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Accurate EEG source localization is crucial for mapping resting-state network dynamics and it plays a key role in estimating source-level functional connectivity. However, EEG source estimation techniques encounter numerous methodological challenges, with a key one being the selection of the regularization parameter in minimum norm estimation. This choice is particularly intricate because the optimal amount of regularization for EEG source estimation may not align with the requirements of EEG connectivity analysis, highlighting a nuanced trade-off. In this study, we employed a methodological approach to determine the optimal regularization coefficient that yields the most effective reconstruction outcomes across all simulations involving varying signal-to-noise ratios for synthetic EEG signals. To this aim, we considered three resting state networks: the Motor Network, the Visual Network, and the Dorsal Attention Network. The performance was assessed using three metrics, at different regularization parameters: the Region Localization Error, source extension, and source fragmentation. The results were validated using real functional connectivity data. We show that the best estimate of functional connectivity is obtained using 10 -2 , while 10 -1 has to be preferred when source localization only is at target., 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. Published by Elsevier Inc.)

Combining Non-Invasive Brain Stimulation (NIBS) techniques with the recording of brain electrophysiological activity is an increasingly widespread approach in neuroscience. Particularly successful has been the simultaneous combination of Transcranial Magnetic Stimulation (TMS) and Electroencephalography (EEG). Unfortunately, the strong magnetic pulse required to effectively interact with brain activity inevitably induces artifacts in the concurrent EEG acquisition. Therefore, a careful but aggressive pre-processing is required to efficiently remove artifacts. Unfortunately, as already reported in the literature, different preprocessing approaches can introduce variability in the results. Here we aim at characterizing the three main TMS-EEG preprocessing pipelines currently available, namely ARTIST (Wu et al., 2018), TESA (Rogasch et al., 2017) and SOUND/SSP-SIR (Mutanen et al., 2018, 2016), providing an insight to researchers who need to choose between different approaches. Differently from previous works, we tested the pipelines using a synthetic TMS-EEG signal with a known ground-truth (the artifacts-free to-be-reconstructed signal). In this way, it was possible to assess the reliability of each pipeline precisely and quantitatively, providing a more robust reference for future research. In summary, we found that all pipelines performed well, but with differences in terms of the spatio-temporal precision of the ground-truth reconstruction. Crucially, the three pipelines impacted differently on the inter-trial variability, with ARTIST introducing inter-trial variability not already intrinsic to the ground-truth signal., Competing Interests: Declaration of competing interest UZ received grants from the European Research Council (ERC), German Ministry of Education and Research (BMBF), German Research Foundation (DFG), and consulting fees from CorTec GmbH. All the other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Objective. The corticospinal responses of the motor network to transcranial magnetic stimulation (TMS) are highly variable. While often regarded as noise, this variability provides a way of probing dynamic brain states related to excitability. We aimed to uncover spontaneously occurring cortical states that alter corticospinal excitability. Approach. Electroencephalography (EEG) recorded during TMS registers fast neural dynamics-unfortunately, at the cost of anatomical precision. We employed analytic Common Spatial Patterns technique to derive excitability-related cortical activity from pre-TMS EEG signals while overcoming spatial specificity issues. Main results. High corticospinal excitability was predicted by alpha-band activity, localized adjacent to the stimulated left motor cortex, and suggesting a travelling wave-like phenomenon towards frontal regions. Low excitability was predicted by alpha-band activity localized in the medial parietal-occipital and frontal cortical regions. Significance. We established a data-driven approach for uncovering network-level neural activity that modulates TMS effects. It requires no prior anatomical assumptions, while being physiologically interpretable, and can be employed in both exploratory investigation and brain state-dependent stimulation., (Creative Commons Attribution license.)

Background: The analysis and interpretation of transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) relies on successful cleaning of the artifacts, which typically mask the early (0-30 ms) TEPs. Independent component analysis (ICA) is possibly the single most utilized methodology to clean these signals., Objective: ICA-based cleaning is reliable provided that the input data are composed of independent components. Differently, in case the underlying components are to some extent dependent, ICA algorithms may yield erroneous estimates of the components, resulting in incorrectly cleaned data. We aim to ascertain whether TEP signals are suited for ICA., Methods: We present a systematic analysis of how the properties of simulated artifacts imposed on measured artifact-free TEPs affect the ICA results. The variability of the artifact waveform over the recorded trials is varied from deterministic to stochastic. We measure the accuracy of ICA-based cleaning for each level of variability., Results: Our findings indicate that, when the trial-to-trial variability of an artifact component is small, which can result in dependencies between underlying components, ICA-based cleaning biases towards eliminating also non-artifactual TEP data. We also show that the variability can be measured using the ICA-derived components, which in turn allows us to estimate the cleaning accuracy., Conclusion: As TEP artifacts tend to have small trial-to-trial variability, one should be aware of the possibility of eliminating brain-derived EEG when applying ICA-based cleaning strategies. In practice, after ICA, the artifact component variability can be measured, and it predicts to some extent the cleaning reliability, even when not knowing the clean ground-truth data., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.J.I. is an advisor and a minority shareholder of Nexstim Plc. The other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Post-stroke delirium (PSD) is a frequent and with regard to outcome unfavorable complication in acute stroke. The neurobiological mechanisms predisposing to PSD remain poorly understood, and biomarkers predicting its risk have not been established. We tested the hypothesis that hypoexcitable or disconnected brain networks predispose to PSD by measuring brain reactivity to transcranial magnetic stimulation with electroencephalography (TMS-EEG)., Methods: We conducted a cross-sectional study in 33 acute stroke patients within 48 hours of stroke onset. Brain reactivity to single-pulse TMS of dorsolateral prefrontal cortex, primary motor cortex and superior parietal lobule of the right hemisphere was quantified by response intensity, effective connectivity, perturbational complexity index (PCI ST ), and natural frequency of the TMS-EEG response. PSD development was clinically tracked every 8 hours before and for 7 days following TMS-EEG., Results: Fourteen patients developed PSD while 19 patients did not. The PSD group showed lower excitability, effective connectivity, PCI ST and natural frequency compared to the non-PSD group. The maximum PCI ST over all three TMS sites demonstrated largest classification accuracy with a ROC-AUC of 0.943. This effect was independent of lesion size, affected hemisphere and stroke severity. Maximum PCI ST and maximum natural frequency correlated inversely with delirium duration., Conclusions: Brain reactivity to TMS-EEG can unravel brain network states of reduced excitability, effective connectivity, perturbational complexity and natural frequency that identify acute stroke patients at high risk for development of delirium., Significance: Findings provide novel insight into the pathophysiology of pre-delirium brain states and may promote effective delirium prevention strategies in those patients at high risk., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS-EEG) is widely used for studying cortical reactivity and connectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS-EEG equipment and approaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS-EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS-EEG covered all aspects that should be considered in TMS-EEG experiments, providing methodological recommendations (when possible) for effective TMS-EEG recordings and analysis. The panel identified and discussed the challenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS-EEG methodology and thus may promote standardization of experimental and computational procedures across groups., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PJ has received consulting fees and shares a patent with Nexstim Oyj. PL has received consulting fees from Nexstim Oyj. HRS has received honoraria as speaker from Sanofi Genzyme, Denmark, Lundbeck AS, 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. TPM has successfully applied for funding for a collaborative research project (project not started at the time of the submission) with Bittium Biosignals Oy (Kuopio, Finland). SC is advisor and share-holder of Intrinsic Power, a spinf-off of the University of Milan., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Electroencephalography (EEG) is increasingly used to investigate brain responses to transcranial magnetic stimulation (TMS). A relevant issue is that TMS is associated with considerable auditory and somatosensory stimulation, causing peripherally evoked potentials (PEPs) in the EEG, which contaminate the direct cortical responses to TMS (TEPs). All previous attempts to control for PEPs suffer from significant limitations., Objective/hypothesis: To design an optimized sham procedure to control all sensory input generated by subthreshold real TMS targeting the hand area of the primary motor cortex (M1), enabling reliable separation of TEPs from PEPs., Methods: In 23 healthy (16 female) subjects, we recorded EEG activity evoked by an optimized sham TMS condition which masks and matches auditory and somatosensory co-stimulation during the real TMS condition: auditory control was achieved by noise masking and by using a second TMS coil that was placed on top of the real TMS coil and produced a calibrated sound pressure level. Somatosensory control was obtained by electric stimulation (ES) of the scalp with intensities sufficient to saturate somatosensory input. ES was applied in both the sham and real TMS conditions. Perception of auditory and somatosensory inputs in the sham and real TMS conditions were compared by psychophysical testing. Transcranially evoked EEG signal changes were identified by subtraction of EEG activity in the sham condition from EEG activity in the real TMS condition., Results: Perception of auditory and somatosensory inputs in the sham vs. real TMS conditions was comparable. Both sham and real TMS evoked a series of similar EEG signal deflections and induced broadband power increase in oscillatory activity. Notably, the present procedure revealed EEG potentials and a transient increase in beta band power at the site of stimulation that were only present in the real TMS condition., Discussion: The results validate the effectiveness of our optimized sham approach. Despite the presence of typical responses attributable to sensory input, the procedure provided evidence for direct cortical activation by subthreshold TMS of M1. The findings are relevant for future TMS-EEG experiments that aim at measuring regional brain target engagement controlled by an optimized sham procedure., Competing Interests: Declaration of Competing Interest P.C.G. and C.Z. report funding through the EXIST translational research program from the German Federal Ministry for Economic Affairs and Energy. H.S. 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. U.Z. received grants from the German Ministry of Education and Research (BMBF), European Research Council (ERC), German Research Foundation (DFG), Janssen Pharmaceuticals NV and Takeda Pharmaceutical Company Ltd., and consulting fees from Bayer Vital GmbH, Pfizer GmbH and CorTec GmbH, all not related to this work. The other authors declare no further competing financial interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity., Objective: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD., Methods: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition., Results: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels., Conclusions: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The effect of a stimulus to the brain depends not only on the parameters of the stimulus but also on the dynamics of brain activity at the time of the stimulation. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time brain state-dependent stimulation system allows the study of relations of dynamics of brain activity, cortical excitability, and plasticity induction. Here, we demonstrate a newly developed method to synchronize the timing of brain stimulation with the phase of ongoing EEG oscillations using a real-time data analysis system. This real-time EEG-triggered TMS of the human motor cortex, when TMS is synchronized with the surface EEG negative peak of the sensorimotor µ-alpha (8-14 Hz) rhythm, has shown differential corticospinal excitability and plasticity effects. The utilization of this method suggests that real-time information about the instantaneous brain state can be used for efficacious plasticity induction. Additionally, this approach enables personalized EEG-synchronized brain stimulation which may lead to the development of more effective therapeutic brain stimulation protocols.

Repetitive transcranial magnetic stimulation (rTMS) can induce excitability changes of a stimulated brain area through synaptic plasticity mechanisms. High-frequency (100 Hz) triplets of rTMS synchronized to the negative but not the positive peak of the ongoing sensorimotor μ-rhythm isolated with the concurrently acquired electroencephalography (EEG) resulted in a reproducible long-term potentiation like increase of motor evoked potential (MEP) amplitude, an index of corticospinal excitability (Zrenner et al. 2018, Brain Stimul 11:374-389). Here, we analyzed the EEG and TMS-EEG data from (Zrenner et al., 2018) to investigate the effects of μ-rhythm-phase-dependent burst-rTMS on EEG-based measures of cortical excitability. We used resting-state EEG to assess μ- and β-power in the motor cortex ipsi- and contralateral to the stimulation, and single-pulse TMS-evoked and induced EEG responses in the stimulated motor cortex. We found that μ-rhythm-phase-dependent burst-rTMS did not significantly change any of these EEG measures, despite the presence of a significant differential and reproducible effect on MEP amplitude. We conclude that EEG measures of cortical excitability do not reflect corticospinal excitability as measured by MEP amplitude. Most likely this is explained by the fact that rTMS induces complex changes at the molecular and synaptic level towards both excitation and inhibition that cannot be differentiated at the macroscopic level by EEG., Competing Interests: The authors have declared that no competing interests exist.

Background: The analysis of cortical responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) has been successfully applied to study human cortical physiology. However, in addition to the (desired) activation of cortical neurons and fibers, TMS also causes (undesired) indirect brain responses through auditory and somatosensory stimulation, which may contribute significantly to the overall EEG signal and mask the effects of intervention on direct cortical responses., Objectives: To test differences in EEG responses to real TMS at intensities above and below resting motor threshold (RMT) and a realistic sham stimulation., Methods: 12 healthy subjects participated in one session in which single-pulse TMS was applied to the left motor cortex in 3 different blocks, 150 pulses per block: 110%RMT, 90%RMT and realistic sham stimulation. Cortical responses were collected by a 64 electrode EEG system. TMS evoked potentials (TEPs) and TMS induced oscillations were analyzed., Methods: 12 healthy subjects participated in one session in which single-pulse TMS was applied to the left motor cortex in 3 different blocks, 150 pulses per block: 110%RMT, 90%RMT and realistic sham stimulation. Cortical responses were collected by a 64-channel EEG system. TMS evoked potentials (TEPs) and TMS induced oscillations were analyzed., Results: TEPs from all conditions differed significantly, with TEPs from 110%RMT showing overall highest amplitudes and realistic sham lowest amplitudes. Sham stimulation had only minor effects on induced cortical oscillations compared to pre-stimulus baseline, TMS at 90%RMT resulted in a significant increase (50-200 m s) followed by a decrease (200-500 m s) in power of alpha and beta oscillations; TMS at 110% RMT led to an additional increase in beta power at late latencies (650-800 m s)., Conclusions: Real TMS of motor cortex results in cortical responses significantly different from realistic sham. These differences very likely reflect to a significant extent direct activation of neurons, rather than sensory evoked activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with potential for cost-effective therapeutic neuromodulation. Although positive therapeutic effects were found by stimulating the dorsolateral prefrontal cortex (DLPFC), few studies have investigated physiological effects of DLPFC-tDCS., Objectives: To investigate effects of tDCS with different parameter settings applied to the left DLPFC on cortical responses, measured by resting-state electroencephalography (rs-EEG) and transcranial magnetic stimulation (TMS)-evoked/induced EEG responses., Methods: 22 healthy subjects underwent 5 tDCS sessions with different tDCS parameter settings in a double-blinded randomized crossover design (1: 1.5 mA, anode left-DLPFC, cathode right-DLPFC; 2: 1.5 mA, cathode left-DLPFC, anode right-DLPFC; 3: 0.5 mA, anode left-DLPFC, cathode right-DLPFC; 4: 1.5 mA, anode left-DLPFC, cathode left deltoid muscle; 5: sham stimulation). Rs-EEG and TMS-EEG were recorded before and after tDCS., Results: Rs-EEG power spectrum analysis showed no difference comparing baseline with post stimulation in any of the tDCS conditions. TMS-EEG evoked potential amplitude decreased in parietal cortex after 1.5 mA left-DLPFC anodal tDCS, and TMS-induced gamma and theta oscillations decreased after all conditions using left-DLPFC anodal tDCS. Left-DLPFC cathodal tDCS did not lead to significant change. None of the post-intervention changes was different when comparing the effects across conditions, including sham., Conclusions: Our study does not provide evidence that a single tDCS session results in significant changes in rs-EEG, using the current stimulation parameters. Significant changes in EEG responses to TMS pulses were observed following the anodal 1.5 mA tDCS interventions, although these changes were not statistically significant in a group comparison., (Copyright © 2018 Elsevier Inc. 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.)

Objective: Clinical data suggest early involvement of the corticospinal tract (CST) in spinocerebellar ataxia type 2 (SCA2). Here we tested if early CST degeneration can be detected in prodromal SCA2 mutation carriers by electrophysiological markers of CST integrity., Methods: CST integrity was tested in 15 prodromal SCA2 mutation carriers, 19 SCA2 patients and 25 age-matched healthy controls, using corticomuscular (EEG-EMG) and intermuscular (EMG-EMG) coherence measures in upper and lower limb muscles., Results: Significant reductions of EEG-EMG and EMG-EMG coherences were observed in the SCA2 patients, and to a similar extent in the prodromal SCA2 mutation carriers. In prodromal SCA2, EEG-EMG and EMG-EMG coherences correlated with the predicted time to ataxia onset., Conclusions: Findings indicate early CST neurodegeneration in SCA2. EEG-EMG and EMG-EMG coherence may serve as biomarkers of early CST neurodegeneration in prodromal SCA2 mutation carriers., Significance: Findings are important for developing preclinical disease markers in the context of currently emerging disease-modifying therapies of neurodegenerative disorders., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Clinical signs of corticospinal tract dysfunction are a common feature of spinocerebellar ataxia type 2 (SCA2) patients. The objective of this study is to assess dysfunction of the corticospinal tract in SCA2 using corticomuscular coherence. Testing corticomuscular coherence and rating of ataxia severity and non-ataxia symptoms were performed in 19 SCA2 patients and 24 age-matched controls. Central motor conduction times (CMCT) to upper and lower right limbs were obtained for the SCA2 group using Transcraneal magnetic stimulation (TMS). SCA2 patients exhibited a significant reduction of corticomuscular coherence for lower limbs, but not for upper limbs. This difference remained significant, even when excluding those individuals with clinical signs of corticospinal tract dysfunction. Corticomuscular coherence for lower limbs correlated inversely with CMCT to tibialis anterior muscle. Corticomuscular coherence could be a valuable electrophysiological tool to assess the corticospinal tract involvement in SCA2, even in the absence of clinical signs of corticospinal tract dysfunction.

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.

Electro- and magnetoencephalography allow for non-invasive investigation of human brain activation and corresponding networks with high temporal resolution. Still, no correct network detection is possible without reliable source localization. In this paper, we examine four different source localization schemes under a common Variational Bayesian framework. A Bayesian approach to the Minimum Norm Model (MNM), an Empirical Bayesian Beamformer (EBB) and two iterative Bayesian schemes (Automatic Relevance Determination (ARD) and Greedy Search (GS)) are quantitatively compared. While EBB and MNM each use a single empirical prior, ARD and GS employ a library of anatomical priors that define possible source configurations. The localization performance was investigated as a function of (i) the number of sources (one vs. two vs. three), (ii) the signal to noise ratio (SNR; 5 levels) and (iii) the temporal correlation of source time courses (for the cases of two or three sources). We also tested whether the use of additional bilateral priors specifying source covariance for ARD and GS algorithms improved performance. Our results show that MNM proves effective only with single source configurations. EBB shows a spatial accuracy of few millimeters with high SNRs and low correlation between sources. In contrast, ARD and GS are more robust to noise and less affected by temporal correlations between sources. However, the spatial accuracy of ARD and GS is generally limited to the order of one centimeter. We found that the use of correlated covariance priors made no difference to ARD/GS performance.

In EEG and MEG studies on brain functional connectivity and source interactions can be performed at sensor or source level. Beamformers are well-established source-localization tools for MEG/EEG signals, being employed in source connectivity studies both in time and frequency domain. However, it has been demonstrated that beamformers suffer from a localization bias due to correlation between source time courses. This phenomenon has been ascertained by means of theoretical proofs and simulations. Nonetheless, the impact of correlated sources on localization outputs with real data has been disputed for a long time. In this paper, by means of a phantom, we address the correlation issue in a realistic MEG environment. Localization performances in the presence of simultaneously active sources are studied as a function of correlation degree and distance between sources. A linear constrained minimum variance (LCMV) beamformer is applied to the oscillating signals generated by the current dipoles within the phantom. Results show that high correlation affects mostly dipoles placed at small distances (1, 5 centimeters). In this case the sources merge. If the dipoles lie 3 centimeters apart, the beamformer localization detects attenuated power amplitudes and blurred sources as the correlation level raises.

Brain state is constantly changing, however, TMS protocols designed to modulate brain excitability don’t currently take into account the instantaneous state at the time of stimulation. Brain state variability at the time of stimulation may contribute to the variability of the outcome. Here, we investigate the question of whether the phase of sensorimotor mu-alpha activity at the time of the TMS pulse affects the induction of corticospinal plasticity. A randomized controlled trial was conducted using a cross-over double-blind design. 12 healthy individuals were included and on different days received different plasticity induction protocol consisting of 200 TMS triple pulses over the left M1 hand area with an inter-pulse-interval of 10 ms. Pulses were either triggered by the positive or negative phase peak of local sensorimotor activity. A custom closed-loop signal processing system based on Simulink was used to estimate phase and trigger the stimulator with millisecond accuracy. The intervention lasted 200–300 s. Corticospinal excitability was assessed by EMG potentials measured from the right hand muscles at different time-points before and after the intervention. Two control conditions were included, (1) an open-loop “replay”, and (2) an occipital EEG trigger. Muscle potentials evoked 15 and 30 min after the induction protocol differed significantly between stimulation synchronized to the positive phase (group average −14% after 30 min) and the negative phase (magnitude +36%). No significant difference was observed in the control conditions. Individually, 11 out of the 12 subjects showed an effect consistent with the group, with the average difference in muscle potential magnitude after 30 min amounting to 50% of the baseline. The instantaneous brain state at the time of stimulation significantly affects the outcome of the triplet stimulus protocol. Stimulation during the negative phase of local oscillatory alpha activity causes an LTP like effect lasting at least 30 min, and during the positive phase an LTD like effect. It appears that open-loop stimuli can cancel each other out when same sequence of stimuli is applied irrespective of phase. This result motivates the further development of closed-loop EEG-triggered neuromodulatory brain stimulation methods. [ABSTRACT FROM AUTHOR]

Question Closed-loop methods that trigger the TMS pulse based on the EEG signal are increasingly available, however, current systems rely on the data of a small number of channels and the signal at sensor level cannot be localized to a specific brain area. The challenge is to analyze a sufficient number of EEG channels in real-time to enable spatially localized estimation of individual brain network activity. Methods EEG data is acquired using a high-density TMS compatible recording system and streamed online to a real-time digital processing system based on Simulink. A sliding window of data is used to estimate the sources that give rise to the EEG signal using a spatial filter computation executed on the processor as the signal is acquired. The forward model is computed based on the MRI data using a FEM model to solve the forward problem. The leadfields are calculated employing the neuronavigated electrode positions and then employed to compute the real-time LCMV beamforming. Instantaneous phase is estimated at multiple source-level location simultaneously using parallel sliding windows of band-pass filtered data preceding the current time, each extended into the future in real-time using autoregressive model, with instantaneous phase estimated using a Hilbert transform. Results A latency of <1 ms is achieved in estimating the phase at source level with custom real-time software. A validation study with healthy individuals shows that the instantaneous phase of three distinctly localised brain areas within the motor network both intra- and inter-hemispherically can be estimated in real-time with reòiable accuracy. Conclusions A novel technique enabling TMS triggered by the instantaneous phase-state of the individual network is presented. This is a significant extension of the current state-of-the-art and could enable the development of more effective personalized closed-loop neuromodulatory stimulation protocols. [ABSTRACT FROM AUTHOR]

A somewhat surprising feature of the TMS evoked EEG and EMG potentials is their large variability. A number of factors are known to contribute to the variability of TMS responses but one factor about which tantalizingly little is known is the impact of instantaneous brain state at the time of stimulation. Here, we investigate the relationship between the phase of local mu-alpha oscillations at the time of stimulation with the magnitude of cortico-spinally evoked motor EMG potentials and the shape of the cortico-cortically evoked EEG potential. 12 healthy subjects were included the study and during a single session received TMS pulses over left motor cortex at an intensity to evoke EMG potentials at the right hand with 1 mV peak-to-peak amplitude. Phase triggers were generated based on the instantaneous phase of local sensorimotor rhythm using a Hjorth filter in the 5 EEG channels centered on electrode C3. The phase was estimated using a sliding window of data that was filtered, autoregressively forward predicted and hilbert transformed around the current time point in real-time using a custom closed-loop signal processing system based on Mathworks Simulink. The session consisted of a randomized sequence of 600 epochs in total, 300 triggered by the positive peak, and 300 triggered by the negative trough of the oscillations. Half of the trials were randomly not stimulated. Stimulated trials with pre-innervation in the EMG channel during the 500 ms preceding the stimulus were manually excluded. TMS evoked EEG potentials were analyzed by comparing the difference between stimulated and non-stimulated epochs after manually excluding trials with EEG artifacts, in order to subtract the oscillatory background activity. The magnitude of evoked motor potentials as measured by average peak-to-peak EMG potentials significantly differed by ca. 20% on average between the epochs evoked during the positive peak of ongoing alpha activity and the epochs evoked during the negative trough. At the level of the individual analysis, all of the 12 subjects showed a difference consistent with the group data (higher EMG amplitudes when stimulating in the negative trough of mu-alpha activity). The evoked EEG potentials showed a similar effect with the amplitude of the individual peaks higher when stimulating during the trough as compared to when stimulating during the peak. [ABSTRACT FROM AUTHOR]

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]