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A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine
Psychiatry Research 188 (2011) 203–207
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine Danilo Rocha de Jesus a,⁎, Alexei Gil a, Leonardo Barbosa a, Maria Inês Lobato a, Pedro Vieira da Silva Magalhães a, Gabriela Pereira de Souza Favalli a, Marco Antonio Marcolin b, Zafiris Jeffrey Daskalakis c, Paulo da Silva Belmonte-de-Abreu a a b c
Department of Psychiatry, Federal University of Rio Grande do Sul-RS, Brazil Institute of Psychiatry, University of Sao Paulo, Faculty of Medicine, Sao Paulo-SP, Brazil Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
a r t i c l e
i n f o
Article history: Received 20 May 2010 Received in revised form 17 November 2010 Accepted 17 November 2010 Keywords: Auditory hallucinations rTMS Clinical Trial General psychopathology Quality of life
a b s t r a c t Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50–70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Schizophrenia is a complex and heterogeneous psychiatric disorder. It is known that about 30% of the patients with schizophrenia do not respond adequately to pharmacological treatment. In this context, refractory criteria were developed. The Schizophrenia Algorithm of the International Psychopharmacology Algorithm Project (IPAP) defines that a patient is considered to be refractory if he or she failed to respond to two trials of 4 to 6 weeks' duration of monotherapy with two different second generation antipsychotics (SGAs) (or two trials with a first generation antipsychotic (FGA), if SGAs are not available). For these patients, treatment with clozapine may be considered. Auditory hallucinations (AHs) of spoken speech occur in 50–70% of patients with schizophrenia and often produce high levels of distress and functional disability. It is known that 25% of these patients suffer ⁎ Corresponding author. Postal address: 19 Princess Street, Toronto, Ontario, Canada, Zip code: M5A 4C8. Tel.: + 1 647 860 7227. E-mail address: [email protected] (D.R. de Jesus). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.11.022
from refractory AHs (Shergill et al., 1998). Neuroimaging studies suggest that activation of brain regions underlying speech perception play a role in producing AHs (Dierks et al., 1999; Shergill et al., 2000; Suzuki et al., 1993; Silbersweig et al., 1995; Lennox et al., 2000; Woodruff et al., 1994, 1997). Low frequency repetitive transcranial magnetic stimulation (e.g., 1 Hz rTMS) has been shown to reduce excitability of the cortex (Chen et al., 1997). Therefore, when applied to the left temporoparietal cortex (LTPC), it may reduce the excitability of this area, which is critical to speech perception (Fiez et al., 1996) and has been implicated in the genesis of AHs (Silbersweig et al., 1995; Lennox et al., 2000). In animal studies, 1 Hz rTMS can produce similar effects to long-term depression, and they can last many weeks (Post et al., 1999; for review see Hoffman and Cavus, 2002). Previous studies have shown that 1 Hz rTMS applied to the LTPC can reduce the severity of the AHs (Hoffman et al., 2000, 2005; Rosa et al., 2007; Poulet et al., 2005; Fitzgerald et al., 2005; Vercammen et al., 2009). A recent review conducted by Fitzgerald and Daskalakis (2008) found that rTMS may be able to substantially reduce the experience of auditory hallucinations in patients for whom symptoms persist despite optimal medication
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treatment. Vercammen et al. (2009) conducted a study in which 38 patients with schizophrenia suffering from frequent medicationresistant AHs were randomly allocated to receive left-sided rTMS, bilateral rTMS or sham. They found that compared to bilateral or sham stimulation, rTMS of the left temporoparietal region appears most effective in reducing auditory hallucinations, and additionally may have an effect on general psychopathology. Rosa et al. (2007) conducted a double-masked, sham-controlled, parallel design study comparing 1 Hz rTMS applied to the LTPC to sham stimulation in association with clozapine treatment. Eleven patients were enrolled. Rosa et al. concluded that active rTMS in association with clozapine can be administered safely to treat auditory hallucinations, although its clinical utility was considered questionable. That is, no significant clinical effects were observed in the sample studied, possibly because of the small sample and/or due to the high degree of refractoriness in the patients. The purpose of this study was to examine the effects of 1 Hz rTMS applied to the LTPC in a larger sample size (n = 17) of clozapinetreated patients with refractory schizophrenia (RS) using an extended rTMS protocol. Moreover, we also examined general psychopathology severity, quality of life and functionality in these patients, as rTMS may have both regional and distant cortical effects as a result of interhemispheric transsynaptic signal propagation (Ilmoniemi et al., 1997) that may translate into a broad improvement in psychotic symptoms. 2. Methods 2.1. Subjects Patients met diagnostic criteria for schizophrenia (using OPCRIT 4.0) and were considered as having RS, with daily AHs occurring at least five times per day despite treatment with a stable dose of at least 400 mg/day of clozapine for a period longer than 4 months and at least two adequate trials of antipsychotic medications in the past, including at least one atypical antipsychotic drug other than clozapine. Subjects were all right-handed (self-reported), men and women from 18 to 65 years old, with a Brief Psychiatric Rating Scale (BPRS) score of at least 27. Women in fertile age must have been using an appropriate contraceptive method. Exclusion criteria included suicide risk, pregnancy, prior history of seizures, neurosurgery or head trauma, use of pacemaker or intracranial metallic clip, neurological disease, significant unstable medical condition, estimated IQ ≤ 80, current alcohol or drug abuse, or inability to provide informed consent. A total of 17 patients were enrolled. All patients were naive to rTMS treatments. The study protocol was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre. A signed, informed consent was obtained from every patient. At baseline, the two groups were similar in terms of gender, income, number of psychiatric hospitalizations, age of onset of auditory hallucinations, dosage of clozapine, BPRS, FAST, Quality of Life Scale, Auditory Hallucinations Rating Scale, and Clinical Global Impressions scores. 2.2. rTMS protocol Patients were randomly allocated to rTMS and sham groups. Randomization was made by Sequentially-Numbered, Opaque, Sealed Envelopes (SNOSE). The two groups were similar in terms of age, gender and BPRS scores. The study used a doubled-masked, parallel design. Study participants, clinical raters, and all personnel responsible for the clinical care of the patient remained masked to allocated condition and allocation parameters. A Neurosoft Neuro-MS (Neurosoft Ltd, Russia) and figure-8 coil were utilized in the rTMS sessions. Stimulation was administered at an intensity of 90% of the motor threshold, which was ascertained prior to the first session of each week. Motor threshold (MT) was based on visualization of trace motor movements in 5/10 tries when stimulating primary motor cortex. This method has been reported to be as sensitive as EMG-based methods of detecting MT (Pridmore et al., 1998). Active stimulation was administered to the LTPC, exactly halfway between the left temporal (T3) and left parietal (P3) sites according to the International 10–20 EEG electrode position system. Stimulation frequency was 1 Hz while subjects were lying down on a bed. There was no break in the stimulation trains. Sham stimulation was administered using the same coil, applied 5 cm lateral to F3, perpendicular to the parasagittal plane, above the left temporal muscle. In this position the coil–cortex distance is essentially larger (more than 3 cm v. 1–1.5 cm) compared to F3, and the electromagnetic field reaching the cortex was therefore substantially weaker. To avoid the possible effectiveness of the sham stimulation, the coil was angled at 45°, touching the skull not with the centre but with the rim opposite the handle, and the stimulation intensity was reduced to 80% of MT (Herwig et al., 2007). This form of sham stimulation had the effect of inducing local sensations above the temporal muscle similar to the disturbances caused by the real stimulation (Praeg et al., 2005). Clozapine use was continued during the trial, without dose changes. Patients received
8 min of active/sham stimulation on day I, 16 min on day II, and 20 min for the next 18 days, making a total of 20 sessions, 5 sessions/week (Monday through Friday) for 4 weeks. After the completion of the study, patients randomized to the sham condition were offered active rTMS utilizing the same parameters as the masked phase of the trial. 2.3. Clinical Measures The 18-item Brief Psychiatric Rating Scale (BPRS) was used as the primary outcome variable and to assess positive and negative symptoms, as well as conceptual disorganization and general psychopathology. It is a psychopathological assessment scale composed of 18 items which have been extensively used in the assessment of patients with schizophrenia. It has also been used in the assessment of the therapeutic response to antipsychotics by Kane et al., and in the development of criteria for refractory schizophrenia (Alves et al., 2005). Using the 18-item BPRS factor analysis proposed by Alves et al (2005) for patients with refractory schizophrenia, we analyzed scores of the two groups on each of the four factors, namely: Negative/Disorganization, composed of emotional withdrawal, disorientation, blunted affect, mannerisms/posturing and conceptual disorganization; Excitement, composed of excitement, hostility, tension, grandiosity, and uncooperativeness, grouped variables that evoke brain excitement or a manic-like syndrome; Positive, composed of unusual thought content, suspiciousness, and hallucinatory behavior; and Depressive, composed of depressive mood, guilt feelings, and motor retardation, clearly related to a depressive syndrome. AHs are known to have a negative impact on the quality of life of the patients with schizophrenia (Van de Willige et al., 2005). To measure the effect of change in AHs scores on the quality of life, the Quality of Life Scale (QLS, Heinrichs et al., 1984) was used. The tool is a 21-item scale completed by clinically trained staff after a semi-structured interview and chart review that assesses quality of life. Items are scored on a 7-point scale with higher ratings representing higher levels of satisfaction. The Clinical Global Impressions (CGI) scale was used to assess overall clinical improvement. A 7-item Auditory Hallucinations Rating Scale (AHRS) was used to assess hallucination frequency, number of distinct speaking voices, perceived loudness, vividness, attentional salience, length of hallucinations (single words, phrases, sentences, or extended discourse), and degree of distress. The FAST scale was used to assess functionality. It consists of 24 items, grouped in six specific areas of functionality: autonomy, work, cognitive functioning, finances, interpersonal relationships and leisure. The higher the score, the worse is the patient´s functionality. All scales were ascertained at baseline, day 7, day 14, day 21, day 28 and day 60. The later assessment happened 30 days after the last active/placebo rTMS session, 60 days from baseline. All clinical assessments were undertaken by a psychiatrist from the Schizophrenia program of Hospital de Clinicas de Porto Alegre and a third-year resident of Psychiatry, both well trained in the scales that were used in this study. Also, the senior author discussed and reviewed all scores with the raters. 2.4. Statistical analysis Scores from rating scales were analyzed from week 0 to 8 as continuous data. MannWhitney's U test was used to test for group differences in score changes from baseline to endpoint. To evaluate within-group changes, Wilcoxon's signed-rank test was used. We also used multivariate repeated measures analysis of variance (ANOVA) to test group differences in trajectory changes. This approach is useful as it is not constrained by sphericity, unlike the traditional repeated measures ANOVA. All tests are two-tailed.
3. Results Demographic data and BPRS, QLS, FAST, AHRS and CGI scores at baseline are shown in Table 1. Changes in BPRS scores from baseline to endpoint were significantly greater in the active group (Z = 3.04, p = 0.002). In the repeated measures ANOVA, total BPRS scores were significantly lower in the active compared to the sham group (F = 6.63, df = 5, p = 0.016). The only significant difference between groups was seen in the Excitement factor (F = 7.23, df = 5, p = 0.003). No significant difference was seen in negative/disorganization symptoms (F = 1.23, df = 5, p = 0.36), positive symptoms (F = 0.97, df = 5, p = 0.48) or depressive symptoms (F = 1.21, df = 5, p = 0.37), and the Negative/ Disorganization, Positive and Depressive factors of the BPRS, respectively. BPRS, AHRS and CGI scores are presented in Table 2. BPRS scores over time are illustrated in Fig. 1. In analyses of within-group changes in the BPRS scores, every patient in the active group had a reduction in BPRS scores relative to baseline assessments (Z = 2.52, p = 0.012). This effect was not seen in the sham group (Z = 0.42, p = 0.67). The active group did not have a significant deterioration and showed some improvement, although not statistically significant, from weeks 4 to 8 (Z = 0.41, p = 0.68), while the sham group displayed a significant worsening (Z = 2.03, p- = 0.042) (Fig. 2). There were no significant differences between
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Table 1 Characteristics of 17 patients sample. Active group (n = 8)
Sham group p (n = 9)
Age ª Gender (F/M) Years of education (as grades completed) ª Monthly income ª γ Marital status (Single/Married) No. of psychiatric hospitalizations b Age of onset of Auditory Hallucinations ª Number of months since last hallucination free period of a month or greater ª Dosage of clozapine, mg b BPRS ª AHRS ª FAST ª
46 ± 9.84 3/5 11.25 ± 2.1 893.3 ± 602 8/0 3.5 (12) 21 ± 3.1 233.25 ± 67.5
36.5 ± 6.36 2/7 10.44 ± 2.8 973 ± 541 9/0 4 (4) 20.5 ± 3 186.4 ± 58.7
700 (200) 36.25 ± 8.27 31 ± 3.62 49 ± 10.32
QLS ª
51.38 ± 20
CGI ª
5.5 ± 1.19
650 (100) 33.11 ± 7.55 26.78 ± 7.15 49.44 ± 13.15 44.56 ± 20.23 5.11 ± 1
0.03 0.51 0.77 0.9 0.74 0.147 0.822 0.43 0.145 0.941 0.496 0.491
Fig. 1. Total BPRS scores for active rTMS versus sham stimulation. Changes in BPRS scores from baseline to endpoint were significantly greater in the active group (Z = 3.04, p = 0.002). Error bar is standard error. Abbreviations: BPRS = Brief Psychiatric Rating Scale, rTMS = repetitive transcranial magnetic stimulation.
ª Data reported as mean ± standard deviation. b Data reported as median and interquartile range. γ USD.
4. Discussion
active and sham groups in terms of QLS, AHRS, CGI and FAST scores (p N 0.05). There was a significant difference in the mean ages between groups (active group= 46 ± 9.84, sham group= 36.5 ± 6.36, p = 0.03). After the completion of the study, despite being offered active treatment, no subjects from the sham group agreed to receive active rTMS immediately after the treatment course and only one received it 3 months later, limiting any meaningful interpretation of the data.
3.1. Safety/tolerability The procedure was well tolerated. Only two patients of the active treatment group (11.7 %) referred to light headache after the first three sessions that was transient and responsive to acetaminophen. No seizures occurred.
The results of this study showed that subthreshold active 1 Hz rTMS of the left temporoparietal cortex had a positive effect on general psychopathology in patients with refractory schizophrenia treated with clozapine. By contrast, there was no significant difference between active and sham rTMS on the severity of auditory hallucinations. However, the effect of rTMS on general psychopathology in the active group as reflected by BPRS scores shows that active rTMS applied to the temporoparietal cortex of patients with schizophrenia treated with clozapine can have therapeutic effects that do not just overlap with the effects of clozapine. Finally there were also no significant effects on other measures of psychopathology, functionality or quality of life, i.e., CGI, FAST and QLS scores. Active rTMS was associated with significant improvement of BPRS scores compared to sham stimulation, mainly in the Excitement factor (items tension, grandiosity, hostility, uncooperativeness and excitement), that may be related to a state of brain hyperexcitability (Daskalakis et al., 2002). A possible explanation for this could be an
Table 2 Effects of rTMS on BPRS, CGI and AHRS scores over time. Measure BPRS scores Total Active Sham Positive factor Active Sham Negative/Disorganization factor Active Sham Excitement factor Active Sham Depressive factor Active Sham CGI scores Active Sham AHRS scores Active Sham a
mean ± standard deviation.
Baseline
Week 1
Week 2
Week 3
Week 4
Week 8
36.25 ± 8.27 33.11 ± 7.55
26.25 ± 8.56 31.67 ± 11.57
24.75 ± 9.19 28.33 ± 10.87
26.88 ± 9.17 29.44 ± 10.78
25.13 ± 8.18 28 ± 7.34
23.88 ± 7.99 29.56 ± 7.29
10.13 ± 3 10.56 ± 3.24
9.75 ± 4.06 11.44 ± 4.39
10.37 ± 3.85 10.66 ± 3.46
9.5 ± 2.87 9.66 ± 3.42
10.25 ± 4.2 9.22 ± 2.48
9.75 ± 4.16 9.22 ± 2.48
8.88 ± 2.35 8.56 ± 2.96
6.62 ± 2.82 8.55 ± 4.06
5.75 ± 2.65 7.33 ± 3.16
7 ± 2.92 7.77 ± 3.11
6.8 ± 1.95 7.33 ± 2.34
9.5 ± 3.81 12.56 ± 4.79
5.5 ± 2.82 3.56 ± 4.15
1.25 ± 1.38 3.88 ± 4.22
1.5 ± 0.92 3.77 ± 5.38
3.62 ± 3.73 4.66 ± 4.55
1.5 ± 1.41 3.88 ± 4.37
1.25 ± 1.28 3.89 ± 4.37
5.88 ± 2.9 4 ± 3.12
3.25 ± 2.12 3.33 ± 2.59
2.25 ± 1.16 3.33 ± 2.69
4.12 ± 2.85 3.33 ± 2.82
2.37 ± 2.26 3.55 ± 3.24
2.25 ± 2.18 3.56 ± 3.24
5.5 ± 1.19 5.1 ± 1.05
5 ± 1.06 5.11 ± 1.05
5.13 ± 1.12 5.33 ± 1
5 ± 1.06 5.11 ± 1.05
5.13 ± 1.12 5.11 ± 1.05
5 ± 1.06 5.11 ± 1.05
25.88 ± 4.99 25.22 ± 8.81
27.13 ± 3.35 25.44 ± 8.61
31 ± 3.62 26.78 ± 7.15
29.63 ± 4.2 26.44 ± 9
29.25 ± 3.53 24.44 ± 9
30.25 ± 4.9 24.67 ± 8.9
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Fig. 2. BPRS scores for each subject from active rTMS and sham groups. Subjects from the active group had a significant reduction in BPRS scores from baseline to endpoint (Z = 3.04, p = 0.002). Abbreviations: BPRS = Brief Psychiatric Rating Scale, rTMS = repetitive transcranial magnetic stimulation.
improvement on the cortical inhibition (CI) on the active group. CI refers to the mechanisms through which cortical output is regulated by inhibitory gamma-aminobutyric acid (GABA) interneurons. CI deficits assessed by TMS paradigms, such as paired-pulse inhibition and facilitation (ppTMS), cortical silent period (CSP) and transcallosal inhibition (TCI), have been demonstrated in patients with schizophrenia (Daskalakis et al., 2002). CI is regulated by GABAA and GABAB neurotransmission. Treatment with clozapine is associated with greater CI in persons with schizophrenia, and this increase may be related to potentiation of GABAB receptor mediated inhibition (Daskalakis et al., 2008; Liu et al., 2009). Moreover, the same authors confirmed that CI deficits are related to severity of psychotic symptoms. Repetitive TMS has also been shown to potentiate cortical GABAB receptor mediated inhibition (Daskalakis et al., 2006), which can lead to symptomatic improvement. Hence, the combination of rTMS and clozapine may act synergistically towards further enhancing GABAB inhibitory mechanisms in patients with refractory schizophrenia, who demonstrate the greatest GABAergic deficits. Similarly to our findings, Vercammen et al. (2009) found that 12 sessions of 1 Hz rTMS applied to the left temporoparietal cortex of patients with medication-resistant schizophrenia may have an effect on general psychopathology, as assessed by scores on the Positive and Negative Syndrome Scale, whereas bilateral or sham stimulation were not effective. The mean age was significantly different between groups (active = 46±9.84, sham=36.5±6.36, p=0.03). However, there was no correlation between age and BPRS scores at baseline or at the end of the treatment. The treatment parameters were comparable to those used in previous rTMS studies in schizophrenia, except for the number and duration of rTMS sessions. In this study, 20 sessions with duration of 20 min each (except for the first two sessions) and without breaks in the stimulation trains were performed, whereas in the vast majority of previous studies the number of sessions varied from 6 to 15, with mean duration of 16 min and with breaks in the stimulation trains. It is known that, similarly to pharmacological treatment, there is a clear trend for therapeutic efficacy to relate to the “dose” of treatment, in terms of the intensity of stimulation, the number of pulses provided per day and the number of days of treatment (Fitzgerald et al., 2005).
The fact that we tended to use longer treatment durations without stimulation breaks suggests that the potential to find temporal effects of rTMS was greater. This study has several limitations. The most important was the limited small sample size that could explain the lack of effect on the severity of AHs. Interestingly, we found a positive effect in general psychopathology but not in AHs, as aforementioned. This could be due to the poor reliability of some patients to report their AHs ( D'Alfonso et al., 2002; Rosa et al., 2007), mainly when reporting number of distinct speaking voices, perceived loudness, vividness and attentional salience, whereas general psychopathology includes both objective and subjective measures, determining changes in general psychopathology to be easier to index. Moreover, rTMS may have both regional and distant cortical effects as a result of interhemispheric transsynaptic signal propagation (Ilmoniemi et al., 1997). Thus, rTMS of the LTPC can affect other cortical areas and determine positive effects in different psychopathological dimensions. The lack of effect on quality of life and functionality could also be explained by the small power and sample size, but also because changes in aspects such as work, leisure, interpersonal relationships and social network may need more time to be observed and depend on psychosocial and individual factors. The high refractoriness of the patients enrolled in this study is associated with low levels of quality of life and functionality, and probably determined the relatively low response to the treatments available. Finally, our results suggest that subthreshold 1 Hz rTMS applied to the LTPC can be safely used in patients with refractory schizophrenia and can lead to symptomatic improvement in psychopathological dimensions that are not directly related to the stimulation site. This is relevant because, despite the advances in psychopharmacological treatments, at the present time very limited help is available to these patients. Conflicts of Interest All authors declare that they have no conflicts of interest. Role of the funding source Funding for this study was provided by Fundo de Incentivo a Pesquisa (FIPE) from Hospital de Clínicas de Porto Alegre, UFRGS (Project No. 06382). FIPE had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Authors de Jesus, Belmonte de Abreu, Marcolin and Favalli designed the study and wrote the protocol. Authors de Jesus and Daskalakis managed the literature searches and analyses. Author Magalhães undertook the statistical analysis, and authors Gil and Barbosa did clinical examinations. Authors de Jesus and Lobato did rTMS treatments. All authors participated on the preparation of the manuscript. All authors contributed to and have approved the final manuscript. Acknowledgements This work was supported by the Fundo de Incentivo a Pesquisa (FIPE) from Hospital de Clínicas de Porto Alegre (Project No. 06382). The Neuro-MS magnetic stimulator was kindly donated by Gerdau S.A.
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine Danilo Rocha de Jesus a,⁎, Alexei Gil a, Leonardo Barbosa a, Maria Inês Lobato a, Pedro Vieira da Silva Magalhães a, Gabriela Pereira de Souza Favalli a, Marco Antonio Marcolin b, Zafiris Jeffrey Daskalakis c, Paulo da Silva Belmonte-de-Abreu a a b c
Department of Psychiatry, Federal University of Rio Grande do Sul-RS, Brazil Institute of Psychiatry, University of Sao Paulo, Faculty of Medicine, Sao Paulo-SP, Brazil Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
a r t i c l e
i n f o
Article history: Received 20 May 2010 Received in revised form 17 November 2010 Accepted 17 November 2010 Keywords: Auditory hallucinations rTMS Clinical Trial General psychopathology Quality of life
a b s t r a c t Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50–70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Schizophrenia is a complex and heterogeneous psychiatric disorder. It is known that about 30% of the patients with schizophrenia do not respond adequately to pharmacological treatment. In this context, refractory criteria were developed. The Schizophrenia Algorithm of the International Psychopharmacology Algorithm Project (IPAP) defines that a patient is considered to be refractory if he or she failed to respond to two trials of 4 to 6 weeks' duration of monotherapy with two different second generation antipsychotics (SGAs) (or two trials with a first generation antipsychotic (FGA), if SGAs are not available). For these patients, treatment with clozapine may be considered. Auditory hallucinations (AHs) of spoken speech occur in 50–70% of patients with schizophrenia and often produce high levels of distress and functional disability. It is known that 25% of these patients suffer ⁎ Corresponding author. Postal address: 19 Princess Street, Toronto, Ontario, Canada, Zip code: M5A 4C8. Tel.: + 1 647 860 7227. E-mail address: [email protected] (D.R. de Jesus). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.11.022
from refractory AHs (Shergill et al., 1998). Neuroimaging studies suggest that activation of brain regions underlying speech perception play a role in producing AHs (Dierks et al., 1999; Shergill et al., 2000; Suzuki et al., 1993; Silbersweig et al., 1995; Lennox et al., 2000; Woodruff et al., 1994, 1997). Low frequency repetitive transcranial magnetic stimulation (e.g., 1 Hz rTMS) has been shown to reduce excitability of the cortex (Chen et al., 1997). Therefore, when applied to the left temporoparietal cortex (LTPC), it may reduce the excitability of this area, which is critical to speech perception (Fiez et al., 1996) and has been implicated in the genesis of AHs (Silbersweig et al., 1995; Lennox et al., 2000). In animal studies, 1 Hz rTMS can produce similar effects to long-term depression, and they can last many weeks (Post et al., 1999; for review see Hoffman and Cavus, 2002). Previous studies have shown that 1 Hz rTMS applied to the LTPC can reduce the severity of the AHs (Hoffman et al., 2000, 2005; Rosa et al., 2007; Poulet et al., 2005; Fitzgerald et al., 2005; Vercammen et al., 2009). A recent review conducted by Fitzgerald and Daskalakis (2008) found that rTMS may be able to substantially reduce the experience of auditory hallucinations in patients for whom symptoms persist despite optimal medication
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treatment. Vercammen et al. (2009) conducted a study in which 38 patients with schizophrenia suffering from frequent medicationresistant AHs were randomly allocated to receive left-sided rTMS, bilateral rTMS or sham. They found that compared to bilateral or sham stimulation, rTMS of the left temporoparietal region appears most effective in reducing auditory hallucinations, and additionally may have an effect on general psychopathology. Rosa et al. (2007) conducted a double-masked, sham-controlled, parallel design study comparing 1 Hz rTMS applied to the LTPC to sham stimulation in association with clozapine treatment. Eleven patients were enrolled. Rosa et al. concluded that active rTMS in association with clozapine can be administered safely to treat auditory hallucinations, although its clinical utility was considered questionable. That is, no significant clinical effects were observed in the sample studied, possibly because of the small sample and/or due to the high degree of refractoriness in the patients. The purpose of this study was to examine the effects of 1 Hz rTMS applied to the LTPC in a larger sample size (n = 17) of clozapinetreated patients with refractory schizophrenia (RS) using an extended rTMS protocol. Moreover, we also examined general psychopathology severity, quality of life and functionality in these patients, as rTMS may have both regional and distant cortical effects as a result of interhemispheric transsynaptic signal propagation (Ilmoniemi et al., 1997) that may translate into a broad improvement in psychotic symptoms. 2. Methods 2.1. Subjects Patients met diagnostic criteria for schizophrenia (using OPCRIT 4.0) and were considered as having RS, with daily AHs occurring at least five times per day despite treatment with a stable dose of at least 400 mg/day of clozapine for a period longer than 4 months and at least two adequate trials of antipsychotic medications in the past, including at least one atypical antipsychotic drug other than clozapine. Subjects were all right-handed (self-reported), men and women from 18 to 65 years old, with a Brief Psychiatric Rating Scale (BPRS) score of at least 27. Women in fertile age must have been using an appropriate contraceptive method. Exclusion criteria included suicide risk, pregnancy, prior history of seizures, neurosurgery or head trauma, use of pacemaker or intracranial metallic clip, neurological disease, significant unstable medical condition, estimated IQ ≤ 80, current alcohol or drug abuse, or inability to provide informed consent. A total of 17 patients were enrolled. All patients were naive to rTMS treatments. The study protocol was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre. A signed, informed consent was obtained from every patient. At baseline, the two groups were similar in terms of gender, income, number of psychiatric hospitalizations, age of onset of auditory hallucinations, dosage of clozapine, BPRS, FAST, Quality of Life Scale, Auditory Hallucinations Rating Scale, and Clinical Global Impressions scores. 2.2. rTMS protocol Patients were randomly allocated to rTMS and sham groups. Randomization was made by Sequentially-Numbered, Opaque, Sealed Envelopes (SNOSE). The two groups were similar in terms of age, gender and BPRS scores. The study used a doubled-masked, parallel design. Study participants, clinical raters, and all personnel responsible for the clinical care of the patient remained masked to allocated condition and allocation parameters. A Neurosoft Neuro-MS (Neurosoft Ltd, Russia) and figure-8 coil were utilized in the rTMS sessions. Stimulation was administered at an intensity of 90% of the motor threshold, which was ascertained prior to the first session of each week. Motor threshold (MT) was based on visualization of trace motor movements in 5/10 tries when stimulating primary motor cortex. This method has been reported to be as sensitive as EMG-based methods of detecting MT (Pridmore et al., 1998). Active stimulation was administered to the LTPC, exactly halfway between the left temporal (T3) and left parietal (P3) sites according to the International 10–20 EEG electrode position system. Stimulation frequency was 1 Hz while subjects were lying down on a bed. There was no break in the stimulation trains. Sham stimulation was administered using the same coil, applied 5 cm lateral to F3, perpendicular to the parasagittal plane, above the left temporal muscle. In this position the coil–cortex distance is essentially larger (more than 3 cm v. 1–1.5 cm) compared to F3, and the electromagnetic field reaching the cortex was therefore substantially weaker. To avoid the possible effectiveness of the sham stimulation, the coil was angled at 45°, touching the skull not with the centre but with the rim opposite the handle, and the stimulation intensity was reduced to 80% of MT (Herwig et al., 2007). This form of sham stimulation had the effect of inducing local sensations above the temporal muscle similar to the disturbances caused by the real stimulation (Praeg et al., 2005). Clozapine use was continued during the trial, without dose changes. Patients received
8 min of active/sham stimulation on day I, 16 min on day II, and 20 min for the next 18 days, making a total of 20 sessions, 5 sessions/week (Monday through Friday) for 4 weeks. After the completion of the study, patients randomized to the sham condition were offered active rTMS utilizing the same parameters as the masked phase of the trial. 2.3. Clinical Measures The 18-item Brief Psychiatric Rating Scale (BPRS) was used as the primary outcome variable and to assess positive and negative symptoms, as well as conceptual disorganization and general psychopathology. It is a psychopathological assessment scale composed of 18 items which have been extensively used in the assessment of patients with schizophrenia. It has also been used in the assessment of the therapeutic response to antipsychotics by Kane et al., and in the development of criteria for refractory schizophrenia (Alves et al., 2005). Using the 18-item BPRS factor analysis proposed by Alves et al (2005) for patients with refractory schizophrenia, we analyzed scores of the two groups on each of the four factors, namely: Negative/Disorganization, composed of emotional withdrawal, disorientation, blunted affect, mannerisms/posturing and conceptual disorganization; Excitement, composed of excitement, hostility, tension, grandiosity, and uncooperativeness, grouped variables that evoke brain excitement or a manic-like syndrome; Positive, composed of unusual thought content, suspiciousness, and hallucinatory behavior; and Depressive, composed of depressive mood, guilt feelings, and motor retardation, clearly related to a depressive syndrome. AHs are known to have a negative impact on the quality of life of the patients with schizophrenia (Van de Willige et al., 2005). To measure the effect of change in AHs scores on the quality of life, the Quality of Life Scale (QLS, Heinrichs et al., 1984) was used. The tool is a 21-item scale completed by clinically trained staff after a semi-structured interview and chart review that assesses quality of life. Items are scored on a 7-point scale with higher ratings representing higher levels of satisfaction. The Clinical Global Impressions (CGI) scale was used to assess overall clinical improvement. A 7-item Auditory Hallucinations Rating Scale (AHRS) was used to assess hallucination frequency, number of distinct speaking voices, perceived loudness, vividness, attentional salience, length of hallucinations (single words, phrases, sentences, or extended discourse), and degree of distress. The FAST scale was used to assess functionality. It consists of 24 items, grouped in six specific areas of functionality: autonomy, work, cognitive functioning, finances, interpersonal relationships and leisure. The higher the score, the worse is the patient´s functionality. All scales were ascertained at baseline, day 7, day 14, day 21, day 28 and day 60. The later assessment happened 30 days after the last active/placebo rTMS session, 60 days from baseline. All clinical assessments were undertaken by a psychiatrist from the Schizophrenia program of Hospital de Clinicas de Porto Alegre and a third-year resident of Psychiatry, both well trained in the scales that were used in this study. Also, the senior author discussed and reviewed all scores with the raters. 2.4. Statistical analysis Scores from rating scales were analyzed from week 0 to 8 as continuous data. MannWhitney's U test was used to test for group differences in score changes from baseline to endpoint. To evaluate within-group changes, Wilcoxon's signed-rank test was used. We also used multivariate repeated measures analysis of variance (ANOVA) to test group differences in trajectory changes. This approach is useful as it is not constrained by sphericity, unlike the traditional repeated measures ANOVA. All tests are two-tailed.
3. Results Demographic data and BPRS, QLS, FAST, AHRS and CGI scores at baseline are shown in Table 1. Changes in BPRS scores from baseline to endpoint were significantly greater in the active group (Z = 3.04, p = 0.002). In the repeated measures ANOVA, total BPRS scores were significantly lower in the active compared to the sham group (F = 6.63, df = 5, p = 0.016). The only significant difference between groups was seen in the Excitement factor (F = 7.23, df = 5, p = 0.003). No significant difference was seen in negative/disorganization symptoms (F = 1.23, df = 5, p = 0.36), positive symptoms (F = 0.97, df = 5, p = 0.48) or depressive symptoms (F = 1.21, df = 5, p = 0.37), and the Negative/ Disorganization, Positive and Depressive factors of the BPRS, respectively. BPRS, AHRS and CGI scores are presented in Table 2. BPRS scores over time are illustrated in Fig. 1. In analyses of within-group changes in the BPRS scores, every patient in the active group had a reduction in BPRS scores relative to baseline assessments (Z = 2.52, p = 0.012). This effect was not seen in the sham group (Z = 0.42, p = 0.67). The active group did not have a significant deterioration and showed some improvement, although not statistically significant, from weeks 4 to 8 (Z = 0.41, p = 0.68), while the sham group displayed a significant worsening (Z = 2.03, p- = 0.042) (Fig. 2). There were no significant differences between
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Table 1 Characteristics of 17 patients sample. Active group (n = 8)
Sham group p (n = 9)
Age ª Gender (F/M) Years of education (as grades completed) ª Monthly income ª γ Marital status (Single/Married) No. of psychiatric hospitalizations b Age of onset of Auditory Hallucinations ª Number of months since last hallucination free period of a month or greater ª Dosage of clozapine, mg b BPRS ª AHRS ª FAST ª
46 ± 9.84 3/5 11.25 ± 2.1 893.3 ± 602 8/0 3.5 (12) 21 ± 3.1 233.25 ± 67.5
36.5 ± 6.36 2/7 10.44 ± 2.8 973 ± 541 9/0 4 (4) 20.5 ± 3 186.4 ± 58.7
700 (200) 36.25 ± 8.27 31 ± 3.62 49 ± 10.32
QLS ª
51.38 ± 20
CGI ª
5.5 ± 1.19
650 (100) 33.11 ± 7.55 26.78 ± 7.15 49.44 ± 13.15 44.56 ± 20.23 5.11 ± 1
0.03 0.51 0.77 0.9 0.74 0.147 0.822 0.43 0.145 0.941 0.496 0.491
Fig. 1. Total BPRS scores for active rTMS versus sham stimulation. Changes in BPRS scores from baseline to endpoint were significantly greater in the active group (Z = 3.04, p = 0.002). Error bar is standard error. Abbreviations: BPRS = Brief Psychiatric Rating Scale, rTMS = repetitive transcranial magnetic stimulation.
ª Data reported as mean ± standard deviation. b Data reported as median and interquartile range. γ USD.
4. Discussion
active and sham groups in terms of QLS, AHRS, CGI and FAST scores (p N 0.05). There was a significant difference in the mean ages between groups (active group= 46 ± 9.84, sham group= 36.5 ± 6.36, p = 0.03). After the completion of the study, despite being offered active treatment, no subjects from the sham group agreed to receive active rTMS immediately after the treatment course and only one received it 3 months later, limiting any meaningful interpretation of the data.
3.1. Safety/tolerability The procedure was well tolerated. Only two patients of the active treatment group (11.7 %) referred to light headache after the first three sessions that was transient and responsive to acetaminophen. No seizures occurred.
The results of this study showed that subthreshold active 1 Hz rTMS of the left temporoparietal cortex had a positive effect on general psychopathology in patients with refractory schizophrenia treated with clozapine. By contrast, there was no significant difference between active and sham rTMS on the severity of auditory hallucinations. However, the effect of rTMS on general psychopathology in the active group as reflected by BPRS scores shows that active rTMS applied to the temporoparietal cortex of patients with schizophrenia treated with clozapine can have therapeutic effects that do not just overlap with the effects of clozapine. Finally there were also no significant effects on other measures of psychopathology, functionality or quality of life, i.e., CGI, FAST and QLS scores. Active rTMS was associated with significant improvement of BPRS scores compared to sham stimulation, mainly in the Excitement factor (items tension, grandiosity, hostility, uncooperativeness and excitement), that may be related to a state of brain hyperexcitability (Daskalakis et al., 2002). A possible explanation for this could be an
Table 2 Effects of rTMS on BPRS, CGI and AHRS scores over time. Measure BPRS scores Total Active Sham Positive factor Active Sham Negative/Disorganization factor Active Sham Excitement factor Active Sham Depressive factor Active Sham CGI scores Active Sham AHRS scores Active Sham a
mean ± standard deviation.
Baseline
Week 1
Week 2
Week 3
Week 4
Week 8
36.25 ± 8.27 33.11 ± 7.55
26.25 ± 8.56 31.67 ± 11.57
24.75 ± 9.19 28.33 ± 10.87
26.88 ± 9.17 29.44 ± 10.78
25.13 ± 8.18 28 ± 7.34
23.88 ± 7.99 29.56 ± 7.29
10.13 ± 3 10.56 ± 3.24
9.75 ± 4.06 11.44 ± 4.39
10.37 ± 3.85 10.66 ± 3.46
9.5 ± 2.87 9.66 ± 3.42
10.25 ± 4.2 9.22 ± 2.48
9.75 ± 4.16 9.22 ± 2.48
8.88 ± 2.35 8.56 ± 2.96
6.62 ± 2.82 8.55 ± 4.06
5.75 ± 2.65 7.33 ± 3.16
7 ± 2.92 7.77 ± 3.11
6.8 ± 1.95 7.33 ± 2.34
9.5 ± 3.81 12.56 ± 4.79
5.5 ± 2.82 3.56 ± 4.15
1.25 ± 1.38 3.88 ± 4.22
1.5 ± 0.92 3.77 ± 5.38
3.62 ± 3.73 4.66 ± 4.55
1.5 ± 1.41 3.88 ± 4.37
1.25 ± 1.28 3.89 ± 4.37
5.88 ± 2.9 4 ± 3.12
3.25 ± 2.12 3.33 ± 2.59
2.25 ± 1.16 3.33 ± 2.69
4.12 ± 2.85 3.33 ± 2.82
2.37 ± 2.26 3.55 ± 3.24
2.25 ± 2.18 3.56 ± 3.24
5.5 ± 1.19 5.1 ± 1.05
5 ± 1.06 5.11 ± 1.05
5.13 ± 1.12 5.33 ± 1
5 ± 1.06 5.11 ± 1.05
5.13 ± 1.12 5.11 ± 1.05
5 ± 1.06 5.11 ± 1.05
25.88 ± 4.99 25.22 ± 8.81
27.13 ± 3.35 25.44 ± 8.61
31 ± 3.62 26.78 ± 7.15
29.63 ± 4.2 26.44 ± 9
29.25 ± 3.53 24.44 ± 9
30.25 ± 4.9 24.67 ± 8.9
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Fig. 2. BPRS scores for each subject from active rTMS and sham groups. Subjects from the active group had a significant reduction in BPRS scores from baseline to endpoint (Z = 3.04, p = 0.002). Abbreviations: BPRS = Brief Psychiatric Rating Scale, rTMS = repetitive transcranial magnetic stimulation.
improvement on the cortical inhibition (CI) on the active group. CI refers to the mechanisms through which cortical output is regulated by inhibitory gamma-aminobutyric acid (GABA) interneurons. CI deficits assessed by TMS paradigms, such as paired-pulse inhibition and facilitation (ppTMS), cortical silent period (CSP) and transcallosal inhibition (TCI), have been demonstrated in patients with schizophrenia (Daskalakis et al., 2002). CI is regulated by GABAA and GABAB neurotransmission. Treatment with clozapine is associated with greater CI in persons with schizophrenia, and this increase may be related to potentiation of GABAB receptor mediated inhibition (Daskalakis et al., 2008; Liu et al., 2009). Moreover, the same authors confirmed that CI deficits are related to severity of psychotic symptoms. Repetitive TMS has also been shown to potentiate cortical GABAB receptor mediated inhibition (Daskalakis et al., 2006), which can lead to symptomatic improvement. Hence, the combination of rTMS and clozapine may act synergistically towards further enhancing GABAB inhibitory mechanisms in patients with refractory schizophrenia, who demonstrate the greatest GABAergic deficits. Similarly to our findings, Vercammen et al. (2009) found that 12 sessions of 1 Hz rTMS applied to the left temporoparietal cortex of patients with medication-resistant schizophrenia may have an effect on general psychopathology, as assessed by scores on the Positive and Negative Syndrome Scale, whereas bilateral or sham stimulation were not effective. The mean age was significantly different between groups (active = 46±9.84, sham=36.5±6.36, p=0.03). However, there was no correlation between age and BPRS scores at baseline or at the end of the treatment. The treatment parameters were comparable to those used in previous rTMS studies in schizophrenia, except for the number and duration of rTMS sessions. In this study, 20 sessions with duration of 20 min each (except for the first two sessions) and without breaks in the stimulation trains were performed, whereas in the vast majority of previous studies the number of sessions varied from 6 to 15, with mean duration of 16 min and with breaks in the stimulation trains. It is known that, similarly to pharmacological treatment, there is a clear trend for therapeutic efficacy to relate to the “dose” of treatment, in terms of the intensity of stimulation, the number of pulses provided per day and the number of days of treatment (Fitzgerald et al., 2005).
The fact that we tended to use longer treatment durations without stimulation breaks suggests that the potential to find temporal effects of rTMS was greater. This study has several limitations. The most important was the limited small sample size that could explain the lack of effect on the severity of AHs. Interestingly, we found a positive effect in general psychopathology but not in AHs, as aforementioned. This could be due to the poor reliability of some patients to report their AHs ( D'Alfonso et al., 2002; Rosa et al., 2007), mainly when reporting number of distinct speaking voices, perceived loudness, vividness and attentional salience, whereas general psychopathology includes both objective and subjective measures, determining changes in general psychopathology to be easier to index. Moreover, rTMS may have both regional and distant cortical effects as a result of interhemispheric transsynaptic signal propagation (Ilmoniemi et al., 1997). Thus, rTMS of the LTPC can affect other cortical areas and determine positive effects in different psychopathological dimensions. The lack of effect on quality of life and functionality could also be explained by the small power and sample size, but also because changes in aspects such as work, leisure, interpersonal relationships and social network may need more time to be observed and depend on psychosocial and individual factors. The high refractoriness of the patients enrolled in this study is associated with low levels of quality of life and functionality, and probably determined the relatively low response to the treatments available. Finally, our results suggest that subthreshold 1 Hz rTMS applied to the LTPC can be safely used in patients with refractory schizophrenia and can lead to symptomatic improvement in psychopathological dimensions that are not directly related to the stimulation site. This is relevant because, despite the advances in psychopharmacological treatments, at the present time very limited help is available to these patients. Conflicts of Interest All authors declare that they have no conflicts of interest. Role of the funding source Funding for this study was provided by Fundo de Incentivo a Pesquisa (FIPE) from Hospital de Clínicas de Porto Alegre, UFRGS (Project No. 06382). FIPE had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Authors de Jesus, Belmonte de Abreu, Marcolin and Favalli designed the study and wrote the protocol. Authors de Jesus and Daskalakis managed the literature searches and analyses. Author Magalhães undertook the statistical analysis, and authors Gil and Barbosa did clinical examinations. Authors de Jesus and Lobato did rTMS treatments. All authors participated on the preparation of the manuscript. All authors contributed to and have approved the final manuscript. Acknowledgements This work was supported by the Fundo de Incentivo a Pesquisa (FIPE) from Hospital de Clínicas de Porto Alegre (Project No. 06382). The Neuro-MS magnetic stimulator was kindly donated by Gerdau S.A.
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