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Background: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls., Materials and Methods: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons., Results: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms., Conclusion: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials., (© 2022. The Author(s).)

Transcranial magnetic stimulation combined with electroencephalography is a powerful tool to probe human cortical excitability. The EEG response to TMS stimulation is altered by drugs active in the brain, with characteristic "fingerprints" obtained for drugs of known mechanisms of action. However, the extraction of specific features related to drug effects is not always straightforward as the complex TMS-EEG induced response profile is multi-dimensional. Analytical approaches can rely on a-priori assumptions within each dimension or on the implementation of cluster-based permutations which do not require preselection of specific limits but may be problematic when several experimental conditions are tested. We here propose an alternative data-driven approach based on PARAFAC tensor decomposition, which provides a parsimonious description of the main profiles underlying the multidimensional data. We validated reliability of PARAFAC on TMS-induced oscillations before extracting the features of two common anti-epileptic drugs (levetiracetam and lamotrigine) in an integrated manner. PARAFAC revealed an effect of both drugs, significantly suppressing oscillations in the alpha range in the occipital region. Further, this effect was stronger under the intake of levetiracetam. This study demonstrates, for the first time, that PARAFAC can easily disentangle the effects of subject, drug condition, frequency, time and space in TMS-induced oscillations.

Concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) has emerged as a powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS-EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objective of this article is to present a comprehensive review of studies that have used TMS-EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical framework, we first give an overview of TMS-EEG methodology and discuss the current state of knowledge regarding the use of TMS-EEG to assess excitability, inhibition, plasticity and connectivity following neuromodulatory techniques in the healthy brain. We then review the insights afforded by TMS-EEG into the pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS-EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS-EEG as a clinical tool., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Inhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2-3 ms (short-interval intracortical inhibition, SICI) or ∼100 ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively., Objective/hypothesis: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI., Methods: PpTMS-EEG was applied to the left motor cortex in 16 healthy subjects in a randomized, double-blind placebo-controlled crossover design, testing the effects of a single oral dose 20 mg of diazepam, a positive modulator at the GABAA receptor, vs. 50 mg of the GABAB receptor agonist baclofen on SICI of TEPs., Results: We found significant SICI of the N100 and P180 TEPs prior to drug intake. Diazepam reduced SICI of the N100 TEP, while baclofen enhanced it. Compared to our previous ppTMS-EEG results on LICI, the SICI effects on TEPs, including their drug modulation, were largely analogous., Conclusions: Findings suggest a similar interaction of paired-pulse effects on TEPs irrespective of the interstimulus interval. Therefore, SICI and LICI as measured with TEPs cannot be directly derived from SICI and LICI measured with MEPs, but may offer novel insight into paired-pulse responses recorded directly from the brain rather than muscle., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late event-related desynchronization (ERD-peaking at ~300 ms after TMS), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.

Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (<50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.

The aim of this study was to determine the physiology of short-interval intracortical inhibition (SICI) directly at the level of the human cortex by means of pharmaco-TMS-EEG. We recorded a 64-channel EEG during application of a magnetic test stimulus (TS100) 2 ms after a conditioning stimulus (CS70) over the left primary motor cortex at an intensity of 100% and 70% resting motor threshold for the right APB muscle, respectively. Subjects were given a single oral dose of diazepam (20 mg) or baclofen (50 mg) in this placebo controlled, pseudo-randomized, double-blinded crossover study. Diazepam, but not baclofen, suppressed saccade peak velocity, in line with a GABAA alpha1 mediated effect. CS70 evoked clearly discernible and reproducible TEPs (P25, N45, P70, N100, P180) similar to TS100. In the paired-pulse condition, corrected for these CS70-induced TEPs, CS70 suppressed the P25, N45, N100, and P180, whereas the P70 was not changed. Diazepam increased SICI of the early phase of the N100, whereas SICI of the late phase of the N100 was suppressed. Baclofen suppressed SICI of the late phase of SICI only. These data demonstrate that SICI is characterized by temporally and spatially distinct modulation of TMS-evoked EEG responses. [ABSTRACT FROM AUTHOR]

Objective To determine the physiology of short-interval intracortical inhibition (SICI) directly at the cortical level. Methods We recorded a 64 channel EEG during application of a magnetic test stimulus (TS100) 2 ms after a conditioning stimulus (CS70) over the left primary motor cortex at an intensity of 100% and 70% resting motor threshold for the right APB muscle, respectively. Subjects were given a single oral dose of diazepam or baclofen in this placebo controlled, pseudo-randomized, double-blinded crossover study. Results CS70 evoked clearly discernible and reproducible EEG potentials (TEPs) similar to TS100, i.e. a P25, N45, P70, N100, and P180 potential. In the paired-pulse condition, corrected for these CS70-induced TEPs, CS70 modulated all TS-evoked EEG potentials, i.e. suppressed the P25, N45, N100, and P180, whereas the P70 was increased. Preliminary analyses of the pharmacological data from eleven subjects further suggested an increase of SICI of the P25 potential by diazepam, in line with a GABAA-receptor mediated mechanism. Conclusions Our data provide evidence for the physiological mechanisms of SICI at the level of the human cortex with high temporal and spatial resolution. Key message SICI is characterized by temporally and spatially distinct modulation of TMS-evoked EEG responses. [ABSTRACT FROM AUTHOR]

Objective Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system frequently affecting the corpus callosum, the largest interhemispheric fiber bundle, at an early stage of the disease. Here, we employed transcranial magnetic stimulation (TMS) combined with high-density 64-channel electroencephalography (EEG) to investigate cortical excitability and interhemispheric connectivity in 13 patients with early relapsing-remitting MS (RRMS) with mean EDSS 1 ± 1 compared to 16 age- and gender-matched healthy controls. Methods TMS was applied to the left and right M1 separately. Latencies and amplitudes of TMS-evoked EEG potential (TEP) components N45, N100, P180, N280 in the stimulated and non-stimulated hemisphere were analyzed using two different approaches: a cluster-based permutation analysis and an automated extraction of maximum and minimum values. Results Compared to healthy control subjects, RRMS patients did not show any significant differences in TEP latencies or amplitudes in the stimulated or non-stimulated hemisphere, neither for left nor for right M1 stimulation (all p > 0.05). Conclusion and key message We conclude that basic excitability and connectivity measures of TMS-EEG data are unaltered in early RRMS patients, which may indicate a high level of functional compensation for structural deficits in these patients, e.g. by activation of alternate routes of TEP propagation. [ABSTRACT FROM AUTHOR]

Introduction: The combined use of Transcranial Magnetic Stimulation (TMS) and Electroencephalography (EEG) enables a direct investigation of cortical-evoked responses in humans. The physiology of the peaks characterizing the TMS-evoked EEG responses has not been clearly elucidated yet. EEG is able to detect fast-inhibitory post synaptic potentials (fIPSPs, <50ms), which are linked to GABA-A receptor activity. Thus, the early TMS-evoked potentials (TEPs) could be generated and/or mediated by GABA-A receptors. Objectives: In the present study we characterized the pharmaco-physiology of TEPs in healthy volunteers by using two GABA-A receptors positive modulators: alprazolam and zolpidem. The main aim of the study was to test to which extent early TEPs are affected by fast inhibitory neurotransmission through the GABA-A receptor. Materials and methods: Twenty healthy subjects participated in a pseudorandomized, placebo-controlled, double-blind crossover design, using a single oral dose of alprazolam (1mg), a classical benzodiazepine preferentially binding on alpha1, alpha2, alpha3 and alpha5 subunit bearing subtypes of the GABA-A receptor, and zolpidem (10mg), which mainly binds at the alpha1 subtype. TEPs were recorded by TMS-EEG before and 90min after drug administration and the effects of the drugs on the TEP amplitudes were statistically evaluated. Results: A non parametric cluster-based permutation analysis of amplitudes at channel-level was run for placebo, alprazolam and zolpidem administration. Both alprazolam and zolpidem, increased the amplitude of the negative potential at 45ms after stimulation (N45). Moreover, a strong positive correlation was found between their modulation on the N45 magnitude. In addition, alprazolam but not zolpidem decreased the amplitudes of the later TEPs, in particular, the negative at 100ms (N100) and the positive at 180ms (P180). Conclusion: We provide first-time evidence that the N45 potential may reflect a biological marker of alpha1 containing GABA-A receptor activity. The broader modulation of several TEP components by alprazolam could be explained by its wider pharmacological profile, as it is responsible for the activation of several subtypes of GABA-A receptors. [Copyright &y& Elsevier]