Anodal transcranial Direct Current Stimulation over the cerebellum and primary motor cortex improves tardive dyskinesia: A pilot study

Schizophrenia is a chronic and disabling mental disorder that affects approximately 1% of the world's population [[1]McGrath J. Saha S. Chant D. Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality.Epidemiol Rev. 2008; 30: 67-76Google Scholar]. Despite therapeutic advances in psychopharmacology, antipsychotic medications continue to contribute to the onset of Tardive Dyskinesia (TD) [[2]D'Abreu A. Akbar U. Friedman J.H. Tardive dyskinesia: epidemiology.J Neurol Sci. 2018; 389 (January): 17-20Google Scholar]. In general, the course of TD is difficult to handle, since patients who develop psychotic symptoms need to remain on antipsychotics to prevent relapses [[1]McGrath J. Saha S. Chant D. Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality.Epidemiol Rev. 2008; 30: 67-76Google Scholar]. TD is characterized by stereotyped, involuntary and repetitive movements, usually of face, tongue, arms, legs, and other body's parts [[3]Kiriakakis V. Bhatia K.P. Quinn N.P. Marsden C.D. The natural history of tardive dystonia. A long-term follow-up study of 107 cases.Brain. 1998; 121 (Nov): 2053-2066Google Scholar]. After onset of symptoms, the movements may persist for years or decades [[3]Kiriakakis V. Bhatia K.P. Quinn N.P. Marsden C.D. The natural history of tardive dystonia. A long-term follow-up study of 107 cases.Brain. 1998; 121 (Nov): 2053-2066Google Scholar]. TD is considered an iatrogenic condition caused by long-term use of antipsychotics or other dopamine antagonists, affecting 20–25% of treated patients [[2]D'Abreu A. Akbar U. Friedman J.H. Tardive dyskinesia: epidemiology.J Neurol Sci. 2018; 389 (January): 17-20Google Scholar] [[3]Kiriakakis V. Bhatia K.P. Quinn N.P. Marsden C.D. The natural history of tardive dystonia. A long-term follow-up study of 107 cases.Brain. 1998; 121 (Nov): 2053-2066Google Scholar]. Currently, TD treatment approach focus mainly on drug therapy, such as selective vesicular monoamine transporter-2 inhibitors (VMAT2) [[4]Van Harten P. There has been very little progress in treating or preventing antipsychotic-induced tardive dyskinesia.Evid Base Ment Health. 2018; 21: e10Google Scholar], and other invasive methods, such as deep brain stimulation (DBS) [[5]Meng D.-W. Liu H.-G. Yang A.-C. Zhang K. Zhang J.-G. Long-term effects of subthalamic nucleus deep brain stimulation in tardive dystonia. vol. 129. Chinese medical journal, China2016: 1257-1258Google Scholar]. However, there is little evidence demonstrating effectiveness of such approaches [[4]Van Harten P. There has been very little progress in treating or preventing antipsychotic-induced tardive dyskinesia.Evid Base Ment Health. 2018; 21: e10Google Scholar]. Previous studies have shown significant effects of different cerebellar neurostimulation techniques on movement disorders [[6]Franca C. de Andrade D.C. Teixeira M.J. Galhardoni R. Silva V. Barbosa E.R. et al.Effects of cerebellar neuromodulation in movement disorders: a systematic review.Brain Stimul. 2018; 11 (Mar): 249-260Google Scholar], such as cerebellar ataxia, tremor, cervical dystonia and Parkinson's disease [[6]Franca C. de Andrade D.C. Teixeira M.J. Galhardoni R. Silva V. Barbosa E.R. et al.Effects of cerebellar neuromodulation in movement disorders: a systematic review.Brain Stimul. 2018; 11 (Mar): 249-260Google Scholar]. Indeed, some researchers have already used transcranial Direct Current Stimulation (tDCS) as a treatment for schizophrenia, evaluating effects over its common positive and negative symptoms [[7]Moffa A.H. Brunoni A.R. Nikolin S. Loo C.K. Transcranial direct current stimulation in psychiatric disorders: a comprehensive review.Psychiatr Clin. 2018; 41 (Sep): 447-463Google Scholar] but not for tardive dyskinesia, and none explored the potential benefits of anodal tDCS over the cerebellum or the primary motor cortex (M1). Within this context, there is an unmet need for new treatment approaches for TD. Therefore, we aim to explore the potential benefits and side effects of anodal tDCS over the cerebellum and primary motor cortex in schizophrenic patients suffering from TD. This is descriptive study of consecutive 4 patients attending the Psychiatry outpatient clinic of the University Hospital from the University of Brasilia. The tDCS was used to apply a direct current of 2mA during 20 minutes for 5 consecutive days through surface electrodes covered by saline-soaked sponges as described elsewhere. A gradual and regressive current (+15s fade-in and fade-out), controlled by a voltmeter, was used while turning on and turning off. Patients remained at rest, sitting on a chair, during all sessions. The interventions were performed in two phases, with a 3-month interval between them for washout purposes. The electrode position was determined by the International EEG 10–20 System. In Phase I, the anodal electrode was positioned over the central cerebellum (2cm below the inion), while in Phase II, the anodal electrode was positioned over the left motor cortex M1 (C3). In both phases, the reference electrode was positioned over the right supraorbital region (Fp2). Only adult patients with a diagnosis of schizophrenia (according to the DSM-V), meeting TD criteria, were included. Subjects have had not changed antipsychotic therapy in the last 4 weeks. The exclusion criteria were pregnant women, metal implant carriers, patients with relevant psychiatric comorbidity (chemical dependence, risk of suicide), neurological diseases (epilepsy, stroke, dementia) and clinical diseases (malignant tumors, infections, heart failure). The times of assessment were baseline (T0), immediately after the first session (T1) and after the 5th session (T2). The Abnormal Involuntary Movement Scale (AIMS) was used to measure the TD symptoms as a primary outcome. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression - Schizophrenia (CGI-SCH) were used for clinical evaluation, being considered secondary outcomes. It is important to highlight that electrode montages were performed by the PI and the scales were applied by another trained psychiatrist for this purpose. Additionally, all AIMS rating scale administrations were video recorded in 3 of 4 patients (see supplementary material). 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All subjects gave written informed consent in accordance with the Declaration of Helsinki. We described here 4 patients with chronic schizophrenia and TD on antipsychotics drugs that successfully finished tDCS treatment. The antipsychotic treatment was presented according to recommendations of chlorpromazine equivalence. The scales results from each patient can be seeing at Table 1. All patients had an objective reduction in abnormal movements after cerebellar stimulation according to AIMS scale. Surprisingly, the improvement was maintained after 3 months washout period and we demonstrated an additional benefit after the M1 stimulation phase. In parallel with TD improvement, we observed improvement in schizophrenia clinical outcomes through CGI-SH, in both stimulation phases. PANSS total score and its domains showed an overall positive effect of the treatment too (Table 1).Table 1Tardive dyskinesia and schizophrenia clinical evaluation after anodal transcranial direct current stimulation over the cerebellum and primary motor cortex.Time Line - Cerebellum -> Primary Motor CortexAIMS ScoreT0T1T23 months washoutT3T4T5# 13527 (−22.9%)21 (−40%)–2510 (−60%)24 (−4%)# 23019 (−36.7%)19 (−36.7%)–2016 (−20%)15 (−25%)# 33123 (−25.8%)21 (−32.3%)–2116 (−23.8%)10 (−23.8)# 41615 (−6.3%)12 (−25%)–1514 (−6,7%)14 (−6,7%)CGI-SH Score# 12314 (−39.1%)8 (−65.2%)–1310 (23.1%)9 (−30.8%)# 298 (−11.1%)8 (−11.1%)–98 (−11.1%)8 (−11.1%)# 31614 (−12.5%)9 (−43,8%)–129 (−25%)8 (−33.3%)# 41815 (−16.7%)16 (−11.1%)–1615 (−6.3%)12 (−25%)PANSS (Positive/Negative/Global/Total)# 112/27/58/97–11 (−8.3%)/18 (−33.3%)/22 (62.1%)/51 (−47.4%)–8/36/48/92–8 (0%)/30 (−16.7%)/36 (−25%)/74 (−19.6%)# 29/11/22/42–7 (−22.2%)/10 (−9.1%)/17 (−22.7%)/34 (−19%)–7/12/19/38–8 (14.3%)/11 (−8.3%)/17 (−10.5%)/36 (−5.3%)# 315/26/42/83–8 (−46.7%)/12 (−53,8%)/24 (−42.9%)/44 (−47%)–7/7/18/32–7 (0%)/12 (71.4%)/18 (0%)/37 (15.6%)# 421/20/49/90–18 (−14.3%)/17 (−15%)/40 (−18.4%)/75 (−16.7%)–35/29/60/124–19 (−45.7%)/19 (−34.5%)/47 (−21.7%)/85 (−31.5%)AIMS = Abnormal Involuntary Movement Scale; CGI-SCH= Clinical Global Impression - Schizophrenia; PANSS= Positive and Negative Syndrome Scale. Open table in a new tab AIMS = Abnormal Involuntary Movement Scale; CGI-SCH= Clinical Global Impression - Schizophrenia; PANSS= Positive and Negative Syndrome Scale. tDCS is a powerful noninvasive neuromodulation technique that interacts with brain function by means of a low-intensity direct current (1–2 mA) flowing from the cathode to the anode electrodes positioned on the scalp. We demonstrated an important reduction in TD abnormal movements and improvement of schizophrenia clinical symptoms measured by validated rating scales. In addition, the cerebellar a-tDCS had a greater effect than the M1 a-tDCS, as presented in results section. The tDCS effects can persist after end of stimulation for weeks and may be related to neuroplasticity processes through long-term potentiation (LTP) and long-term depression (LTD) [[8]Kronberg G. Bridi M. Abel T. Bikson M. Parra L.C. Direct current stimulation modulates LTP and LTD: activity dependence and dendritic effects.Brain Stimul. 2017; 10 (Jan): 51-58Google Scholar]. a-tDCS over the cerebellum and M1 also showed a significant decrease in negative symptoms, as previously shown in some studies with stimulation [[9]Brunelin J. Mondino M. Haesebaert F. Saoud M. Suaud-Chagny M.F. Poulet E. Efficacy and safety of bifocal tDCS as an interventional treatment for refractory schizophrenia. vol. 5. Brain stimulation, United States2012: 431-432Google Scholar]. It is known that there is a close link between negative symptoms and cognition(9). Perhaps this is the underlying mechanism that contributed to the improvement of negative symptoms. Moreover, this could be the PANSS component that is most influenced by the placebo effect, once the patient gets used to researcher. This result, despite involving a small sample, suggests that the neuronal connections between cerebellum and M1 to basal ganglia are somehow involved in the TD pathophysiology, as evidence to brain systems and networks. If cerebellar activation by tDCS improves TD, then, an important hypothesis can be proposed as cerebellum plays an important role in interconnection of M1 and basal ganglia, and in the modulation of dyskinetic movements. The side effects found here were congruent to other studies [[10]Aparício L.V.M. Guarienti F. Razza L.B. Carvalho A.F. Fregni F. Brunoni A.R. A systematic review on the acceptability and tolerability of transcranial direct current stimulation treatment in neuropsychiatry trials.Brain Stimul. 2016; 9: 671-681Google Scholar]. A mild side effect found in this study and worth mentioning is the skin burn under the cathode. TD is high prevalent, considered iatrogenic and causes major impact on quality of life due to incapacity and loss of autonomy. Studies that explore this movement disorder stress the importance of prevention through proper prescription of neuroleptics as well as early intervention with approved approaches. tDCS may become a feasible alternative. We demonstrated here tDCS as a potential treatment approach for TD with positive effects over schizophrenia disease. Raphael Boechat-Barros and Thiago Xavier Correa: conceptualization, writing of original draft, methodology; Joaquim P. Brasil-Neto: project administration and supervision; Felipe von Glehn: writing, review & editing; Final approval: Raphael Boechat-Barros, Joaquim P. Brasil-Neto, Felipe von Glehn and Thiago Xavier Correa. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.