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Purpose: Transcranial magnetic stimulation-induced motor responses have been considered to mainly reflect the electrophysiological characteristics of the central motor system. However, certain motor phenomena, such as the magnitude of repetition suppression measured with motor evoked potentials (MEPs), could also in part be influenced by metabolic processes in the peripheral muscles and in both the peripheral and central nervous system. Repetition suppression is an inhibitory phenomenon in which the amplitude of MEP decreases in comparison to that of the first MEP in a train of transcranial magnetic stimulation pulses. This study aimed to identify possible metabolic processes influencing repetition suppression., Methods: The metabolic profiles from serum samples and repetition suppression from the right abductor pollicis brevis muscle were measured in 73 subjects (37 female subjects). Repetition suppression was measured using trains of transcranial magnetic stimulation stimuli consisting of 4 identical single pulses at 1-second intervals. The trains were repeated every 20 seconds, and 30 trains were given with a stimulation intensity of 120% of the resting motor threshold of the abductor pollicis brevis. Thus, a total of 120 stimuli were administered., Results: The main finding was a significant negative relationship between serum creatine levels and the magnitude of repetition suppression (standardized β coefficient (β) = -0.43; P < 0.001). In other words, higher creatine levels corresponded to a smaller decrement in the MEP amplitude in response to repetition. When MEPs were not repeated, no relationship was observed (β = 0.09; P = 0.454). Creatine is used to form phosphocreatine, which in turn is needed to resynthesize adenosine triphosphate from adenosine diphosphate in situations requiring high amounts of energy in muscles and neural cells., Conclusions: For the first time, this study demonstrated a connection between repeated MEPs and peripheral serum metabolites linked to muscle function. These findings could explain some of the intersubject variability commonly observed in MEPs when the pulses are repeated.

Modulatory effects of transcranial magnetic stimulation (TMS) strongly depend on the stimulation parameters. Here, we compared the immediate, task-locked inhibitory effects on speech-related muscles and the tolerability of different TMS protocols during a language production task. Repetitive TMS (rTMS) and paired-pulse TMS (PP) were applied in 13 healthy subjects over the primary motor cortex (M1) during a finger-tapping/tongue-twisting tasks. The lowest subject-specific TMS intensity leading to movement disruptions was used for TMS over left-sided speech-related areas during picture naming. Here, time-locked PP and rTMS (10/30/50 Hz; randomized sequence) were applied. Cortical silent periods (cSPs) were analyzed from electromyography obtained from various face muscles. 30 Hz- and 50 Hz-rTMS reliably evoked tongue movement disruption (ICC = 0.65) at lower rTMS intensities compared to 10 Hz-rTMS or PP. CSPs were elicited from the left hemisphere by all TMS protocols, most reliably by PP (p < 0.001). Also, cSPs with longest durations were induced by PP. Exploratory analyses of PP suggest that the trials with strongest motor inhibitory effects (presence of cSP) were associated with more articulatory naming errors, hence hinting at the utility of TMS-elicited, facial cSP for mapping of language production areas. Higher-frequency rTMS and PP evoked stronger inhibitory effects as compared to 10 Hz-rTMS during a language task, thus enabling a probably more efficient and tolerable routine for language mapping. The spatial distribution of cranial muscle cSPs implies that TMS might affect not only M1, but also distant parts of the language network.

Navigated transcranial magnetic stimulation (nTMS) can be applied to locate cortical muscle representations. Usually, single TMS pulses are targeted to the motor cortex with the help of neuronavigation and by measuring motor evoked potential (MEP) amplitudes from the peripheral muscles. The efficacy of single-pulse TMS to induce MEPs has been shown to increase by applying facilitatory paired-pulse TMS (ppTMS). Therefore, the aim was to study whether the facilitatory ppTMS could enable more efficient motor mapping. Biphasic single-pulse TMS and ppTMS with inter-stimulus intervals (ISIs) of 1.4 and 2.8 ms were applied to measure resting motor thresholds (rMTs) as a percentage of the maximal stimulator output and to determine the cortical representation areas of the right first dorsal interosseous muscle in healthy volunteers. The areas, shapes, hotspots, and center of gravities (CoGs) of the representations were calculated. Biphasic ppTMS with ISI of 1.4 ms resulted in lower rMTs than those obtained with the other protocols (p = 0.001). With ISI of 2.8 ms, rMT was lower than with single-pulse TMS (p = 0.032). The ppTMS mapping was thus performed with lower intensity than when using single-pulse TMS. The areas, shapes, hotspots, and CoGs of the muscle representations were in agreement. Hence, biphasic ppTMS has potential in the mapping of cortical hand representations in healthy individuals as an alternative for single-pulses, but with lower stimulation intensity by utilizing cortical facilitatory mechanism. This could improve application of nTMS in subjects with low motor tract excitability.

Loud sounds have been demonstrated to increase motor cortex excitability when transcranial magnetic stimulation (TMS) is synchronized with auditory evoked N100 potential measured from electroencephalography (EEG). The N100 potential is generated by an afferent response to sound onset and feature analysis, and upon novel sound it is also related to the arousal reaction. The arousal reaction is known to originate from the ascending reticular activating system of the brain stem and to modulate neuronal activity throughout the central nervous system. In this study we investigated the difference in motor evoked potentials (MEPs) when deviant and novelty stimuli were randomly interspersed in a train of standard tones. Twelve healthy subjects participated in this study. Three types of sound stimuli were used: 1) standard stimuli (800 Hz), 2) deviant stimuli (560 Hz), and 3) novelty stimuli (12 different sounds). In each stimulus sequence 600 stimuli were given. Of these, 90 were deviant stimuli randomly placed between the standard stimuli. Each of 12 novel sounds was presented once in pseudorandomized order. TMS was randomly mixed with the sound stimuli so that it was either synchronized with the individual N100 or trailed the sound onset by 200 ms. All sounds elicited an increase in motor cortex excitability. The type of sound had no significant effect. We also demonstrated that TMS timed at 200-ms intervals caused a significant increment of MEPs. This contradicted our hypothesis that MEP amplitudes to TMS synchronized with N100 would be greater than those to TMS at 200 ms after a sound and remains unexplained. NEW & NOTEWORTHY We demonstrated modulation of motor cortical excitability with parallel auditory stimulus by combining navigated transcranial magnetic stimulation (TMS) with auditory stimuli. TMS was synchronized with auditory evoked potentials considered to be generated by the unconscious attention call process in the auditory system.

The most thoroughly studied transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) potential (TEP), N100, is often defined as a measure of cortical inhibition. We explored the association of the N100 amplitude with attention in 51 young healthy adults. Navigated TMS with simultaneous EEG registering was applied over the left primary motor cortex at the intensity of 110% of the resting motor threshold. Attention was assessed with the Paced Auditory Serial Addition Test (PASAT). We found a negative Pearson correlation (p = .023, r = -0.317) between the left centroparietal N100 amplitude and the PASAT score. Of the participants, the 17 with the highest PASAT scores and 17 with the lowes scores were selected for further analysis, in which a significant between-group difference in the left centroparietal N100 was found (p = .017). The topographic specificity of this finding was further confirmed with linear mixed model (LMM) analysis, in which significant differences were detected in the N100 amplitude; most prominently in the left centroparietal region (p = .001). A smaller N100 amplitude was associated with better performance in the attention task. Our findings suggest that the GABA-B-ergic TEP N100 is associated with attentional processes and thus represents cortical inhibition beyond motor inhibition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) induced I-wave behavior can be demonstrated at neuronal population level using paired-pulses and by observing short-interval cortical facilitation (SICF). Advancements in stimulator technology have made it possible to apply biphasic paired-pulses to induce SICF., Objective: Our aim was to characterize the SICF I-wave interaction by biphasic paired-pulses with the ultimate objective to enhance TMS effects via SICF in various TMS-applications., Methods: We used biphasic paired-pulses in 15 volunteers to characterize corticospinal SICF using various 1.2-8.0ms inter-stimulus intervals, and measuring SICF input-output response., Results: SICF interaction with the first I-wave (I1) was observed in the output responses (motor evoked potentials; MEPs) in all subjects. Most subjects (≥80%) also exhibited later SICF I-wave interaction. SICF at I1 was present at all applied intensities below 140% of resting motor threshold. At I2, we observed SICF only with intensities just above motor threshold., Conclusions: Biphasic paired-pulses can reliably induce SICF shown by the facilitatory I-wave interaction, and could therefore be applied with repetitive bursts to enhance responsiveness to TMS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Navigated transcranial magnetic stimulation (nTMS) can be applied to locate and outline cortical motor representations. This may be important, e.g., when planning neurosurgery or focused nTMS therapy, or when assessing plastic changes during neurorehabilitation. Conventionally, a cortical location is considered to belong to the motor cortex if the maximum electric field (E-field) targeted there evokes a motor-evoked potential in a muscle. However, the cortex is affected by a broad E-field distribution, which tends to broaden estimates of representation areas by stimulating also the neighboring areas in addition to the maximum E-field location. Our aim was to improve the estimation of nTMS-based motor maps by taking into account the E-field distribution of the stimulation pulse. The effect of the E-field distribution was considered by calculating the minimum-norm estimate (MNE) of the motor representation area. We tested the method on simulated data and then applied it to recordings from six healthy volunteers and one stroke patient. We compared the motor representation areas obtained with the MNE method and a previously introduced interpolation method. The MNE hotspots and centers of gravity were close to those obtained with the interpolation method. The areas of the maps, however, depend on the thresholds used for outlining the areas. The MNE method may improve the definition of cortical motor areas, but its accuracy should be validated by comparing the results with maps obtained with direct cortical stimulation of the cortex where the E-field distribution can be better focused.

Repetition suppression (RS) is evident as a weakened response to repeated stimuli after the initial response. RS has been demonstrated in motor-evoked potentials (MEPs) induced with transcranial magnetic stimulation (TMS). Here, we investigated the effect of inter-train interval (ITI) on the induction of RS of MEPs with the attempt to optimize the investigative protocols. Trains of TMS pulses, targeted to the primary motor cortex by neuronavigation, were applied at a stimulation intensity of 120% of the resting motor threshold. The stimulus trains included either four or twenty pulses with an inter-stimulus interval (ISI) of 1 s. The ITI was here defined as the interval between the last pulse in a train and the first pulse in the next train; the ITIs used here were 1, 3, 4, 6, 7, 12, and 17 s. RS was observed with all ITIs except with the ITI of 1 s, in which the ITI was equal to ISI. RS was more pronounced with longer ITIs. Shorter ITIs may not allow sufficient time for a return to baseline. RS may reflect a startle-like response to the first pulse of a train followed by habituation. Longer ITIs may allow more recovery time and in turn demonstrate greater RS. Our results indicate that RS can be studied with confidence at relatively short ITIs of 6 s and above.

Motor functions improve during childhood and adolescence, but little is still known about the development of cortical motor circuits during early life. To elucidate the neurophysiological hallmarks of motor cortex development, we investigated the differences in motor cortical excitability and connectivity between healthy children, adolescents, and adults by means of navigated suprathreshold motor cortex transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG). We demonstrated that with development, the excitability of the motor system increases, the TMS-evoked EEG waveform increases in complexity, the magnitude of induced activation decreases, and signal spreading increases. Furthermore, the phase of the oscillatory response to TMS becomes less consistent with age. These changes parallel an improvement in manual dexterity and may reflect developmental changes in functional connectivity. Hum Brain Mapp 38:2599-2615, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Although the relationship between neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) has been widely studied in motor mapping, it is unknown how the motor response type or the choice of motor task affect this relationship., New Method: Centers of gravity (CoGs) and response maxima were measured with blood-oxygen-level dependent (BOLD) and arterial spin labeling (ASL) fMRI during motor tasks against nTMS CoGs and response maxima, which were mapped with motor evoked potentials (MEPs) and silent periods (SPs)., Results: No differences in motor representations (CoGs and response maxima) were observed in lateral-medial direction (p=0.265). fMRI methods localized the motor representation more posterior than nTMS (p<0.001). This was not affected by the BOLD fMRI motor task (p>0.999) nor nTMS response type (p>0.999). ASL fMRI maxima did not differ from the nTMS nor BOLD fMRI CoGs (p≥0.070), but the ASL CoG was deeper in comparison to other methods (p≤0.042). The BOLD fMRI motor task did not influence the depth of the motor representation (p≥0.745). The median Euclidean distances between the nTMS and fMRI motor representations varied between 7.7mm and 14.5mm and did not differ between the methods (F≤1.23, p≥0.318)., Comparison With Existing Methods: The relationship between fMRI and nTMS mapped excitatory (MEP) and inhibitory (SP) responses, and whether the choice of motor task affects this relationship, have not been studied before., Conclusions: The congruence between fMRI and nTMS is good. The choice of nTMS motor response type nor BOLD fMRI motor task had no effect on this relationship., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To assess the inter-hemispheric differences in neuronal function and structure of the motor cortex in a small group of chronic stroke patients having suffered a restricted ischemic lesion affecting hand motor representation. GABAergic intracortical inhibition, known to be affected by stroke lesion, was also investigated., Methods: Eight patients exhibiting little or no motor impairment were studied using transcranial magnetic stimulation (TMS) and diffusion weighted imaging (DWI) >15months from diagnosis. Resting motor threshold (MT) for 50μV and 2mV motor evoked potentials, and short-interval intracortical inhibition (SICI) were measured from hand muscles. Apparent diffusion coefficients (ADCs) were analyzed from the DWI for the primary motor cortex (M1), the supplementary motor area (SMA) and thalamus for reflecting changes in neuronal organization., Results: The MTs did not differ between the affected (AH) and unaffected hemisphere (UH) in 50μV responses, while the MTs for 2mV responses were higher (p=0.018) in AH. SICI was weakened in AH (p=0.008). ADCs were higher in the affected M1 compared to the unaffected M1 (p=0.018) while there were no inter-hemispheric differences in SMA or thalamus., Conclusions: Inter-hemispheric asymmetry and neuronal organization demonstrated abnormalities in the M1. However, no confident inference can be made whether the observed alterations in neurophysiological and imaging measures have causal role for motor rehabilitation in these patients., Significance: Neurophysiological changes persist and are detectable using TMS years after stroke even though clinical symptoms have normalized., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Purpose: Corticospinal silent period (SP) may be interrupted by a burst of muscle activity followed by a second (late) SP, generally assumed to be a continuation from the primary SP. Our objective was to characterize the input-output behavior of the late SP., Methods: Transcranial magnetic stimulation was applied on the cortical representation area of the right-hand muscles of 12 healthy subjects. Single-pulse transcranial magnetic stimulation was given with varying stimulation intensities normalized to the individual resting motor threshold (60% to 130% of the resting motor threshold) during voluntary muscle contraction. Electromyogram was recorded from first dorsal interosseous and abductor pollicis brevis muscles. Primary and late SPs were analyzed as absolute SPs, and input-output characteristics were assessed., Results: The late SP exhibited fundamentally different input-output characteristics from that of the primary SP. The late SP most likely presented itself at stimulation intensities of 90% to 100% of the resting motor threshold., Conclusions: Different input-output characteristics of the late SP compared with the primary SP indicate that the late SP possess mechanisms different from the primary SP. The exact origin of the late SP remains unclear. Understanding the origins of the late SP could provide valuable insight on corticospinal inhibitory processes.

Objective: We evaluated the induction of corticospinal silent period (SP) using transcranial magnetic stimulation (TMS) at stimulation intensities normalized to resting motor threshold (rMT) or silent period thresholds (SPTs). The aim was to reduce the characteristic inter-individual variation in SP measurements in healthy population to improve the sensitivity of such measurements., Methods: The cortical representation area of the right hand musculature of 12 healthy subjects was stimulated with navigated TMS with varying stimulating intensities. Subsequently, the individual SPTs for eliciting SPs of 20, 30, and 50ms in duration were determined from the input-output characteristics., Results: While SPT for 20 and 50ms SPs differed from rMT, the SPT for 30ms was similar to rMT. Nevertheless, the inter-individual variation in SP duration was reduced significantly at 120% of SPT30 when compared with SP durations obtained at 120% of rMT., Conclusions: Inter-individual variation in the SP duration decreases when applying TMS at stimulation intensities normalized to the individual SPTs instead to the rMT. This makes the SP duration more specific to inhibition and less affected by changes in cortical excitability., Significance: Use of individual SPTs may improve the sensitivity of the SP measures in studies with inter-individual design., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)