for neurological disorders such as Parkinson's disease, essential tremor and dystonia. Emerging technological advances focusing on when and how to stimulate allow for an extension and refinement of DBS promising scientific and clinical breakthroughs. We reflect on the unprecedented opportunities that MRI-based connectomics and neurophysiology based closed-loop DBS provide for patients with movement disorders, epilepsy and neuropsychiatric diseases. Next, we explore low-intensity focused transcranial ultrasound stimulation (TUS) as an emergent non-invasive neuromodulation technique. Unlike electrical or magnetic methods, TUS combines millimeter spatial precision with the ability to reach deep brain targets, making it the closest non-invasive analogue to DBS. We summarize its candidate mechanisms of action, highlight advances in transducer hardware and skull aberration-correction strategies, and review early clinical studies across movement disorders, epilepsy, pain, and psychiatric indications. Together, these developments illustrate how TUS is progressing from proof-of-concept experiments toward biomarker-guided therapeutic protocols. In conclusion, this chapter provides an outlook on the future of invasive and non-invasive techniques, emphasizing the need for continued research and innovation to overcome challenges in translating experimental successes into effective clinical therapies.

Transcranial ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation. The International Transcranial Ultrasonic Stimulation Safety and Standards consortium (ITRUSST) has established consensus on considerations for nonsignificant biophysical risk of TUS, drawing upon the literature and established regulations for biomedical devices. Here, we assume the application of TUS to individuals without contraindications, compromised thermoregulation, vascular vulnerabilities, or administered ultrasound contrast agents. In this context, we present a concise yet comprehensive set of levels for nonsignificant risks of TUS application. For mechanical effects, it is non-significant risk if the mechanical index (MI) or the mechanical index for transcranial application (MItc) does not exceed 1.9. For thermal effects, it is non-significant risk if any of the following three levels are met: the peak temperature rise does not exceed 2°C or the peak absolute temperature does not exceed 39°C, assuming a baseline temperature of 37°C, the thermal dose does not exceed 2 CEM43 in brain tissue, 16 CEM43 in bone tissue, and 21 CEM43 in skin tissue, or specific values of the thermal index (TI) for a given exposure time. This report reflects a consensus expert opinion and can inform, but not replace, regulatory guidelines or official international standards. Similarly, this consensus can inform, but not replace, ethical evaluation, which weighs the total burden, risks, and benefits of the proposed action. The stated levels are not safety limits per se, and further data is needed to establish the threshold for significant risk. We review literature relevant to our considerations and discuss limitations and future developments of our approach.

Background Deep brain ultrasound offers a novel means of modulating human cognition by noninvasively targeting subcortical structures that were previously accessible only through invasive procedures. While decades of research have mapped cortical circuits of attention, the causal roles of deep hubs such as the basal ganglia and thalamus remain poorly understood in the healthy human brain. Objectives/Hypothesis To test whether low intensity transcranial ultrasound stimulation (TUS) of two nodes in the basal ganglia-thalamic network, the globus pallidus internus (GPi) and the pulvinar, causally alters visual attention. We hypothesized that TUS-induced modulations in attentional performance would be site specific, reflecting distinct circuit functions. Results Across sessions, focal TUS accelerated reaction time in a visual search task, indicating augmented attention. Reaction time improvements were observed after stimulation relative to baseline. A dissociation emerged across sites: both GPi and pulvinar enhanced reaction times, but pulvinar yielded more robust benefits for target present trials at peripheral eccentricities, and improved search efficiency in the same trials. Conclusions These findings provide causal evidence that human attentional control can be steered at deep subcortical sites. TUS offers a practical approach for dissecting circuit level contributions to cognition and a potential noninvasive avenue for enhancing attention and other cognitive or affective functions. ### Competing Interest Statement The authors have declared no competing interest. Canadian Institutes of Health Research, FDN 154292, PJT 198046 Natural Science and Engineering Research Council, RGPIN-2020-04176

INTRODUCTION:Real-time monitoring during MR-guided focused ultrasound (MRgFUS) procedures has been considered essential to monitor tremor improvement and side effects in the alignment and/or verify phase before the actual MRgFUS treatment and following the ablative sonications. However, a subgroup of patients does not tolerate being awake during the entire procedure for a variety of reasons. CASE PRESENTATIONS:We performed MRgFUS treatments in three Parkinson's disease/Parkinsonism patients under general anesthesia. These patients had previously failed an attempt to undergo the procedure awake. All 3 patients who had the procedure under general anesthesia experienced significant improvement of their symptoms and experienced only transient adverse effects (e.g., balance problems, left facial droop) that were no longer evident at their first postoperative visit. CONCLUSION:Our findings suggest that MRgFUS treatment under general anesthesia could possibly be done safely and may represent a valid therapeutic option for patients unable to tolerate the procedure awake.

Noninvasive brain stimulation (NIBS) methods can modulate brain plasticity, the fundamental process by which synaptic connections are strengthened or weakened in response to synaptic activity or external stimuli. This review synthesizes current knowledge regarding how NIBS techniques induce long-lasting synaptic changes resembling long-term potentiation (LTP) and long-term depression (LTD). We place special emphasis on metaplasticity, the process by which prior neural activity influences subsequent plasticity responses. We highlight how various stimulation parameters, brain state, and individual differences shape plasticity outcomes, and emphasize the challenges in achieving consistent therapeutic effects. Additionally, we discuss the potential clinical impact of applying metaplasticity concepts in the treatment of neurological and psychiatric disorders. We outline critical areas for future research and emphasize the importance of developing personalized NIBS protocols that are closely aligned with underlying biological mechanisms to improve therapeutic outcomes.

BACKGROUND:The efficacy and adverse events (AEs) of bilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomies for essential tremor (ET) have not been compared to those of deep brain stimulation (DBS). Furthermore, it is uncertain whether second-side thalamotomies can be positioned differently from the first without compromising effectiveness. OBJECTIVE:We aimed to indirectly compare bilateral MRgFUS and DBS, while identifying optimal lesion/stimulation locations. METHODS:We retrospectively examined 41 ET patients who received either bilateral thalamic DBS (n = 22) or MRgFUS (n = 19) surgery. The primary outcome was the comparison of modalities for change in Clinical Rating Scale for Tremor (CRST) from baseline to post second surgery. We characterized AEs, generated probabilistic maps, and tracked streamlines intersecting lesions. First-side lesions were always intentionally placed ventrally (z = 0/+2 mm above the intercommissural plane [ICP]), and second-side lesions were placed dorsally (z = +3 mm above ICP). RESULTS:Tremor scores improved significantly after second surgeries (MRgFUS: 56.3 ± 7.1 to 24.2 ± 10.4, P < 0.001; DBS: 58.8 ± 11.6 to 25.0 ± 13, P < 0.05, mean follow-up: 23/26 months), with no differences between modalities. Following first surgeries, scores were MRgFUS: 37.9 ± 7.9 and DBS: 35.2 ± 13.6, with significant improvement from baseline (P < 0.001, mean follow-up: 40/73 months). All AEs were grade 1-2, with AE-free rates of 41% for DBS and 32% for MRgFUS. First-side lesions exhibited maximal efficacy in the ventral Vim, extending to posterior subthalamic area (PSA), whereas second-side lesions demonstrated maximal efficacy in the dorsomedial Vim-Vop border. DBS maps corroborated this finding and confined to Vim-Vop border. Lesions intersecting with networks interconnected with the supplementary motor area, in addition to M1, were associated with improved outcomes. CONCLUSIONS:The efficacies of bilateral MRgFUS and DBS appear comparable. MRgFUS probabilistic maps vary with different targeting methods, revealing two distinct sweet spots: dorsal Vim-Vop border and ventral Vim/PSA. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transcranial ultrasound stimulation (TUS) offers precise, non-invasive neuromodulation, though its impact on human deep brain structures remains underexplored. Here we examined TUS-induced changes in the basal ganglia of 10 individuals with movement disorders (Parkinson’s disease and dystonia) and 15 healthy participants. Local field potentials were recorded using deep brain stimulation (DBS) leads in the globus pallidus internus (GPi). Compared to sham, theta burst TUS (tbTUS) increased theta power during stimulation, while 10 Hz TUS enhanced beta power, with effects lasting up to 40 min. In healthy participants, a stop-signal task assessed tbTUS effects on the GPi, with pulvinar stimulation serving as an active sham. GPi TUS prolonged stop-signal reaction times, indicating impaired response inhibition, whereas pulvinar TUS had no effect. These findings provide direct electrophysiological evidence of TUS target engagement and specificity in deep brain structures, suggesting its potential as a noninvasive DBS strategy for neurological and psychiatric disorders. Transcranial ultrasound stimulation (TUS) is a non-invasive method to modulate deep brain activity. Using direct recordings from implanted electrodes, we showed that TUS engages the human globus pallidus internus, with effects on neural oscillations and behavior.

BACKGROUND:Many patients with Parkinson's disease (PD) have motor impairments despite dopaminergic therapy. Low-intensity transcranial ultrasound stimulation (TUS) is a non-invasive neuromodulation method with high spatial precision. The effects of motor cortex (M1) and internal globus pallidus (GPi) TUS on PD motor signs and cortical excitability are still uncertain. OBJECTIVES:To compare the effects of M1 theta burst TUS (tbTUS), GPi region tbTUS, and dual-site (M1 + GPi region) tbTUS on neurophysiology and motor signs in PD patients. METHODS:Sequential bilateral real M1/sham GPi, real GPi/sham M1, and simultaneous dual-site tbTUS were administered in three separate study visits in random order to 13 PD patients. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) scores and transcranial magnetic stimulation measures of cortical excitability were recorded at baseline and at several time points up to 60 min after sonication. RESULTS:MDS-UPDRS-III scores and bradykinesia subscores decreased compared with baseline after GPi tbTUS at 30 min after sonication. Motor evoked potential (MEP) ratio to baseline increased after M1 tbTUS compared with GPi tbTUS at 10 min after sonication (T10). The stimulation intensity to elicit 1 mV MEP ratio to baseline in the GPi tbTUS condition was higher compared with baseline and with M1 tbTUS and dual-site tbTUS at T10. MEP amplitudes and MDS-UPDRS-III scores did not significantly change after the M1 and dual-site tbTUS conditions. CONCLUSIONS:Bilateral GPi region tbTUS is a potential non-invasive approach for improving motor signs in PD patients, particularly bradykinesia. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30 min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80 s train of active or sham tbTUS was delivered to the left M1 in 20 healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10 ms but not long-interval IHI at interstimulus interval of 40 ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80 s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1 measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

BACKGROUND:Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE:The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS:We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS:tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS:tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.