Clinical Neurophysiology 130 (2019) 802–844 Contents lists available at ScienceDirect Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph Review Clinical utility and prospective of TMS–EEG ⇑ Sara Tremblay a,b, , Nigel C. Rogasch c, Isabella Premoli d, Daniel M. Blumberger a, Silvia Casarotto e, Robert Chen f, Vincenzo Di Lazzaro g, Faranak Farzan h, Fabio Ferrarelli i, Paul B. Fitzgerald j,k, Jeanette Hui a, Risto J. Ilmoniemi l, Vasilios K. Kimiskidis m, Dimitris Kugiumtzis n, Pantelis Lioumis a, Alvaro Pascual-Leone o, Maria Concetta Pellicciari p, Tarek Rajji a, Gregor Thut q, Reza Zomorrodi a, Ulf Ziemann r, Zafiris J. Daskalakis a a Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Toronto, ON, Canada b Royal Ottawa Institute of Mental Health Research, Ottawa, ON, Canada c Brain and Mental Health Research Hub, School of Psychological Sciences, Monash Institute of Cognitive and Clinical Neuroscience, and Monash Biomedical Imaging, Monash University, Australia d Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK e Department of Biomedical and Clinical Sciences ‘‘L. Sacco”, University of Milan, Milan, Italy f Krembil Research Institute, University Health Network and Division of Neurology, Department of Medicine, University of Toronto, Canada g Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy h Simon Fraser University, School of Mechatronic Systems Engineering, B.C., Canada i Department of Psychiatry, University of Pittsburgh, PA, USA j Epworth Healthcare, The Epworth Clinic, Camberwell, Victoria, Australia k Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Victoria, Australia l Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland m Laboratory of Clinical Neurophysiology, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece n Department of Electrical and Computer Engineering, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece o Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, MA 02215, USA p Non-invasive Brain Stimulation Unit, Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy q Centre for Cognitive Neuroimaging, Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK r Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany See Editorial, pages 791–792 article info highlights Article history: An overview of TMS-EEG methodology and neurophysiological derivations. Accepted 8 January 2019 A comprehensive review of TMS-EEG as a clinical tool to study healthy and disease brain states. Available online 19 January 2019 A discussion of current challenges in the field of TMS-EEG and recommendations for future studies. Keywords: Transcranial magnetic stimulation (TMS) abstract Electroencephalography (EEG) TMS–EEG Biomarker Concurrent transcranial magnetic stimulation and electroencephalography (TMS–EEG) has emerged as a Clinical populations powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several Treatment cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS–EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objec- tive of this article is to present a comprehensive review of studies that have used TMS–EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical frame- work, we first give an overview of TMS–EEG methodology and discuss the current state of knowledge regarding the use of TMS–EEG to assess excitability, inhibition, plasticity and connectivity following neu- romodulatory techniques in the healthy brain. We then review the insights afforded by TMS–EEG into the ⇑ Corresponding author at: Royal Ottawa Institute of Mental Health Research, 1145 Carling Ave., Ottawa, Ontario K1Z 7K4, Canada. Fax: +1 613 792 3935. E-mail address: [email protected] (S. Tremblay). https://doi.org/10.1016/j.clinph.2019.01.001 1388-2457/Ó 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved. S. Tremblay et al. / Clinical Neurophysiology 130 (2019) 802–844 803 pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS–EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS–EEG as a clinical tool. Ó 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved. Contents 1. Introduction . ...................................................................................................... 804 2. TMS–EEG principles and methodology . ................................................................................... 804 2.1. Co-registration of TMS and EEG . ......................................................................... 804 2.2. Origin of TMS-EEG responses . ......................................................................... 804 3. Artifacts in TMS–EEG signals. ................................................................................... 805 3.1. TMS–EEG artifacts . ......................................................................................... 805 3.2. Offline procedures for artifact removal . ......................................................................... 806 4. Outcome measures of TMS–EEG and neurophysiological derivations. ............................................. 806 4.1. TEPs and cortical evoked activity . ......................................................................... 806 4.1.1. Current knowledge on TEPs . .............................................................................. 806 4.1.2. How do we measure TEPs? . .............................................................................. 807 4.2. TMS-related cortical oscillations . ......................................................................... 808 4.2.1. How do we measure TMS-related cortical oscillations? . ........................................ 808 4.3. Source localization and cortical connectivity ......................................................................... 809 4.3.1. How do we perform source localization and measure connectivity? . ........................................ 810 5. TMS–EEG in the study of healthy human neurophysiology . ................................................................ 810 5.1. TMS protocols for assessment of cortical inhibition and excitation. ...................................................... 810 5.1.1. Long-interval intracortical inhibition (LICI) . ........................................................... 810 5.1.2. Cortical silent period (CSP) . .............................................................................. 811 5.1.3. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) . ..................... 811 5.1.4. Short latency afferent inhibition (SAI). ........................................................... 814 5.1.5. Summary of findings in healthy subjects . ........................................................... 814 5.2. Pharmacology of TMS–EEG . ......................................................................... 814 5.2.1. Gabaergic activity . .............................................................................. 814 5.2.2. Other pharmacological interventions . ........................................................... 814 5.2.3. Summary of findings on pharmacology of TMS-EEG . ........................................................... 816 5.3. TMS–EEG and non-invasive brain stimulation protocols to study plasticity . ................................... 816 5.3.1. Regular repetitive transcranial magnetic stimulation ........................................................... 817 5.3.2. Theta-burst stimulation . .............................................................................. 817 5.3.3. Transcranial direct current stimulation (tDCS) . ........................................................... 820 5.3.4. Paired-associative stimulation .............................................................................. 820 5.3.5. Summary of findings on plasticity. ........................................................... 821 6. Clinical applications . ................................................................................... 821 6.1. Psychiatry . ......................................................................................... 821 6.1.1. Schizophrenia . .............................................................................. 821 6.1.2. Mood disorders. .............................................................................. 825 6.1.3. Substance use disorders . .............................................................................