Y P O C T O N Clinical Applications of tDCS: past, O present and future D E S A Felipe Fregni, MD, PhD, MPH, MMSc, MEd E Spaulding Neuromodulation Center L Spaulding Rehabilitation Hospital P Massachusetts General Hospital Harvard Medical School
Y Is there an unmet clinical need for P O development of tDCS as a clinical tool? C T - Current treatments O N O - Brain plasticity D E S - Development of novel markers A E L P
Y Failure of current pharmacological treatments for P chronic diseases in neurology, psychiatry and O rehabilitation C T O • Main principle of pharmacological treatment may lead N to detrimental long-term effects – concept of dynamic O effect D E S • Example of aberrant plasticity in Parkinson’s disease A and chronic pain E L P
Y P Role of neuroplasticity: O example of failure of dopaminergic drugs C T Adaptive Learning Non-adaptive Learning O N O D E S A E L P Zhuang 2013
Y Another example: P O Aberrant plasticity in chronic pain: does analgesic drug enhance aberrant plasticity? C T O N O D E S A E L P Drugs can enhance learning of anticipation Apkarian, 2013 of pain and modulation of perception circuits
Y Therapeutic effects of noninvasive brain P O stimulation C T O • Duration of effects (“repair” vs. “interaction” model – N Ridding, 2007) – Repair model – corrects an imbalance in function (for O example – Levodopa for PD) D E – Interaction model – help the brain to restore itself – S promotion of plasticity A E L P
Y P Neural guided application of tDCS O C T • Functional plasticity is accompanied by structural O plasticity. N • Functional plasticity in intact cortex begins O immediately after injury. D • Neurosciences and clinical sciences should be E coupled for therapeutic purposes. S A E L P
Y P Basic Idea of Neuromodulation O C T O N O D E S A E L P
Y P Basic Idea of Neuromodulation O C T O N O D E S A E L = P
Y P Basic Idea of Neuromodulation O C T O N O D E S A E L = P
Y Activity/stimulation vs. Chemical P O Activation C T O N O D E S A E Chemical – ON/OFF – maladaptive learning L = P Activity/stimulation – long-lasting changes How about combination??
Y Rationale for Electrotherapy P O C • Broad spectrum ( neuropsychiatry, T neuropsychology, rehabilitation, cognitive O performance… ) N • Individualized therapy O D • Targeted brain modulation ( space + time ) E • Adverse effects ( minimal complications + counter- S indications ) A E • Mechanism of actions vs. mechanisms of disease L • Cost P
Y P What is different now? O C T • Knowledge on mechanisms of neuroplasticity O – in healthy and disease N O D • Better control and focality of stimulation E S A E L P
Y What are the options? P O C T O N O D E S A E L P Figure from Marom Bikson
Y Transcranial Direct Current Stimulation (tDCS) P O C • Optimal tool to modulate T practice-related learning neural O activation. N • Changes in network associated with practice. O Enhancement might be useful for • D initial stages of learning during skill acquisition and at later E stages for learning consolidation. S Combined therapy with • A pharmacological, physical, and E cognitive/behavioral approaches L P
Y P Future devices? O C • Better TENS stimulation devices? T O N • Other non-invasive cranial nerve stimulation O devices? D E S • Using other forms of neural stimulation alone A or in combination: mechanical, thermal E L P
Y P O C T O N Past and Present: what have we learned in O the past 30 years of research with tDCS D E S A E L P
Y 17 years of tDCS….or 50 years of brain P O polarization? C T • Parameters of stimulation O N • Safety protocols O • Clinical Trials D E • Combined protocols S A E L P
Y P O C What did we learn regarding T parameters of stimulation? O N O Main effects will depend not only of parameters of D stimulation but combination parameters + ongoing neural activity E S A E L P
Y P Parameters of Stimulation - tDCS O C Anodal vs. cathodal effect • T Anodal: depolarization Cathodal: • O hyperpolarization N Effects may depend on task and • baseline cortical activity O D E Nitsche et al, 2000 S A E L P Fregni et al, 2006
Y P Location of stimulation - tDCS O C • Reference electrode has a critical T impact O • Different strategies: 1x1; 1x0; 2x1; 4x1 N O D E S A Nitsche et al, 2011 E L P Mendonca et al, 2011
Y P Safety – tDCS I O C T Animal study – Liebetanz et al, O • 2009 N O D E S A E L P
Y P O Safety – tDCS II C T O N O D E S A E L P
Y P O C T O N O D E S A E Datta et al., 2010 L P
Y P Safety of tDCS III O C • Brunoni et al., 2011 – Systematically reviewed T reports of AE ’ s in human studies of patients and O healthy subjects. N – 172 articles (209 studies) included – 117 studies assessed AE ’ s O – 74 studies reported at least 1 AE D • Findings for Active Stimulation: E – Most commonly reported effects are mild S – Itching (39.3%) A – Tingling (22.2%) E – Headache (14.8%) L – Burning sensation (8.7%) P – Discomfort (10.4%)
Y P Efficacy/clinical effects - tDCS O C • Several small studies have shown tDCS is T O efficacious N O • But effects sizes are small in some of these D studies or heterogeneity is large across studies E S A E L P
Y P Problem of small studies O C T O N O D E S A E L P
Y P Meta-analysis O C • Tinnitus meta-analysis: 17 identified only 2 RCTs were included. Overall T 39.5% responded to active tDCS with a mean tinnitus intensity reduction O of 13.5%. Not enough studies – Song et al, 2012 N • Chronic stroke meta-analysis: 8 studies - pooled analysis showed a significant increase in scores in favor of tDCS compared to sham O (SMD=0.49, 95% CI=0.18-0.81, p=0.005) – small effect size - Butler et al, D 2013 Major depression meta-analysis: 6 studies - active tDCS was found to be • E more effective than sham tDCS for the reduction of depression severity S (Hedges' g=0.743, 95% confidence interval 0.21-1.27) - results differed A more than expected by chance (Q=15.52, df=6, p=0.017, I2=61.35) – E significant heterogeneity - Kalu et al., 2012 L P
Y Methods of focalizing/enhancing the P O effects of NIBS C T O N • Combination protocols O • Optimal dosages D E S A E L P
Y P Combination protocols - pain O C T O N O D E S A E L P
Y P Combination protocols - stroke O C T O N O D E S A E L P
Y Combination protocols – major P O depression C T O N O D E S A E L P
Y P O C T O N O D E S A E L P
Y P O C T O Future of Non-invasive Brain Stimulation: N given what we have learned what is next? O D E S A E L P
Y P Areas of Investigation O C • Chronic use T O • Safety N • Portability O • Automatic detection and regulation of D stimulation: developing novel markers E S • Novel and modified devices A E L P
Y P Novel Patents O C T O N O D E S A E L P
Y P O Developing closed loop systems (real- C time monitoring/stimulation) – T O combination with metacognitive N strategies O D • Challenge: finding good markers of response E S A E L P
Y Developing Novel Markers: P O Markers for chronic pain C • Neuroimaging T O N O D E S A E L P Wager et al, 2013
Y Intracortical inhibition/TMS cortical P excitability O C Primary motor cortex T plasticity in osteoarthritis O chronic pain N O D Maria da Graça Tarrago, Liciane F Medeiros, Iraci L. S. Torres, E Liliane P Vidor, Alicia Deitos, Aline Brietzke, Felipe Fregni , S Wolnei Caumo A E L P
Y P Or Quantitative EEG/ERP? O C T O N O D E S A E L P
Y P Our Fibromyalgia trial O To find the optimal protocol for FM (optimal dosage) and preliminary C assessment of ERP as a response marker T Collaborative Team: O Spaulding/Harvard : Laura Castillo, Rivail Brandao, Nigel Geboth, Livia N Coutinho, Sarah Daly CUNY/CCNY: Marom Bikson O D E S A E L P
Y P Basic protocol O C T O N O D E S A E L P
Y P O C T O N O D E S A E L P
Y P Preliminary results - Behavioral O C T O N O D E S A E L P
Y P O C T O N O D E S A E L P
Y P ERP – Baseline – N2/P2 O C T O N O D E S A E L P
Y P ERP after 11 days O C T O N O D E S A E L P
Y Other markers: real-time FFT EEG P O analysis C T O N O D E S A E L P
Y P O C T O N O D E S A E L P
Y Portable EEG devices/stimulation P O devices C T O N O D E S A E L P
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