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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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrea Antal has received honoraria from NeuroCare GmbH, Germany and Savir GmbH, Germany. Peter T. Fox has received patents in multiple jurisdictions for various TMS technologies, including the cortical column cosine model (C3) and the delivery of transcranial magnetic stimulation in accordance with the C3 model in an image-guided or robotically controlled manner. These patents are assigned to the University of Texas Board of Regents and have been licensed for commercialization by the University of Texas to a private entity in which Dr. Fox has ownership interest. Mark Hallett is an inventor of patents held by NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he has received license fee payments from the NIH (from Brainsway). He is on the Medical Advisory Boards of CALA Health and Brainsway (both unpaid positions). He is on the Editorial Board of approximately 15 journals and receives royalties and/or honoraria from publishing from Cambridge University Press, Oxford University Press, Springer, Wiley, Wolters Kluwer, and Elsevier. He has research grants from Medtronic, Inc. for a study of DBS for dystonia and CALA Health for studies of a device to suppress tremor. Hartwig R. Siebner has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant from Sanofi Genzyme, Denmark, Lophora, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief (Neuroimage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark. Yoshikazu Ugawa has received honoraria from Takeda Pharmaceutical Company Limited, Eisai Co., Ltd., FP Pharmaceutical Corporation, Otsuka Pharmaceutical Co., Ltd., Elsevier Japan K. K., Kyowa Hakko Kirin Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, NIHON PHARMACEUTICAL Co., Ltd., and Novartis Pharma K.K. He has received royalties as journal editor from CHUGAI-IGAKUSHA, Igaku-Shoin Ltd, Medical View Co. Ltd., and Blackwell Publishing K.K. Walter Paulus has received honoraria as speaker from Philips, Medipark Clinic and as a consultant from Abott and Precisis AG. A.V. Peterchev has received research funding, travel support, patent royalties, consulting fees, equipment loans, hardware donations, and/or patent application support from Rogue Research, Tal Medical/Neurex, Magstim, MagVenture, Neuronetics, BTL Industries, and Advise Connect Inspire. Ulf Ziemann received grants from Janssen Pharmaceuticals NV and Takeda Pharmaceutical Company Ltd., and consulting fees from Bayer Vital GmbH, Pfizer GmbH and CorTec GmbH. All other authors have no conflict of interest to report., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Most humans have the ability to activate the auricular muscles. Although (intentional) control suggests an involvement of higher cortical centers underlying posterior auricular muscle (PAM) activation, the cortical representation of the auricular muscles is still unknown., Methods: With the purpose of identifying a possible cortical representation area we performed automated robotic and image-guided transcranial magnetic stimulation (TMS) mapping (n = 8) and functional magnetic resonance imaging (fMRI) (n = 13). For topographical comparison, a similar experimental protocol was applied for the first dorsal interosseus muscle (FDI) of the hand., Results: The calculated centers of gravity (COGs) of both muscles were located on the precentral gyrus with the PAM COGs located more laterally compared to the FDI. The distance between the mean PAM and mean FDI COG was 26.3 mm. The TMS mapping results were confirmed by fMRI, which showed a dominance of cortical activation within the precentral gyrus during the corresponding motor tasks. The correspondence of TMS and fMRI results was high., Conclusion: The involvement of the primary motor cortex in PAM activation might point to an evolved function of the auricular muscles in humans and/or the ability of intentional (and selective) muscle activation., Competing Interests: The authors have declared that no competing interests exist.

Background: Although neuronavigation is increasingly used for optimizing coil positioning, the inter-session reliability of hotspot location remains unsatisfactory, probably due to the variability of motor evoked potentials (MEPs) and residual investigator bias., Purpose: To increase the reliability and accuracy of hotspot location we introduce a novel automated hotspot-hunting procedure (AHH)., Methods: AHH is based on resting motor thresholds (RMTs) instead of MEP amplitudes. By combining robotic coil positioning with a closed loop target search algorithm AHH runs independently from the investigator. AHH first identifies all targets with an RMT below a defined intensity of stimulator output (MEP-positive) and then locates the motor hotspot of a target muscle by measuring RMTs at all identified MEP-positive targets. Results were compared to robotic MEP amplitude TMS mapping (MAM) using a 7×7 predefined target grid and suprathreshold intensities and manual hotspot search (MHS). Sequence of stimulation was randomized from pulse to pulse in AHH and MAM. Each procedure was tested in 8 subjects., Results: Inter-session CoG shift was significantly reduced with AHH (1.4mm (SEM: 0.4)) as compared to MAM (7.0mm (SEM: 1.8)) (p=0.018) and MHS (9.6mm (SEM: 2.2)) (p=0.007). No statistical difference was observed between MAM and MHS. RMTs were reliable between sessions., Conclusion: Our method represents the first fully automated, i.e. investigator-independent, TMS hotspot-hunting procedure. Measuring RMTs instead of MEP amplitudes leads to significantly increased accuracy and reliability of CoG locations. Moreover, by assessing thresholds AHH is the first procedure to fulfill the original hotspot definition., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Non-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h., Objective: We aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory., Methods: The impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval)., Results: The during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity., Conclusion: Repeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Externally induced neuroplasticity may be of therapeutic value in several neuro-psychiatric disorders. To facilitate research on mechanisms and to make possible the design of prospective, advanced stimulation protocols without exposing human subjects to risk, we have developed a primate model which allows us to assess changes of motor cortical excitability using transcranial magnetic stimulation (TMS)., Methods: TMS hand muscle representation and cortical excitability were determined in two awake trained rhesus monkeys. Neuroplastic changes of cortical excitability were established by 13min of paired associative stimulation (PAS) with interstimulus intervals of either 15 or 5ms., Results: The representational areas of FDI and APB muscles (3.02-4.96cm(2)) were located between the spur of the arcuate and the superior precentral sulcus, indicating the potential to carry out spatially selective cortical stimulation. PAS with an interstimulus interval of 15ms strongly increased cortical excitability for up to two hours, while 5ms interval had no effect., Conclusions: This first systematic TMS and PAS primate study demonstrates that the trained rhesus monkeys represent an exceptional animal model that allows cortical TMS mapping as well as non-invasive assessment and induction of cortical neuroplasticity., Significance: This animal model offers additional advantageous options not possible with humans, namely an alternative to invasive, morphological or molecular analyses, making it highly suitable for preclinical development of advanced neuroplasticity paradigms without exposing human subjects to risk., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

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Introduction Conflicting results have been reported on the importance of optimal TMS coil rotation. Maintaining a constant coil rotation angle manually remains a challenge. However, the exact impact of rotation angle on resting motor thresholds (RMTs) has not been investigated to date. Objective Using a robot-guided and a fully automated threshold hunting procedure, we aimed at determining the relevance of optimal rotation for determining RMT. Methods FDI hotspot was located with the automated hotspot hunting procedure ( n = 7). RMTs were then determined applying the threshold-hunting algorithm at different rotation angles (360° in steps of 15°, 15 pulses per rotation angle) in a randomized order over all pulses. The coil handle in posterior position was set as 0°. The procedure was repeated with steps of 5° within a 60° range of lowest thresholds of the first session. Threshold values were normalized for individual min and max. Results With 15° steps mean threshold was lowest at angles of 30° and 45°. Using 5° steps revealed a minimum mean threshold at 40° (mean threshold: 29.0; SEM: 0.05). A second minimum was found at the opposite angle. Highest RMTs were observed at angles between 135° and 180° and 285° and 315°. The relation between the rotation angle and deviation of the measured RMTs (from the minimum RMT at the optimal rotation angle) was non-linear with a floor effect between 5° and 15°. Conclusion Optimal coil rotation angle for FDI was found at 40°. Interestingly, within a range between 25° and 55° the effect of different coil rotation angles on the RMTs was not relevant, i.e. lower than the error of the threshold hunting procedure. The results therefore suggest that manual coil positioning at a rotation angle of 40° with little positional errors is uncritical when assessing motor thresholds of the FDI. [ABSTRACT FROM AUTHOR]

Introduction Strength and extension of the TMS-induced electromagnetic field increase with stimulation intensity at the expense of spatial accuracy.The concept of focality has not been investigated systematically in vivo yet. Objective To determine the focality of a given TMS coil we developed a linear mapping approach that assesses the correlation of intensity and spatial accuracy. Methods A line of 21 targets was placed in anterior–posterior direction through the center of gravity (COG) of the FDI hotspot with 2 mm spacing ( N = 8, Magstim 200 2 , 70 mm figure-8 coil).Recruitment curves were measured at each target with 15 pulses per intensity (threshold intensity + 1, 2 and 3% of maximum stimulator output (MSO)) with a randomized order over all targets and intensities.The probability was calculated as the ratio of pulses resulting in an MEP ⩾ 50 μV to the total number of pulses for each stimulation point and intensity.The intensities were categorized by the lowest intensity with a probability of 1 ( P 1) and lower ( P 1-1%, P 1-2% and P 1-3%).The bilateral data was centered on the COG, a logistic function ( P = A /(1+( x / x 0 ) p ) was fitted to the unilateral data to describe the relation of coil position, stimulation intensity and probability (MEP ⩾ 50 μV). The extent of FDI representation in relation to intensity was determined as two times the difference between the COG and the minimum of the 2nd derivative.Additionally, we calculated the slope width between the minimum and maximum of the 2nd derivative to determine the range at which the effective electric field leaves the hotspot, resulting in the highest decrease of probability.The extent of FDI and the slope width were plotted against the intensities to describe their correlation. Results A sigmoid relation between response rate and stimulation intensity was observed for all intensities.The plateau width (FDI extent) increased linear by 6.4 ± 1.3 mm/%MSO. In contrast, the slope width was 6.1 ± 0.2 mm across all intensities. Conclusion The results prove a linear relation of near threshold TMS intensities and focality with a decrease of spatial accuracy by 6.5 mm/%MSO when using a standard figure-8 coil.By calculating the slope widths of the intensity curves (6.1 mm) we propose a novel approach to determine the extent of a motor cortical representation that is not influenced by intensity. [ABSTRACT FROM AUTHOR]

Introduction: Coil positioning is a crucial factor for transcranial magnetic stimulation (TMS). Manual positioning of flat TMS coil against the curved head allows for errors in translation and rotation. As scalp markings are an ineffective way to ensure consistency in coil positioning, image-guided neuronavigation is used to reduce errors. However, as manual neuronavigation increases time for coil positioning it is less suitable when the coil has to be moved between pulses during TMS mapping. The use of a robot for coil positioning may overcome these drawbacks of manual neuronavigation. Objectives: We aimed at assessing the practicability and efficacy of the using a robot for a neuronavigated TMS mapping of the cortical representation of the first dorsal interosseus (FDI) of humans and rhesus monkey. Materials and methods: For FDI mapping, 12 supra-threshold stimuli (120% RMT) were applied in a randomized order to each grid point of a 7×7 grid with a spacing of 10mm in 8 subjects (mean age 26 y, 6 male) with a Magstim 200 stimulator and a standard 70mm figure-8 coil. Surface EMG was recorded from contralateral FDI. An Adept Viper s850 robotic arm moved the coil to each grid point on an MRI-based head model in a random order. An IR camera obtained actual positional data of the head. This allowed tracking of head movements and respective online movement compensation by the robot. Centers of gravity were projected onto the brain surface and co-registered to an MNI152 T1 1mm brain template. A similar setup was used for FDI mapping in a male adult rhesus monkey on a 4x5 grid with 5mm spacing. TMS was applied with a Magstim 25mm figure-8 coil. The mapping was performed during multiple sessions during which the monkey’s head was attached to a frame with frontal and occipital head posts. Relaxation of FDI was rewarded with water after each pulse. Results: TMS Mapping sessions took about 80–90min in each subject with a pulse interval of 8s. Preparations lasted about 20min. A closely spaced TMS representation of FDI could be identified in each subject within the precentral gyrus. The shape of the representation area resembled ovals with a mean maximum MEP amplitude of 1.35mV (SD: 0.52). Mean stereotaxic coordinates of the centers of gravity were (−36, −12, 67) in MNI152 space. In the animal experiment, the monkey adapted to the setup within 4weeks. The preparation time for each session was about 10min. Across all sessions muscle relaxation was present during 64% of the pulses. The pulse interval was 13.4s. Four repetitions of a complete grid could be recorded in a single session of about 45min duration. MEPs from contralateral FDI were elicited from a highly defined elliptical area (1×1.5cm) within the precentral gyrus. Conclusion: Due to the combination of fast high-precision coil positioning and online head tracking, robot-assisted and image-guided TMS is exquisitely suited to perform randomized TMS mappings in the human with acceptable preparation times. In addition, this method allows for precise TMS mapping of the considerably smaller rhesus brain where high-precision coil positioning with a high inter-session reliability is required for multiple session mappings with grid sizes in the millimeter scale. [ABSTRACT FROM AUTHOR]