TMS-evoked EEG Potentials Research Articles

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials

BackgroundInhibition 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. MethodsPpTMS-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. ResultsWe 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. ConclusionsFindings 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.

Online Transcranial Magnetic Stimulation Protocol for Measuring Cortical Physiology Associated with Response Inhibition.

We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) characterization of primary motor cortex (M1) excitability and inhibition. Motor response inhibition prevents unwanted actions and is abnormal in several neuropsychiatric conditions. TMS is a non-invasive technology that can quantify M1 excitability and inhibition using single- and paired-pulse protocols and can be precisely timed to study cortical physiology with high temporal resolution. We modified the original Slater-Hammel (S-H) stop signal task to create a "racecar" version with TMS pulses time-locked to intra-trial events. This task is self-paced, with each trial initiating after a button push to move the racecar towards the 800 ms target. GO trials require a finger-lift to stop the racecar just before this target. Interspersed randomly are STOP trials (25%) during which the dynamically adjusted stop signal prompts subjects to prevent finger-lift. For GO trials, TMS pulses were delivered at 650 ms after trial onset; whereas, for STOP trials, the TMS pulses occurred 150 ms after the stop signal. The timings of the TMS pulses were decided based on electroencephalography (EEG) studies showing event-related changes in these time ranges during stop signal tasks. This task was studied in 3 blocks at two study sites (n=38) and we recorded behavioral performance and event-related motor-evoked potentials (MEP). Regression modelling was used to analyze MEP amplitudes using age as a covariate with multiple independent variables (sex, study site, block, TMS pulse condition [single- vs. paired-pulse], trial condition [GO, successful STOP, failed STOP]). The analysis showed that TMS pulse condition (p<0.0001) and its interaction with trial condition (p=0.009) were significant. Future applications for this online S-H/TMS paradigm include the addition of simultaneous EEG acquisition to measure TMS-evoked EEG potentials. A potential limitation is that in children, the TMS pulse sound couldaffect behavioral task performance.

Online Transcranial Magnetic Stimulation Protocol for Measuring Cortical Physiology Associated with Response Inhibition

We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) characterization of primary motor cortex (M1) excitability and inhibition. Motor response inhibition prevents unwanted actions and is abnormal in several neuropsychiatric conditions. TMS is a non-invasive technology that can quantify M1 excitability and inhibition using single- and paired-pulse protocols and can be precisely timed to study cortical physiology with high temporal resolution. We modified the original Slater-Hammel (S-H) stop signal task to create a "racecar" version with TMS pulses time-locked to intra-trial events. This task is self-paced, with each trial initiating after a button push to move the racecar towards the 800 ms target. GO trials require a finger-lift to stop the racecar just before this target. Interspersed randomly are STOP trials (25%) during which the dynamically adjusted stop signal prompts subjects to prevent finger-lift. For GO trials, TMS pulses were delivered at 650 ms after trial onset; whereas, for STOP trials, the TMS pulses occurred 150 ms after the stop signal. The timings of the TMS pulses were decided based on electroencephalography (EEG) studies showing event-related changes in these time ranges during stop signal tasks. This task was studied in 3 blocks at two study sites (n=38) and we recorded behavioral performance and event-related motor-evoked potentials (MEP). Regression modelling was used to analyze MEP amplitudes using age as a covariate with multiple independent variables (sex, study site, block, TMS pulse condition [single- vs. paired-pulse], trial condition [GO, successful STOP, failed STOP]). The analysis showed that TMS pulse condition (p<0.0001) and its interaction with trial condition (p=0.009) were significant. Future applications for this online S-H/TMS paradigm include the addition of simultaneous EEG acquisition to measure TMS-evoked EEG potentials. A potential limitation is that in children, the TMS pulse sound could affect behavioral task performance.

The Effect of Lamotrigine and Levetiracetam on TMS-Evoked EEG Responses Depends on Stimulation Intensity.

The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) has uncovered underlying mechanisms of two anti-epileptic medications: levetiracetam and lamotrigine. Despite their different mechanism of action, both drugs modulated TMS-evoked EEG potentials (TEPs) in a similar way. Since both medications increase resting motor threshold (RMT), the current aim was to examine the similarities and differences in post-drug TEPs, depending on whether stimulation intensity was adjusted to take account of post-drug RMT increase. The experiment followed a placebo controlled, double blind, crossover design, involving a single dose of either lamotrigine or levetiracetam. When a drug-induced increase of RMT occurred, post-drug measurements involved two blocks of stimulations, using unadjusted and adjusted stimulation intensity. A cluster based permutation analysis of differences in TEP amplitude between adjusted and unadjusted stimulation intensity showed that lamotrigine induced a stronger modulation of the N45 TEP component compared to levetiracetam. Results highlight the impact of adjusting stimulation intensity.

Intermittent theta-burst stimulation induces correlated changes in cortical and corticospinal excitability in healthy older subjects

ObjectiveWe studied the correlation between motor evoked potentials (MEPs) and early TMS-evoked EEG potentials (TEPs) from single-pulse TMS before and after intermittent Theta Burst Stimulation (iTBS) to the left primary motor cortex (M1) in 17 healthy older participants. MethodsTMS was targeted to the hand region of M1 using a MRI-guided navigated brain stimulation system and a figure-of-eight biphasic coil. MEPs were recorded from the right first dorsal interosseous muscle using surface EMG. TEPs were extracted from a 61-channel EEG recording. Participants received 90 single TMS pulses at 120% of resting motor threshold before and after iTBS. ResultsAcross all participants, the change in N15-P30 TEP and MEP amplitudes were significantly correlated (r=0.69; p<0.01). Average TEP responses did not change significantly after iTBS, whereas MEP amplitudes showed a significant increase. ConclusionsChanges in corticospinal reactivity and cortical reactivity induced by iTBS are related. However, the effect of iTBS on TEPs, unlike MEPs, is not straightforward. SignificanceOur findings help elucidate the relationship between changes in cortical and corticospinal excitability in healthy older individuals. Going forward, TEPs may be used to evaluate the effects of theta-burst stimulation in non-motor brain regions.

The impact of GABAergic drugs on TMS-induced brain oscillations in human motor cortex

Brain responses to transcranial magnetic stimulation (TMS) as measured with electroencephalography (EEG) have so far been assessed either by TMS-evoked EEG potentials (TEPs), mostly reflecting phase-locked neuronal activity, or time-frequency-representations (TFRs), reflecting oscillatory power arising from a mixture of both evoked (i.e., phase-locked) and induced (i.e., non-phase-locked) responses. Single-pulse TMS of the human primary motor cortex induces a specific pattern of oscillatory changes, characterized by an early (30–200 ms after TMS) synchronization in the α- and β-bands over the stimulated sensorimotor cortex and adjacent lateral frontal cortex, followed by a late (200–400 ms) α- and β-desynchronization over the stimulated and contralateral sensorimotor cortex. As GABAergic inhibition plays an important role in shaping oscillatory brain activity, we sought here to understand if GABAergic inhibition contributes to these TMS-induced oscillations. We tested single oral doses of alprazolam, diazepam, zolpidem (positive modulators of the GABAA receptor), and baclofen (specific GABAB receptor agonist). Diazepam and zolpidem enhanced, and alprazolam tended to enhance while baclofen decreased the early α-synchronization. Alprazolam and baclofen enhanced the early β-synchronization. Baclofen enhanced the late α-desynchronization, and alprazolam, diazepam and baclofen enhanced the late β-desynchronization. The observed GABAergic drug effects on TMS-induced α- and β-band oscillations were not explained by drug-induced changes on corticospinal excitability, muscle response size, or resting-state EEG power. Our results provide first insights into the pharmacological profile of TMS-induced oscillatory responses of motor cortex.

Age-related changes of cortical excitability and connectivity in healthy humans: non-invasive evaluation of sensorimotor network by means of TMS-EEG

The sensorimotor cortical system undergoes structural and functional changes across its lifespan. Some of these changes are physiological and parallel the normal aging process, while others might represent pathophysiological mechanisms underlying neurodegenerative disorders. In the last years, the study of possible age-related modifications in brain sensorimotor functional characteristics has been the focus of several research projects. Here we have used the transcranial magnetic stimulation (TMS)-electroencephalography (EEG) navigated co-registration to investigate the influence of physiological aging on the excitability and connectivity of the human sensorimotor cortical system. To this end, we compared the TMS-evoked EEG potentials (TEPs) collected after stimulating the dominant primary motor cortex (M1) in healthy young subjects (mean age 24.5years) with those collected in healthy older adults (mean age 67.6years). We have shown that, after stimulation of the left motor cortex, TEPs are significantly affected by physiological aging. This phenomenon has a clear spatio-temporal specificity and we speculate that normal aging per se leads to some changes in the excitability of specific cortical neural assemblies whereas other alterations could reflect compensatory mechanisms to such changes.

P200 Synchronized tACS entrained oscillatory activity modulates long-range neuronal transmission efficacy

Question Synchronized brain oscillations are considered a basis for inter-regional neuronal communication ( Engel, 2001 , Buzsaki, 2000 ). However, the causal role of synchronized neural oscillations in regulating the efficacy of signal transmission in brain networks has so far not been directly demonstrated. Methods To address this relationship, we employed the simultaneous use of transcranial alternating current stimulation (tACS), TMS and EEG. Through tACS we entrained theta oscillatory activity in two regions of the human frontoparietal network; the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC). We applied 6 Hz tACS to the DLPFC and PPC simultaneously in an in-phase or anti-phase manner. For assessing resultant changes in transmission in the network, we simultaneously applied weak single-pulse TMS over the DLPFC at four different phases of tACS (90°, 180°, 270°, 360°) and measured the spread of TMS-evoked EEG potentials (TEPs). The amount of current spread is modulated by the functional status of the neural network, and thereby provides a measure of changes in signaling efficacy ( Ilmoniemi, 1997 ). Results We found that the amplitude of TEPs depended on the phase of the entrained 6 Hz activity. The phase-dependent changes of TEPs propagated to the occipital area in the in-phase condition, while, in the anti-phase condition, the phase-dependency of TEPs disappeared in the occipital area, suggesting that the tACS-induced de-synchronization of the frontoparietal network limited the communication of the network. Conclusions A recent study has shown that introducing synchronized theta activity in the frontoparietal network with tACS modulates working memory performance ( Polania, 2012 ). Our results add to the neurophysiological explanation of these findings. We demonstrate that tACS-induced theta oscillations modulate signaling efficacy in a phase-dependent manner, and that the induced state of phase-synchrony across the frontoparietal network further modulates signaling efficacy. This supports the causal role of synchronized endogenous oscillatory activity in modulating neuronal communication.

P092 Cortico-spinal and cortico-cortical excitability is influenced by the phase of oscillatory alpha activity at the time of the stimulus

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.

P275 Clinical trial: EEG alpha real-time phase-triggered TMS to modulate left vs. right DLPFC activity for the treatment of depression

TMS is an effective neuromodulatory tool in the treatment of stroke and depression. In the case of stroke, an imbalance between the affected and unaffected hemisphere in the M1-M1 interhemispheric motor network is presumed; in the case of depression, left dorsolateral prefrontal cortex (DLPF) is presumed underactive vs. right. Whereas motor network excitability can be assessed with hand muscle contractions, no such “direct” readout is available for frontal networks. Furthermore, classical rTMS protocols suffer from large variability, requiring large numbers of patients to demonstrate a (small) group effect. An ongoing clinical pilot trial addresses this conundrum using a novel brain-state triggered TMS protocol previously shown to be more effective and reliable at bi-directionally modulating cortical excitability in the motor system than classical protocols. Can we translate the basic research results from the motor network to a clinical application involving the prefrontal network? 18 patients with depression receive different interventions on different days. The main intervention consists of 200 brain-state triggered triple-pulses (inter-pulse-interval 10 ms) applied over left DLPFC triggered by the negative peak phase of local ongoing 10 Hz oscillations (to increase excitability) or on the right DLPFC during the positive peak phase (to decrease excitability), with a sham coil on the respective other side. There are two control conditions consisting of the offline replay of the same stimulus sequence and a classical TBS protocol (continuous over right DLPFC, intermittent over left). Resting-state EEG, spectral power ratio, TMS evoked EEG potentials (from both right and left DLPFC, randomized interleaved, using a two-coil set-up), before and at multiple times after the intervention are recorded, as well as a depression inventory. Neuronavigation with individual MRI anatomy is used. We demonstrate the applicability of local brain network state triggered therapeutic TMS protocols to modulate cortical excitability therapeutically and quantify suitable neurophysiological markers (interhemispheric spectral power, left vs. right prefrontal network TMS evoked EEG potentials) to track effectiveness in a network where direct readouts are not available.

27. Effects of aging on motor cortex excitability and connectivity: A TMS-EEG study

The sensorimotor cortical system undergoes structural and functional changes across the lifespan, some of these changes are physiological and parallel the normal aging while others might represent pathophysiological mechanism underlying some neurodegenerative disorders. Over the past decade numerous studies have been conducted to identify age-related changes in its functional properties. Here, we have used simultaneous electroencephalography (EEG) and transcranial magnetic stimulation (TMS) to study the effects of physiological aging on the excitability and the connectivity of the dominant hemisphere’s sensorimotor cortical system. To this end, we compared the TMS-evoked EEG potentials (TEPs) collected in healthy young individuals with the ones collected in healthy old individuals. We have shown that the TEPs are significantly affected by physiological aging and this phenomenon has clear spatio-temporal specificity.

Lamotrigine and levetiracetam exert a similar modulation of TMS-evoked EEG potentials.

SummaryObjectiveAntiepileptic drug (AED) treatment failures may occur because there is insufficient drug in the brain or because of a lack of relevant therapeutic response. Until now it has not been possible to measure these factors. It has been recently shown that the combination of transcranial magnetic stimulation and electroencephalography (TMS‐EEG) can measure the effects of drugs in healthy volunteers. TMS‐evoked EEG potentials (TEPs) comprise a series of positive and negative deflections that can be specifically modulated by drugs with a well‐known mode of action targeting inhibitory neurotransmission. Therefore, we hypothesized that TMS‐EEG can detect effects of two widely used AEDs, lamotrigine and levetiracetam, in healthy volunteers.MethodsFifteen healthy subjects participated in a pseudo‐randomized, placebo‐controlled, double‐blind, crossover design, using a single oral dose of lamotrigine (300 mg) and levetiracetam (3,000 mg). TEPs were recorded before and 120 min after drug intake, and the effects of drugs on the amplitudes of TEP components were statistically evaluated.ResultsA nonparametric cluster‐based permutation analysis of TEP amplitudes showed that AEDs both increased the amplitude of the negative potential at 45 msec after stimulation (N45) and suppressed the positive peak at 180 msec (P180). This is the first demonstration of AED‐induced modulation of TMS‐EEG measures.SignificanceDespite the different mechanism of action that lamotrigine and levetiracetam exert at the molecular level, both AEDs impact the TMS‐EEG response in a similar way. These TMS‐EEG fingerprints observed in healthy subjects are candidate predictive markers of treatment response in patients on monotherapy with lamotrigine and levetiracetam.

TMS-EEG signatures of GABAergic neurotransmission in the human cortex.

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.

IS 24. TMS-EEG to measure excitability and connectivity of human cortical circuits

Recording TMS-evoked EEG potentials (TEPs) that are unconfounded by electromagnetic and biological artifacts is challenging. Neuronavigation guided TMS-EEG recordings performed in brain-injured patients showed that, when confounding factors are appropriately controlled, TMS elicits a significant EEG response only when is targeted on a scalp region overlying healthy cortical tissue and no response when is targeted over scalp areas overlying dead portions of the cortex while, in healthy subjects TEPs are highly reproducible over time. Thus, TEPs seem to purely reflect the response of the cortical tissue to TMS and can be used reliably to detect changes of excitability and connectivity in physiological, psychiatric and neurological conditions. For instance, in awake healthy subjects each cortical region tends to generate TEPs characterized by a dominant frequency (natural frequency) either when directly or indirectly activated by a TMS pulse. On the contrary, the tendency of different cortical circuits to oscillate at a specific frequency when directly perturbed is lost in schizophrenic patients. Most importantly, TMS-EEG measurements showed that effective connectivity is reduced during loss of consciousness in deep sleep, anesthesia and vegetative state. Interestingly, effective cortical connectivity recovered during REM sleep, and in acute brain injured patients before they could reestablish a functional communication with the environment. Overall, these observations suggest that TMS-EEG may represent a valuable tool to probe directly and non-invasively cortical excitability and connectivity in humans.

P 49. Modulation of spontaneous and TMS-evoked alpha oscillations by top-down visual attention

Simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows the direct assessment of cortico-thalamic responsiveness by TMS-evoked EEG potentials (TEPs). Notably, the frequency composition of TEPs corresponds to the dominant spontaneous oscillation at the respective stimulation site, e.g. ′alpha′ in the visual cortex (Rosanova et al., J Neurosci 2009). Furthermore, TEPs change dramatically with shifts in neuromodulatory levels during sleep (Massimini et al., Science 2005; Bergmann et al., J Neurosci 2012), suggesting that both are generated by the same neuronal mechanisms. Indeed, rhythmic TMS of the parieto-occipital cortex can mimic alpha band (8–12 Hz) oscillations in the EEG (Thut et al., Curr Biol 2011) as well as their known impact on perceptual performance (Romei et al., J Neurosci 2010) due to gating by inhibition (Jensen et al., TICS 2012). However, does the alpha-like TEP as response to visual cortex stimulation actually resemble spontaneous alpha oscillations or rather visual evoked potentials (VEPs)? Importantly, VEPs are amplified by visual attention (Rajagovindan and Ding, J Cog Neurosci, 2011), whereas spontaneous alpha oscillations are suppressed (Foxe et al., Neurorep 1998; Fu et al., Cog Brain Res 2001). To test the similarity between transcranially evoked and spontaneous alpha oscillations, we currently investigate whether they show comparable responses to covert shifts in attention, i.e., decrease and increase in amplitude when attending the visual and auditory modality, respectively (Foxe and Snyder, Front Psychol 2011). Here, we measure TEPs my means of simultaneously applied 61-channel EEG and neuronavigated single-pulse TMS to the visual cortex while subjects attend to either visual or auditory noise patterns in order to detect slight contrast modulations. Since auditory stimuli have been shown to evoke an alpha-like response in the visual cortex (Romei, Gross and Thut, Curr Biol 2012), we use a constant stream of auditory masking noise as well as sham TMS to control for these effects. Preliminary results suggest that the TMS-evoked alpha oscillation is in fact modulated by top-down visual attention in analogy to spontaneous alpha oscillations, suggesting that both are generated by the same underlying neural mechanisms.

P 206. Monitoring short term effects of repetitive transcranial magnetic stimulation (TMS) by TMS-evoked potentials in children

Repetitive transcranial magnetic stimulation (rTMS) allows non-invasive stimulation of the human brain. However, no suitable marker has yet been established to monitor the immediate rTMS effects on cortical areas in children. TMS-evoked EEG potentials (TEPs) could present a well-suited marker for real-time monitoring. Monitoring is particularly important in children where only few data about rTMS effects and safety are currently available. In a single-blind sham-controlled study, 25 school-aged children with ADHD received subthreshold 1 Hz-rTMS to the primary motor cortex. The TMS-evoked N100 was measured by 64-channel-EEG pre, during and post rTMS, and compared to sham stimulation as an intraindividual control condition. TMS-evoked N100 amplitude decr eased during 1 Hz-rTMS and, at the group level, reached a stable plateau after approximately 500 pulses. N100 amplitude to supra-threshold single pulses post rTMS confirmed the amplitude reduction in comparison to the pre-rTMS level while sham stimulation had no influence. EEG source analysis indicated that the TMS-evoked N100 change reflected rTMS effects in the stimulated motor cortex. Amplitude changes in TMS-evoked N100 and MEPs (pre versus post 1 Hz-rTMS) correlated significantly, but this correlation was also found for pre versus post sham stimulation. The TMS-evoked N100 represents a promising candidate marker to monitor rTMS effects on cortical excitability in children with ADHD. TMS-evoked N100 can be employed to monitor real-time effects of TMS for subthreshold intensities. Though TMS-evoked N100 was a more sensitive parameter for rTMS-specific changes than MEPs in our sample, further studies are necessary to demonstrate whether clinical rTMS effects can be predicted from rTMS-induced changes in TMS-evoked N100 amplitude and to clarify the relationship between rTMS-induced changes in TMS-evoked N100 and MEP amplitudes. The TMS-evoked N100 amplitude reduction after 1 Hz-rTMS could either reflect a globally decreased cortical response to the TMS pulse or a specific decrease in inhibition.

EEG-guided transcranial magnetic stimulation reveals rapid shifts in motor cortical excitability during the human sleep slow oscillation.

Evoked cortical responses do not follow a rigid input-output function but are dynamically shaped by intrinsic neural properties at the time of stimulation. Recent research has emphasized the role of oscillatory activity in determining cortical excitability. Here we employed EEG-guided transcranial magnetic stimulation (TMS) during non-rapid eye movement sleep to examine whether the spontaneous <1 Hz neocortical slow oscillation (SO) is associated with corresponding fluctuations of evoked responses. Whereas the SO's alternating phases of global depolarization (up-state) and hyperpolarization (down-state) are clearly associated with fluctuations in spontaneous neuronal excitation, less is known about state-dependent shifts in neocortical excitability. In 12 human volunteers, single-pulse TMS of the primary motor cortical hand area (M1(HAND)) was triggered online by automatic detection of SO up-states and down-states in the EEG. State-dependent changes in cortical excitability were traced by simultaneously recording motor-evoked potentials (MEPs) and TMS-evoked EEG potentials (TEPs). Compared to wakefulness and regardless of SO state, sleep MEPs were smaller and delayed whereas sleep TEPs were fundamentally altered, closely resembling a spontaneous SO. However, both MEPs and TEPs were consistently larger when evoked during SO up-states than during down-states, and amplitudes within each SO state depended on the actual EEG potential at the time and site of stimulation. These results provide first-time evidence for a rapid state-dependent shift in neocortical excitability during a neuronal oscillation in the human brain. We further demonstrate that EEG-guided temporal neuronavigation is a powerful tool to investigate the phase-dependent effects of neuronal oscillations on perception, cognition, and motor control.

Transcranial magnetic stimulation-evoked EEG/cortical potentials in physiological and pathological aging

The frontal cortex undergoes macrostructural and microstructural changes across the lifespan. These changes can be entirely physiological, such as the ones occurring in elderly individuals who are cognitively intact, or pathological, such as the ones occurring in patients with Alzheimer's disease. Here, we use simultaneous electroencephalography (EEG) and transcranial magnetic stimulation (TMS) to study how the excitability of the frontal cortex changes during healthy and pathological aging. Hence, we compared the TMS-evoked EEG potentials collected in healthy elderly individuals with the ones collected in healthy young individuals, and in patients with Alzheimer's disease. We have shown that the EEG response to TMS of the left superior frontal cortex is not affected by physiological aging but is markedly altered by cognitive impairment.