Multi-locus transcranial magnetic stimulation with pulse-width modulation.

Distilling the essence of TMS-evoked EEG potentials (TEPs): A call for securing mechanistic specificity and experimental rigor

Transcranial magnetic stimulation (TMS) can induce motor evoked potentials (MEPs). In TMS applications, near-threshold stimulation intensities (SIs) are often used for characterizing corticospinal excitability using MEPs. We aimed to characterize the individual near-threshold recruitment of MEPs and to test the assumptions related to selection of the suprathreshold SI. We utilized MEP data from a right-hand muscle induced at variable SIs. The single-pulse TMS (spTMS) data from previous studies (27 healthy volunteers), as well as data from new measurements (10 healthy volunteers) that included also MEPs modulated by paired-pulse TMS (ppTMS), were included. The probability of MEP (pMEP) was represented with individually fitted cumulative distribution function (CDF) with two parameters: resting motor threshold (rMT) and spread relative to rMT. MEPs were recorded with 110% and 120% of rMT as well as with Mills-Nithi upper threshold (UT). The individual near-threshold characteristics varied with CDF parameters: the rMT and the relative spread (median: 0.052). The rMT was lower with ppTMS than with spTMS (p < 0.001), while the relative spread remained similar (p = 0.812). At suprathreshold SIs, the probability of MEP was similar between UT and 110% of rMT (pMEP > 0.88), and higher for 120% of rMT (pMEP > 0.98). The individual near-threshold characteristics determine how probably MEPs are produced at common suprathreshold SIs. At the population level, the used SIs UT and 110% of rMT produced MEPs at similar probability. The individual variability in the relative spread parameter was large; therefore, the method of determining the proper suprathreshold SI for TMS applications is of crucial importance.

Four electric field modeling methods of Dosing Prefrontal Transcranial Magnetic Stimulation (TMS): Introducing APEX MT dosimetry

Oscillatory brain activity coordinates the response of cortical neurons to synaptic inputs in a phase-dependent manner. Larger motor-evoked responses are obtained in a hand muscle when transcranial magnetic stimulation (TMS) is synchronized to the phase of the sensorimotor μ-rhythm. In this study we further showed that TMS applied at the negative vs. positive peak of the μ-rhythm is associated with higher absolute amplitude of the evoked EEG potential at 100ms after stimulation. This demonstrates that cortical responses are sensitive to excitability fluctuation with brain oscillations Our results indicate that brain state-dependent stimulation is a new useful technique for the investigation of stimulus-related cortical dynamics. Oscillatory brain activity coordinates the response of cortical neurons to synaptic inputs in a phase-dependent manner. Transcranial magnetic stimulation (TMS) of the human primary motor cortex elicits larger motor-evoked potentials (MEPs) when applied at the negative vs. positive peak of the sensorimotor μ-rhythm recorded with EEG, demonstrating that this phase represents a state of higher excitability of the cortico-spinal system. Here, we investigated the influence of the phase of the μ-rhythm on cortical responses to TMS as measured by EEG. We tested different stimulation intensities above and below resting motor threshold (RMT), and a realistic sham TMS condition. TMS at 110% RMT applied at the negative vs. positive peak of the μ-rhythm was associated with higher absolute amplitudes of TMS-evoked potentials at 70ms (P70) and 100ms (N100). Enhancement of the N100 was confirmed with negative peak-triggered 90% RMT TMS, while phase of the μ-rhythm did not influence evoked responses elicited by sham TMS. These findings extend the idea that TMS applied at the negative vs. positive peak of the endogenous μ-oscillation recruits a larger portion of neurons as a function of stimulation intensity. This further corroborates that brain oscillations determine fluctuations in cortical excitability and establishes phase-triggered EEG-TMS as a sensitive tool to investigate the effects of brain oscillations on stimulus-related cortical dynamics.

TMS assessed cortical representation scales with stimulation intensity and muscle activation

What is the central question of this study? A transcranial magnetic stimulation (TMS)-induced twitch applied on isolated single breaths over the motor cortex somatotopic representation of the tongue briefly recruits submental muscles and improves airflow dynamics of flow-limited respiratory cycles without arousing sleep apnoea patients. However, the mechanical impact of the TMS-induced twitch applied during consecutive breathing cycles on airflow dynamics remains unknown. What is the main finding and what is its importance? Our results show that application of TMS with the stimulator output set at the sleep submental motor threshold intensity on consecutive respiratory cycles increases inspiratory flow and reduces the turbulent airflow component. These results indicate an improvement of airflow pattern after two single consecutive TMS-induced twitches without arousing sleep apnoea patients. Transcranial magnetic stimulation (TMS)-induced twitches applied on isolated breaths briefly recruit upper airway dilator muscles and improve airflow and inspiratory volume without arousing apnoeic patients from sleep, but the effects of applying such twitches consecutively on airflow dynamics is unknown. The objective of this study was to quantify the effects of five consecutive TMS-induced twitches applied on sleep-induced obstructive hypopnoeic breaths in 10 obstructive sleep apnoea patients. Submental muscle motor threshold (SUBMT) and motor-evoked potential were measured during wakefulness and sleep. The TMS-induced twitches were applied during stable non-rapid eye movement (NREM) sleep, at the beginning of inspiration of consecutive flow-limited respiratory cycles, with the stimulator output set at sleep SUBMT. Maximal inspiratory flow, inspiratory volume, inspiratory time, shifts of electroencephalogram frequency and pulse rate variability were assessed. During sleep, SUBMT increased (wakefulness, 25.3 ± 4.9%; NREM sleep, 27.0 ± 6.2%; P = 0.02). During each series of stimulations there was a rise in maximal inspiratory flow (from 306.7 ± 123.2 to 359.8 ± 154.1 ml s(-1); P = 0.0002) and in inspiratory volume (from 346.1 ± 128.1 to 414.9 ± 171.2 ml; P = 0.02) without differences in thoraco-abdominal efforts and inspiratory time. These responses were observed in the absence of arousals and ceased immediately after TMS interruption. Transcranial magnetic stimulation-induced cortical and/or autonomic arousal was observed in 30.2% of all series of stimulation. Consecutive twitch TMS of submental muscles may lead to arousals in a minority of patients but can be applied on consecutive respiratory cycles during sleep and can significantly improve maximal inspiratory flow and inspiratory volume of flow-limited cycles.

ObjectiveThe effects and possible mechanisms of cerebellar high-frequency repetitive transcranial magnetic stimulation (rTMS) on swallowing-related neural networks were studied using resting-state functional magnetic resonance imaging (rs-fMRI).MethodA total of 23 healthy volunteers were recruited, and 19 healthy volunteers were finally included for the statistical analysis. Before stimulation, the cerebellar hemisphere dominant for swallowing was determined by the single-pulse TMS. The cerebellar representation of the suprahyoid muscles of this hemisphere was selected as the target for stimulation with 10 Hz rTMS, 100% resting motor threshold (rMT), and 250 pulses, with every 1 s of stimulation followed by an interval of 9 s. The motor evoked potential (MEP) amplitude of the suprahyoid muscles in the bilateral cerebral cortex was measured before and after stimulation to evaluate the cortical excitability. Forty-eight hours after elution, rTMS was reapplied on the dominant cerebellar representation of the suprahyoid muscles with the same stimulation parameters. Rs-fMRI was performed before and after stimulation to observe the changes in amplitude of low-frequency fluctuation (ALFF) and regional homology (ReHo) at 0.01–0.08 Hz, 0.01–0.027 Hz, and 0.027–0.073 Hz.ResultsAfter cerebellar high-frequency rTMS, MEP recorded from swallowing-related bilateral cerebral cortex was increased. The results of rs-fMRI showed that at 0.01–0.08 Hz, ALFF was increased at the pons, right cerebellum, and medulla and decreased at the left temporal lobe, and ReHo was decreased at the left insular lobe, right temporal lobe, and corpus callosum. At 0.01–0.027 Hz, ALFF was decreased at the left temporal lobe, and ReHo was decreased at the right temporal lobe, left putamen, and left supplementary motor area.ConclusionRepetitive transcranial magnetic stimulation of the swallowing cortex in the dominant cerebellar hemisphere increased the bilateral cerebral swallowing cortex excitability and enhanced pontine, bulbar, and cerebellar spontaneous neural activity, suggesting that unilateral high-frequency stimulation of the cerebellum can excite both brainstem and cortical swallowing centers. These findings all provide favorable support for the application of cerebellar rTMS in the clinical practice.

IntroductionREM Sleep Behavior Disorder (RBD) has been highlighted to identify a patient with prodromal Parkinson’s disease (PD). Although many studies focus on biomarkers to predict an RBD patient’s evolution from prodromal PD to clinical PD, the neurophysiological perturbation of cortical excitability has not yet been well elucidated. Moreover, no study describes the difference between RBD with and without abnormal TRODAT-1 SPECT.MethodsBy measuring the amplitude of motor evoked potentials (MEP), the cortical excitability changes after transcranial magnetic stimulation (TMS) were evaluated in 14 patients with RBD and eight healthy controls (HC). Seven of the 14 patients with RBD showed abnormal TRODAT-1 (TRA-RBD), and seven were normal (TRN-RBD). The tested parameters of cortical excitability include resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), contralateral silence period (CSP), and input–output recruitment curve.ResultsThe RMT and AMT showed no difference among the three studied groups. There was only SICI at inter-stimuli-interval 3 ms revealing group differences. The TRA-RBD demonstrated significant differences to HC in these aspects: decreased SICI, increased ICF, shortening of CSP, and augmented MEP amplitude at 100% RMT. Moreover, the TRA-RBD had a smaller MEP facilitation ratio at 50% and 100% of maximal voluntary contraction when compared to TRN-RBD. The TRN-RBD did not present any difference to HC.ConclusionWe showed that TRA-RBD shared similar cortical excitability changes with clinical PD. These findings would provide further insight into the concept that RBD is the highly prevalent entity in prodromal PD.

Event Abstract Back to Event Hysteresis Effects of Cortico-Spinal Excitability during Transcranial Magnetic Stimulation Caroline Moller1*, Noritoshi Arai1, 2, Jorg Lucke3 and Ulf Ziemann1 1 Goethe University, Motor Cortex Group, Department of Neurology, Germany 2 Toyama Hospital, Department of Neurology, Japan 3 Frankfurt Institute for Advanced Studies, Germany Input-output (IO) curves of motor evoked potentials (MEP) are an important and widely used method to assess motor cortical excitability by transcranial magnetic stimulation (TMS). IO curves are measured by applying TMS stimuli at a range of different intensities and the slope and amplitude of the curve is a sensitive marker for excitability changes of neuronal systems under different physiological or pathological conditions. However, it is not known whether the sequence in which the curves are obtained may by itself influence corticospinal activation.Here, we investigated the effects of history dependence, known also as hysteresis effects on IO curves. To test this IO curves from the first dorsal interosseous (FDI) muscle of 14 healthy volunteers were obtained in three different sequences of stimulus intensity order: Increasing from low to high intensities, decreasing from high to low intensities and randomizing intensities. Intensities ranged from 80% to 170% of the individual resting motor threshold (RMT). At each intensity level 5 trials were recorded and averaged. Sequences were measured with two different inter-trial intervals (ITI, 5s and 20s), and in the resting vs. voluntarily active muscle. All recordings with the resting muscle were carefully checked for voluntary muscle activation to control for unspecific arousal effects. In the resting muscle and at ITI = 5s, IO curves measured with the decreasing sequence were significantly shifted to the left compared to the increasing sequence while the IO curve obtained with the randomized sequence ran in between. Hysteresis was most pronounced in the upper part of the IO curves at intensities of 130% RMT and above. No significant hysteresis was seen at ITI = 20s or in the active FDI. Our findings implicate that hysteresis could significantly influence IO curves. High intensity stimuli at the beginning of the decreasing sequence seemed to have an enhancing effect on consecutive stimuli during the same recording. As no hysteresis effects were present with the longer ITI of 20s we propose that short-term plasticity may be a possible mechanism to account for this effect. Conference: Bernstein Conference on Computational Neuroscience, Frankfurt am Main, Germany, 30 Sep - 2 Oct, 2009. Presentation Type: Poster Presentation Topic: Learning and plasticity Citation: Moller C, Arai N, Lucke J and Ziemann U (2009). Hysteresis Effects of Cortico-Spinal Excitability during Transcranial Magnetic Stimulation. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference on Computational Neuroscience. doi: 10.3389/conf.neuro.10.2009.14.124 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Aug 2009; Published Online: 27 Aug 2009. * Correspondence: Caroline Moller, Goethe University, Motor Cortex Group, Department of Neurology, Frankfurt, Germany, moeller@med.uni-frankfurt.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Caroline Moller Noritoshi Arai Jorg Lucke Ulf Ziemann Google Caroline Moller Noritoshi Arai Jorg Lucke Ulf Ziemann Google Scholar Caroline Moller Noritoshi Arai Jorg Lucke Ulf Ziemann PubMed Caroline Moller Noritoshi Arai Jorg Lucke Ulf Ziemann Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The aim of this study was to verify the hypothesis that transcranial magnetic stimulation (TMS) parameters over the hand region of the motor cortex, such as resting motor threshold (rMT) and motor evoked potential (MEP) latency, predict the behavioural performance of karate athletes in the response time (RT) test. Twenty-five male karate athletes (24.9±4.9years) and 25 matched non-athletes (26.2±4.5years) were recruited. Using TMS, we investigated cortico-spinal system excitability. Compared with controls, the athletes showed faster RT (p<0.001), lower rMT (p<0.01), shorter MEP latency (p<0.01), and higher MEP amplitude (p<0.01); moreover, there was a significant positive linear correlation between RT and rMT (p<0.001), between RT and MEP latency (p<0.0001), and a negative correlation between RT and MEP amplitude (p<0.001). The practice of competitive sports affects both the central and peripheral nervous system. Subjects that showed higher cortical excitability showed also higher velocity, at which the neural signal is propagated from the motor cortex to the muscle and consequently better RT. The lower rMT and the shorter MEP latency observed in athletes support the effects of training in determining specific brain organizations to meet specific sport challenges.

The resting motor threshold (rMT) is the basic unit of transcranial magnetic stimulation (TMS) dosing. Traditional methods of determining rMT involve finding a threshold of either visible movement or electromyography (EMG) motor-evoked potentials, commonly approached from above and below and then averaged. This time-consuming method typically uses many TMS pulses. Mathematical programs can efficiently determine a threshold by calculating the next intensity needed based on the prior results. Within our group of experienced TMS researchers, we sought to perform an illustrative study to compare one of these programs, the Maximum-Likelihood Strategy using Parameter Estimation by Sequential Testing (MLS-PEST) approach, to a modification of the traditional International Federation of Clinical Neurophysiology (IFCN) method for determining rMT in terms of the time and pulses required and the rMT value. One subject participated in the study. Five researchers determined the same subject's rMT on 4 separate days-twice using EMG and twice using visible movement. On each visit, researchers used both the MLS-PEST and the IFCN methods, in alternating order. The MLS-PEST approach was significantly faster and used fewer pulses to estimate rMT. For EMG-determined rMT, MLS-PEST and IFCN derived similar rMT, whereas for visible movement MLS-PEST rMT was higher than for IFCN. The MLS-PEST algorithm is a promising alternative to traditional, time-consuming methods for determining rMT. Because the EMG-PEST method is totally automated, it may prove useful in studies using rMT as a quickly changing variable, as well as in large-scale clinical trials. Further work with PEST is warranted.

BackgroundAlzheimer’s disease (AD) is linked to abnormal cortical excitability. Recent studies have suggested that amyloid‐related cortical hyperexcitability may drive faster clinical decline and be related to spreading of tau. However, we lack non‐invasive methods to quickly and directly assay cortical excitability in AD patients. We generate an Input‐Output response curve (I/O Curve) using transcranial magnetic stimulation (TMS) with electromyography (EMG) to investigate mechanisms of cortical excitability in AD.MethodsParticipants included 52 biomarker‐positive early AD (CDR=0.5‐1, age 70±8, 37% female) and 51 cognitively normal older adults (CN; age 70±6.5, 53% female). Single‐pulse TMS was applied to left motor cortex to measure resting motor threshold (RMT). An I/O Curve was generated by delivering 10 pulses each at eight stimulation intensities (30‐100% maximum stimulator output (%MSO)). We recorded motor‐evoked potentials (MEP) from the right first dorsal interosseous muscle. RMTs were compared between AD and CN using a linear model controlling for scalp‐to‐cortex distance (SCD) and protocol (i.e., EEG cap). For the I/O curve, stimulation intensity was normalized to RMT (%MSO/RMT) and binned in 15% increments. MEP amplitudes along the I/O Curve were analyzed using a linear mixed effects model with effects of Group, %MSO/RMT, and Group*%MSO/RMT; covariates of age, sex, education, and APOE4 alleles; and participant‐level random effects. Contrasts were conducted comparing the groups at each point along the I/O curve.ResultsRMT was lower in AD than in CN (η² p =0.12, medium effect size, p = 0.004, Figure 1); SCD was a significant covariate (p = 0.006). The I/O Curve revealed an increased response in the AD group, with significant effects of Group (η² p =0.10, medium effect size; p = 0.007), %MSO/RMT (η² p =0.71, p <0.001), and Group*%MSO/RMT (η² p =0.05, small effect size, p = 0.013). Covariates were not significant. Increased excitability in AD was greatest at higher stimulation intensities (120‐135%MSO/RMT: Cohen’s d=0.286, small effect size, p = 0.015; 135‐150%MSO/RMT: Cohen’s d=0.495, medium effect size, p <0.001, Figure 2).ConclusionsTMS‐EMG confirms evidence of increased cortical excitability in AD. This was evident at lower intensities with the RMT model (implicating voltage‐gated Na+ channels) and higher intensities with the I/O Curve (implicating AMPA receptors). TMS may be useful to measure target engagement of novel therapies targeting cortical excitability in AD.

Repetitive transcranial magnetic stimulation of the motor cortex (rTMS) can be used to modify motor cortical excitability in human subjects. At stimulus intensities near to or above resting motor threshold, low-frequency rTMS (approximately 1 Hz) decreases motor cortical excitability, whereas high-frequency rTMS (5-20 Hz) can increase excitability. We investigated the effect of 10 min of intermittent rTMS on motor cortical excitability in normal subjects at two frequencies (2 or 6 Hz). Three low intensities of stimulation (70, 80, and 90% of active motor threshold) and sham stimulation were used. The number of stimuli were matched between conditions. Motor cortical excitability was investigated by measurement of the motor-evoked potential (MEP) evoked by single magnetic stimuli in the relaxed first dorsal interosseus muscle. The intensity of the single stimuli was set to evoke baseline MEPs of approximately 1 mV in amplitude. Both 2- and 6-Hz stimulation, at 80% of active motor threshold, reduced the magnitude of MEPs for approximately 30 min (P < 0.05). MEPs returned to baseline values after a weak voluntary contraction. Stimulation at 70 and 90% of active motor threshold and sham stimulation did not induce a significant group effect on MEP magnitude. However, the intersubject response to rTMS at 90% of active motor threshold was highly variable, with some subjects showing significant MEP facilitation and others inhibition. These results suggest that, at low stimulus intensities, the intensity of stimulation may be as important as frequency in determining the effect of rTMS on motor cortical excitability.

Effects of stimulus waveform on transcranial magnetic stimulation metrics in proximal and distal arm muscles

Transcranial magnetic stimulation (TMS) studies typically focus on suprathreshold motor evoked potentials (MEPs), overlooking small MEPs representing subthreshold corticomotor pathway activation. Assessing subthreshold excitability could provide insights into corticomotor pathway integrity and function, particularly in neurological conditions like stroke. The aim of the study wasto examine the test-retest reliability of metrics derived from a novel compositional analysis of MEP data from older adults. The study also compared the composition between the dominant (D) and non-dominant (ND) sides and explored the association between subthreshold responses and resting motor threshold. In this proof-of-concept study, 23 healthy older adults participated in two identical experimental sessions. Stimulus-response (S-R) curves and threshold matrices were constructed using single-pulse TMS across intensities to obtain MEPs in four upper limb muscles. S-R curves had reliable slopes for every muscle (Intraclass Correlation Coefficient range = 0.58-0.88). Subliminal and suprathreshold elements of the threshold matrix showed good-excellent reliability (D subliminal ICC = 0.83; ND subliminal ICC = 0.79; D suprathreshold ICC = 0.92; ND suprathreshold ICC = 0.94). By contrast, subthreshold elements of the matrix showed poor reliability, presumably due to a floor effect (D subthreshold ICC = 0.39; ND subthreshold ICC = 0.05). No composition differences were found between D and ND sides (suprathreshold BF01 = 3.85; subthreshold BF01 = 1.68; subliminal BF01 = 3.49). The threshold matrix reliably assesses subliminal and suprathreshold MEPs in older adults. Further studies are warranted to evaluate the utility of compositional analyses for assessing recovery of corticomotor pathway function after neurological injury.