Pre-stimulus Phase Research Articles

The effect of the peristimulus alpha phase on visual perception through real-time phase-locked stimulus presentation.

The alpha phase has been theorized to reflect fluctuations in cortical excitability and thereby impose a cyclic influence on visual perception. Despite its appeal, this notion is not fully substantiated, as both supporting and opposing evidence has been recently reported. In contrast to previous research, this study examined the effect of the peristimulus instead of prestimulus phase on visual detection through a real-time phase-locked stimulus presentation approach. Specifically, we monitored phase data from magnetoencephalography (MEG) recordings over time, with a newly developed algorithm based on adaptive Kalman filtering. This information guided online presentations of masked stimuli that were phased-locked to different stages of the alpha cycle while healthy humans concurrently performed detection tasks. Behavioral evidence showed that the overall detection rate did not significantly vary according to the four predetermined peristimulus alpha phases. Nevertheless, the follow-up analyses highlighted that the phase at 90° relative to 180° likely enhanced detection. Corroborating neural parietal activity showed that early interaction between alpha phases and incoming stimuli orchestrated the neural representation of the hits and misses of the stimuli. This neural representation varied according to the phase and in turn shaped the behavioral outcomes. In addition to directly investigating to what extent fluctuations in perception can be ascribed to the alpha phases, this study suggests that phase-dependent perception is not as robust as previously presumed, and might also depend on how the stimuli are differentially processed as a result of a stimulus-phase interaction, in addition to reflecting alternations of the perceptual states between phases.Significance statementAlpha activity, a widely observed neural phenomenon, is postulated to be essential for organizing visual perception. However, our previous understanding of the functional relevance of the alpha phase is primarily inferred from the prestimulus or externally entrained phase. This study monitors real-time phase activity and presents stimuli that are phased-locked to different stages of the alpha cycle. This new approach allows us to investigate whether and how the alpha phases, during which stimuli are concurrently presented, directly lead to behavioral and neural changes in perception. Our evidence suggests that the extent to which the alpha phases affect perception depends on an early interaction between the phase and incoming stimuli, which is involved in shaping the perceptual fates of the stimuli.

Pre-stimulus alpha-band phase gates early visual cortex responses

Alpha-band (8-13 Hz) oscillations have been shown to phasically inhibit perceptual reports in human observers, yet the underlying physiological mechanism of this effect is debated. According to contrasting models, based primarily on animal experiments, alpha activity is thought to either originate from specialized cells in the visual thalamus and periodically inhibit the relay of visual information to the primary visual cortex (V1) in a feedforward manner, or to propagate from higher visual areas back to V1 in a feedback manner. Human neurophysiological evidence in favor of either hypothesis, both, or neither, has been limited. To help address this issue, we explored the link between pre-stimulus alpha phase and visual electroencephalography (EEG) responses thought to arise from afferent input onto human V1. Specially-designed visual stimuli were used to elicit large amplitude C1 event-related potentials (ERP), with polarity, topography, and timing indicative of striate genesis. Single-trial circular-linear associations between pre-stimulus phase and post-stimulus global field power (GFP) during the C1 time window revealed significant effects peaking in the alpha frequency band. Control analyses ruling out the potential confound of post-stimulus data bleeding into the pre-stimulus window demonstrated that GFP amplitude decreases as pre-stimulus alpha phase deviates from an individual's preferred phase. These findings demonstrate an early locus – suggesting that the phase of pre-stimulus alpha oscillations could modulate visual processing by gating the feedforward flow of sensory input between the thalamus and V1, although other models are potentially compatible.

Prestimulus Low-Alpha Frontal Networks Are Associated with Pareidolias in Parkinson's Disease.

Background: Pareidolias are visual phenomena wherein ambiguous, abstract forms or shapes appear meaningful due to incorrect perception. In Parkinson's disease (PD), patients susceptible to visual hallucinations experience visuo-perceptual deficits in the form of pareidolias. Although pareidolias necessitate top-down modulation of visual processing, the cortical dynamics of internally generated perceptual priors on these visual misperceptions is unknown. Objectives: To study prestimulus-related electroencephalography (EEG) spectral and network abnormalities in PD patients experiencing pareidolias. Methods: Twenty-one PD in-patients and 10 age-matched controls were evaluated. Neuropsychological assessments included tests for cognition, attention, and executive functions. Pareidolias were quantified by using the "noise pareidolia test" with simultaneous EEG recording. The PD patients were subdivided into two groups-those with high pareidolia counts (n = 10) and those without (n = 11). The EEG was analyzed 1000 msec before stimulus presentation in the spectral domain (theta, low-alpha, and high-alpha frequencies) with corresponding graph networks to evaluate network properties. Statistical analysis included analysis of variance and multiple regression to evaluate the differences. Results: The PD patients with high pareidolia counts were older with lower scores on neuropsychological tests. Their prestimulus EEG low-alpha band showed a tendency toward higher frontal activity (p = 0.07). Graph networks showed increased normalized clustering coefficient (p = 0.05) and lower frontal degree centrality (p = 0.005). These network indices correlated positively to patients' pareidolia scores. Discussion: We suggest that pareidolias in PD are a consequence of an abnormal top-down modulation of visual processing; they are defined by their frontal low-alpha spectral and network alterations in the prestimulus phase due to a dissonance between patients' internally generated mental processing with external stimuli. Impact statement Pareidolias in Parkinson's disease (PD) are considered to be promising early markers of visual hallucinations and an indicator of PD prognosis. In certain susceptible PD patients, pareidolias can be evoked and studied. Here, via electroencephalography, we aimed at understanding this visual phenomenon by studying how neural information is processed before stimulus presentation in such patients. Using spectral and graph network measures, we revealed how top-down modulated internally generated processes affect visual perception in patients with pareidolias. Our findings highlight how prestimulus network alterations in the frontal cortex shape poststimulus pareidolic manifestations in PD.

Pre-stimulus alpha-band power and phase fluctuations originate from different neural sources and exert distinct impact on stimulus-evoked responses.

Ongoing oscillatory neural activity before stimulus onset influences subsequent visual perception. Specifically, both the power and the phase of oscillations in the alpha-frequency band (9-13Hz) have been reported to predict the detection of visual stimuli. Up to now, the functional mechanisms underlying pre-stimulus power and phase effects on upcoming visual percepts are debated. Here, we used magnetoencephalography recordings together with a near-threshold visual detection task to investigate the neural generators of pre-stimulus power and phase and their impact on subsequent visual-evoked responses. Pre-stimulus alpha-band power and phase opposition effects were found consistent with previous reports. Source localization suggested clearly distinct neural generators for these pre-stimulus effects: Power effects were mainly found in occipital-temporal regions, whereas phase effects also involved prefrontal areas. In order to be functionally relevant, the pre-stimulus correlates should influence post-stimulus processing. Using a trial-sorting approach, we observed that only pre-stimulus power modulated the Hits versus Misses difference in the evoked response, a well-established post-stimulus neural correlate of near-threshold perception, such that trials with stronger pre-stimulus power effect showed greater post-stimulus difference. By contrast, no influence of pre-stimulus phase effects were found. In sum, our study shows distinct generators for two pre-stimulus neural patterns predicting visual perception, and that only alpha power impacts the post-stimulus correlate of conscious access. This underlines the functional relevance of prestimulus alpha power on perceptual awareness, while questioning the role of alpha phase.

The phase of Theta oscillations modulates successful memory formation at encoding

Several studies have shown that attention and perception can depend upon the phase of ongoing neural oscillations at stimulus onset. Here, we extend this idea to the memory domain. We tested the hypothesis that ongoing fluctuations in neural activity impact memory encoding in two experiments using a picture paired-associates task in order to gauge episodic memory performance. Experiment 1 was behavioural only and capitalized on the principle of phase resetting. We tested if subsequent memory performance fluctuates rhythmically, time-locked to a resetting cue presented before the to-be-remembered pairs at different time intervals. We found an indication that behavioural performance was periodically and selectively modulated at Theta frequency (~4 Hz). In Experiment 2, we focused on pre-stimulus ongoing activity using scalp EEG while participants performed a paired-associates task. The pre-registered analysis, using large electrode clusters and generic Theta and Alpha spectral ranges, returned null results of the pre-stimulus phase-behaviour correlation. However, as expected from prior literature, we found that variations in stimulus-related Theta-power predicted subsequent memory performance. Therefore, we used this post-stimulus effect in Theta power to guide a post-hoc pre-stimulus phase analysis in terms of scalp and frequency of interest. This analysis returned a correlation between the pre-stimulus Theta phase and subsequent memory. Altogether, these results suggest that pre-stimulus Theta activity at encoding may impact later memory performance.

Preparatory ERPs in visual, auditory, and somatosensory discriminative motor tasks.

Previous event-related potential (ERP) studies mainly from the present research group showed a novel component, that is, the prefrontal negativity (pN), recorded in visual-motor discriminative tasks during the pre-stimulus phase. This component is concomitant to activity related to motor preparation, that is, the Bereitschaftspotential (BP). The pN component has been reported in experiments based on the visual modality only; for other modalities (acoustic and/or somatosensory) the presence of the pN warrants further investigation. This study represents a first step toward this direction; indeed, we aimed at describing the pN and the BP components in discriminative response tasks (DRTs) for three sensory modalities. In experiment 1 ERPs were recorded in 29 adults in visual and auditory DRT; an additional group of 15 adults participated to a somatosensory DRT (experiment 2). In line with previous results both the pN and the BP were clearly detectable in the visual modality. In the auditory modality the prefrontal pN was not detectable directly; however, the pN could be derived by subtraction of separate EEG traces recorded in a "passive" version of the same auditory task, in which motor responses were not required. In the somatosensory modality both the pN and the BP were detectable, although with lower amplitudes with respect to other two sensory modalities. Overall, regardless of the sensory modality, anticipatory task-related pN and BP components could be detected (or derived by subtraction) over both the prefrontal and motor cortices. These results support the view that anticipatory processes share common components among sensory modalities.

Induction of LTD-like corticospinal plasticity by low-frequency rTMS depends on pre-stimulus phase of sensorimotor μ-rhythm

BackgroundNeural oscillations reflect rapidly changing brain excitability states. We have demonstrated previously with EEG-triggered transcranial magnetic stimulation (TMS) of human motor cortex that the positive vs. negative peak of the sensorimotor μ-oscillation reflect corticospinal low-vs. high-excitability states. In vitro experiments showed that induction of long-term depression (LTD) by low-frequency stimulation depends on the postsynaptic excitability state.Objective/Hypothesis: We tested the hypothesis that induction of LTD-like corticospinal plasticity in humans by 1 Hz repetitive TMS (rTMS) is enhanced when rTMS is synchronized with the low-excitability state, but decreased or even shifted towards long-term (LTP)-like plasticity when synchronized with the high-excitability state. MethodsWe applied real-time EEG-triggered 1-Hz-rTMS (900 pulses) to the hand area of motor cortex in healthy subjects. In a randomized double-blind three-condition crossover design, pulses were synchronized to either the positive or negative peak of the sensorimotor μ-oscillation, or were applied at random phase (control). The amplitude of motor evoked potentials was recorded as an index of corticospinal excitability before and after 1-Hz-rTMS. Results1-Hz-rTMS at random phase resulted in a trend towards LTD-like corticospinal plasticity. RTMS in the positive peak condition (i.e., the low-excitability state) induced significant LTD-like plasticity. RTMS in the negative peak condition (i.e., the high-excitability state) showed a trend towards LTP-like plasticity, which was significantly different from the other two conditions. ConclusionThe level of corticospinal depolarization reflected by phase of the μ-oscillation determines the degree of corticospinal plasticity induced by low-frequency rTMS, a finding that may guide future personalized therapeutic stimulation.

Does the Phase of Ongoing EEG Oscillations Predict Auditory Perception?

Effective processing of information from the environment requires the brain to selectively sample relevant inputs. The visual perceptual system has been shown to sample information rhythmically, oscillating rapidly between more and less input-favorable states. Evidence of parallel effects in auditory perception is inconclusive. Here, we combined a bilateral pitch-identification task with electroencephalography (EEG) to investigate whether the phase of ongoing EEG predicts auditory discrimination accuracy. We compared prestimulus phase distributions between correct and incorrect trials. Shortly before stimulus onset, each of these distributions showed significant phase concentration, but centered at different phase angles. The effects were strongest in theta and beta frequency bands. The divergence between phase distributions showed a linear relation with accuracy, accounting for at least 10% of inter-individual variance. Discrimination performance oscillated rhythmically at a rate predicted by the neural data. These findings indicate that auditory discrimination threshold oscillates over time along with the phase of ongoing EEG activity. Thus, it appears that auditory perception is discrete rather than continuous, with the phase of ongoing EEG oscillations shaping auditory perception by providing a temporal reference frame for information processing.

Interhemispheric symmetry of \xb5-rhythm phase-dependency of corticospinal excitability

Oscillatory activity in the µ-frequency band (8–13 Hz) determines excitability in sensorimotor cortex. In humans, the primary motor cortex (M1) in the two hemispheres shows significant anatomical, connectional, and electrophysiological differences associated with motor dominance. It is currently unclear whether the µ-oscillation phase effects on corticospinal excitability demonstrated previously for the motor-dominant M1 are also different between motor-dominant and motor-non-dominant M1 or, alternatively, are similar to reflect a ubiquitous physiological trait of the motor system at rest. Here, we applied single-pulse transcranial magnetic stimulation to the hand representations of the motor-dominant and the motor-non-dominant M1 of 51 healthy right-handed volunteers when electroencephalography indicated a certain µ-oscillation phase (positive peak, negative peak, or random). We determined resting motor threshold (RMT) as a marker of corticospinal excitability in the three µ-phase conditions. RMT differed significantly depending on the pre-stimulus phase of the µ-oscillation in both M1, with highest RMT in the positive-peak condition, and lowest RMT in the negative-peak condition. µ-phase-dependency of RMT correlated directly between the two M1, and interhemispheric differences in µ-phase-dependency were absent. In conclusion, µ-phase-dependency of corticospinal excitability appears to be a ubiquitous physiological trait of the motor system at rest, without hemispheric dominance.

Pre-stimulus phase and amplitude regulation of phase-locked responses are maximized in the critical state.

Understanding why identical stimuli give differing neuronal responses and percepts is a central challenge in research on attention and consciousness. Ongoing oscillations reflect functional states that bias processing of incoming signals through amplitude and phase. It is not known, however, whether the effect of phase or amplitude on stimulus processing depends on the long-term global dynamics of the networks generating the oscillations. Here, we show, using a computational model, that the ability of networks to regulate stimulus response based on pre-stimulus activity requires near-critical dynamics-a dynamical state that emerges from networks with balanced excitation and inhibition, and that is characterized by scale-free fluctuations. We also find that networks exhibiting critical oscillations produce differing responses to the largest range of stimulus intensities. Thus, the brain may bring its dynamics close to the critical state whenever such network versatility is required.

The shaky ground truth of real-time phase estimation

Instantaneous phase of brain oscillations in electroencephalography (EEG) is a measure of brain state that is relevant to neuronal processing and modulates evoked responses. However, determining phase at the time of a stimulus with standard signal processing methods is not possible due to the stimulus artifact masking the future part of the signal. Here, we quantify the degree to which signal-to-noise ratio and instantaneous amplitude of the signal affect the variance of phase estimation error and the precision with which “ground truth” phase is even defined, using both the variance of equivalent estimators and realistic simulated EEG data with known synthetic phase. Necessary experimental conditions are specified in which pre-stimulus phase estimation is meaningfully possible based on instantaneous amplitude and signal-to-noise ratio of the oscillation of interest. An open source toolbox is made available for causal (using pre-stimulus signal only) phase estimation along with a EEG dataset consisting of recordings from 140 participants and a best practices workflow for algorithm optimization and benchmarking. As an illustration, post-hoc sorting of open-loop transcranial magnetic stimulation (TMS) trials according to pre-stimulus sensorimotor μ-rhythm phase is performed to demonstrate modulation of corticospinal excitability, as indexed by the amplitude of motor evoked potentials.

Attention strengthens across-trial pre-stimulus phase coherence in visual cortex, enhancing stimulus processing

Attention selectively routes the most behaviorally relevant information from the stream of sensory inputs through the hierarchy of cortical areas. Previous studies have shown that visual attention depends on the phase of oscillatory brain activities. These studies mainly focused on the stimulus presentation period, rather than the pre-stimulus period. Here, we hypothesize that selective attention controls the phase of oscillatory neural activities to efficiently process relevant information. We document an attentional modulation of pre-stimulus inter-trial phase coherence (a measure of deviation between instantaneous phases of trials) of low frequency local field potentials (LFP) in visual area MT of macaque monkeys. Our data reveal that phase coherence increases following a spatial cue deploying attention towards the receptive field of the recorded neural population. We further show that the attentional enhancement of phase coherence is positively correlated with the modulation of the stimulus-induced firing rate, and importantly, a higher phase coherence is associated with a faster behavioral response. These results suggest a functional utilization of intrinsic neural oscillatory activities for an enhanced processing of upcoming stimuli.

Consistent pre-stimulus influences on auditory perception across the lifespan

As we get older, perception in cluttered environments becomes increasingly difficult as a result of changes in peripheral and central neural processes. Given the aging society, it is important to understand the neural mechanisms constraining perception in the elderly. In young participants, the state of rhythmic brain activity prior to a stimulus has been shown to modulate the neural encoding and perceptual impact of this stimulus – yet it remains unclear whether, and if so, how, the perceptual relevance of pre-stimulus activity changes with age. Using the auditory system as a model, we recorded EEG activity during a frequency discrimination task from younger and older human listeners. By combining single-trial EEG decoding with linear modelling we demonstrate consistent statistical relations between pre-stimulus power and the encoding of sensory evidence in short-latency EEG components, and more variable relations between pre-stimulus phase and subjects’ decisions in longer-latency components. At the same time, we observed a significant slowing of auditory evoked responses and a flattening of the overall EEG frequency spectrum in the older listeners. Our results point to mechanistically consistent relations between rhythmic brain activity and sensory encoding that emerge despite changes in neural response latencies and the relative amplitude of rhythmic brain activity with age.

The phase of pre-stimulus brain oscillations correlates with cross-modal synchrony perception.

In everyday life multisensory events, such as a glass crashing on the floor, the different sensory inputs are often experienced as simultaneous, despite the sensory processing of sound and sight within the brain are temporally misaligned. This lack of cross-modal synchrony is the unavoidable consequence of different light and sound speeds, and their different neural transmission times in the corresponding sensory pathways. Hence, cross-modal synchrony must be reconstructed during perception. It has been suggested that spontaneous fluctuations in neural excitability might be involved in the temporal organisation of sensory events during perception and account for variability in behavioural performance. Here, we addressed the relationship between ongoing brain oscillations and the perception of cross-modal simultaneity. Participants performed an audio-visual simultaneity judgement task while their EEG was recorded. We focused on pre-stimulu activity, and found that the phase of neural oscillations at 13±2Hz 200ms prior to the stimulus correlated with subjective simultaneity of otherwise identical sound-flash events. Remarkably, the correlation between EEG phase and behavioural report occurred in the absence of concomitant changes in EEG amplitude. The probability of simultaneity perception fluctuated significantly as a function of pre-stimulus phase, with the largest perceptual variation being accounted for phase angles nearly 180º apart. This pattern was strongly reliable for sound-flash pairs but not for flash-sound pairs. Overall, these findings suggest that the phase of ongoing brain activity might underlie internal states of the observer that influence cross-modal temporal organisation between the senses and, in turn, subjective synchrony.

Exploring the relationship of phase and peak-frequency EEG alpha-band and beta-band activity to temporal judgments of stimulus duration

ABSTRACTPre-stimulus phase has been shown to influence temporal judgments concerning order, causality and simultaneity. One hypothesis is that phase cycles frame discrete perceptual snapshots over time. Yet, existing studies have explored the effect of pre-stimulus phase on fine-grained temporal judgments whereas no study has shown whether pre-stimulus phase influences sub-second temporal judgments lasting several phase cycles. If effects of phase on fine-grained temporal judgments reflect perceptual framing, then the perception of longer intervals might show some dependency on the frequency of phase cycles. Higher frequencies should promote increased temporal resolution and discrimination. We tested the relationship between the phase and frequency of oscillations and temporal judgments for longer durations. Participants judged the relative duration of two successive intervals lasting several phase cycles each. Pre-stimulus alpha-band and beta-band phase was associated with subsequent temporal judgments, although not sensitivity, therein providing evidence that pre-stimulus phase is related to temporal judgments that span a longer time-scale than has been previously demonstrated. Although we report evidence that peak-frequency of the alpha-band is related to one measure of task performance, this study does not provide evidence that higher peak frequencies of alpha- or beta-band activity are related to improved duration discrimination of longer intervals.

The rhythms of predictive coding? Pre-stimulus phase modulates the influence of shape perception on luminance judgments

Predictive coding is an influential model emphasizing interactions between feedforward and feedback signals. Here, we investigated the temporal dynamics of these interactions. Two gray disks with different versions of the same stimulus, one enabling predictive feedback (a 3D-shape) and one impeding it (random-lines), were simultaneously presented on the left and right of fixation. Human subjects judged the luminance of the two disks while EEG was recorded. The choice of 3D-shape or random-lines as the brighter disk was used to assess the influence of feedback signals on sensory processing in each trial (i.e., as a measure of post-stimulus predictive coding efficiency). Independently of the spatial response (left/right), we found that this choice fluctuated along with the pre-stimulus phase of two spontaneous oscillations: a ~5 Hz oscillation in contralateral frontal electrodes and a ~16 Hz oscillation in contralateral occipital electrodes. This pattern of results demonstrates that predictive coding is a rhythmic process, and suggests that it could take advantage of faster oscillations in low-level areas and slower oscillations in high-level areas.

Oscillatory phase shapes syllable perception

The role of oscillatory phase for perceptual and cognitive processes is being increasingly acknowledged. To date, little is known about the direct role of phase in categorical perception. Here we show in two separate experiments that the identification of ambiguous syllables that can either be perceived as /da/ or /ga/ is biased by the underlying oscillatory phase as measured with EEG and sensory entrainment to rhythmic stimuli. The measured phase difference in which perception is biased toward /da/ or /ga/ exactly matched the different temporal onset delays in natural audiovisual speech between mouth movements and speech sounds, which last 80 ms longer for /ga/ than for /da/. These results indicate the functional relationship between prestimulus phase and syllable identification, and signify that the origin of this phase relationship could lie in exposure and subsequent learning of unique audiovisual temporal onset differences.

Functional Connectivity of EEG Signals Under Laser Stimulation in Migraine.

In previous studies, migraine patients showed abnormalities in pain-related evoked responses, as reduced habituation to repetitive stimulation. In this study, we aimed to apply a novel analysis of EEG bands synchronization and directed dynamical influences under painful stimuli in migraine patients compared to non-migraine healthy volunteers. Thirty-one migraine without aura outpatients (MIGR) were evaluated and compared to 19 controls (CONT). The right hand was stimulated by means of 30 consecutive CO2 laser stimuli. EEG signal was examined by means of Morlet wavelet, synchronization entropy (SE), and Granger causality (GC), and the statistically validated results were mapped on the corresponding scalp locations. The vertex complex of averaged laser-evoked responses (LEPs) showed reduced habituation compared to CONT. In the prestimulus phase, enhanced SE in the 0, 5–30 Hz range was present in MIGR and CONT between the bilateral temporal–parietal and the frontal regions around the midline. Migraine patients showed an anticipation of EEG changes preceding the painful stimulation compared to CONT. In the poststimulus phase, the same cortical areas were more connected in MIGR vs CONT. In both groups of patients and CONT, the habituation index was negatively correlated with the GC scores. A different pattern of cortical activation after painful stimulation was present in migraine. The increase in cortical connections during repetitive painful stimulation may subtend the phenomenon of LEPs reduced habituation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in migraine patients.

Migraine and functional connectivity: an innovative pathophysiological perspective.

Migraine is a chronic disorder of neuro-vascular origin, characterized by abnormal neuronal excitability and altered processing of multimodal stimuli. Methods able to detect subtle changes of EEG rhythms under painful stimulation may improve the knowledge of mechanisms of pain processing in normal subjects and patients with chronic pain syndromes. The study of the dynamical relationships between signals recorded at different scalp locations can help to confirm and formulate hypotheses on the physiological mechanisms related to stimuli processing. Correlations, spectral coherence and phase synchronization, which allow to understand the extent to which two variables are statistically connected or shared, influenced by a third variable, together with analyses of the directionality of these dynamical interactions, may potentially contribute to understanding the mechanism of pain processing in migraine. Functional and effective connectivity in terms of synchronization and information transfer were able to reveal differences in visual reactivity between migraine patients and controls, so these methods may presumably outline a different way to process nociceptive laser stimuli in migraine, giving further knowledge on how the cortex changes its inter-connections under painful inputs. Thirty-one migraine without aura outpatients (MwoA) were evaluated and compared to 19 controls (CONT). The right hand was stimulated by means of 30 consecutive CO2 laser stimuli. EEG signal was examined by means of Morlet wavelet, synchronization entropy and Granger causality, and the statistic results embedded into a scalp model. The vertex complex of averaged laser evoked responses (LEPs) showed reduced habituation compared to controls. In the pre-stimulus phase enhanced synchronization entropy in the 0, 5-30 Hz range was present in MwoA and CONT between the bilateral temporal parietal and the frontal regions around the midline. Migraine patients showed an anticipation of EEG changes preceding the painful stimulation compared to controls. In the post-stimulus phase, the same cortical areas were more connected in MwoA vs CONT. In the totality of patients and controls, the habituation index was negatively correlated with the Granger Causality scores. A different pattern of cortical activation after painful stimulation was present in migraine. The increase in cortical connections during repetitive painful stimulation may subtend the phenomenon of LEPs reduced habituation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in migraine patients. Written informed consent to publication was obtained from the patient(s).

Experimentally induced stress validated by EMG activity.

Experience of stress may lead to increased electromyography (EMG) activity in specific muscles compared to a non-stressful situation. The main aim of this study was to develop and validate a stress-EMG paradigm in which a single uncontrollable and unpredictable nociceptive stimulus was presented. EMG activity of the trapezius muscles was the response of interest. In addition to linear time effects, non-linear EMG time courses were also examined. Taking into account the hierarchical structure of the dataset, a multilevel random regression model was applied. The stress paradigm, executed in N = 70 subjects, consisted of a 3-minute baseline measurement, a 3-minute pre-stimulus stress period and a 2-minute post-stimulus phase. Subjects were unaware of the precise moment of stimulus delivery and its intensity level. EMG activity during the entire experiment was conform a priori expectations: the pre-stimulus phase showed a significantly higher mean EMG activity level compared to the other two phases, and an immediate EMG response to the stimulus was demonstrated. In addition, the analyses revealed significant non-linear EMG time courses in all three phases. Linear and quadratic EMG time courses were significantly modified by subjective anticipatory stress level, measured just before the start of the stress task. Linking subjective anticipatory stress to EMG stress reactivity revealed that subjects with a high anticipatory stress level responded with more EMG activity during the pre-stimulus stress phase, whereas subjects with a low stress level showed an inverse effect. Results suggest that the stress paradigm presented here is a valid test to quantify individual differences in stress susceptibility. Further studies with this paradigm are required to demonstrate its potential use in mechanistic clinical studies.