A simulation study: comparing independent component analysis and signal-space projection - source-informed reconstruction for rejecting muscle artifacts evoked by transcranial magnetic stimulation.

Introduction: The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows researchers to explore cortico-cortical connections. To study effective connections, the first few tens of milliseconds of the TMS-evoked potentials are the most critical. Yet, TMS-evoked artifacts complicate the interpretation of early-latency data. Data-processing strategies like independent component analysis (ICA) and the combined signal-space projection-source-informed reconstruction approach (SSP-SIR) are designed to mitigate artifacts, but their objective assessment is challenging because the true neuronal EEG responses under large-amplitude artifacts are generally unknown. Through simulations, we quantified how the spatiotemporal properties of the artifacts affect the cleaning performances of ICA and SSP-SIR. Methods: We simulated TMS-induced muscle artifacts and superposed them on pre-processed TMS-EEG data, serving as the ground truth. The simulated muscle artifacts were varied both in terms of their topography and temporal profiles. The signals were then cleaned using ICA and SSP-SIR, and subsequent comparisons were made with the ground truth data. Results: ICA performed better when the artifact time courses were highly variable across the trials, whereas the effectiveness of SSP-SIR depended on the congruence between the artifact and neuronal topographies, with the performance of SSP-SIR being better when difference between topographies was larger. Overall, SSP-SIR performed better than ICA across the tested conditions. Based on these simulations, SSP-SIR appears to be more effective in suppressing TMS-evoked muscle artifacts. These artifacts are shown to be highly time-locked to the TMS pulse and manifest in topographies that differ substantially from the patterns of neuronal potentials. Discussion: Selecting between ICA and SSP-SIR should be guided by the characteristics of the artifacts. SSP-SIR might be better equipped for suppressing time-locked artifacts, provided that their topographies are sufficiently different from the neuronal potential patterns of interest, and that the SSP-SIR algorithm can successfully find those artifact topographies from the high-pass-filtered data. ICA remains a powerful tool for rejecting artifacts that are not strongly time locked to the TMS pulse.

Exploring Motor Network Connectivity in State-Dependent Transcranial Magnetic Stimulation: A Proof-of-Concept Study.

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focus on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the Motor Network (MN) and how the MN state affects responses to the transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to the left M1 in eight subjects at rest, with simultaneous EEG. Motor-evoked potentials (MEPs) were measured from the right hand. The source space functional connectivity of the left M1 to the whole brain was assessed using the imaginary part of the phase locking value at the frequency of the sensorimotor µ-rhythm in a 1 s window before the pulse. Group-level connectivity revealed functional links between the left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At the single-subject level, this relation is more highly expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity-based NIBS.

Adapted Beamforming: A Robust and Flexible Approach for Removing Various Types of Artifacts from TMS-EEG Data.

Electroencephalogram (EEG) recorded as response to transcranial magnetic stimulation (TMS) can be highly informative of cortical reactivity and connectivity. Reliable EEG interpretation requires artifact removal as the TMS-evoked EEG can contain high-amplitude artifacts. Several methods have been proposed to uncover clean neuronal EEG responses. In practice, determining which method to select for different types of artifacts is often difficult. Here, we used a unified data cleaning framework based on beamforming to improve the algorithm selection and adaptation to the recorded signals. Beamforming properties are well understood, so they can be used to yield customized methods for EEG cleaning based on prior knowledge of the artifacts and the data. The beamforming implementations also cover, but are not limited to, the popular TMS-EEG cleaning methods: independent component analysis (ICA), signal-space projection (SSP), signal-space-projection-source-informed-reconstruction method (SSP-SIR), the source-estimate-utilizing noise-discarding algorithm (SOUND), data-driven Wiener filter (DDWiener), and the multiple-source approach. In addition to these established methods, beamforming provides a flexible way to derive novel artifact suppression algorithms by considering the properties of the recorded data. With simulated and measured TMS-EEG data, we show how to adapt the beamforming-based cleaning to different data and artifact types, namely TMS-evoked muscle artifacts, ocular artifacts, TMS-related peripheral responses, and channel noise. Importantly, beamforming implementations are fast to execute: We demonstrate how the SOUND algorithm becomes orders of magnitudes faster via beamforming. Overall, the beamforming-based spatial filtering framework can greatly enhance the selection, adaptability, and speed of EEG artifact removal.

Measuring the accuracy of ICA-based artifact removal from TMS-evoked potentials.

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.

Evoked EEG Responses to TMS Targeting Regions Outside the Primary Motor Cortex and Their Test-Retest Reliability.

Transcranial magnetic stimulation (TMS)-evoked electroencephalography (EEG) potentials (TEPs) provide unique insights into cortical excitability and connectivity. However, confounding EEG signals from auditory and somatosensory co-stimulation complicate TEP interpretation. Our optimized sham procedure established with TMS of primary motor cortex (Gordon in JAMA 245:118708, 2021) differentiates direct cortical EEG responses to TMS from those caused by peripheral sensory inputs. Using this approach, this study aimed to investigate TEPs and their test-retest reliability when targeting regions outside the primary motor cortex, specifically the left angular gyrus, supplementary motor area, and medial prefrontal cortex. We conducted three identical TMS-EEG sessions one week apart involving 24 healthy participants. In each session, we targeted the three areas separately using a figure-of-eight TMS coil for active TMS, while a second coil away from the head produced auditory input for sham TMS. Masking noise and electric scalp stimulation were applied in both conditions to achieve matched EEG responses to peripheral sensory inputs. High test-retest reliability was observed in both conditions. However, reliability declined for the 'cleaned' TEPs, resulting from the subtraction of evoked EEG response to the sham TMS from those to the active, particularly for latencies > 100 ms following the TMS pulse. Significant EEG differences were found between active and sham TMS at latencies < 90 ms for all targeted areas, exhibiting distinct spatiotemporal characteristics specific to each target. In conclusion, our optimized sham procedure effectively reveals EEG responses to direct cortical activation by TMS in brain areas outside primary motor cortex. Moreover, we demonstrate the impact of peripheral sensory inputs on test-retest reliability of TMS-EEG responses.

Predicting motor behavior: an efficient EEG signal processing pipeline to detect brain states with potential therapeutic relevance for VR-based neurorehabilitation.

Virtual reality (VR)-based motor therapy is an emerging approach in neurorehabilitation. The combination of VR with electroencephalography (EEG) presents further opportunities to improve therapeutic efficacy by personalizing the paradigm. Specifically, the idea is to synchronize the choice and timing of stimuli in the perceived virtual world with fluctuating brain states relevant to motor behavior. Here, we present an open source EEG single-trial based classification pipeline that is designed to identify ongoing brain states predictive of the planning and execution of movements. 9 healthy volunteers each performed 1080 trials of a repetitive reaching task with an implicit two-alternative forced choice, i.e., use of the right or left hand, in response to the appearance of a visual target. The performance of the EEG decoding pipeline was assessed with respect to classification accuracy of right vs. left arm use, based on the EEG signal at the time of the stimulus. Different features, feature extraction methods, and classifiers were compared at different time windows; the number and location of informative EEG channels and the number of calibration trials needed were also quantified, as well as any benefits from individual-level optimization of pipeline parameters. This resulted in a set of recommended parameters that achieved an average 83.3% correct prediction on never-before-seen testing data, and a state-of-the-art 77.1% in a real-time simulation. Neurophysiological plausibility of the resulting classifiers was assessed by time-frequency and event-related potential analyses, as well as by Independent Component Analysis topographies and cortical source localization. We expect that this pipeline will facilitate the identification of relevant brain states as prospective therapeutic targets in closed-loop EEG-VR motor neurorehabilitation.

TMS combined with EEG: Recommendations and open issues for data collection and analysis.

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.

Corticospinal excitability is highest at the early rising phase of sensorimotor µ-rhythm.

Alpha oscillations are thought to reflect alternating cortical states of excitation and inhibition. Studies of perceptual thresholds and evoked potentials have shown the scalp EEG negative phase of the oscillation to correspond to a short-lasting low-threshold and high-excitability state of underlying visual, somatosensory, and primary motor cortex. The negative peak of the oscillation is assumed to correspond to the state of highest excitability based on biophysical considerations and considerable effort has been made to improve the extraction of a predictive signal by individually optimizing EEG montages. Here, we investigate whether it is the negative peak of sensorimotor µ-rhythm that corresponds to the highest corticospinal excitability, and whether this is consistent between individuals. In 52 adult participants, a standard 5-channel surface Laplacian EEG montage was used to extract sensorimotor µ-rhythm during transcranial magnetic stimulation (TMS) of primary motor cortex. Post-hoc trials were sorted from 800 TMS-evoked motor potentials (MEPs) according to the pre-stimulus EEG (estimated instantaneous phase) and MEP amplitude (as an index of corticospinal excitability). Different preprocessing transformations designed to improve the accuracy by which µ-alpha phase predicts excitability were also tested. By fitting a sinusoid to the MEP amplitudes, sorted according to pre-stimulus EEG-phase, we found that excitability was highest during the early rising phase, at a significant delay with respect to the negative peak by on average 45° or 10 ms. The individual phase of highest excitability was consistent across study participants and unaffected by two different EEG-cleaning methods that utilize 64 channels to improve signal quality by compensating for individual noise level and channel covariance. Personalized transformations of the montage did not yield better prediction of excitability from µ-alpha phase. The relationship between instantaneous phase of a brain oscillation and fluctuating cortical excitability appears to be more complex than previously hypothesized. In TMS of motor cortex, a standard surface Laplacian 5-channel EEG montage is effective in extracting a predictive signal and the phase corresponding to the highest excitability appears to be consistent between individuals. This is an encouraging result with respect to the clinical potential of therapeutic personalized brain interventions in the motor system. However, it remains to be investigated, whether similar results can be obtained for other brain areas and brain oscillations targeted with EEG and TMS.

Source-based artifact-rejection techniques for TMS-EEG.

Neuronal electroencephalography (EEG) signals arise from the cortical postsynaptic currents. Due to the conductive properties of the head, these neuronal sources produce relatively smeared spatial patterns in EEG. We can model these topographies to deduce which signals reflect genuine TMS-evoked cortical activity and which data components are merely noise and artifacts. This review will concentrate on two source-based artifact-rejection techniques developed for TMS-EEG data analysis, signal-space-projection-source-informed reconstruction (SSP-SIR), and the source-estimate-utilizing noise-discarding algorithm (SOUND). The former method was designed for rejecting TMS-evoked muscle artifacts, while the latter was developed to suppress noise signals from EEG and magnetoencephalography (MEG) in general. We shall cover the theoretical background for both methods, but most importantly, we will describe some essential practical perspectives for using these techniques effectively. We demonstrate and explain what approaches produce the most reliable inverse estimates after cleaning the data or how to perform non-biased comparisons between cleaned datasets. All noise-cleaning algorithms compromise the signals of interest to a degree. We elaborate on how the source-based methods allow objective quantification of the overcorrection. Finally, we consider possible future directions. While this article concentrates on TMS-EEG data analysis, many theoretical and practical aspects, presented here, can be readily applied in other EEG/MEG applications. Overall, the source-based cleaning methods provide a valuable set of TMS-EEG preprocessing tools. We can objectively evaluate their performance regarding possible overcorrection. Furthermore, the overcorrection can always be taken into account to compare cleaned datasets reliably. The described methods are based on current electrophysiological and anatomical understanding of the head and the EEG generators; strong assumptions of the statistical properties of the noise and artifact signals, such as independence, are not needed.

Removing artifacts from TMS-evoked EEG: A methods review and a unifying theoretical framework.

Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) is a technique for studying cortical excitability and connectivity in health and disease, allowing basic research and potential clinical applications. A major methodological issue, severely limiting the applicability of TMS-EEG, relates to the contamination of EEG signals by artifacts of biologic or non-biologic origin. To solve this problem, several methods, based on independent component analysis (ICA), principal component analysis (PCA), signal space projection (SSP), and other approaches, have been developed over the last decade. This article is divided into two parts. In the first part, we review the theoretical background of the currently available TMS-EEG artifact removal methods. In the second part, we formally introduce the mathematics underpinnings of the cleaning methods. We classify them into spatial and temporal filters based on their properties. Since the most frequently used TMS-EEG cleaning approach are spatial filter methods, we focus on them and introduce beamforming as a unified framework of the most popular spatial filtering techniques. This unifying approach enables the comparative assessment of these methods by highlighting their differences in terms of assumptions, challenges, and applicability for different types of artifacts and data. The different properties and challenges of the methods discussed are illustrated with both simulated and recorded data. This article targets non-mathematical and mathematical audiences. Accordingly, those readers interested in essential background information on these methods can focus on Section 2. Whereas theory-oriented readers may find Section 3 helpful for making informed decisions between existing methods and developing the methodology further.

Closed-loop optimization of transcranial magnetic stimulation with electroencephalography feedback.

BACKGROUND: Transcranial magnetic stimulation (TMS) is widely used in brain research and treatment of various brain dysfunctions. However, the optimal way to target stimulation and administer TMS therapies, for example, where and in which electric field direction the stimuli should be given, is yet to be determined. OBJECTIVE: To develop an automated closed-loop system for adjusting TMS parameters (in this work, the stimulus orientation) online based on TMS-evoked brain activity measured with electroencephalography (EEG). METHODS: We developed an automated closed-loop TMS-EEG set-up. In this set-up, the stimulus parameters are electronically adjusted with multi-locus TMS. As a proof of concept, we developed an algorithm that automatically optimizes the stimulation orientation based on single-trial EEG responses. We applied the algorithm to determine the electric field orientation that maximizes the amplitude of the TMS-EEG responses. The validation of the algorithm was performed with six healthy volunteers, repeating the search twenty times for each subject. RESULTS: The validation demonstrated that the closed-loop control worked as desired despite the large variation in the single-trial EEG responses. We were often able to get close to the orientation that maximizes the EEG amplitude with only a few tens of pulses. CONCLUSION: Optimizing stimulation with EEG feedback in a closed-loop manner is feasible and enables effective coupling to brain activity.

Automated search of stimulation targets with closed-loop transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) protocols often include a manual search of an optimal location and orientation of the coil or peak stimulating electric field to elicit motor responses in a target muscle. This target search is laborious, and the result is user-dependent. Here, we present a closed-loop search method that utilizes automatic electronic adjustment of the stimulation based on the previous responses. The electronic adjustment is achieved by multi-locus TMS, and the adaptive guiding of the stimulation is based on the principles of Bayesian optimization to minimize the number of stimuli (and time) needed in the search. We compared our target-search method with other methods, such as systematic sampling in a predefined cortical grid. Validation experiments on five healthy volunteers and further offline simulations showed that our adaptively guided search method needs only a relatively small number of stimuli to provide outcomes with good accuracy and precision. The automated method enables fast and user-independent optimization of stimulation parameters in research and clinical applications of TMS.

Automatic and robust noise suppression in EEG and MEG: The SOUND algorithm.

Electroencephalography (EEG) and magnetoencephalography (MEG) often suffer from noise- and artifact-contaminated channels and trials. Conventionally, EEG and MEG data are inspected visually and cleaned accordingly, e.g., by identifying and rejecting the so-called "bad" channels. This approach has several shortcomings: data inspection is laborious, the rejection criteria are subjective, and the process does not fully utilize all the information in the collected data. Here, we present noise-cleaning methods based on modeling the multi-sensor and multi-trial data. These approaches offer objective, automatic, and robust removal of noise and disturbances by taking into account the sensor- or trial-specific signal-to-noise ratios. We introduce a method called the source-estimate-utilizing noise-discarding algorithm (the SOUND algorithm). SOUND employs anatomical information of the head to cross-validate the data between the sensors. As a result, we are able to identify and suppress noise and artifacts in EEG and MEG. Furthermore, we discuss the theoretical background of SOUND and show that it is a special case of the well-known Wiener estimators. We explain how a completely data-driven Wiener estimator (DDWiener) can be used when no anatomical information is available. DDWiener is easily applicable to any linear multivariate problem; as a demonstrative example, we show how DDWiener can be utilized when estimating event-related EEG/MEG responses. We validated the performance of SOUND with simulations and by applying SOUND to multiple EEG and MEG datasets. SOUND considerably improved the data quality, exceeding the performance of the widely used channel-rejection and interpolation scheme. SOUND also helped in localizing the underlying neural activity by preventing noise from contaminating the source estimates. SOUND can be used to detect and reject noise in functional brain data, enabling improved identification of active brain areas.

Blind Source Separation of Event-Related EEG/MEG.

OBJECTIVE: Blind source separation (BSS) can be used to decompose complex electroencephalography (EEG) or magnetoencephalography data into simpler components based on statistical assumptions without using a physical model. Applications include brain-computer interfaces, artifact removal, and identifying parallel neural processes. We wish to address the issue of applying BSS to event-related responses, which is challenging because of nonstationary data. METHODS: We introduce a new BSS approach called momentary-uncorrelated component analysis (MUCA), which is tailored for event-related multitrial data. The method is based on approximate joint diagonalization of multiple covariance matrices estimated from the data at separate latencies. We further show how to extend the methodology for autocovariance matrices and how to apply BSS methods suitable for piecewise stationary data to event-related responses. We compared several BSS approaches by using simulated EEG as well as measured somatosensory and transcranial magnetic stimulation (TMS) evoked EEG. RESULTS: Among the compared methods, MUCA was the most tolerant one to noise, TMS artifacts, and other challenges in the data. With measured somatosensory data, over half of the estimated components were found to be similar by MUCA and independent component analysis. MUCA was also stable when tested with several input datasets. CONCLUSION: MUCA is based on simple assumptions, and the results suggest that MUCA is robust with nonideal data. SIGNIFICANCE: Event-related responses and BSS are valuable and popular tools in neuroscience. Correctly designed BSS is an efficient way of identifying artifactual and neural processes from nonstationary event-related data.

Dealing with artifacts in TMS-evoked EEG.

The artifact problem in TMS-evoked EEG is analyzed in an attempt to clarify the nature of the problem and to present solutions. The best way to deal with artifacts is to avoid them; the removal or suppression of the unavoidable artifacts should be based on accurate information about their characteristics and the properties of the signal of interest.

Multi-trial evoked EEG and independent component analysis.

BACKGROUND: Independent component analysis (ICA) is increasingly used to decompose EEG data into components. The analysis is based on the assumption that the hidden components are statistically independent. Here, we investigate the use of ICA on evoked multi-trial non-stationary EEG data. We show that the multi-trial data do not fulfill the assumption of the independence of the hidden components. This discrepancy questions the use of ICA in analyzing evoked EEG. NEW METHOD: To overcome the problem with the independence assumption, we introduce a novel way to preprocess multi-trial data. In this preprocessing, the hidden components gain a property which we call the null conditional mean (NCM). We show that this property is sufficient to make the ICA separation to work. The suggested methodology has the additional advantage that it suppresses the stimulus-evoked artifacts, such as the strong muscular artifacts in the transcranial magnetic stimulation (TMS)-evoked EEG, which may otherwise prevent the use of ICA. RESULTS: The theoretical results, which support the mean subtraction method, were proved. We also confirmed the efficiency of the method with several numerical simulations, which resembled TMS-EEG measurement data. COMPARISON WITH EXISTING METHOD: As compared with conventional ICA of multi-trial data, the results substantially improved when using NCM data. CONCLUSIONS: The proposed methodology facilitates in uncovering hidden components that, with other existing methods, easily remain uncovered in evoked EEG or MEG data.

Uncovering neural independent components from highly artifactual TMS-evoked EEG data.

Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) is a powerful tool for studying cortical excitability and connectivity. To enhance the EEG interpretation, independent component analysis (ICA) has been used to separate the data into independent components (ICs). However, TMS can evoke large artifacts in EEG, which may greatly distort the ICA separation. The removal of such artifactual EEG from the data is a difficult task. In this paper we study how badly the large artifacts distort the ICA separation, and whether the distortions could be avoided without removing the artifacts. We first show that, in the ICA separation, the time courses of the ICs are not affected by the large artifacts, but their topographies could be greatly distorted. Next, we show how this distortion can be circumvented. We introduce a novel technique of suppression, by which the EEG data are modified so that the ICA separation of the suppressed data becomes reliable. The suppression, instead of removing the artifactual EEG, rescales all the data to about the same magnitude as the neural EEG. For the suppressed data, ICA returns the original time courses, but instead of the original topographies, it returns modified ones, which can be used, e.g., for the source localization. We present three suppression methods based on principal component analysis, wavelet analysis, and whitening of the data matrix, respectively. We test the methods with numerical simulations. The results show that the suppression improves the source localization.

Removal of large muscle artifacts from transcranial magnetic stimulation-evoked EEG by independent component analysis.

We present two techniques utilizing independent component analysis (ICA) to remove large muscle artifacts from transcranial magnetic stimulation (TMS)-evoked EEG signals. The first one is a novel semi-automatic technique, called enhanced deflation method (EDM). EDM is a modification of the deflation mode of the FastICA algorithm; with an enhanced independent component search, EDM is an effective tool for removing the large, spiky muscle artifacts. The second technique, called manual method (MaM) makes use of the symmetric mode of FastICA and the artifactual components are visually selected by the user. In order to evaluate the success of the artifact removal methods, four different quality parameters, based on curve comparison and frequency analysis, were studied. The dorsal premotor cortex (dPMC) and Broca's area (BA) were stimulated with TMS. Both methods removed the very large muscle artifacts recorded after stimulation of these brain areas. However, EDM was more stable, less subjective, and thus also faster to use than MaM. Until now, examining lateral areas of the cortex with TMS-EEG has been restricted because of strong muscle artifacts. The methods described here can remove those muscle artifacts, allowing one to study lateral areas of the human brain, e.g., BA, with TMS-EEG.