Circuit-based neuromodulation for obsessive-compulsive disorder: a systematic review, meta-analysis, and translational case study.

Circuit-based neuromodulation for obsessive–compulsive disorder: a systematic review, meta-analysis, and translational case study - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. 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Learn more: PMC Disclaimer | PMC Copyright Notice J Psychiatry Neurosci . 2026 Mar 31;51:1–16. doi: 10.1139/jpn-24-0163 Search in PMC Search in PubMed View in NLM Catalog Add to search Circuit-based neuromodulation for obsessive–compulsive disorder: a systematic review, meta-analysis, and translational case study Ruoyu Ma Ruoyu Ma a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft Find articles by Ruoyu Ma a , Shu Wang Shu Wang a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Conceptualization, Formal analysis, Methodology, Writing – original draft Find articles by Shu Wang a, ✉ , Zixiao Yin Zixiao Yin a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Writing – review & editing Find articles by Zixiao Yin a , Yifei Gan Yifei Gan a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Data curation Find articles by Yifei Gan a , Zehua Zhao Zehua Zhao a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Software, Visualization Find articles by Zehua Zhao a , Tianshuo Yuan Tianshuo Yuan a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Data curation Find articles by Tianshuo Yuan a , Yingchuan Chen Yingchuan Chen a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Supervision Find articles by Yingchuan Chen a , Tingting Du Tingting Du b Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China Supervision Find articles by Tingting Du b , Valerie Voon Valerie Voon c Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom Supervision, Writing – review & editing Find articles by Valerie Voon c , Guanyu Zhu Guanyu Zhu a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China Project administration, Resources, Supervision, Writing – review & editing Find articles by Guanyu Zhu a, ✉ , Jianguo Zhang Jianguo Zhang a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China b Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China d Beijing Key Laboratory of Neurostimulation, Beijing 100070, China Funding acquisition, Project administration, Resources, Supervision Find articles by Jianguo Zhang a, b, d, ✉ Author information Article notes Copyright and License information a Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China b Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China c Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom d Beijing Key Laboratory of Neurostimulation, Beijing 100070, China ✉ Corresponding authors: Jianguo Zhang (email: [email protected] ); Guanyu Zhu (email: [email protected] ); Shu Wang (email: [email protected] ) The authors declare no conflict of interest. The article was originally published with minor errors (article type) that have now been corrected. ✉ Corresponding author. Roles Ruoyu Ma : Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft Shu Wang : Conceptualization, Formal analysis, Methodology, Writing – original draft Zixiao Yin : Writing – review & editing Yifei Gan : Data curation Zehua Zhao : Software, Visualization Tianshuo Yuan : Data curation Yingchuan Chen : Supervision Tingting Du : Supervision Valerie Voon : Supervision, Writing – review & editing Guanyu Zhu : Project administration, Resources, Supervision, Writing – review & editing Jianguo Zhang : Funding acquisition, Project administration, Resources, Supervision Received 2024 Dec 10; Accepted 2026 Jan 27; Collection date 2026. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) , which permits distribution and reproduction of the article in any medium, provided that the original publication is properly cited, the use is non-commercial, and no modifications or adaptations are made. PMC Copyright notice PMCID: PMC13082450  PMID: 41894167 Abstract Background: Obsessive–compulsive disorder (OCD) remains refractory to conventional pharmacological and psychotherapeutic treatments in a substantial proportion of patients. Neuromodulation has emerged as a promising intervention, but optimal neural circuit targets remain unclear. This systematic review and meta-analysis aimed to evaluate the efficacy of invasive and non-invasive neuromodulation for OCD using a circuit-based framework and to translate these findings into clinical practice. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials investigating neuromodulation for OCD. PubMed/MEDLINE, Web of Science, and the Cochrane Library were searched from database inception to December 2023. Eligible studies included adult patients with a primary diagnosis of OCD receiving invasive or non-invasive neuromodulation, with symptom outcomes assessed using the Yale–Brown Obsessive-Compulsive Scale (Y-BOCS). Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Random- or fixed-effects meta-analyses were performed using mean differences or standardized mean differences, depending on heterogeneity. The review was registered in PROSPERO (CRD42024518326). Results: Twenty-seven randomized controlled trials involving 868 patients met inclusion criteria. Overall, neuromodulation significantly reduced OCD symptoms compared with control conditions. Circuit-based subgroup analyses indicated that modulation of the fronto-limbic circuit—primarily via invasive deep brain stimulation—was associated with the largest and most consistent Y-BOCS improvements, while sensorimotor, dorsal cognitive, and ventral affective circuits also demonstrated significant but more heterogeneous effects. Invasive neuromodulation showed greater efficacy than non-invasive approaches. These findings informed a translational multi-target deep brain stimulation case, demonstrating clinically meaningful symptom improvement (Y-BOCS decreased from 25 to 16 after 6 months). Limitations: Heterogeneity across non-invasive studies, short follow-up durations, and limited circuit-specific data constrain interpretation of long-term and symptom–domain-specific effects. Conclusions: This systematic review, meta-analysis, and case study suggest that circuit-based neuromodulation—particularly targeting the fronto-limbic circuit—may offer the most consistent benefit for treatment-refractory OCD. Larger, longer-term, and circuit-informed trials are needed to optimize individualized neuromodulation strategies. Keywords: obsessive-compulsive disorder, deep brain stimulation, brain circuits 1. Introduction Obsessive–compulsive disorder (OCD) is a chronic and disabling psychiatric condition characterized by intrusive obsessions and repetitive compulsions that substantially impair quality of life. 1 Despite established first-line treatments, including pharmacotherapy and cognitive behavioral therapy, up to 30%–40% of patients remain treatment-refractory, highlighting a critical unmet clinical need. 2 In this context, neuromodulation has emerged as a promising therapeutic strategy for refractory OCD 3 – 7 . Accumulating evidence suggests that OCD arises from dysfunction across distributed neural circuits rather than isolated brain regions. 8 – 12 Accordingly, neuromodulation studies have targeted a range of cortical and subcortical structures, often yielding comparable clinical effects, implying convergence at the circuit level. Neuromodulation for OCD encompasses both invasive and non-invasive approaches. Invasive techniques, most notably deep brain stimulation (DBS), directly target subcortical nodes within fronto-striatal and limbic circuits and are typically reserved for severe, treatment-refractory cases. In contrast, non-invasive modalities such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) modulate cortical components of these networks and offer a more favorable safety profile, albeit with greater variability in clinical efficacy. Despite these differences, converging evidence suggests that both invasive and non-invasive modalities may influence overlapping neural circuits implicated in OCD. However, existing meta-analyses have largely focused on single targets or individual neuromodulation modalities, without integrating invasive and non-invasive approaches within a unified circuit-based framework. 13 , 14 Moreover, heterogeneity in target selection and outcome reporting has limited the translation of these findings into circuit-informed clinical decision-making. To enable a circuit-based synthesis of neuromodulation outcomes, we adopted a symptom-oriented neural circuit framework for OCD. 10 , 15 – 17 Within this framework, OCD-related circuits were categorized into four major domains based on functional relevance and neuromodulation targets 18 : (1) the fronto-limbic circuit, primarily implicated in emotional regulation and anxiety-related symptoms (e.g., anterior limb of the internal capsule); (2) the dorsal cognitive circuit, associated with executive control and cognitive flexibility (e.g., dorsolateral prefrontal cortex and pre-supplementary motor area); (3) the sensorimotor circuit, involved in habitual and compulsive motor behaviors (e.g., supplementary motor area (SMA)); and (4) the ventral affective circuit, related to reward processing and motivational drive (e.g., orbitofrontal cortex and nucleus accumbens). This classification served as the conceptual basis for grouping neuromodulation targets and conducting circuit-level analyses in the present study. To address this gap, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy of invasive and non-invasive neuromodulation for OCD from a circuit-based perspective, comparing outcomes across neural targets and stimulation modalities. By synthesizing evidence at the circuit level, we aimed to clarify the neurobiological basis of neuromodulation effects and inform symptom-specific target selection. In addition, we present a translational deep brain stimulation case to illustrate the real-world clinical application of this framework. Based on this approach, we hypothesized that neuromodulation targeting specific OCD-related neural circuits—particularly the fronto-limbic circuit—would be associated with greater and more consistent symptom improvement, and that cross-modality, circuit-level integration could enhance individualized treatment strategies. 2. Materials and methods The study consists of two major components: a systematic review and meta-analysis in summarizing current available evidence and a case study in implementing the theories and results into clinical practice and also reporting efficacy and safety ( Fig. 1A ). The systematic review and meta-analysis were conducted following the workflow of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement 19 (a standard PRISMA flowchart is seen in Supplementary Table S1, PRISMA checklist 2020 is seen in Supplementary Table S2) and had been registered on PROSPERO (CRD42024518326). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 20 statement was applied in conducting and reporting the case study (Supplementary Table S3). This study was conducted under the approval of the institutional review board (IRB) of Beijing Tiantan Hospital (IRB#: KY 2022-006-02). The patient was informed previously and provided with written consent. This study was conducted following the 1964 Helsinki Declaration and its later amendments. Fig. 1. Open in a new tab Study procedure (A), neuromodulation circuits (B), and quality assessment of included studies (B; n = 28) (C). Abbreviations: rTMS: repetitive transcranial magnetic stimulation; tDCS: transcranial direct current stimulation; cTBS: continuous theta burst stimulation; STN-DBS: subthalamic nucleus deep brain stimulation; ALIC-DBS: anterior limb of internal capsule deep brain stimulation; NAC-DBS: nucleus accumbens deep brain stimulation. 2.1. Systematic search The PubMed/MEDLINE, Cochrane Library, and Web of Science databases were queried. Additional records as unpublished data or grey literature was identified through other sources such as ClinicalTrials.gov and Cochrane Register. The advanced search strategies including free words and Medical Subject Headings (MeSH) terms (if available) were applied. A sample search strategy in PubMed is shown as follows: (“Obsessive-Compulsive Disorder”[MeSH] OR “OCD” OR “Obsessive-Compulsive Disorder”) AND (“Electric Stimulation Therapy”[MeSH] OR “Neuromodulation” OR “Neurostimulation” OR “DBS” OR “Deep Brain Stimulation” OR “TMS” OR “rTMS” OR “dTMS” OR “Transcranial Magnetic Stimulation” OR “tDCS” OR “Transcranial Direct Current Stimulation” OR “VNS” OR “Vagus Nerve Stimulation”) AND (“Randomized Controlled Trial”[Publication Type] OR “Clinical Trial”[Publication Type]). The searching period of records was the database construction time to December 2023. 2.2. Eligible criteria Studies were included if they met the following criteria: (1) patients with a primary diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders Fourth or Fifth edition (DSM-IV or DSM-V) or International Classification of Diseases criteria; (2) Invasive or non-invasive neurostimulation was conducted as the primary intervention; (3) reported outcomes should include any assessments on OCD symptoms; (4) randomized sham-controlled trials; (5) published in English. Studies were excluded according to several criteria: (1) non-randomized controlled trials and studies; (2) reviews, meta-analyses, comments, letters, and editorials lacking de novo patients; (3) single case reports; (4) studies only investigating neuroimaging, neuropsychiatric, behavioral, and/or electrophysiological changes without available information related to OCD symptoms; (5) non-human studies; (6) studies focusing on non-OCD indications for neurostimulation; (7) technical reports on the safety or procedural aspects of neuromodulations for OCD. 2.3. Selection process All search results from the included databases were exported to Endnote 21 (Clarivate, Philadelphia, PA). Two reviewers (RM, SW) independently screened the title of each record retrieved. One reviewer (RM) screened the abstracts and full texts of all remaining records and another reviewer (SW) reported for eligibility and final inclusion. In any case where several records reported on all or part of the same cohort of patients, the study with the most detailed dataset for the largest number of patients was selected for inclusion. Duplicate records were identified and removed using EndNote 21 through automated matching of titles, authors, and publication year, with additional manual screening to ensure accuracy. Title/abstract screening and full-text eligibility assessment were conducted independently by two reviewers (RM and SW). Discrepancies were resolved by discussion and consensus. 2.4. Data collection and organization The following data items were extracted where available: general study characteristics, including study location, first author, publication year, study design, inclusion and exclusion criteria, sample size, treatment response criteria, response rates, and reported complications or adverse events. Patient-level data included stimulation target(s), primary diagnosis, sex, age at OCD onset, age at DBS surgery (when applicable), psychiatric comorbidities, concomitant medications, baseline and follow-up Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) scores with corresponding time points, percentage Y-BOCS reduction at last follow-up (with ≥35% defined as treatment response), follow-up duration, and stimulation parameters. Change in Y-BOCS scores served as the primary outcome. Secondary outcomes included changes in depressive symptoms assessed by the Hamilton Depression Rating Scale (HAM-D/HDRS-17/HDRS-24), Montgomery–Åsberg Depression Rating Scale (MADRS), and Beck Depression Inventory (BDI), changes in anxiety symptoms assessed by the Hamilton Anxiety Rating Scale (HAM-A/HARS), and State–Trait Anxiety Inventory (STAI-1/X1 and STAI-2/X2), as well as reported adverse events. If patient-level data were not available, pooled means were collected. Data extraction was conducted independently by two reviewers (RM and SW), with discrepancies resolved by discussion and consensus. When outcome data were incomplete or unclear, information was extracted from the published text, tables, and figures where possible; studies with insufficient data for quantitative synthesis were excluded from meta-analysis and described narratively. Circuit classification followed the symptom-oriented OCD neural circuit framework proposed by Shepherd et al. Although VNS was included in the initial search strategy to ensure completeness, it was not incorporated into the circuit-based meta-analysis. This decision was based on the peripheral nature of VNS and the lack of consistent evidence linking its effects to a specific OCD-related neural circuit, as well as the limited number of randomized controlled trials reporting standardized Y-BOCS outcomes. 2.5. Quality assessment Two reviewers completed all risk of bias (RoB) assessments independently. For RCTs, the revised Cochrane tool version 2.0 for assessing risk of bias in randomized trials was used to critically evaluate six domains of bias: randomization, period/carryover (for crossover trials), assignment to intervention, missing outcome, outcome measurement, and selection of reported results. All bias assessments were performed by two researchers who were blinded to each other's ratings. Following individual assessment, incongruencies were mediated and results were aggregated and visualized using the RoB 2.0 Excel tool. Inconsistency in assessments was resolved by further reviewing original records for consensus, and a senior experienced researcher was asked to make the final decision when needed. 2.6. Evidence-based practice The basal ganglia play a central role in modulating multiple neural circuits implicated in OCD, and DBS targets these regions to restore circuit-level balance. As growing evidence supports its efficacy in treatment-refractory OCD, DBS is increasingly considered a viable option when conventional therapies, including medication, psychotherapy, and non-invasive neuromodulation, have failed. 21 Therefore, we performed DBS on a 29-year-old female patient with a 5-year history of OCD. She grappled with a range of symptoms including dystychiphobia (phobia of accidents), unwanted memories, or repetitive thoughts. Despite undergoing extensive standard treatments such as pharmacotherapy of adequate dose and duration, behavioral therapy, exposure response prevention, and electroconvulsive therapy, her condition did not improve. Given the ineffectiveness of these interventions, she was considered a candidate for DBS. After being fully informed about the procedure and its potential implications, she consented to participate in the study. In all the included DBS RCT studies described above, the targets include the STN (ventral cognitive circuit), ALIC (fronto-limbic circuit), and Nacc (ventral-affective circuit). She had both cognitive and emotion-related syndrome. Based on these findings, we opted to explore the potential benefits of bilateral stimulation of these three targets to assess all possible therapeutic alternatives comprehensively. Given the close anatomical proximity between the Nacc and ALIC, our strategy involved the use of a single electrode to target both regions simultaneously—positioning the bottom two contacts within the Nacc and the top two in the ALIC. A high-resolution 3T magnetic resonance imaging (MRI) brain scan with a resolution of 1 mm 3 was conducted 1 day prior to the operation. On the day of the surgery, with a Leksell stereotactic frame in place, a detailed computed tomography (CT) head scan with thin layers (spacing 0.625 mm) was performed. The CT and MRI images were then fused to craft the trajectory plan for implantation and to accurately locate the bilateral STN, Nacc + ALIC electrodes. The targeting was precisely guided by T1-weighted MRI. The DBS electrode implantation itself was carried out under general anesthesia under the guidance of the Leksell microstereotactic system provided by Elekta Instrument AB, Stockholm, Sweden. The preoperative surgical plan is shown in Fig. 2 . Fig. 2. Open in a new tab Pre-surgical planning of a patient with obsessive–compulsive disorder (OCD) practice with deep brain stimulation (DBS), the two green crossings are the planned implanted targets. Once the target location was verified, four quadripolar electrodes (PINS, Beijing, China) were inserted along the same trajectory to the designated nucleus STN (PINS L301), and Nacc + ALIC target position (PINS L302). Then the electrodes were connected to externalized batteries for efficacy testing. To ensure safety and accuracy, a post-operative CT scan was conducted. This step aimed to rule out any intracranial hemorrhage and to confirm the precise placement of the electrodes by integrating the post-operative CT images with the preoperative MRI scans. After the externalized stimulation tests, these electrodes were connected to an implantable pulse generator (IPG), which was placed in the subclavicular area under general anesthesia. The IPG was activated 1 month following the surgery. After this initial period, the patient regularly received adjustments to their stimulation settings (1, 3, 6 month post-operatively) and medication regimen until the optimal control of their symptoms was achieved. The patient's outcomes were analyzed by descriptive analysis and connectivity analysis. The process of localizing the electrodes involved a multi-step approach. Initially, the Precise and Convenient Electrode Reconstruction (PaCER) method along with the refined TRAC/CORE techniques were applied for the initial construction of the electrode models. These preliminary reconstructions underwent a manual inspection and were further refined by RYM and SW. To achieve precise visualization of the Nacc, the OCD Tract Target was employed. 22 For the graphical depiction of the electrode positions, 2D slices were created using the high-resolution 7-T 100 µm ex vivo human brain MRI template as the background for reference. This entire reconstruction workflow was executed using the Lead-DBS toolbox (version 3.0), ensuring that the final electrode placements were both accurate and reliable. Connectivity visualization was subsequently performed using the MGH-USC Human Connectome Project 32 modality, 23 focusing on stimulation-based outcomes. These analyses were conducted using the stimulation parameters set 6 months post-surgery. Additionally, seed-based connectivity analysis was performed using the same modality, specifically targeting the G_Frontal_Sup-1-L as the seed point. The stimulation parameters were based on the setting of the latest programming. 2.7. Statistical analysis Meta-analysis was carried out using RevMan 5.4.1 software. Continuous variables were presented as mean ± SD. Descriptive analysis was carried out for data that did not allow pooling. The differences of measured parameters before and after the intervention were calculated and analyzed using mean difference (MD) or standardized mean difference (SMD) along with the 95% confidence interval (CI). Statistical heterogeneity was measured using the χ 2 -test and I 2 . A P value < 0.05 was statistically significant; I 2 < 50% was considered as acceptable heterogeneity. The random-effects model was used for heterogeneous cases, and fixed-effect model was otherwise used for cases with high homogeneity. Prespecified subgroup analyses were conducted according to neuromodulation modality (invasive vs. non-invasive), targeted neural circuit (fronto-limbic, dorsal cognitive, sensorimotor, and ventral affective circuits), and follow-up duration when available. Sensitivity analyses were prespecified and performed by excluding studies at high risk of bias and by sequentially removing individual studies to assess the robustness of pooled estimates. Publication bias was assessed by visual inspection of funnel plots when sufficient studies were available; for outcomes with a limited number of studies, formal assessment of publication bias was not considered reliable. 3. Results 3.1. Characteristics of included studies The study selection process is summarized in the PRISMA flow diagram ( Fig. 1A ). A total of 406 records were searched after duplicates were removed. The screening and full-text analysis excluded 253 and 125 articles according to the eligibility criteria. Finally, 27 studies with 868 patients were included and analyzed. The detailed information of the included studies is shown in Supplementary Table S4. Among the included 27 studies, 6 focused on DBS, 4 on tDCS, and 17 on TMS. All patients were adults (no less than 18 years) and were balanced in gender proportions (49.5% vs. 50.5% for male vs. female). Most of the studies (26/27, 96.3%) finished a short-term follow-up in less than 12 months. 3.2. Risk of bias assessment Risk of bias was assessed using the Cochrane RoB 2.0 tool ( Fig. 1C ). Among the 27 included studies, 22 (81.5%) were rated as having low risk of bias. Three studies (11.1%) were rated as having “some concerns”, primarily due to incomplete reporting regarding assessor blinding and baseline group comparability. Two studies (7.4%) were deemed high risk of bias due to substantial methodological limitations, including lack of adequate randomization procedures and deviations from intended interventions. These two high-risk studies were excluded from the final meta-analysis. Sensitivity analysis confirmed that their exclusion did not affect the overall results or conclusions. 3.3. Overall effect of neuromodulation on OCD symptoms Overall, Y-BOCS outcome measures suggested significant postoperative improvements only in the experimental stimulation group for all the included studies (MD: −2.29, 95% CI: −3.05, −1.53; P < 0.001), suggesting clinical benefits of neuromodulation on OCD symptoms ( Fig. 3 ). However, the results showed high heterogeneity ( P < 0.001, I 2 = 71%). In analyzing efficacy of OCD symptoms of different neuromodulation methods, we conducted subgroup analyses, and the results suggested that both invasive (MD: −7.99, 95% CI: −11.09, −4.89; P < 0.001) and noninvasive (MD: −1.93, 95% CI: −3.05, −1.53; P < 0.001) neuromodulation significantly improved OCD symptoms than the control group (Supplementary Fig. 1A). The invasive subgroup analysis achieved low heterogeneity ( P = 0.45, I 2 = 0%), while the noninvasive subgroup analysis had high heterogeneity ( P < 0.001, I 2 = 71%). Fig. 3. Open in a new tab Forest plot of overall neuromodulation efficacy of obsessive–compulsive disorder (OCD) symptoms. 3.4. Circuit-based and modality subgroup analysis Regarding circuit-based analysis of neuromodulation efficacy of OCD symptoms (Supplementary Fig. 1B), fronto-limbic (MD: −10.19, 95% CI: −14.99, −5.38; P < 0.001), sensorimotor (MD: −2.96, 95% CI: −4.31, −1.60; P < 0.001), ventral affective (MD: −1.99, 95% CI: −3.47, −0.50; P = 0.009), and dorsal cognitive (MD: −1.32, 95% CI: −2.52, −0.11; P = 0.03) circuits all had significant improvements in OCD symptom than the control group with high heterogeneity for sensorimotor and dorsal cognitive circuits respectively ( P = 0.02, I 2 = 56%; and P < 0.001, I 2 = 80%) and low heterogeneity for ventral affective and fronto-limbic circuits respectively ( P = 0.03, I 2 = 18%; and P = 0.35, I 2 = 5%) (Supplementary Fig. 1B). Additional subgroup analyses were conducted by further grouping circuit-based analyses for invasive ( Fig. 4A ) and noninvasive ( Fig. 4B ) neuromodulation. Invasive neuromodulation was effective for the fronto-limbic, ventral affective, and sensorimotor circuits, whereas non-invasive neuromodulation was effective for the dorsal cognitive and sensorimotor circuits. There were no notable differences in effects on the dorsal cognitive, fronto-limbic, and ventral affective circuits when comparing with sham treatments. Fig. 4. Open in a new tab Efficacy of obsessive–compulsive disorder (OCD) symptoms in different neuromodulate methods (A), and circuit-based analysis on efficacy of OCD symptoms (B). Further sensitivity analyses were performed by excluding studies with high risk of bias followed by randomly excluding one study from the calculations. No significant alternative changes were observed. Furthermore, funnel plots (Supplementary Fig. S2) revealed no significant publication bias. Notably, subgroup analyses indicated that sensorimotor circuit modulation—particularly with non-invasive approaches—showed numerically larger symptom reductions in some comparisons. However, these findings were accompanied by substantial heterogeneity and variability in study design. To summarize, although high heterogeneity may be related to limitations of sample size, modulating the fronto-limbic circuit appears to be associated with optimal OCD symptomatic improvement outcome. However, stimulating other circuits also positively influences OCD symptoms, albeit with milder efficacy. 3.5. Secondary outcomes and safety Secondary outcomes, including depressive and anxiety symptoms, were prespecified and are reported below. We also investigated potential neuromodulation efficacy of other psychiatric symptoms ( Fig. 5 ) such as depression and anxiety. Significant improvements were observed in depression symptoms as assessed by HAMD (Hamilton Depression Rating Scale) (MD: −1.89, 95% CI: −2.81, −0.96; P < 0.001), MADRS (Montgomery–Asberg Depression Rating Scale) (MD: −3.00, 95% CI: −5.22, −0.77; P = 0.008), and BDI (Beck's Depression Inventory) (MD: −2.52, 95% CI: −3.96, −1.08; P < 0.001) compared to the control group. Heterogeneity was high for HAMD and MADRS ( P = 0.03, I 2 = 47% and P = 0.008, I 2 = 71%), but low for BDI ( P = 0.23, I 2 = 28%). Regarding anxiety symptoms, significant improvements were noted in HAMA (MD: −1.98, 95% CI: −2.99, −0.97; P < 0.001) and BAI (Beck Anxiety Inventory) (MD: −2.58, 95% CI: −5.32, −0.16; P = 0.06) but not in BAS (Behavioral Activation Sensitivity) (MD: −0.79, 95% CI: −2.47, 0.90; P = 0.36) and STAI (MD: −4.15, 95% CI: −14.83, 6.53; P = 0.45). Heterogeneity was high for HAMA (P < 0.001, I 2 = 69%) and low for BAI and BAS ( P = 0.97, I 2 = 0% and P = 0.25, I 2 = 28%). Overall, neuromodulation showed efficacy in alleviating anxiety and depression symptoms (SMD: −1.99, 95% CI: −2.54, −1.44; P < 0.001), with high heterogeneity ( P < 0.001, I 2 = 55%). Sensitivity analysis, as described, yielded no significant changes ( Fig. 5 ). Furthermore, examination of funnel plots (Supplementary Fig. S2) showed no evidence of significant publication bias. Fig. 5. Open in a new tab Neuromodulation efficacy of other psychiatric symptoms. Based on the findings from our systematic review and meta-analysis, modulation of the fronto-limbic circuit—particularly the ALIC—emerged as the most effective strategy for symptom reduction in OCD. This circuit-based insight provided a rational foundation for clinical decision-making in our practice (Supplementary Fig. S4). To illustrate the translational relevance of these findings, we implemented a multi-target DBS strategy in a patient with treatment-refractory OCD, targeting the ALIC, NAcc, and STN. The case is presented in the following section as a proof-of-concept application of the evidence-based framework established in this review. Overall, neuromodulation was generally well-tolerated. Most reported adverse events were mild-to-moderate and transient, and no unexpected serious treatment-related adverse events were consistently observed across studies. Owing to heterogeneity in reporting, safety outcomes were summarized descriptively. Taken together, these findings suggest a favorable overall safety profile of neuromodulation interventions in the included studies. 3.6. Implementation evidence-based clinical practice In our reported OCD case, four electrodes were successfully placed according to the surgical plan based on the systematic review, with a pair of PINS L301 electrodes placed at bilateral STN (AC-PC coordinates: R-STN: X 93.6, Y 95.5, Z 109.0; L-STN: X 112.5, Y 97.0, Z 108.5) and one pair of PINS L302 electrodes placed within the Nacc and the ALIC; specifically, the bottom contact pair is positioned within the Nacc, while the middle contact pairs are situated within the ALIC (AC-PC coordinates: R-Nacc: X 95.1, Y 111.6, Z 108.5; L-Nacc: X 111.3, Y 111.7, Z 108.5; R-ALIC: X 92.3, Y 112.9, Z 103.5; L-ALIC: X 113.3, Y 113.2, Z 103.4). After electrode implantation, the patient underwent three sessions of device programming, including IPG activation, as is illustrated in Supplementary Fig. S3. Each pair of contacts of every electrode was tested, and the patient's responses were meticulously documented. During the externalization period, the patient complained of long-lasting panic and feeling of depression when stimulating STN (1–2+, 9–10+, 60 μs, 130 Hz, 4 V), and felt fear and anxiety when stimulating upper contacts of the STN (2–3+, 10–11+, 60 μs, 130 Hz, 4 V), and according to the psychiatrist's observation, the patient's cognitive ability fluctuated along with her emotion; therefore, STN was eliminated as the optimal choice. In terms of Nacc + ALIC, stimulating the lower contacts within the Nacc triggered episodes of mirthful laughter, with no immediate alleviation of the patient's obsessive thoughts. In contrast, stimulation through the upper contacts (2–3+; 10–11+) in the ALIC resulted in an immediate and sustained sensation of tranquility, accompanied by a marked reduction in obsessive thoughts (60 μs, 130 Hz, 5 V). This effect persisted for the subsequent 6 months. Connectivity visualizations were generated for both stimulation settings for Nacc and ALIC stimulation as shown in Fig. 6A , it was observed that stimulation at the Nacc contacts activation resulted in more increased connectivity with the superior frontal cortex, which could also corroborate with the previous study. 24 Fig. 6. Open in a new tab Simulated activated tracts and clinical outcomes of reported patients. The left row indicates stimulating NAcc (red area) on both sides and the activated tracts, the right row indicates stimulating ALIC (red area) on both sides and the corresponding activated tracts. Blue area: Nacc; Green area: ventral pallidum; Deep purple area: caudate necleus; Light purple area: projected cortical area. Colorful lines: simulated activated tracts (A). Changes of different scales at pre-operative stage and post-operative follow-ups of the reported case (B). Abbreviations: YBOCS-TOTAL: the total score of Yale-Brown Obsessive-Compulsive Scale; HAMA: Hamilton Anxiety Scale; HAMD: Hamilton Depression Scale; CGI: Clinical Global Impression Scale; SI: severity of illness; GI: global improvement; EI: efficacy index. In terms of symptoms, the patient had moderate OCD severity at baseline with a YBOCS total score of 25, alongside moderate anxiety and depression (HAMA 13, HAMD 15). The CGI (Clinical Global Impression Scale) score was 14, reflecting significant overall disease impact. One-month after the DBS, a temporary worsening in OCD symptoms was observed (YBOCS 33) as stimulation was not yet initiated; yet anxiety and depression levels decreased (HAMA 6, HAMD 5), with a slight improvement in the CGI score to 10. At 3-month follow-up, following 2 months of chronic stimulation, there was a notable reduction in OCD severity (YBOCS 18) and further improvements in anxiety and depression, which were sustained to the 6-month follow-up (YBOCS 16, HAMA 5, HAMD 5) ( Fig. 5 ). The CGI score also improved over time, indicating reduced symptom severity and enhanced treatment efficacy. These results underscore the potential of DBS to significantly alleviate OCD symptoms and improve overall mental health over a 6-month period. The preoperative and postoperative scores of the YBOCS along with other psychiatric assessment scales are detailed in Table 1 . A graphical representation of the trend across these scores over time is depicted in Fig. 6B . Table 1. Baseline and postoperative assessments of the patients with OCD accepted DBS treatment. Assessments Baseline 1-month 3-month 6-month YBOCS-TOTAL 25 33 18 16 -Compulsive thoughts 13 15 9 8 -Compulsive behaviors 12 18 9 8 HAMA 13 6 4 5 HAMD 15 5 4 5 CGI 14 10 6.5 8 -SI 6 5 4 3 -GI 7 4 1 2 -EI 1 1 1.5 3 Open in a new tab Note: OCD, obsessive–compulsive disorder; DBS, deep brain stimulation; YBOCS: Yale-Brown Obsessive-Compulsive Scale; HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton Depression Rating Scale; CGI: Clinical Global Impression Scale; SI: severity of illness; GI: global impression; EI: efficacy index. During the extended follow-up of the DBS-treated patient, no long-term adverse events or device-related complications were observed. In summary, the result of our exploratory case study also corroborated along with our meta-analysis suggests that the fronto-limbic circuit (specifically ALIC for DBS) may be the optimal circuit to target for neuromodulation for OCD. 4. Discussion It is important to acknowledge that the classification of OCD-related neural circuits, while useful for analytical clarity, is not rigid. Many brain regions, such as the orbitofrontal cortex (OFC) and nucleus accumbens (NAc), are functionally involved in multiple circuits and may contribute to both emotional and cognitive aspects of OCD. Our categorization was based on the framework proposed by Shephard et al., which offers a symptom-oriented taxonomy that aligns with current neuromodulation targets. 18 However, these networks are inherently overlapping and dynamic, and future studies with advanced connectomic and symptom-mapping approaches may yield more precise or reorganized circuit models. 4.1. Circuit-based evidence of neuromodulation for OCD Previous original and review studies highlight five neural circuits correlating with particular OCD characteristics and their evolution. 18 , 25 While OCD is commonly linked to dysfunctional cortico-striato-thalamo-cortical circuits, changes in structures beyond these circuits also contribute to the underlying pathology. Therefore, the classification method chosen in this article provides a more detailed correlation between symptoms, structures, and circuits, which can potentially shed light on the future neuromodulation strategies for OCD. 4.1.1. Fronto-limbic circuit The fronto-limbic circuit plays a role in generating emotional responses and evaluates whether those responses are appropriate or require regulation, and it is connected with the hippocampus and regions from other circuits that are involved in top-down behavioral control. 26 , 27 The key nodes in this circuit that is also involved with OCD neuromodulation is ALIC. In our included studies, only three studies targeted this neurocircuit, and all of them were ALIC/BNST-DBS (invasive) studies, with total of 25 OCD patients enrolled, yet they demonstrated the most effective YBOCS improvement outcomes among all the circuits studied. 28 , 29 Cognitive behavioral therapy for OCD also appears to modulate fronto-limbic dysfunction via exposure and response prevention. 30 There are other structures that are also classified as part of the fronto-limbic circuit, including amygdala and ventromedial prefrontal cortex, yet larger amount of data are needed to prove the superiority of modulating the fronto-limbic network. Although the sensorimotor circuit showed strong effects in some subgroups, especially with non-invasive methods, this was driven by more heterogeneous studies. In contrast, fronto-limbic modulation—particularly ALIC-DBS—demonstrated more consistent benefits in high-quality trials. Future head-to-head comparisons are needed to clarify the relative advantages of each circuit across modalities. We acknowledge that, in certain subgroup analyses, neuromodulation of the sensorimotor circuit—particularly via non-invasive modalities—appeared to yield numerically greater Y-BOCS reductions than fronto-limbic modulation. Several factors may account for this apparent discrepancy. First, sensorimotor circuit studies comprised a substantially larger sample size, especially in rTMS and tDCS trials, which may inflate pooled effect estimates. Second, these studies demonstrated markedly higher heterogeneity, reflecting variability in stimulation parameters, cortical targets (e.g., SMA), and follow-up durations. In contrast, fronto-limbic interventions—primarily invasive DBS targeting the ALIC/BNST—were supported by smaller but methodologically more homogeneous trials with consistent long-term follow-up, potentially yielding more stable and reliable effect estimates. Finally, sensorimotor modulation may preferentially influence compulsive motor components in the short term, whereas fronto-limbic modulation may exert broader and more sustained effects on affective and cognitive dimensions of OCD. These considerations suggest that apparent effect size differences should be interpreted cautiously and do not necessarily contradict the overall superiority of fronto-limbic modulation observed across high-quality studies. 4.1.2. Dorsal cognitive circuit In OCD, the dorsal cognitive circuit plays a crucial role in impairments related to goal-directed behaviors, including working memory and the ability to exert top-down control over emotional responses. 25 , 31 , 32 The preSMA and DLPFC are key structures in this circuit targeted for neuromodulation. Our review included 13 studies focusing on this circuit, with nine employing TMS to stimulate the DLPFC and four targeting the preSMA. The studies varied, targeting the right DLPFC, left DLPFC, or both sides. 33 – 42 The question of laterality in TMS treatment for OCD is actively debated. Evidence indicates that low-frequency stimulation of the right DLPFC and high-frequency bilateral stimulation of the DLPFC might be beneficial. One study noted modest, lateralized effects on OCD symptoms with 1 Hz rTMS directed at the right DLPFC, hinting at a possible preference for targeting the right hemisphere in certain cases. 43 Nevertheless, our meta-analysis did not show a definitive preference for laterality. 4.1.3. Sensorimotor circuit The sensorimotor circuit, encompassing both cortical and subcortical areas is crucial for the initiation and regulation of motor actions and the integration of sensory inputs. 25 , 44 This circuit is implicated in the distressing sensations or perceptions that prompt repetitive behaviors in OCD, as well as the excessive habit formation associated with certain compulsions. The SMA is a primary node targeted for neuromodulation in OCD, typically through non-invasive methods like tDCS and rTMS. In our analysis, 131 patients treated within this circuit showed notable improvement, with an average decrease of nearly three points on the YBOCS, making it the second most effective circuit following the fronto-limbic circuit in terms of symptom reduction. However, despite its clinical relevance, the role of the sensorimotor circuit appears less prominent than fronto-limbic pathways in subgroup-level efficacy analyses, raising questions regarding the relationship between therapeutic targets and electrophysiological signatures. An apparent divergence was observed between subgroup-level clinical efficacy, which predominantly implicated fronto-limbic circuits, and the electrophysiological features identified in this study, which were primarily derived from sensorimotor-related signals. This finding likely reflects the multiscale organization of OCD-related neural circuits rather than a true inconsistency. Fronto-limbic networks, including OFC–ACC–striatal pathways, are central to symptom generation and affective–cognitive control, whereas sensorimotor circuits contribute to habit formation and the execution of compulsive behaviors. Local field potentials capture localized, fast-timescale oscillatory dynamics that may index circuit state or network excitability rather than symptom domains directly. 45 In particular, the subthalamic nucleus integrates motor, associative, and limbic information, and sensorimotor oscillations within this structure may serve as accessible biomarkers of broader circuit modulation 46 . 4.1.4. Ventral cognitive circuit The ventral cognitive circuit is proposed to be fundamentally involved in response inhibition in OCD, which is the ability to withhold inappropriate behaviors. 47 Response inhibition is mediated in part by STN, which is the key node for neuromodulation in this circuit; it plays a role in regulating emotional and motivational behaviors through its connections with fronto-limbic and ventral affective circuits. 48 Only one study was included that utilized STN-DBS for treating OCD. In this study, patients experienced a median decrease in YBOCS scores from 30 to 19 However, improvements in anxiety were not observed, and side effects such as temporary anxiety, headaches, and post-operative dyskinesia were reported. 48 While in our reported case, short term STN-DBS did not improve the patient's OCD symptoms, but instead resulted to numbness and dizziness, and temporary anxiety, and according to the psychiatrist, the patient's cognitive abilities also fluctuated along with her level of anxiety. Our result differed a little with the included study in terms of OCD symptoms but showed similar side effects such as anxiety. We hypothesize that these issues may be linked to the stimulation of different subregions of electrode placement, particularly the ventral contacts, potentially causing more severe psychiatric side effects. 4.1.5. Ventral affective circuit Pathological ventral affective circuit changes in OCD may lead to altered reward responsiveness, which is the alterations in the ability to anticipate, and respond to rewards. The key nodes within this circuit are OFC and ventral striatum (particularly the NAcc), and the thalamus. 25 , 49 , 50 Our study reviewed fewer investigations focusing on this circuit compared to other neural circuits. We included seven studies in total; three of these studies used invasive DBS targeting the NAcc, while the other four employed non-invasive techniques like tDCS, cTBS, and TMS on the OFC. Studies using NAcc-DBS showed significant effectiveness, whereas those involving non-invasive methods on the OFC had notably lesser efficacy. The aspect of laterality also emerged as a significant theme, with two studies targeting the left OFC and one targeting the right OFC. There is evidence suggesting that tDCS on the left OFC may be more effective, a finding supported by Acevedo et al., who noted that positioning the cathode on the left OFC could enhance efficacy. 51 In our reported case, using the bottom contacts to stimulate the NAcc led to temporary episodes of panic, depression, and anxiety, without notable improvements in OCD symptoms. Several studies have similarly reported that NAcc-DBS can trigger panic and anxiety. These findings suggest that DBS might have varying impacts on unconditioned and conditioned anxiety, which could depend on the specific area stimulated. 52 In summary, three out of the five circuits (sensorimotor, dorsal cognitive circuit, and ventral cognitive circuit) have garnered sufficient attention with an adequate number of studies to substantiate their impact on OCD symptoms. However, further validation is required for fronto-limbic circuit and ventral cognitive circuit. Overall, it is still too early to determine the best target circuit for OCD. Further high-level evidence studies, such as randomized controlled trials (RCTs), are needed at the circuitry level to determine the optimal option and further to explore the potential connectivity between targets. Another important consideration is the high rate of psychiatric comorbidities in OCD, particularly depression and anxiety, which may complicate the interpretation of treatment outcomes. While our focus was on OCD symptoms, neuromodulation likely affects multiple domains. Additional analysis showed significant improvements in depression and anxiety, suggesting broader therapeutic potential. However, it remains unclear whether Y-BOCS reductions reflect direct effects on OCD circuits or indirect benefits via improved comorbid symptoms. Fronto-limbic structures like the ALIC and NAcc are involved in both emotional regulation and compulsive behaviors, making circuit-specific effects hard to isolate. Our case showed symptom-specific responses by contact location, suggesting functional segregation, though findings are exploratory. Future RCTs should separately assess obsessive, compulsive, and comorbid symptoms, and incorporate neuroimaging to map symptom changes onto circuit activity. In conclusion, the fronto-limbic circuit appears to be the most promising target for modulating OCD symptoms, particularly for individuals exhibiting compulsive and repetitive behaviors. This is supported by our case report, where stimulation of the ALIC provided the most significant symptom relief. Connectivity-derived models established by Li et al. predicted clinical improvements based on the overlap of stimulation with the identified tract. These models were validated across different patient cohorts targeting the ALIC, NAcc, and STN, further supporting our conclusion. 24 However, it remains premature to definitively identify the best circuit to target for OCD treatment. More rigorous studies, such as randomized controlled trials (RCTs), are necessary at the circuit level to identify the most effective target and to further investigate the connectivity between potential targets. 4.2. Efficacy of invasive and noninvasive neuromodulation for OCD In our study encompassing 27 reviews, we distinguished between six invasive and 19 non-invasive neurostimulation techniques for OCD treatment, all showing notable efficacy in reducing symptoms according to YBOCS scale. Improvements in depressive and anxiety symptoms were observed following DBS; however, these findings should be interpreted as exploratory secondary outcomes. While mood and anxiety symptoms are frequently comorbid in OCD and may improve alongside core obsessive–compulsive symptoms, the present analysis was not designed or powered to establish independent treatment effects on these domains. Moreover, mood-related improvements may reflect indirect network modulation or secondary benefits of symptom relief rather than direct neuromodulatory effects. 53 Future studies with predefined psychiatric endpoints and targeted assessments will be necessary to clarify the specificity and mechanisms underlying these observations. To bridge the gap between circuit-level evidence derived from group analyses and patient-specific neurophysiological dynamics, we further present a representative DBS case. This case is intended to serve a translational purpose by illustrating how circuit-informed targeting and local field potential features may converge at the individual level. Rather than providing definitive mechanistic conclusions, the case highlights the feasibility of integrating electrophysiological observations with clinical outcomes within a circuit-based framework. Our surgical strategy involved the precise placement of a quadripolar electrode to modulate the ventral affective and fronto-limbic circuit, specifically the Nacc within ventral affective circuit, and the fronto-limbic circuit via the ALIC. This intervention was pursued after traditional treatments, including pharmacological and cognitive behavioral therapies, had failed to produce satisfactory results. The outcome of this DBS surgery was profound, offering significant symptomatic relief for the patient, a development thoroughly detailed in our study's Results section. Continuous follow-up assessments have documented a sustained improvement in the patient's OCD symptoms, underscoring the transformative potential of DBS for individuals with refractory OCD. This case report not only demonstrates the therapeutic promise of DBS but also opens new avenues for the application of neurostimulation techniques in the management of psychiatric disorders, warranting further research and exploration. 4.3. Safety of invasive and noninvasive neuromodulation for OCD Based on all the included studies, 19 out of 27 studies reported no adverse events or side effects, two tDCS study reported transient headache and dizziness. 54 , 55 One cTBS study reported increased anxiety. 56 However, DBS manifested much more adverse events, mostly were non-permanent, including nausea, increase in depressive symptoms, and stimulation related adverse events, such as hypomanic symptoms headaches, taste reduction, etc. 53 Another DBS study targeting BNST showed severe adverse events, including suicide attempts, fractures, epileptic seizures, but none of which were life-threatening or resulted in any permanent injury. 28 In our proof-of-concept case report, we did not observe adverse events or side effects, which further proved the safety of this target. The patient responded to Nacc-DBS with transient mirthful laughter, consistent with findings in previous studies. 57 This response may be attributed to the Nacc's role as a key node in the reward circuit, associated with feelings of pleasure and satisfaction. Additionally, as part of the ventral affective circuit, the Nacc is interconnected with various limbic system components, including the amygdala and hippocampus, which regulate emotion and memory. Stimulation of the Nacc can thus modulate these connections, potentially influencing emotional processing and increasing susceptibility to laughter. 58 , 59 Across the included studies, DBS for OCD was generally well-tolerated, with most adverse events being transient or manageable through parameter adjustment or standard clinical care. Stimulation-related side effects most commonly included mood fluctuations, anxiety exacerbation, hypomanic symptoms, and transient cognitive or sleep disturbances, while surgery-related complications such as infection or hemorrhage were infrequent. However, the majority of studies were limited by relatively short follow-up durations, and systematic assessments of long-term neuropsychiatric safety remain scarce. The durability of mood and cognitive effects, potential delayed adverse events, and the long-term impact of chronic stimulation across different targets have not been adequately characterized. Taken together, these findings suggest that neuromodulation—particularly when appropriately targeted and parameterized—is generally safe in the short term. For patients with severe, treatment-refractory symptoms, invasive approaches such as DBS may be justified despite a higher side-effect burden, whereas non-invasive neuromodulation may be more suitable for individuals with milder symptoms or lower risk tolerance. Clinical decision-making should therefore balance expected efficacy against individual risk profiles and long-term safety considerations. 4.4. Future perspectives of neuromodulation for OCD Invasive and non-invasive treatments, despite their differing methodologies, fundamentally aim to modulate distributed brain circuits. While targeting these circuits can offer therapeutic benefits, treatment effectiveness varies substantially across individuals, likely reflecting underlying biological heterogeneity. Importantly, the conclusions of the present study are primarily supported by studies assessed as having low risk of bias, strengthening the reliability of the observed efficacy and safety patterns despite residual heterogeneity across targets and study designs. Building on this evidence base, future research could pivot towards closed-loop control strategies, using personalized monitoring to accurately assess a patient's circuit status and applying closed-loop stimulation based on these data. 60 This approach, by adjusting to real-time physiological feedback, promises more targeted and effective treatments. 5. Limitations Several limitations should be acknowledged. First, most included studies reported only total Y-BOCS scores, limiting analyses of domain-specific neuromodulation effects. Future studies should report obsessive and compulsive subscores separately to better characterize symptom-specific responses. Second, given the high comorbidity of OCD with depression and anxiety, it remains unclear whether symptom improvement reflects direct modulation of OCD-related circuits or secondary mood effects. Although affective symptoms improved in our analysis, current evidence cannot fully disentangle direct from indirect mechanisms, underscoring the need for domain-specific assessments and neuroimaging in future trials. Third, despite randomized designs ensuring group comparability, follow-up durations—particularly for neuromodulation interventions—were relatively short, leaving long-term efficacy uncertain. Additionally, heterogeneity in control conditions (e.g., sham stimulation, medication, psychotherapy) may affect outcome comparability. The literature search was completed in December 2023, and more recent studies published during the peer-review process may not be captured, which should be considered when interpreting the findings. Future trials with standardized comparators, longer follow-up, and updated evidence synthesis are warranted. Finally, a formal GRADE assessment was not performed due to substantial heterogeneity in neuromodulation modalities, targets, and outcome measures; future updates may incorporate GRADE as the evidence base becomes more standardized. 6. Conclusion In conclusion, our systematic review and meta-analysis suggest that neuromodulation targeting the fronto-limbic circuit—particularly the ALIC—offers the most consistent therapeutic benefit for OCD, with additional contributions from the sensorimotor, ventral affective, and dorsal cognitive circuits. By integrating this evidence into clinical practice, we demonstrated the potential of circuit-informed DBS to alleviate symptoms in a patient with treatment-resistant OCD. This study highlights the value of bridging theory and practice through a circuit-based approach to neuromodulation. Future large-scale and long-term studies are warranted to further validate these findings and optimize individualized treatment strategies. Acknowledgements We would like to express our sincere gratitude to Dr. Casey Halpern from the University of Pennsylvania for his insightful feedback, Dr. En-ting Liu from Tsinghua University for providing technical support, and Dr. Rujin Wang from Beijing Tiantan Hospital, Capital Medical University, for his help with data collection for the case study. Contributor Information Shu Wang, Email: [email protected]. Guanyu Zhu, Email: [email protected]. Jianguo Zhang, Email: [email protected]. Data availability The extracted datasets supporting the conclusions of this study are available from the corresponding author upon reasonable request. Author contributions Conceptualization: RM, SW Data curation: RM, YG, TY Formal analysis: RM, SW Funding acquisition: JZ Investigation: RM Methodology: SW Project administration: GZ, JZ Resources: GZ, JZ Software: ZZ Supervision: YC, TD, VV, GZ, JZ Visualization: ZZ Writing – original draft: RM, SW Writing – review & editing: ZY, VV, GZ Funding information This study is conducted in Beijing Tiantan Hospital, Capital Medical University supported by the National Natural Science Foundation of China (82201634), and Young Elite Scientists Sponsorship Program by BAST (BYESS2023393). Supplementary material Supplementary data are available with the article at https://doi.org/10.1139/jpn-24-0163 . Supplementary Material 1 (PDF/ 609 KB) jpn-24-0163suppla.pdf (609.6KB, pdf) Supplementary Material 2 (PDF/ 336 KB) jpn-24-0163supplb.pdf (336KB, pdf) Supplementary Material 3 (PDF/ 11.9 MB) jon-24-0163supplc.pdf (12MB, pdf) Supplementary Material 4 (PDF/ 28.2 KB) jon-24-0163suppld.pdf (28.3KB, pdf) Supplementary Material 5 (PDF/ 74.4 KB) jpn-24-0163supple.pdf (74.5KB, pdf) Supplementary Material 6 (PDF/ 58.6 KB) jpn-24-0163supplf.pdf (58.6KB, pdf) Supplementary Material 7 (PDF/ 106 KB) jpn-24-0163supplg.pdf (106.6KB, pdf) Supplementary Material 8 (PDF/ 128 KB) jpn-24-0163supplh.pdf (128.6KB, pdf) References (1). Diagnostic and statistical manual of mental disorders: DSM-5™. 5th ed.; American Psychiatric Publishing, Inc. xliv, 947–xliv: Arlington, V. A., 2013, p 947. [ Google Scholar ] (2). Pallanti S.; Quercioli L.. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2006, 30(3), 400–412. doi: 10.1016/j.pnpbp.2005.11.028. PMID: 16503369 [ DOI ] [ PubMed ] [ Google Scholar ] (3). 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Supplementary Materials Supplementary Material 1 (PDF/ 609 KB) jpn-24-0163suppla.pdf (609.6KB, pdf) Supplementary Material 2 (PDF/ 336 KB) jpn-24-0163supplb.pdf (336KB, pdf) Supplementary Material 3 (PDF/ 11.9 MB) jon-24-0163supplc.pdf (12MB, pdf) Supplementary Material 4 (PDF/ 28.2 KB) jon-24-0163suppld.pdf (28.3KB, pdf) Supplementary Material 5 (PDF/ 74.4 KB) jpn-24-0163supple.pdf (74.5KB, pdf) Supplementary Material 6 (PDF/ 58.6 KB) jpn-24-0163supplf.pdf (58.6KB, pdf) Supplementary Material 7 (PDF/ 106 KB) jpn-24-0163supplg.pdf (106.6KB, pdf) Supplementary Material 8 (PDF/ 128 KB) jpn-24-0163supplh.pdf (128.6KB, pdf) Data Availability Statement The extracted datasets supporting the conclusions of this study are available from the corresponding author upon reasonable request. 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