TMS-evoked EEG Potentials Research Articles

Involvement of muscarinic acetylcholine receptor-mediated cholinergic neurotransmission in TMS–EEG responses

The combination of transcranial magnetic stimulation and electroencephalography (TMS–EEG) is emerging as a valuable tool for investigating brain functions in health and disease. However, the detailed neural mechanisms underlying TMS–EEG responses, including TMS-evoked EEG potentials (TEPs) and TMS-induced EEG oscillations (TIOs), remain largely unknown. Combining TMS–EEG with pharmacological interventions provides a unique opportunity to elucidate the roles of specific receptor-mediated neurotransmissions in these responses. Here, we investigated the involvement of muscarinic acetylcholine receptor (mAChR)-mediated cholinergic neurotransmission in TMS–EEG responses by evaluating the effects of mAChR antagonists on TEPs and TIOs in twenty-four healthy participants using a randomized, placebo-controlled crossover design. TEPs and TIOs were measured before and after administering a single oral dose of scopolamine (a non-selective mAChR antagonist), biperiden (an M1 mAChR antagonist), or placebo, with TMS targeting the left medial prefrontal cortex (mPFC), angular gyrus (AG), and supplementary motor area (SMA). The results indicated that mAChR-mediated cholinergic neurotransmission played a role in TEPs, but not TIOs, in a target-specific manner. Specifically, scopolamine significantly increased the amplitude of a local TEP component between approximately 40 and 63 ms post-stimulus when TMS was applied to the SMA, but not the mPFC or AG. Biperiden produced a similar but less pronounced effect. Importantly, the effects of these mAChR antagonists on TEPs were independent of those on sensory-evoked EEG potentials caused by TMS-associated sensory stimulation. These findings expand our understanding of TMS–EEG physiology, providing insights for its application in physiological and clinical research.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Biomarkers for prognostic functional recovery poststroke: A narrative review.

Background and objective: Prediction of poststroke recovery can be expressed by prognostic biomarkers that are related to the pathophysiology of stroke at the cellular and molecular level as well as to the brain structural and functional reserve after stroke at the systems neuroscience level. This study aimed to review potential biomarkers that can predict poststroke functional recovery. Methods: A narrative review was conducted to qualitatively summarize the current evidence on biomarkers used to predict poststroke functional recovery. Results: Neurophysiological measurements and neuroimaging of the brain and a wide diversity of molecules had been used as prognostic biomarkers to predict stroke recovery. Neurophysiological studies using resting-state electroencephalography (EEG) revealed an interhemispheric asymmetry, driven by an increase in low-frequency oscillation and a decrease in high-frequency oscillation in the ipsilesional hemisphere relative to the contralesional side, which was indicative of individual recovery potential. The magnitude of somatosensory evoked potentials and event-related desynchronization elicited by movement in task-related EEG was positively associated with the quantity of recovery. Besides, transcranial magnetic stimulation (TMS) studies revealed the potential values of using motor-evoked potentials (MEP) and TMS-evoked EEG potentials from the ipsilesional motor cortex as prognostic biomarkers. Brain structures measured using magnetic resonance imaging (MRI) have been implicated in stroke outcome prediction. Specifically, the damage to the corticospinal tract (CST) and anatomical motor connections disrupted by stroke lesion predicted motor recovery. In addition, a wide variety of molecular, genetic, and epigenetic biomarkers, including hemostasis, inflammation, tissue remodeling, apoptosis, oxidative stress, infection, metabolism, brain-derived, neuroendocrine, and cardiac biomarkers, etc., were associated with poor functional outcomes after stroke. However, challenges such as mixed evidence and analytical concerns such as specificity and sensitivity have to be addressed before including molecular biomarkers in routine clinical practice. Conclusion: Potential biomarkers with prognostic values for the prediction of functional recovery after stroke have been identified; however, a multimodal approach of biomarkers for prognostic prediction has rarely been studied in the literature. Future studies may incorporate a combination of multiple biomarkers from big data and develop algorithms using data mining methods to predict the recovery potential of patients after stroke in a more precise way.

Neurophysiologic Correlates of Preclinical Alzheimer's Disease

AbstractBackgroundAlzheimer’s disease (AD) is associated with neurophysiologic changes, including cortical hyperexcitability and reduced long‐term potentiation (LTP)‐like plasticity, that can be investigated using transcranial magnetic stimulation (TMS). AD is preceded by a preclinical phase of beta‐amyloid accumulation without clinical or cognitive symptoms. Our goal is to test the relationship of TMS‐based neurophysiologic markers against established cognitive and MRI‐based measures of preclinical AD. If neurophysiologic changes precede the clinical manifestation of AD, they could serve as prognostic markers and targets for therapeutic interventions to slow its progression.MethodData was acquired from eight cognitively unimpaired older adults (three females, ages 65‐78 years) as part of an ongoing study (BrightFocus™ Foundation‐A2021288S, IRB#‐2020P000889). Cognition was evaluated with the 5‐item Preclinical Alzheimer’s Cognitive Composite (PACC5), which is sensitive to early AD‐associated decline. Global cortical atrophy was assessed from MRI as the mean thickness across the AD Cortical Signature Network (ACSN)—regions showing morphologic changes that precede the clinical manifestation of AD. Cortical excitability was assessed as the average amplitude of TMS‐evoked EEG potentials (TEPs) elicited from TMS to motor cortex, while LTP‐like cortical plasticity was assessed as the change in TEPs following intermittent theta‐burst stimulation (iTBS). The strength of associations between the neurophysiologic, imaging, and cognitive measures were performed using non‐parametric Spearman Rho coefficients.ResultSpearman coefficients revealed a large association between reduced cortical thickness (more atrophy) and worse cognition (Rho=0.71), as expected. Higher excitability (larger TEPs) showed a large association with worse cognition (Rho=‐0.54) and a small association with reduced cortical thickness (Rho=‐0.29). Lower cortical plasticity (smaller change in TEPs post‐iTBS) showed a medium association with worse cognition (Rho=0.46) and a large association with reduced cortical thickness (Rho=0.86).ConclusionIn cognitively unimpaired older adults, TMS‐EEG measures of cortical excitability and LTP‐like plasticity are strongly correlated, respectively, with cognitive and MRI‐based markers of Preclinical AD. These finding suggest cortical hyperexcitability and reduced LTP‐like plasticity, which are present in AD, may occur before its clinical manifestation. If these results are confirmed in a larger cohort with biomarker testing, these markers could help prognosticate the development of AD symptoms and serve as targets for therapeutic intervention.

Modulation of I-Wave Generating Pathways With Repetitive Paired-Pulse Transcranial Magnetic Stimulation: A Transcranial Magnetic Stimulation–Electroencephalography Study

ObjectivesRepetitive paired-pulse transcranial magnetic stimulation (iTMS) at indirect (I) wave intervals increases motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation (TMS) to primary motor cortex (M1). However, the effects of iTMS at early and late intervals on the plasticity of specific I-wave circuits remain unclear. This study therefore aimed to assess how the timing of iTMS influences intracortical excitability within early and late I-wave circuits. To investigate the cortical effects of iTMS more directly, changes due to the intervention were also assessed using combined TMS-electroencephalography (EEG). Material and MethodsEighteen young adults (aged 24.6 ± 4.2 years) participated in four sessions in which iTMS targeting early (1.5-millisecond interval; iTMS1.5) or late (4.0-millisecond interval; iTMS4.0) I-waves was applied over M1. Neuroplasticity was assessed using both posterior-to-anterior (PA) and anterior-to-posterior (AP) stimulus directions to record MEPs and TMS-evoked EEG potentials (TEPs) before and after iTMS. Short-interval intracortical facilitation (SICF) at interstimulus intervals of 1.5 and 4.0 milliseconds was also used to index I-wave activity. ResultsMEP amplitude was increased after iTMS (p < 0.01), and this was greater for PA responses (p < 0.01) but not different between iTMS intervals (p = 0.9). Irrespective of iTMS interval and coil current, SICF was facilitated after the intervention (p < 0.01). Although the N45 produced by AP stimulation was decreased by iTMS1.5 (p = 0.04), no other changes in TEP amplitude were observed. ConclusionsThe timing of iTMS failed to influence which I-wave circuits were potentiated by the intervention. In contrast, decreases in the N45 suggest that the neuroplastic effects of iTMS may include disinhibition of intracortical inhibitory processes.

Utilising TMS-EEG to Assess the Response to Cerebellar-Brain Inhibition

Cerebellar-brain inhibition (CBI) is a transcranial magnetic stimulation (TMS) paradigm indexing excitability of cerebellar projections to motor cortex (M1). Stimulation involved with CBI is often considered to be uncomfortable, and alternative ways to index connectivity between cerebellum and the cortex would be valuable. We therefore sought to assess the utility of electroencephalography in conjunction with TMS (combined TMS-EEG) to record the response to CBI. A total of 33 volunteers (25.7 ± 4.9 years, 20 females) participated across three experiments. These investigated EEG responses to CBI induced with a figure-of-eight (F8; experiment 1) or double cone (DC; experiment 2) conditioning coil over cerebellum, in addition to multisensory sham stimulation (experiment 3). Both F8 and DC coils suppressed early TMS-evoked EEG potentials (TEPs) produced by TMS to M1 (P < 0.05). Furthermore, the TEP produced by CBI stimulation was related to the motor inhibitory response to CBI recorded in a hand muscle (P < 0.05), but only when using the DC coil. Multisensory sham stimulation failed to modify the M1 TEP. Cerebellar conditioning produced changes in the M1 TEP that were not apparent following sham stimulation, and that were related to the motor inhibitory effects of CBI. Our findings therefore suggest that it is possible to index the response to CBI using TMS-EEG. In addition, while both F8 and DC coils appear to recruit cerebellar projections, the nature of these may be different.

EEG Evoked Potentials to Repetitive Transcranial Magnetic Stimulation in Normal Volunteers: Inhibitory TMS EEG Evoked Potentials.

The impact of repetitive magnetic stimulation (rTMS) on cortex varies with stimulation parameters, so it would be useful to develop a biomarker to rapidly judge effects on cortical activity, including regions other than motor cortex. This study evaluated rTMS-evoked EEG potentials (TEP) after 1 Hz of motor cortex stimulation. New features are controls for baseline amplitude and comparison to control groups of sham stimulation. We delivered 200 test pulses at 0.20 Hz before and after 1500 treatment pulses at 1 Hz. Sequences comprised AAA = active stimulation with the same coil for test–treat–test phases (n = 22); PPP = realistic placebo coil stimulation for all three phases (n = 10); and APA = active coil stimulation for tests and placebo coil stimulation for treatment (n = 15). Signal processing displayed the evoked EEG waveforms, and peaks were measured by software. ANCOVA was used to measure differences in TEP peak amplitudes in post-rTMS trials while controlling for pre-rTMS TEP peak amplitude. Post hoc analysis showed reduced P60 amplitude in the active (AAA) rTMS group versus the placebo (APA) group. The N100 peak showed a treatment effect compared to the placebo groups, but no pairwise post hoc differences. N40 showed a trend toward increase. Changes were seen in widespread EEG leads, mostly ipsilaterally. TMS-evoked EEG potentials showed reduction of the P60 peak and increase of the N100 peak, both possibly reflecting increased slow inhibition after 1 Hz of rTMS. TMS-EEG may be a useful biomarker to assay brain excitability at a seizure focus and elsewhere, but individual responses are highly variable, and the difficulty of distinguishing merged peaks complicates interpretation.

Potential Neurophysiological Mechanisms of 1Hz-TMS to the Right Prefrontal Cortex for Depression: An Exploratory TMS-EEG Study in Healthy Participants.

Background: The present study aimed to examine the acute neurophysiological effects of 1Hz transcranial magnetic stimulation (TMS) administered to the right dorsolateral prefrontal cortex (DLPFC) in healthy participants. Methods: TMS combined with simultaneous electroencephalography (EEG) recording was conducted for 21 healthy participants. For the right DLPFC, 1Hz-TMS (100 pulses/block × 17 sessions) was applied in the resting-state, while for the left DLPFC, 1Hz-TMS (100 pulses/block × 2 sessions) was administered during the verbal fluency tasks (VFTs). For TMS-EEG data, independent component analysis (ICA) was applied to extract TMS-evoked EEG potentials to calculate TMS-related power as well as TMS-related coherence from the F4 and F3 electrode sites during the resting-state and VFTs. Results: TMS-related power was significantly increased in alpha, beta, and gamma bands by 1Hz-TMS at the stimulation site during the resting-state, while TMS-related power was significantly increased in alpha and beta bands but not in the gamma band during the VFTs. On the other hand, TMS-related coherence in alpha and beta bands significantly increased but not in gamma band by 1Hz-TMS that was administered to the right DLPFC in resting-state, whereas there were no significant changes in coherence for all frequency bands by 1Hz-TMS that applied to the left DLPFC during the VFTs. Conclusions: Collectively, 1Hz-repetitive TMS (rTMS) to the right DLPFC may rapidly neuromodulate EEG activity, which might be associated with a therapeutic mechanism for depression.

Transcranial Evoked Potentials Can Be Reliably Recorded with Active Electrodes.

Electroencephalographic (EEG) signals evoked by transcranial magnetic stimulation (TMS) are usually recorded with passive electrodes (PE). Active electrode (AE) systems have recently become widely available; compared to PE, they allow for easier electrode preparation and a higher-quality signal, due to the preamplification at the electrode stage, which reduces electrical line noise. The performance between the AE and PE can differ, especially with fast EEG voltage changes, which can easily occur with TMS-EEG; however, a systematic comparison in the TMS-EEG setting has not been made. Therefore, we recorded TMS-evoked EEG potentials (TEPs) in a group of healthy subjects in two sessions, one using PE and the other using AE. We stimulated the left primary motor cortex and right medial prefrontal cortex and used two different approaches to remove early TMS artefacts, Independent Component Analysis and Signal Space Projection—Source Informed Recovery. We assessed statistical differences in amplitude and topography of TEPs, and their similarity, by means of the concordance correlation coefficient (CCC). We also tested the capability of each system to approximate the final TEP waveform with a reduced number of trials. The results showed that TEPs recorded with AE and PE do not differ in amplitude and topography, and only few electrodes showed a lower-than-expected CCC between the two methods of amplification. We conclude that AE are a viable solution for TMS-EEG recording.

Real-Time Artifacts Reduction during TMS-EEG Co-Registration: A Comprehensive Review on Technologies and Procedures.

Transcranial magnetic stimulation (TMS) excites neurons in the cortex, and neural activity can be simultaneously recorded using electroencephalography (EEG). However, TMS-evoked EEG potentials (TEPs) do not only reflect transcranial neural stimulation as they can be contaminated by artifacts. Over the last two decades, significant developments in EEG amplifiers, TMS-compatible technology, customized hardware and open source software have enabled researchers to develop approaches which can substantially reduce TMS-induced artifacts. In TMS-EEG experiments, various physiological and external occurrences have been identified and attempts have been made to minimize or remove them using online techniques. Despite these advances, technological issues and methodological constraints prevent straightforward recordings of early TEPs components. To the best of our knowledge, there is no review on both TMS-EEG artifacts and EEG technologies in the literature to-date. Our survey aims to provide an overview of research studies in this field over the last 40 years. We review TMS-EEG artifacts, their sources and their waveforms and present the state-of-the-art in EEG technologies and front-end characteristics. We also propose a synchronization toolbox for TMS-EEG laboratories. We then review subject preparation frameworks and online artifacts reduction maneuvers for improving data acquisition and conclude by outlining open challenges and future research directions in the field.

P248 Realistic multisensory sham stimulation procedure to distinguish somatosensory and auditory components from TMS-evoked EEG potentials

P248 Realistic multisensory sham stimulation procedure to distinguish somatosensory and auditory components from TMS-evoked EEG potentials

P233 Dissecting TMS-evoked EEG potentials – TMS evokes local activity in the stimulated cortical region that can be separated from sensory evoked responses

P233 Dissecting TMS-evoked EEG potentials – TMS evokes local activity in the stimulated cortical region that can be separated from sensory evoked responses

The effects of NMDA receptor blockade on TMS-evoked EEG potentials from prefrontal and parietal cortex

Measuring the brain’s response to transcranial magnetic stimulation (TMS) with electroencephalography (EEG) offers unique insights into the cortical circuits activated following stimulation, particularly in non-motor regions where less is known about TMS physiology. However, the mechanisms underlying TMS-evoked EEG potentials (TEPs) remain largely unknown. We assessed TEP sensitivity to changes in excitatory neurotransmission mediated by n-methyl-d-aspartate (NMDA) receptors following stimulation of non-motor regions. In fourteen male volunteers, resting EEG and TEPs from prefrontal (PFC) and parietal (PAR) cortex were measured before and after administration of either dextromethorphan (NMDA receptor antagonist) or placebo across two sessions in a double-blinded pseudo-randomised crossover design. At baseline, there were amplitude differences between PFC and PAR TEPs across a wide time range (15–250 ms), however the signals were correlated after ~80 ms, suggesting early peaks reflect site-specific activity, whereas late peaks reflect activity patterns less dependent on the stimulated sites. Early TEP peaks were not reliably altered following dextromethorphan compared to placebo, although findings were less clear for later peaks, and low frequency resting oscillations were reduced in power. Our findings suggest that early TEP peaks (<80 ms) from PFC and PAR reflect stimulation site specific activity that is largely insensitive to changes in NMDA receptor-mediated neurotransmission.

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

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

TMS-induced oscillations to evaluate pharmacodynamics properties of a newly developed anti-epileptic drug (XEN1101)

Introduction: TMS-evoked EEG potentials (TEPs) reflects cortical inhibitory and excitatory processes and for this reason have been used to investigate the impact of anti-epileptic drugs. In addition to TEPs, brain responses to TMS can be quantified in terms of EEG rhythm changes. The spatiotemporal profile of oscillations induced (i.e. non-phase locked) by TMS of the human motor cortex was described as a synchronization (30-300ms) – desynchronization (300-500ms) pattern in the alpha and beta-bands. XEN1101 is a novel voltage-gated potassium (Kv7.2/3) channel opener, being developed by Xenon Pharmaceuticals as a treatment for epilepsy. In this Phase I, double-blind, randomized, crossover, placebo-controlled trial we aimed to define XEN1101 fingerprints on TMS-induced oscillations.

A setup for studying very early TMS-evoked EEG potentials: prospects and pitfalls

A setup for studying very early TMS-evoked EEG potentials: prospects and pitfalls

Effects of antiepileptic drugs on cortical excitability in humans: A TMS-EMG and TMS-EEG study.

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double-blinded randomized placebo-controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco-physiological characterization of TEPs will facilitate utilization of TMS-EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.

The non-transcranial TMS-evoked potential is an inherent source of ambiguity in TMS-EEG studies

Transcranial Magnetic Stimulation (TMS) excites populations of neurons in the stimulated cortex, and the resulting activation may spread to connected brain regions. The distributed cortical response can be recorded with electroencephalography (EEG). Since TMS also stimulates peripheral sensory and motor axons and generates a loud “click” sound, the TMS-evoked EEG potentials (TEPs) reflect not only neural activity induced by transcranial neuronal excitation but also neural activity due to somatosensory and auditory processing. In 17 healthy young individuals, we systematically assessed the contribution of multisensory peripheral stimulation to TEPs using a TMS-compatible EEG system. Real TMS was delivered with a figure-of-eight coil over the left para-median posterior parietal cortex or superior frontal gyrus with the coil being oriented perpendicularly or in parallel to the target gyrus. We also recorded the EEG responses evoked by realistic sham stimulation over the posterior parietal and superior frontal cortex, mimicking the auditory and somatosensory sensations evoked by real TMS. We applied state-of-the-art procedures to attenuate somatosensory and auditory confounds during real TMS, including the placement of a foam layer underneath the coil and auditory noise masking. Despite these precautions, the temporal and spatial features of the cortical potentials evoked by real TMS at the prefrontal and parietal site closely resembled the cortical potentials evoked by realistic sham TMS, both for early and late TEP components. Our findings stress the need to include a peripheral multisensory control stimulation in the design of TMS-EEG studies to enable a dissociation between truly transcranial and non-transcranial components of TEPs.

Cortical Excitability and Interhemispheric Connectivity in Early Relapsing-Remitting Multiple Sclerosis Studied With TMS-EEG.

Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing–remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0–2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.

Platform Session – NIBS: Quantifying the stereotypy of TMS-evoked EEG potentials using a cosine similarity metric

Introduction TMS-evoked EEG potentials (TEPs) can be used to probe connectivity and consciousness in healthy and diseased brains. A downside of this technique is that TMS causes neural artifacts, such as auditory and somatosensory-evoked responses, which may mask the true response to cortical stimulation, particularly at longer latencies. To avoid misinterpreting TEPs, methods for detecting neural artifact are required. One potentially helpful assumption is that neural artifacts have stereotyped topographies, while the true response to focal cortical stimulation will be spatially differentiated between stimulation conditions. Based on this assumption we used cosine similarity as a measure of response similarity and compared waveforms from real and sham stimulation at three scalp locations. Methods In 20 healthy volunteers, we delivered 150 active and 50 sham pulses to the right dorsolateral prefrontal cortex, left primary motor cortex, and left parietal cortex at 100% resting motor threshold. Sham stimulation was performed by placing a ∼2 cm spacer between the coil and scalp. TEPs were recorded with a 32-channel TMS-compatible EEG system and preprocessed using Fieldtrip® software. The derivatives of the preprocessed TEPs were calculated and then binarized for every time point at each channel. Cosine similarity at each time-point was calculated between conditions using all channels. Results The cosine similarity metric showed that for each comparison (e.g. motor vs. parietal, real vs. sham, etc.), the early ( ∼ 100 ms across all comparisons, coinciding with the N100 component. These quantitative results closely match qualitative assessment of the whole-brain topographies, lending credibility to our use of the cosine similarity technique as a measure of stereotypy. Conclusion Our results indicate that while early TEP components reflect site-specific responses to direct cortical stimulation, later responses become progressively stereotyped across stimulation sites, suggesting that these late components are neural artifact. Due to the exponential-like decay in differentiation seen in each comparison, we propose that only TEP components occurring earlier than 50–70 ms are safely interpretable as responses to cortical stimulation. Auditory and somatosensory stimulation controls and/or further refinements in signal processing may be necessary to extract true responses to cortical stimulation from later components.