Diverse Advanced Approaches of Transcranial Magnetic Stimulation in Obsessive-Compulsive Disorder

Abstract

Obsessive-Compulsive Disorder (OCD) significantly contributes to mental health morbidity. Empirical evidence supports the use of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT) with exposure and response prevention (ERP) as primary treatment options. However, approximately 40–60% of patients do not achieve satisfactory results with these interventions. This result has led to the exploration of non-invasive brain stimulation alternatives, focusing on advanced repetitive transcranial magnetic stimulation (rTMS) paradigms. This chapter discusses these paradigms, including prolonged intermittent theta burst stimulation (piTBS), accelerated rTMS (aTMS), deep TMS (dTMS), priming TMS (pTMS), synchronized TMS (sTMS), various forms of theta burst stimulation (TBS) such as intermittent, continuation, and bilateral TBS, and magnetic seizure therapy (MST).

1. Introduction

Transcranial magnetic stimulation (TMS) was introduced as a neurophysiological tool in 1985, following the development of a portable device by Anthony Barker and colleagues. This innovation allowed for non-invasive stimulation of the cerebral cortex [1]. Subsequently, TMS has been widely used for assessing the motor system, examining the functionality of different brain regions, and investigating the pathophysiology of various neuropsychiatric disorders. Notably, TMS has been adopted as a therapeutic intervention for conditions including major depressive disorder (MDD) [2] and obsessive-compulsive disorder (OCD) [3, 4].

Repetitive TMS (rTMS), which involves rhythmic and repetitive application of TMS, was approved by the US Food and Drug Administration (FDA) in 2008 for treating medication-resistant depression [5]. rTMS is classified into high-frequency (HF) (≥5 Hz) and low-frequency (LF) (≤1 Hz) forms [3, 6]. HF-rTMS stimulates targeted areas, whereas LF-rTMS aims to inhibit stimulation [7]. Evidence from numerous studies supports the antidepressant effectiveness of HF-rTMS (such as 10 Hz) targeting the left dorsolateral prefrontal cortex (DLPFC) or LF-rTMS (such as 1 Hz) applied to the right DLPFC [8, 9].

OCD is a prevalent and chronic disorder that contributes significantly to global disability [10]. Consensus statements and treatment guidelines, grounded in empirical research, recommend the utilization of selective serotonin reuptake inhibitors (SSRIs, such as sertraline and fluvoxamine) or a combination of cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) as primary therapeutic approaches [11, 12]. However, 40–60% of patients do not achieve satisfactory results with these interventions [13]. Multiple randomized controlled trials (RCTs) have examined the effects of rTMS on the cortico-striatal-thalamic-cortical (CSTC) circuits, which are implicated in OCD. These trials have specifically targeted brain regions such as the DLPFC, anterior cingulate cortex (ACC), supplementary motor area (SMA), orbitofrontal cortex (OFC), and medial prefrontal cortex [14, 15, 16]. For instance, LF-rTMS aimed at the SMA yielded significant benefits in some RCTs [15, 17]; however, this was not the case in all studies [18, 19]. Similarly, the outcomes of RCTs investigating rTMS targeting DLPFC in OCD have been inconsistent [20, 21]. Notably, a recent meta-analysis revealed that rTMS can be beneficial for patients with OCD who have not responded to previous SSRI therapy [3]. Therefore, it is crucial to explore novel rTMS paradigms to enhance response and remission rates and overall treatment outcomes in patients with OCD. In this chapter, English databases such as the Cochrane Library, PubMed, EMBASE and PsycINFO were systematically searched by three independent investigators (XJL, CML, and XHY) from inception to 10 November 2023, to identify relevant studies examining the efficacy and safety of various advanced rTMS paradigms [e.g., prolonged intermittent theta burst stimulation (piTBS), accelerated rTMS (aTMS), deep TMS (dTMS), priming TMS (pTMS), synchronized TMS (sTMS), theta burst stimulation (TBS) (including the intermittent, continuation, and bilateral forms of TBS), and magnetic seizure therapy (MST)] for patients with OCD.

2. TMS

2.1 rTMS

rTMS is a non-invasive neuromodulation method that administers a series of TMS pulses at a consistent frequency to modulate neuronal activity through a magnetic field pulse [22]. In 2018, rTMS received approval from the FDA for treating OCD [23], offering new treatment avenues for patients with this condition. Recent research indicates that the therapeutic efficacy of rTMS is influenced by various stimulation parameters, such as unilateral or bilateral, treatment frequency and intensity, and the targeted brain regions [24]. Both unilateral and bilateral rTMS have shown greater effectiveness than sham rTMS in treating OCD in clinical settings [24]. The frequency of stimulation in rTMS plays a critical role, where LF-rTMS at ≤1 Hz produces an inhibitory effect, and HF-rTMS at ≥5 Hz produces an excitatory effect on cortical excitability in targeted areas [25]. The choice of stimulation areas significantly affects rTMS outcomes [24]. The DLPFC, OFC, and SMA (or pre-supplementary motor area [pre-SMA]) are identified as the most effective stimulation sites. These regions are part of the CSTC, which is hypothesized to be associated with the pathophysiology of OCD [26]. Furthermore, rTMS may be able to alter cortical excitability and neuroplasticity in OCD patients. Over the past two decades, numerous studies have explored the effectiveness of rTMS in treating various psychiatric disorders [27], with a predominant focus on MDD [28]. However, established and comprehensive rTMS treatment approaches for OCD are still lacking. Further investigation is required to identify and optimize rTMS treatment strategies to achieve optimal clinical effectiveness for OCD.

Growing evidence indicates that rTMS is generally effective and safe for the treatment of OCD [29]. A pairwise meta-analysis of 21 RCTs involving 662 patients showed that rTMS for OCD is efficacious across all protocols [29]. Additionally, this meta-analysis reported several side effects associated with rTMS treatment in patients diagnosed with OCD [29], such as headache, sedation, concentration difficulties, scalp pain, weakness, fatigue, mood swings, memory impairment, dizziness, fainting, and facial nerve stimulation. However, all side effects were generally mild and transient, and rTMS was well-tolerated by most patients. Notably, this meta-analysis did not report any severe adverse events, such as cognitive dysfunction or seizures [29].

2.1.1 Unilateral rTMS

The initial clinical trial indicated that right prefrontal rTMS could affect prefrontal mechanisms associated with OCD [30]. In this trial, 12 patients diagnosed with OCD received rTMS at parameters of 80% motor threshold and 20 Hz for 2 seconds per minute, lasting 20 minutes. This intervention targeted the right lateral prefrontal and left lateral prefrontal regions on alternate days. The severity of symptoms was evaluated for 8 hours post-rTMS administration. All participants completed the study, and there was a significant reduction in compulsive urges for 8 hours following right lateral prefrontal rTMS. In another study by SEO et al., LF-rTMS (1 Hz) targeting the right DLPFC was used as a therapeutic intervention for OCD [31]. This study showed a substantial reduction in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores, offering preliminary evidence for the effectiveness of rTMS stimulation of the right DLPFC in managing OCD. However, there is currently no consensus on the optimal frequency (low or high) for unilateral rTMS in OCD treatment.

Moreover, several randomized, double-blinded, sham-controlled studies examining the effects of rTMS on the left DLPFC at different frequencies did not report significant improvements in OCD symptoms. For instance, a research by Sachdev et al. [32] involved 18 participants and investigated the efficacy of a two-week rTMS course targeting the left DLPFC in treating treatment-resistant OCD. The rTMS protocol in one study employed a frequency of 10 Hz, set at 110% of the motor threshold, with 25-second intervals between trains and 1500 stimulations per session. In another study [33], 33 right-handed patients underwent LF-rTMS treatment at 1 Hz, set at 110% of the motor threshold. Post-treatment assessments using the Clinical Global Impression (CGI), Hamilton Anxiety Rating Scale (HAMA), Y-BOCS, and Beck Anxiety Inventory (BAI) revealed no significant differences in psychopathology scores between the active rTMS and sham rTMS groups.

Recent studies indicate that rTMS targeting the left OFC may significantly impact the OCD treatment [24]. A study involving 25 patients found that LF-rTMS applied to the left OFC led to a partial response in 13 patients (13/25, 52%) and a complete response in 11 (11/25, 44%) [34]. The Y-BOCS scores significantly decreased from the baseline after 20 rTMS sessions, with no significant changes during the subsequent 1-month follow-up. However, LF-rTMS to the right OFC showed only a 19% response rate, without symptom improvement after 1 month [35]. Research also suggests the importance of the number of OFC treatments, indicating that at least 20 rTMS sessions within the OFC are necessary for a significant impact [36].

2.1.2 Bilateral rTMS

Bilateral rTMS is gaining recognition as a promising therapeutic approach for individuals with OCD. In bilateral treatments, the primary focus is on stimulating the DLPFC and SMA. Recent meta-analyses have substantiated the efficacy of bilateral rTMS over sham stimulation in treating OCD [24, 29, 37]. A notable meta-analysis, which included six cortical targets (bilateral DLPFC, left DLPFC, right DLPFC, SMA, OFC, and medial prefrontal cortex [mPFC]) and analyzed 26 studies, identified bilateral DLPFC stimulation as a well-tolerated rTMS modality, demonstrating significant effects and emerging as the optimal approach [37]. Overall, rTMS exhibited a modest and substantial reduction in Y-BOCS scores. (Hedges’ g = 0.77, p < 0.0001), with bilateral DLPFC targeting yielding the most considerable effect size (Hedges’ g = 1.04, p < 0.0001). Both HF- and LF-rTMS yielded comparable results. Furthermore, studies with follow-up data indicated that the benefits of active rTMS were significantly more significant than sham treatment, even after 4 weeks.

The SMA is recognized as an effective target for rTMS in OCD treatment [38]. A multicenter study involving 27 treatment facilities across 10 countries revealed that 41.8% of these centers chose the SMA as the target for TMS in treating OCD [39]. In a 4-week double-blinded trial, 57 patients with untreated OCD were randomly assigned to receive either active or sham rTMS [40]. The participants received 1-Hz rTMS directed at the SMA daily, 5 days a week, over 4 weeks. Patients in the active rTMS group exhibited significantly lower Y-BOCS scores than those in the sham group. This research further revealed that the 5-Hydroxytryptamine Transporter Linked Polymorphic Region (5-HTTLPR) polymorphism in the SLC6A4 gene could be a reliable biomarker for predicting rTMS treatment response in patients with OCD. Furthermore, the SMA was identified as a prime target for rTMS due to its extensive connections with regions involved in cognitive processes and motor control [41].

A recent case report [42] introduced a novel approach to treating treatment-resistant OCD, combining rTMS and iTBS across three distinct brain areas (bilateral SMA, left and right DLPFC) within a single session. The case involved an 18-year-old female patient who showed significant symptom improvement after 6 weeks of treatment. The outcomes included a notable reduction in the duration of OCD symptoms, improved control over obsessions, and ameliorated depressive symptoms. The patient’s Y-BOCS score reduced from 34 at baseline to 11 after 6 weeks, and the Hamilton Depression Rating Scale (HAMD-17) score decreased from 18 to eight in the same period. No clinically significant side effects were noted. These findings suggest that sequential treatment targeting different brain regions could be feasible and beneficial for those with treatment-resistant OCD. However, larger-scale studies are necessary to corroborate these results further.

2.1.3 Comparison of bilateral and unilateral rTMS

A recent systematic review and meta-analysis [43], encompassing 31 trials, compared bilateral rTMS with unilateral rTMS. The analysis assessed differences in effect sizes when stimulating the bilateral, left, and right DLPFC regions. Findings suggested that bilateral DLPFC stimulation may result in a more significant decrease in Y-BOCS scores compared to stimulating either the left DLPFC or right DLPFC (Hedge’s g = −0.85, p < 0.001 vs. Hedge’s g = −0.17, p = 0.32 vs. Hedge’s g = −0.64, p < 0.001). Furthermore, the study explored variations in treatment efficacy in trials using rTMS targeted at the left DLPFC with either HF or LF; however, no significant effects were observed. A separate analysis for rTMS stimulation on the right DLPFC revealed a considerable impact for LF stimulation (Hedge’s g = −0.87, p < 0.001). Regarding other specific brain regions, an open, sham-controlled trial involving 20 patients (10 in the experimental group) found no significant effects when comparing sham treatment with sequential 1 Hz stimulation (110% threshold) of the right DLPFC and bilateral pre-SMA [44]. Moreover, no significant changes in cognitive functioning were observed post-stimulation. However, it is crucial to customize treatment approaches according to each patient’s unique needs and preferences, considering the diverse effects of different therapeutic interventions.

Currently, there is a notable gap in the literature regarding RCTs that directly compare the efficacy of bilateral rTMS and unilateral rTMS in treating OCD. The most effective dosing strategy for rTMS is yet to be determined, necessitating further research to assess the relative effectiveness of bilateral and unilateral rTMS.

2.1.4 Accelerated rTMS

aTMS represents a progression in the use of rTMS for OCD treatment. This approach involves increasing the frequency of daily stimulations and extending the treatment duration. Unlike the conventional rTMS protocol (which lasts approximately 38 minutes per day over 2–4 weeks), aTMS is more practical and time-saving. This advantage has contributed to its widespread adoption in treating MDD and its subsequent application in OCD treatment. However, evidence supporting the use of aTMS in OCD treatment is still limited, and it remains an experimental technique.

A case study focused on a 37-year-old woman diagnosed with OCD [45]. She received LF-rTMS (1 Hz) targeting the SMA, delivering 1600 pulses per session, twice daily, at least 5 days a week, for 42 sessions over 4 weeks. The rTMS was administered at 100% of the resting motor threshold. Upon completing the rTMS sessions, her Y-BOCS score reduced to 18 out of 40, indicating a significant improvement of approximately 49%. This improvement significantly enhanced the patient’s quality of life and led to the complete resolution of her depressive symptoms. The patient reported no adverse effects during or after the rTMS therapy. She maintained stability on the exact dosage of escitalopram up to her second follow-up, 2 months post-hospital discharge.

In a recent study involving nine patients diagnosed with OCD [46], a unique approach was adopted, consisting of a one-week, magnetic resonance imaging-guided, individualized, double-daily rTMS protocol. The rTMS was delivered at a frequency of 1 Hz and an intensity of 110% of the resting motor threshold, amounting to 7200 pulses per day. Bilateral stimulation was applied to the SMA region. The study reported a significant 25% improvement in OCD symptoms after treatment, with the beneficial effects persisting up to 3 months post-treatment. The study further observed decreased connectivity between the SMA and subcortical brain regions. None of the participants reported any adverse effects. These findings suggest that the aTMS protocol used in this study is both safe and effective, offering substantial evidence for its potential as a viable treatment option for OCD.

In summary, rTMS serves as a tertiary modality in managing OCD, complementing pharmacological and psychological treatments, and has been clinically applied. Currently, there are no published direct comparative studies between bilateral and unilateral rTMS, and aTMS, in the treatment of OCD. Further research is required to identify this purpose’s most effective stimulation paradigm.

2.2 dTMS

dTMS technology has evolved as an advanced version of traditional rTMS. The dTMS H7 Coil is specifically designed to target the medial prefrontal cortex (mPFC)-dACC (3 cm³) and further stimulates other cortical regions, such as the OFC (8.4 cm³), DLPFC (10.5 cm³), and SMA (6.8 cm³), at suprathreshold levels (>100 V/m) [47, 48]. The H-coil utilized in dTMS, distinct from traditional TMS coils, is part of a wearable helmet that the user securely wears. This H-coil comprises two layers, each with four elliptically shaped windings stacked above each other. Their major and minor axes vary between 70 and 130 mm and 55–105 mm, respectively [48]. The magnetic field from the H-coil diminishes more slowly, allowing stimulation of neurons across a broader and deeper region. The subdural depth and H-coil stimulation volume are approximately 3 cm and 40.3 cm³, respectively [48].

In 2018, the FDA approved the dTMS H7 Coil for OCD treatment, following favorable outcomes from a pilot study and a multicenter RCT conducted by Carmi et al. [49, 50]. 2 years later, the D-B80 coil was approved by the FDA for therapeutic applications. The multicenter RCT involving 99 patients with OCD revealed that active 20 Hz dTMS treatment resulted in a significantly higher reduction in Y-BOCS scores compared to sham treatment, with reductions of 6.0 points and 3.3 points, respectively. Moreover, response rates were 38.1% and 11.1% in the active and sham treatment groups, respectively [50]. At the one-month follow-up, the active treatment group exhibited a response rate of 45.2%, while the sham group had a response rate of 17.8%. These findings highlighted significant differences between the two groups, which persisted during the follow-up. Safety-wise, the HF-dTMS using the H7 coil was well-tolerated, with no severe adverse events such as seizures reported. The most common side effect was a mild headache during or immediately after stimulation, consistent with findings from previous comprehensive reviews [6].

Beyond RCTs, real-world data analysis from 219 patients with OCD across 22 clinical sites using the H7 Coil revealed overall first and sustained response rates of 72.6% and 52.4%, respectively [51]. Furthermore, patients who underwent 29 dTMS sessions exhibited a response rate of 57.9%, surpassing the multicenter trial results [50]. The improved real-world outcomes might be attributed to the longer duration of dTMS neuromodulation and the flexibility to employ augmentation strategies, infrequently available options within the confines of an RCT design. Furthermore, Harmelech et al. [52] investigated the long-term efficacy of dTMS as a therapeutic intervention for OCD. The study included clinical centers from multicenter trials and those providing post-market data. Findings revealed that the average duration of dTMS effectiveness for OCD was approximately 1.98 years (standard deviation = 0.13) or longer, with 62% of patients maintaining this durability at the time of the survey. Symptomatic ratings did not determine this durability; it is defined pragmatically as the time elapsed from the conclusion of dTMS treatment to when a change in treatment was deemed necessary.

A recent network meta-analysis (NMA) identified ondansetron, dTMS, therapist-administered CBT, and aripiprazole as the top four treatments for OCD, based on the surface under the cumulative ranking percentage values (85.4%, 83.2%, 80.3%, and 67.9%, respectively) [53]. In sensitivity analyses, dTMS emerged as the most effective treatment strategy for treatment-resistant OCD. However, the NMA faced significant heterogeneity due to subject variations across studies, including differences in baseline treatment resistance levels and treatment modalities. This heterogeneity is a standard limitation in NMAs on treatment-resistant OCD [54]. Furthermore, Gregory et al. [55] assessed the cost-effectiveness of dTMS compared to established treatments such as antidepressant medication (ADM), ADM with antipsychotic augmentation, real-world cognitive-behavioral therapy (ADM + CBT Effectiveness), clinical trial CBT (ADM + CBT), and others, for individuals with treatment-refractory OCD. The study concluded that dTMS is cost-effective across different levels of care, from outpatient medication management and CBT to more intensive, facility-based treatments. Moreover, dTMS was suggested as a valuable, incremental strategy in scenarios where more intensive treatment options are inaccessible or financially impractical or when patients experience long wait times for access to these higher levels of care.

The neuroanatomical basis of dysfunction in OCD has been thoroughly researched and is known to involve the CSTC circuitry [56]. A recent study compared the two FDA-cleared coils for dTMS and suggested that while the H7 coil can stimulate certain OCD-specific prefrontal regions within the CSTC, the D-B80 coil may not have this capability [47]. Expanding on this research, a 2022 study by Tzirini et al. explored the characteristics of these coils’ induced electric field [48]. They analyzed the field distribution by positioning the coils over the prefrontal cortex of a head phantom in a treatment setup for OCD. Furthermore, numerical simulations were conducted using eight models from the Population Head Model repository with two sets of conductivity values, three Virtual Population anatomical head models, and their homogeneous counterparts. The findings showed that the H7 coil produced significantly higher maximal electric fields and stimulated brain volumes two to five times larger than the other coil. Furthermore, the rate of electric field decay over distance was considerably slower for the H7 coil. Specifically, at the scalp level, the field strength with the D-B80 coil was 306% of that at a depth of 3 cm, whereas with the H7 coil, it was 155%. The H7 coil demonstrates a considerable capability to generate higher intensities within larger brain volumes, including specific regions implicated in OCD, such as the dACC, DLPFC, inferior frontal gyrus, OFC, and pre-SMA, in contrast to the D-B80 coil. Given the substantial disparities between these two coils, it is imperative to conduct separate assessments and validations of their clinical efficacy in future OCD treatment research.

Currently, there is a limited body of research elucidating the mechanisms through which dTMS operates in the treatment of OCD. Recently, Arıkan et al. [57] conducted a neurophysiological study to investigate the effects of dTMS using the H7 coil on both electrophysiological parameters and clinical outcomes in individuals with OCD. This retrospective, single-center study involved 29 patients with OCD, comprising 15 women and 14 men, who underwent 30 dTMS sessions. Baseline and endpoint measurements were obtained through quantitative electroencephalography (EEG) recordings and the Y-BOCS. The findings yielded positive treatment outcomes in all 29 patients, with a minimum 35% reduction in Y-BOCS scores. Analysis of quantitative EEG recordings indicated a significant decrease in theta, alpha, and beta rhythms. Furthermore, the reduction in the severity of OCD symptoms was associated with a specific decrease in beta activity within the left central region. Consequently, it can be inferred that the therapeutic response mechanism may be linked to the reduction in beta-band power induced by dTMS. However, the absence of a sham-control condition in the study raises questions about the specificity of the observed EEG alterations. Furthermore, the lack of changes in beta-EEG power among non-responders is a source of uncertainty, considering that all patients included in the study were responders. Therefore, these results should be considered preliminary and require validation in a prospective study.

In general, while the study involving the dTMS H7 coil provided evidence for the effectiveness of mPFC-dACC stimulation, the studies involving D-B80 and figure-8 coils, which were small and heterogeneous, did not identify definitive targets [47]. In the field of dTMS treatment for OCD, further exploration is necessary to improve its efficacy. This exploration includes and is not limited to (1) personalizing treatment based on promising evidence for predictors and moderators of response to mPFC-dACC stimulation; (2) investigating the underlying mechanisms of dTMS treatment for OCD using various methods such as neuroimaging and molecular biochemistry; (3) considering the relatively complex operation of dTMS, including the induction of moderate to severe discomfort in patients with OCD and the simultaneous inhibition of compulsive behavior during treatment; and (4) conducting a comprehensive clinician interview, which involves utilizing the Y-BOCS symptom checklist, assessing the Y-BOCS severity score, and establishing a personalized hierarchy of OCD triggers before initiating dTMS therapy. Moreover, it is imperative to engage in discussions with the TMS technician regarding the unique manifestations of the patient’s OCD and regularly monitor the patient’s progress using the Y-BOCS severity score every week. Furthermore, considering the potential improvement or alteration of symptoms during the treatment course for OCD, patients may develop increased resistance to provocation. Therefore, comprehensive technical operation guidelines should be formulated early to facilitate its broader application.

2.3 Priming TMS

Priming TMS, an innovative approach in rTMS, involves preconditioning LF stimulation trains with subthreshold stimulation at an HF [57]. Research has demonstrated its significant ability to enhance the neural response to the subsequent LF stimulation train [58]. Notably, it has been observed that a brief pretreatment with stimulation in the 5–6 Hz range substantially enhances the effectiveness of subsequent 1-Hz stimulation in inducing a reduction in synaptic efficacy [59]. Current research on pTMS has primarily centered on the field of depression [5], and there is a lack of large-sample RCTs to assess the efficacy of pTMS in patients with OCD systematically. Vidya et al. [60] conducted an RCT of a comparable nature to investigate the impact of adjunctive pTMS targeting the SMA in individuals with treatment-resistant OCD. The study comprised 30 patients with OCD who continued to experience symptoms despite a sufficient trial of SSRIs. These individuals were randomly assigned to one of two groups: the pTMS group, which received active priming stimulation (6-Hz rTMS at 80% of the resting motor threshold), followed by 1-Hz rTMS, or the rTMS-only group, which received sham stimulation followed by 1-Hz rTMS. Both groups underwent ten sessions of these interventions over 2 weeks. The study revealed significant enhancements in all aspects of psychopathology for both groups over time. Notably, the pTMS group demonstrated superior outcomes to the rTMS-only group, as evidenced by a reduction in the compulsion score of the Y-BOCS and reductions in scores on the HAMA and HAMD-17.

It is noteworthy that this study represents the first examination of pTMS in individuals diagnosed with OCD. However, the small size impacts the overall statistical power of the applied tests. It is imperative to integrate neuroimaging and neurophysiological techniques alongside clinical assessment in future studies to enhance our comprehension of the precise neuronal mechanisms of pTMS over the SMA and its correlation with clinical improvement. Incorporating a larger sample size in conjunction with these techniques would enable the identification of neural patterns associated with clinical improvement. This identification facilitates a more comprehensive understanding of the specific neuronal mechanisms underlying pTMS over the SMA.

2.4 Synchronized TMS

sTMS represents an innovative approach to non-invasive brain stimulation. Using a trio of rotating neodymium magnets, sTMS can deliver extremely low-energy, sinusoidal magnetic fields that synchronize with an individual’s intrinsic alpha frequency (IAF). This approach offers the potential for a brain stimulation system that can be used conveniently at home [61]. Previous studies have shown promise in using sTMS to alleviate depressive symptoms in individuals with MDD [62]. However, there is a lack of scholarly investigations into applying sTMS in OCD. Given that OCD’s primary neurobiological basis involves heightened activation within the CSTC, it is plausible that sTMS, which can modulate cortical oscillations selectively, could offer therapeutic benefits by regulating cortical activity within the IAF range [63, 64].

3. TBS

TBS is a patterned version of rTMS. It comprises continuous TBS (cTBS) and intermittent TBS (iTBS), both of which are novel neuromodulation techniques widely employed in clinical practice for the treatment of psychiatric disorders [65]. In contrast to conventional rTMS protocols, the standard TBS protocol involves delivering bursts of three 50 Hz pulses (or 20 Hz) at 5 Hz intervals. This protocol is hypothesized to exert a more rapid and longer-lasting influence on brain synaptic plasticity [66]. Specifically, cTBS applies an uninterrupted train of bursts, consisting of either 300 or 600 pulses, to reduce cortical excitability. In contrast, iTBS aims to increase cortical excitability and involves 20 trains of 10 bursts, where each burst comprises short bursts of three stimuli at 50 Hz, repeated at 5 Hz, and given at 8-second intervals, resulting in a total of 600 stimuli delivered over 200 seconds [65]. Previous meta-analyses [67] have demonstrated that iTBS exhibits antidepressant effects similar to those of HF-rTMS, with comparable safety profiles. However, as a relatively new modality of rTMS, there is still a lack of evidence regarding the efficacy and safety of TBS for OCD. Earlier studies have indicated that the potential mechanism of TBS in treating OCD involves the modulation of CSTC abnormal functioning, primarily through its impact on glutamatergic and γ-aminobutyric-acid (GABA) ergic interneurons [68]. Over the past decade, there has been a growing number of studies investigating the efficacy and safety of TBS in patients with OCD. These studies have utilized various TBS models, including iTBS, cTBS, and accelerated TBS, targeting different brain regions such as the DLPFC, OFC, and SMA. TBS offers advantages such as shorter treatment duration, lower stimulation intensity than traditional TMS, increased acceptability, tolerability, and greater cost-effectiveness, collectively enhancing its clinical utility in OCD treatment.

3.1 iTBS

In 2019, Naro et al. conducted the inaugural randomized crossover pilot study to investigate the efficacy and safety of adjunctive standard iTBS (600 pulses per session) at 80% of the active motor threshold (aMT) [65]. This study targeted the left DLPFC in treating ten patients with treatment-resistant OCD. Over 1 month, this prefrontal iTBS monotherapy observed significant reductions in OCD symptoms among the active iTBS groups at the treatment endpoint. The positive effects of the treatment were sustained for up to 3 months. No adverse effects were reported in the sham iTBS groups [69]. These findings provide preliminary evidence for iTBS as a promising protocol for alleviating OCD symptoms. Subsequently, Syed et al. introduced a novel iTBS protocol using a double cone coil (deep TMS) to target both the dmPFC and ACC. This open-labeled case series included 12 patients with treatment-resistant OCD, and their results indicated that 5/12 of them (41.7%) met the response criteria, defined as achieving a > 35% reduction in Y-BOCS scores [70]. Recently, a novel case study explored the use of combined rTMS/iTBS protocols, involving LF-rTMS applied to the right DLPFC and the bilateral SMA, followed by the iTBS targeting the left DLPFC in the treatment of a patient with treatment-resistant OCD. After 30 treatment sessions spanning a 6-week course of treatment, a significant reduction in the Y-BOCS score was observed (Baseline: 34; 6th week: 11), and no substantial side effects were reported [42]. However, further high-quality RCTs are needed to determine the optimum iTBS protocol for treating OCD.

3.2 cTBS

Prior research has shown that cTBS can reduce cortical excitability for up to 50 minutes after a 40-second stimulation, whereas a 20-second application of cTBS results in decreased cortical excitability lasting for 20 minutes [71, 72]. In 2006, Mantovani et al. identified that inhibiting the function of the SMA may be beneficial in improving OCD symptoms [73]. Based on this finding, Harika-Germaneau et al. conducted a robust, randomized, double-blinded, sham-controlled trial involving 30 participants in 2019. Their study investigated the efficacy and safety of adjunctive cTBS (600 pulses; stimulus intensity: 70% resting motor threshold [RMT]) over the SMA for patients with treatment-resistant OCD. However, following 30 sessions of cTBS, there were no significant group differences in terms of the predefined study response criteria (>25% reduction in Y-BOCS scores) between the active cTBS and sham groups at both the post-cTBS treatment assessment (21.4% vs. 35.7%, p = 0.403) and the 12-week follow-up evaluation (28.4% vs. 35.7%, p = 0.69) [74]. Moreover, a recent randomized single-blinded, sham-controlled study conducted in China last year aimed to assess the efficacy and safety of cTBS involving 1200 pulses at a stimulus intensity of 110% RMT applied to the bilateral SMA for 54 patients with OCD. The study found that active cTBS did not significantly reduce OCD symptoms compared to sham stimulation [75]. Notably, the variability in cTBS stimulation parameters, including treatment pulses (600–1200 pulses per session) and stimulation intensity (70–120% RMT), has led to some confusion in clinical practice. Interestingly, a recent preliminary open-label trial involving 29 participants employed an LF (1 Hz) cTBS protocol targeting the bilateral SMA in the treatment of patients with moderately drug-resistant OCD. This trial yielded a positive outcome with a response rate of 37.3% [76]. However, further high-quality RCTs are warranted to replicate these findings in future investigations. Overall, cTBS has demonstrated safety and good tolerability in the treatment of patients with OCD [74, 75, 76].

3.2.1 Accelerated and intensive cTBS

To the best of our knowledge, an entire course of traditional TMS treatment (typically lasting 4–6 weeks) may increase the daily transportation burden for outpatients and pose challenges for medical institutions [77]. Previous research has demonstrated that accelerated/ intensive cTBS protocols (2 sessions/day) can facilitate metaplasticity and offer the advantage of time efficiency [78]. In an initial study, Williams et al. [79] conducted a pilot investigation utilizing an accelerated cTBS protocol consisting of ten sessions per day, targeting the right frontal cortex, for the treatment of seven patients with OCD over a 5-day treatment period. This approach achieved a response rate of >1 time point in 71% of cases, with minimal side effects, providing preliminary evidence regarding the effectiveness and safety of accelerated cTBS for treatment-refractory OCD. Subsequently, a recent case report further supported this evidence [80]. However, research assessing the potential of accelerated cTBS to improve OCD symptoms in patients with treatment-resistant OCD has yielded inconsistent results. For instance, Dutta et al. [81] were the first to investigate accelerated cTBS protocols (two sessions per day, totaling 1200 pulses) targeting the left OFC in treating 33 patients with OCD. They observed a significant group-by-time interaction effect concerning obsessions and compulsions. Conversely, another study reported adverse outcomes for cTBS over the right OFC in patients with OCD [82]. In contrast to the OFC studies, a randomized sham-controlled study conducted last year examined the impact of adjunctive neuronavigation-guided accelerated cTBS protocols, consisting of two daily sessions totaling 1800 pulses over the SMA, in patients with OCD. This study found that the active TBS group achieved a more significant reduction in the Y-BOCS total score than the sham group [83]. Recently, a case series by Noda et al. reported promising results when using bilateral SMA-targeted cTBS administered twice daily in six patients with OCD. This approach achieved a response rate of 67% (4/6) without apparent adverse events, suggesting that bilateral cTBS could serve as a viable alternative for OCD treatment [84].

3.3 Bilateral TBS

To the best of our knowledge, there has been only one prior case study demonstrating the therapeutic potential of bilateral TBS (combining iTBS and cTBS) for OCD treatment [85]. In this study, researchers initially applied ten sessions of cTBS (1200 pulses per session) over the right DLPFC, followed by another ten sessions of iTBS (1200 pulses per session) targeting the left DLPFC in the treatment of a 33-year-old patient with OCD and comorbid depression. The patient’s Y-BOCS score improved from 19 to 9 after the two stages of treatment with cTBS and iTBS [85]. However, cTBS and iTBS were administered in separate sessions. Currently, no published RCT has examined the effectiveness of bilateral TBS protocols that sequentially apply iTBS and cTBS for OCD treatment.

4. MST

MST is an innovative neuromodulation treatment that employs HF magnetic stimulation to induce generalized seizures [86]. In contrast to electroconvulsive therapy (ECT), MST minimizes its impact on deeper brain structures. It reduces adverse neurocognitive effects by specifically targeting localized brain regions and inducing seizures in superficial cortex areas [87]. Consequently, MST has been proposed as a potential substitute for ECT [88]. Recent meta-analysis findings indicate that MST offers shorter recovery times and results in lower levels of cognitive impairments in individuals with MDD compared to ECT [89]. Furthermore, emerging evidence supports the clinical efficacy of MST in MDD [90], bipolar depression [88], and schizophrenia [86] and suggests potential benefits in OCD.

MST has been considered as a potentially more effective option compared to rTMS. This notion is supported by studies demonstrating higher response rates in ECT for MDD [91], where generalized seizure activity is hypothesized to be the underlying mechanism [92]. MST may offer the advantage of precise stimulation by targeting specific brain regions associated with OCD’s pathophysiology. However, it is essential to note that no direct comparisons between MST and rTMS for OCD treatment have been published to date.

An open-label pilot study [93], which represents the initial report of using MST in a sample of participants (n = 10) diagnosed with OCD, revealed that only one participant who underwent frontal MST at 100 Hz experienced a clinically significant decrease in Y-BOCS scores. In contrast, the remaining participants did not observe any reduction in their OCD symptoms. Furthermore, no notable changes were observed in MDD, quality of life, or suicidality within the group. Consequently, additional research is necessary to thoroughly assess the efficacy of MST in individuals diagnosed with OCD.

5. Conclusion

Neurostimulation techniques, particularly rTMS, serve as a significant tertiary treatment alternative for OCD, complementing pharmacological and psychological interventions. The utilization of diverse advanced paradigms of TMS may be most effective in the initial stages of the stepped care pathway, potentially in conjunction with SSRIs or CBT. This approach has noteworthy implications for the development of clinical services, as diverse advanced paradigms of TMS, including conventional rTMS, are not commonly accessible as standard treatments for OCD within numerous healthcare systems [3]. A meta-analysis found that rTMS exhibits a minimal occurrence of adverse effects and is well-tolerated in the treatment of OCD [38]. Therefore, it could serve as a viable alternative to SSRIs or CBT in specific subsets of patients who are unsuitable candidates for or have contraindications to conventional first-line treatments.

This chapter provides an overview of contemporary variations of rTMS utilized in managing OCD, including piTBS, aTMS, dTMS, pTMS, sTMS, iTBS, cTBS, bilateral TBS, and MST. By identifying reliable early response indicators to rTMS in patients with OCD, such as patient characteristics or neurophysiological findings, appropriate stimulation protocols and modalities can be selected. For instance, potential predictors of poor response to rTMS in OCD treatment include a higher Y-BOCS score and comorbid depression [36]. The presence of an action-monitoring deficit is a fundamental trait of OCD [94]. The dACC, which plays a significant role in error monitoring and cognitive control, exhibits heightened activity in individuals with more severe OCD symptoms [95]. By enhancing rapid error monitoring, rTMS targeting the dACC in patients with OCD simultaneously improves real-time behavioral adjustment and clinical symptoms, suggesting a connection between errors monitoring impairment and the underlying pathophysiology of OCD [94]. Consequently, evaluating the impact of rTMS on error monitoring function can provide valuable insights into the mechanisms underlying the effective treatment of OCD with rTMS, thereby enhancing the therapeutic outcomes of this intervention. With increasing clarity in clinical effects and reliable prognostic indicators, it becomes essential to thoroughly examine the fundamental mechanisms associated with every novel TMS protocol, facilitating the exploration of personalized medicine. Furthermore, uncertainties persist regarding the optimal dosing strategy for each novel TMS protocol, necessitating further research to assess the neurophysiological effects and clinical implications of variables such as the number of daily sessions, total sessions, and intervals between sessions.

Disclosure/conflicts of interest

The authors declare no conflicts of interest in conducting this study or preparing the manuscript.

Financial support

This study was funded by the National Natural Science Foundation of China (82101609), China International Medical Exchange Foundation (Z-2018-2035-2002), the Science and Technology Program of Guangzhou (2023A03J0839 and 2023A03J0436), Science and Technology Planning Project of Liwan District of Guangzhou (202201012), The Natural Science Foundation Program of Guangdong (2023A1515011383), National Clinical Key specialty construction project [(2023) 33], Guangzhou Municipal Key Discipline in Medicine (2021–2023), Guangzhou High-level Clinical Key Specialty, Department of Emergency Medicine of National clinical key specialty, and Guangzhou Research-oriented Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Abbreviations

5-HTTLPR	5-Hydroxytryptamine Transporter Linked Polymorphic Region
ACC	anterior cingulate cortex
ADM	antidepressant medication
aMT	active motor threshold
aTMS	accelerated rTMS
BAI	Beck Anxiety Inventory
CBT	cognitive-behavioral therapy
CGI	Clinical Global Impression
CSTC	cortico-striatal-thalamic-cortical
cTBS	continuous TBS
DLPFC	dorsolateral prefrontal cortex
dACC	dorsal anterior cingulate cortex
dTMS	deep transcranial magnetic stimulation
ECT	electroconvulsive therapy
EEG	electroencephalography
ERP	exposure and response prevention
FDA	Food and Drug Administration
HAMA	Hamilton Anxiety Rating Scale
HAMD-17	Hamilton Depression Rating Scale (17 items version)
HF	high-frequency
IAF	intrinsic alpha frequency
iTBS	intermittent TBS
LF	low-frequency
MDD	major depressive disorder
MST	magnetic seizure therapy
mPFC	medial prefrontal cortex
NMA	network meta-analysis
OCD	Obsessive-Compulsive Disorder
OFC	orbitofrontal cortex
piTBS	prolonged intermittent theta burst stimulation
pTMS	priming TMS
RCTs	randomized controlled trials
RMT	resting motor threshold
rTMS	repetitive transcranial magnetic stimulation
SMA	supplementary motor area
SSRIs	selective serotonin reuptake inhibitors
sTMS	synchronized TMS
TBS	theta burst stimulation
Y-BOCS	Yale-Brown Obsessive-Compulsive Scale.