Adjunctive Low-frequency Repetitive Transcranial Magnetic Stimulation over the Right Dorsolateral Prefrontal Cortex in Patients with Treatment-resistant Obsessive-compulsive Disorder: A Randomized Controlled Trial.

OBJECTIVE: The ratio of 2nd to 4th digit length (2D:4D) is a sexually dimorphic trait. Men have a relatively shorter second digit than fourth digit. This ratio is thought to be influenced by higher prenatal testosterone level or greater sensitivity to androgen. The purpose of this study is to investigate the relationship between alcohol dependence and 2D:4D in a Korean sample and whether 2D:4D can be a biologic marker in alcohol dependence.
OBJECTIVE: The present study aimed to evaluate the efficacy of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (DLPFC) for the treatment of obsessive-compulsive disorder (OCD).
METHODS: Twenty-seven patients with treatment resistant OCD were randomly assigned to 3 week either active (n=14) or sham (n=13) rTMS. The active rTMS parameters consisted of 1 Hz, 20-minute trains (1,200 pulses/day) at 100% of the resting motor threshold (MT). OCD symptoms, mood, and anxiety were assessed at baseline and every week throughout the treatment period.
RESULTS: A repeated-measures analysis of variance (ANOVA) was used to evaluate changes on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Our results revealed a significant reduction in YBOCS scores in the active group compared with the sham group after 3 weeks. Similarly, a repeated-measures ANOVA revealed significant effect of time and time×group interaction on scores on the Hamilton Depression Rating Scale and the Clinical Global Impression-Severity scale. There were no reports of any serious adverse effects following the active and sham rTMS treatments.
CONCLUSION: LF rTMS over the right DLPFC appeared to be superior to sham rTMS for relieving OCD symptoms and depression in patients with treatment-resistant OCD. Further trials with larger sample sizes should be conducted to confirm the present findings.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Obsessive-compulsive disorder (OCD) is a chronic and highly debilitating neuropsychiatric disorder with a lifetime prevalence of 2–3%.1,2) Ego dystonic symptoms of OCD cause significant distress to patients as well as their family.3) The substantial impairments that OCD causes in terms of interpersonal and occupational functioning have led to considerable social costs as well as this disorder’s reputation as among the most disabling psychiatric conditions.4)

Current first-line treatment strategies for OCD include high doses of selective serotonin reuptake inhibitors (SSRIs) or clomipramine in conjunction with cognitive-behavioral therapy.5) However, pharmacological treatment regimens are typically broadened to include various psychotropic agents, particularly antipsychotics.6) Even with a diverse array of therapeutic options, approximately 30–60% of OCD patients show only partial responses to treatment or are unable to tolerate the side effects related to these medications.7) Additionally, a substantial portion of patients experiences persistent symptoms that impair their global functioning.8)

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that may be an alternative strategy to effectively treat patients with OCD. rTMS delivers electromagnetic pulses to selective areas of the cerebral cortex via the direct application of an insulated wire coil to the scalp. The stimulating coil passes a rapidly alternating electrical current that generates a briefly pulsed magnetic field and results in the depolarization of the conducting neuronal tissue located just under the coil.9)

The dorsolateral prefrontal cortex (DLPFC) is one of the most interesting rTMS sites for the treatment of OCD patients because the pathophysiology of OCD is related to hyperactivity in specific cortical-subcortical loops that include the orbitofrontal cortex, anterior cingulate cortex, caudate nucleus, and DLPFC.10) The DLPFC may represent a starting point for the induction of remote stimulation in connected cortico-subcortical circuits.11) Neuroimaging studies have shown that untreated OCD patients exhibit hypermetabolism and hyperperfusion in the prefrontal cortex,12) that there is a normalization of prefrontal cortical activity following the administration of medication or neurosurgical treatments,13) and that rTMS has a direct influence on prefrontal cortical activity.14)

However, there have been only few studies that have applied rTMS stimulation over the DLPFC for the treatment of OCD patients and they have produced conflicting results.15–22) It is important to note that these studies employed heterogeneous designs in terms of stimulation site (right vs. left side), stimulus parameters (low frequency [LF] vs. high frequency [HF]), session frequency and duration, sham conditions, and coil shape. Moreover, each of these studies used a small sample. The data from these studies are insufficient to provide conclusive results regarding the optimum protocol for the treatment of OCD patients.

The present study aimed to evaluate the efficacy of LF rTMS over the right DLPFC for the treatment of OCD patients. Although there is no consensus on side and frequency to stimulate DLPFC for OCD, several studies reported that metabolic rates was elevated in the right prefrontal cortex at resting state and treatment produced primarily right-sided changes in cerebral activity.16,23–25) Thus, it was hypothesized that the administration of LF rTMS on the right DLPFC over 3 weeks, as an adjunctive treatment to pharmacotherapy, would improve the symptoms of patients with treatment-resistant OCD when compared with sham treatment.

METHODS

Subjects

The present study recruited patients with a primary diagnosis of OCD according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR). The inclusion criteria for this study required that the subjects be right-handed, 18–60 years of age, and had experienced residual OCD symptoms of at least a moderate severity according to the Yale-Brown Obsessive Compulsive Scale (YBOCS; score ≥16) despite treatment with two anti-OCD medications.21) Subjects with comorbid psychiatric disorders other than depression; a history of epilepsy, drug abuse, significant head injury, or any neurosurgical procedure; metal implants; and pacemakers as well as those who had received electroconvulsive therapy in the past 6 months were excluded from the present study. Written informed consent was obtained from all patients prior to participation in the study, and the study protocol was approved by the Institutional Review Board of St. Mary’s Hospital in Seoul, Korea (SCMC05EA078).

Procedure

The patients were randomly assigned to receive either a sham procedure or active LF rTMS based on a computer-generated randomization schedule. The rTMS procedure was conducted using a TAMAS stimulator with a figure-eight coil (REMED, Daejeon, Korea; http://www.remed.kr). The stimulation parameters were performed for 3 weeks as follows: 1 Hz, 20-minute trains (1,200 pulses/day) at 100% of the resting motor threshold (MT) once per day 5 days per week. The resting MT was determined using the thumb-movement visualization method via the stimulation of the primary motor cortex area for the left abductor pollicis brevis (APB) muscle. The stimulation site for the rTMS was over the right DLPFC, which was identified by measuring 5 cm anterior to and in a parasagittal line from the point of the maximum stimulation of the contralateral APB muscle. The sham rTMS procedure was identical to that of the active rTMS, except that a sham coil was used.

Since the rTMS sessions in the present study were performed as adjunctive therapies to ongoing medication regimens, the pharmacotherapies were continued in same dosages for the whole duration of the study (Table 1). The patients and the rater were blind to the group assignments but, for technical reasons, the clinicians who administered the rTMS were not blind. The OCD symptoms of the patients were assessed at baseline and every week during the treatment period. The YBOCS score26,27) was the main outcome measure of the present study but additional information was gathered using the Clinical Global Impression-Severity (CGI-S) scale,28) the seven-item Hamilton Depression Rating Scale (HAMD),29) the Hamilton Anxiety Rating Scale (HAMA),30) and the Beck Depression Inventory (BDI).31)

Table 1

Demographic and clinical characteristics of the subjects

Variable	Active rTMS (n=14)	Sham rTMS (n=13)
Age (yr)	34.6±9.8	36.3±12.5
Gender (male/female)	8/6	6/7
Marital status (married)	8 (57.1)	7 (53.8)
Duration of illness (yr)	9.8±8.0	11.7±9.5
Comorbid MDD	12 (85.7)	10 (76.9)
Medication in use
Antidepressant	14 (100)	13 (100)
Antipsychotics	8 (57.1)	9 (69.2)
Mood stabilizer	1 (7.1)	0 (0)
Benzodiazepine	8 (57.1)	7 (53.8)

Values are presented as mean±standard deviation, number only, or number (%).

rTMS, repetitive transcranial magnetic stimulation; MDD, major depressive disorder.

Statistical Analysis

The summary statistics are presented as means and standard deviations (SD) for continuous variables and as numbers and percentages for discrete variables. The demographic and clinical data for the active and sham groups were compared using t-tests, chi-square tests, or Mann-Whitney U-tests, as appropriate. A repeated-measures analysis of variance (ANOVA) using a mixed-effects model with a symmetric covariance structure was used to evaluate the group- and time-dependent effects of rTMS on the mean scores of the psychometric scales. Post hoc analysis was performed with the Bonferroni correction. Patients with a reduction ≥25% in their YBOCS score were classified as responders. A p value <0.05 (two-tailed) was considered to indicate statistical significance, and all statistical analyses were conducted using Statistical Analysis System, ver. 9.1 (SAS Institute, Cary, NC, USA).

RESULTS

Of the 28 patients initially recruited for the present study, one dropped out prior to the start of treatment due to follow-up loss. Therefore, the final sample included in the analyses consisted of 27 patients: 14 in the active group and 13 in the sham group. All patients completed at least 70% of all treatment sessions (>10 sessions), and the procedure was well-tolerated. The active and sham groups did not significantly differ in terms of any clinical or demographic characteristics (Table 1).

Figure 1 illustrates the mean YBOCS scores over time throughout the treatment period. After 3 weeks of treatment, the patients in the active group had a mean reduction of 10.7 points (SD, 8.2 points), whereas the sham group had a mean reduction of 3.7 points (SD, 3.7 points). A repeated-measures ANOVA revealed a non-significant effect of group (F=0.328, p=0.572), a highly significant effect of time (F=22.502, p<0.001), and a significant time×group interaction (F=4.751, p=0.005). Post hoc analysis revealed a significant difference between the two groups at week 3 (F=4.217, p=0.008).

Fig. 1

Comparison of Yale-Brown Obsessive Compulsive Scale (YBOCS) scores in active and sham rTMS (repeated transcranial magnetic stimulation) groups.

*Repeated-measures ANOVA, group×time interaction.

Table 2 describes changes in the HAMD, HAMA, BDI, and CGI-S scores over time throughout the treatment period. Similar to the results for the YBOCS scores, a repeated-measures ANOVA analyzing the HAMD and CGI-S scores revealed a significant effect of time (p< 0.001 and p<0.001, respectively) and a significant group×time interaction (p=0.028 and p=0.030, respectively). Post hoc analysis revealed significant differences between the two groups in the HAMD at week 2 and in the CGI-S at week 3 (F=2.557, p=0.009 and F=2.900, p=0.008, respectively).

Table 2

Mean scores of outcome measures at baseline, week 1, week 2, and week 3 for active and sham treatment groups

	Active rTMS (n=14)				Sham rTMS (n=13)				ANOVA*	ANOVA†
	Baseline	Week 1	Week 2	Week 3	Baseline	Week 1	Week 2	Week 3
HAMD	19.9±6.7	18.8±7.7	14.4±7.5	14.1±6.9	20.8±6.0	20.6±6.4	20.1±5.7	19.3±5.9	F=7.1, df=3, p<0.001	F=3.2, df=3, p=0.028
HAMA	22.8±6.9	20.1±8.1	19.1±13.4	17.2±13.7	26.1±6.7	24.3±6.4	22.0±6.1	21.7±6.5	F=5.8, df=3, p=0.001	NS
BDI	23.7±7.7	22.1±9.7	17.2±7.6	16.7±11.3	26.4±6.9	24.0±7.3	22.2±5.0	21.9±5.2	F=6.2, df=3, p=0.003	NS
CGI-S	4.8±0.7	4.5±1.0	4.0±0.8	3.2±0.9	5.0±0.5	4.9±0.7	4.6±0.6	4.3±0.6	F=18.0, df=3, p<0.001	F=3.5, df=3, p=0.030

Values are mean±standard deviation, unless otherwise indicated.

rTMS, repetitive transcranial magnetic stimulation; HAMD, Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale; BDI, Beck Depression Inventory; CGI-S, Clinical Global Impression-Severity; df, degree of freedom; NS, not significant.

Repeated-measures ANOVA, main effect of time;

repeated-measures ANOVA, group×time interaction.

However, the HAMA and BDI scores reflected only a significant effect of time (p=0.001 and p=0.003, respectively) with no significant group or group×time interaction effects.

An analysis of the percentage reduction in YBOCS scores after rTMS treatment showed that seven patients in the active group (50.0%) and three patients in the sham group (23.1%) were classified as responders (p=0.148). Comparisons between responder and non-responder in the active group showed no significant differences in demographic characteristics, medication, and baseline scores of YBOCS, HAMD, HAMA, BDI, and CGI-S. There were no reports of any serious adverse effects following the rTMS or sham treatments, and the most common complaint following active treatment was localized scalp pain (n=3); however, this did notpersist after the stimulation. Headache was reported by two patients in the active group, but this was resolved spontaneously within a few hours of treatment.

DISCUSSION

The present study investigated the effects of LF rTMS applied over the right DLPFC in patients with treatment-resistant OCD. The 3-week adjunctive rTMS treatment significantly improved the obsessive symptoms of the patients as well as their comorbid depressive symptoms.

The key component of OCD pathophysiology is linked to hyperactivity of the orbitofrontal-subcortical circuit.10,32) It involves dysfunction in structures such as the orbitofrontal cortex, DLPFC, anterior cingulate cortex, and striatum.33,34) Among these structures, the DLPFC is the most accessible site to rTMS stimulation owing to its superficial location.35) The DLPFC is a higher-order brain region that is implicated in executive processes and cognitive control, including the ability to focus thought and flexibly shift that focus according to the environment.36) The DLPFC can be an important gateway for indirect effect on subcortical structure.33) Two effective treatment strategies for OCD such as cognitive behavioral therapy and SSRIs led to a decrease in the hypermetabolism observed in the DLPFC.37) The rTMS stimulation to the DLPFC could possibly normalize orbitofrontal cortex hyperactivity via activation of the inhibitory indirect pathway or via direct connections between the DLPFC and orbitofrontal cortex.38) In healthy subjects, HF rTMS to the DLPFC was found to modulate dopamine release in orbitofrontal cortex and caudate nucleus,39,40) whereas LF rTMS reduced regional blood floor in the orbitofrontal cortex.41)

Neuroimaging studies of OCD have not provided consistent data which suggest hemisphere-dependent functional difference of the DLPFC. Functional magnetic resonance imaging (fMRI) studies generally reported that activation change was found in bilateral DLPFC during symptom provocation task.37,42) Nevertheless, there were also several studies implicating hemispheric asymmetries in OCD.23,24,43) These studies suggested predominantly right-sided changes in cerebral activity correlated with treatment response. A recent rTMS study reported that the stimulation to the bilateral pre-SMA increased right hemisphere resting MT, thereby normalizing baseline motor cortex hyper-excitability.44) On the other hand, the application of rTMS over the DLPFC suggests a rather strong laterality effect. LF rTMS applied over the right DLPFC affects the same parts of cortico-subcortical circuits as does HF rTMS applied over the left side DLPFC.45,46) The laterality effect of prefrontal rTMS is prominent in patients with depression and also observed in healthy subjects and patients with mania.14,47,48) The neurophysiological mechanism of rTMS, particularly the role of stimulation frequency and laterality remain unclear. However, rTMS applied over the DLPFC induced cerebral blood floor changes which were not restricted to the stimulated site, but involved both sides of cortico-subcortical circuits including the bilateral orbitofrontal cortex.41) In this regard, our findings suggest that the right DLPFC might be one of the promising loci of rTMS stimulation for modulating orbitofrontal-subcortical circuit in OCD. The laterality-frequency interaction of the prefrontal rTMS will continue to be an ongoing research challenge in OCD.

Previous open trials of rTMS on OCD have shown that stimulation over the DLPFC is effective to reduce OCD symptoms.15,20) Of the nine randomized sham-controlled trials that have been conducted to date, five applied rTMS to the prefrontal cortex and reported conflicting results regarding the amelioration of OCD symptoms (Table 3).17–19,21,22) These studies found that rTMS either resulted in a significant reduction in the YBOCS scores of both the active and sham groups without producing statistically significant differences between the treatment groups at the study endpoints17–19) or does not result in any therapeutic efficacy for treatment-resistant OCD subjects in either treatment group.21,22) These studies, which all focused on the DLPFC, generally showed that the active rTMS condition was not superior to the sham rTMS condition; however, there are several reasons that these findings may have been inconclusive. For example, the small sample sizes of the studies restrict the generalizability of the results and, moreover, these studies employed a variety of stimulation parameters, application sites, and numbers of sessions. The short treatment durations (generally 2 weeks) may have also been related to the negative results, as previous studies have shown that the main determinants of the efficacy of rTMS include intensity, number of pulses, and number of sessions.49)

Table 3

Controlled trials of repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex for the treatment of obsessive-compulsive disorder

Author, year	Patient (n)	Stimulation site	Frequency (Hz)	MT (%)	Duration (min)	Total sessions	Sham strategy
Alonso et al., 200122)	18	Rt. DLPFC		110	20	18 (6 weeks)	1 Hz rTMS at 20% MT
Prasko et al., 200618)	30	Lt. DLPFC		110	20	10 (2 weeks)	An angle of 90°, with the same parameter with active rTMS
Sachdev et al., 200719)	18	Lt. DLPFC		110	15	10 (2 weeks)	Sham coil
Sarkhel et al., 201021)	42	Rt. DLPFC	10	110	10	10 (2 weeks)	An angle of 45°, using one wing of figure-eight coil, with the same parameter with active rTMS
Mansur et al., 201117)	27	Rt. DLPFC	10	110	20	30 (6 weeks)	Sham coil

MT, motor threshold; Rt., right; Lt., left; DLPFC, dorsolateral prefrontal cortex; rTMS, repetitive transcranial magnetic stimulation.

Of these studies, Alonso et al.22) adopted an approach that was similar to that of the present study, in which LF stimulation was applied over the right DLPFC. The reasons for the discrepancies between the findings of these two studies are unclear but, despite the similarity of the stimulus parameters and application site, several differences in terms of the technical points of these two studies should be noted. First, Alonso et al.22) employed a circular coil, which tends to induce a less focal current than the current induced by a figure-eight shaped coil.50) Second, the sham condition in the Alonso study22) was performed using 1 Hz rTMS at 20% MT, which may have been active and could have interfered with the results from the placebo group. Third, these authors administered rTMS three times per week for 6 weeks and, despite the similar number of total sessions, the longer intervals between rTMS sessions may have influenced the treatment outcomes.16)

The present study had several limitations. First, the small sample size may restrict the generalizability of the results. Second, the lack of a double-blind procedure may have also confounded the results obtained in the placebo group. Third, the DLPFC was located using the “5 cm rule,”51) which does not consider the shape and size of a patients’ head. The use of a MRI-based neuro-navigation system would have improved the precision of the rTMS application. Fourth, the lack of a long-term follow-up period resulted in the absence of information regarding the maintenance of treatment gains following the rTMS procedure. Fifth, there would be considerable variability in neurophysiological response to rTMS among subjects in the current study.52) Besides the genetic factor which decides intrinsic neuronal property,53) medications such as benzodiazepine could also affect the threshold for rTMS by inducing changes in cortical excitability.54) Especially, a long-term use of benzodiazepine was found to be associated with increased motor excitability threshold.54) Although no difference was found in current benzodiazepine usage between active and sham group and between responders and non-responders among active rTMS group, we cannot rule out the possibility of undetectable medication effects considering long illness duration of the patients in the current study. Finally, previous studies have suggested that the reduction in YBOCS scores may not be specific to the anti-obsessional effects induced by rTMS, but that they are related to non-specific antidepressant effects.18,19)

Despite these limitations, the present findings suggest that LF rTMS applied over the right DLPFC may be a stimulation protocol that effectively treats patients with OCD. Further studies should be conducted to determine the optimal stimulation characteristics for the delivery of rTMS.