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

• Published in: Clinical neurophysiology Vol. 140; pp. 59 - 97
• Main Authors: Siebner, Hartwig R., Funke, Klaus, Aberra, Aman S., Antal, Andrea, Bestmann, Sven, Chen, Robert, Classen, Joseph, Davare, Marco, Di Lazzaro, Vincenzo, Fox, Peter T., Hallett, Mark, Karabanov, Anke N., Kesselheim, Janine, Beck, Mikkel M., Koch, Giacomo, Liebetanz, David, Meunier, Sabine, Miniussi, Carlo, Paulus, Walter, Peterchev, Angel V., Popa, Traian, Ridding, Michael C., Thielscher, Axel, Ziemann, Ulf, Rothwell, John C., Ugawa, Yoshikazu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2022
• Subjects: Action Potentials; Brain - physiology; Consensus; Evoked Potentials, Motor - physiology; Humans; Mechanism of action; Motor cortex; Neurology; Neurons - physiology; Physiology; Transcranial Magnetic Stimulation; LICI; PAS; TES; A-P; M1; PT; rCMRglu; P-A; POST; PMd; ANT; CBI; S-D; cTBS; PFC; IPS; L-M; Motor cortex; PMv; D-wave; Physiology; SICI; Mechanism of action; ISI; SICF; CSP; M1-HAND; rCBF; Transcranial magnetic stimulation; EEG; MT; VGSC; BEM; iTBS; FEM; fMRI; LAI; GABA; MEP; SAF; SAI; TMS; I-waves; rTMS; PET; TEP; Short-interval intracortical inhibition; Long-latency afferent inhibition; TMS evoked EEG potential; Short-interval intracortical facilitation; Direct wave; Continuous theta-burst stimulation; Motor threshold; Functional magnetic resonance imaging; Intermittent theta-burst stimulation; Long-interval intracortical inhibition; Ventral premotor cortex; Intraparietal sulcus; Voltage-gated sodium channel Indices; posterior; Phosphene threshold; Primary motor cortex; Transcranial electric stimulation; Strength–duration; Posterior-to-anterior; γ-aminobutyric acid; Interstimulus interval; Motor evoked potential; Finite Element Methods; Short-latency afferent inhibition; Indirect waves; Electroencephalography; anterior; Short-latency afferent facilitation; Boundary element method; Regional metabolic rate of glucose; Cerebellar-brain inhibition; Dorsal premotor cortex; Hand representation of primary motor cortex; Cortical silent period; Repetitive transcranial magnetic stimulation; Prefrontal cortex; Lateral-to-medial; Anterior-to-posterior; Paired associative stimulation; Regional cerebral blood flow; Positron emission tomography
• ISSN: 1388-2457; 1872-8952; 1872-8952
• DOI: 10.1016/j.clinph.2022.04.022

•TMS primarily targets the gyri at the hemispheric surface due to limited depth penetration.•The direct response to TMS is complex, involving a mixture of neuronal populations.•Myelinated axon terminals of pyramidal cells and inhibitory interneurons in the crown of the gyri constitute low-threshold targets for TMS.•Neuronal excitation propagates along axons and across synapses from the primary stimulation site to connected regions in a state-dependent fashion.•TMS always causes substantial peripheral somatosensory and auditory co-stimulation. 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.