Introduction

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous psychiatric disorder characterized by pathologically activated brain activity [1]. Selective serotonin reuptake inhibitors and cognitive behavioral therapy, the first-line treatments for OCD, are ineffective in up to 60% of patients, underscoring the disease’s refractory nature [2, 3]. Non-invasive neuromodulation techniques such as transcranial magnetic stimulation (TMS) that are safe and relatively convenient to use have gradually become the mainstay of OCD treatment.

Theta-burst stimulation, a form of TMS, allows for more frequent sessions, potentially reducing treatment duration. Continuous theta burst stimulation (cTBS) is believed to induce long-lasting inhibitory effects with shorter stimulation duration and lower intensity compared to traditional repetitive TMS (rTMS), but further research is needed to confirm its efficacy in OCD treatment [4,5,6]. Numerous cTBS studies have aimed to enhance symptoms in patients with severe OCD symptoms. In a randomized controlled trial (RCT), cTBS delivered over the supplementary motor area (SMA) of patients with refractory OCD (one session/day for 30 days) induced no significant improvement in OCD symptoms compared with the sham group [7]. In another RCT, cTBS stimulation delivered over the right orbitofrontal cortex of patients with severe OCD symptoms (two sessions/day for five days), failed to demonstrate a positive effect [8]. A recent high-quality RCT [9] treated the prefrontal cortex as a stimulation target in patients with moderate to severe symptoms (one session/day for 20 days) but impressively failed to obtain positive results. Overall, studies on OCD published in 2019–2023 indicated an unsatisfactory efficacy of cTBS for patients with OCD [7,8,9,10]. Accordingly, it seems that cTBS is ineffective for OCD. However, the lack of consideration of different OCD severities, modest sample size, absence of a multicenter design incorporating inpatients and outpatients, and lack of personalized imaging-guided targeting may constrain the conclusive findings of cTBS efficacy for OCD [8, 9].

To gain a more comprehensive understanding of the actual efficacy of cTBS for individuals with OCD, this first-of-its-kind study integrated a sufficiently large sample size and utilized an external validation design across two centers. First, we compared the effects of accelerated cTBS (10 sessions/day for five days) to sham stimulation on inpatients with OCD in a preliminary experiment using a personalized pre-supplementary motor area (pre-SMA) target adopted from our previous study on rTMS in OCD [11]. Next, in an external validation experiment at the other center, we used an outpatient routine cTBS stimulation protocol (one session/day for 15 days) to verify the effectiveness of cTBS in this population. Given the evidence that cTBS is poorly effective in treatment-resistant or refractory OCD and that the severity of OCD appears to be an important factor affecting the efficacy of non-invasive stimulation, we further explored whether patients with OCD exhibiting different symptom severities would respond to cTBS treatment in different ways.

Materials and methods

In the preliminary experiment (partly from ClinicalTrials.gov. NCT05221632), 50 inpatients with a diagnosis of OCD (Diagnostic and Statistical Manual, 5th edition) and a total Yale-Brown Obsessive-Compulsive Scale (YBOCS) score of ≥16 or obsession/compulsion subscale of ≥10 were enrolled to receive cTBS (10 sessions/day for five continuous days) or sham over the right pre-SMA after safety screening. Ten sessions (administered at 80% resting motor threshold) were delivered per day at 50-min intersession intervals. Each session included 1800 pulses in a continuous train of 600 theta bursts, and each burst contained three pulses at 50 Hz repeated at 5 Hz. Patients in the sham group received stimulation through a placebo coil, which led to similar skin sensations and significantly reduced biological activity compared to active stimulation. Information about the groups was hidden from the patients.

In the extension experiment, 32 outpatients with a lower OCD symptom severity received one cTBS session per day for 15 consecutive days to generalize the treatment effects. Fifteen cTBS sessions were administered at 80% resting motor threshold, and each session included 1800 cTBS pulses.

Before the experiments, each participant provided written informed consent. This research was conducted in accordance with the tenets of the Declaration of Helsinki. The institutional Ethics Committee of the Hangzhou Seventh People’s Hospital and the institutional ethics committee of Anhui Medical University approved the protocol. The participants reported no history of significant head trauma, neurological or psychological disorders, substance abuse, organic brain defects, or metal implants. The stimulation was performed using a Magstim Rapid2 stimulator (Magstim Company, Whitland, UK) with a 70‐mm air‐cooled figure‐of‐eight coil. The coil was positioned to target the right pre-SMA as described in our previous study [11], the pre-SMA voxel with the highest correlation with the subthalamic nucleus was selected as the personalized cTBS target (Supplementary Fig. S1). All participants recorded TMS treatment adverse effects after each treatment using self-reports.

Response rates are important indicators of treatment efficacy. A percentage change of ≥ 35% in the YBOCS score is commonly used as a clinical standard for OCD that represents a positive response to treatment [12]. Based on the YBOCS score, OCD can be classified as: mild, 6–15 points (subscale 6–9 points); moderate, 16–25 points (subscale, 10–14 points); and severe, ≥ 25 points (subscale, >15 points) [13]. Statistical analyses were performed using JASP software (https://jasp-stats.org). Statistical significance was set at p < 0.05. All intergroup differences were examined with an independent sample t-test (two-tailed) or chi-square test. Two-way repeated-measures analysis of variance was used to assess the main effects of group and time in the preliminary experiment. Post hoc Bonferroni corrections were used for multiple comparisons. Based on the basic analysis, the baseline severity of OCD symptoms was also used as a stratification or grouping factor for further chi-square tests, paired sample t-tests, and repeated-measures analyses of variance. We employed the family-wise error (FWE) correction method to control the overall error rate.

Based on an observed effect size of ω = 0.64 of the chi-square test in the preliminary experiment, the post hoc analysis of the preliminary experiment validated a sufficient statistical power (1-β = 0.99) provided by this sample size to detect the anticipated “within-between interaction” in a mixed analysis of variance [7]. Using cTBS and sham treatments as prior experimental data with an approximate effect size of ω = 0.6, 30 patients were required in the outpatient group to achieve a statistical power of 0.99. Therefore, an overall sample size of 32 patients was adequate for accurate analysis.

Results

Demographic information analysis

The CONSORT flow diagram of the preliminary experiment is shown in Fig. 1. In the preliminary experiment consisting of inpatients only, no significant differences were observed between the cTBS and sham groups in terms of demographics such as mean (SD) age (26.61 [6.99] vs. 28.55 [8.97] years), sex ratio (males/females: 16/7 vs. 15/7), mean (SD) education level (13.43 [2.17] vs. 12.82 [2.4] years), or the clinical assessments of the baseline YBOCS (23.13 [6.68] vs. 23 [6.14]), more details are listed in Table 1. The extension experiment recruited only outpatients with lower OCD symptom severity at baseline (YBOCS: 17.81 [5.95]) compare to inpatients in the preliminary experiment with no significant demographic differences between the two groups (Supplementary Table S1). Thirty-two outpatients, including 16 males and 16 females with a mean (SD) age of 27.25 (8.00) years and mean (SD) education level of 14.39 (2.49) years, were included.

Fig. 1: CONSORT flow diagram.
figure 1

A Preliminary experiment. B Extension experiment based on the preliminary experiment’s findings. To achieve a statistical power of 0.99, 30 patients were required in the outpatient group. cTBS, continuous theta burst stimulation.

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Table 1 Baseline demographic characteristics and clinical assessments in inpatients with OCD in the preliminary experiment.
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The effect of cTBS in the preliminary experiment

For the preliminary experiment of inpatients, a marginally significant time × group interaction was observed in the YBOCS score (F = 3.25, p = 0.08; η2 = 0.07; Fig. 2A). Additionally, a significant time × group interaction was identified in the obsessive subscale of the YBOCS (O-YBOCS) (F = 4.43, p = 0.04, η2 = 0.09; Fig. 2B), but the results from the compulsive subscale of the YBOCS (C-YBOCS) did not demonstrate such effects (Supplementary Table S2). Our results suggest that the response rate was higher in the cTBS than sham group (χ2 = 3.94, p = 0.047; Fig. 2C). Moreover, we explored the potential impact of baseline OCD symptom severity on the cTBS results. An analysis of the percentage change in YBOCS score after grouping by severity showed that the time × group interaction was significant in patients with moderate OCD symptoms (F = 8.68, p = 0.007, η2 = 0.26), but no such effect was found in patients with severe OCD symptoms (F = 0.14, p = 0.71, η2 = 0.01; Fig. 2D). We also observed the same phenomenon in the percentage change in O-YBOCS score: the time × group interaction was significant in patients with moderate OCD symptoms (F = 10.16, p = 0.004, η2 = 0.29), but no such effect was found in patients with severe OCD symptoms (F = 0.01, p = 0.92, η2 = 0.001; Fig. 2E). Considering symptom severity, the response rate results indicate a significant difference among patients with moderate OCD symptoms (χ2 = 4.59, p = 0.032) but not among patients with severe OCD symptoms (Fig. 2F).

Fig. 2: Continuous theta burst stimulation (cTBS) intervention effects on OCD symptoms in the preliminary versus extension experiments.
figure 2

In the preliminary experiment, changes in YBOCS (A) and O-YBOCS (B) scores and response rate between groups (C). Considering different levels of OCD symptom severity patients to determine changes in YBOCS (D) and O-YBOCS (E) scores and response rate between groups (F). In the extension experiment, changes in YBOCS (G) and O-YBOCS (H) scores. Considering patients with different OCD symptom severity levels to determine changes in YBOCS (I) and O-YBOCS (J) scores. Percentage change = (pre-treatment – post-treatment)/pre-treatment. YBOCS, Yale-Brown Obsessive-Compulsive Scale. O-YBOCS, obsessive subscale of YBOCS. #p < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001. To control the overall error rate, we employed the FWE correction method.

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In addition, to assess the generalizability of cTBS in outpatients with lower symptom severity, the effect size obtained in the first trial was used to calculate an adequate sample size for the extension group to expand the results to a wider clinical population (Fig. 1).

The effect of cTBS in the extension experiment

For the extension experiment of outpatients, after 15 days of cTBS treatment, significant changes in the YBOCS and O-YBOCS scores were observed in the extension group (t = 5.56, p < 0.001, Cohen’s d = 0.98; t = 6.34, p < 0.001, Cohen’s d = 1.12, respectively) (Fig. 2G, H). The responder criteria were met by 50% (16/32) of the participants. After grouping the outpatients according to OCD symptom severity, a significant difference in OCD outpatients with moderate symptoms was observed before and after the cTBS intervention (t = 4.70, p < 0.001, Cohen’s d = 1.08). However, among the outpatients with mild and severe symptoms, no significant improvement was observed after FWE correction. Regarding the change in O-YBOCS score (Fig. 2J), after grouping according to symptom severity, the outpatient group with moderate symptoms showed significant improvement (t = 5.05, p < 0.001, Cohen’s d = 1.158). Conversely, no significant improvement was observed in patients with mild or severe OCD symptoms after FWE correction.

Safety and side effects

No serious adverse events occurred during treatment. Only one inpatient in the preliminary experiment and two outpatients in the extension experiment reported a mild headache that resolved with rest, while the remaining patients were free of adverse events and seizures.

Discussion

Contrary to previous studies that consistently showed that cTBS is an ineffective method for treating OCD [7,8,9,10], this study demonstrated response rates to cTBS that were comparable to those of first-line OCD treatments, especially for OCD patients with moderate symptoms [3]. Our findings underscore the OCD symptom severity levels for which cTBS should be used and highlight the role of OCD symptom severity in mediating the cTBS effect. We categorized symptoms based on severity and assessed the effect of cTBS using various indicators, including the YBOCS total score, O-YBOCS score, and responder rate. Patients with moderate symptoms before treatment were more likely to benefit from the cTBS intervention. In addition, the high efficacy in patients with moderate OCD symptoms was validated in outpatients and inpatients across the two centers.

These findings imply that many negative results from previous cTBS studies may have been confounded by the heterogeneity of the recruited patients with OCD. In other words, when patients with higher OCD symptom severity were recruited, it was more likely that the differences between the active and sham groups would be not statistically significant. In a study by Li et al. [14], cTBS intervention in the bilateral SMA significantly improved the symptoms of patients with moderate to severe OCD symptoms after treatment. In this study, responders had lower baseline symptoms and lesser overall OCD symptoms than non-responders. This is partly consistent with our findings; unfortunately, the study by Li et al. did not further analyze the severity of symptoms and lacked a sham control group, whereas our study included patients with different disease severities of OCD. We found that cTBS had a greater effect on improving obsessive-compulsive symptoms in patients with moderate OCD symptoms.

It is known that cTBS has fewer side effects than medications [2, 3], for patients with moderate OCD symptoms, cTBS may be a potent competitor for selective serotonin reuptake inhibitors and cognitive behavioral therapy in early intervention [2, 3]. OCD and its associated clinical symptoms are the result of insufficient inhibition of the cortico-striatal-thalamo-cortical circuits. Patients with severe OCD symptoms demonstrate pronounced disruptions in both brain topology and behavioral patterns, potentially hindering the efficacy of cTBS as a means of symptom alleviation [5]. Conversely, patients with moderate symptoms exhibit comparatively milder disturbances in brain function and behavior. Thus, the application of cTBS targeting the pre-SMA offers a promising avenue for reinstating cortical inhibition in this subgroup, with the potential to enhance clinical outcomes. This observation may elucidate the association between treatment efficacy and symptom severity.

In previous studies of cTBS in the treatment of OCD have shown mixed results regarding the simultaneous improvement of obsessive thinking and compulsive behavior [8, 14, 15], or the absence of significant improvement [16]. In contrast to previous research, this study observed a distinct pattern following cTBS intervention, wherein patients primarily exhibited improvements in obsessive thinking without significant changes in compulsive behavior. This difference may stem from various factors: firstly, the effects of cTBS on compulsive behaviors might necessitate a longer duration to manifest fully, explaining the lack of immediate changes observed. Secondly, the neurobiological mechanisms underlying OCD symptoms could differ, resulting in varied responses to cTBS [17]. Our findings highlight the complexity of OCD and the necessity for further research to elucidate the mechanisms of cTBS. Future studies should explore its long-term effects on both obsessive thinking and compulsive behavior for a comprehensive understanding of its therapeutic potential in the treatment of OCD.

There are some limitations. Firstly, we focused on immediate improvement post-stimulation. Due to the impact of the COVID-19 pandemic, regular clinical visits were limited, hampering follow-up assessments. Secondly, our sample skewed towards more males, consistent with prior research showing no gender correlation with treatment outcomes [18, 19]. Although no gender-based disparities in OCD treatment outcomes were reported [20], future studies should strive for gender balance to better understand the efficacy of cTBS. Finally, while our study had a relatively large sample size compared to previous cTBS investigations. To clarify the long-term effect of cTBS on OCD and extend the results to a broader clinical population, further study and adequate follow-up data, as well as more mechanistic studies, are needed.

In conclusion, this preliminary experiment with external validation cross two central, identified OCD symptoms as playing an important role in improvements resulting from cTBS for the first time, especially in patients with moderate OCD symptoms. Our findings indicate that cTBS delivered over the right pre-SMA may be a promising alternative treatment, especially in patients with OCD within a certain range of symptom severity and should be tested in larger clinical trials.