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Modulation of Corollary Discharge Dysfunction in Schizophrenia by tDCS: Preliminary Evidence
... Les auteurs mettent en avant le haut niveau de résistance thérapeutique inclus pour expliquer leurs résultats. Deux études en ouvert ont montré une réduction des hallucinations acoustico-verbales de 30% sur la Auditory Hallucination Rating Scale (AHRS) chez 5 des 6 patients inclus (Nawani et al, 2014). De façon similaire, Bose et al ont mis en évidence une réduction de 32% des hallucinations acoustico-verbales après tDCS dans une étude ouverte incluant 21 patients (Bose et al, 2014). ...
... Deux études en ouvert ont montré une réduction des hallucinations acoustico-verbales de 30% sur la Auditory Hallucination Rating Scale (AHRS) chez 5 des 6 patients inclus (Nawani et al, 2014). De façon similaire, Bose et al ont mis en évidence une réduction de 32% des hallucinations acoustico-verbales après tDCS dans une étude ouverte incluant 21 patients (Bose et al, 2014). ...
... Pour commencer, le traitement du trouble obsessionnel compulsif (TOC) par tDCS a été décrit dans plusieurs rapports de cas, dont un nombre notable a montré une réduction significative des rituels et des obsessions (Narayanaswamy et al, 2014 ;Mondino et al, 2015d ;Chahbra et al, 2016). On note tout de même dans un autre rapport de cas qu'un patient souffrant de TOC et ayant reçu une cure de tDCS n'a présenté qu'une réduction isolée de l'anxiété et des symptômes dépressifs (Volpato et al, 2013). ...
... One study also used the Hamilton Program for Schizophrenia Voices Questionnaire to measure AVH. 28 Ten studies found a significant decrease in AVH after active tDCS, [22][23][24][25][26][27]29,31,34,35 1 reported a trend toward a significant decrease in AVH, 28 and 3 reported no significant effects of tDCS on AVH. 30,32,33 Mean decreases in AVH (pre-post changes) varied from 4.9% 28 to 46% 31 after active stimulation and −7.5% 31 to 31% 33 after sham stimulation. ...
... Furthermore, a better comprehension of the effects of tDCS on brain activity could contribute to the optimization of tDCS efficacy in treating AVH. 23,28,34,50,66 Clinical indication should be clarified toward a personalized medicine approach. ...
... 1 in France,24,29,31,34 1 in India,22,23,25-27,35 1 in South Korea,28 and 2 groups in the United States 32,33 ). In total, 313 patients were included in these studies, and among them, 231 received active tDCS.Regarding the demographic and clinical characteristics of the patients, almost all studies included those diagnosed as having schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Editon (DSM-IV)22,23,[25][26][27]29,[31][32][33][34][35] or DSM-5 24 criteria. Three studies also included patients with schizoaffective disorder.30,32,33 ...
Some 25% to 30% of patients with schizophrenia report auditory verbal hallucinations (AVHs) that fail to respond adequately to antipsychotic treatments. In such cases, transcranial direct current stimulation (tDCS) has been proposed as a therapeutic option. Here, we aim to provide an exhaustive review of the literature examining the clinical effects of tDCS on AVH in patients with schizophrenia. A systematic search in the PubMed and Web of Science databases yielded 14 results, 7 randomized controlled trials (RCTs) and 7 open-label studies. Among them, 4 RCTs and 7 open-label studies reported a significant reduction of AVH after repeated sessions of tDCS, whereas 3 RCTs did not show any advantage of active tDCS over sham tDCS. Altogether, current studies showed an overall decrease of approximately 26% of AVH after active tDCS and 11% after sham tDCS. One suitable approach to decreasing AVH was to deliver twice-daily sessions of tDCS over 5 consecutive days (10 sessions at 20 minutes each, 2 mA) with the anode over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Demographic and clinical parameters such as young age, nonsmoking status, and higher frequencies of AVH occurrence seemed to be predictors of clinical improvement. Further RCTs, with larger sample sizes, are needed to confirm the usefulness of tDCS for AVH.
... Transcranial Direct Current Stimulation (tDCS), a non-invasive, safe neuromodulation technique, is a reemerging intervention (Brunoni et al., 2012) with promising potential to treat schizophrenia (Mondino et al., 2015a). In an open label study, we reported add-on tDCS to ameliorate CD deficit in SCZ patients with persistent AVH (Nawani et al., 2014). In this report, 1) we replicate this observation using a randomized, double-blind, parallel-arm, sham-controlled design in an independent sample of SCZ patients, and 2) explore the role of amelioration of CD deficit as mechanistic basis of tDCS action through mediation analysis. ...
... Thirteen DSM-IV-TR SCZ patients with persistent AVH were examined in this study with written informed consent as approved by the ethics committee [Trial No. CTRI/2014/12/005307]; these patients are a random subset of a previous clinical study (Bose et al., 2018) who underwent neurophysiological assessment of CD at pre and post tDCS time points. Using an auditory paradigm (Ford et al., 2010;Nawani et al., 2014), N1 component of event-related potential that reflects cortical responsiveness of auditory cortex to sounds, was elicited in two conditionsi) Talk (with online auricular feedback of self-spoken speech sounds) and ii) Listen (passive playback of recorded self-spoken speech sounds). The attenuated N1 amplitude of talk condition relative to listen condition denotes cortical suppression during talk and is indicative of successful corollary discharge. ...
Deficient corollary discharge (CD) has been linked to agency related anomalies in schizophrenia (SCZ), especially with pathophysiology of auditory verbal hallucination (AVH). Transcranial Direct Current Stimulation (tDCS), a non-invasive, safe neuromodulation technique, is a re-emerging intervention with promising potential to treat schizophrenia. In an open label study, we reported add-on tDCS to ameliorate CD deficit in SCZ patients with persistent AVH. In this report, 1) we replicate this observation using a randomized, double-blind, parallel-arm, sham-controlled design in an independent sample of SCZ patients, and 2) explore role of CD amelioration as mechanistic basis of tDCS action through mediation analysis.
... tDCS is a classical neuromodulation technique used for the treatment of schizophrenia patients who experience persistent hallucinations. Here, we identified 17 articles studying the r e v u e n e u r o l o g i q u e 1 7 2 ( 2 0 1 6 ) 6 5 3 -6 7 9 effect of tDCS on AVH in schizophrenia, including eleven clinical case studies (65%) [109][110][111][112][113][114][115][116][117][118][119], five double-blinded randomized controlled trials versus placebo (29%) [120][121][122][123]125] and one open study [124] (Table 3). Globally, these studies used a homogeneous set of tDCS parameters. ...
... The number of sessions varied from five [118,123] to 20 [115]. AVH were assessed with the AHRS [110][111][112][113][114]117,119,120,123], the PANSS [115,123,125], the PSYRATS [114,118] and the HCS [109]. ...
Auditory verbal hallucinations (AVH) are among the most characteristic symptoms of schizophrenia and have been linked to likely disturbances of structural and functional connectivity within frontal, temporal, parietal and sub-cortical networks involved in language and auditory functions. Resting-state functional magnetic resonance imaging (fMRI) has shown that alterations in the functional connectivity activity of the default-mode network (DMN) may also subtend hallucinations. Non-invasive neurostimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) have the ability to modulate activity of targeted cortical sites and their associated networks, showing a high potential for modulating altered connectivity subtending schizophrenia. Notwithstanding, the clinical benefit of these approaches remains weak and variable. Further studies in the field should foster a better understanding concerning the status of networks subtending AVH and the neural impact of rTMS in relation with symptom improvement. Additionally, the identification and characterization of clinical biomarkers able to predict response to treatment would be a critical asset allowing better care for patients with schizophrenia.
... Using EEG, Nawani et al. [47] investigated the effect of tDCS on auditory hallucinations and the N100 amplitude of auditory evoked potential while patients were presented with speech stimuli as compared to when they were asked to produce speech. In healthy volunteers, the N100 amplitude is typically augmented when they listen to speech as compared to when they speak. ...
... This impairment has been associated with left temporal cortex abnormalities [48] and fronto-temporal dysconnectivity [49] observed in these patients. In their study, Nawani et al. [47] described no difference in N100 amplitude between speak and listen conditions before tDCS. Following tDCS, they reported that auditory hallucinations were reduced and the N100 amplitude was significantly smaller in the speak condition as compared to listen. ...
Schizophrenia is a severe and frequent neuropsychiatric disorder. Despite antipsychotic medications, up to 30% of patients with schizophrenia still report disabling treatment-resistant symptoms. Transcranial direct current stimulation (tDCS) has been proposed as a novel method to alleviate such symptoms. Here, we review studies investigating the effects of tDCS on symptoms, cognition, brain activity and cortical plasticity in patients with schizophrenia. We provide an up-to-date and comprehensive overview of the use of tDCS in patients with schizophrenia. More specifically, we first present the effects of tDCS on treatment-resistant symptoms of schizophrenia. We report that tDCS applied over the fronto-temporal regions reduced auditory hallucinations, with a mean 34% reduction of symptoms. Moreover, tDCS applied over both prefrontal cortices reduced negative symptoms and catatonia. We discuss the need for further sham-controlled studies to confirm these effects. Second, we present the impact of tDCS on cognitive functions in patients with schizophrenia. Positive effects of tDCS have been reported on learning, working memory, attention and source-monitoring. Third, we review the effects of tDCS on brain activity in patients with schizophrenia. Although only few studies investigated the effects of tDCS using neuroimaging technics, these studies are helpful at identifying the mechanisms of action of tDCS in schizophrenia. Fourth, we present tDCS studies on cortical plasticity showing reduced cortical plasticity in patients with schizophrenia that tDCS may beneficially modulate. Lastly, we discuss the safety aspects of tDCS in patients with schizophrenia and potential directions to improve efficacy for this clinical populations.
... Nawani et al. [38] investigated the clinical and neurophysiological effects of tDCS (anode over the left DLPFC, cathode over the left temporoparietal region) in five patients with refractory auditory verbal hallucinations. After 5 days of tDCS performed twice daily, there was a significant improvement in these symptoms. ...
... The Andrade study [46] explored the long-term use of tDCS (cathode over the left temporoparietal cortex, anode over the left DLPFC), with once-to twice-daily tDCS sessions for Tingling [46] Rakesh et al. [40] Homan et al. T3P3 None [42] Nawani et al. [45] Nawani et al. [38] Brunelin et al. [37] Mattai et al. nearly 3 years, with sustained improvement, in a clozapinerefractory patient with schizophrenia. Interestingly, when the sessions were performed in alternate days, the benefits attenuated or were lost. ...
Although recent clinical studies using transcranial direct current stimulation (tDCS) for schizophrenia showed encouraging results, several tDCS montages were employed and their current flow pattern has not been investigated. We performed a systematic review to identify clinical tDCS studies in schizophrenia. We then applied computer head modeling analysis for prediction of current flow. Out of 41 references, we identified 12 relevant studies. The most employed montage was anode and cathode over the left dorsolateral prefrontal and temporoparietal cortex, respectively. Computational model analysis predicted activation and under-activation under the anode and the cathode, respectively, occurring in areas respectively associated with negative and positive symptoms. We also identified tDCS-induced electrical currents in cortical areas between the electrodes (frontoparietal network) and, to a lesser extent, in deeper structures involved in schizophrenia pathophysiology. Mechanisms of tDCS effects in schizophrenia and the usefulness of computer modeling techniques for planning tDCS trials in schizophrenia are discussed.
... A weak efference copy of the intended overt and covert speech leads to corollary discharge dysfunction with resultant AVH in SZ (80). Moreover, after addon treatment with fronto-temporoparietal tDCS, the strength of efference copy is shown to improve in SZ-AVH (81); this may mediate the therapeutic effects of tDCS (82). Thus, the relevance of the precentral gyrus in predicting the clinical response of AVH to tDCS may be understood in the context of the link between the precentral gyrus and efference copy. ...
Transcranial direct current stimulation (tDCS) is a promising adjuvant treatment for persistent auditory verbal hallucinations (AVH) in Schizophrenia (SZ). Nonetheless, there is considerable inter-patient variability in the treatment response of AVH to tDCS in SZ. Machine-learned models have the potential to predict clinical response to tDCS in SZ. This study aims to examine the feasibility of identifying SZ patients with persistent AVH (SZ-AVH) who will respond to tDCS based on resting-state functional connectivity (rs-FC). Thirty-four SZ-AVH patients underwent resting-state functional MRI at baseline followed by add-on, twice-daily, 20-min sessions with tDCS (conventional/high-definition) for 5 days. A machine learning model was developed to identify tDCS treatment responders based on the rs-FC pattern, using the left superior temporal gyrus (LSTG) as the seed region. Functional connectivity between LSTG and brain regions involved in auditory and sensorimotor processing emerged as the important predictors of the tDCS treatment response. L1-regularized logistic regression model had an overall accuracy of 72.5% in classifying responders vs. non-responders. This model outperformed the state-of-the-art convolutional neural networks (CNN) model—both without (59.41%) and with pre-training (68.82%). It also outperformed the L1-logistic regression model trained with baseline demographic features and clinical scores of SZ patients. This study reports the first evidence that rs-fMRI-derived brain connectivity pattern can predict the clinical response of persistent AVH to add-on tDCS in SZ patients with 72.5% accuracy.
... Upon full assessment of the 22 records, 3 were already included in our quality assessment and the remaining 19 did not satisfy our inclusion criteria. Of the total 119 studies, 74 investigated rTMS including 48 trials (Bagati et al., 2009;Bais et al., 2017Bais et al., , 2014Blumberger et al., 2012;Brunelin et al., 2006;Chen et al., 2019;d'Alfonso et al., 2002;de Jesus et al., 2011;de Weijer et al., 2014;Demirtas-Tatlidede et al., 2010;Dlabac-de Lange et al., 2015;Fitzgerald et al., 2008Fitzgerald et al., , 2007Fitzgerald et al., , 2005Hoffman et al., 2013Hoffman et al., , 2005Hoffman et al., , 2003Hoffman et al., , 1999Homan et al., 2012;Horacek et al., 2007;Jandl et al., 2006;Kim et al., 2014;Kimura et al., 2016;Kindler et al., 2013aKindler et al., , 2013bKlirova et al., 2013;Koops et al., 2016;Lai et al., 2010;Lee et al., 2005;Loo et al., 2010;Maïza et al., 2013;McIntosh et al., 2004;Montagne-Larmurier et al., 2009;Novák et al., 2006;Oh and Kim, 2011;Paillère-Martinot et al., 2017;Plewnia et al., 2014;Poulet et al., 2005;Rosa et al., 2007;Rosenberg et al., 2011;Schönfeldt-Lecuona et al., 2004;Slotema et al., 2012Slotema et al., , 2011Sommer et al., 2007;van Lutterveld et al., 2012;Vercammen et al., 2010Vercammen et al., , 2009Wagner et al., 2019) and 26 case reports (Bor et al., 2009;Chung et al., 2007;Dollfus et al., 2008;Eberle et al., 2010;Favalli et al., 2007;Fitzgerald et al., 2006;Fitzgerald and Daskalakis, 2011;Franck et al., 2003;Garg et al., 2019;Ghanbari Jolfaei et al., 2016;Giesel et al., 2012;Goyal et al., 2015;Jardri et al., 2012Jardri et al., , 2009Jardri et al., , 2007Langguth et al., 2006;Poulet et al., 2009Poulet et al., , 2008Poulet et al., , 2006Rachid et al., 2013;Schreiber et al., 2002;Schulz et al., 2015;Sidhoumi et al., 2010;Subramanian et al., 2013;Thirthalli et al., 2008;Wang et al., 2019), and 45 investigated tES including 26 trials (Agarwal et al., 2016;Bose et al., 2014Bose et al., , 2018Bose et al., , 2019Brunelin et al., 2012aBrunelin et al., , 2015Chang et al., 2018Chang et al., , 2019Chhabra et al., 2018;Fitzgerald et al., 2014;Fröhlich et al., 2016;Kantrowitz et al., 2019;Kao et al., 2020;Kim et al., 2020;Koops et al., 2018;Lindenmayer et al., 2019;Mellin et al., 2018;Mondino et al., 2015bMondino et al., , 2016Mondino et al., , 2020Shivakumar et al., 2015;Sreeraj et al., 2018Sreeraj et al., , 2020Subramaniam et al., 2015;Valiengo et al., 2019;Yoon et al., 2019) and 19 case reports (Andrade, 2013;Bose et al., 2017Bose et al., , 2015Brunelin et al., 2012b;Jacks et al., 2014;Janovik et al., 2019;Kallel et al., 2016;Mezger et al., 2020;Nawani et al., 2014bNawani et al., , 2014aPalm et al., 2013;Praharaj et al., 2015;Schwippel et al., 2017;Shenoy et al., 2015;Shiozawa et al., 2014Shiozawa et al., , 2013Shivakumar et al., 2014;Thimmashetty et al., 2020;Wysokiński, 2020). Of the 74 rTMS records, 67 reported on independent study samples and 7 reported on samples that overlapped with these. ...
Novel treatment modalities, such as non-invasive brain stimulation (NIBS), typically focus on patient groups that have failed multiple treatment interventions. Despite its promise, the clinical translation of NIBS in schizophrenia has been limited. One important obstacle to implementation is the inconsistent reporting of treatment resistance in the clinical trial literature contributing to heterogeneity in reported effects. In response, we develop a numerical approach to synthesize quality of assessment of Treatment-Resistant Schizophrenia (TRS) and apply this to studies investigating therapeutic response to NIBS in patients with schizophrenia. Literature search conducted through PubMed database identified 119 studies investigating Transcranial Magnetic Stimulation and Transcranial Electrical Stimulation in treating resistant schizophrenia symptoms. A quality score out of 11 was assigned to each study based on adherence to the international consensus guidelines for TRS developed by the Treatment Response and Resistance in Psychosis (TRRIP) group. Results revealed an overall paucity of studies with thorough assessment and/or reporting of TRS phenomenon, as evidenced by a mean quality score of 3.38/11 (SD: 1.01) for trials and 5.16/11 (SD: 1.57) for case reports, though this improved minimally since the publication of consensus criteria. Most studies considered treatment-resistance as a single dimensional construct by reporting resistance of a single symptom, and failed to establish treatment adherence, resistance time course and functional impairment. We conclude that the current NIBS literature in schizophrenia do not reflect its true effects on treatment-resistance. There is an urgent need to improve assessment and reporting standards of clinical trials that target TRS.
... HC had larger Lateralized readiness potential (LRP) -a measure of motor plan -preceding button press for tone delivery and N1 suppression than SCZ Positive correlation between LRP amplitude and N1 suppression across both the groups Implication Even when efference copy is indirectly related to the sound associated with it and the sound does not strictly come from "self" SCZ exhibit efference copy and CD dysfunction Pre-movement activity reflects the efference copy Self-delivery of tones also produces robust N1 suppression and involves auditory cortex Using this paradigm CD mechanism can be studies in lab animals. Neurophysiological recordings used with lab animals and humans are comparable, making both the 'talk' and 'button press' paradigms and the physiological assay translatable across species (Nawani et al., 2014) ERP Paradigm: Subjects were asked to press a button with the index finger of their right hand, at will, every 1 to 2 seconds. They were stopped after about 2 minutes of pressing or after about 50 to 60 presses. ...
... This phenomenon might be attributed to the fact that placing the cathodic electrode over the Wernicke region can reduce cerebral blood flow and decrease functional connectivity between left TPJ and inner speech production brain areas (Mondino et al., 2016). A recent study showed that tDCS applying on frontal and temporal-parietal regions modulates the neural signal transformation from motor to sensory regions (corollary discharge function) in patients with AVH (Nawani et al., 2014). ...
Auditory hallucinations are the most common psychiatric symptoms of schizophrenia with high recurrence and refractoriness. Transcranial direct current stimulation (tDCS), a novel, non-invasion and affordable brain stimulation technique, has been recently applying on the schizophrenia patients to treat the auditory hallucinations. To analyze the efficacy of tDCS treatment on such symptoms and to reveal its potential working mechanisms, we carried out a structured literature search in PubMed, Embase and Cochrane Library database up to May 12, 2018. Five studies that met inclusion criteria with a total of 137 patients were included in this meta-analysis. After pooling all the data, we found that there was no significant effect between active group and sham group of tDCS (p = 0.18). When we removed one study that did not collaboratively stimulate the frontal-temporal sites, the active tDCS group marks a significant improvement of therapeutic effect compared with sham group (p = 0.007). Our findings suggested that tDCS could be a promising tool to alleviate auditory hallucinations, provided that the simulation sites and protocols are targeting at the sensorimotor frontal-parietal network.
... Furthermore, there is evidence that transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, can reduce the frequency of AVH in hallucinating schizophrenia patients (Brunelin et al., 2012;Mondino et al., 2015;though see Fitzgerald et al., 2014, for a null result), attenuate cortical activity in response to self-produced vocalisations (Nawani et al., 2014), and modulate false perceptions in a non-clinical population (Moseley et al., 2014), when applied in a frontotemporal montage (i.e., with electrodes positioned over prefrontal and superior temporal regions). A recent tDCS study attempted to link findings regarding the neural basis of reality monitoring and auditory hallucinations, by modulating reality monitoring performance using tDCS applied to the left STG, in a non-clinical population. ...
Source monitoring, or the ability to recall the origin of information, is a crucial aspect of remembering past experience. One facet of this, reality monitoring, refers to the ability to distinguish between internally generated and externally generated information, biases in which have previously been associated with auditory verbal hallucinations in schizophrenia. Neuroimaging evidence suggests that medial prefrontal and superior temporal (STG) regions may play a role in reality monitoring for auditory verbal information, with evidence from a previous neurostimulation experiment also suggesting that modulation of excitability in STG may affect reality monitoring task performance. Here, two experiments are reported that used transcranial direct current stimulation (tDCS) to modulate excitability in medial prefrontal and superior temporal cortex, to further investigate the role of these brain regions in reality monitoring. In the first experiment (N = 36), tDCS was applied during the encoding stage of the task, while in the second experiment, in a separate sample (N = 36), it was applied during the test stage. There was no effect of tDCS compared to a sham condition in either experiment, with Bayesian analysis providing evidence for the null hypothesis in both cases. This suggests that tDCS applied to superior temporal or medial prefrontal regions may not affect reality monitoring performance, and has implications for theoretical models that link reality monitoring to the therapeutic effect of tDCS on auditory verbal hallucinations.
... In schizophrenia patients with persistent auditory verbal hallucinations, add-on tDCS (in open-label design) resulted in significant reduction of auditory hallucination severity with concurrent amelioration of corollary discharge deficit. 74) This observation was replicated recently in randomized, double-blind, sham-controlled design; importantly, the magnitude of cortical suppression during corollary discharge had a significant positive correlation with reduction in auditory hallucination scores. 75) These observations are in conformation with previous report of neuroplastic effect of tDCS enhancing auditory processing efficiency. ...
Corollary discharge mechanism refers to the suppression of sensory consequences of self-generated actions; a process that serves to distinguish between self and non-self based on discrimination of origination of action. It explains, say for example, why we cannot tickle ourselves. This review discusses how corollary discharge model is an essential neural integration mechanism central to the motor functioning of animal kingdom. In this article, research conducted in the field of corollary discharge has been reviewed to understand the neuroanatomical and neurophysiological basis of corollary discharge and gain insight into the biochemical basis of its dysfunction. This review article also explores the role of corollary discharge and its dysfunction in the presentation of symptoms of schizophrenia, discussing the findings from corollary discharge studies on schizophrenia population. Lastly, the link between schizophrenia psychopathology and corollary discharge dysfunction has been highlighted, and an attempt has been made to establish a case for correction of corollary discharge deficit in schizophrenia through neuromodulation.
... Zwei offene Studien ohne Placebokontrolle konnten eine Reduktion akustischer Halluzinationen um etwa 30% auf der Auditory Hallucination Rating Scale (AHRS) in 5 bzw. 6 Patienten nachweisen (28,29). Ebenso eine Verminderung akustischer Halluzinationen um 32% konnte in einer offenen Studie mit 21 Patienten beobachtet werden (30). ...
Ziel: Die transkranielle Gleichstromstimulation ist ein nicht invasives Verfahren zur Neuromodulation, das seit etwa zehn Jahren intensiv in der Behandlung von neuropsychia trischen Erkrankungen erforscht wird. Es wird ein Überblick über Einsatz und Entwicklung des Verfahrens bei psychiatrischen Erkrankungen gegeben. Material und Methoden: Eine Literaturrecherche wurde über die Literaturdatenbank des US-amerikanischen National Institute of Mental Health (Pubmed) durchgeführt mit den Stichworten “tDCS” bzw. “transcranial direct current stimulation” und dem jeweiligen gesuchten Krankheitsbild. Ergebnisse: Vor allem in der Behandlung der Depression liegen doppelblinde randomisierte klinische Studien vor, die eine Wirksamkeit der tDCS belegen konnten, wobei diese mit steigender Therapieresistenz abnimmt. In der Behandlung der Schizophrenie liegen wenige Studien zur Verbesserung von klinischer Symptomatik oder Kognition vor. Relativ gut erforscht ist der Einsatz der tDCS bei der Behandlung der Tabakabhängigkeit bezüglich Reduktion des Rauchverlangens, ebenso bei der Alkoholabhängigkeit. Die Modulation des Essverlangens konnte in mehreren Studien nachgewiesen werden. Für die Behandlung der Alzheimer Demenz liegen gemischte Resultate aus Studien vor. Die Behandlung sonstiger psychiatrischer Erkrankungen, ebenso wie die Behandlung psychiatrischer Komorbidität bei neurologischen Erkrankungen, ist meist nur auf Ebene von Fallberichten beschrieben. Schlussfolgerung: Nur für wenige Krankheitsbilder besteht eine ausreichend gute Datenlage, um die tDCS als Zusatztherapie empfehlen zu können. Für eine Zulassung der tDCS als etablierte Therapie sind noch umfassende systematische Untersuchungen bei den meisten psychiatrischen Erkrankungen nötig. Insgesamt gilt die Anwendung als sicher und nebenwirkungsarm, selbst bei intensivierter Anwendung. Dennoch bedarf es weiterer Standardisierung des Verfahrens bezüglich Elektrodenpositionierung, Stromstärke, Dauer und Frequenz der Anwendung sowie Gesamtzahl der Anwendungen.
Summary
Objective: Transcranial direct current stimulation is a non-invasive tool for neuromodulation and has been investigated in neuro - psychiatric disorders over the last 10 years. In this review, we provide an overview of application and evolvement of this therapeutic tool in psychiatric disorders over the last years. Regarding depressive disorders and schizophrenia, this review follows up directly on two publications (2013 and 2014) on the respective disorders. Regarding other psychiatric disorders, an overview over studies mostly published in recent years is given. Materials and methods: A literature search was performed using the database of the National Institute of Health (Pubmed) with the terms “tDCS”, “transcranial direct current stimulation”, and the respective disorder searched. Results: For the treatment of depression, a couple of double-blind randomized controlled trials were found that show efficacy of tDCS as an adjunct to psychopharmacologic treatment. Efficacy of treatment is declining with increasing treatment resistance. For the treatment of schizophrenia, only a few clinical trials report improvement of psychopathologic symptoms or cognition. There is relatively good data for the use of tDCS in the treatment of tobacco addiction and the reduction of nicotine craving, as well as for the treatment of alcohol addiction. There is also some data on modulation of food craving by tDCS. The treatment of dementia (i.e. Alzheimer) is evaluated in several studies and brought diverging results. The improvement of other psychiatric disorders such as general anxiety disorder, obsessive- compulsive disorder, Tourette’s syndrome, or psychiatric symptoms in neurologic disorders is reported in case reports only. Application of tDCS during pregnancy is discussed. Safety aspects were evaluated and brought no additional information to the sound knowledge of a safe and well tolerable use of tDCS. Conclusions: For only a few psychiatric disorders, i.e. depressive disorders, and to some extent schizophrenia and addiction disorders, there is enough data available to suggest tDCS as an adjunct treatment to psychopharmacologic therapy. There is a lack of sufficient and reliable data to establish tDCS as a regular treatment tool in most psychiatric disorders. Application of tDCS is safe and well tolerable even when using intensive stimulation protocols. However there is a need for standardization of electrode positioning, current strength, duration and frequency of application and total number of applications. Finally, regulatory authorities in most countries are not able to suggest tDCS due to lacking evidence of efficacy.
... Interestingly, dysfunction of corollary discharge circuitry has been identified in patients diagnosed with schizophrenia (Feinberg, 1978;Feinberg and Guazzelli, 1999), with the underlying mechanisms still being investigated, including assessments of eye movements (Ford et al., 2001;Ford and Mathalon, 2004;Nawani et al., 2014;Pack, 2014;Richard et al., 2014). Nevertheless, as was noted earlier, there is a clear similarity between the proposed (computational) forward models and the actual anatomy of the first order and higher order nuclei of the thalamus, with at least some of the driver messages that these nuclei receive conveying efference copies/corollary discharges. ...
The mediodorsal nucleus of the thalamus (MD) has been implicated in executive functions (such as planning, cognitive control, working memory, and decision-making) because of its significant interconnectivity with the prefrontal cortex (PFC). Yet, whilst the roles of the PFC have been extensively studied, how the MD contributes to these cognitive functions remains relatively unclear. Recently, causal evidence in monkeys has demonstrated that in everyday tasks involving rapid updating (e.g., while learning something new, making decisions, or planning the next move), the MD and frontal cortex are working in close partnership. Furthermore, researchers studying the MD in rodents have been able to probe the underlying mechanisms of this relationship to give greater insights into how the frontal cortex and MD might interact during the performance of these essential tasks. This review summarizes the circuitry and known neuromodulators of the MD, and considers the most recent behavioral, cognitive, and neurophysiological studies conducted in monkeys and rodents; in total, this evidence demonstrates that MD makes a critical contribution to cognitive functions. We propose that communication occurs between the MD and the frontal cortex in an ongoing, fluid manner during rapid cognitive operations, via the means of efference copies of messages passed through transthalamic routes; the conductance of these messages may be modulated by other brain structures interconnected to the MD. This is similar to the way in which other thalamic structures have been suggested to carry out forward modeling associated with rapid motor responding and visual processing. Given this, and the marked thalamic pathophysiology now identified in many neuropsychiatric disorders, we suggest that changes in the different subdivisions of the MD and their interconnections with the cortex could plausibly give rise to a number of the otherwise disparate symptoms (including changes to olfaction and cognitive functioning) that are associated with many different neuropsychiatric disorders. In particular, we will focus here on the cognitive symptoms of schizophrenia and suggest testable hypotheses about how changes to MD-frontal cortex interactions may affect cognitive processes in this disorder.
... Later studies have documented this tDCSinduce LTP changes in human subjects as well (10-12) through modulation of transmembrane potential through altered intracellular ions concentration across synapse (13). These tDCS induced changes in neuroplasticity have been shown in both healthy subjects as well as schizophrenia patients (14)(15)(16). ...
Objective: Recent observations demonstrate a significant ameliorative effect of add-on transcranial Direct Current Stimulation (tDCS) on auditory verbal hallucinations (AVHs) in schizophrenia. Of the many SNPs, NRG1 rs35753505 and COMT rs4680 polymorphisms have shown to have a strong association with neuroplasticity effect in schizophrenia.
Methods: Schizophrenia patients (N=32) with treatment resistant auditory hallucinations were administered with an add-on tDCS. The COMT (rs4680) and NRG1 (rs35753505) genotypes were determined. The COMT genotypes were categorised into Val group (GG; N=15) and Met group (GG/AG; N=17) and NRG1 genotypes were categorised into AA group (N=12) and AG/GG group (N=20).
Results: The reduction in AHS score was significantly affected by COMT-GG genotype [Time x COMT interaction: F(1,28)=10.55, p=0.003, ɳ2=0.27]. Further, COMT-GG effect was epistatically influenced by the co-occurrence of NRG1-AA genotype [Time X COMT X NRG1 interaction: F(1,28)=8.09, p=0.008, ɳ2 =0.22]. Irrespective of genotype, females showed better tDCS response than males [Time X Sex interaction: F(1,21)=4.67, p=0.04, ɳ2=0.18]
Conclusion: COMT-GG and NRG1-AA genotypes aid the tDCS induced improvement in AVHs in schizophrenia patients. Our preliminary observations need replication and further systematic research to understand the neuroplastic gene determinants that modulate the effect of tDCS.
... Interestingly, the brain regions modulated by fronto-temporal tDCS (Mondino et al., 2016) are part of network that sub-serve neurocognitive mechanisms proposed for AVH genesis like aberrant source-monitoring (Wang et al., 2011), corollary discharge deficit (Ford and Mathalon, 2005) and sensory gating abnormalities (Bak et al., 2014). Interestingly, the tDCS protocol used in this study has been shown to improve source-monitoring (Mondino et al., 2015b), ameliorate corollary discharge deficit (Nawani et al., 2014a), modulate sensory gating (Kim et al., 2017) in schizophrenia patients with AVH. While these studies have offered interesting leads on the neurobiological basis for the ameliorative effects of tDCS on AVH, we need further research to delineate the differential contribution of temporo-parietal versus frontal stimulation. ...
Persistent auditory verbal hallucinations (AVH) that are refractory to antipsychotic medications are reported in about 20-30% of schizophrenia patients. Transcranial Direct Current Stimulation (tDCS), a non-invasive and safe neuromodulatory technique, has attracted significant interest as an add-on treatment for refractory AVH in schizophrenia. Studies examining the efficacy of tDCS for refractory AVH in schizophrenia have reported inconsistent findings. In this study, using a randomized, double-blind, sham-controlled design (RCT), we sought to examine the effect of add-on tDCS [anode corresponding to left dorsolateral prefrontal cortex and cathode to left temporo-parietal junction; 2-mA, twice-daily sessions for 5-days] to treat refractory AVH in schizophrenia patients (N=25); following this RCT phase, patients that had less than 30% reduction in AVH severity were offered an open-label extension (OLE) active stimulation to evaluate the effect of cross-over to verum tDCS. In the RCT phase, repeated measures ANOVA with tDCS type [verum (N=12) vs. sham (N=13)] as between subjects factor demonstrated a significant tDCS-type X time-point interaction [F=21.5, p<0.001, partial-η2=0.48] with significantly greater reduction of AVH score in verum tDCS group as compared to sham group. In the OLE phase, sham-to-verum crossed over patients (N=13) showed significantly greater reduction in AVH severity than their corresponding change during RCT phase (t=2.9; p=0.01). Together, these observations add further support to the beneficial effects of add-on tDCS to treat refractory AVH schizophrenia.
... 1-3mA) through electrodes always placed over point midway between F3 and FP1 (left dorsolateral prefrontal cortex) and the cathode located over a point midway between T3 and P3 (left temporo-parietal junction). [9][10][11][12] The time of stimulation can be set from 5 to 20 minutes. [13][14][15][16] There have been some concerns about tDCS despite more than half a century of use. ...
Background
Transcranial direct current stimulation (tDCS) is a non-invasion brain stimulation, which has been suggested as a safe and promising treatment for auditory hallucinations, however, no systematic review has been conducted to evaluate the effects of tDCS on auditory hallucinations (AH).
Objective
To investigate the efficacy and safety of tDCS for auditory hallucinations among patients with schizophrenia.
Methods
We searched relevant randomized controlled trials (RCTs) from PubMed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, Chinese Biological Medical Literature Database, and Taiwan Electronic Periodical Services (TEPS) before February 13, 2016. Studies were selected based on pre-defined inclusion and exclusion criteria. The quality of each included study was assessed by the risk of bias table. The levels of evidence of primary outcomes were evaluated using GRADE criteria. Data synthesis was conducted using RevMan 5.3.
Results
304 papers were screened. Finally, three studies with a combined sample size of 87 patients were included in the meta-analysis. Two studies were classified as having ‘low risk of bias’, one study was classified as having ‘unclear’. Inconsistent results and the overall level of evidence of primary outcome was graded as ‘low’.
Conclusions
The sample sizes of the published studies were small and the results were inconsistent. We could not draw any strong conclusions from these trials. Further high quality RCTs with large sample sizes are needed to assess the efficacy of tDCS for auditory hallucinations in patients with schizophrenia.
... prefrontal dysfunctions are associated with a variety of neurological and psychiatric diseases, prefrontal tDCS holds promise as a means of improving impaired brain function in neurological (for review see Flöel, 2014) and psychiatric diseases (Fregni and Pascual-Leone, 2007;Iyer et al., 2005;Kuo et al., 2014). Clinical applications of prefrontal tDCS have been investigated in patients with disorders of consciousness (Thibaut et al., 2014), chronic pain (Arul-Anandam et al., 2009;Valle et al., 2009), Parkinson's disease Fregni et al., 2006d), major depression (MD) Brunoni et al., 2013;Dell'Osso et al., 2012;Ferrucci et al., 2009;Kalu et al., 2012;Loo et al., 2012;Loo et al., 2010;Martin et al., 2013Martin et al., , 2011Palm et al., 2012;Rigonatti et al., 2008), schizophrenia (Barr et al., 2012;Bose et al., 2014;Brunelin et al., 2012;Fitzgerald et al., 2014;Nawani et al., 2014;Vercammen et al., 2011), craving (Boggio et al., 2009Conti and Nakamura-Palacios, 2014;da Silva et al., 2013;Nakamura-Palacios et al., 2012), attention deficit hyperactivity disorder (ADHD) (Prehn-Kristensen et al., 2014) and tinnitus (Frank et al., 2012;. ...
Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs.
... Significant bulk of these publications has illustrated the clinical utility of tDCS in schizophrenia as a monotherapy, add-on treatment in acute phase of psychosis resulting in quicker amelioration of symptoms (92) insight facilitation into illness (93). In addition, studies from India have reported certain important leads towards the understanding of possible neurobiological basis for beneficial effects of tDCS in schizophrenia (94). However, all these studies are of openlabel nature; currently, controlled studies with stringent research design are in progress to ascertain the potential leads obtained in earlier reports. ...
... While all participants experienced improvements, being a non-smoker (Brunelin et al., 2015) and carrying a particular variant of a neuroplasticity-related gene (catechol-O-methyltransferase [COMT]) (Shivakumar et al., 2015 ) were both associated with having a greater therapeutic response. A number of case reports/series describing patients with refractory schizophrenia have also offered support (Brunelin et al., 2012b; Jacks et al., 2014; Nawani et al., 2014a Nawani et al., , 2014b Rakesh et al., 2013; Shenoy et al., 2015; Shivakumar et al., 2014). For instance, Shenoy et al. (2015) recorded near-total improvement of the exacerbation of AVHs during pregnancy, noted a delayed but persistent improvement in negative symptoms, and Rakesh et al. (2013) observed complete cessation of AVHs immediately after the first two tDCS sessions and at post-intervention re- assessment. ...
... schizophrenia patients and their unaffected relatives (Hasan et al., 2013a, 2012, 2011, 2013b) and has also been proposed to underlie symptom pathophysiology (Mondino et al., 2015a). Furthermore, improvement in symptom severity may be due to adaptive modulation of cortical plasticity (Nawani et al., 2014a, 2014b). tDCS has been demonstrated to be effective in reducing auditory hallucinations by presumably decreasing hyperactivity of the temporo-parietal junction (TPJ) in the first monocentric proof-ofprinciple trial (Brunelin et al., 2012). ...
Abstract
Transcranial direct current stimulation (tDCS) has generated interest as a treatment modality for schizophrenia. Dopamine, a critical pathogenetic link in schizophrenia, is also known to influence tDCS effects. We evaluated the influence of antipsychotic drug type (as defined by dopamine D2 receptor affinity) on the impact of tDCS in schizophrenia. DSM-IV-TR-diagnosed schizophrenia patients [N=36] with persistent auditory hallucinations despite adequate antipsychotic treatment were administered add-on tDCS. Patients were divided into three groups based on the antipsychotic’s affinity to D2 receptors. An auditory hallucinations score (AHS) was measured using the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS). Add-on tDCS resulted in a significant reduction inAHS. Antipsychotic drug type had a significant effect on AHS reduction. Patients treated with high affinity antipsychotics showed significantly lesser improvement compared to patients on low affinity antipsychotics or a mixture of the two. Furthermore, a significant sex-by-group interaction occurred; type of medication had an impact on tDCS effects only in women. Improvement differences could be due to the larger availability of the dopamine receptor system in patients taking antipsychotics with low D2 affinity. Sex-specific differences suggest potential estrogen-mediated effects. This study reports a first-time observation on the clinical utility of antipsychotic drug type in predicting tDCS effects in schizophrenia.
... 29 In most of these studies, tDCS sessions were delivered twice a day for 5 consecutive days (10 sessions). 14,18,[20][21][22][23][24][25][26][27][28][29] One study has investigated the effects of 15 once-daily tDCS sessions over 3 consecutive weeks and failed to report a significant effect on AVH. 30 However, brain correlates of the AVH reduction was not systematically investigated. Only a case study reported that cathodal tDCS applied over the left superior temporal gyrus coupled with anodal tDCS over the right supraorbital area was able to decrease cerebral blood flow in AVHrelated brain areas (ie, Wernicke's area, Broca's area and left Heschl's gyrus) in association with AVH reduction. ...
Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring.
© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
... Moreover, in these preliminary findings, the results seem to have a large effect size and the benefits lasted for sufficient duration, which makes them potentially clinically relevant (7). Recently, it has been shown that the improvement in auditory hallucination severity may be due to adaptive modulation of neuroplasticity (11,12). ...
Background and Aim Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders.
A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. Result Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials.
Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry.
... Significant bulk of these publications has illustrated the clinical utility of tDCS in schizophrenia as a monotherapy, add-on treatment in acute phase of psychosis resulting in quicker amelioration of symptoms (92) insight facilitation into illness (93). In addition, studies from India have reported certain important leads towards the understanding of possible neurobiological basis for beneficial effects of tDCS in schizophrenia (94). However, all these studies are of openlabel nature; currently, controlled studies with stringent research design are in progress to ascertain the potential leads obtained in earlier reports. ...
The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. Therefore, a group of research and clinician experts on tDCS were convened to review the research and clinical use of tDCS. This report reviews the regulatory status of tDCS and summarizes the results according to research, off-label, and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan, and the US. Research use, off label treatment, and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.
... Significant bulk of these publications has illustrated the clinical utility of tDCS in schizophrenia as a monotherapy, add-on treatment in acute phase of psychosis resulting in quicker amelioration of symptoms (92) insight facilitation into illness (93). In addition, studies from India have reported certain important leads towards the understanding of possible neurobiological basis for beneficial effects of tDCS in schizophrenia (94). However, all these studies are of openlabel nature; currently, controlled studies with stringent research design are in progress to ascertain the potential leads obtained in earlier reports. ...
The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. Therefore, a group of research and clinician experts on tDCS were convened to review the research and clinical use of tDCS. This report reviews the regulatory status of tDCS and summarizes the results according to research, off-label, and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan, and the US. Research use, off label treatment, and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.
... These results highlighted the ability of fronto-temporal tDCS to reduce the externalization bias and AVH frequency in patients with schizophrenia. This is consistent with a recent study showing that tDCS modulates the corollary discharge dysfunction in patients with AVH (Nawani et al., 2014). Moreover, our study brought evidence for a close relationship between source-monitoring processes and AVH and suggested a shared underlying brain pathway including left prefrontal areas and temporo-parietal areas (Moseley et al., 2013). ...
Background
The dorsolateral prefrontal cortex (DLPFC) is a key node of the frontal cognitive circuit. It is involved in executive control and many cognitive processes. Abnormal activities of DLPFC are likely associated with many psychiatric diseases. Modulation of DLPFC may have potential beneficial effects in many neural and psychiatric diseases. One of the widely used non-invasive neuromodulation technique is called transcranial direct current stimulation (or tDCS), which is a portable and affordable brain stimulation approach that uses direct electrical currents to modulate brain functions.
Objective
This review aims to discuss the results from the past two decades which have shown that tDCS can relieve clinical symptoms in various neurological and psychiatric diseases.
Methods
Here, we performed searches on PubMed to collect clinical and preclinical studies that using tDCS as neuromodulation technique, DLPFC as the stimulation target in treating neuropsychiatric disorders. We summarized the stimulation sites, stimulation parameters, and the overall effects in these studies.
Results
Overall, tDCS stimulation of DLPFC could alleviate the clinical symptoms of schizophrenia, depression, drug addiction, attention deficit hyperactivity disorder and other mental disorders.
Conclusion
The stimulation parameters used in these studies were different from each other. The lasting effect of stimulation was also not consistent. Nevertheless, DLPFC is a promising target for non-invasive stimulation in many psychiatric disorders. TDCS is a safe and affordable neuromodulation approach that has potential clinical uses. Larger clinical studies will be needed to determine the optimal stimulation parameters in each condition.
Neuroplasticity represents the dynamic structural and functional reorganization of the central nervous system, including its connectivity, due to environmental and internal demands. It is recognized as a major physiological basis for adaption of cognition and behaviour, and, thus, of utmost importance for normal brain function. Cognitive dysfunctions are major symptoms in psychiatric disorders, which are often associated with pathological alteration of neuroplasticity. Transcranial direct current stimulation (tDCS), a recently developed non-invasive brain stimulation technique, is able to induce and modulate cortical plasticity in humans via the application of relatively weak current through the scalp of the head. It has the potential to alter pathological plasticity and restore dysfunctional cognitions in psychiatric diseases. In the last decades, its efficacy to treat psychiatric disorders has been explored increasingly. This review will give an overview of pathological alterations of plasticity in psychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects.
Transcranial direct current stimulation (tDCS) is a technique of noninvasive cortical stimulation allowing significant modification of brain functions. Clinical application of this technique was reported for the first time in March 2005. This paper presents a detailed list of the 340 articles (excluding single case reports) which have assessed the clinical effect of tDCS in patients, at least when delivered to cortical targets. The reviewed conditions were: pain syndromes, Parkinson's disease, dystonia, cerebral palsy, post-stroke limb motor impairment, post-stroke neglect, post-stroke dysphagia, post-stroke aphasia, primary progressive aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer's disease and other types of dementia, tinnitus, depression, auditory hallucinations and negative symptoms of schizophrenia, addiction and craving, autism, and attention disorders. The following data were collected: (i) clinical condition; (ii) study design; (iii) sample size; (iv) anode and cathode locations; (v) stimulation intensity and electrode area; (vi) number and duration of sessions; (vii) clinical outcome measures and results. This article does not include any meta-analysis and aims simply at providing a comprehensive overview of the raw data reported in this field to date, as an aid to researchers.
This chapter proposes an overview of current evidence and future directions for using tDCS in schizophrenia. To date, the effects of tDCS have been investigated in three main outcomes: (1) to alleviate auditory verbal hallucinations using a frontotemporal tDCS montage (the anode placed over the left dorsolateral prefrontal cortex coupled with the cathode placed over the left temporoparietal junction); (2) to alleviate negative symptoms using a frontal montage (the anode placed over the left dorsolateral prefrontal cortex coupled with the cathode placed over the right dorsolateral prefrontal cortex, the right supraorbital region or extra-cephalically); and (3) to enhance cognitive functions, using different tDCS montages. Promising results have been reported for these three outcomes. tDCS can decrease the severity of symptoms such as auditory verbal hallucinations and negative symptoms by about 30 % and enhance a wide range of cognitive functions (e.g., working memory, self-monitoring, facial emotion recognition). However, most studies to date are case-reports and open labeled studies with small samples. Thus, large randomized controlled studies are needed to confirm the usefulness of tDCS in schizophrenia.
It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson's disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.
Some 25%–30% of patients with schizophrenia have auditory verbal hallucinations that are refractory to antipsychotic drugs. Outcomes in studies of repetitive transcranial magnetic stimulation suggest the possibility that application of transcranial direct-current stimulation (tDCS) with inhibitory stimulation over the left temporo-parietal cortex and excitatory stimulation over the left dorsolateral prefrontal cortex could affect hallucinations and negative symptoms, respectively. The authors investigated the efficacy of tDCS in reducing the severity of auditory verbal hallucinations as well as negative symptoms.
Thirty patients with schizophrenia and medication-refractory auditory verbal hallucinations were randomly allocated to receive 20 minutes of active 2-mA tDCS or sham stimulation twice a day on 5 consecutive weekdays. The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the left temporo-parietal cortex.
Auditory verbal hallucinations were robustly reduced by tDCS relative to sham stimulation, with a mean diminution of 31% (SD=14; d=1.58, 95% CI=0.76–2.40). The beneficial effect on hallucinations lasted for up to 3 months. The authors also observed an amelioration with tDCS of other symptoms as measured by the Positive and Negative Syndrome Scale (d=0.98, 95% CI=0.22–1.73), especially for the negative and positive dimensions. No effect was observed on the dimensions of disorganization or grandiosity/excitement.
Although this study is limited by the small sample size, the results show promise for treating refractory auditory verbal hallucinations and other selected manifestations of schizophrenia.
The neural basis of motor response inhibition has drawn considerable attention in recent imaging literature. Many studies have used the go/no-go or stop signal task to examine the neural processes underlying motor response inhibition. In particular, showing greater activity during no-go (stop) compared with go trials and during stop success compared with stop error trials, the right inferior prefrontal cortex (IFC) has been suggested by numerous studies as the cortical area mediating response inhibition. Many of these same studies as well as others have also implicated the presupplementary motor area (preSMA) in this process, in accord with a function of the medial prefrontal cortex in goal-directed action. Here we used connectivity analyses to delineate the roles of IFC and preSMA during stop signal inhibition. Specifically, we hypothesized that, as an integral part of the ventral attention system, the IFC responds to a stop signal and expedites the stop process in the preSMA, the primary site of motor response inhibition. This hypothesis predicted that preSMA and primary motor cortex would show functional interconnectivity via the basal ganglia circuitry to mediate response execution or inhibition, whereas the IFC would influence the basal ganglia circuitry via connectivity with preSMA. The results of Granger causality analyses in 57 participants confirmed this hypothesis. Furthermore, psychophysiological interaction showed that, compared with stop errors, stop successes evoked greater effective connectivity between the IFC and preSMA, providing additional support for this hypothesis. These new findings provided evidence critically differentiating the roles of IFC and preSMA during stop signal inhibition and have important implications for our understanding of the component processes of inhibitory control.
Scales to measure the severity of different dimensions of auditory hallucinations and delusions are few. Biochemical and psychological treatments target dimensions of symptoms and valid and reliable measures are necessary to measure these.
The inter-rater reliability and validity of the Psychotic Symptom Rating Scales (PSYRATS: auditory hallucination subscale and delusions subscale), which measure several dimensions of auditory hallucinations and delusions were examined in this study.
The two scales were found to have excellent inter-rater reliability. Their validity as compared with the KGV scale (Krawiecka et al. 1977) was explored.
It is concluded that the PSYRATS are useful assessment instruments and can complement existing measures.
Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinson's disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.
The aim of the present study was to specify the involvement of the basal ganglia in motor response selection and response inhibition. Two samples were studied. The first sample consisted of patients diagnosed with Parkinson's disease (PD) who received deep-brain stimulation (DBS) of the subthalamic nucleus (STN). The second sample consisted of patients who received DBS for the treatment of PD or essential tremor (ET) in the ventral intermediate nucleus of the thalamus (Vim). Stop-signal task and go/no-go task performances were studied in both groups. Both groups performed these tasks with (on stimulation) and without (off stimulation) DBS to address the question of whether stimulation is effective in improving choice reaction time (RT) and stop-signal RT. The results show that DBS of the STN was associated with significantly enhanced inhibitory control, as indicated by shorter stop-signal RTs. An additional finding is that DBS of the STN led to significantly shorter choice RT. The effects of DBS on responding and response inhibition were functionally independent. Although DBS of the Vim did not systematically affect task performance in patients with ET, a subgroup of Vim-stimulated PD patients showed enhanced stop-signal RTs in on stimulation versus off stimulation. This result suggests that the change in performance to stop signals may not be directly related to STN function, but rather results from a change in PD function due to DBS in general. The findings are discussed in terms of current functional and neurobiological models that relate basal ganglia function to the selection and inhibition of motor responses.
The ability to stop motor responses depends critically on the right inferior frontal cortex (IFC) and also engages a midbrain region consistent with the subthalamic nucleus (STN). Here we used diffusion-weighted imaging (DWI) tractography to show that the IFC and the STN region are connected via a white matter tract, which could underlie a "hyperdirect" pathway for basal ganglia control. Using a novel method of "triangulation" analysis of tractography data, we also found that both the IFC and the STN region are connected with the presupplementary motor area (preSMA). We hypothesized that the preSMA could play a conflict detection/resolution role within a network between the preSMA, the IFC, and the STN region. A second experiment tested this idea with functional magnetic resonance imaging (fMRI) using a conditional stop-signal paradigm, enabling examination of behavioral and neural signatures of conflict-induced slowing. The preSMA, IFC, and STN region were significantly activated the greater the conflict-induced slowing. Activation corresponded strongly with spatial foci predicted by the DWI tract analysis, as well as with foci activated by complete response inhibition. The results illustrate how tractography can reveal connections that are verifiable with fMRI. The results also demonstrate a three-way functional-anatomical network in the right hemisphere that could either brake or completely stop responses.
Evidence is accumulating that brain regions communicate with each other in the temporal domain, relying on coincidence of
neural activity to detect phasic relationships among neurons and neural assemblies. This coordination between neural populations
has been described as “self-organizing,” an “emergent property” of neural networks arising from the temporal synchrony between
synaptic transmission and firing of distinct neuronal populations. Evidence is also accumulating that communication and coordination
failures between different brain regions may account for a wide range of problems in schizophrenia, from psychosis to cognitive
dysfunction. We review the knowledge about the functional neuroanatomy and neurochemistry of neural oscillations and oscillation
abnormalities in schizophrenia. Based on this, we argue that we can begin to use oscillations, across frequencies, to do translational
studies to understand the neural basis of schizophrenia.
Evidence is accumulating that schizophrenia is characterized by dysfunction of efference copy/corollary discharge mechanisms that normally allow us to unconsciously recognize and disregard sensations resulting from our own actions. This dysfunction may give rise to subtle but pervasive sensory/perceptual aberrations in schizophrenic patients, altering their experience of their own overt and covert actions, as well as their interactions with the environment. It may also contribute to symptoms such as hallucinations and delusions, and may disrupt the motivation to engage with people and in activities.
We developed neurophysiological paradigms to study motor-sensory feed-forward processes, or efference copy/corollary discharge mechanisms, in the speech-auditory system, and showed these processes to be deficient in chronic schizophrenia. Specifically, we observed neural responses during talking that made evident the suppressive consequences of a successful corollary discharge mechanism. We also observed synchronous neural activity preceding talking that we believe reflects the efference copy in action. Recently, we extended this neurophysiological research to the somatosensory system, again finding evidence of deficient motor-sensory feed-forward processes in schizophrenia. If dysfunction of this elemental mechanism is reliable, valid, and not the result of antipsychotic medications, it might represent a major new class of electrophysiological measures sensitive to a fundamental and ubiquitous pathophysiological process in schizophrenia.
Transcranial direct current stimulation (tDCS) has been reported to ameliorate auditory hallucinations that are nonresponsive/minimally responsive to antipsychotic treatment in schizophrenia. The neurobiological basis of the tDCS effects in ameliorating auditory hallucinations is yet to be explored. In this case report, for the first time, using the novel method for noninvasive assessment of cortical plasticity, we demonstrate potential neuroplasticity effect of tDCS in improving treatment-resistant auditory hallucinations in a schizophrenic patient.
Treatment of nonresponsive auditory hallucinations in schizophrenia have been reported to improve with transcranial direct-current stimulation. This case description illustrates the use of add-on transcranial direct-current stimulation for rapid amelioration of auditory hallucinations in schizophrenia during the acute phase. Because transcranial direct-current stimulation is safe, largely well tolerated, and relatively inexpensive, this add-on treatment option is worth exploring through further rigorous studies.
We reviewed novel brain stimulation approaches that modify neuroplasticity and are used in the treatment and study of schizophrenia. We searched PubMed and Scholars Portal using search terms related to schizophrenia, brain stimulation, and neuroplasticity. Various brain stimulation approaches simulating a range of experimental protocols that induce synaptic long-term potentiation or depression have been developed. By far, repetitive transcranial magnetic stimulation (rTMS) has been the most widely used in the field of schizophrenia. Its application has been associated with mixed results in treating treatment-resistant symptoms and cognitive deficits associated with schizophrenia. Compared to the other approaches, rTMS is probably the least similar to plasticity-inducing cellular paradigms. Other approaches, such as paired associative stimulation, theta-burst stimulation, and transcranial direct current stimulation, are in their incipient stages in the study and treatment of schizophrenia, with promising early results. Numerous brain stimulation approaches have been developed to treat resistant dimensions of schizophrenia. Notwithstanding some promising reports, optimization of the methods and large randomized controlled trials are still needed.
In this paper, we present a vocal production protocol for studying the neurophysiological action of the corollary discharge, a mechanism that allows animals to ignore sensations resulting from their own actions, and tag them as 'self'. Electroencephalograms are recorded while subjects say 'ah' about 100 times with minimal throat, jaw and tongue movements (Talk condition). This sequence of sounds is recorded and played back during the Listen condition. Event-related potentials are synchronized to the onset of speech sounds during the Talk and Listen conditions. Neural responses from the auditory cortex to the spoken sound as it is being spoken during the Talk condition are compared with neural responses to the same sounds when played back during the Listen condition. The successful action of the corollary discharge is seen when the response of the auditory cortex is suppressed during the Talk compared with the Listen condition. The protocol takes about 5 min to complete.
Weak transcranial DC stimulation (tDCS) of the human motor cortex results in excitability shifts during and after the end of stimulation, which are most probably localized intracortically. Anodal stimulation enhances excitability, whereas cathodal stimulation reduces it. Although the after-effects of tDCS are NMDA receptor-dependent, nothing is known about the involvement of additional receptors. Here we show that pharmacological strengthening of GABAergic inhibition modulates selectively the after-effects elicited by anodal tDCS. Administration of the GABA(A) receptor agonist lorazepam resulted in a delayed, but then enhanced and prolonged anodal tDCS-induced excitability elevation. The initial absence of an excitability enhancement under lorazepam is most probably caused by a loss of the anodal tDCS-generated intracortical diminution of inhibition and enhancement of facilitation, which occurs without pharmacological intervention. The reasons for the late-occurring excitability enhancement remain unclear. Because intracortical inhibition and facilitation are not changed in this phase compared with pre-tDCS values, excitability changes originating from remote cortical or subcortical areas could be involved.
The critical role of the subthalamic nucleus (STN) in the control of movement and parkinsonian symptoms is well established. Research in animals suggests that the cerebral cortex plays an important role in regulating the activity of the STN but this control is not known in humans. The most extensive cortical innervation of the STN originates from motor areas. Here, we used transcranial magnetic stimulation (TMS) during intraoperative single-unit recordings from STN, in six patients with Parkinson's disease (PD) undergoing implantation of deep brain stimulators, to determine whether TMS of the motor cortex (MC) modulates the activity of STN and to investigate in vivo the functional organization of the corticosubthalamic circuit in the human brain. Single-pulse TMS of the MC induced an excitation in 74.9% of neurons investigated. This activation was followed by a long-lasting inhibition of the STN neuronal activity that did not correlate with PD severity. Responsive neurons to TMS of the hand area of motor cortex were located mainly in the lateral and dorsal region of the subthalamus while unresponsive cells had a prevalently medial distribution. This is the first report of TMS-induced modulation of STN neuronal activity in humans. These findings open up new avenues for in vivo studies of corticosubthalamic interactions in human brain and PD.
Rapid Improvement of auditory verbal hallucinations in schizophrenia following add-on treatment with tDCS:e43e4. Figure 1. The figure shows the group average of N100 waveforms (Cz) generated in the 'talk' and 'listen' conditions before and after treatment with tDCS in schizophrenia patients
- V Shivakumar
- Rakesh A G Bose
- H Nawani
- A Subramaniam
- Sm
Shivakumar V, Bose A, Rakesh G, Nawani H, Subramaniam A, Agarwal SM, et al. Rapid Improvement of auditory verbal hallucinations in schizophrenia following add-on treatment with tDCS. J ECT 2013;29:e43e4. Figure 1. The figure shows the group average of N100 waveforms (Cz) generated in the 'talk' and 'listen' conditions before and after treatment with tDCS in schizophrenia patients (N ¼ 5).
Effective connectivity reveals important roles for both the hyperdirect (fronto-subthalamic) and the indirect (fronto-striatal-pallidal) fronto-basal ganglia pathways during response inhibition
- S Jahfari
- L Waldorp
- Van
- Wildenberg Wp
- Scholte Hs
- Kr
- Forstmann
- Bu
Jahfari S, Waldorp L, van den Wildenberg WP, Scholte HS, Ridderinkhof KR, Forstmann BU. Effective connectivity reveals important roles for both the hyperdirect (fronto-subthalamic) and the indirect (fronto-striatal-pallidal) fronto-basal ganglia pathways during response inhibition. J Neurosci 2011 May 4;31(18):6891e9.
Neural basis of tDCS effects on auditory verbal hallucinations in schizophrenia: a case report evidence for cortical neuroplasticity modulation.
- Nawani H.
- Kalmady S.V.
- Bose A.
- Shivakumar V.
- Rakesh G.
- Subramaniam A.