Clinical Neurophysiology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph Review TMS and drugs revisited 2014 ⇑ Ulf Ziemann a, , Janine Reis b, Peter Schwenkreis c, Mario Rosanova d,e, Antonio Strafella f,g, Radwa Badawy h,i, Florian Müller-Dahlhaus a a Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, Tübingen, Germany b Department of Neurology, Albert-Ludwigs-University Freiburg, Freiburg, Germany c Department of Neurology, BG-University Hospital Bergmannsheil Bochum, Bochum, Germany d Department of Biomedical and Clinical Sciences ‘‘Luigi Sacco”, University of Milan, Milan, Italy e Fondazione Europea di Ricerca Biomedica, FERB Onlus, Milan, Italy f Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson Disease Program, Toronto Western Hospital, UHN, University of Toronto, Ontario, Canada g Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada h Department of Neurology, Saint Vincent’s Hospital, Fitzroy, The University of Melbourne, Parkville, Victoria, Australia i Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia article info highlights Article history: • Pharmaco-TMS improved our understanding of the effects of TMS on the human brain. Accepted 24 August 2014 • Pharmaco-TMS-EEG is a new research field to measure directly drug effects on brain excitability and Available online xxxx connectivity. • Pharmaco-TMS can monitor and possibly predict drug responses in neurological and psychiatric Keywords: Transcranial magnetic stimulation patients. Pharmacology Motor evoked potential Electroencephalography abstract Excitability Connectivity Plasticity The combination of pharmacology and transcranial magnetic stimulation to study the effects of drugs on Cortex TMS-evoked EMG responses (pharmaco-TMS-EMG) has considerably improved our understanding of the effects of TMS on the human brain. Ten years have elapsed since an influential review on this topic has been published in this journal (Ziemann, 2004). Since then, several major developments have taken place: TMS has been combined with EEG to measure TMS evoked responses directly from brain activity rather than by motor evoked potentials in a muscle, and pharmacological characterization of the TMS-evoked EEG potentials, although still in its infancy, has started (pharmaco-TMS-EEG). Furthermore, the knowledge from pharmaco-TMS-EMG that has been primarily obtained in healthy subjects is now applied to clinical settings, for instance, to monitor or even predict clinical drug responses in neurological or psychiatric patients. Finally, pharmaco-TMS-EMG has been applied to understand the effects of CNS active drugs on non-invasive brain stimulation induced long-term potentiation-like and long-term depression-like plasticity. This is a new field that may help to develop rationales of pharmacological treatment for enhancement of recovery and re-learning after CNS lesions. This up-dated review will highlight important knowledge and recent advances in the contribution of pharmaco-TMS-EMG and pharmaco-TMS-EEG to our understanding of normal and dysfunctional excitability, connectivity and plasticity of the human brain. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. ⇑ Corresponding author at: Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany. Tel.: +49 7071 2982049. E-mail address: [email protected] (U. Ziemann). http://dx.doi.org/10.1016/j.clinph.2014.08.028 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Please cite this article in press as: Ziemann U et al. TMS and drugs revisited 2014. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.08.028 2 U. Ziemann et al. / Clinical Neurophysiology xxx (2014) xxx–xxx Contents 1. Effects of CNS active drugs with a known specific mode of action on TMS-EMG measures of corticospinal and motor excitability. 00 1.1. Introduction. ................................................................................................ 00 1.2.1. Motor threshold . .................................................................................. 00 1.2.2. Motor evoked potential (MEP) amplitude and MEP input–output curve . ............................ 00 1.2.3. Cortical silent period (CSP) duration . .................................................................. 00 1.2.4. Short-interval intracortical inhibition (SICI) . .................................................................. 00 1.2.5. Intracortical facilitation (ICF) . .................................................................. 00 1.2.6. Short-interval intracortical facilitation (SICF) . .................................................................. 00 1.2.7. Long-interval intracortical inhibition (LICI) . .................................................................. 00 1.2.8. Short-latency afferent inhibition (SAI) . .................................................................. 00 2. Effects of CNS active drugs with incompletely known or multiple modes of action on TMS-EMG measures of corticospinal and motor cortical excitability . .......................................................................................................... 00 3. Effects of anesthetics and analgesics on TMS-EMG measures of corticospinal and motor cortical excitability . ................. 00 4. Effects of CNS active drugs on TMS-EEG measures of motor cortical excitability and connectivity . ................................. 00 4.1. TMS-EEG to measure key parameters of cortical functioning in humans . .......................................... 00 4.2. Technical aspects and advantages of TMS-EEG . ............................................................. 00 4.2.1. Reliability of TMS-EEG measurements . .................................................................. 00 4.3. Physiology and pharmacology of primary motor cortex TEPs ............................................................. 00 4.3.1. Early components of motor cortex TEPs . .................................................................. 00 4.3.2. Late components of motor cortex TEPs. .................................................................. 00 4.3.3. TMS-evoked EEG oscillations of the motor cortex . ............................................... 00 4.3.4. Towards an understanding of the neurophysiological underpinnings of TEPs . ............................ 00 5. TMS/RTMS induced changes in endogenous neurotransmitters and neuromodulators . ................................. 00 6. Effects of CNS active drugs on TMS-EMG measures of motor cortical LTP- and LTD-like plasticity . ................................. 00 6.1. Introduction. ................................................................................................ 00 6.2. Mechanisms of synaptic plasticity . ............................................................................. 00 6.3. Modulation of synaptic plasticity – cellular evidence. ............................................................. 00 6.3.1. The dopaminergic system .................................................................................. 00 6.3.2. The cholinergic system. .................................................................................. 00 6.3.3. The serotonergic system . .................................................................................. 00 6.3.4. The adrenergic system . .................................................................................. 00 6.4. Effects of CNS active drugs on human motor cortical plasticity. .......................................... 00 6.4.1. The glutamatergic system .................................................................................. 00 6.4.2. Voltage-gated ion channels . .................................................................. 00 6.4.3. The GABAergic system . .................................................................................. 00 6.4.4. The dopaminergic system .................................................................................. 00 6.4.5. The cholinergic system. .................................................................................. 00 6.4.6. The serotonergic system . .................................................................................. 00 6.4.7. The noradrenergic system .................................................................................. 00 6.5. Summary and conclusions . ............................................................................. 00 7. Effects of CNS active drugs on TMS-EMG measures of motor cortical excitability in epilepsy . ................................. 00 Conflict of interest . .......................................................................................... 00 References . .......................................................................................................... 00 1. Effects of CNS active drugs with a known specific mode of on these behavioral effects and related them to the TMS-EMG action on TMS-EMG measures of corticospinal and motor excitability measures. It will be crucial for future pharmaco-TMS excitability studies to integrate