Author: Hartwig R Siebner¹, Klaus Funke², Aman S Aberra³, Andrea Antal⁴, Sven Bestmann⁵, Robert Chen⁶, Joseph Classen⁷, Marco Davare⁸, Vincenzo Di Lazzaro⁹, Peter T Fox¹⁰, Mark Hallett¹¹, Anke N Karabanov¹², Janine Kesselheim¹³, Mikkel M Beck¹³, Giacomo Koch¹⁴, David Liebetanz⁴, Sabine Meunier¹⁵, Carlo Miniussi¹⁶, Walter Paulus⁴, Angel V Peterchev¹⁷, Traian Popa¹⁸, Michael C Ridding¹⁹, Axel Thielscher²⁰, Ulf Ziemann²¹, John C Rothwell²², Yoshikazu Ugawa²³
Affiliation: 1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: h.siebner@drcmr.dk. 2 Department of Neurophysiology, Medical Faculty, Ruhr-University Bochum, Bochum, Germany. 3 Department of Biomedical Engineering, Duke University, Durham, NC, USA. 4 Department of Clinical Neurophysiology, University Medical Center, Georg-August-University, Göttingen, Germany. 5 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. 6 Krembil Brain Institute, University Health Network and Division of Neurology, University of Toronto, Toronto, Ontario, Canada. 7 Department of Neurology, University of Leipzig, Leipzig, Germany. 8 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. 9 Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Rome, Italy. 10 Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States. 11 Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 12 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Department of Nutrition and Exercise, University of Copenhagen, Copenhagen, Denmark. 13 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. 14 Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy; Non-invasive Brain Stimulation Unit, Laboratorio di NeurologiaClinica e Comportamentale, Fondazione Santa Lucia IRCCS, Rome, Italy. 15 Sorbonne Université, Faculté de Médecine, INSERM U 1127, CNRS 4 UMR 7225, Institut du Cerveau, F-75013, Paris, France. 16 Center for Mind/Brain Sciences (CIMeC), University of Trento, Italy; Cognitive Neuroscience Section, IRCCS Centro San Giovanni di DioFatebenefratelli, Brescia, Italy. 17 Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Psychiatry & Behavioral Sciences, School of Medicine, Duke University, Durham, NC, USA; Department of Electrical & Computer Engineering, Duke University, Durham, NC, USA; Department of Neurosurgery, School of Medicine, Duke University, Durham, NC, USA. 18 Center for Neuroprosthetics (CNP) and Brain Mind Institute (BMI), Swiss Federal Institute of Technology (EPFL), Geneva, Switzerland; Center for Neuroprosthetics (CNP) and Brain Mind Institute (BMI), Swiss Federal Institute of Technology (EPFL Valais), Clinique Romande de Réadaptation, Sion, Switzerland. 19 University of South Australia, IIMPACT in Health, Adelaide, Australia. 20 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark. 21 Department of Neurology & Stroke, University Tübingen, Tübingen, Germany; Hertie Institute for Clinical Brain Research, University Tübingen, Tübingen, Germany. 22 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. 23 Department of Neurology, Fukushima Medical University, Fukushima, Japan; Fukushima Global Medical Science Centre, Advanced Clinical Research Centre, Fukushima Medical University, Fukushima, Japan.
Conference/Journal: Clin Neurophysiol
Date published: 2022 May 18
Other: Volume ID: 140 , Pages: 59-97 , Special Notes: doi: 10.1016/j.clinph.2022.04.022. , Word Count: 341

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.

Keywords: Mechanism of action; Motor cortex; Physiology; Transcranial magnetic stimulation.

PMID: 35738037 DOI: 10.1016/j.clinph.2022.04.022

Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper