Circuit-based Evidence and Practice of Neuromodulation for Obsessive-Compulsive Disorder: Towards the Optimal Neural Circuit

doi:10.21203/rs.3.rs-4806412/v1

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Circuit-based Evidence and Practice of Neuromodulation for Obsessive-Compulsive Disorder: Towards the Optimal Neural Circuit

https://doi.org/10.21203/rs.3.rs-4806412/v1

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Obsessive-Compulsive Disorder (OCD) is characterized by persistent intrusive thoughts and compulsive behaviors that are often resistant to traditional treatment methods such as medication and psychotherapy. Neuromodulation, targeting specific brain circuits, has emerged as a promising alternative for treating refractory OCD. This study aims to synthesize the effectiveness of various neuromodulation techniques, focusing particularly on their impact on neural circuitry based on existing symptom and treatment taxonomies. Through a systematic search of major databases, randomized controlled trials of both invasive and non-invasive neuromodulation techniques targeting different brain circuits were analyzed. The primary outcome was measured by changes in the Yale-Brown Obsessive-Compulsive Scale. The comprehensive search included 868 patients and demonstrated significant improvement in OCD symptoms through neuromodulation. The most substantial improvements were observed when targeting the fronto-limbic circuit. Additional significant symptom relief was noted in interventions affecting the sensorimotor and ventral affective circuits, with invasive methods outperforming non-invasive ones. In addition, a detailed case study of Deep Brain Stimulation from our center targeting the subthalamic nucleus, nucleus accumbens, and anterior limb of the internal capsule (ALIC) highlighted substantial symptom relief by specifically modulating the fronto-limbic circuit (targeting ALIC), aligning with the results of the meta-analysis. The findings underline the importance to tailor neuromodulation treatments to individual patients’ needs on the circuitry basis, optimizing outcomes in OCD management.

Health sciences/Diseases/Psychiatric disorders

Health sciences/Diseases

Obsessive-Compulsive Disorder (OCD) is a prevalent and persistent condition characterized by unwanted recurring thoughts (obsessions) and repetitive actions (compulsions) ¹. These symptoms can profoundly affect different areas of life, such as work, study, and social connections ². Despite existing treatments like medication and psychotherapy, many patients affected by OCD still face considerable challenges especially the medication refractory symptoms, highlighting the need for innovative therapeutic strategies ^2–4. Neuromodulation, which involves the use of electrical or magnetic fields to alter brain activity, has emerged as a promising approach ^5–9. This method offers a spectrum of treatments ranging from non-invasive techniques, such as Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), to invasive procedures like deep brain stimulation (DBS). Notably, stimulating different structures produce similar effects on the same symptoms, indicating that these targets may be interconnected within the same neural circuits.

Although several meta-analyses have been conducted on neuromodulation for OCD, current analyses often focus on a single target or, even at the neural circuit level, include either invasive or non-invasive methods, lacking comprehensiveness and potentially missing the connections between deep brain nuclei and the cortical regions ^10–12. Additionally, some meta-analyses include lower-level evidence, which may not be sufficiently convincing ¹².

The development of OCD is complex, involving various brain regions and showing remarkable individual variability. Identifying effective therapeutic targets at the circuit level tailored to specific OCD phenotypes is crucial for achieving long-term treatment success. Currently, a clear connection between neural circuits and OCD phenotypes has not been established. The prevalent classification for OCD-related neural circuits, such as cortico-striatalthalamo-cortical (CSTC) network and limbic network, included too many anatomical structures with a wide range of symptoms, making it hard to pinpoint effective modulation target ^{13 14}. Therefore, it is necessary to classify OCD based on disease progression and specific symptoms.

A previous review divided OCD-related neural circuits into more detailed classifications based on different symptoms, functions, and treatments. Previous studies have organized neural circuits by analyzing the relationships between different OCD symptoms and the roles of various structures, alongside neuropsychological and neuroimaging characteristics. This classification can be further validated through clinical neuromodulation of the relevant structures. OCD-related neural circuits have been categorized as follows, with the key nodes noted in parentheses: the fronto-limbic circuit (anterior limb of internal capsule, ALIC), which plays a role in emotional reactions such as fear and anxiety; the dorsal cognitive circuit (dorsal lateral prefrontal cortex, DLPFC; pre-supplementary motor area, preSMA), associated with working memory and goal-oriented behavior; the sensorimotor circuit (supplementary motor area, SMA), which is involved in excessive habit formation; the ventral cognitive circuit (subthalamic nucleus, STN), linked to compromised response inhibition; and the ventral affective circuit (orbitofrontal cortex, OFC; nucleus accumbens, Nacc), which influences altered reward anticipation ¹⁵.

By examining the outcomes and various neuromodulation methods on different target on OCD, this study aims to bridge this gap by conducting a meta-analysis of the latest research, to enhance our understanding of OCD’s neurobiological underpinnings, and also directs future research and clinical practices towards developing targeted treatments. Furthermore, we implemented DBS in an OCD patient based on current evidence found and demonstrated successful symptom management, underlining the potential of this approach in modifying specific brain circuits for therapeutic benefit, realizing “from theory to practice”.

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 ¹⁶ (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) ¹⁷ 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.

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 “tACS” OR “Transcranial Alternating 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 trails; (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.

2.4. Data collection and organization

The following data items were collected where available: general study information including study location, first author, publication year, study design, patient inclusion and exclusion criteria, sample size, treatment response criteria, response rate, and rates of complications or adverse events.

Patient-level data including stimulation target(s), primary diagnosis, patient sex, age at onset of OCD, age at DBS surgery, comorbid psychiatric diagnoses, active medications, preoperative/baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, all follow-up Y-BOCS scores (with time points in months), percent Y-BOCS score reduction at last follow-up (≥ 35% indicates responsive), length of follow-up (in months), stimulation parameters, quality of life outcomes, baseline depression scale (Hamilton Depression Rating Scale (HAM-D, HDRS-17, HDRS-24), Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI)), baseline anxiety scale (Hamilton Anxiety Rating Scale (HAM-A and HARS), State-Trait Anxiety Inventory (STAI-1/X1 and STAI-2/X2) and all follow-up scores. If patient-level data were not available, pooled means were collected. All data were manually recorded in a single spreadsheet by two reviewers who worked in conjunction.

Regarding the classification of OCD implicated circuits, we adopted the categorization outlined by Shepherd et al., identified the key nodes discussed in the Introduction section and depicted these neural circuits along with associated neurostimulation techniques in Fig. 1B.

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 (Fig. 1C). 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.

2.5. Evidence-based practice

Basal ganglia are considered to be the nodes modulating multiple circuits, thus DBS, an invasive treatment, might be the last resort for refractory OCD after medication, psychotherapy and non-invasive neurostimulation ¹⁸. Therefore, we performed DBS on a 29-year-old female patient with a five-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 1mm³, was conducted one 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 deep brain stimulation (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. 1D.

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 one month following the surgery. After this initial period, patients 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 ¹⁹. 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 ²⁰, focusing on stimulation-based outcomes. These analyses were conducted with stimulation parameters as they were set six months post-surgery. Additionally, seed-based connectivity analysis was carried out utilizing 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 χ²-test and I². A P-value < 0.05 was statistically significant; I² < 50% was considered as acceptable heterogeneity. The random-effects model was used for homogeneous cases, and fixed-effect model was otherwise used for cases with high heterogeneity. The factors that might have contributed to heterogeneity were subjected to subgroup analysis. Sensitivity analysis was applied where necessary.

3.1. Characteristics of included studies

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 (Fig. 1A). 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. These studies aimed at four circuits: 12 targeted the dorsal cognitive Circuit (including the DLPFC and preSMA), 4 examined the fronto-limbic circuit (ALIC and BNST), 7 focused on the sensorimotor circuit (STN and SMA), and 4 modulated the ventral affective circuit (OFC and Nacc). 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. The RoB 2.0 quality assessments suggested high methodological quality (low risk of bias) for most of the studies (22/27, 81.5%). Only 3 studies (11.1%) raised some concerns, and 2 studies (7.4%) were considered as high risk of bias. Randomization process and deviations from the intended interventions were the two most affected domains in influencing their methodological quality.

3.2. Neuromodulation efficacy of OCD symptoms

Overall, Y-BOCS outcome measures suggested significant postoperative improvements only in the 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. 2). However, the results showed high heterogeneity (P < 0.001, I² = 71%). In analyzing efficacy of OCD symptoms of different neuromodulation methods (Supplementary Fig. 1A), we conducted subgroup analyses, 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. The invasive subgroup analysis achieved low heterogeneity (P = 0.45, I² = 0%), while the noninvasive subgroup analysis had high heterogeneity (P < 0.001, I² = 71%).

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, I² = 56%; and P < 0.001, I² = 80%) and low heterogeneity for ventral affective and fronto-limbic circuits respectively (P = 0.03, I² = 18%; and P = 0.35, I² = 5%).

Additional subgroup analyses were conducted by further grouping circuit-based analyses for invasive (Fig. 3A) and noninvasive (Fig. 3B) neuromodulation. Invasive neuromodulation was effective for the fronto-limbic, ventral affective, and sensorimotor circuits whereas for 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.

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 Figure S2) revealed no significant publication bias.

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.

3.3. Neuromodulation efficacy of other psychiatric symptoms

We also investigated potential neuromodulation efficacy of other psychiatric symptoms (Fig. 4) 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, I² = 47% and P = 0.008, I² = 71%), but low for BDI (P = 0.23, I² = 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, I² = 69%) and low for BAI and BAS (P = 0.97, I² = 0% and P = 0.25, I² = 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, I² = 55%). Sensitivity analysis, as described, yielded no significant changes. Furthermore, examination of funnel plots (Supplementary Figure S2) showed no evidence of significant publication bias.

3.4. Implementation evidence-based clinical practice

In our reported OCD case, four electrodes were successfully placed according to the surgical plan, 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 Figure 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+, 60us, 130Hz, 4V), and felt fear and anxiety when stimulating upper contacts of the STN (2–3+, 10–11+, 60us, 130Hz, 4V), 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. This effect persisted for the subsequent six months. Connectivity visualizations were generated for both stimulation settings for Nacc and ALIC stimulation as shown in Fig. 5A, 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 ²¹.

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). 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. 5B.

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.

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

Abbreviations: 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.

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 ^{15 22} . While OCD is commonly linked to dysfunctional cortico-striato-thalamo-cortical (CSTC) 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 ^{23 24}. The key nodes in this circuit which 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 ^25-27. Cognitive behavioral therapy for OCD also appears to modulate fronto-limbic dysfunction via exposure and response prevention ²⁸. 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 is needed to prove the superiority of modulating the fronto-limbic network.

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 ^{22 29 30}. The preSMA and DLPFC are key structures in this circuit targeted for neuromodulation. Our review included thirteen 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 ^31-42. 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 ^{22 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 supplementary motor area (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 3 points on the YBOCS, making it the second most effective circuit following the fronto-limbic circuit in terms of symptom reduction.

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 ⁴⁵. 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 ^{46 47}. 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 ⁴⁷. 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 ^{22 48 49}.

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 ⁵⁰. 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 ⁵¹.

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.

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 ²¹. 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 nineteen non-invasive neurostimulation techniques for OCD treatment, all showing notable efficacy in reducing symptoms according to YBOCS scale. Moreover, these interventions also significantly improved related psychological disorders such as anxiety and depression, as demonstrated by scores on the HAMA, HAMD, MDRS, and BDI.

Building on these findings, we highlight a pioneering case report where DBS was applied to a patient with treatment-resistant OCD, targeting two neural circuits for potential symptom alleviation. 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 ^{52 53}. One cTBS study reported increased anxiety ⁵⁴. 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. ⁵⁵. 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 ²⁶. 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 ⁵⁶. 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 ^57-59.

4.4. Future perspectives of neuromodulation for OCD

Invasive and non-invasive treatments, despite their differing methodologies, fundamentally aim to modulate various circuits within the brain. While different treatments targeting these circuits can offer therapeutic benefits, the extent of their effectiveness varies significantly among individuals due to unique biological differences.

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 this data ⁶⁰. This approach, by adjusting to real-time physiological feedback, promises more targeted and effective treatments.

In conclusion, both invasive and noninvasive neuromodulation are effective in treating OCD and its comorbid depression and anxiety symptoms. Stimulating fronto-limbic, sensorimotor, ventral affective, and dorsal cognitive circuits all have significant effects in improving OCD symptoms, despite potential limitations due to small sample sizes included, modulating the fronto-limbic circuit seems to be linked with the best outcomes for improving OCD symptoms. We applied evidence-based clinical practice and found out that ALIC, as one of the nodes within the fronto-limbic circuit, was the optimal DBS target for the individual OCD patient, corroborating our previous findings. Further studies with higher levels of evidence and larger cohorts are needed, with more tailored neurostimulation methods for individual patients that lay the foundation of the future closed-loop DBS.

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.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

Ruoyu Ma: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft. Shu Wang: Conceptualization, Formal analysis, Methodology, Writing – original draft. Zixiao Yin: Writing – review and editing. Yifei Gan: Data curation. Zehua Zhao; Software, Visualization. Tianshuo Yuan: Data curation. Yingchuan Chen: Supervision. Tingting Du: Supervision. Valerie Voon: Supervision, Writing – review and editing. Guanyu Zhu: Writing – review and editing, Project administration, Supervision, Resources. Jianguo Zhang^: Funding acquisition, Project administration, Resources, Supervision.

Funding

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).

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The authors have declared there is NO conflict of interest to disclose

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Circuit-based Evidence and Practice of Neuromodulation for Obsessive-Compulsive Disorder: Towards the Optimal Neural Circuit

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Abstract

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1. Introduction

2. Materials and Methods

2.1. Systematic search

2.2. Eligible criteria

2.3. Selection process

2.4. Data collection and organization

2.5. Quality assessment

2.5. Evidence-based practice

2.7. Statistical analysis

3. Results

3.1. Characteristics of included studies

3.2. Neuromodulation efficacy of OCD symptoms

3.3. Neuromodulation efficacy of other psychiatric symptoms

3.4. Implementation evidence-based clinical practice

4. Discussion

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References

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