Repetitive Transcranial Magnetic Stimulation for the Treatment of Resistant Depression: A Scoping Review

Treatment-resistant depression (TRD) is associated with significant disability, and due to its high prevalence, it results in a substantive socio-economic burden at a global level. TRD is the inability to accomplish and/or achieve remission after an adequate trial of antidepressant treatments. Studies comparing repetitive transcranial magnetic stimulation (rTMS) with electroconvulsive therapy (ECT) and pharmacotherapy have revealed evidence of the therapeutic efficacy of rTMS in TRD. These findings suggest a crucial role for rTMS in the management of TRD. This article aims to conduct a comprehensive scoping review of the current literature concerning the use of rTMS and its therapeutic efficacy as a treatment modality for TRD. PubMed, PsycINFO, Medline, Embase, and Cinahl were used to identify important articles on rTMS for TRD. The search strategy was limited to English articles within the last five years of data publication. Articles were included if they reported on a completed randomized controlled trial (RCT) of rTMS intervention for TRD. The exclusion criteria involved studies with rTMS for the treatment of conditions other than TRD, and study and experimental protocols of rTMS on TRD. In total, 17 studies were eligible for inclusion in this review. The search strategy spanned studies published in the last five years, to the date of the data search (14 February 2022). The regional breakdown of the extracted studies was North American (n = 9), European (n = 5), Asian (n = 2) and Australian (n = 1). The applied frequencies of rTMS ranged from 5 Hz to 50 Hz, with stimulation intensities ranging from 80% MT to 120% MT. Overall, 16 out of the 17 studies suggested that rTMS treatment was effective, safe and tolerated in TRD. For patients with TRD, rTMS appears to provide significant benefits through the reduction of depressive symptoms, and while there is progressive evidence in support of the same, more research is needed in order to define standardized protocols of rTMS application in terms of localization, frequency, intensity, and pulse parameters.


Introduction
Major depressive disorder (MDD) is a mood disorder characterized by a depressed mood and/or a lack of interest or pleasure in previously rewarding or enjoyable activities, fatigue, disturbed sleep, the loss of appetite, and somatic and psychological symptoms [1,2]. MDD is a significant public health concern that affects approximately 300 million people globally, is a major leading cause of morbidity, and contributes immensely to the global burden of disease [3,4]. Effective treatment of MDD is available in the form of psychopharmacology, psychotherapy, electroconvulsive therapy (ECT), and other non-invasive brain stimulation methods [5], but affected patients frequently experience relapses and persistent life dysfunction [6], with associated suicidal ideation [7].
The most effective treatment of TRD remains uncertain due to the limited validated pharmacological and psychotherapeutic approaches [37,38]. Given this limited evidence on the optimal treatment approach for TRD, rTMS has been evaluated as a treatment strategy [39]. Thus, increasing studies have been conducted that have focused on rTMS application in individuals diagnosed with TRD. The approval by the FDA for its use in the treatment of TRD reflects the evolving research on rTMS, for which the optimal technique of application continues to be investigated. rTMS is progressively becoming a common treatment modality, the parameters of which are still being defined. This review seeks to map an up-to-date synthesis of the currently available literature evidence supporting the therapeutic efficacy of rTMS in TRD while acknowledging that rTMS is a general approach rather than a single entity.

Methodology
In order to identify literature concerning rTMS for the treatment of TRD, five databases (PubMed, Embase, PsycINFO, CINAHL, and Medline) were electronically searched. The authors developed and executed a search strategy within the designated databases which included terms related to "treatment-resistant depression", "repetitive transcranial magnetic stimulation", "randomized control trials", and "treatment". The main aim of this review is to synthesize the evidence and assess the scope of current and updated literature on the use of rTMS in TRD. Furthermore, due the rapid advancement in this field with the use of newer techniques and parameters for rTMS applications, we opted to explore these recent updates in this review; therefore, the search strategy was limited to the last five years of data publication (from 2017 to February 2022). Language restrictions were applied, and only articles published in English were included. Two researchers independently conducted the title and abstract screening, and reviewed all of the full-text articles that met the inclusion criteria. Conflicts that arose out of the review process were discussed and resolved by the two reviewers. Table 1 displays the agreement of the two researchers in the full-text review.

Kappa =
Observed agreement − chance agreement 1 − chance agreement

Inclusion and Exclusion Criteria
Articles were included if they reported on a completed randomized controlled trial (RCT) of rTMS as a treatment intervention for TRD and were published within the last five years. The exclusion criteria involved studies with rTMS as a form of treatment for conditions other than TRD; studies and experimental protocols of rTMS on TRD were also excluded. Studies with rTMS as a combined therapy with pharmacotherapy or any other interventions were excluded, as were studies of rTMS treatment on treatment-resistant bipolar depression.

Data Extraction
A qualitative descriptive approach was used during the extraction to categorize the included studies based on the names of the authors, year of publication, study design, number of participants, targeted brain region, targeted symptoms, measurement tools, duration of treatment, coil/rTMS stimulations, outcome/significant improvements/effect size, assessment and follow-up, conclusion, and side effects of the interventionas displayed on Table 2.

Results
We identified 85 studies from the electronic databases through the search strategy and the use of the Covidence software. The software automatically screened and removed 16 duplicate studies from the searched items; 69 studies were screened against the eligibility criteria set based on the title and abstract only. The screening was performed independently by the two reviewers, and where conflicts in classification existed, the articles in question were discussed and a consensus was reached between the two reviewers. The title and abstract screening brought the total number of records left for full-text screening to 30 studies after 39 were deemed irrelevant, and were therefore excluded from the records. The remaining items were full texts screened by the two reviewers, and excluded 13 studies from the study. Studies were excluded primarily based on the wrong intervention, where the studies used CBT but were not specifically internet-based. In other studies, the target population had conditions other than TRD. There were studies with wrongful study designs, and some with wrongful outcomes. A total of 17 studies were legible and extracted for this scoping review. Figure 1 shows the PRISMA flow diagram displaying the search results and process.
Regarding the agreement of the researchers for full text review, Kappa analysis was conducted as shown in Table 1.
Kappa denotes a substantial agreement between the two researchers. Table 2 shows the extracted studies. Though the search strategy encompassed studies published in the last five years to the date of the data search (14 February 2022), we did not find any paper published in 2022 that met the inclusion criteria. Out of the 17 reviewed studies, we found n = 4, 23.5% each within 2019 and 2020, and n = 3, 17.6% from 2017, 2018, and 2021, respectively. Most of the studies were conducted in the USA (n = 7); Canada conducted two studies, and the UK, Greece, China, Netherlands, Australia, France, Croatia, and Japan all conducted one study each.

Overview of the Extracted Studies
All 17 studies incorporated the RCT method, though in different formats and forms such as parallel, double-blind, open labels, and single-, two-, or four-arm forms. The sample size for the various trials ranged from n = 27 to n = 414. The participants in the various studies were all patients diagnosed with TRD or patients who had failed at least two adequate trials of different major classes of antidepressants. Out of the 17 papers, 15 were conducted in an adult population within the ≥18 age bracket. Two of the studies were conducted on older adults aged 60 and above. Only one study evaluated the effectiveness of rTMS in adolescents with a diagnosis of TRD.

Targeted Symptoms
All 17 studies evaluated the reduction in the severity of depression symptoms, the rate of responses or remissions, and the reduction on depression measuring scales. Several studies investigated other confounding factors that positively or negatively affect the results of rTMS. For instance, Carpenter et al. (2017) and Kavanaugh et al. (2018) targeted the effectiveness and safety of a two-coil rTMS device in their study subjects. Zhao et al. (2019), in their study, investigated the effects of rTMS on the serum levels of brain-derived neurotrophic factor, interleukin-1b, and tumour necrosis factor-alpha in elderly patients with refractory depression.

Targeted Brain Region of rTMS
The brain site for rTMS application employed by the studies ranged from the left PFC (n = 5) [42,46,49,50,53] to the left DLPFC (n = 4) [35,48,52,56]. Four studies indicated DLPFC without specifying either the left or right [45,47,51,55], with one study evaluating the difference in effectiveness between the left and right DLPFC [27]. Two of the remaining studies [43,44] assessed the effectiveness of left DLPFC against dorsomedial PFC, and one study evaluated the differences in effectiveness between unilateral and bilateral left DLPFC [54].  , in their study, investigated the effects of rTMS on the serum levels of brain-derived neurotrophic factor, interleukin-1b, and tumour necrosis factor-alpha in elderly patients with refractory depression.

Targeted Brain Region of rTMS
The brain site for rTMS application employed by the studies ranged from the left PFC (n = 5) [42,46,49,50,53] to the left DLPFC (n = 4) [35,48,52,56]. Four studies indicated DLPFC without specifying either the left or right [45,47,51,55], with one study evaluating the difference in effectiveness between the left and right DLPFC [27]. Two of the remaining studies [43,44] assessed the effectiveness of left DLPFC against dorsomedial PFC, and one study evaluated the differences in effectiveness between unilateral and bilateral left DLPFC [54].

Outcome Measures
A wide range of scales was used to measure positive symptoms and the reduction in symptom scales; for example, the Hospital Depression Rating Scale (HDRS) was the outcome measure in nine of the 17 studies, while the Hamilton Depression Scale (HAM-D) was used in six of the included studies. Other scales such as the Clinical Global Impression-Severity (CGI-S), Quick Inventory of Depressive Symptomatology (QIDS), Personal Health Questionnaire (PHQ-9), and Beck Depression Inventory (BDI-II) were also used to measure some of the primary or secondary outcomes in the included studies. Blumberger et al. (2018) defined their primary outcome as the reduction in the HDRS-17 score from the baseline to the end of treatment (either 20 or 30 treatments). If participants received most of the scheduled sessions and a 4-week, 5-week, or 6-week assessment was available, they were assessed for the primary endpoint. The safety outcomes included adverse event reporting, neurocognitive assessments, vital signs, and Columbia Suicide Rating Scale (C-SSRS) and Young Mania Rating Scale (YMRS) assessments for the various studies.

Outcome Results
Regarding the antidepressant efficacy of rTMS per the findings of this review, all 17 included studies evaluated its effectiveness and deemed it to be effective for the treatment of TRD, except for one study, in which the authors concluded that the standard 4-week rTMS treatment was not effective in chronic, severe TRD patients [46].

Efficacy of the Two-coil rTMS Device
An important observation made in this review is that it also included studies focusing on important confounding factors that either enhance or inhibit the efficacy of rTMS in patients with TRD. For instance, in their study, Kavanaugh et al. (2018) [43] sought to examine neurocognitive data from a randomized, double-blind, sham-controlled trial of an investigational two-coil rTMS device in TRD patients. The two-coil rTMS device is reported to stimulate deeper areas of the brain compared to the standard TMS devices, which primarily stimulate cortical brain areas, and may therefore have different adverse neurocognitive effects. The patients received 20 min daily rTMS with 10 Hz stimulation in the active and sham groups. The neurocognitive safety was evaluated at the baseline and within 72 h of the final treatment session. There were no observed negative neurocognitive effects of the two-coil rTMS device. The results revealed a significant effect of active rTMS on the quality of episodic memory; the baseline quality of episodic memory predicted depression treatment response and remission. The results were consistent with another RCT conducted by Carpenter et al. (2017), in which the researchers concluded that the delivery of rTMS with the two-coil device produced significant antidepressant effects after only 4 weeks of treatment and was well tolerated, with an effect size (Cohen's d) f ITT d = 0.58; PP = 0.52 [44].

Tolerability and Side Effects
The overall effectiveness of any treatment intervention must acknowledge both its efficacy and regarding any safety and tolerability factors. In this regard, rTMS treatment appears to be reasonably well-tolerated, and the most common side effects were transient headaches, dizziness, and scalp discomfort at the stimulation site. However, Croarkin et al. (2021) [51] reported that one participant in both the sham group and active group developed suicidal ideation; the researchers classified this as not being related to the study device. In that same study, a patient was observed to have developed worsening depression during week four, and another had a suicide attempt during week six. Still, all of these adverse effects were classified as being unrelated to the study device. Yesavage, et al. (2018) [47] also reported cases of suicidal ideation in three active and four sham participants, though no suicides or seizures occurred during the study.

Frequency, Intensity of Stimulation, and Duration of Treatment
The frequency of rTMS ranged from as low as 5 Hz to as high as 50 Hz. The majority of the studies (13 out of 17) applied the 10 Hz frequency, and two studies applied the 50 Hz frequency. The intensity of stimulation reviewed in the included studies also ranged from the 80% to the 120% motor threshold, but most of the studies (11) applied the 120% motor threshold in their investigations. The duration of active rTMS treatments in the included studies ranged from 3 weeks to 6 weeks, while the only maintenance treatment reviewed lasted for about 11 months. Concerning the number of magnetic pulses given per treatment session, there was a range varying from 600 pulses to 4000 pulses.

Variations in the Brain Target
Accuracy in targeting functional brain networks is deemed essential for the treatment efficacy of rTMS in TRD. One study tested whether variations in targeting precision contributed to the failure to find an advantage of active over sham treatments [51]. In this study, the researchers used data from a failed clinical trial of rTMS in veterans to test whether treatment response was associated with the rTMS coil location in the active but not sham stimulation, and compared fMRI functional connectivity between those stimulation locations. The results indicated that the response to rTMS was related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate.

Comparing the Efficacy and Tolerability of the Different Forms of rTMS
In order to establish the true efficacy of rTMS in depression-related conditions, current studies are beginning to focus attention on the different forms of rTMS, and are comparing their effectiveness and tolerability to the standard rTMS. For instance, Blumberger et al. (2018) [35] aimed to evaluate the clinical effectiveness, safety, and tolerability of iTBS compared with the standard 10 Hz rTMS in adult treatment-resistant depression patients. The participants were randomized to receive iTBS or 10 Hz rTMS. Both groups were assessed at 4-6 weeks for the primary outcome. The HRSD-17 scores for the 10 HZ rTMS improved from a baseline of 23.5 (SD 4.4) to 13.4 (7.8), and from 23.6 (4.3) to 13.4 (7.9) in the iTBS group. The adjusted difference was 0.103 (lower 95% CI-1.16; p = 0.0011). The conclusion was that iTBS is non-inferior to standard 10 Hz rTMS in reducing depressive symptoms in TRD patients, with the advantage that the utilization of iTBS can increase the number of patients treated in a day without affecting the clinical efficacy of the treatment.

Maintenance rTMS Treatment
Regarding the efficacy of maintenance rTMS after an acute response in depression, Benadhira et al. (2017) [48] evaluated the role of maintenance rTMS in TRD patients who responded to one month of active rTMS in an open-labelled study (phase I). They assessed the benefits of a randomized protocol of maintenance rTMS for up to eleven months (phase II). Clinical assessment was at the baseline, weekly during the first month, and then monthly for the maintenance phase. The results indicated that the antidepressant effect of maintenance rTMS sessions appeared three months after the treatment (Month 4). Maintenance rTMS was well tolerated, and no side effects were reported. The study suggests that rTMS could represent a novel strategy for reducing relapse in TRD patients who respond to rTMS treatment. This result contrasts a trial in which patients were randomized to once-a-month rTMS maintenance treatment and an observation-only group, the results of which failed to predict any statistically significant difference between the two groups at the end of a 1-year study period [57].

Relationship between the Pulse Number and the Response to rTMS in TRD
There has been a steady increase in the stimulation dosage of rTMS application from the early stages of rTMS trials to date. These increases include the stimulation intensity relative to the motor threshold and the number of pulses used in each treatment session. However, very few studies have sought to evaluate the differences in pulse numbers and the response to rTMS in patients. Fitzgerald et al. (2020) [27] investigated whether the response to rTMS is greater when it is applied at a higher pulse than a lower pulse. The participants were grouped into four treatment groups: 1.
The treatment was applied for four weeks, five days/week, for 20 treatment sessions. In terms of results, there was no consistent association between the antidepressant effect of rTMS and the number of TMS pulses across the ranges. Thus, increasing the TMS pulse in individual sessions did not seem to be a potential method to substantially improve clinical outcomes.

Effect of rTMS on the Serum BDNF, IL-1b, and TNF-a Levels in TRD
Inflammatory factors such as interleukin (IL)-1 [58], tumor necrosis factor (TNF)-a [59], nuclear factor-kappaB (NF-jB) [60], and brain-derived neurotrophic factor (BDNF) have been implicated in the causative mechanism of depression [61]. However, there are limited studies on the specific effects of rTMS on these inflammatory factors in patients with TRD. In the study by Zhao et al. (2019) [56], elderly depressed patients were randomized into two groups of 29, with one group receiving rTMS and the other as a control group, while another group of 30 healthy volunteers were given rTMS. The serum levels of BDNF, IL-1b, and TNF-a were measured before the study and at 48 h, and 1, 2, 3, and 4 weeks after the first TMS treatment. rTMS increased serum BDNF levels and decreased serum IL-1b and TNF-alpha levels in patients with depression, but it had no effect on any of these factors in healthy individuals.

Discussions
The studies included in this review were RCTs published within the last five years, between 2017 and 2022 (though none of the eligible studies were extracted from 2022). Overall, these studies are characterized by their varying sample sizes, ranging from small to large, and are heterogeneous in terms of their demographic and clinical variables, and in terms of their choices of brain targets of rTMS stimulation, treatment duration, and stimulus intensity. The 17 studies reviewed here suggest that rTMS appears to have a robust therapeutic effect in the treatment of TRD. The regional breakdown of the extracted studies revealed that most studies (n = 9) were conducted in North America. Depression is a global burden and a debilitating condition that exacts a serious personal, social, and economic toll [62]; it is associated with extreme consequences such as increased mortality, disability, and secondary morbidity [63]. The World Health Organization has recently reported that depression ranks among the leading causes of disability worldwide [64].
All but one study [46] reported consistent improvements in depressive symptoms through higher or accelerated doses and patient-centred stimulation protocols across the major outcome domains. These positive outcomes were enhanced by accurate and advanced neuro-navigational technologies, the degree of precision in the techniques of the detection of the DLPFC, and the application of modern coil geometries. Because rTMS treatment is rapidly gaining popularity as a treatment modality for TRD, there should be a focus of attention on global accessibility, reliability, and efficacy through standardized protocols and evidence-based guidelines.
Though the primary objective of all 17 studies was the reduction and remission of depressive symptoms in TRD patients, some of the studies evaluated other confounding factors that affect the efficacy of rTMS intervention in the management of TRD. Two out of the 17 studies evaluated a two-coil rTMS device [43,44]. Though the antidepressant mechanism of multi-coil stimulation and whether it differs from that of standard single-coil stimulation are still being investigated, studies have reported that the depth and direction of the electromagnetic field capable of penetrating the scalp and tissues of the brain for the activation of neurons during the process of rTMS application are dependent on the shape and size of the coil through which the current is passed [30,31]. Until recently, most rTMS depression interventions were performed using figure-of-eight or butterflyshaped coils deemed to emit relatively superficial cortical stimulations. However, the pathophysiology of depression is assumed to involve a variety of deeper frontal brain regions [65,66]. Therefore, the two-coil rTMS device was specifically designed to target brain pathways for possible deeper cortical stimulations, and may represent a novel technique for neurostimulation for patients with TRD.
There were limited data on maintenance rTMS treatment for TRD. Only one out of the 17 reviewed papers evaluated the efficacy of maintenance rTMS after an acute response in the treatment of TRD. Their results indicated that the antidepressant effect of maintenance rTMS sessions appeared three months after the treatment. Maintenance rTMS was well tolerated, and no side effects were reported [48]. This result contrasts with an earlier study that investigated 12-month outcomes comparing two maintenance TMS approaches: a scheduled, single TMS session delivered monthly versus an observation-only group, which found that there were no significant group differences in any outcome measure [57]. This suggests that although rTMS could represent a novel strategy for reducing relapse in TRD patients who respond to rTMS treatment, there is little information on its maintenance use. As explained in the literature, maintenance treatment is not the mere reintroduction of rTMS in situations of a relapse; rather, it is an intentional, timely, scheduled regimen of rTMS treatment for a fixed period after acute rTMS treatment [21]. Much more research needs to be conducted, and the true effect of maintenance rTMS treatment in TRD must be ascertained. Regarding brain targets, the DLPFC was the most frequent (n = 9) rTMS site targeted with the primary preference for the left DLPFC; none of the studies applied rTMS to the right DLPFC. Only one study compared the relationship between the pulse number and the response to rTMS in depression between the left and right DLPFC [27]. The left PFC was also utilized in six studies, which reported improvement in depressive symptoms. The left DLPFC represents an essential brain region for neurocognitive performance connecting to the frontosubcortical brain regions [67]. The dysfunctions of this brain region are believed to be involved in the pathogenesis of symptoms of depression and cognitive impairment [68,69]. The stimulation of the DLPFC is significantly associated with the enhancement of the neurocognitive domains, and rTMS appears to reduce depressive symptoms, with a subsequent improvement in the neurocognitive functions of TRD patients [30,70,71].
According to our findings, all 17 of the reviewed studies applied rTMS with a high frequency-ranging from 18 Hz to 50 Hz-in their subjects. Studies have it that the effectiveness of rTMS treatment regarding the modulation of neural activities greatly depends on the frequency applied and other stimulation parameters [72]. High-frequency rTMS over the DLPFC has been used in the most recent trials-a choice guided by the positive outcome results for this approach [73]. This possibly explains the positive outcomes brought about by our reviewed studies, as the rTMS targets were mostly the left DLPFC with high frequencies. Again, our results revealed a trend in which all of the included papers applied rTMS with high stimulus intensity ranging from 80 MT to 120 MT. Though not all RCTs that apply higher stimulating intensities end up with larger effect sizes, stimulus intensity is deemed to be an essential component in the induction of lasting changes in cortical excitability, which is believed to be responsible for the antidepressant effect of rTMS [73]. This report is consistent with our findings, as all of the studies applied high stimulating intensities and still had the desired treatment effects.
Overall, rTMS treatment in the management of TRD seems safe and tolerable. All 17 studies reported on the treatment side effects and tolerability of rTMS. The most common side effects across all of the studies were scalp pain, transient headaches, dizziness, and discomfort at the stimulation site, but these side effects did not lead to the discontinuation of the treatment. However, two studies reported cases of suicidal ideation and a worsening in depressive symptoms, though no suicides or seizures occurred during the treatments [49,53]. Consistent with data from earlier studies [74][75][76][77], our results add to the evidence that supports the safe and tolerable nature of rTMS in TRD.

Cost and Policy Implications for rTMS in TRD
The global burden of disease study 2010 ranked MDD as the second leading cause of disability globally, accounting for an estimated 2.5% of global disability-adjusted life-years and 8.2% of global years lived with disabilities [78]. Among the many treatment modalities for the management of TRD, rTMS is considered to be a clinically safe, productive, and patient-preferred treatment modality in resistant depression. However, the treatment benefits of rTMS need to be weighed against its treatment-related cost. A study evaluated the cost-effectiveness of rTMS vs. ECT for TRD from Singapore's societal perspective. The results demonstrated that, compared to ECT, rTMS was associated with lower total cost (SGD 23,072 vs. SGD 34,922) and Quality-Adjusted Life Years (QALYs) (0.6862 vs. 0.7243) over one year. Thus, rTMS was considered to be highly cost-effective relative to ECT [79]. Their result was consistent with a prospective economic evaluation of ECT and rTMS in the United States. The model provided support for the economic benefit of rTMS versus ECT alone in non-psychotic depression. Their results revealed that the cost of the acute treatment of rTMS was $1422.00, versus $7758.40 for ECT [80].
The comparative cost-effectiveness can help to inform decisions on resource allocation and treatment utilization. Globally, healthcare resources are mostly scarce relative to needs or wants, and the essence of an economic evaluation is to inform the choices that decisionmakers face in critical situations. However, there is a paucity of literature on the cost-utility analysis of TRD management. Therefore, investigating the resource implications and costeffectiveness of rTMS offers crucial information that may help the choice of treatment for people with treatment-resistant depression. Future studies should focus on the cost-benefit analysis of rTMS in TRD.

Limitations
There are several limitations to this review. One main limitation relates to the small number of studies that were included for qualitative synthesis and analysis. However, our search strategy considered only studies published in English within the last five years (2017-2022). Secondly, although we carefully tried to identify all of the necessary studies for this review per our eligibility criteria, we still may have missed some relevant studies, particularly those published in other languages. Finally, the eligibility criteria only took into account RCTs, and furthermore, no meta-analysis was run on the reported data.

Conclusions
rTMS treatment is progressively gaining popularity in the treatment of depressive conditions, and there is evidence in support of the efficacy of rTMS in TRD. The treatment is considered effective, safe, and tolerable in the management of TRD. However, while progressive evidence supports its efficacy in an acute setting, there is limited literature to support long-term benefits and maintenance treatment in patients with TRD. Large-scale clinical trials are needed to compare the therapeutic efficacy and efficiency of the newer forms of rTMS with the consistency of the stimulating parameters across all of the treatment arms. Finally, in order to be able to establish a standardization of rTMS application, more studies are required to address frequency, intensity, pulse numbers, and localization.