2.1 Study design
We retrospectively analyzed a dataset of pharmaco-resistant OCD outpatients who received an rTMS treatment between July 2015 and May 2017. Patients were referred to the Atieh Clinical Neuroscience Center in Tehran, Iran, to receive rTMS. 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) were included in this report. 69 patients were initially included, but four patients did not either finish the treatment course without any reported reason or meet the minimum symptom severity to be included and thus the final analysis was conducted on 65 patients. A priori sample size calculation showed that based on a medium effect size (f=0.5) which is suggested for NIBS studies [37], a critical p-value of 0.05, and a critical power level of 0.95, the required sample size is 42. 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) [38]. 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 dosage and duration) and (5) stable medication regimen 12 weeks before the intervention 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 [39], patients with implanted devices, metal bodies, cardiac arrhythmia, unstable medical conditions, or pregnancy, were also excluded. Fifty-one 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) [40]. Motor threshold determination was based on visual inspection of the respective finger movement. Patients received either (1) SMA rTMS, or 2) bilateral DLPFC rTMS. For 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 [41]. In the SMA-rTMS protocol, TMS was delivered at 120% of AMT. Stimulation frequency was 1 Hz, which was applied 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). For DLPFC rTMS, all patients received bilateral stimulation, based on results of previous studies that showed mixed effects of unilateral rTMS [33]. For DLPFC rTMS, the position of the coil was 5 cm anterior along a parasagittal line from the site of optimum APB stimulation [42]. Stimulation was delivered over the right and left DLPFC respectively. First, 15 min of 1 Hz stimulation 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. The left DLPFC was stimulated immediately afterwards by applying 10 Hz stimulation at 120% AMT via 60 stimulation trains of a duration of 5 s each, with 10 s inter-train intervals, 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) [43] and Beck Depression Inventory (BDI-II) [44] one week before rTMS treatment (pre-treatment) and after the 20th session of rTMS (post-treatment) (Fig. 1). Participants received SMA or DLPFC rTMS based on the clinical impression of a psychiatrist according to the reported symptoms. Although no significant difference was found in participants’ depressive symptoms based on the questionnaires, those who reported more depressive symptoms were allocated to DLPFC rTMS. Baseline symptom severity for inclusion 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 score, based on some previous studies [31, 45] and is suggested to represent a relevant clinical improvement (i.e., improvement of Clinical Global Impression (CGI)). Although 35% of symptom reduction is taken as ”response” criterion in other studies [46], we chose a more liberal criterion to achieve a more balanced response distribution for 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) [47]. 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 valid outcome indicators [47]. Therefore, results of this questionnaire are suited as clinical predictors of treatment response, as shown by previous rTMS studies [35]. 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 6-10 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, which are rated on a Likert scale ranging from 0 to 3, resulting in raw scores ranging from 0 to 63, and are indicative for the presence of anxiety or depression. The BAI is well suited to monitor anxiety treatment outcomes [48], and the obtained anxiety state is correlated with OCD symptoms [49, 50]. Similarly, the BDI-II scores are associated with OCD symptoms [50] in line with the fact that around one-third of OCD patients suffer from comorbid depression [51]. Both measures have adequate psychometric properties [52, 53].
2.6 Statistical analysis
Data analyses were conducted using IBM, SPSS (version 24). In order to examine rTMS efficacy, mixed model analysis of variance (ANOVA) was conducted with “protocol” (DLPFC rTMS vs. SMA rTMS) as the between-subject and time (pre-intervention vs. post-intervention) as the within-subject factors. Mauchly’s test was used to evaluate sphericity of the data and in case of violation of sphericity, degrees of freedom were corrected using the Greenhouse–Geisser estimates of sphericity. The normality and homogeneity of the data were confirmed by Shapiro-Wilk and Levin tests, respectively. For identifying demographic and clinical predictors of response to rTMS treatment, we split the participants to “responders” and “non-responders” and conducted a binary logistic regression. To control for potential confounding variables, we added these into the model, as it adjusts itself for potential confounders using adjusted odds-ratio [54]. The goodness of fit was evaluated by the Hosmer-Lemeshaw statistic, which also adjusts for potential covariates, and the variable selection 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), and clinical factors based on the 3-factor and 2-factor model of Y-BOCS, as well as all 10 items of the Y-BOCS that are assumed to measure different OCD symptoms. Given that the Y-BOCS items are not independent of each other, we first defined 3 and 2 factors - based on respective models derived from single items [55, 56] - as clinical predictors in separate analyses. Afterward and in a separate analysis, each individual item was treated as a potential clinical predictor of response to rTMS treatment. We ran the regression analysis separately for the demographic variables, Y-BOCS factors, and the Y-BOCS items in order not to increase the number of predictors as suggested [57]. To diagnose multicollinearity, we used the linear regression procedure and entered all covariates in the model. A significance level of p < 0.05 was used for all statistical comparisons.
2.7 Data availability
The datasets used and/or analyzed for the present study are available from the corresponding author upon reasonable request.