Many patients suffering with neurological and psychiatric disorders remain disabled despite modern medical and surgical approaches. Novel, safe, minimally invasive, and widely deployable therapies are urgently needed. Recent advances in focused ultrasound technology are opening a number of new therapeutic frontiers. Here, we review the emergence of transcranial focused ultrasound as a possible therapeutic tool for human brain disorders in the framework of 3 distinct applications: (1) high-intensity focused ultrasound (HIFU) to create therapeutic lesions in dysfunctional brain targets, (2) low-intensity focused ultrasound (LIFU) to open the blood-brain barrier (BBB), and (3) LIFU to stimulate neural elements to modulate the activity in neural circuits. These applications are discussed in the context of the historical evolution of transcranial focused ultrasound and the possible mechanism of action through which the various applications of ultrasound exert their effects, and we provide an overview of their clinical therapeutic potential.

BACKGROUND:The long-latency reflex (LLR), particularly LLR II elicited by peripheral stimulation, is considered a transcortical reflex and may reflect cortical-subcortical excitability. Its relevance as a biomarker for subthalamic nucleus deep brain stimulation (STN-DBS) optimization in Parkinson's disease remains unclear. OBJECTIVE:To examine whether LLR II responses are modulated by STN-DBS stimulation parameters and dopaminergic medication, and to explore the potential mechanisms underlying STN-DBS-related motor improvement. METHODS:Thirteen Parkinson's disease patients with STN-DBS underwent median nerve stimulation to assess LLR II, quantified as the peak abductor pollicis brevis electromyography (EMG) response at 50-70 ms, normalized to prestimulus baseline EMG, across different stimulation intensities, contacts, and frequency conditions, including 60 Hz, 130 Hz, and an energy-matched condition. A single DBS pulse was also paired with the cortical N20 response at N20 - 2 ms (T1) or N20 + 10 ms (T2) to assess timing-dependent effects. Sixteen Parkinson's disease patients without DBS were tested in medication-on and -off states. Motor severity was assessed using tested-side Unified Parkinson's Rating Scale Part III (UPDRS III) subscores. RESULTS:LLR II ratio was higher at 70% and 100% of clinical stimulation intensity than during DBS-off (P = 0.0029 and P = 0.042, respectively). LLR II was higher at the most effective than at the least-effective contact (P = 0.042). The clinically most-effective frequency showed higher LLR II than DBS-off and the least-effective frequency (both P = 0.048). In the single-pulse DBS experiment, LLR II increased only at T2 compared to DBS-off (P = 0.047). No medication-state difference was observed. CONCLUSIONS:LLR II was modulated by clinically effective STN-DBS parameters but was insensitive to dopaminergic medication, supporting its utility as a biomarker of DBS-related sensorimotor circuit modulation, potentially involving the hyperdirect pathway. © 2026 International Parkinson and Movement Disorder Society.

Spinocerebellar ataxia type 27B is a recently described autosomal dominant, late-onset cerebellar ataxia caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Despite being recognized as a frequent adult-onset ataxia, its full clinical spectrum remains incompletely understood. To characterize the neurological, cognitive, and paraclinical phenotype of patients with heterozygous FGF14 repeat expansions (>200) and expand the currently known motor and non-motor features, as well as to assess the co-occurrence of other repeat expansions. In this cross-sectional single-center study, patients with heterozygous FGF14 repeat expansions underwent standardized neurological examination and cognitive screening. Paraclinical data were reviewed when available. 18 patients were included in the study (mean age at onset: 64 [37–79], at examination: 76 [61–94]). They all presented with gait ataxia, most commonly a lateral veering gait with corrective sidesteps. In addition to the core known cerebellar phenotype, we identified other movement-disorder manifestations, including myokymia, myoclonus, dystonia, and parkinsonism, with nigrostriatal degeneration confirmed in one patient. Cognitive impairment was common, with two-thirds of patients fulfilling criteria for cerebellar cognitive–affective syndrome (mean MoCA: 25 [21–29], CCAS: 86.9/120 [62–108]). Worse CCAS and MoCA performance was associated with increasing ataxia severity. FGF14 repeat expansions ranged from 210 to 520, and co-occurrence with heterozygous expansions in RFC1 or ATXN8/ATXN8OS were identified in three patients. Earlier diagnostic misclassification as transient ischemic attack was reported in 33

Advances in clinical neurophysiology have transformed the understanding and assessment of myoclonus. Neurophysiological techniques have made it possible to identify the neural generators of myoclonus and have provided the foundation for modern classification systems that integrate clinical phenomenology with physiological mechanisms. Many of these developments were shaped by the work of several research groups worldwide, with major influence from the contributions of Professor Mark Hallett. His studies helped to establish the central role of neurophysiology in the investigation of myoclonus. Through careful neurophysiological experiments and clinical observations, his work clarified the mechanisms underlying cortical and brainstem myoclonus and contributed substantially to the characterization of functional jerks. This review summarizes current approaches to the clinical neurophysiological evaluation of myoclonus and outlines the evolution of classification systems leading to the recent consensus framework proposed by the International Association of Parkinsonism and Related Disorders. Key neurophysiological techniques used in clinical practice are discussed, and emerging quantitative approaches, including machine-learning of neurophysiological signals, are also highlighted as potential tools to improve diagnostic precision and standardization in the evaluation of myoclonus.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that causes debilitating symptoms in both the motor and cognitive domains. The neurophysiological markers of PD include 'oscillopathies' such as diffuse neural oscillatory slowing, dysregulated beta band activity, and changes in interhemispheric functional connectivity; however, the relative importance of these markers as determinants of disease status is unclear. In this case-control study, we used resting state magnetoencephalography (MEG) data (n = 199 participants, 78 PD, 121 controls) from the OMEGA repository to investigate changes in spectral power and functional networks in PD. Using a Contrast of Parameter Estimates approach, we modelled the effects of PD while controlling for population-level confounds. Permutation testing revealed significant increases in theta (p = 0.0001) and decreases in gamma band spectral power (p = 0.0001). We also used a partial least squares-based classifier to find linear combinations of MEG features which independently predict PD. We found MEG-based predictions to be highly sensitive and specific, reaching an optimal AUC-ROC of 0.87 ± 0.04. Interpretation of the model indicates oscillatory slowing can be separated into components that can robustly identify individual cases of PD. This suggests MEG can reveal dissociable, complementary neural processes which contribute to PD.

Transcranial ultrasound stimulation (TUS) of the motor cortex (M1) has been found to modulate interhemispheric inhibition (IHI) after sonication (offline effect). However, the effects of M1 TUS on IHI during sonication (online effect) remain unknown. The current study examined the effects of online M1 TUS on IHI from the sonicated M1 to the contralateral M1 and on the contralateral M1 excitability in 15 healthy subjects. IHI was measured with paired-pulse transcranial magnetic stimulation (TMS) at 10 ms (short-latency IHI, SIHI) or 40 ms (long-latency IHI, LIHI) interstimulus interval (ISI), and the contralateral M1 excitability was measured with single-pulse TMS. The results showed that online TUS decreased the sonicated M1 to the contralateral M1 at LIHI but not at SIHI, while the contralateral TUS M1 excitability was unchanged. TUS may modulate complex circuits that mediate LIHI. These findings showed that TUS can be used to investigate the functional interactions between the two hemispheres. KEY POINTS: Offline non-invasive brain stimulations have been shown to modulate interhemispheric inhibition. The current study examined the effects of online primary motor cortex (M1) transcranial ultrasound stimulation (TUS) on interhemispheric inhibition from the sonicated M1 to the contralateral M1, and the contralateral M1 excitability. TUS decreased long- but not short-latency interhemispheric inhibition from the sonicated M1 to the contralateral M1. TUS could be a tool for investigating functional interactions between the two hemispheres.

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: Gamma-band activity has been linked to cognitive-affective processing in depression. However, its role in deep brain stimulation (DBS) response in treatment-resistant depression (TRD) remains unclear. This exploratory study investigated whether ventral capsule/ventral striatum DBS (VCVS-DBS) modulates gamma activity during cognitive-affective processing and whether DBS-related gamma changes are associated with improvement in depressive symptoms. Methods: Seven participants with TRD completed an affective Multi-Source Interference Task during DBS ON and OFF. Source-localized electroencephalography estimated local gamma power, synchrony, and effective connectivity in fronto-cingulate regions. DBS- and task-related effects were identified with cluster-based permutation testing, and follow-up analyses used Bayesian modelling. Results: During cognitive control under affective context, VCVS-DBS was associated with increased mid-gamma (41–55 Hz) power in left dorsal anterior cingulate cortex (L-dACC) and right ventrolateral prefrontal cortex (R-VLPFC) after affective stimuli. In the time window where power increases overlapped (0.76–0.86 s), DBS was also associated with increased mid-gamma synchrony between these regions. The DBS-related increase in synchrony—not local power—was associated with clinical improvement (Bayesian Spearman ρ = 0.52). Granger causality further indicated that effective connectivity shifted toward greater L-dACC influence over R-VLPFC during DBS. Exploratory cross-validation suggested that DBS-related synchrony change and baseline effective connectivity together accounted for individual differences in clinical improvement. Limitations: The primary limitation was the necessarily small sample size, which was partially addressed using Bayesian analyses leveraging extensive within-participant data. Conclusions: These preliminary findings suggest that VCVS-DBS may engage a fronto-cingulate gamma network involved in cognitive-affective control in TRD. They further suggest that clinical response may depend on both baseline dACC–VLPFC network organization and DBS-related modulation of gamma synchrony, highlighting potential relevance to cognitive-affective regulation across psychiatric disorders. Given the small sample size, these findings should be considered hypothesis-generating and require confirmation in larger cohorts.

Dystonia is increasingly recognized as a disorder of brain networks. This review integrates multimodal evidence from human studies to characterize the network-level pathophysiology of dystonia. Structural MRI studies using voxel-based morphometry and diffusion imaging reveal alterations in gray matter volume and white matter connectivity across the sensorimotor cortex, basal ganglia, cerebellum, and thalamus. Functional imaging modalities, including PET, fMRI, EEG, MEG, and fNIRS, demonstrate aberrant activity and connectivity in cortico-striato-pallido-thalamocortical and cerebello-thalamocortical loops. Invasive electrophysiological recordings from deep brain stimulation (DBS) provide high-resolution insights into abnormal oscillatory activity and effective connectivity within these circuits. Non-invasive brain stimulation (NIBS) techniques such as TMS, TES, and TUS provide a means of actively interrogating those networks through transient perturbation. They also provide an avenue for personalized neuromodulation. Computational models, including The Virtual Brain platform, enable integration of multimodal data to simulate dynamic network behavior. Across focal, generalized, and genetic forms of dystonia, shared patterns of network dysfunction are observed, though phenotypic and genotypic subtypes exhibit distinct topographies and circuit-level alterations. These findings underscore the importance of network dysfunction underlying dystonia. This network perspective informs the development of more targeted and individualized diagnostic and therapeutic approaches, including circuit-guided neuromodulation and closed-loop brain stimulation. Advancing multimodal and integrative methodologies will be essential to unraveling the complex dynamics underlying dystonia and translating mechanistic insights into precision interventions.

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.

Background Low-intensity focused transcranial ultrasound stimulation (TUS) is a noninvasive neuromodulation technique with high spatial precision and the ability to target deep brain structures. Although it has been extensively studied in the past decade, the strength and mechanism of modulation are not fully characterized through conventional measures such as local field potential and electroencephalography. Behavioral tasks can offer relevant insights into the functional outcomes of TUS that neurophysiologic or imaging measures have not captured. The consolidation of the findings of existing task-based studies can guide future experimental designs to better assess these neuromodulatory effects. Materials and Methods This rapid review systematically evaluates the brain regions, task paradigms, and sonication parameters used in TUS studies with humans and nonhuman primates. The eligibility criteria were developed using the Population, Intervention, Comparison, Outcomes, and Study Design framework to retrieve peer-reviewed, task-oriented TUS studies. Searches were conducted across Web of Science, Pubmed, Scopus, Cochrane, and IEEE Xplore data bases on January 6, 2026. Articles were independently screened using the Covidence systematic review software to avoid biases. Results We identified 41 studies across nine distinct cortical and subcortical regions, with varying sonication protocols and outcomes. Conclusions Our findings suggest that TUS is a promising tool for behavioral modulation. However, parameter optimization frameworks are necessary for this technology to yield significant and consistently reproducible results.

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.

Abstract Objective Reliable prognostic biomarkers in depression remain elusive. The objective of this study was to assess whether interleaved intermittent theta-burst stimulation-fMRI (iTBS-fMRI) can measure real-time target engagement, and prospectively test whether target engagement was associated with subsequent response to accelerated, connectivity-guided iTBS in treatment-resistant depression. Methods This single-centre trial ( NCT05813093 ) included 71 patients (42 with treatment-resistant depression [TRD], 29 ultra-treatment-resistant [UTRD]) who received personalized left dorsolateral prefrontal cortex (dlPFC) targeting based on functional connectivity with the subgenual anterior cingulate cortex (sgACC). Participants underwent one sham-controlled iTBS-fMRI session followed by five days of open-label accelerated iTBS (40 sessions; 600 pulses each). The primary outcome was change in HAM-D 17 . Primary imaging analyses examined active-sham interleaved iTBS-fMRI effects in the sgACC and left dlPFC regions, and their relationship with clinical outcomes. Results Accelerated iTBS was associated with rapid, sustained symptom reductions (ΔHAM-D 17 -9.01, p<0.001); overall response and remission rates were 40.8% (TRD: 47.6%, UTRD: 31.0%) and 16.9% (TRD: 16.7%, UTRD: 17.2%), with benefit maintained at 4 and 12 weeks. During interleaved iTBS-fMRI, active stimulation elicited significant target engagement within the sgACC-associated seedmap used for targeting (p=0.029). This brain response correlated with subsequent clinical improvement in depression and anxiety, but not other symptoms, and provided additional prognostic value independent of established clinical and demographic predictors. Conclusions Connectivity-guided accelerated iTBS was associated with rapid antidepressant effects in both TRD and UTRD participants with less pronounced effects in UTRD. Online target engagement measured by interleaved iTBS-fMRI is a candidate mechanistic biomarker that may aid prognosis in the future.

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.

BACKGROUND:Magnetic continuous theta burst stimulation (cTBS) is known to suppress human motor cortical excitability. Whether transcranial ultrasound stimulation (TUS) delivered in a continuous theta burst pattern (ctbTUS) produces similar inhibitory effects and whether co-applying ctbTUS with cTBS enhances these effects remains unclear. METHODS:Four stimulation conditions: ctbTUS + sham cTBS (ctbTUS), sham ctbTUS + cTBS (cTBS), sham ctbTUS + sham cTBS (sham), and ctbTUS + cTBS (cosTBS) were applied. Fifteen participants underwent neurophysiological testing with motor-evoked potentials (MEPs) recorded at 0, 10, 20, and 60 min post-stimulation, normalized to pre-intervention baselines. Additionally, 18 participants underwent resting-state functional MRI (rsfMRI) to assess functional connectivity (FC) between the hand representation of the motor cortex (M1) and other brain regions. Simulated skull density, transducer-skull space, and online-inhibition characteristics were evaluated as modulatory factors. RESULTS:ctbTUS induced inhibitory after-effects measured by MEP amplitude lasting up to 60 min (p = 0.001). However, cosTBS reduced this inhibition, although immediate MEP suppression remained (p = 0.024). rsfMRI revealed reduced FC between M1 and bilateral pre/post-central gyri and increased cerebellar FC after ctbTUS, but such after-stimulation patterns were absent after cosTBS. Higher pseudo-computed-tomography-derived skull density was associated with more negative ΔFC (or FC suppression, β = -0.844, p = 0.004). Participants with online inhibition showed greater offline MEP suppression (p = 0.004). CONCLUSIONS:ctbTUS induced inhibitory after-effects lasting up to 60 min but cosTBS decreased this suppression, likely via calcium-dependent plasticity or homeostatic plasticity effects. Skull density, and individual sensitivity to TUS are critical factors influencing TUS efficacy.