2.1 Study design
We retrospectively analyzed the dataset from pharamco-resistant OCD outpatients who received rTMS treatment from July 2015 to May 2017. Our study is not, however, a retrospective medical record study. Patients were referred to Atieh Clinical Neuroscience Center in Tehran, Iran to receive rTMS treatment. The center admits patients with psychiatric disorders (e.g. depression, OCD), neurological disorders (e.g. stroke, dementia) and pediatric neurodevelopmental disorders (e.g. attention-deficit hyperactivity disorder, autism, learning disabilities). Typical interventions include non-invasive brain stimulation, pharmacological, behavioural and psychological interventions.
2.2 Participants
Sixty-five pharmaco-resistant OCD outpatients (Mean age = 32.25, SD = 10.23, 35 females) who completed the treatment were included in this study. A priori sample size calculation based on power analysis showed that based on medium effect size (f=0.5), a critical p-value of 0.05, a power of 0.95, the required sample size for or study design is 42 and we achieved a power of 0.99. The OCD diagnosis was based on the Structural Clinical Interview by a licensed psychiatrist according to the DSM 5 diagnostic criteria, confirmed by patient scores on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [32]. The inclusion criteria were: (1) 18-65 years old, (2) current OCD diagnosis based on DSM-5 (3) moderate to severe OCD score on the Y-BOCS (scores 16 and higher) (4) response failure to previous or current use of medication/psychotherapy (response failure was defined as scores > 16 at Y-BOCS despite at least two SSRI trials of adequate dose and duration) and (5) stable medication regimen 12 weeks before the interventions and unchanged during the treatment (4-6 weeks) [9]. Exclusion criteria included previous treatment with electroconvulsive therapy, and presence or history of psychosis, substance abuse, suicide attempt and/or active suicide ideation, neurological disorder, epilepsy, seizures, and head injury or loss of consciousness. According to the safety criteria for rTMS [33], patients with potential contraindications to rTMS, including implanted devices, foreign metal bodies, cardiac arrhythmia, unstable medical conditions, or pregnancy, were also excluded. Forty-nine of the patients were taking selective serotonin reuptake inhibitors (SSRIs) during rTMS treatment and the remaining patients had a history of SSRI medication use. Most of the patients had no history of psychotherapy. All patients provided written informed consent to treatment. Demographic and clinical characteristics of patients are summarized in Tables 1 and 2.
2.3 rTMS treatment parameters
RTMS was administrated with a Neuro MS rTMS device (Neurosoft, Russia) using a 70-mm figure-of-8-shaped coil (air film coil). Active motor threshold (AMT) was defined as the minimum stimulus intensity that produced a liminal motor evoked response during active contraction of the abductor policies brevis muscle (APB) (at about 20 % maximum contraction) [34]. Motor threshold determination was based on visual inspection of hand movement. The patients received either (1) SMA rTMS, or 2) bilateral DLPFC rTMS. For the SMA rTMS, the coil was positioned over the SMA, which was localized via the 10–20 EEG system, and defined as 15% of the distance between nasion and inion anterior to the vertex in the sagittal plane [35]. In the SMA-rTMS protocol, TMS was delivered at 120% of AMT. Stimulation frequency was 1-Hz, for 30 min, resulting in a total of 1800 pulses per session. Stimulation was performed once a day, 3 days per week for 7 weeks, resulting in 20 sessions (36,000 pulses over 20 sessions). In DLPFC rTMS, all patients received bilateral stimulation given previous studies that showed mixed effects of unilateral stimulation of rTMS [28]. In DLPFC rTMS, the position of the coil was 5 cm anterior along a parasagittal line from the site of optimum APB stimulation [36]. The coil was placed over the left or right DLPFC. For bilateral DLPFC rTMS, stimulation was delivered over the right and left DLPFC respectively. First, 15 min of 1-Hz stimulation trains at 120% AMT, resulting in a total of 900 pulses per session, was applied over the right DLPFC, resulting in a total of 18,000 pulses over 20 sessions. Left DLPFC was stimulated immediately afterward by applying 10-Hz stimulation at 120% AMT for 60 stimulation trains of a duration of 5 s each, with 10 s inter-train interval, resulting in a total of 3000 pulses per session in 15 min (60,000 pulses over 20 sessions).
2.4 Clinical procedure
All patients underwent a baseline clinical assessment with the Y-BOCS, Beck Anxiety Inventory (BAI) [37] and Beck Depression Inventory (BDI-II) [38] one week before rTMS treatment (pre-treatment) and at the end of treatment after the 20th session of rTMS (post-treatment) (Fig. 2). Participants received SMA or DLPFC rTMS based on their symptoms type and those with higher levels of anxiety and depressive state received DLPFC rTMS. Baseline symptom severity was defined as a score of 16 or higher on the Y-BOCS (Mean = 22.20, SD = 7.01), which is the cut-off criterion for moderate OCD (8-15 mild, 16-23 moderate, 24-31 severe, 32-40 extreme). Treatment response was defined as a reduction of at least 30% in the Y-BOCS total scores based on some previous studies [26, 39] and is suggested to represent a relevant clinical improvement in some studies (i.e., improvement of Clinical Global Impression (CGI)). It is of note that 35% of symptom reductions are also used in other studies and seem to be more common [40] however, we kept 30% of reduction to keep more responders in the binary regression analysis. The protocol was conducted in accordance with the latest version of the Declaration of Helsinki and was approved by the Institutional Review Board and ethical committee at the local university and Atieh Clinical Neuroscience Centre.
2.5 Measures
Y-BOCS: The Y-BOCS is the most widely used clinician-rated interview for assessing OCD symptom severity with adequate psychometric characteristics (i.e., inter-rater reliability and predictive validity) [41]. It contains 10 items, and each item is rated from 0 (no symptoms) to 4 (extreme symptoms). The Y-BOCS is sensitive to change, and during-treatment score reductions are a valid indicator of outcome [41]. Therefore, the items can be used as clinical predictors to treatment response. Similar to previous rTMS studies that used the BDI-II items as clinical predictors of response to rTMS in depression [30], we used each item as a potential clinical predictor of response to rTMS treatment. The Y-BOCS items weigh obsessions and compulsions equally. Obsession items assess spent time on obsessions (item 1), interference (item 2) and distress (item 3) due to obsessive thoughts, resistance against obsessions (item 4) and degree of control over obsessive thoughts (item 5). Items 6 to 10 assess respective variables (i.e., spent time, interference, distress, resistance, and degree of control) for compulsions respectively.
BAI & BDI-II: Both BAI and BDI-II consist of 21 items with a Likert scale ranging from 0 to 3 and raw scores ranging from 0 to 63 and are indicative for the presence of an anxiety or depression state. The BAI is well suited to monitor anxiety treatment outcomes [42], and the obtained anxiety state is correlated with OCD symptoms [43, 44]. Similarly, the BDI-II scores are associated with OCD symptoms [44], which is not surprising due to the fact that around one-third of OCD patients suffer from comorbid depression [45]. Both measures have adequate psychometric properties.
2.6 Statistical analysis
Data analyses were conducted using the statistical package SPSS for Windows, version 24.0 (IBM, SPSS, Inc., Chicago, IL). In order to examine the effectiveness of rTMS, mixed model analysis of variance (ANOVA) was conducted with protocol (DLPFC rTMS vs. SMA rTMS) as the between-subject factors and time (pre-intervention vs. post-intervention). Mauchly’s test was used to evaluate the sphericity of the data before performing the repeated measures ANOVA and in case that the assumption of sphericity was violated, the degrees of freedom were corrected using the Greenhouse–Geisser estimates of sphericity. The normality and homogeneity of the data were confirmed by the Shapiro-Wilk and Levin tests, respectively. For identifying demographic and clinical predictors of response to rTMS treatment in OCD patients, we split the participants to “responders” and “non-responders” and conducted a binary logistic regression. To control for potential confounding variables, we added them into the model as the model can itself adjust for potential co-founders sing adjusted odds-ratio [46]. The model goodness of fit was done using the Hosmer-Lemeshaw statistic, which also adjusts for potential covariates, and the variable section was based on the “stepwise forward” strategy due to a large set of potential independent variables. The model was run in 2 steps in both analyses. Independent variables were age, gender, education, marital status (as demographic variables), all 10 items of the Y-BOCS that are assumed to measure different OCD symptoms. We ran the regression analysis separately on the Y-BOCS predictors in order not to increase number of predictors depending on our sample size as suggested [47]. To diagnose multicollinearity, we used the linear regression procedure and entered all covariates in the model to diagnose potential multicollinearity. A significance level of p < 0.05 was used for all statistical comparisons.
2.7 Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.