Theta-Patterned, Frequency-Modulated Priming Stimulation Enhances Low-Frequency, Right Prefrontal Cortex Repetitive Transcranial Magnetic Stimulation (rTMS) in Depression: A Randomized, Sham-Controlled Study

This was a prospective, hospital-based, sham-controlled rTMS study conducted over a period of 9 months, from April to December 2008 at the Centre for Cognitive Neurosciences of Central Institute of Psychiatry, Ranchi, India. The study was approved by the ethical committee of our Institute. Figure 1 shows the CONSORT diagram of flow of participants through the trial. The sample consisted of 40 right-handed, normotensive patients of either sex, ages between 18 and 60 years, fulfilling the diagnosis of unipolar or bipolar, moderate-to-severe depression according to ICD–10 Diagnostic Criteria for Research,³¹ and giving written informed consent. Patients with epilepsy, current neurological condition, comorbid psychiatric disorders, history of drug abuse, significant head injury, neurosurgical procedure, subjects with cardiac pacemakers or other metal parts in the body, and those who had received ECT in the past 6 months were excluded from the study. The selected 40 patients were alternatively assigned to receive either active priming rTMS (N=20) or sham priming stimulation (N=20), with the first patient receiving active treatment, the second receiving sham stimulation, and so on.

A semistructured pro-forma was used for recording sociodemographic and clinical details. To assess handedness, a 15-item Hindi version of the Handedness Preference Schedule³² was used. A 21-item, clinician-administered Structured Interview Guide for the Hamilton Depression Scale (SIGH–D)³³ and 18-item Brief Psychiatric Rating Scale (BPRS)³⁴ were used to assess severity of depressive and psychotic symptoms, respectively. Treatment-emergent manic symptoms were assessed with the 11-item Young Mania Rating Scale (YMRS).³⁵ The Clinical Global Impression scale (CGI)³⁶ was used to assess overall illness severity and response to treatment.

The motor threshold (MT) for the left abductor pollicis brevis (APB) was determined using a Neuropack Sigma evoked-potential measuring system (Nihon Kohden, Japan) and a figure-eight shaped coil at 1-Hz frequency according to the Rossini-Rothwell algorithm.³⁷ According to this, MT was defined as the lowest intensity that produced 5 motor evoked potential (MEP) responses of at least 50 μV in 10 trials when the left APB is at rest. Mapping studies have found that the greatest responses for APB or first dorsal interosseous (FDI) stimulation are derived from coil (center) placement in a lateral-sagittal orientation at a point 2 cm. behind and 4 cm. to the left of the nasion-inion line.³⁸ Starting from this region, the stimulations were given at 1 Hz, and the coil was methodically moved across the right fronto-parietal region of the cranium, centered at the above-indicated point, until the motor cortex for the APB was located. Up to 10 single pulses were given at each level of intensity. Beginning at 50% intensity, it was increased by 5% and the procedure repeated until MT for APB was achieved. The right DLPFC rTMS stimulation site was determined by measuring 5 cm. anterior and in a parasagittal line from the point of maximum stimulation of the contralateral APB muscle.³⁹ The site was then marked for reference with an indelible skin-marker.³⁸

Right 1-Hz stimulation in both arms of the trial (active priming and sham priming) were provided, using a Magstim Rapid device (The Magstim Company Limited, Whitland, UK) in one continuous, 15-minute train, at 110% of the resting MT, delivering 900 stimulations per session, using an air-cooled, figure-eight shaped coil. The priming stimulation that preceded the 1-Hz train was provided at 4 Hz–8 Hz (frequency-modulated in theta range). Twenty trains of 20 stimulations (total of 400 pulses), each at 90% of the resting MT, were applied in sequences of 7 trains, at 4 Hz, 7 trains at 6 Hz, and 6 trains at 8 Hz. For the sham group, the same stimulation condition was used, but with the sham coil.

The SIGH–D, BPRS, YMRS, and CGI were administered at baseline, after the 5th rTMS, after the 10th rTMS, and 2 weeks post-rTMS by the first author, AN. The rater was not blind to the treatment assignment, although the patients were blind to their treatment status. The stimulation sessions were performed as adjuncts to the ongoing medications.

The results obtained were analyzed by the software program, Statistical Package for Social Sciences (SPSS Version 10.0 for Windows; SPSS, Inc.; Chicago, IL, U.S.). Sociodemographic, clinical, and pharmacological profiles were compared by independent-sample t-tests for continuous variables and chi-square test for categorical variables. In three patients, the final rating could not be completed (two in the active, one in the sham group); therefore, they were excluded from the final analysis. The effect of priming rTMS was determined with two-way, repeated-measures ANOVA, with Group (active and sham) and Time (baseline, after 5th rTMS, after 10th rTMS, and 2 weeks post-rTMS) as factors. Greenhouse-Geisser correction was applied because the sphericity assumption was violated. Post-hoc independent t-tests were carried out to find the differences in scores at all time-points. Effect size (η²) was calculated to quantify the strength of the treatment procedure in bringing about changes in various clinico-psychopathological variables. Covariate analysis was done to identify factors that explain the differences in baseline SIGH–D scores. Pearson's correlation coefficient was calculated between SIGH–D scores and sociodemographic and clinical variables. Stepwise linear-regression analysis was carried out using SIGH–D scores as the outcome variable to identify the predictors of response. In this study, a level of significance α of<0.05 (two-tailed) was taken to consider a result statistically significant.

There were no major adverse events during or after rTMS. Two patients (10%) in the active group and one patient (5%) in the sham group complained of headache lasting a few hours after rTMS, which resolved after they were given analgesics; headache did not recur in later sessions of rTMS. Other side effects reported were scalp tenderness in four patients (20%) in the active and three (15%) in the sham group; one patient (5%) in the sham group reported discomfort caused by twitching of the temporalis muscle during stimulation. None of patients switched to mania.

Sociodemographic and clinical characteristics of the sample have been summarized in Table 1. Mean age of patients in the active priming rTMS group was 32.25 (SD: 10.38) years, and 30.50 (SD: 9.52) years in the sham priming rTMS group; there was no difference between them. In both the groups, 14 patients (70%) had unipolar, and 6 (30%) had bipolar depression. Table 2 shows medication details of both groups. The active group (N=19) received a mean dose of 426.31 (SD: 152.17) mg of chlorpromazine-equivalent of antipsychotics, versus 477.78 (SD: 159.24) mg/day in the sham group (N=18); this difference was not significant (t[35] = –1.01; NS). Mean doses of lithium were 956.25 (SD: 111.60) mg/day in the active group (N=8), versus 1,080 (SD: 125.49) mg/day in the sham group (N=5), and a trend toward difference was seen (t[11] = –1.858; p=0.09). In the active group (N=3), mean benzodiazepines (calculated in diazepam-equivalent) dose was 15.00 (SD: 8.66) mg/day, versus 14.16 (SD: 6.64) mg per day in the sham group; there was no difference between the groups. One patient in the sham group had received carbamazepine at 600 mg/day as a mood-stabilizer. There were nine patients on sertraline, nine on escitalopram, three on fluoxetine, four on amitriptyline, and one patient each on bupropion and imipramine. Mean MT was 53 (SD: 2.99) and 52.75 (SD: 3.43) in active priming and sham priming rTMS, respectively, with no significant difference between them.

Table 3 shows mean SIGH–D, BPRS, and CGI–S scores in the active and sham groups. For SIGH–D scores, two-way, repeated-measures ANOVA showed significant main effect of Time (F[2.12,74.23]=296.39; p<0.001, Greenhouse-Geisser–corrected; effect size: η²=0.894), but no effect of Group (F[1,35]=0.52; p=0.474). There was a significant Group x Time interaction in SIGH–D scores (F[2.12,74.23]=3.53; p=0.032, Greenhouse-Geisser–corrected; effect size: η²=0.092) showing significant improvement in the active group over time. Post-hoc independent t-test between the two groups showed a trend toward significance in baseline SIGH–D scores, with a higher score in the active priming group (t[35]=1.951; p=0.059), whereas, at other time-points, there was no difference (Figure 2). Covariate analysis for age, age at onset of illness, and episode duration were not significant for baseline SIGH–D scores between active and sham priming groups. After controlling for antipsychotic dose (chlorpromazine-equivalent per day), there was a trend toward greater reduction in SIGH–D scores in the active priming group over time (F[2.14,66.39]=2.51; p=0.086, Greenhouse-Geisser–corrected; effect size: η²=0.075).

Controlling for BPRS scores at baseline, the reduction in SIGH–D scores between the two groups over time was no longer significant (F[2.42,82.23]=2.01; p=0.131, Greenhouse-Geisser–corrected). On further analysis of SIGH–D, we found that 12 patients (66.7%) receiving active priming rTMS were in remission (score of ≤8 on SIGH–D) at 2 weeks post-rTMS, versus 12 (63.2%) in the sham priming group. The number-needed-to-treat (NNT) analysis showed that 29 patients would need to be treated to benefit one person receiving active priming rTMS as compared with sham priming rTMS.

For BPRS scores, two-way repeated-measures ANOVA showed significant main effect of Time (F[1.70,59.48]=138.25; p<0.001, Greenhouse-Geisser–corrected; effect size: η²=0.798), but no effect of Group (F[1,35]=2.19; NS) or Group x Time interaction (F[1.70,59.48]=0.50; p=0.580, Greenhouse-Geisser–corrected). For CGI–S scores, two-way repeated-measures ANOVA showed a significant main effect of Time (F[2.08,72.65]=155.34; p<0.001, Greenhouse-Geisser–corrected; effect size: η²=0.816), but no effect of Group (F[1,35]=0.154; NS) or Group x Time interaction (F[2.08,72.65]=1.14; p=0.326, Greenhouse-Geisser–corrected).

In the patients receiving priming stimulation, SIGH–D score after the 5th rTMS showed significant positive correlation with age (r=0.581; p<0.05) and age at onset of illness (r=0.641; p<0.05; Figure 3), whereas SIGH–D score at baseline, after the 10th rTMS and 2 weeks post-rTMS did not show any significant correlation. In the sham priming group, we found no significant correlation between SIGH–D scores with sociodemographic or clinical parameters.

Stepwise linear-regression analysis was carried out using the SIGH–D score after the 5th and 10th rTMS, as well as 2 weeks post-rTMS, as outcome variables and age of patient, age at illness onset, and episode duration as predictors in both active and sham priming group. Only age at onset significantly predicted SIGH–D scores after the 5th rTMS (F [change]=11.19; p=0.004; β=0.384; R²=0.411) in the active priming group.