Combining TMS and EEG Offers New Prospects in Cognitive Neuroscience

The combination of brain stimulation by transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) imaging has become feasible due to recent technical developments. The TMS-EEG integration provides real-time information on cortical reactivity and connectivity through the analysis of TMS-evoked potentials (TEPs), and how functional activity links to behavior through the study of TMS-induced modulations thereof. It reveals how these effects vary as a function of neuronal state, differing between individuals and patient groups but also changing rapidly over time during task performance. This review discusses the wide range of possible TMS-EEG applications and what new information may be gained using this technique on the dynamics of brain functions, hierarchical organization, and cortical connectivity, as well as on TMS action per se. An advance in the understanding of these issues is timely and promises to have a substantial impact on many areas of clinical and basic neuroscience.     

Transcranial magnetic stimulation--a new tool for functional imaging of the brain

Recent progress in the theory and technology of transcranial magnetic stimulation (TMS) is leading to novel approaches in brain mapping. TMS becomes a powerful functional brain mapping tool when other imaging methods are used to record TMS-evoked activity or when peripheral effects are observed as a function of stimulus location. TMS-evoked activity currently can be recorded by EEG, PET, and fMRI. In addition to providing indices of cortical excitability, these methods allow one to study brain connectivity directly, without the need for behavioral activations. When the coordinate systems in the different imaging modalities are combined, anatomical structures seen in MRI and activation sites determined by PET, fMRI, or MEG/EEG can be used for the selection of target areas in the brain. PET and fMRI can be used to map the spatial distribution of TMS-evoked activity. On the other hand, the combination of TMS and high-resolution EEG may often be the method of choice for basic neuroscience and for clinical diagnosis, for example, in the assessment of brain connectivity in patients suffering from neurodegenerative diseases or head injuries.     

Electrophysiological correlates of short-latency afferent inhibition: a combined EEG and TMS study

Cutaneous stimulation produces short-latency afferent inhibition (SAI) of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). Since the demonstration of SAI is primarily based on the attenuation of MEPs, its cortical origin is not yet fully understood. In the present study we combined TMS with concurrent electroencephalography (EEG) in order to obtain direct cortical correlates of SAI. TMS-evoked EEG responses and MEPs were analysed with and without preceding electrical stimulation of the index finger cutaneous afferents in ten healthy volunteers. We show that the attenuation of MEPs by cutaneous stimulation has its counterpart in the attenuation of the N100 EEG response. Moreover, the attenuation of the cortical N100 component correlated positively with the strength of SAI, indicating that the transient changes in cortical excitability can be reflected in the amplitude dynamics of MEPs. We hypothesize that the hyperpolarization of the pyramidal cells due to SAI lowers the capacity of TMS to induce the inhibitory current needed to elicit N100, thus leading to its attenuation. We suggest that the observed interaction of two inhibitory processes, SAI and N100, provides further evidence for the cortical origin of SAI. R. Bikmullina and D. Kičić equally contributed to the study.     

Evoked potentials in large-scale cortical networks elicited by TMS of the visual cortex

Single pulses of transcranial magnetic stimulation (TMS) result in distal and long-lasting oscillations, a finding directly challenging the virtual lesion hypothesis. Previous research supporting this finding has primarily come from stimulation of the motor cortex. We have used single-pulse TMS with simultaneous EEG to target seven brain regions, six of which belong to the visual system [left and right primary visual area V1, motion-sensitive human middle temporal cortex, and a ventral temporal region], as determined with functional MRI-guided neuronavigation, and a vertex "control" site to measure the network effects of the TMS pulse. We found the TMS-evoked potential (TMS-EP) over visual cortex consists mostly of site-dependent theta- and alphaband oscillations. These site-dependent oscillations extended beyond the stimulation site to functionally connected cortical regions and correspond to time windows where the EEG responses maximally diverge (40, 200, and 385 ms). Correlations revealed two site-independent oscillations ～350 ms after the TMS pulse: a theta-band oscillation carried by the frontal cortex, and an alpha-band oscillation over parietal and frontal cortical regions. A manipulation of stimulation intensity at one stimulation site (right hemisphere V1-V3) revealed sensitivity to the stimulation intensity at different regions of cortex, evidence of intensity tuning in regions distal to the site of stimulation. Together these results suggest that a TMS pulse applied to the visual cortex has a complex effect on brain function, engaging multiple brain networks functionally connected to the visual system with both invariant and site-specific spatiotemporal dynamics. With this characterization of TMS, we propose an alternative to the virtual lesion hypothesis. Rather than a technique that simulates lesions, we propose TMS generates natural brain signals and engages functional networks.     

The relationship between peripheral and early cortical activation induced by transcranial magnetic stimulation

The purpose of this study was to assess the relationship between peripheral muscle responses (motor evoked potentials, MEP) evoked by transcranial magnetic stimulation (TMS) and the early components of the TMS-evoked EEG response, both of which reflect cortical excitability. Left primary motor cortex of five healthy volunteers was stimulated with 100% of the motor threshold. The relationship between MEP amplitudes and the peak-to-peak amplitudes of the N15–P30 complex of the evoked EEG signal was determined at the single-trial level. MEP and N15–P30 amplitudes were significantly correlated in all five subjects. The results support the view that the amount of direct activation of neurons in M1 evoked by TMS affects both subsequent cortical activation and the activation of the target muscle. Cortical excitability is altered in some neuronal disorders and modulated locally during various tasks. It could thus be used as a marker of the state of health in many cases and as a method to study brain function. The present results improve our understanding of the early components of the TMS-evoked EEG signal, which reflect cortical excitability, and may thus have widespread use in clinical and scientific studies.     

Mapping causal interregional influences with concurrent TMS–fMRI

Transcranial magnetic stimulation (TMS) produces a direct causal effect on brain activity that can now be studied by new approaches that simultaneously combine TMS with neuroimaging methods, such as functional magnetic resonance imaging (fMRI). In this review we highlight recent concurrent TMS–fMRI studies that illustrate how this novel combined technique may provide unique insights into causal interactions among brain regions in humans. We show how fMRI can detect the spatial topography of local and remote TMS effects and how these may vary with psychological factors such as task-state. Concurrent TMS–fMRI may furthermore reveal how the brain adapts to so-called virtual lesions induced by TMS, and the distributed activity changes that may underlie the behavioural consequences often observed during cortical stimulation with TMS. We argue that combining TMS with neuroimaging techniques allows a further step in understanding the physiological underpinnings of TMS, as well as the neural correlated of TMS-evoked consequences on perception and behaviour. This can provide powerful new insights about causal interactions among brain regions in both health and disease that may ultimately lead to developing more efficient protocols for basic research and therapeutic TMS applications. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Side effects of transcranial magnetic stimulation biased task performance in a cognitive neuroscience study

Summary: Transcranial magnetic stimulation (TMS) is increasingly used as a research tool for functional brain mapping in cognitive neuroscience. Despite being mostly tolerable, side effects of TMS could influence task performance in behavioural TMS studies. In order to test this issue, healthy subjects assessed the discomfort caused by the stimulation during a verbal working memory task. We investigated the relation between subjective disturbance and task performance. Subjects were stimulated during the delay period of a delayed-match-to-sample task above cortical areas that had been identified before to be involved in working memory. Task performance and subjective disturbance due to side effects were monitored. The subjects’ grade of discomfort correlated with the error rates: the higher the discomfort, the more errors were made. Conclusively, TMS side effects may bias task performance in cognitive neuroscience studies and may thereby lead to misinterpretation of results. We emphasize the importance of controlling side effects of the stimulation as a source of biasing effects in TMS studies.     

Cutaneomotor integration in humans is somatotopically organized at various levels of the nervous system and is task dependent

Integration of tactile afferent signals with motor commands is crucial for the performance of purposeful movements such as during manipulation of an object in the hand. To study the somatotopic organization of sensorimotor integration we applied electrical peripheral conditioning stimuli to a digit located near (homotopic stimulation) or distant from (heterotopic stimulation) relaxed or isometrically contracted intrinsic hand muscles at variable time intervals prior to transcranial magnetic stimulation (TMS). Cutaneous stimulation has previously been shown to modulate the amplitude of the motor evoked potential (MEP) and to shorten the duration of the silent period (SP) evoked by TMS. In relaxed target muscles the time-dependent modulation of TMS-evoked motor responses by homotopic conditioning stimulation differed from modulation by heterotopic stimulation. Similar differences in the modulation pattern evoked by homotopic and heterotopic conditioning stimulation were observed for two distinct target muscles of the hand (abductor digiti minimi, abductor pollicis brevis muscle). Differences in modulation were maximal when the conditioning stimulation was applied 25–30 ms and 150–200 ms prior to TMS. Comparison of the modulation of the amplitudes of MEPs evoked by transcranial electrical stimulation (TES) and the modulation of those evoked by TMS suggests that differences between homotopic and heterotopic stimulation originate subcortically at 25- to 30-ms and, at least partially, cortically at 150- to 200-ms interstimulus intervals. In isometrically contracted intrinsic hand muscles the degree to which the SP was shortened reflected the location and the timing of the conditioning stimulus. Shortening was maximal when the conditioning stimulus was applied nearest to the contracted target muscle and 20 ms prior to the test stimulus. In contrast to the SP duration, the MEP size in voluntarily contracted target muscles was unaffected by the location of the conditioning stimulus. The somatotopic gradient of SP shortening was abolished when the two target muscles were simultaneously activated isometrically. Together, our findings suggest that somatotopy of input-output relationships is implemented at both a spinal and a cortical level in the human central nervous system and may also depend on the motor task involved. Received: 25 August 1998 / Accepted: 11 June 1999     

Modulation of slow cortical potentials by transcranial magnetic stimulation in humans

We studied the effects of transcranial magnetic stimulation (TMS) on slow cortical potentials (SCPs) of the brain elicited during performance of a feedback and reward task. Ten healthy participants were trained to self-regulate their SCP amplitude using visual feedback and reward for increased or decreased amplitudes. Subjects participated in 27 runs (each comprising 70 trials) under three different conditions: single-pulse TMS delivered with the coil centered over Cz (vertex), over a lateral scalp position (LSP), which increased task difficulty, and in the absence of stimulation. Cz stimulation led to a non-significant enhancement of negative SCPs, while LSP stimulation led to a significant increase of positive SCPs. These results are consistent with the idea that enhanced task difficulty, as in LSP stimulation, enhances cognitive processing load leading to an increase of positive SCPs. Additionally, the data raise the hypothesis that TMS delivered to bilateral midcentral regions could modulate the amplitude of negative SCPs.     

Modulation of rodent cortical motor excitability by somatosensory input

It is assumed that somatosensory input is required for motor learning and recovery from focal brain injury. In rodents and other mammals, corticocortical projections between somatosensory and motor cortices are modified by patterned input. Whether and how motor cortex function is modulated by somatosensory input to support motor learning is largely unknown. Recent human evidence suggests that input changes motor excitability. Using transcranial magnetic stimulation (TMS), this study tested whether motor cortex excitability is affected by patterned somatosensory stimulation in rodents. Motor potentials evoked in gastrocnemius muscles in response to TMS (MEP(TMS)) and to cervical electrical stimulation (MEP(CES)) were recorded bilaterally. Initially, the first negative peak of the MEP(TMS) was identified as a cortical component because it disappeared after decortication in three animals. Subsequently, we studied the effects of 2 h of electrical stimulation of one sciatic nerve on the cortical component of the MEP(TMS), i.e., on motor cortex excitability. After stimulation, its amplitude increased by 117 +/- 45% ( P<0.01) in the stimulated limb. A significantly smaller effect was found in the unstimulated limb ( P<0.02) and no effect was observed in unstimulated control animals. The subcortically evoked MEP(CES) were not affected by stimulation. It is concluded that somatosensory input increases motor excitability in rat. This increase outlasts the stimulation period and is mediated by supraspinal structures, likely motor cortex. Modulation of motor cortex excitability by somatosensory input may play a role in motor learning and recovery from lesion.     

A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex

Synaptic plasticity is conspicuously dependent on the temporal order of the pre- and postsynaptic activity. Human motor cortical excitability can be increased by a paired associative stimulation (PAS) protocol. Here we show that it can also be decreased by minimally changing the interval between the two associative stimuli. Corticomotor excitability of the abductor pollicis brevis (APB) representation was tested before and after repetitively pairing of single right median nerve simulation with single pulse transcranial magnetic stimulation (TMS) delivered over the optimal site for activation of the contralateral APB. Following PAS, depression of TMS-evoked motor-evoked potentials (MEPs) was induced only when the median nerve stimulation preceded the TMS pulse by 10 ms, while enhancement of cortical excitability was induced using an interstimulus interval of 25 ms, suggesting an important role of the sequence of cortical events triggered by the two stimulation modalities. Experiments using F-wave studies and electrical brain stem stimulation indicated that the site of the plastic changes underlying the decrease of MEP amplitudes following PAS (10 ms) was within the motor cortex. MEP amplitudes remained depressed for approximately 90 min. The decrease of MEP amplitudes was blocked when PAS(10 ms) was performed under the influence of dextromethorphan, an N-methyl-d-aspartate-receptor antagonist, or nimodipine, an L-type voltage-gated calcium-channel antagonist. The physiological profile of the depression of human motor cortical excitability following PAS(10 ms) suggests long-term depression of synaptic efficacy to be involved. Together with earlier findings, this study suggests that strict temporal Hebbian rules govern the induction of long-term potentiation/long-term depression-like phenomena in vivo in the human primary motor cortex.     

Reorganisation of the Right Occipito-Parietal Stream for Auditory Spatial Processing in Early Blind Humans. A Transcranial Magnetic Stimulation Study

It is well known that, following an early visual deprivation, the neural network involved in processing auditory spatial information undergoes a profound reorganization. In particular, several studies have demonstrated an extensive activation of occipital brain areas, usually regarded as essentially “visual”, when early blind subjects (EB) performed a task that requires spatial processing of sounds. However, little is known about the possible consequences of the activation of occipitals area on the function of the large cortical network known, in sighted subjects, to be involved in the processing of auditory spatial information. To address this issue, we used event-related transcranial magnetic stimulation (TMS) to induce virtual lesions of either the right intra-parietal sulcus (rIPS) or the right dorsal extrastriate occipital cortex (rOC) at different delays in EB subjects performing a sound lateralization task. Surprisingly, TMS applied over rIPS, a region critically involved in the spatial processing of sound in sighted subjects, had no influence on the task performance in EB. In contrast, TMS applied over rOC 50 ms after sound onset, disrupted the spatial processing of sounds originating from the contralateral hemifield. The present study shed new lights on the reorganisation of the cortical network dedicated to the spatial processing of sounds in EB by showing an early contribution of rOC and a lesser involvement of rIPS.     

Transcranial magnetic stimulation and brain atrophy: a computer-based human brain model study

This paper is aimed at exploring the effect of cortical brain atrophy on the currents induced by transcranial magnetic stimulation (TMS). We compared the currents induced by various TMS conditions on several different MRI derived finite element head models of brain atrophy, incorporating both decreasing cortical volume and widened sulci. The current densities induced in the cortex were dependent upon the degree and type of cortical atrophy and were altered in magnitude, location, and orientation when compared to healthy head models. Predictive models of the degree of current density attenuation as a function of the scalp-to-cortex distance were analyzed, concluding that those which ignore the electromagnetic field–tissue interactions lead to inaccurate conclusions. Ultimately, the precise site and population of neural elements stimulated by TMS in an atrophic brain cannot be predicted based on healthy head models which ignore the effects of the altered cortex on the stimulating currents. Clinical applications of TMS should be carefully considered in light of these findings.     

Impact of repetitive transcranial magnetic stimulation of the parietal cortex on metabolic brain activity: a<Superscript> 14</Superscript>C-2DG tracing study in the cat

Transcranial magnetic stimulation (TMS) is increasingly utilized in clinical neurology and neuroscience. However, detailed knowledge of the impact and specificity of the effects of TMS on brain activity remains unresolved. We have used ¹⁴C-labeled deoxyglucose (¹⁴C-2DG) mapping during repetitive TMS (rTMS) of the posterior and inferior parietal cortex in anesthetized cats to study, with exquisite spatial resolution, the local and distant effects of rTMS on brain activity. High-frequency rTMS decreases metabolic activity at the primary site of stimulation with respect to homologue areas in the unstimulated hemisphere. In addition, rTMS induces specific distant effects on cortical and subcortical regions known to receive substantial efferent projections from the stimulated cortex. The magnitude of this distal impact is correlated with the strength of the anatomical projections. Thus, in the anesthetized animal, the impact of rTMS is upon a distributed network of structures connected to the primary site of application.B.R. Payne has passed away since this paper was completed.     

Human brain cortical correlates of short-latency afferent inhibition: a combined EEG-TMS study

When linking in time electrical stimulation of the peripheral nerve with transcranial magnetic stimulation (TMS), the excitability of the motor cortex can be modulated to evoke clear inhibition, as reflected by the amplitude decrement in the motor-evoked potentials (MEPs). This specific property, designated short-latency afferent inhibition (SAI), occurs when the nerve-TMS interstimulus interval (ISI) is approximately 25 ms and is considered to be a corticothalamic phenomenon. The aim of the present study was to use the electroencephalographic (EEG) responses to navigated-TMS coregistration to better characterize the neuronal circuits underlying SAI. The present experimental set included magnetic resonance imaging (MRI)-navigated TMS and 60-channel TMS-compatible EEG devices. TMS-evoked EEG responses and MEPs were analyzed in eight healthy volunteers; ISIs between median nerve and cortical stimulation were determined relative to the latency of the individual N20 component of the somatosensory-evoked potential (SEP) obtained after stimulation of the median nerve. ISIs from the latency of the N20 plus 3 ms and N20 plus 10 ms were investigated. In all experimental conditions, TMS-evoked EEG responses were characterized by a sequence of negative deflections peaking at approximately 7, 44, and 100 ms alternating with positive peaks at approximately 30, 60, and 180 ms post-TMS. Moreover, ISI N20+3 ms modulated both EEG-evoked activity and MEPs. In particular, it inhibited MEP amplitudes, attenuated cortical P60 and N100 responses, and induced motor cortex beta rhythm selective decrement of phase locking. The findings of the present experiment suggest the cortical origin of SAI that could result from the cortico-cortical activation of GABAergic-mediated inhibition onto the corticospinal neurons modulated by cholinergic activation able to reducing intralaminar inhibition and promoting intracolumnar inhibition.     

Phosphene threshold as a function of contrast of external visual stimuli

Transcranial magnetic stimulation (TMS) of the occipital lobe is frequently used to induce visual percepts by direct stimulation of visual cortex. The threshold magnetic field strength necessary to elicit a visual percept is often regarded as a measure of electrical excitability of visual cortex. Using single-pulse TMS during visual motion stimulus presentation, we investigated the relationship between different degrees of visual cortical preactivation and cortical phosphene threshold (PT). The two possible, mutually exclusive, predictions on the outcome of this experiment were that a) PT increases with stronger preactivation because of a decrease in the signal-to-noise ratio, or b) that PT decreases with increased preactivation because of the increase in neuronal response towards some threshold. PTs for single-pulse stimulation of the occipital lobe were determined for eight subjects while they passively viewed a horizontally drifting luminance-modulated sinewave grating. Gratings used were of four different luminance contrasts while the spatial and temporal frequencies remained constant. PTs were shown to increase significantly as the background grating increased in contrast. These results suggest that the neural activity underlying the perception of a phosphene can be considered a type of signal that can be partially masked by another signal, in this case the visual cortical activation produced by passive viewing of drifting gratings.

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This revised version was published online in May 2005. The preceding version was showing a false article.     

Cortical excitability is not depressed in movement-modulated stretch response of human thumb flexor

There is strong evidence that the predominant pathway of the long-latency stretch reflex for flexor pollicis longus crosses the motor cortex. This reflex response is diminished during active thumb movements. We tested the hypothesis that this could be due to a decrease in the excitability of the transcortical component during movement. During isometric, concentric and eccentric thumb movements, transcranial magnetic stimulation (TMS) of the motor cortex was given at a time when the reflex signal was traversing the motor cortex. TMS was also given earlier in separate runs when the signal was traversing the spinal cord under each of the three contractile conditions. The electromyogram was analysed for non-linear summation between stretch responses and the potential evoked by the cortical stimulus. The response to TMS alone was uniform across the three types of contraction, and the lack of cortical involvement in the short-latency reflex was confirmed. The TMS-evoked response summed in a non-linear manner with the long-latency reflex response, confirming that the excitability of the motor cortex was increased as the reflex signal passed through it. The long-latency response was markedly depressed during isotonic compared with isometric contractions. However, the non-linear summation was not greater during the isometric contractions. Thus, the depressed reflex responses during isotonic movements do not stem from reduced motor cortical responsiveness or afferent input to the transcortical pathway, and may instead reflect modulation of cutaneous reflexes during isotonic contractions. Electronic Publication     

Diminution of training-induced transient motor cortex plasticity by weak transcranial direct current stimulation in the human

Training of a thumb movement in the opposite direction of a twitch in response to transcranial magnetic stimulation (TMS) induces a transient directional change of post-training TMS-evoked movements towards the trained direction. Functional synaptic mechanisms seem to underlie this rapid training-induced plasticity. Transcranial direct current stimulation (tDCS) induces outlasting changes of cerebral excitability, thus presenting as promising tool for neuroplasticity research. We studied the influence of tDCS, applied over the motorcortex during training, on angular deviation of post-training to pre-training TMS-evoked thumb movements. With tDCS of anodal and cathodal polarity the training-induced directional change of thumb movements was significantly reduced during a 10 min post-training interval, indicating an interference of tDCS with mechanisms of rapid training-induced plasticity.     

How does temporal preparation speed up response implementation in choice tasks? Evidence for an early cortical activation

We investigated the influence of temporal preparation on information processing. Single‐pulse transcranial magnetic stimulation (TMS) of the primary motor cortex was delivered during a between‐hand choice task. The time interval between the warning and the imperative stimulus varied across blocks of trials was either optimal (500 ms) or nonoptimal (2500 ms) for participants' performance. Silent period duration was shorter prior to the first evidence of response selection for the optimal condition. Amplitude of the motor evoked potential specific to the responding hand increased earlier for the optimal condition. These results revealed an early release of cortical inhibition and a faster integration of the response selection‐related inputs to the corticospinal pathway when temporal preparation is better. Temporal preparation may induce cortical activation prior to response selection that speeds up the implementation of the selected response.     

Increase in tibialis anterior motor cortex excitability following repetitive electrical stimulation of the common peroneal nerve

The purpose of this study was to investigate whether repetitive electrical stimulation of the common peroneal nerve (CPN) is associated with changes in the motor response of the tibialis anterior (TA) muscle elicited by focal magnetic stimulation of the motor cortex. Motor evoked potentials (MEP) with a stimulation intensity of 125% of the threshold of the relaxed right TA were obtained before, during, and after repetitive electrical stimulation of the CPN (trains of five pulses of 1 ms, at a frequency of 200 Hz, repeated every second with a 30-min duration). The MEP of the TA muscle elicited after repetitive electrical stimulation were increased by 104% (range: 18-263%), and the increase was maintained for up to 110 min (range: 15-110 min) after the end of nerve stimulation. This increase in the MEP of the TA muscle was associated with a decrease in the threshold from the stimulation-response curve. Furthermore, during that period the early component of the TA stretch reflex as well as the latency of the MEP did not significantly change. To further test the origin of the increased MEP, complementary experiments showed that MEP elicited by transcranial electrical stimulation (TES) were also increased, but to a lesser degree (approximately 50%) than MEP elicited by TMS. It can be concluded that short-term nerve repetitive electrical stimulation of the lower extremities in healthy human participants can lead to a long-term increase in the contralateral MEP. As TES is believed to mainly activate the axon and not the soma of the cortical cells, the increased MEP cannot be explained exclusively by changes in the motor cortex cell excitability, but also by changes in subcortical neural structures involved in the excitation of spinal motoneurons. The results of this study allow the speculation that it would be possible to use repetitive electrical stimulation in the rehabilitation of patients with lower limb muscle weakness and spasticity.