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Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
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Case study
Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study Young-Ji Lee a, Bon-Hoon Koo a, Wan-Seok Seo a, Hye-Geum Kim a, Ji-Yean Kim b, Eun-Jin Cheon a,⇑ a b
Department of Psychiatry, Yeungnam University College of Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea Department of Psychology, Yeungnam University College of Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
a r t i c l e
i n f o
Article history: Received 23 March 2017 Accepted 18 June 2017 Available online xxxx Keywords: Obsessive-compulsive disorder Repeated transcranial magnetic stimulation Supplementary motor area
a b s t r a c t Obsessive-compulsive disorder (OCD) is a severely distressing disorder represented by obsessions and compulsions. A significant proportion of OCD patients fail to improve with conventional treatment methods. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as an alternative for OCD treatment. Functional neuroimaging studies indicate that OCD is associated with increased activity in the supplementary motor area (SMA), a region that plays an important role in the pathophysiology of this disorder. In this study, we assessed the efficacy of augmentation with 1 Hz rTMS over the SMA in treatment-resistant OCD patients. The participants received 1 Hz rTMS over the SMA in 20 daily sessions for 4 weeks. We observed significant reduction in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score at the 4th week of the treatment. Reduction in compulsion contributed to the reduction of global Y-BOCS whereas there was no significant reduction in obsession. Clinical global impression-global improvement also showed significant change at the 2nd and 4th week of the treatment. No additional significant changes or significant adverse effects were seen. These findings suggest that 1 Hz rTMS over the SMA can be an efficient and safe add-on therapeutic method in treatment-resistant patients with OCD. Further controlled studies in larger samples are required to confirm the effect of 1 Hz rTMS over the SMA in OCD. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Obsessive-compulsive disorder (OCD) is a severely distressing disorder represented by recurrent intrusive thoughts (obsessions) and repetitive behavior (compulsions). OCD is the 4th most common psychiatric disorder. Despite recent developments in drug and behavioral treatments for OCD, more than 8 weeks are usually needed to obtain maximal therapeutic benefit, and about 40–60% of cases remain refractory to treatment [1]. Although the neurobiology and etiology of OCD remain largely unknown [2], the dominant model focuses on malfunction of the cortico-striato-thalamo circuitry related to deficits in inhibition of irrelevant information and response control [2–4]. Consistent with this model, neurophysiologic and neuroimaging studies suggest that motor and premotor areas are hyperactive in OCD [5– 7]. In particular, the supplementary motor area (SMA) has exten⇑ Corresponding author at: Department of Psychiatry, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea. E-mail address: [email protected] (E.-J. Cheon).
sive connections with regions involved in both cognitive and motor function [8,9] and plays a role in response control [2,3], which is proven to be hyperactive in OCD patients during response inhibition tasks [10]. In the past, severe treatment-resistant OCD was one of the most common psychiatric conditions treated with lesional neurosurgery. Deep brain stimulation (DBS), which is a reversible neuromodulatory surgical intervention, has been used as a treatment option for OCD since 1999 [11,12]. However, non-invasive brain stimulation techniques have been recently in the spotlight because they have less cost and less risk than DBS. Among them, repetitive transcranial magnetic stimulation (rTMS) is a typical technique [13]. rTMS is a noninvasive technique that generates repetitive, brief, and powerful magnetic pulses by stimulating coil applied over the scalp that induces an electric current in the brain. rTMS is affected by parameters such as intensity, frequency, pulse number, and duration [14]. In general, high-frequency (>5 Hz) rTMS promotes cortical excitability [15,16], while low-frequency (1 Hz) rTMS inhibits cortical excitability [17].
http://dx.doi.org/10.1016/j.jocn.2017.06.057 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Y.-J. Lee et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Since 1997, rTMS has been used in treatment-resistant OCD with varying outcomes depending on the frequency and site of stimulation [18,19]. However, rTMS studies targeting the SMA and using low-frequency stimulation showed some efficacy in OCD symptomatology [18–24]. Nevertheless, there were not sufficient evidences to confirm using low-frequency rTMS over the SMA for OCD treatment [18]. In this study, we reassessed the efficacy and safety of augmentation with 1 Hz rTMS over the SMA in treatment-resistant OCD patients, added on previous trials. 2. Materials and methods 2.1. Participants Patients enrolled in this study were adults aged 18 or older, diagnosed with OCD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text-Revised (DSM-IVTR), who were resistant to treatment. Patients with OCD are considered treatment-resistant if they experience residual OCD symptoms more than moderately severe (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score 16) despite treatment with optimal anti-OCD medications [25]. Subjects were recruited from a psychiatric department of the university hospital in South Korea from May 2013 to December 2015. Patients with psychosis, bipolar disorder, brain injury, neurological disorder, metal implants, cardiovascular disease, and pregnancy were excluded from participation. In addition, participants who were absent from the rTMS treatment more than 4 times were discontinued from the study. All participants provided written informed consents. This study was reviewed and approved by the Hospital Institutional Review Board.
psychiatric symptoms mentioned in the safety and clinical application guidelines for the use of TMS [35]. Subjects were rated using Y-BOCS, CGI-GI, BDI, BAI, SCL-90-R, and K-MMSE at baseline, after 2 weeks, and after 4 weeks of rTMS treatment. Adverse effects and compliance were assessed after every rTMS session. 2.4. Statistical analysis All statistical analyses were performed with PASW version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA). Frequency analysis were applied to investigate demographic and clinical data of subjects. Repeated-measures analysis of variance was applied to compare the clinical measures (Y-BOCS, CGI-GI, BDI, BAI, SCL-90-R, and KMMSE) of baseline, 2nd week, and 4th week. Last Observation Carried Forward was applied for missing data. All analyses were conducted with statistical significance level less than 0.05. 3. Results 3.1. Demographics and baseline clinical characteristics Fourteen patients were initially screened. However, five patients were excluded: One patient had been treated for Tourette disorder with rTMS prior to this study and four patients could not comply with the treatment schedule. Tables 1–3 show the characteristics of the participants. 3.2. Outcomes Y-BOCS was used to evaluate three domains: obsession, compulsion, and total. There was a significant decrease in Y-BOCS total, which gradually decreased after the start of rTMS treatment, and in
2.2. Procedure and study design This was a prospective, open-labeled, pilot study. In this study, rTMS was administered with TAMAS (CR Technology, Seongnam, Korea) using a 70 mm, 8 shaped coil. Before every rTMS session, we used a visual determination method [26] to define the resting motor threshold (RMT). The coil was positioned over the SMA, which was targeted using the International 10–20 system. The SMA was determined as the point at 15% of the distance between the inion and nasion anterior to the vertex (Cz). Subjects received 1 Hz, 20 min train (1200 stimuli/day) at 90–100% RMT, once a day, 5 days a week, for 4 weeks, resulting in 20 sessions. The dosage of some medications (SSRIs, antipsychotics, benzodiazepines, and hypnotics) was maintained unchanged from 2 weeks before the study until the end of it. Regarding other medications for extrapyramidal symptoms (e.g. benztropine, propranolol), changes permitted. 2.3. Baseline and follow-up assessments To evaluate severity of the subject’s OCD symptoms, the Korean version of Y-BOCS [27] and the Clinical Global Impression-Global Improvement scale (CGI-GI) [28] were used. Other related psychiatric conditions, such as anxiety and depression, were evaluated using the Korean version of Beck’s Depression Inventory I (BDI) [29,30], the Korean version of Beck’s Anxiety Inventory I (BAI) [31,32], and the Symptom Checklist-90-Revised (SCL-90-R) [33]. The effect of rTMS on cognitive function was evaluated by the Korean Mini-Mental State Examination (K-MMSE) [34]. Adverse effects were assessed by Adverse Events Checklist including symptoms such as convulsions, hearing loss, syncope, local pain, headache, subjective discomfort, cognitive impairment, and acute
Table 1 Demographic and clinical characteristics of the participants. Characteristic
Value
Female/male, (n) Age, year Age of onset, year Duration of illness, year Duration of current episode, month
2/7 30.22 (21–43) 24.33 (15–41) 6.11 (2–12) 35.67 (4–69)
Table 2 Drug treatments across participants. Drugs
No. patients (n = 9)
Escitalopram and paroxetine Escitalopram and quetiapine Escitalopram and paliperidone Escitalopram and fluoxetine Sertraline and risperidone Duloxetine and amisulpride Paroxetine and quetiapine Paroxetine, paliperidone and amisulpride Fluoxetine, risperidone and quetiapine
1 1 1 1 1 1 1 1 1
Table 3 Comorbidities among experimental conditions. Comorbidity
Frequency
Mood unipolar Mood unipolar and Schizoid personality disorder Intermittent explosive disorder and paranoid personality disorder Borderline personality disorder
2 (22.2) 1 (11.1) 1 (11.1) 1 (11.1)
Values are presented as numbers of patients (percentages of the sample).
Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Y.-J. Lee et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 4 Changes of scores from the baseline to the second and fourth week of rTMS treatment. Variable
Baseline
2 weeks
4 weeks
F
p value
YBOCS Total YBOCS-obsession YBOCS-compulsion CGI MMSE
27.00 ± 4.79 12.08 ± 2.07 14.92 ± 3.34 4.38 ± 0.77 28.82 ± 2.44
24.38 ± 6.74 11.25 ± 3.88 13.13 ± 4.73 3.17 ± 0.58* 29.00 ± 1.73
22.44 ± 5.68 10.78 ± 4.35 11.67 ± 4.24 3.23 ± 0.60* 29.71 ± 0.49
.925 .480 4.624 15.323 4.000
.447 .638 .052 .001 .184
Values are presented as mean ± standard deviation. rTMS, repetitive Transcranial Magnetic Stimulation; Y-BOCS, Yale-Brown Obsessive Compulsive Scale; CGI, Clinical Global Impression; MMSE, Mini-Mental State Examination. Statistical values obtained by repeated one-way ANOVA. *p < 0.05.
the 4th week, showing significant change (p < 0.05). Y-BOCS obsession did not show significant change between pre- and post-rTMS treatment. However, Y-BOCS compulsion showed significant decrease at the 4th week (p < 0.05) (Table 4, Fig. 1). CGI-GI was significantly improved from 2 weeks to 4 weeks after rTMS treatment (p < 0.05) (Table 4, Fig. 2). BDI, BAI, SCL-90-R, and K-MMSE did not show significant changes (Table 5). 3.3. Safety In this study, two patients reported adverse events. The events were mild headache and mild dizziness 3 days after starting the treatment. They all disappeared naturally. 4. Discussion In this present small, open-label exploratory study, symptoms in treatment-resistant OCD patients significantly decreased after 20 sessions of 1 Hz rTMS over the SMA without cognitive decline or severe adverse effects.
30
YBOCS-Obsession
YBOCS-Compulsion
25 20
14.92
13.13
11.67
12.08
11.25
10.78
baseline
2 weeks
4 weeks
15 10 5 0
Fig. 1. The changes of mean scores on Y-BOCS from the baseline to the second and fourth week of the rTMS treatment. Y-BOCS, Yale-Brown Obsessive Compulsive Scale; rTMS, repetitive transcranial magnetic stimulation. *p < 0.05.
5
4.38
4
3.17*
3.23*
2 weeks
4 weeks
3 2 1 0
baseline
Fig. 2. Changes in CGI from the baseline to the second and fourth week of the rTMS treatment. CGI, Clinical Global Impression; rTMS, repetitive Transcranial Magnetic Stimulation. *p < 0.05.
Until now, there have been several studies using rTMS in treatment-resistant OCD. Among them, studies targeting the dorsolateral prefrontal cortex have shown mixed results. However, six studies targeting the SMA and using low-frequency stimulation showed consistently effective results about OCD symptoms [18– 24]. These results are consistent with our finding, which suggests that 1 Hz rTMS over the SMA may be an efficient method as an add-on therapy in treatment-resistant patients with OCD. However, although some previous studies have shown that normalization of hyperactivity in the SMA may be directly related to clinical improvement in patients with OCD [10,22,23], the mechanism by which neuromodulation of the SMA through rTMS acts on neural patterns in correlation with the course of the symptoms is still unclear [18]. Therefore, neuroimaging and neurophysiologic studies may be needed to investigate neuronal actions of low frequency rTMS over the SMA. For clarity, it is important to conceptualize obsessions as thoughts and compulsions as behavior [1]. In this study, the improvement of Y-BOCS score was mainly due to the improvement in the compulsions, while obsessions did not show significant decrease. In 1997, Greenberg et al. [36] found that a single session of high-frequency rTMS over the right lateral prefrontal cortex significantly decreased compulsive urges, but obsessions seemed unaffected. In 2003, Nuttin et al. [37] performed bilateral anterior capsular DBS in six patients with severe OCD. The authors found significant reduction in both obsessions and compulsions; however, further details about the relative degree of improvement in each of these components were not provided [11]. In 2003, both electrical stimulation and lesion in the nucleus accumbens in a rodent model of OCD resulted in reduced spontaneous alternative behavior (which reflects compulsions) [38]. However, this study differs from our study in treatment techniques. Until now, there is no report distinguishing changes in compulsion and obsession in studies using rTMS over the SMA. Further studies addressing this distinction will be needed. Studies in primates have shown networks linking the SMA to cortical, thalamic, and basal ganglia neurons [39,40]. A neuroimaging study suggested that the SMA is hyperactive in OCD patients and this hyperactivity might relate to deficient inhibitory control of behavior [5]. Therefore, the SMA can be an attractive target for modulating subcortical regions and influencing OCD symptoms, especially in compulsive behaviors. Except for OCD symptoms decrease, this study showed no significant anti-depressant and/or anxiolytic effects. This result is not consistent with the results of most rTMS trials. The difference may occur because the SMA is not a region typically involved in depression circuitry [41]. Even so, for our result, 1 Hz rTMS over the SMA seems to be specific for OCD symptoms. Further studies including depressive patients will be needed to allow more definite conclusions.
Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Y.-J. Lee et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Table 5 Additional changes of scales from the baseline to the second and 4th week of rTMS treatment. Variable
Baseline
2 weeks
4 weeks
F
p value
BDI BAI SCL-90R Somatization Obsessive-compulsive Interpersonalsensitivity Depression Anxiety Hostility Phobic anxiety Paranoid ideation Psychoticism General Severity Index Positive symptomdistress level Positive symptom total
19.45 ± 9.03 16.36 ± 9.42
22.75 ± 9.00 16.00 ± 11.40
18.78 ± 10.28 10.78 ± 9.13
.953 .818
.430 .231
0.53 ± 0.44 1.79 ± 0.81 1.50 ± 0.97 1.53 ± 0.80 1.17 ± 0.72 0.91 ± 0.82 0.83 ± 0.66 1.10 ± 1.01 1.28 ± 0.80 1.22 ± 0.69 55.45 ± 16.14 1.79 ± 0.80
0.37 ± 0.39 1.76 ± 0.54 1.49 ± 1.04 1.39 ± 0.57 1.00 ± 0.46 0.63 ± 0.65 0.71 ± 0.64 1.17 ± 0.63 0.98 ± 0.58 1.06 ± 0.55 52.40 ± 19.03 1.80 ± 0.45
0.46 ± 0.48 1.43 ± 0.82 1.25 ± 0.81 1.36 ± 0.81 0.98 ± 0.52 0.67 ± 0.66 0.85 ± 0.65 1.06 ± 0.67 1.03 ± 0.73 1.07 ± 0.57 51.11 ± 22.06 1.82 ± 0.55
.143 .246 2.603 1.251 .006 4.103 .936 1.393 .473 .227 .375 1.293
.871 .793 .189 .379 .994 .107 .464 .347 .654 .806 .709 .369
Values are presented as mean ± standard deviation. rTMS, repetitive Transcranial Magnetic Stimulation; BDI, Beck’s Depression Inventory I–Korean version; BAI, Beck’s Anxiety Inventory I–Korean version; SCL-90R, Symptom Checklist-90-Revised. Statistical value obtained by repeated one-way ANOVA.
In this study, headache and dizziness were observed as potential side effects related to rTMS, and they disappeared spontaneously within 1–2 days. There were no serious side effects such as seizures, acute psychiatric symptoms, and no changes in cognitive functioning. Our results are consistent with most previous rTMS studies [21], confirming that rTMS over the SMA can be considered safe and well tolerated. However, this study has several limitations. It consists in an open design with a small sample size and no control group. So, it is difficult to rule out the placebo effect and generalize the results of the study. Nevertheless, OCD has been reported to have low rate of placebo response rate compared with other mental diseases [42,43]. Patients participating in this study had relatively long medication-resistant conditions, so this study may be presumed to have lesser placebo response. Another limitation is the allowance of concomitant medications. Although we held the patients at the same doses for 2 weeks prior to study entry and throughout it, we cannot exclude the possibility of a synergistic effect between rTMS and the medications. Additional studies with drug-free patients will be needed to clarify this aspect. Despite these limitations, the results of this study should be considered tentative because we reaffirmed the efficacy and safety of augmentation with 1 Hz rTMS over the SMA in treatment-resistant OCD patients, consistent with previous studies targeting the SMA. In the future, additional investigations involving double-blind controlled, long-term follow-up and large samples can further extend the present study’s findings. Conflicts of interest and source of funding None declared. This research was supported by the 2014 Yeungnam University Research Grant. References [1] Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Synopsis of Psychiatry: Behavioral Sciences/clinical Psychiatry: Lippincott Williams & Wilkins; 2014. [2] Chamberlain SR, Blackwell AD, Fineberg NA, et al. The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci Biobehav Rev 2005;29:399–419. [3] van den Heuvel OA, Veltman DJ, Groenewegen HJ, et al. Frontal-striatal dysfunction during planning in obsessive-compulsive disorder. Arch Gen Psychiatry 2005;62:301–9. [4] Saxena S, Brody AL, Schwartz JM, et al. Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998:26–37.
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Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Case study
Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study Young-Ji Lee a, Bon-Hoon Koo a, Wan-Seok Seo a, Hye-Geum Kim a, Ji-Yean Kim b, Eun-Jin Cheon a,⇑ a b
Department of Psychiatry, Yeungnam University College of Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea Department of Psychology, Yeungnam University College of Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
a r t i c l e
i n f o
Article history: Received 23 March 2017 Accepted 18 June 2017 Available online xxxx Keywords: Obsessive-compulsive disorder Repeated transcranial magnetic stimulation Supplementary motor area
a b s t r a c t Obsessive-compulsive disorder (OCD) is a severely distressing disorder represented by obsessions and compulsions. A significant proportion of OCD patients fail to improve with conventional treatment methods. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as an alternative for OCD treatment. Functional neuroimaging studies indicate that OCD is associated with increased activity in the supplementary motor area (SMA), a region that plays an important role in the pathophysiology of this disorder. In this study, we assessed the efficacy of augmentation with 1 Hz rTMS over the SMA in treatment-resistant OCD patients. The participants received 1 Hz rTMS over the SMA in 20 daily sessions for 4 weeks. We observed significant reduction in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score at the 4th week of the treatment. Reduction in compulsion contributed to the reduction of global Y-BOCS whereas there was no significant reduction in obsession. Clinical global impression-global improvement also showed significant change at the 2nd and 4th week of the treatment. No additional significant changes or significant adverse effects were seen. These findings suggest that 1 Hz rTMS over the SMA can be an efficient and safe add-on therapeutic method in treatment-resistant patients with OCD. Further controlled studies in larger samples are required to confirm the effect of 1 Hz rTMS over the SMA in OCD. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Obsessive-compulsive disorder (OCD) is a severely distressing disorder represented by recurrent intrusive thoughts (obsessions) and repetitive behavior (compulsions). OCD is the 4th most common psychiatric disorder. Despite recent developments in drug and behavioral treatments for OCD, more than 8 weeks are usually needed to obtain maximal therapeutic benefit, and about 40–60% of cases remain refractory to treatment [1]. Although the neurobiology and etiology of OCD remain largely unknown [2], the dominant model focuses on malfunction of the cortico-striato-thalamo circuitry related to deficits in inhibition of irrelevant information and response control [2–4]. Consistent with this model, neurophysiologic and neuroimaging studies suggest that motor and premotor areas are hyperactive in OCD [5– 7]. In particular, the supplementary motor area (SMA) has exten⇑ Corresponding author at: Department of Psychiatry, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea. E-mail address: [email protected] (E.-J. Cheon).
sive connections with regions involved in both cognitive and motor function [8,9] and plays a role in response control [2,3], which is proven to be hyperactive in OCD patients during response inhibition tasks [10]. In the past, severe treatment-resistant OCD was one of the most common psychiatric conditions treated with lesional neurosurgery. Deep brain stimulation (DBS), which is a reversible neuromodulatory surgical intervention, has been used as a treatment option for OCD since 1999 [11,12]. However, non-invasive brain stimulation techniques have been recently in the spotlight because they have less cost and less risk than DBS. Among them, repetitive transcranial magnetic stimulation (rTMS) is a typical technique [13]. rTMS is a noninvasive technique that generates repetitive, brief, and powerful magnetic pulses by stimulating coil applied over the scalp that induces an electric current in the brain. rTMS is affected by parameters such as intensity, frequency, pulse number, and duration [14]. In general, high-frequency (>5 Hz) rTMS promotes cortical excitability [15,16], while low-frequency (1 Hz) rTMS inhibits cortical excitability [17].
http://dx.doi.org/10.1016/j.jocn.2017.06.057 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Y.-J. Lee et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Since 1997, rTMS has been used in treatment-resistant OCD with varying outcomes depending on the frequency and site of stimulation [18,19]. However, rTMS studies targeting the SMA and using low-frequency stimulation showed some efficacy in OCD symptomatology [18–24]. Nevertheless, there were not sufficient evidences to confirm using low-frequency rTMS over the SMA for OCD treatment [18]. In this study, we reassessed the efficacy and safety of augmentation with 1 Hz rTMS over the SMA in treatment-resistant OCD patients, added on previous trials. 2. Materials and methods 2.1. Participants Patients enrolled in this study were adults aged 18 or older, diagnosed with OCD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text-Revised (DSM-IVTR), who were resistant to treatment. Patients with OCD are considered treatment-resistant if they experience residual OCD symptoms more than moderately severe (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score 16) despite treatment with optimal anti-OCD medications [25]. Subjects were recruited from a psychiatric department of the university hospital in South Korea from May 2013 to December 2015. Patients with psychosis, bipolar disorder, brain injury, neurological disorder, metal implants, cardiovascular disease, and pregnancy were excluded from participation. In addition, participants who were absent from the rTMS treatment more than 4 times were discontinued from the study. All participants provided written informed consents. This study was reviewed and approved by the Hospital Institutional Review Board.
psychiatric symptoms mentioned in the safety and clinical application guidelines for the use of TMS [35]. Subjects were rated using Y-BOCS, CGI-GI, BDI, BAI, SCL-90-R, and K-MMSE at baseline, after 2 weeks, and after 4 weeks of rTMS treatment. Adverse effects and compliance were assessed after every rTMS session. 2.4. Statistical analysis All statistical analyses were performed with PASW version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA). Frequency analysis were applied to investigate demographic and clinical data of subjects. Repeated-measures analysis of variance was applied to compare the clinical measures (Y-BOCS, CGI-GI, BDI, BAI, SCL-90-R, and KMMSE) of baseline, 2nd week, and 4th week. Last Observation Carried Forward was applied for missing data. All analyses were conducted with statistical significance level less than 0.05. 3. Results 3.1. Demographics and baseline clinical characteristics Fourteen patients were initially screened. However, five patients were excluded: One patient had been treated for Tourette disorder with rTMS prior to this study and four patients could not comply with the treatment schedule. Tables 1–3 show the characteristics of the participants. 3.2. Outcomes Y-BOCS was used to evaluate three domains: obsession, compulsion, and total. There was a significant decrease in Y-BOCS total, which gradually decreased after the start of rTMS treatment, and in
2.2. Procedure and study design This was a prospective, open-labeled, pilot study. In this study, rTMS was administered with TAMAS (CR Technology, Seongnam, Korea) using a 70 mm, 8 shaped coil. Before every rTMS session, we used a visual determination method [26] to define the resting motor threshold (RMT). The coil was positioned over the SMA, which was targeted using the International 10–20 system. The SMA was determined as the point at 15% of the distance between the inion and nasion anterior to the vertex (Cz). Subjects received 1 Hz, 20 min train (1200 stimuli/day) at 90–100% RMT, once a day, 5 days a week, for 4 weeks, resulting in 20 sessions. The dosage of some medications (SSRIs, antipsychotics, benzodiazepines, and hypnotics) was maintained unchanged from 2 weeks before the study until the end of it. Regarding other medications for extrapyramidal symptoms (e.g. benztropine, propranolol), changes permitted. 2.3. Baseline and follow-up assessments To evaluate severity of the subject’s OCD symptoms, the Korean version of Y-BOCS [27] and the Clinical Global Impression-Global Improvement scale (CGI-GI) [28] were used. Other related psychiatric conditions, such as anxiety and depression, were evaluated using the Korean version of Beck’s Depression Inventory I (BDI) [29,30], the Korean version of Beck’s Anxiety Inventory I (BAI) [31,32], and the Symptom Checklist-90-Revised (SCL-90-R) [33]. The effect of rTMS on cognitive function was evaluated by the Korean Mini-Mental State Examination (K-MMSE) [34]. Adverse effects were assessed by Adverse Events Checklist including symptoms such as convulsions, hearing loss, syncope, local pain, headache, subjective discomfort, cognitive impairment, and acute
Table 1 Demographic and clinical characteristics of the participants. Characteristic
Value
Female/male, (n) Age, year Age of onset, year Duration of illness, year Duration of current episode, month
2/7 30.22 (21–43) 24.33 (15–41) 6.11 (2–12) 35.67 (4–69)
Table 2 Drug treatments across participants. Drugs
No. patients (n = 9)
Escitalopram and paroxetine Escitalopram and quetiapine Escitalopram and paliperidone Escitalopram and fluoxetine Sertraline and risperidone Duloxetine and amisulpride Paroxetine and quetiapine Paroxetine, paliperidone and amisulpride Fluoxetine, risperidone and quetiapine
1 1 1 1 1 1 1 1 1
Table 3 Comorbidities among experimental conditions. Comorbidity
Frequency
Mood unipolar Mood unipolar and Schizoid personality disorder Intermittent explosive disorder and paranoid personality disorder Borderline personality disorder
2 (22.2) 1 (11.1) 1 (11.1) 1 (11.1)
Values are presented as numbers of patients (percentages of the sample).
Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Y.-J. Lee et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 4 Changes of scores from the baseline to the second and fourth week of rTMS treatment. Variable
Baseline
2 weeks
4 weeks
F
p value
YBOCS Total YBOCS-obsession YBOCS-compulsion CGI MMSE
27.00 ± 4.79 12.08 ± 2.07 14.92 ± 3.34 4.38 ± 0.77 28.82 ± 2.44
24.38 ± 6.74 11.25 ± 3.88 13.13 ± 4.73 3.17 ± 0.58* 29.00 ± 1.73
22.44 ± 5.68 10.78 ± 4.35 11.67 ± 4.24 3.23 ± 0.60* 29.71 ± 0.49
.925 .480 4.624 15.323 4.000
.447 .638 .052 .001 .184
Values are presented as mean ± standard deviation. rTMS, repetitive Transcranial Magnetic Stimulation; Y-BOCS, Yale-Brown Obsessive Compulsive Scale; CGI, Clinical Global Impression; MMSE, Mini-Mental State Examination. Statistical values obtained by repeated one-way ANOVA. *p < 0.05.
the 4th week, showing significant change (p < 0.05). Y-BOCS obsession did not show significant change between pre- and post-rTMS treatment. However, Y-BOCS compulsion showed significant decrease at the 4th week (p < 0.05) (Table 4, Fig. 1). CGI-GI was significantly improved from 2 weeks to 4 weeks after rTMS treatment (p < 0.05) (Table 4, Fig. 2). BDI, BAI, SCL-90-R, and K-MMSE did not show significant changes (Table 5). 3.3. Safety In this study, two patients reported adverse events. The events were mild headache and mild dizziness 3 days after starting the treatment. They all disappeared naturally. 4. Discussion In this present small, open-label exploratory study, symptoms in treatment-resistant OCD patients significantly decreased after 20 sessions of 1 Hz rTMS over the SMA without cognitive decline or severe adverse effects.
30
YBOCS-Obsession
YBOCS-Compulsion
25 20
14.92
13.13
11.67
12.08
11.25
10.78
baseline
2 weeks
4 weeks
15 10 5 0
Fig. 1. The changes of mean scores on Y-BOCS from the baseline to the second and fourth week of the rTMS treatment. Y-BOCS, Yale-Brown Obsessive Compulsive Scale; rTMS, repetitive transcranial magnetic stimulation. *p < 0.05.
5
4.38
4
3.17*
3.23*
2 weeks
4 weeks
3 2 1 0
baseline
Fig. 2. Changes in CGI from the baseline to the second and fourth week of the rTMS treatment. CGI, Clinical Global Impression; rTMS, repetitive Transcranial Magnetic Stimulation. *p < 0.05.
Until now, there have been several studies using rTMS in treatment-resistant OCD. Among them, studies targeting the dorsolateral prefrontal cortex have shown mixed results. However, six studies targeting the SMA and using low-frequency stimulation showed consistently effective results about OCD symptoms [18– 24]. These results are consistent with our finding, which suggests that 1 Hz rTMS over the SMA may be an efficient method as an add-on therapy in treatment-resistant patients with OCD. However, although some previous studies have shown that normalization of hyperactivity in the SMA may be directly related to clinical improvement in patients with OCD [10,22,23], the mechanism by which neuromodulation of the SMA through rTMS acts on neural patterns in correlation with the course of the symptoms is still unclear [18]. Therefore, neuroimaging and neurophysiologic studies may be needed to investigate neuronal actions of low frequency rTMS over the SMA. For clarity, it is important to conceptualize obsessions as thoughts and compulsions as behavior [1]. In this study, the improvement of Y-BOCS score was mainly due to the improvement in the compulsions, while obsessions did not show significant decrease. In 1997, Greenberg et al. [36] found that a single session of high-frequency rTMS over the right lateral prefrontal cortex significantly decreased compulsive urges, but obsessions seemed unaffected. In 2003, Nuttin et al. [37] performed bilateral anterior capsular DBS in six patients with severe OCD. The authors found significant reduction in both obsessions and compulsions; however, further details about the relative degree of improvement in each of these components were not provided [11]. In 2003, both electrical stimulation and lesion in the nucleus accumbens in a rodent model of OCD resulted in reduced spontaneous alternative behavior (which reflects compulsions) [38]. However, this study differs from our study in treatment techniques. Until now, there is no report distinguishing changes in compulsion and obsession in studies using rTMS over the SMA. Further studies addressing this distinction will be needed. Studies in primates have shown networks linking the SMA to cortical, thalamic, and basal ganglia neurons [39,40]. A neuroimaging study suggested that the SMA is hyperactive in OCD patients and this hyperactivity might relate to deficient inhibitory control of behavior [5]. Therefore, the SMA can be an attractive target for modulating subcortical regions and influencing OCD symptoms, especially in compulsive behaviors. Except for OCD symptoms decrease, this study showed no significant anti-depressant and/or anxiolytic effects. This result is not consistent with the results of most rTMS trials. The difference may occur because the SMA is not a region typically involved in depression circuitry [41]. Even so, for our result, 1 Hz rTMS over the SMA seems to be specific for OCD symptoms. Further studies including depressive patients will be needed to allow more definite conclusions.
Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057
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Y.-J. Lee et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Table 5 Additional changes of scales from the baseline to the second and 4th week of rTMS treatment. Variable
Baseline
2 weeks
4 weeks
F
p value
BDI BAI SCL-90R Somatization Obsessive-compulsive Interpersonalsensitivity Depression Anxiety Hostility Phobic anxiety Paranoid ideation Psychoticism General Severity Index Positive symptomdistress level Positive symptom total
19.45 ± 9.03 16.36 ± 9.42
22.75 ± 9.00 16.00 ± 11.40
18.78 ± 10.28 10.78 ± 9.13
.953 .818
.430 .231
0.53 ± 0.44 1.79 ± 0.81 1.50 ± 0.97 1.53 ± 0.80 1.17 ± 0.72 0.91 ± 0.82 0.83 ± 0.66 1.10 ± 1.01 1.28 ± 0.80 1.22 ± 0.69 55.45 ± 16.14 1.79 ± 0.80
0.37 ± 0.39 1.76 ± 0.54 1.49 ± 1.04 1.39 ± 0.57 1.00 ± 0.46 0.63 ± 0.65 0.71 ± 0.64 1.17 ± 0.63 0.98 ± 0.58 1.06 ± 0.55 52.40 ± 19.03 1.80 ± 0.45
0.46 ± 0.48 1.43 ± 0.82 1.25 ± 0.81 1.36 ± 0.81 0.98 ± 0.52 0.67 ± 0.66 0.85 ± 0.65 1.06 ± 0.67 1.03 ± 0.73 1.07 ± 0.57 51.11 ± 22.06 1.82 ± 0.55
.143 .246 2.603 1.251 .006 4.103 .936 1.393 .473 .227 .375 1.293
.871 .793 .189 .379 .994 .107 .464 .347 .654 .806 .709 .369
Values are presented as mean ± standard deviation. rTMS, repetitive Transcranial Magnetic Stimulation; BDI, Beck’s Depression Inventory I–Korean version; BAI, Beck’s Anxiety Inventory I–Korean version; SCL-90R, Symptom Checklist-90-Revised. Statistical value obtained by repeated one-way ANOVA.
In this study, headache and dizziness were observed as potential side effects related to rTMS, and they disappeared spontaneously within 1–2 days. There were no serious side effects such as seizures, acute psychiatric symptoms, and no changes in cognitive functioning. Our results are consistent with most previous rTMS studies [21], confirming that rTMS over the SMA can be considered safe and well tolerated. However, this study has several limitations. It consists in an open design with a small sample size and no control group. So, it is difficult to rule out the placebo effect and generalize the results of the study. Nevertheless, OCD has been reported to have low rate of placebo response rate compared with other mental diseases [42,43]. Patients participating in this study had relatively long medication-resistant conditions, so this study may be presumed to have lesser placebo response. Another limitation is the allowance of concomitant medications. Although we held the patients at the same doses for 2 weeks prior to study entry and throughout it, we cannot exclude the possibility of a synergistic effect between rTMS and the medications. Additional studies with drug-free patients will be needed to clarify this aspect. Despite these limitations, the results of this study should be considered tentative because we reaffirmed the efficacy and safety of augmentation with 1 Hz rTMS over the SMA in treatment-resistant OCD patients, consistent with previous studies targeting the SMA. In the future, additional investigations involving double-blind controlled, long-term follow-up and large samples can further extend the present study’s findings. Conflicts of interest and source of funding None declared. This research was supported by the 2014 Yeungnam University Research Grant. References [1] Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Synopsis of Psychiatry: Behavioral Sciences/clinical Psychiatry: Lippincott Williams & Wilkins; 2014. [2] Chamberlain SR, Blackwell AD, Fineberg NA, et al. The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci Biobehav Rev 2005;29:399–419. [3] van den Heuvel OA, Veltman DJ, Groenewegen HJ, et al. Frontal-striatal dysfunction during planning in obsessive-compulsive disorder. Arch Gen Psychiatry 2005;62:301–9. [4] Saxena S, Brody AL, Schwartz JM, et al. Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998:26–37.
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Please cite this article in press as: Lee Y-J et al. Repetitive transcranial magnetic stimulation of the supplementary motor area in treatment-resistant obsessive-compulsive disorder: An open–label pilot study. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.057