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Background: Motor responses evoked by transcranial magnetic stimulation (TMS) using posterior-anterior (PA) and anterior-posterior (AP) current directions have distinct latencies and thresholds. However, the underlying reasons for these differences remain unclear., Objective: To quantify the differences in activation sites between PA- and AP-TMS., Methods: Motor evoked potentials (MEPs) were recorded from five hand and arm muscles in nine healthy participants using both PA- and AP-TMS. Active motor thresholds were determined at 11 magnetic coil positions on the scalp. Probabilistic modelling was used to combine the measured threshold data with calculated electric field data from individual MRI-based models. This approach constructed 70 probability distributions of the activation site, dependent on the muscle and TMS direction., Results: Modelling indicated that both PA- and AP-TMS more likely activated structures in white matter than in grey matter. PA-TMS activation sites were primarily in the white or grey matter in the precentral gyrus, while the AP-TMS activations were deeper and more posterior and lateral, likely within white matter under the postcentral and/or precentral gyri. Tractography and biophysical axon models provided a potential explanation on the location of activation sites: AP-TMS may activate the bends of white matter axons farther from M1 than PA-TMS, such that the conduction velocity along the neural tract could potentially explain the longer MEP latency of AP-TMS. The differences in activation sites among the five hand and arm muscles were small., Conclusion: While a direct experimental confirmation of the activation sites is still needed, the results suggest that electric field analysis combined with tractography and biophysical axon modelling could be a useful computational tool for analysing and optimizing TMS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Theta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS., Objective: To compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS., Methods: Forty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed., Results: The facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS., Conclusion: QPS is more effective and stable for synaptic plasticity induction than TBS., Competing Interests: Conflict/declaration of interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Both pre-supplementary motor area (pre-SMA) and SMA-proper (SMA) must play important roles in visuomotor sequence learning. However, functional differences between the pre-SMA and SMA have not been well studied in humans., Objective: To elucidate the functional differences between the pre-SMA and SMA in sequence learning in humans., Methods: To induce LTP/LTD, we administered quadripulse transcranial magnetic stimulation (QPS) with an inter-stimulus interval of 5 or 50 ms (QPS-5/50) over the pre-SMA or SMA in healthy volunteers. The sham stimulation was also done as a control. We studied the effects of LTP/LTD in the pre-SMA/SMA on a new sequence learning and the performance of well-learned sequence by using sequence learning task called the "2 × 10 task". Effects on the simple choice reaction time task were also studied for comparison., Results: QPS-5 over the pre-SMA increased the error rate without any changes in movement speed. When administered over the SMA, QPS-5 decreased, and QPS-50 increased the rate of reaction time reduction across trials without changes in the error rate. QPS over neither the pre-SMA nor SMA affected the performances of a well-learned sequence or a simple choice reaction time task., Conclusions: Our findings that QPS over the pre-SMA correlated with sequence learning performance and that over the SMA with execution speed are consistent with the previous results in animals and humans. Our results lend further support to the utility of QPS for modulating motor learning in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) plays an important role in treatment of mental and neurological illnesses, and neurosurgery. However, it is difficult to target specific brain regions accurately because the complex anatomy of the brain substantially affects the shape and strength of the electric fields induced by the TMS coil. A volume conductor model can be used for determining the accurate electric fields; however, the construction of subject-specific anatomical head structures is time-consuming., Objective: The aim of this study is to propose a method to estimate electric fields induced by TMS from only T1 magnetic resonance (MR) images, without constructing a subject-specific anatomical model., Methods: Very large sets of electric fields in the brain of subject-specific anatomical models, which are constructed from T1 and T2 MR images, are computed by a volume conductor model. The relation between electric field distribution and T1 MR images is used for machine learning. Deep neural network (DNN) models are applied for the first time to electric field estimation., Results: By determining the relationships between the T1 MR images and electric fields by DNN models, the process of electric field estimation is markedly accelerated (to 0.03 s) due to the absence of a requirement for anatomical head structure reconstruction and volume conductor computation. Validation shows promising estimation accuracy, and rapid computations of the DNN model are apt for practical applications., Conclusion: The study showed that the DNN model can estimate the electric fields from only T1 MR images and requires low computation time, suggesting the possibility of using machine learning for real-time electric field estimation in navigated TMS., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The masked-priming paradigm is used to test unconscious inhibitory processes of the brain. A tendency towards responses that are incompatible with the prime, designated as negative compatibility effect (NCE), emerges when the perception of a priming visual stimulus is "masked" afterwards. This effect presumably stems from a subliminal inhibitory process against the masked-prime. Prior lesions as well as activation studies suggest a key role of SMA in this effect., Objective: This study was conducted to elucidate a causal role of SMA in the subliminal response inhibition represented by the NCE., Methods: Using a repeated-measures pre-post design with a group of healthy people, physiological measures (resting and active motor thresholds and motor evoked potential (MEP) amplitude) and behavioral ones (choice reaction time (CRT), positive compatibility effect (PCE) and NCE) were obtained before and after three quadripulse stimulation (QPS), namely sham, M1-QPS, and SMA-QPS, on different days. CRT and PCE served as indices for different aspects of motor execution., Results: Motor thresholds were not altered after any QPS, although the M1-QPS increased MEP amplitude. Neither CRT nor PCE was altered significantly after QPS protocols. NCE was abolished after the SMA-QPS., Conclusions: Abolished NCE after the SMA-QPS in the absence of MEP changes suggests that (1) SMA plays a cardinal role in the NCE, and (2) the network involved in NCE is different from that of MEP generation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Paired associative stimulation (PAS) induces long-term potentiation (LTP)-like effects when interstimulus intervals (ISIs) between electrical peripheral nerve stimulation and transcranial magnetic stimulation (TMS) to M1 are approximately 21-25 ms (PAS LTP ). It was previously reported that two forms of motor learning (i.e., mode-free and model-based learning) can be differentially modulated by PAS LTP depending on the different synaptic inputs to corticospinal neurons (CSNs), which relate to posterior-to-anterior (PA) or anterior-to-posterior (AP) currents induced by TMS (PA or AP inputs, respectively). However, the effects of long-term depression (LTD)-inducing PAS with an ISI of approximately 10 ms (PAS LTD ) on motor learning and its dependency on current direction have not yet been tested., Objective: To investigate whether, and how, PAS LTD affects distinct types of motor learning., Methods: Eighteen healthy volunteers participated. We adopted the standard PAS using suprathreshold TMS with the target muscle relaxed, as well as subthreshold PAS during voluntary contraction, which was suggested to selectively recruit PA or AP inputs depending on the orientation of the TMS coil. We examined the effects of suprathreshold and subthreshold PAS LTD on the performance of model-free and model-based learning, as well as the corticospinal excitability, indexed as the amplitudes of motor evoked potentials (MEPs)., Results: PAS LTD inhibited model-free learning and MEPs only when subthreshold AP currents were applied. The PAS LTD protocols tested here showed no effects on model-based learning., Conclusions: PAS LTD affected model-free learning, presumably by modulating CSN excitability changes, rather than PA inputs, which are thought to be related to model-free learning., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) activates target brain structures in a non-invasive manner. The optimal orientation of the TMS coil for the motor cortex is well known and can be estimated using motor evoked potentials. However, there are no easily measurable responses for activation of other cortical areas and the optimal orientation for these areas is currently unknown., Objective: This study investigated the electric field strength, optimal coil orientation, and relative locations to optimally stimulate the target cortex based on computed electric field distributions., Methods: A total of 518,616 stimulation scenarios were studied using realistic head models (2401 coil locations × 12 coil angles × 18 head models). Inter-subject registration methods were used to generate an atlas of optimized TMS coil orientations on locations on the standard brain., Results: We found that the maximum electric field strength is greater in primary somatosensory cortex and primary motor cortex than in other cortical areas. Additionally, a universal optimal coil orientation applicable to most subjects is more feasible at the primary somatosensory cortex and primary motor cortex. We confirmed that optimal coil angle follows the anatomical shape of the hand motor area to realize personalized optimization of TMS. Finally, on average, the optimal coil positions for TMS on the scalp deviated 5.5 mm from the scalp points with minimum cortex-scalp distance. This deviation was minimal at the premotor cortex and primary motor cortex., Conclusion: Personalized optimal coil orientation is preferable for obtaining the most effective stimulation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Responses to continuous theta burst stimulation (cTBS) applied to the human primary motor cortex are highly variable between individuals. However, little is known about how to improve the after-effects of cTBS by adjusting the protocol characteristics., Objective: We examined whether current directions adopted in the measurement of cortical motor excitability indexed as motor evoked potentials (MEPs) affect the responses to cTBS. We also tested whether the stimulus intensity of cTBS influences the after-effects., Methods: Thirty-one healthy volunteers participated. The after-effects of cTBS with the conventional intensity of 80% of individual active motor threshold (AMT) (cTBS 80% ) were tested by measuring MEP amplitudes induced by not only posterior-anterior (PA) but also anterior-posterior (AP) and biphasic (PA-AP) currents. We also investigated cTBS with 65% AMT (cTBS 65% ) and 100% AMT (cTBS 100% ) in subjects who showed depression of MEP amplitudes after cTBS 80% , as well as cTBS 65% in subjects in whom facilitation of MEPs was induced by cTBS 80%. RESULTS: Current directions in MEP measurement had no influence on the cTBS responses. In subjects whose MEPs were depressed by cTBS 80% , cTBS 100% partly induced MEP facilitation, while cTBS 65% abolished the after-effects. In subjects who showed MEP facilitation by cTBS 80% , cTBS 65% partly induced MEP depression., Conclusions: Stimulus intensity of cTBS influenced the responses to cTBS, and lowering stimulus intensity induced the expected after-effects of cTBS in some subjects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Despite recent developments in navigation and modeling techniques, the type and location of the structures that are activated by transcranial magnetic stimulation (TMS) remain unknown., Objective: We studied the relationships between electrophysiological measurements and electric fields induced in the brain to locate the TMS activation site., Methods: The active and resting motor thresholds of the first dorsal interosseous muscle were recorded in 19 subjects (7 female, 12 male, age 22 ± 4 years) using anteromedially oriented monophasic TMS at multiple locations over the left primary motor cortex (M1). Structural MR images were used to construct electric field models of each subject's head and brain. The cortical activation site was estimated by finding where the calculated electric fields best explained the coil-location dependency of the measured MTs., Results: The experiments and modeling showed individual variations both in the measured motor thresholds (MTs) and in the computed electric fields. When the TMS coil was moved on the scalp, the calculated electric fields in the hand knob region were shown to vary consistently with the measured MTs. Group-level analysis indicated that the electric fields were significantly correlated with the measured MTs. The strongest correlations (R 2  = 0.69), which indicated the most likely activation site, were found in the ventral and lateral part of the hand knob. The site was independent of voluntary contractions of the target muscle., Conclusion: The study showed that TMS combined with personalized electric field modeling can be used for high-resolution mapping of the motor cortex., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Responses to plasticity-inducing brain stimulation protocols are highly variable. However, no data are available concerning the variability of responses to quadripulse stimulation (QPS)., Objective: We assessed the QPS parameters of motor cortical plasticity induction in a systematic manner, and later investigated the variability of QPS using optimal parameters., Methods: First, two different interburst intervals (IBI) with the same total number of pulses were compared. Next we investigated three different IBIs with a different total number of pulses but with same duration of intervention. We also compared the after-effects of monophasic and biphasic QPS. Finally, variability of QPS was tested in 35 healthy subjects. Twenty motor evoked potentials (MEPs) were measured every 5-10 min for up to one hour after intervention., Results: QPS at an IBI of 5 s produced MEPs changes that are dependent on the interstimulus interval of the four magnetic pulses, consistent with previous reports. Unexpectedly, QPS at an IBI of 2.5 s did not induce any plasticity, even with the same total number of pulses, that is, 1440. QPS at an IBI of 7.5 s produced a variable response but was likely to be comparable to conventional QPS. Biphasic QPS had shorter lasting after-effects compared with monophasic QPS. Finally, the after-effects of QPS were relatively consistent across subjects: more than 80% of subjects responded as expected in the excitatory QPS at an IBI of 5 s., Conclusions: The IBI, total duration of the procedure and pulse waveform strongly affected the magnitude or duration of the plasticity induced by QPS. In this cohort, 80% of subjects responded to excitatory QPS as expected., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) has been used to reveal excitability changes of the primary motor cortex (M1) in Parkinson's disease (PD). Abnormal rhythmic neural activities are considered to play pathophysiological roles in the motor symptoms of PD. The cortical responses to external rhythmic stimulation have not been studied in PD. We recently reported a new method of triad-conditioning TMS to detect the excitability changes after rhythmic conditioning stimuli, which induce facilitation by 40-Hz stimulation in healthy volunteers., Objective: We applied a triad-conditioning TMS to PD patients to reveal the motor cortical response characteristics to rhythmic TMS., Methods: The subjects included 13 PD patients and 14 healthy volunteers. Three conditioning stimuli over M1 at an intensity of 110% active motor threshold preceded the test TMS at various inter-stimulus intervals corresponding to 10-200 Hz., Results: The triad-conditioning TMS at 40 Hz induced no MEP enhancement in PD patients in either the On or Off state, in contrast to the facilitation observed in the normal subjects. Triad-conditioning TMS at 20-33 Hz in the beta frequency elicited significant MEP suppression in PD patients. The amount of suppression at 20 Hz positively correlated with the UPDRS III score., Conclusion: We observed abnormal M1 responses to rhythmic TMS in PD. The suppression induced by beta frequency stimulation and no facilitation by 40-Hz stimulation may be related to abnormal beta and gamma band activities within the cortical-basal ganglia network in PD patients. The motor cortical response to rhythmic TMS may be an additional method to detect physiological changes in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The utilities of magnetic cervical motor root stimulation are well known for lesions in the lower part of the brachial plexus, but not for lesions in the other parts., Objective: The aim of paper is to show the utilities of magnetic cervical motor root stimulation for lesions in the upper part of the brachial plexus., Methods: We analyzed the brachial plexus using both electrical stimulation at Erb's point and magnetic cervical motor root stimulation in a patient with brachial plexopathy caused by tumor invasion., Results: On the fourth day after onset, magnetic cervical motor root stimulation revealed abnormal findings in the upper part of the brachial plexus. Two weeks after onset, needle electromyography supported the existence of the focal lesion., Conclusion: Magnetic cervical motor root stimulation is useful in detecting abnormal findings in the upper part of the brachial plexus, even at the acute phase., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Imaging studies investigating repetitive transcranial magnetic stimulation (rTMS) mediated hemodynamic consequences revealed inconsistent results, mainly due to differences in rTMS parameters and technical difficulties with simultaneous recordings during rTMS., Objective/hypothesis: Quadri-pulse rTMS (QPS) induces bidirectional long-term plasticity of the human primary motor cortex (M1). To evaluate its on-line effects, near infrared spectroscopy (NIRS) recordings were performed during QPS. We hypothesized that on-line effects during QPS are different from long-term aftereffects., Methods: Using a novel TMS - on-line multi-channel NIRS setup we recorded hemoglobin concentration [Hb] changes at the stimulated M1 and adjacent sensory-motor areas during QPS protocols inducing oppositely directed aftereffects (QPS-5: interstimulus interval (ISI) 5 ms, potentiation; QPS-50: ISI 50 ms, depression). In two experiments we studied NIRS changes during either single or repeated QPS bursts., Results: The repetitive QPS-5 bursts significantly decreased oxyhemoglobin concentration ([oxy-Hb]) in the ipsilateral M1. A single QPS-5 burst decreased [oxy-Hb] in the M1 and premotor cortex. QPS-50 induced no significant NIRS changes at any sites., Conclusions: QPS can significantly alter cortical hemodynamics depending on the stimulation frequency. While bidirectional long-term aftereffects of QPS reflect synaptic efficacy changes, unidirectional on-line effects during QPS may represent pure electrophysiological property changes within the cell membrane or synapse. Since neuronal postexcitatory inhibitory postsynaptic potentials typically peak within the first 10-20 ms, only pulses delivered at higher frequencies may lead to summation of the inhibitory effects, resulting in [oxy-Hb] decrease only after QPS-5. Our new TMS-NIRS setup may be valuable to investigate TMS induced neurovascular coupling mechanisms in humans., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The amplitude of compound muscle action potentials (CMAPs) evoked in response to magnetic cervical motor root stimulation (MRS) has rarely been used as a diagnostic parameter because of the difficulty in obtaining supramaximal CMAPs., Objective: To clarify whether supramaximal CMAPs could be elicited by MRS, and if so, whether their amplitude and area could be used to evaluate the conduction of proximal motor roots., Method: With the use of a custom-made high-power magnetic stimulator, the CMAPs evoked in response to MRS of the first dorsal interosseous, abductor digiti minimi, and abductor pollicis brevis (APB) muscles were compared with those evoked by electrical stimulation at the wrist, brachial plexus, and cervical motor roots. The collision technique was also used to exclude volume conduction. The correlation between MRS-induced CMAP latency and body height was evaluated., Results: In 32 of 36 normal subjects, supramaximal CMAPs were obtained in response to MRS. The size of CMAPs occurring in response to MRS was the same as the size of those occurring in response to high-voltage electrical cervical motor root stimulation. The collision technique revealed that the APB muscle was highly contaminated by volume conduction from adjacent muscles. CMAP latency correlated significantly with body height., Conclusions: Supramaximal CMAPs can be obtained in most normal subjects. In subjects exhibiting confirmed supramaximal CMAPs in response to MRS, not only the latency of these CMAPs but also their amplitude and area can be clinically useful, excluding CMAPs in the APB muscle., (Copyright 2010 Elsevier Inc. All rights reserved.)

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

We briefly summarized several new stimulation techniques. There are many new methods of human brain stimulation, including modification of already known methods and brand-new methods. In this article, we focused on theta burst stimulation (TBS), repetitive monophasic pulse stimulation, paired- and quadri-pulse stimulation, transcranial alternating current stimulation (tACS), paired associative stimulation, controllable pulse shape TMS (cTMS), and deep-brain TMS. For every method, we summarized the state of the art and discussed issues that remain to be addressed.