Low Intensity Ultrasound Neuromodulation for the treatment of Major Depressive Disorder: Systematic Review and Meta‑Analysis of Randomized Controlled Trials

Low Intensity Ultrasound Neuromodulation for the treatment of Major Depressive Disorder: Systematic Review and Meta‑Analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Low Intensity Ultrasound Neuromodulation for the treatment of Major Depressive Disorder: Systematic Review and Meta‑Analysis of Randomized Controlled Trials Nima Norbu Sherpa, Gabriela Prilip, Anna Caroline Moreira Tenório, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7930997/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Major depressive disorder (MDD) affects over 264 million individuals globally, yet about one‑third of patients fail to achieve remission with conventional therapies. Low‑intensity ultrasound neuromodulation (LIUN), which includes low‑intensity focused ultrasound (LIFU) and transcranial pulse stimulation (TPS), offers millimetre‑scale targeting and the ability to reach deep limbic regions without implants or strong electromagnetic fields. Objectives To conduct the first systematic review and meta‑analysis of randomized, sham‑controlled trials assessing the efficacy and safety of LIUN in adults with MDD. Methods We searched PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey through July 2025 for RCTs comparing active LIUN versus sham in MDD. Two reviewers independentlyscreened studies and extracted data. Depressive symptom change was pooled using a random‑effects model to calculate standardized mean differences (SMDs). Heterogeneity was quantified with the I² statistic. Adverse events were narratively summarized. Results Three RCTs (n = 78 randomized; 68 completers) met inclusion criteria—one LIFU trial (Oh et al., 2024 ) and two TPS trials (Cheung et al., 2022 ; QIN, 2025 ). LIUN yielded a small‑to‑moderate reduction in depressive symptoms compared to sham (SMD = –0.55; 95 % CI: − 1.07 to − 0.02; p = 0.04). Between‑stud heterogeneity was low (I² = 23 %). Adverse events—transient headache, scalp ingling, and skin redness—were generally mild and self‑limiting. Qin et al. reported higher rates of transient sensations in the active arm (92 % vs 42 %), whereas Cheung et al. and Oh et a. descrbed minimal or no adverse effects without treatment discontinuation. Conclusions Preliminary evidence suggests LIUN modestly reduces depressive symptoms in MDD with a benign safety profile. However, the small number of heterogeneous trials underscores the need for larger, parameter‑standardized RCTs to confirm efficacy, optimize sonication protocols, and establish long‑term safety. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience major depressive disorder transcranial pulse stimulation (TPS) low‑intensity focused ultrasound (LIFU) randomized controlled trials meta‑analysis and ultrasonic neuromodulation Figures Figure 1 Figure 2 Figure 3 Introduction Major depressive disorder (MDD) remains one of the leading causes of disability across all ages affecting more than 264 million people worldwide (Wang et al., 2025 ). Despite advances in pharmacotherapy and psychotherapy, approximately one‑third of patients do not achieve remission with first‑line treatments (Gülpen et al., 2023 ; Oliveira-Maia et al., 2023 ). An enduring unmet need for novel interventions has driven interest in non‑invasive brain stimulation (NIBS) modalities (Benster et al., 2023 ), such as repetitive transcranial magnetic stimulation (rTMS) (Róbert György Vida et al., 2023 ) and transcranial direct current stimulation (tDCS) (Wang et al., 2024 ). These techniques modulate cortical excitability and network connectivity but are limited by millimetre‑scale focality and an inability to reliably target deep limbic structures implicated in MDD pathophysiology (Guan et al., 2025 ; Reinhart and Woodman, 2015 ). Low‑intensity ultrasound neuromodulation (LIUN) has recently emerged as a promising NIBS alternative (Fomenko et al., 2018 ). LIUN uses acoustic pressure waves—rather than magnetic or electrical fields—to induce mechanical displacement of neuronal membranes (Feng and Li, 2024 ; Fomenko et al., 2018 ). Operating at intensities below thresholds for tissue heating or cavitation (Feng and Li, 2024 ), LIUN can reversibly influence neuronal firing (Cox et al., 2024 ), synaptic efficacy, and large‑scale network dynamics without the need for implants or strong electromagnetic fields (Gorka et al., 2024 ). Two principal LIUN modalities have been explored for major depressive disorder. Transcranial focused ultrasound (tFUS) employs either a 250kHz or 500 kHz carrier delivered in continuous or pulsed bursts of several hundred milliseconds, producing an elliptical, millimetre‑scale focal zone capable of reaching both cortical and subcortical structures (Legon et al., 2014 ). Transcranial pulse stimulation (TPS) delivers single ultrashort (~ 3 µs) Gaussian‑weighted shock pulses at a low duty cycle of approximately 4 Hz, offering millisecond‑scale temporal precision (Matt et al., 2022 ). Preclinical studies demonstrate that LIUN modulates synaptic plasticity and connectivity in mood‑relevant circuits (Chen et al., 2023 ; Pellow et al., 2024 ), and preliminary human pilots report transient mood and cognitive enhancements at intensities well below safety limits (Barksdale et al., 2025 ; Fouragnan et al., 2024 ; Yaakub et al., 2023 ). To date, only three randomized, sham‑controlled trials of LIUN in adults with clinically diagnosed MDD have been published (Cheung et al., 2022 ; Oh et al., 2024 ; QIN, 2025 ).Their small sample sizes and heterogeneity in stimulation parameters preclude definitive conclusions. Here, we present the first systematic review and meta‑analysis of these RCTs to quantify the pooled effect of LIUN on depressive symptom severity and evaluate its safety profile. By synthesizing these early data, we aim to inform optimal sonication parameters, standardize outcome measures, and guide future clinical trials of low intensity ultrasound‑based neuromodulation in MDD. Results Selection and Inclusion of Studies The search identified 1023 articles. After removing duplicates, we screened 784 titles and abstracts and ultimately reviewed 12 full-text articles. Finally, three studies (Cheung et al., 2022 ; Oh et al., 2024 ; QIN, 2025 ) were included in our final meta-analysis. The detailed PRISMA flow diagram is provided in the Fig. 1 Study Characteristics A total of three randomised, sham‑controlled trials assessing low intensity ultrasound neuromodulation in adults with major depressive disorder (MDD) were identified and included in this analysis, yielding 78 participants at randomisation and 68 completers (Cheung et al., 2022 ). The first, study by (Oh et al., 2024 ), was conducted in South Korea and employed a double‑blind design; 23 individuals received low‑intensity focused ultrasound (LIFU) targeted to the right frontal region (F8) over five daily sessions, with 11 allocated to active treatment and 12 to sham. Participant ages averaged 32.4 (± 11.2) years in the active arm and 39.6 (± 12.3) years in the control arm; mean duration since MDD onset was 5.6 (± 6.2) versus 7.7 (± 5.1) years, and mean years of education 14.3 (± 1.7) versus 15.3 (± 3.1). (Cheung et al., 2022 ) performed a single‑blind trial in Hong Kong, enrolling 30 participants (15 active, 15 sham) to receive TPS over the left dorsolateral prefrontal cortex. Each participant underwent nine sessions across three months; active and control groups were of similar age (38.8 ± 15.0 vs. 34.3 ± 16.5 years) and illness duration (mean 98 ± 113 vs. 48.4 ± 38.3 months). The third study, (QIN, 2025 ), also in Hong Kong, employed a double‑blind design with 50 randomised participants (12 active, 12 sham analysed) receiving 12 TPS sessions over four weeks. Demographic and baseline severity data were not reported. Detailed study characteristics are presented in Table 1 . Table 1 Characteristics of included studies Design, setting, sample, diagnostic criteria, intervention and comparator details, primary outcome measure, and follow-up for each trial; values are mean (SD) unless stated, sample sizes reflect the analytic dataset, and when multiple time points were reported the pre-specified primary time point was used; minor discrepancies may occur due to rounding; abbreviations: MDD = major depressive disorder, LIUN = low-intensity ultrasound neuromodulation, LIFU = low-intensity focused ultrasound, TPS = transcranial pulse stimulation, DLPFC = dorsolateral prefrontal cortex. Lead Author Location Blinding Sample size Sample size age MDD onset (Years) Year of education Follow up (months) Intervention Sham Intervention Sham Intervention Sham Intervention Sham Oh et al South Korea Double 23 (10M) 11 (5M) 12 (5M) 32.4 ± 11.2 39.6 ± 12.3 5.6 ± 6.2 7.7 ± 5.1 14.3 ± 1.7 15.3 ± 3.1 2 weeks Cheung Hong Kong Single 30 (10 M) 15 (4M) 15 (4M) 38.8 (15.0) 34.3 (16.5) 98 (113) months 48.4 (38.3) N/A N/A 13 weeks Qin et al Honh Kong double 50 25 25 N/A N/A N/A N/A N/A N/A N/A -------------------------------------------INSERT Table 1 -------------------------------------------------- Efficacy outcomes The meta-analysis showed that transcranial ultrasound stimulation significantly reduced depressive symptoms compared to control conditions, with a standardized mean difference (SMD) of -0.55 (95% CI: -1.07 to -0.02; p = 0.04). Heterogeneity across studies was low (I² = 23%), as shown in Fig. 2. Safety and Tolerability All three trials explicitly monitored and reported the occurrence of treatment‑related adverse events, and none documented any serious or lasting harms. (QIN, 2025 ) collected systematic adverse‑event data in both active and sham arms. In the active group, 11 of 12 participants (92%) experienced at least one transient symptom—most commonly tingling at the stimulation site, mild headache, or brief skin redness—whereas 5 of 12 (42%) in the sham arm reported similar sensations, suggesting a higher event rate when ultrasound was delivered. (Cheung et al., 2022 ) noted only two minor, transient sensations (e.g. slight scalp discomfort) across all 30 participants (active = 15; sham = 15). These events resolved spontaneously without intervention, and no participant discontinued treatment as a result. (Oh et al., 2024 ) did not provide a quantitative tally of adverse events, but the authors stated that safety monitoring identified no adverse symptoms or withdrawals attributable to the LIFU intervention. Across the three studies, adverse events were uniformly mild, self‑limiting, and did not necessitate any treatment modifications, underlining a benign safety profile for both low‑intensity focused ultrasound and transcranial pulse stimulation in MDD populations. Sonication parameter (Oh et al., 2024 ) used a low‑intensity focused ultrasound device (NS‑US100) delivering 200 pulses (1 ms on, 2 ms off) at 250 kHz over a total of 20 minutes (five 30 s stimulations per day across four days), achieving an in situ spatial peak pulse average intensity (ISPPA) of 3 W/cm² and spatial peak temporal average intensity (ISPTA) of 0.6 W/cm², with a mechanical index of 0.27 (estimated peak negative pressure 300 kPa). (Cheung et al., 2022 ) applied TPS (NEUROLITH) consisting of 1 800 pulses (1 000 pulses per session, three sessions/week for six weeks) at 3–4 Hz with an ultrashort 0.003 ms pulse duration, delivering 0.2–0.25 mJ/mm² per pulse; duty cycle and mechanical index were not specified. (QIN, 2025 ) employed an identical TPS protocol over 12 sessions (total 12 000 pulses), but detailed sonication parameters (frequency, pulse width, intensity) were not reported. -------------------------------------------INSERT Table -------------------------------------------------- Table 2 Sonication parameters Device/mode, target and laterality, neuronavigation method, acoustic parameters (frequency, PRF/PRI, duty cycle, burst length), intensity metrics (ISPPA/ISPTA or EFD), and session dose are summarised as reported by each study; cross-study dose comparisons should be interpreted cautiously given differences in reporting frames (free-field vs in situ) and missing acoustic characterisation; abbreviations: ISPPA = spatial-peak pulse-average intensity, ISPTA = spatial-peak temporal-average intensity, EFD = energy flux density, MI = mechanical index, PRF = pulse repetition frequency, PRI = pulse repetition interval. Lead Author Brain region Device Name Median frequency Pulse duration (ms) Pulse repetition interval(ms) Pulse repetition frequency (Hz) Duty Cycl (%) Energy flux density Total duration (min) Total pulses Mechanical index Negative pressure (Pr) Oh et al DLPFC NS-US100; Neurosona 250 KHz 1ms 2ms 500Hz 50% 3 W/cm² (Isppa) 0.6 W/cm² (Ispta) 20 200 0.27 300kPa Cheung DLPFC NEUROLITH N/A 0.003ms N/A 3–4 Hz 0.0009%–0.0012% 0.2–0.25 mJ/mm² per pulse 180 1800 N/A N/A Qin et al DPLFC N/A N/A N/A N/A N/A N/A N/A N/A 12,000 N/A N/A Statistical Analysis We performed the meta-analyses using a random-effects model with the Generic Inverse Variance (GIV) method to account for between-study variability. Standardized mean differences (SMDs) were used to pool continuous outcomes. Heterogeneity was assessed using the Cochran Q test and I 2 statistic; p-values 50% were considered indicative of significant heterogeneity. The Wald-type adjustment was applied to all outcomes. All meta-analyses were conducted using Review Manager (RevMan) version 5.4 (“Cochrane,” 2025). Sensitivity Analysis To assess the impact of individual studies on overall heterogeneity, we conducted leave-one-out sensitivity analyses. The removing (QIN, 2025 ) reduced heterogeneity from 23% to 0%. The sensitivity analysis is provided in the Supplementary Materials. Quality Assessment (Risk of Bias ) Risk of bias was independently assessed by two independent reviewers (ACNT, GP) using the Cochrane RoB 2 tool across five domains (Sterne et al., 2019 ). Overall, Oh et al. ( 2024 ) exhibited low risk of bias in all domains. (Cheung et al., 2022 ) was judged to have some concerns due to its single‑blind design (D2) and incomplete description of outcome assessor blinding (D4), though randomisation, attrition handling and selective reporting were low risk. (QIN, 2025 ) raised concerns at randomisation (D1) and was deemed high risk for selective reporting (D5) owing to omitted baseline and secondary outcomes; other domains were low risk. Collectively, these assessments suggest that while two trials maintained rigorous methodology, one trial’s incomplete reporting may temper confidence in its findings and underscore the importance of cautious interpretation of the pooled estimate. Figure 3 Discussion This systematic review and meta-analysis explored the efficacy and safety of low-intensity ultrasound neuromodulation (LIUN) for treating Major Depressive Disorder (MDD), drawing on evidence from three randomised controlled trials (RCTs) (Cheung et al., 2022 ; Oh et al., 2024 ; QIN, 2025 ). The pooled results demonstrated a modest yet statistically significant reduction in depressive symptoms compared to sham controls (standardised mean difference [SMD] = -0.55; 95% CI: -1.07 to -0.02; p = 0.04). Heterogeneity among the studies was low (I² = 23%), suggesting consistency across the included trials. The observed reduction in depressive symptoms indicates that low-intensity ultrasound neuromodulation holds promise as a potential treatment for MDD, although the clinical significance remains modest. These findings align with preliminary evidence suggesting neuromodulatory efficacy but must be interpreted cautiously given the limited number of studies and relatively small sample sizes involved. The primary target of ultrasound stimulation in these trials was the dorsolateral prefrontal cortex (DLPFC), a region strongly implicated in mood regulation and cognitive processing in MDD (Cui et al., 2024 ; Nejati et al., 2022 ; Pizzagalli and Roberts, 2021 ). Although the exact reason for the beneficial effects observed is not known, it may be attributed to the modulation of neural circuits associated with emotional regulation and cognitive function (Cui et al., 2024 ). Our findings are consistent with previous studies on neuromodulation, which have shown that approaches such as rTMS and tDCS can modestly reduce depressive symptoms (Yang et al., 2024 ). However, unlike rTMS and tDCS, ultrasound neuromodulation has the advantage of deeper brain penetration (Cox et al., 2024 ; Yaakub et al., 2023 ) and precise spatial targeting (Philip and Arulpragasam, 2022 ), potentially offering additional therapeutic potential (Wal et al., 2020 ). Variability was noted in ultrasound sonication parameters across the included studies. (Oh et al., 2024 ) utilized a well-defined LIFU protocol, whereas (Cheung et al., 2022 ) and (QIN, 2025 ) employed TPS with differing pulse repetition frequencies, pulse durations, and session counts. These methodological variations could have influenced both efficacy and tolerability outcomes, suggesting the need for standardized protocols to facilitate direct comparison and consistent clinical interpretation. Variability and Dose–Response in Sonication Protocols The three RCTs employed markedly different stimulation paradigms. (Oh et al., 2024 ) used 200 pulses at 250 kHz (ISPPA 3 W/cm²; ISPTA 0.6 W/cm²) focused on the DLPFC over a single 20-minute session. (Cheung et al., 2022 ) applied transcranial pulse stimulation (TPS) with 300 pulses per 30-minute session (3–4 Hz shock pulses at 0.2–0.25 mJ/mm²) across six sessions. (QIN, 2025 ) delivered 1,000 ultrashort (3 µs) Gaussian pulses at ~ 4 Hz, three times per week for four weeks (total 12,000 pulses). Post hoc analyses across these studies suggest a correlation between increased total pulse count, lower Mechanical Index (MI), and enhanced symptom reduction, albeit with higher rates of mild paresthesia [5]. The absence of a standardized protocol impedes direct dose–response modeling and cross-study comparisons. Safety, Feasibility, and Standardization All three trials reported predominantly mild, transient adverse events—scalp discomfort, tingling, and headache—yet their documentation varied: (QIN, 2025 ) recorded a notably higher incidence in the active arm (92% vs. 42% sham), (Cheung et al., 2022 ) noted only two brief sensory events across 1800 pulses, and (Oh et al., 2024 ) stated no significant adverse outcomes without quantitative detail.The elevated AE rate in Qin et al. could likely reflects the high total pulse count (12,000) and ultrashort shock-pulse format, underscoring the need to balance cumulative dose with patient comfort. However, Oh et al.’s qualitative safety statement limits assessment of rare or delayed events; (Cheung et al., 2022 ) sparse AE tally precludes correlation with specific sonication parameters. We suggest that future LIUN investigations consider adopting more comprehensive, ITRUSST (Murphy et al., 2025 ) -aligned reporting practices to strengthen the rigor and reproducibility of safety assessments. Where possible, studies might provide detailed device and drive-system information—manufacturer/model, transducer geometry (aperture size, curvature, element count), center frequency, matching network and amplifier specifications, and coupling medium—alongside a thorough acoustic field characterization. This could include free‐field measurements (ISPPA, ISPTA, − 3 dB focal-zone dimensions, hydrophone calibration curves) as well as in situ estimates of skull-adjusted MIₜc and TIₜc derived from CT‐based simulations or standardized derating methods. We also recommend tabulating pulse-timing and dose parameters (e.g., pulse duration; PRI/PRF; duty cycle; total pulses and sessions; intersession spacing) to facilitate clear comparisons across protocols. Core safety indices—real-time MR thermometry (voxel-wise ΔT mapping with spatial/temporal resolution, drift correction, cooling logs) and continuous passive cavitation detection (phantom‐validated thresholds, correlated with any clinical observations)—could further enhance transparency. Routine equipment calibration (hydrophone or radiation‐force balance checks; electrical power/impedance verifications within defined tolerances) and basic workflow and tolerability metrics (total procedure duration; patient comfort/anxiety scores; operator feedback) may also prove valuable. Finally, where ethical and practical considerations allow, sharing de-identified, patient-level data (including standardized sonication coordinates and associated metrics in CSV or JSON format) could support cross-study comparisons, meta-analyses, and ultimately the broader goal of safely advancing LIUN methodologies. sonication parameters, thermometry and cavitation traces, CTCAE-graded AEs, and patient tolerability scores, all validated on ≥ 2 software platforms. The quality assessment identified variability in methodological rigour across the studies. (Oh et al., 2024 ) maintained low risk of bias across all domains. However, (Cheung et al., 2022 ) presented some concerns regarding blinding integrity, and (QIN, 2025 ) had a high risk of bias in selective reporting and concerns in randomisation methods. Such methodological limitations may compromise the robustness of pooled results and necessitate cautious interpretation. Future trials should ensure rigorous randomisation and blinding protocols, alongside complete reporting of demographic and clinical baseline characteristics. Heterogeneity and Methodological Limitations Our analysis identified three key study features that likely drove between-trial variability and warrant rigorous attention in future RCTs. 1. Within-Group Variance (QIN, 2025 ) reported an exceptionally large standard deviation in HDRS change for the sham arm (± 6.84), markedly higher than active-arm variances in comparable trials. Elevated within‐group dispersion inflates overall heterogeneity (τ²) and diminishes the precision of pooled effect estimates. Future studies should consistently report variance metrics (SD, IQR) for all arms and conduct sensitivity analyses—such as leave-one-out or meta-regression—to evaluate the impact of high‐variance datasets on overall outcomes. 2. Outcome Measure Consistency Current trials utilized multiple depression scales (HDRS, MADRS) without a pre-specified primary endpoint, complicating effect-size harmonization. To enhance interpretability, we recommend pre-registration of a single primary depression instrument (e.g., HDRS-17) with standardized responder criteria (≥ 50% reduction), while reporting additional scales solely as supportive secondary outcomes. 3. Blinding Verification None of the included RCTs formally assessed post-treatment blinding integrity. Unrecognized unblinding can introduce placebo or nocebo effects, biasing self-reported outcomes, and amplifying heterogeneity. Future RCTs should implement objective blinding indices such as James’ and Bang’s blinding indexes (James et al., 1996 ) after intervention and incorporate these data into risk-of-bias assessments and statistical adjustments. Strengths and Limitations A strength of this meta-analysis is its systematic approach, adherence to PRISMA guidelines (PRISMA, 2020 ), and conservative statistical interpretation. Nonetheless, several limitations must be acknowledged. Primarily, the small number of eligible trials limits the generalisability of the findings. Additionally, variability in sonication parameters and study methodologies may have contributed to outcome heterogeneity. Furthermore, demographic and clinical data were inconsistently reported, constraining subgroup analyses and reducing the ability to generalise findings to broader MDD populations. Future Research Directions Further large-scale, rigorously designed RCTs are required to confirm these preliminary findings and assess long-term efficacy and safety. Future studies should aim for standardisation of ultrasound neuromodulation parameters, rigorous adverse-event reporting, and inclusion of diverse demographic groups. Comparative effectiveness trials against established neuromodulatory interventions (e.g., rTMS, tDCS) and comprehensive neuroimaging assessments to elucidate the underlying neural mechanisms are also recommended. Clinical Implications Clinicians should interpret these findings cautiously, recognising that while preliminary evidence supports LIUN’s potential in MDD treatment, more substantial evidence is needed to recommend its widespread clinical adoption. The mild adverse-event profile is encouraging, yet careful monitoring during treatments remains essential. Methods This study was conducted according to the PRISMA reporting guidelines. The review protocol was prospectively registered in OSF (osf.io/av2e7). Search Strategy A systematic search was conducted usingthe following databases: PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey. After removing the duplicates, the authors independently screened the studies in two phases, first in title and abstract and in second full text. Studies were included based on the inclusion criteria. The discrepancies were solved through consensus among a third author. The search strategy combined MeSH and keyword-based strategies and it's listed: The query search string was: ("Low intensity focused ultrasound" OR "LIFU" OR "Low intensity focused ultrasound stimulation" OR "LIFUS" OR "Low intensity pulsed ultrasound" OR "LIPUS" OR "Focused ultrasound stimulation" OR "FUS" OR "Focused ultrasound neuromodulation" OR "FUN" OR "Transcranial ultrasound stimulation" OR "TUS" OR "Transcranial focused ultrasound stimulation" OR "TFUS" OR "Magnetic Resonance-Guided Focused Ultrasound" OR "MRgFUS" OR "Transcranial pulse stimulation" OR "TPS") AND ("Depressive Disorder, Major"[Mesh] OR "major depressive disorder" OR MDD OR "recurrent depression" OR "severe depression" OR "unipolar depression") Eligibility criteria This Meta Analysis included studies that were (1)randomised controlled trials (including, double-blind, sham-controlled), (2) in adults (3) diagnosed with major depression disorder, (4) any form of TUS, LIPU, TPUS, LIFU as intervention,(4) that compared low intensity ultrasound neuromodulation against a sham or stimulation-off control, (5) reported pre-post changes using validated clinical scales for depression. Studies were excluded if they had (1) a control arm includes participants with a primary psychotic or bipolar diagnosis, substance use disorders, neurological or sleep disorders, intellectual disabilities, (2) trials of depression with psychotic features, (3) systematic and narrative reviews, and meta-analysis. Information sources, search, and selection of sources of evidence The search strategy was systematically conducted in the previous described databases to identify the studies according to the predefined eligibility criteria. The search was conducted on PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey databases and focused on studies that reported data about TUS in adults with major depressive disorder to evaluate the clinical efficacy, safety and tolerability of TUS in reducing symptoms in adults with MDD. The initial search resulted in 1023 references. After deduplication (239 duplicates identified), 784 unique records were screened using reference manager Rayyan. Following title and abstract screening, 132 records were excluded. 12 articles were assessed full-text, and 3 studies were included in the review. This process is illustrated in the PRISMA flow diagram as Fig. 1. Conclusion This systematic review and meta-analysis provides modest preliminary evidence supporting the efficacy and safety of low-intensity ultrasound neuromodulation for treating MDD. The findings suggest potential clinical benefit but highlight the necessity for larger, rigorously designed trials to confirm efficacy, safety, and long-term benefits before widespread clinical implementation. Declarations Primary funding Nima Norbu Sherpa is funded by National Institute for Health and Care Research (NIHR) 306286. Competing Interests Statement The authors declare no competing interests. Author Contribution Conceptualization: NNSMethodology: NNS, GP & ACNTSystematic search: NNS, ACNT & GPScreening and data extraction: NNS, ACNT, MARisk-of-bias assessment: GPFormal analysis: NNS, MAVisualization: NNSWriting—original draft: NNS Writing—review & editing: NNS, GO, ACNT, MASupervision: NNS Funding acquisition: NNSGuarantor: NNS ACKNOWLEDGEMENT NNS is supported by the National Institute for Health and Care Research (NIHR Pre-Doctoral Clinical Fellowship, NIHR500764). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. References Barksdale, B.R., Enten, L., DeMarco, A., Kline, R., Doss, M.K., Nemeroff, C.B., Fonzo, G.A., 2025. 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Brain stimulation 17, 734–751. https://doi.org/10.1016/j.brs.2024.06.005 Philip, N.S., Arulpragasam, A.R., 2022. Reaching for the unreachable: low intensity focused ultrasound for non-invasive deep brain stimulation. Neuropsychopharmacology 48, 251–252. https://doi.org/10.1038/s41386-022-01386-2 Pizzagalli, D.A., Roberts, A.C., 2021. Prefrontal cortex and depression. Neuropsychopharmacology 47. https://doi.org/10.1038/s41386-021-01101-7 PRISMA, 2020. PRISMA 2020 [WWW Document]. PRISMA statement. URL https://www.prisma-statement.org/prisma-2020 QIN, P., 2025. Transcranial pulse stimulation for the treatment of major depressive disorder: A randomized, double-blind, sham-controlled, pilot trial. Brain Stimulation 18, 507. https://doi.org/10.1016/j.brs.2024.12.852 Reinhart, R.M.G., Woodman, G.F., 2015. The surprising temporal specificity of direct-current stimulation. 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BMJ 366, l4898. https://doi.org/10.1136/bmj.l4898 Wal, J.M. van der, Bergfeld, I.O., Lok, A., Mantione, M., Figee, M., Notten, P., Beute, G., Horst, F., Munckhof, P. van den, Schuurman, P.R., Denys, D., 2020. Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression. Journal of Neurology, Neurosurgery & Psychiatry 91, 189–195. https://doi.org/10.1136/jnnp-2019-321758 Wang, J., Yao, X., Ji, Y., Li, H., 2024. Cognitive potency and safety of tDCS treatment for major depressive disorder: a systematic review and meta-analysis. Frontiers in Human Neuroscience 18. https://doi.org/10.3389/fnhum.2024.1458295 Wang, Y., Qin, C., Chen, H., Liang, W., Liu, M., Liu, J., 2025. Global, regional, and national burden of major depressive disorders in adults aged 60 years and older from 1990 to 2021, with projections of prevalence to 2050: Analyses from the Global Burden of Disease Study 2021. Journal of Affective Disorders 374, 486–494. https://doi.org/10.1016/j.jad.2025.01.086 Yaakub, S.N., White, T.A., Roberts, J., Martin, E., Verhagen, L., Stagg, C.J., Hall, S., Fouragnan, E.F., 2023. Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans. Nature Communications 14, 5318. https://doi.org/10.1038/s41467-023-40998-0 Yang, Y., Chen, J., Yu, M., Xiong, C., Zhang, R., Jiang, G., 2024. Comparative efficacy of multiple non-invasive brain stimulation to treat major depressive disorder in older patients: A systematic review and network meta-analysis study based on randomized controlled trials. Psychiatry Research 344, 116340. https://doi.org/10.1016/j.psychres.2024.116340 Additional Declarations No competing interests reported. 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10:24:05","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":137560,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARY1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7930997/v1/34fd9bbf404e2a3979204c17.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Low Intensity Ultrasound Neuromodulation for the treatment of Major Depressive Disorder: Systematic Review and Meta‑Analysis of Randomized Controlled Trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMajor depressive disorder (MDD) remains one of the leading causes of disability across all ages affecting more than 264\u0026nbsp;million people worldwide (Wang et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Despite advances in pharmacotherapy and psychotherapy, approximately one‑third of patients do not achieve remission with first‑line treatments (G\u0026uuml;lpen et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Oliveira-Maia et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). An enduring unmet need for novel interventions has driven interest in non‑invasive brain stimulation (NIBS) modalities (Benster et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), such as repetitive transcranial magnetic stimulation (rTMS) (R\u0026oacute;bert Gy\u0026ouml;rgy Vida et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) and transcranial direct current stimulation (tDCS) (Wang et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). These techniques modulate cortical excitability and network connectivity but are limited by millimetre‑scale focality and an inability to reliably target deep limbic structures implicated in MDD pathophysiology (Guan et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Reinhart and Woodman, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eLow‑intensity ultrasound neuromodulation (LIUN) has recently emerged as a promising NIBS alternative (Fomenko et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). LIUN uses acoustic pressure waves\u0026mdash;rather than magnetic or electrical fields\u0026mdash;to induce mechanical displacement of neuronal membranes (Feng and Li, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Fomenko et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Operating at intensities below thresholds for tissue heating or cavitation (Feng and Li, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), LIUN can reversibly influence neuronal firing (Cox et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), synaptic efficacy, and large‑scale network dynamics without the need for implants or strong electromagnetic fields (Gorka et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTwo principal LIUN modalities have been explored for major depressive disorder. Transcranial focused ultrasound (tFUS) employs either a 250kHz or 500 kHz carrier delivered in continuous or pulsed bursts of several hundred milliseconds, producing an elliptical, millimetre‑scale focal zone capable of reaching both cortical and subcortical structures (Legon et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Transcranial pulse stimulation (TPS) delivers single ultrashort (~\u0026thinsp;3 \u0026micro;s) Gaussian‑weighted shock pulses at a low duty cycle of approximately 4 Hz, offering millisecond‑scale temporal precision (Matt et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Preclinical studies demonstrate that LIUN modulates synaptic plasticity and connectivity in mood‑relevant circuits (Chen et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Pellow et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), and preliminary human pilots report transient mood and cognitive enhancements at intensities well below safety limits (Barksdale et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Fouragnan et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Yaakub et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTo date, only three randomized, sham‑controlled trials of LIUN in adults with clinically diagnosed MDD have been published (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).Their small sample sizes and heterogeneity in stimulation parameters preclude definitive conclusions. Here, we present the first systematic review and meta‑analysis of these RCTs to quantify the pooled effect of LIUN on depressive symptom severity and evaluate its safety profile. By synthesizing these early data, we aim to inform optimal sonication parameters, standardize outcome measures, and guide future clinical trials of low intensity ultrasound‑based neuromodulation in MDD.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSelection and Inclusion of Studies\u003c/p\u003e\u003cp\u003eThe search identified 1023 articles. After removing duplicates, we screened 784 titles and abstracts and ultimately reviewed 12 full-text articles. Finally, three studies (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) were included in our final meta-analysis. The detailed PRISMA flow diagram is provided in the Fig.\u0026nbsp;1\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eStudy Characteristics\u003c/p\u003e\u003cp\u003eA total of three randomised, sham‑controlled trials assessing low intensity ultrasound neuromodulation in adults with major depressive disorder (MDD) were identified and included in this analysis, yielding 78 participants at randomisation and 68 completers (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe first, study by (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), was conducted in South Korea and employed a double‑blind design; 23 individuals received low‑intensity focused ultrasound (LIFU) targeted to the right frontal region (F8) over five daily sessions, with 11 allocated to active treatment and 12 to sham. Participant ages averaged 32.4 (\u0026plusmn;\u0026thinsp;11.2) years in the active arm and 39.6 (\u0026plusmn;\u0026thinsp;12.3) years in the control arm; mean duration since MDD onset was 5.6 (\u0026plusmn;\u0026thinsp;6.2) versus 7.7 (\u0026plusmn;\u0026thinsp;5.1) years, and mean years of education 14.3 (\u0026plusmn;\u0026thinsp;1.7) versus 15.3 (\u0026plusmn;\u0026thinsp;3.1).\u003c/p\u003e\u003cp\u003e(Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) performed a single‑blind trial in Hong Kong, enrolling 30 participants (15 active, 15 sham) to receive TPS over the left dorsolateral prefrontal cortex. Each participant underwent nine sessions across three months; active and control groups were of similar age (38.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.0 vs. 34.3\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5 years) and illness duration (mean 98\u0026thinsp;\u0026plusmn;\u0026thinsp;113 vs. 48.4\u0026thinsp;\u0026plusmn;\u0026thinsp;38.3 months).\u003c/p\u003e\u003cp\u003eThe third study, (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), also in Hong Kong, employed a double‑blind design with 50 randomised participants (12 active, 12 sham analysed) receiving 12 TPS sessions over four weeks. Demographic and baseline severity data were not reported. Detailed study characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eCharacteristics of included studies\u003c/b\u003e Design, setting, sample, diagnostic criteria, intervention and comparator details, primary outcome measure, and follow-up for each trial; values are mean (SD) unless stated, sample sizes reflect the analytic dataset, and when multiple time points were reported the pre-specified primary time point was used; minor discrepancies may occur due to rounding; abbreviations: MDD\u0026thinsp;=\u0026thinsp;major depressive disorder, LIUN\u0026thinsp;=\u0026thinsp;low-intensity ultrasound neuromodulation, LIFU\u0026thinsp;=\u0026thinsp;low-intensity focused ultrasound, TPS\u0026thinsp;=\u0026thinsp;transcranial pulse stimulation, DLPFC\u0026thinsp;=\u0026thinsp;dorsolateral prefrontal cortex.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"13\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLead Author\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLocation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eBlinding\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003eage\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e\u003cp\u003eMDD onset (Years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003eYear of education\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eFollow up (months)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSham\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSham\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSham\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eSham\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOh et al\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSouth Korea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDouble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23 (10M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11 (5M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 (5M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e32.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e39.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e14.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCheung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHong Kong\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSingle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (10 M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 (4M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15 (4M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e38.8 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e34.3 (16.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e98 (113) months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e48.4 (38.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e13 weeks\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQin et al\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHonh Kong\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003edouble\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e-------------------------------------------INSERT Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e--------------------------------------------------\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eEfficacy outcomes\u003c/h2\u003e\u003cp\u003eThe meta-analysis showed that transcranial ultrasound stimulation significantly reduced depressive symptoms compared to control conditions, with a standardized mean difference (SMD) of -0.55 (95% CI: -1.07 to -0.02; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). Heterogeneity across studies was low (I\u0026sup2; = 23%), as shown in Fig.\u0026nbsp;2.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eSafety and Tolerability\u003c/h3\u003e\n\u003cp\u003eAll three trials explicitly monitored and reported the occurrence of treatment‑related adverse events, and none documented any serious or lasting harms.\u003c/p\u003e\u003cp\u003e(QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) collected systematic adverse‑event data in both active and sham arms. In the active group, 11 of 12 participants (92%) experienced at least one transient symptom\u0026mdash;most commonly tingling at the stimulation site, mild headache, or brief skin redness\u0026mdash;whereas 5 of 12 (42%) in the sham arm reported similar sensations, suggesting a higher event rate when ultrasound was delivered. (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) noted only two minor, transient sensations (e.g. slight scalp discomfort) across all 30 participants (active\u0026thinsp;=\u0026thinsp;15; sham\u0026thinsp;=\u0026thinsp;15). These events resolved spontaneously without intervention, and no participant discontinued treatment as a result. (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) did not provide a quantitative tally of adverse events, but the authors stated that safety monitoring identified no adverse symptoms or withdrawals attributable to the LIFU intervention.\u003c/p\u003e\u003cp\u003eAcross the three studies, adverse events were uniformly mild, self‑limiting, and did not necessitate any treatment modifications, underlining a benign safety profile for both low‑intensity focused ultrasound and transcranial pulse stimulation in MDD populations.\u003c/p\u003e\u003cp\u003eSonication parameter\u003c/p\u003e\u003cp\u003e(Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) used a low‑intensity focused ultrasound device (NS‑US100) delivering 200 pulses (1 ms on, 2 ms off) at 250 kHz over a total of 20 minutes (five 30 s stimulations per day across four days), achieving an in situ spatial peak pulse average intensity (ISPPA) of 3 W/cm\u0026sup2; and spatial peak temporal average intensity (ISPTA) of 0.6 W/cm\u0026sup2;, with a mechanical index of 0.27 (estimated peak negative pressure 300 kPa).\u003c/p\u003e\u003cp\u003e(Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) applied TPS (NEUROLITH) consisting of 1 800 pulses (1 000 pulses per session, three sessions/week for six weeks) at 3\u0026ndash;4 Hz with an ultrashort 0.003 ms pulse duration, delivering 0.2\u0026ndash;0.25 mJ/mm\u0026sup2; per pulse; duty cycle and mechanical index were not specified. (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) employed an identical TPS protocol over 12 sessions (total 12 000 pulses), but detailed sonication parameters (frequency, pulse width, intensity) were not reported.\u003c/p\u003e\n\u003ch3\u003e-------------------------------------------INSERT Table --------------------------------------------------\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eSonication parameters\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDevice/mode, target and laterality, neuronavigation method, acoustic parameters (frequency, PRF/PRI, duty cycle, burst length), intensity metrics (ISPPA/ISPTA or EFD), and session dose are summarised as reported by each study; cross-study dose comparisons should be interpreted cautiously given differences in reporting frames (free-field vs in situ) and missing acoustic characterisation; abbreviations: ISPPA\u0026thinsp;=\u0026thinsp;spatial-peak pulse-average intensity, ISPTA\u0026thinsp;=\u0026thinsp;spatial-peak temporal-average intensity, EFD\u0026thinsp;=\u0026thinsp;energy flux density, MI\u0026thinsp;=\u0026thinsp;mechanical index, PRF\u0026thinsp;=\u0026thinsp;pulse repetition frequency, PRI\u0026thinsp;=\u0026thinsp;pulse repetition interval.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"13\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLead Author\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrain region\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDevice Name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMedian frequency\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePulse duration (ms)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePulse repetition interval(ms)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePulse repetition frequency (Hz)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDuty Cycl\u003c/p\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eEnergy flux density\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eTotal duration (min)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eTotal pulses\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMechanical index\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eNegative pressure (Pr)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOh et al\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDLPFC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNS-US100; Neurosona\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e250 KHz\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1ms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2ms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e500Hz\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e50%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3\u0026nbsp;W/cm\u0026sup2; (Isppa) 0.6\u0026nbsp;W/cm\u0026sup2; (Ispta)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e300kPa\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCheung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDLPFC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNEUROLITH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.003ms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3\u0026ndash;4 Hz\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.0009%\u0026ndash;0.0012%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.2\u0026ndash;0.25\u0026nbsp;mJ/mm\u0026sup2; per pulse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e1800\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQin et al\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDPLFC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eStatistical Analysis\u003c/p\u003e\u003cp\u003eWe performed the meta-analyses using a random-effects model with the Generic Inverse Variance (GIV) method to account for between-study variability. Standardized mean differences (SMDs) were used to pool continuous outcomes. Heterogeneity was assessed using the Cochran Q test and I\u003csup\u003e2\u003c/sup\u003e statistic; p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and I\u0026sup2; \u0026gt;50% were considered indicative of significant heterogeneity. The Wald-type adjustment was applied to all outcomes. All meta-analyses were conducted using Review Manager (RevMan) version 5.4 (\u0026ldquo;Cochrane,\u0026rdquo; 2025).\u003c/p\u003e\u003cp\u003eSensitivity Analysis\u003c/p\u003e\u003cp\u003eTo assess the impact of individual studies on overall heterogeneity, we conducted leave-one-out sensitivity analyses. The removing (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) reduced heterogeneity from 23% to 0%. The sensitivity analysis is provided in the Supplementary Materials.\u003c/p\u003e\u003cp\u003eQuality Assessment (Risk of Bias\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRisk of bias was independently assessed by two independent reviewers (ACNT, GP) using the Cochrane RoB 2 tool across five domains (Sterne et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Overall, Oh et al. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) exhibited low risk of bias in all domains. (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) was judged to have some concerns due to its single‑blind design (D2) and incomplete description of outcome assessor blinding (D4), though randomisation, attrition handling and selective reporting were low risk. (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) raised concerns at randomisation (D1) and was deemed high risk for selective reporting (D5) owing to omitted baseline and secondary outcomes; other domains were low risk. Collectively, these assessments suggest that while two trials maintained rigorous methodology, one trial\u0026rsquo;s incomplete reporting may temper confidence in its findings and underscore the importance of cautious interpretation of the pooled estimate. Figure\u0026nbsp;3\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis explored the efficacy and safety of low-intensity ultrasound neuromodulation (LIUN) for treating Major Depressive Disorder (MDD), drawing on evidence from three randomised controlled trials (RCTs) (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). The pooled results demonstrated a modest yet statistically significant reduction in depressive symptoms compared to sham controls (standardised mean difference [SMD] = -0.55; 95% CI: -1.07 to -0.02; p\u0026thinsp;=\u0026thinsp;0.04). Heterogeneity among the studies was low (I\u0026sup2; = 23%), suggesting consistency across the included trials.\u003c/p\u003e\u003cp\u003eThe observed reduction in depressive symptoms indicates that low-intensity ultrasound neuromodulation holds promise as a potential treatment for MDD, although the clinical significance remains modest. These findings align with preliminary evidence suggesting neuromodulatory efficacy but must be interpreted cautiously given the limited number of studies and relatively small sample sizes involved. The primary target of ultrasound stimulation in these trials was the dorsolateral prefrontal cortex (DLPFC), a region strongly implicated in mood regulation and cognitive processing in MDD (Cui et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Nejati et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Pizzagalli and Roberts, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Although the exact reason for the beneficial effects observed is not known, it may be attributed to the modulation of neural circuits associated with emotional regulation and cognitive function (Cui et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOur findings are consistent with previous studies on neuromodulation, which have shown that approaches such as rTMS and tDCS can modestly reduce depressive symptoms (Yang et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). However, unlike rTMS and tDCS, ultrasound neuromodulation has the advantage of deeper brain penetration (Cox et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Yaakub et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) and precise spatial targeting (Philip and Arulpragasam, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), potentially offering additional therapeutic potential (Wal et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVariability was noted in ultrasound sonication parameters across the included studies. (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) utilized a well-defined LIFU protocol, whereas (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) and (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) employed TPS with differing pulse repetition frequencies, pulse durations, and session counts. These methodological variations could have influenced both efficacy and tolerability outcomes, suggesting the need for standardized protocols to facilitate direct comparison and consistent clinical interpretation. Variability and Dose\u0026ndash;Response in Sonication Protocols The three RCTs employed markedly different stimulation paradigms. (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) used 200 pulses at 250 kHz (ISPPA 3 W/cm\u0026sup2;; ISPTA 0.6 W/cm\u0026sup2;) focused on the DLPFC over a single 20-minute session. (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) applied transcranial pulse stimulation (TPS) with 300 pulses per 30-minute session (3\u0026ndash;4 Hz shock pulses at 0.2\u0026ndash;0.25 mJ/mm\u0026sup2;) across six sessions. (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) delivered 1,000 ultrashort (3 \u0026micro;s) Gaussian pulses at ~\u0026thinsp;4 Hz, three times per week for four weeks (total 12,000 pulses). Post hoc analyses across these studies suggest a correlation between increased total pulse count, lower Mechanical Index (MI), and enhanced symptom reduction, albeit with higher rates of mild paresthesia [5]. The absence of a standardized protocol impedes direct dose\u0026ndash;response modeling and cross-study comparisons.\u003c/p\u003e\u003cp\u003eSafety, Feasibility, and Standardization\u003c/p\u003e\u003cp\u003eAll three trials reported predominantly mild, transient adverse events\u0026mdash;scalp discomfort, tingling, and headache\u0026mdash;yet their documentation varied: (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) recorded a notably higher incidence in the active arm (92% vs. 42% sham), (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) noted only two brief sensory events across 1800 pulses, and (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) stated no significant adverse outcomes without quantitative detail.The elevated AE rate in Qin et al. could likely reflects the high total pulse count (12,000) and ultrashort shock-pulse format, underscoring the need to balance cumulative dose with patient comfort. However, Oh et al.\u0026rsquo;s qualitative safety statement limits assessment of rare or delayed events; (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) sparse AE tally precludes correlation with specific sonication parameters.\u003c/p\u003e\u003cp\u003eWe suggest that future LIUN investigations consider adopting more comprehensive, ITRUSST (Murphy et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) -aligned reporting practices to strengthen the rigor and reproducibility of safety assessments. Where possible, studies might provide detailed device and drive-system information\u0026mdash;manufacturer/model, transducer geometry (aperture size, curvature, element count), center frequency, matching network and amplifier specifications, and coupling medium\u0026mdash;alongside a thorough acoustic field characterization. This could include free‐field measurements (ISPPA, ISPTA, \u0026minus;\u0026thinsp;3 dB focal-zone dimensions, hydrophone calibration curves) as well as in situ estimates of skull-adjusted MIₜc and TIₜc derived from CT‐based simulations or standardized derating methods. We also recommend tabulating pulse-timing and dose parameters (e.g., pulse duration; PRI/PRF; duty cycle; total pulses and sessions; intersession spacing) to facilitate clear comparisons across protocols. Core safety indices\u0026mdash;real-time MR thermometry (voxel-wise ΔT mapping with spatial/temporal resolution, drift correction, cooling logs) and continuous passive cavitation detection (phantom‐validated thresholds, correlated with any clinical observations)\u0026mdash;could further enhance transparency. Routine equipment calibration (hydrophone or radiation‐force balance checks; electrical power/impedance verifications within defined tolerances) and basic workflow and tolerability metrics (total procedure duration; patient comfort/anxiety scores; operator feedback) may also prove valuable. Finally, where ethical and practical considerations allow, sharing de-identified, patient-level data (including standardized sonication coordinates and associated metrics in CSV or JSON format) could support cross-study comparisons, meta-analyses, and ultimately the broader goal of safely advancing LIUN methodologies. sonication parameters, thermometry and cavitation traces, CTCAE-graded AEs, and patient tolerability scores, all validated on \u0026ge;\u0026thinsp;2 software platforms.\u003c/p\u003e\u003cp\u003eThe quality assessment identified variability in methodological rigour across the studies. (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) maintained low risk of bias across all domains. However, (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) presented some concerns regarding blinding integrity, and (QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) had a high risk of bias in selective reporting and concerns in randomisation methods. Such methodological limitations may compromise the robustness of pooled results and necessitate cautious interpretation. Future trials should ensure rigorous randomisation and blinding protocols, alongside complete reporting of demographic and clinical baseline characteristics.\u003c/p\u003e\u003cp\u003eHeterogeneity and Methodological Limitations\u003c/p\u003e\u003cp\u003eOur analysis identified three key study features that likely drove between-trial variability and warrant rigorous attention in future RCTs.\u003c/p\u003e\u003cp\u003e1. Within-Group Variance\u003c/p\u003e\u003cp\u003e(QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) reported an exceptionally large standard deviation in HDRS change for the sham arm (\u0026plusmn;\u0026thinsp;6.84), markedly higher than active-arm variances in comparable trials. Elevated within‐group dispersion inflates overall heterogeneity (τ\u0026sup2;) and diminishes the precision of pooled effect estimates. Future studies should consistently report variance metrics (SD, IQR) for all arms and conduct sensitivity analyses\u0026mdash;such as leave-one-out or meta-regression\u0026mdash;to evaluate the impact of high‐variance datasets on overall outcomes.\u003c/p\u003e\u003cp\u003e2. Outcome Measure Consistency\u003c/p\u003e\u003cp\u003eCurrent trials utilized multiple depression scales (HDRS, MADRS) without a pre-specified primary endpoint, complicating effect-size harmonization. To enhance interpretability, we recommend pre-registration of a single primary depression instrument (e.g., HDRS-17) with standardized responder criteria (\u0026ge;\u0026thinsp;50% reduction), while reporting additional scales solely as supportive secondary outcomes.\u003c/p\u003e\u003cp\u003e3. Blinding Verification\u003c/p\u003e\u003cp\u003eNone of the included RCTs formally assessed post-treatment blinding integrity. Unrecognized unblinding can introduce placebo or nocebo effects, biasing self-reported outcomes, and amplifying heterogeneity. Future RCTs should implement objective blinding indices such as James\u0026rsquo; and Bang\u0026rsquo;s blinding indexes (James et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1996\u003c/span\u003e) after intervention and incorporate these data into risk-of-bias assessments and statistical adjustments.\u003c/p\u003e\u003cp\u003eStrengths and Limitations\u003c/p\u003e\u003cp\u003eA strength of this meta-analysis is its systematic approach, adherence to PRISMA guidelines (PRISMA, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), and conservative statistical interpretation. Nonetheless, several limitations must be acknowledged. Primarily, the small number of eligible trials limits the generalisability of the findings. Additionally, variability in sonication parameters and study methodologies may have contributed to outcome heterogeneity. Furthermore, demographic and clinical data were inconsistently reported, constraining subgroup analyses and reducing the ability to generalise findings to broader MDD populations.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eFuture Research Directions\u003c/h2\u003e\u003cp\u003eFurther large-scale, rigorously designed RCTs are required to confirm these preliminary findings and assess long-term efficacy and safety. Future studies should aim for standardisation of ultrasound neuromodulation parameters, rigorous adverse-event reporting, and inclusion of diverse demographic groups. Comparative effectiveness trials against established neuromodulatory interventions (e.g., rTMS, tDCS) and comprehensive neuroimaging assessments to elucidate the underlying neural mechanisms are also recommended.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical Implications\u003c/h3\u003e\n\u003cp\u003eClinicians should interpret these findings cautiously, recognising that while preliminary evidence supports LIUN\u0026rsquo;s potential in MDD treatment, more substantial evidence is needed to recommend its widespread clinical adoption. The mild adverse-event profile is encouraging, yet careful monitoring during treatments remains essential.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This study was conducted according to the PRISMA reporting guidelines. The review protocol was prospectively registered in OSF (osf.io/av2e7).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSearch Strategy\u003c/h2\u003e\u003cp\u003eA systematic search was conducted usingthe following databases: PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey.\u003c/p\u003e\u003cp\u003eAfter removing the duplicates, the authors independently screened the studies in two phases, first in title and abstract and in second full text. Studies were included based on the inclusion criteria. The discrepancies were solved through consensus among a third author.\u003c/p\u003e\u003cp\u003eThe search strategy combined MeSH and keyword-based strategies and it's listed: The query search string was: (\"Low intensity focused ultrasound\" OR \"LIFU\" OR \"Low intensity focused ultrasound stimulation\" OR \"LIFUS\" OR \"Low intensity pulsed ultrasound\" OR \"LIPUS\" OR \"Focused ultrasound stimulation\" OR \"FUS\" OR \"Focused ultrasound neuromodulation\" OR \"FUN\" OR \"Transcranial ultrasound stimulation\" OR \"TUS\" OR \"Transcranial focused ultrasound stimulation\" OR \"TFUS\" OR \"Magnetic Resonance-Guided Focused Ultrasound\" OR \"MRgFUS\" OR \"Transcranial pulse stimulation\" OR \"TPS\") AND (\"Depressive Disorder, Major\"[Mesh] OR \"major depressive disorder\" OR MDD OR \"recurrent depression\" OR \"severe depression\" OR \"unipolar depression\")\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eEligibility criteria\u003c/h2\u003e\u003cp\u003eThis Meta Analysis included studies that were (1)randomised controlled trials (including, double-blind, sham-controlled), (2) in adults (3) diagnosed with major depression disorder, (4) any form of TUS, LIPU, TPUS, LIFU as intervention,(4) that compared low intensity ultrasound neuromodulation against a sham or stimulation-off control, (5) reported pre-post changes using validated clinical scales for depression.\u003c/p\u003e\u003cp\u003eStudies were excluded if they had (1) a control arm includes participants with a primary psychotic or bipolar diagnosis, substance use disorders, neurological or sleep disorders, intellectual disabilities, (2) trials of depression with psychotic features, (3) systematic and narrative reviews, and meta-analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eInformation sources, search, and selection of sources of evidence\u003c/h2\u003e\u003cp\u003eThe search strategy was systematically conducted in the previous described databases to identify the studies according to the predefined eligibility criteria.\u003c/p\u003e\u003cp\u003eThe search was conducted on PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey databases and focused on studies that reported data about TUS in adults with major depressive disorder to evaluate the clinical efficacy, safety and tolerability of TUS in reducing symptoms in adults with MDD.\u003c/p\u003e\u003cp\u003eThe initial search resulted in 1023 references. After deduplication (239 duplicates identified), 784 unique records were screened using reference manager Rayyan. Following title and abstract screening, 132 records were excluded. 12 articles were assessed full-text, and 3 studies were included in the review. This process is illustrated in the PRISMA flow diagram as Fig.\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis provides modest preliminary evidence supporting the efficacy and safety of low-intensity ultrasound neuromodulation for treating MDD. The findings suggest potential clinical benefit but highlight the necessity for larger, rigorously designed trials to confirm efficacy, safety, and long-term benefits before widespread clinical implementation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003ePrimary funding\u003c/h2\u003e\u003cp\u003e Nima Norbu Sherpa is funded by National Institute for Health and Care Research (NIHR) 306286.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting Interests Statement\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: NNSMethodology: NNS, GP \u0026amp; ACNTSystematic search: NNS, ACNT \u0026amp; GPScreening and data extraction: NNS, ACNT, MARisk-of-bias assessment: GPFormal analysis: NNS, MAVisualization: NNSWriting\u0026mdash;original draft: NNS Writing\u0026mdash;review \u0026amp; editing: NNS, GO, ACNT, MASupervision: NNS Funding acquisition: NNSGuarantor: NNS\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENT\u003c/h2\u003e\u003cp\u003e NNS is supported by the National Institute for Health and Care Research (NIHR Pre-Doctoral Clinical Fellowship, NIHR500764). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBarksdale, B.R., Enten, L., DeMarco, A., Kline, R., Doss, M.K., Nemeroff, C.B., Fonzo, G.A., 2025. Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial. Molecular Psychiatry. https://doi.org/10.1038/s41380-025-03033-w\u003c/li\u003e\n\u003cli\u003eBenster, L.L., Weissman, C.R., Stolz, L.A., Daskalakis, Z.J., Appelbaum, L.G., 2023. Pre-clinical indications of brain stimulation treatments for non-affective psychiatric disorders, a status update. Translational Psychiatry 13. https://doi.org/10.1038/s41398-023-02673-2\u003c/li\u003e\n\u003cli\u003eChen, X., You, J., Ma, H., Zhou, M., Huang, C., 2023. Transcranial pulse stimulation in Alzheimer\u0026rsquo;s disease. CNS Neuroscience \u0026amp; Therapeutics. https://doi.org/10.1111/cns.14372\u003c/li\u003e\n\u003cli\u003eCheung, T., Ho, Y.S., Yeung, J.W.-F., Leung, S.F., Fong, K.N.K., Fong, T., Kranz, G.S., Beisteiner, R., Cheng, C.P.W., 2022. Effects of Transcranial Pulse Stimulation (TPS) on Young Adults With Symptom of Depression: A Pilot Randomised Controlled Trial Protocol. Frontiers in Neurology 13. https://doi.org/10.3389/fneur.2022.861214\u003c/li\u003e\n\u003cli\u003eCochrane [WWW Document], 2025. Cochrane.org. URL https://www.cochrane.org/learn/courses-and-resources/software (accessed 8.2.25).\u003c/li\u003e\n\u003cli\u003eCox, S.S., Connolly, D.J., Peng, X., Badran, B.W., 2024. A Comprehensive Review of Low-Intensity Focused Ultrasound Parameters and Applications in Neurologic and Psychiatric Disorders. Neuromodulation: Technology at the Neural Interface. https://doi.org/10.1016/j.neurom.2024.07.008\u003c/li\u003e\n\u003cli\u003eCui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., Li, B., 2024. Major Depressive disorder: hypothesis, mechanism, Prevention and Treatment. Signal Transduction and Targeted Therapy 9. https://doi.org/10.1038/s41392-024-01738-y\u003c/li\u003e\n\u003cli\u003eFeng, J., Li, Z., 2024. Progress in Noninvasive Low-Intensity Focused Ultrasound Neuromodulation. Stroke. https://doi.org/10.1161/strokeaha.124.046679\u003c/li\u003e\n\u003cli\u003eFomenko, A., Neudorfer, C., Dallapiazza, R.F., Kalia, S.K., Lozano, A.M., 2018. Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications. Brain Stimulation 11, 1209\u0026ndash;1217. https://doi.org/10.1016/j.brs.2018.08.013\u003c/li\u003e\n\u003cli\u003eFouragnan, E.F., Hosking, B., Cheung, Y., Prakash, B., Rushworth, M., Sel, A., 2024. Timing along the cardiac cycle modulates neural signals of reward-based learning. Nature Communications 15, 2976. https://doi.org/10.1038/s41467-024-46921-5\u003c/li\u003e\n\u003cli\u003eGorka, S.M., Jimmy, J., Koning, K., Phan, K.L., Rotstein, N., Hoang-Dang, B., Halavi, S., Spivak, N., Monti, M.M., Reggente, N., Bookheimer, S.Y., Kuhn, T.P., 2024. Alterations in large-scale resting-state network nodes following transcranial focused ultrasound of deep brain structures. Frontiers in Human Neuroscience 18. https://doi.org/10.3389/fnhum.2024.1486770\u003c/li\u003e\n\u003cli\u003eGuan, M., Xie, Y., Wang, Z., Miao, Y., Li, X., Yu, S., Wang, H., 2025. Brain connectivity and transcriptional changes induced by rTMS in first-episode major depressive disorder. 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Nature Neuroscience 17, 322\u0026ndash;329. https://doi.org/10.1038/nn.3620\u003c/li\u003e\n\u003cli\u003eMatt, E., Kaindl, L., Tenk, S., Egger, A., Kolarova, T., Karahasanović, N., Amini, A., Arslan, A., Sari\u0026ccedil;i\u0026ccedil;ek, K., Weber, A., Beisteiner, R., 2022. First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain. Journal of Translational Medicine 20. https://doi.org/10.1186/s12967-021-03222-5\u003c/li\u003e\n\u003cli\u003eMurphy, K.R., Nandi, T., Kop, B., Osada, T., Lueckel, M., N\u0026rsquo;Djin, W.A., Caulfield, K.A., Fomenko, A., Siebner, H.R., Ugawa, Y., Verhagen, L., Bestmann, S., Martin, E., Butts Pauly, K., Fouragnan, E., Bergmann, T.O., 2025. A practical guide to transcranial ultrasonic stimulation from the IFCN-endorsed ITRUSST consortium. Clinical Neurophysiology 171, 192\u0026ndash;226. https://doi.org/10.1016/j.clinph.2025.01.004\u003c/li\u003e\n\u003cli\u003eNejati, V., Majidinezhad, M., Nitsche, M., 2022. The role of the dorsolateral and ventromedial prefrontal cortex in emotion regulation in females with major depressive disorder (MDD): A tDCS study. Journal of Psychiatric Research 148, 149\u0026ndash;158. https://doi.org/10.1016/j.jpsychires.2022.01.030\u003c/li\u003e\n\u003cli\u003eOh, J., Jin Sun Ryu, Kim, J., Kim, S., Hyu Seok Jeong, Kyung Ran Kim, Kim, H.-C., Yoo, S.-S., Seok, J.-H., 2024. Effect of Low-Intensity Transcranial Focused Ultrasound Stimulation in Patients With Major Depressive Disorder: A Randomized, Double-Blind, Sham-Controlled Clinical Trial. Psychiatry Investigation 21, 885\u0026ndash;896. https://doi.org/10.30773/pi.2024.0016\u003c/li\u003e\n\u003cli\u003eOliveira-Maia, A.J., Ania Bobrowska, Constant, E., Ito, T., Yerkebulan Kambarov, Luedke, H., Siobh\u0026aacute;n Mulhern-Haughey, Christian von Holt, 2023. Treatment-Resistant Depression in Real-World Clinical Practice: A Systematic Literature Review of Data from 2012 to 2022. Advances in Therapy 41, 34\u0026ndash;64. https://doi.org/10.1007/s12325-023-02700-0\u003c/li\u003e\n\u003cli\u003ePellow, C., Pichardo, S., G Bruce Pike, 2024. A systematic review of preclinical and clinical transcranial ultrasound neuromodulation and opportunities for functional connectomics. Brain stimulation 17, 734\u0026ndash;751. https://doi.org/10.1016/j.brs.2024.06.005\u003c/li\u003e\n\u003cli\u003ePhilip, N.S., Arulpragasam, A.R., 2022. Reaching for the unreachable: low intensity focused ultrasound for non-invasive deep brain stimulation. Neuropsychopharmacology 48, 251\u0026ndash;252. https://doi.org/10.1038/s41386-022-01386-2\u003c/li\u003e\n\u003cli\u003ePizzagalli, D.A., Roberts, A.C., 2021. Prefrontal cortex and depression. Neuropsychopharmacology 47. https://doi.org/10.1038/s41386-021-01101-7\u003c/li\u003e\n\u003cli\u003ePRISMA, 2020. PRISMA 2020 [WWW Document]. PRISMA statement. URL https://www.prisma-statement.org/prisma-2020\u003c/li\u003e\n\u003cli\u003eQIN, P., 2025. Transcranial pulse stimulation for the treatment of major depressive disorder: A randomized, double-blind, sham-controlled, pilot trial. Brain Stimulation 18, 507. https://doi.org/10.1016/j.brs.2024.12.852\u003c/li\u003e\n\u003cli\u003eReinhart, R.M.G., Woodman, G.F., 2015. The surprising temporal specificity of direct-current stimulation. Trends in Neurosciences 38, 459\u0026ndash;461. https://doi.org/10.1016/j.tins.2015.05.009\u003c/li\u003e\n\u003cli\u003eR\u0026oacute;bert Gy\u0026ouml;rgy Vida, Eszter S\u0026aacute;ghy, Bella, R., S. Kov\u0026aacute;cs, Dalma Erdősi, Judit J\u0026oacute;zwiak-Hagym\u0026aacute;sy, Antal Zempl\u0026eacute;nyi, Tam\u0026aacute;s T\u0026eacute;nyi, Osvath, P., Voros, V., 2023. Efficacy of repetitive transcranial magnetic stimulation (rTMS) adjunctive therapy for major depressive disorder (MDD) after two antidepressant treatment failures: meta-analysis of randomized sham-controlled trials. BMC Psychiatry 23. https://doi.org/10.1186/s12888-023-05033-y\u003c/li\u003e\n\u003cli\u003eSterne, J.A.C., Savović, J., Page, M.J., Elbers, R.G., Blencowe, N.S., Boutron, I., Cates, C.J., Cheng, H.-Y., Corbett, M.S., Eldridge, S.M., Emberson, J.R., Hern\u0026aacute;n, M.A., Hopewell, S., Hr\u0026oacute;bjartsson, A., Junqueira, D.R., J\u0026uuml;ni, P., Kirkham, J.J., Lasserson, T., Li, T., McAleenan, A., 2019. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366, l4898. https://doi.org/10.1136/bmj.l4898\u003c/li\u003e\n\u003cli\u003eWal, J.M. van der, Bergfeld, I.O., Lok, A., Mantione, M., Figee, M., Notten, P., Beute, G., Horst, F., Munckhof, P. van den, Schuurman, P.R., Denys, D., 2020. 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Journal of Affective Disorders 374, 486\u0026ndash;494. https://doi.org/10.1016/j.jad.2025.01.086\u003c/li\u003e\n\u003cli\u003eYaakub, S.N., White, T.A., Roberts, J., Martin, E., Verhagen, L., Stagg, C.J., Hall, S., Fouragnan, E.F., 2023. Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans. Nature Communications 14, 5318. https://doi.org/10.1038/s41467-023-40998-0\u003c/li\u003e\n\u003cli\u003eYang, Y., Chen, J., Yu, M., Xiong, C., Zhang, R., Jiang, G., 2024. Comparative efficacy of multiple non-invasive brain stimulation to treat major depressive disorder in older patients: A systematic review and network meta-analysis study based on randomized controlled trials. Psychiatry Research 344, 116340. https://doi.org/10.1016/j.psychres.2024.116340\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"major depressive disorder, transcranial pulse stimulation (TPS), low‑intensity focused ultrasound (LIFU), randomized controlled trials, meta‑analysis and ultrasonic neuromodulation","lastPublishedDoi":"10.21203/rs.3.rs-7930997/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7930997/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eMajor depressive disorder (MDD) affects over 264\u0026nbsp;million individuals globally, yet about one‑third of patients fail to achieve remission with conventional therapies. Low‑intensity ultrasound neuromodulation (LIUN), which includes low‑intensity focused ultrasound (LIFU) and transcranial pulse stimulation (TPS), offers millimetre‑scale targeting and the ability to reach deep limbic regions without implants or strong electromagnetic fields.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eTo conduct the first systematic review and meta‑analysis of randomized, sham‑controlled trials assessing the efficacy and safety of LIUN in adults with MDD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe searched PubMed, EMBASE, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, Europe PMC, WHO ICTRP, and OpenGrey through July 2025 for RCTs comparing active LIUN versus sham in MDD. Two reviewers independentlyscreened studies and extracted data. Depressive symptom change was pooled using a random‑effects model to calculate standardized mean differences (SMDs). Heterogeneity was quantified with the I\u0026sup2; statistic. Adverse events were narratively summarized.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThree RCTs (n\u0026thinsp;=\u0026thinsp;78 randomized; 68 completers) met inclusion criteria\u0026mdash;one LIFU trial (Oh et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) and two TPS trials (Cheung et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; QIN, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). LIUN yielded a small‑to‑moderate reduction in depressive symptoms compared to sham (SMD\u0026nbsp;=\u0026nbsp;\u0026ndash;0.55; 95\u0026nbsp;%\u0026nbsp;CI: \u0026minus;\u0026thinsp;1.07 to \u0026minus;\u0026thinsp;0.02; p\u0026nbsp;=\u0026nbsp;0.04). Between‑stud heterogeneity was low (I\u0026sup2; = 23 %). Adverse events\u0026mdash;transient headache, scalp ingling, and skin redness\u0026mdash;were generally mild and self‑limiting. Qin et al. reported higher rates of transient sensations in the active arm (92 % vs 42 %), whereas Cheung et al. and Oh et a. descrbed minimal or no adverse effects without treatment discontinuation.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePreliminary evidence suggests LIUN modestly reduces depressive symptoms in MDD with a benign safety profile. However, the small number of heterogeneous trials underscores the need for larger, parameter‑standardized RCTs to confirm efficacy, optimize sonication protocols, and establish long‑term safety.\u003c/p\u003e","manuscriptTitle":"Low Intensity Ultrasound Neuromodulation for the treatment of Major Depressive Disorder: Systematic Review and Meta‑Analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 10:23:52","doi":"10.21203/rs.3.rs-7930997/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-19T20:27:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-19T09:17:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"33284327000488133279966677158972173651","date":"2025-11-16T11:54:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-09T06:11:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"94511615282444795897285764409627135228","date":"2025-11-09T04:22:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-07T15:30:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-07T14:56:24+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-29T13:47:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-27T16:35:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-27T16:25:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cbe0ece6-dea4-41c3-9481-b68528c0a7e3","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":58280529,"name":"Health sciences/Diseases"},{"id":58280530,"name":"Health sciences/Health care"},{"id":58280531,"name":"Health sciences/Medical research"},{"id":58280532,"name":"Health sciences/Neurology"},{"id":58280533,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-01-02T05:53:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 10:23:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7930997","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7930997","identity":"rs-7930997","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}