The independence and predictivity of resting pain-free slow alpha frequency as a biomarker of pain: A reply to Mazaheri et al.

In response to Mazaheri et al.'s critique, we revisited our study (Valentini et al., 2022) on the relationship between peak alpha frequency (PAF) and pain. Their commentary prompted us to reassess our data to address the independence between slow and slowing alpha brain oscillations, as well as the predictivity of slow alpha oscillations in pain perception. Bayesian correlation analyses revealed mixed support for independence. Investigating predictivity, we found inconsistent associations between pre-PAF and unpleasantness ratings. We critically reflected on methodological and theoretical issues on the path to PAF validation as a pain biomarker. We emphasized the need for diversified methodology and analytical approaches as well as robust findings across research groups.

Interindividual variability and individual stability of pain- and touch-related neuronal gamma oscillations.

Brief painful laser and innocuous tactile stimuli have been associated with an increase of neuronal oscillations in the gamma range. Although it is indicated that event-related gamma oscillations may be highly variable across individuals, to date no study has systematically investigated interindividual variability and individual stability of induced gamma synchronization. Here, we addressed this question using two EEG datasets. The first dataset contains two repeated sessions of tactile and painful stimulation from 22 participants. The second dataset contains a single session of painful stimulation from 48 participants. In the first dataset, we observed gamma responses in the majority of the included participants. We found a broad interindividual variety of gamma magnitudes, time-frequency (TF) response patterns, and scalp topographies. Some participants showed a gamma response with individually unique time-frequency patterns, others did not exhibit any gamma response. This was reproducible and therefore stable; subjects with a large gamma magnitude in the first session showed a large gamma magnitude and a similar response pattern in the follow-up session. The second dataset confirmed the large between-subject variability, but only a fraction of the included participants exhibited laser-induced gamma synchronization. Our results indicate that current EEG measures do not reflect the complex reality of the diverse individual response patterns to brief pain and touch experiences. The present findings question whether a similar phenomenon would be observed in other neuroscience domains. Group results may be replicable, but could be driven by a subgroup of the sample.NEW & NOTEWORTHY The interpretation of gamma activity in response to noxious and innocuous somatosensory stimuli has sparked controversy. Here, we show that participants' gamma oscillations measured through electroencephalography vary. Although some participants do not show a distinct gamma response, others exhibit stable and reliable response patterns in terms of time, frequency, and magnitude.

Assessing the specificity of the relationship between brain alpha oscillations and tonic pain.

Recent research proposed that the slowing of individual alpha frequency (IAF) could be an objective marker of pain. However, it is unclear whether this research can fully address the requirements of specificity and sensitivity of IAF to the pain experience. Here, we sought to develop a robust methodology for assessing the specificity of the relationship between alpha oscillations and acute tonic pain in healthy individuals. We recorded electroencephalography (EEG) of 36 volunteers during consecutive 5-minute sessions of painful hot water immersion, innocuous warm water immersion and aversive, non-painful auditory stimulus, matched by unpleasantness to the painful condition. Participants rated stimulus unpleasantness throughout each condition. We isolated two regions of the scalp displaying peak alpha activity across participants: centro-parietal (CP) and parieto-occipital (PO) ROI. In line with previous research our findings revealed decreased IAF during hot compared with warm stimulation, however the effect was not specific for pain as we found no difference between hot and sound in the CP ROI (compared to baseline). In contrast, the PO ROI reported the same pattern of differences, but their direction was opposite to the CP in that this ROI revealed faster frequency during hot condition than controls. Finally, we show that IAF in both ROIs did not mediate the relationship between the experimental manipulation and the affective experience. Altogether, these findings emphasize the importance of a robust methodological and analytical design to disclose the functional role of alpha oscillations during affective processing. Likewise, they suggest the absence of a causal role of IAF in the generation of acute pain experience in healthy individuals.

Timing of repetition suppression of event-related potentials to unattended objects.

Current theories of object perception emphasize the automatic nature of perceptual inference. Repetition suppression (RS), the successive decrease of brain responses to repeated stimuli, is thought to reflect the optimization of perceptual inference through neural plasticity. While functional imaging studies revealed brain regions that show suppressed responses to the repeated presentation of an object, little is known about the intra-trial time course of repetition effects to everyday objects. Here, we used event-related potentials (ERPs) to task-irrelevant line-drawn objects, while participants engaged in a distractor task. We quantified changes in ERPs over repetitions using three general linear models that modeled RS by an exponential, linear, or categorical "change detection" function in each subject. Our aim was to select the model with highest evidence and determine the within-trial time-course and scalp distribution of repetition effects using that model. Model comparison revealed the superiority of the exponential model indicating that repetition effects are observable for trials beyond the first repetition. Model parameter estimates revealed a sequence of RS effects in three time windows (86-140, 322-360, and 400-446 ms) and with occipital, temporoparietal, and frontotemporal distribution, respectively. An interval of repetition enhancement (RE) was also observed (320-340 ms) over occipitotemporal sensors. Our results show that automatic processing of task-irrelevant objects involves multiple intervals of RS with distinct scalp topographies. These sequential intervals of RS and RE might reflect the short-term plasticity required for optimization of perceptual inference and the associated changes in prediction errors and predictions, respectively, over stimulus repetitions during automatic object processing.

Painful engrams: Oscillatory correlates of working memory for phasic nociceptive laser stimuli.

Research suggests that working memory (WM) is impaired in chronic pain. Yet, information on how potentially noxious stimuli are maintained in memory is limited in patients as well as in healthy people. We recorded electroencephalography (EEG) in healthy volunteers during a modified delayed match-to-sample task where maintenance in memory of relevant attributes of nociceptive laser stimuli was essential for subsequent cued-discrimination. Participants performed in high and low load conditions (i.e. three vs. two stimuli to keep in WM). Modulation of EEG oscillations in the beta band during the retention interval and in the alpha band during the pre-retention interval reflected performance in the WM task. Importantly, both a non-verbal and a verbal neuropsychological WM test predicted oscillatory modulations. Moreover, these two neuropsychological tests and self-reported personality measures predicted the performance in the nociceptive WM task. Results demonstrate (i) that beta and alpha EEG oscillations can represent WM for nociceptive stimuli; (ii) the association between neuropsychological measures of WM and the brain representation of phasic nociceptive painful stimuli; and (iii) that personality factors can predict memory for nociceptive stimuli at the behavioural level. Altogether, our findings offer a promising approach for investigating cortical correlates of nociceptive memory in clinical pain conditions.

Mortality salience modulates cortical responses to painful somatosensory stimulation: Evidence from slow wave and delta band activity.

Social psychology studies show that awareness of one's eventual death profoundly influences human cognition and behaviour by inducing defensive reactions against end-of-life-related anxiety. Much less is known about the impact of reminders of mortality on brain activity. Here we tested whether reminders of mortality can induce a modulation of the slow electroencephalographic activity triggered by somatosensory nociceptive or auditory threatening stimulation and if this modulation is related to mood and anxiety as well as personality traits. We found a specific slow wave (SW) modulation only for nociceptive stimulation and only following mortality salience induction (compared to reminders of an important failed exam). The enhancement of SW negativity at the scalp vertex was associated with increased state anxiety and negative mood, whereas higher self-esteem was associated with reduced SW amplitude. In addition, mortality salience was linked to an increased amplitude of frontal delta band, which was correlated also with increased positive mood and higher self-esteem. The results indicate that SW and delta spectral activity may represent both proximal and distal defences associated with reminders of death and that neurophysiological correlates of somatosensory representation of painful and threatening stimuli may be useful for existential neuroscience studies.

Functional features of crossmodal mismatch responses.

Research on brain mechanisms of deviance detection and sensory memory trace formation, best indexed by the mismatch negativity, mainly relied on the investigation of responses elicited by auditory stimuli. However, comparable less research reported the mismatch negativity elicited by somatosensory stimuli. More importantly, little is known on the functional features of mismatch deviant and standard responses across different sensory modalities. To directly compare different sensory modalities, we adopted a crossmodal roving paradigm and collected event-related potentials elicited by auditory, non-nociceptive somatosensory, and nociceptive trains of stimuli, during Active and Passive attentional conditions. We applied a topographical segmentation analysis to cluster successive scalp topographies with quasi-stable landscape of significant differences to extract crossmodal mismatch responses. We obtained three main findings. First, across different sensory modalities and attentional conditions, the formation of a standard sensory trace became robust mainly after the second stimulus repetition. Second, the neural representation of a modality deviant stimulus was influenced by the preceding sensory modality. Third, the mismatch negativity significantly covaried between Active and Passive attentional conditions within the same sensory modality, but not between different sensory modalities. These findings provide robust evidence that, while different modalities share a similar process of standard trace formation, the process of deviance detection is largely modality dependent.

Emotional conflict in a model modulates nociceptive processing in an onlooker: a laser-evoked potentials study.

Observing models displaying facial expressions of pain elicits neural activity in onlookers' neural structures involved in first-hand experience of pain and in monitoring conflicting information. We investigated whether the purported conflict between the pain and its emotional expression in a model modulates cortical responses elicited by nociceptive laser stimuli in an onlooker. Seeing happy facial expressions, incongruent with the perceptual status attributed to the model, determined a significant reduction in the laser-evoked N2 potential. One of the main sources of this response is the anterior cingulate cortex, an area involved in pain perception, empathy for pain and conflict detection. A pre-activation of the anterior cingulate cortex due to the detection of the emotional conflict may, therefore, be responsible for the reduction of nociceptive-related response in the same brain area. Thus, top-down variables, like the appraisal of the others' emotional status, modulate onlookers' nociceptive-related neural activity.

Reminders of Mortality: Investigating the Effects of Different Mortality Saliences on Somatosensory Neural Activity.

The Terror Management Theory (TMT) offered a great deal of generative hypotheses that have been tested in a plethora of studies. However, there is a still substantive lack of clarity about the interpretation of TMT-driven effects and their underlying neurological mechanisms. Here, we aimed to expand upon previous research by introducing two novel methodological manipulations aimed to enhance the effects of mortality salience (MS). We presented participants with the idea of the participants' romantic partner's death as well as increased the perceived threat of somatosensory stimuli. Linear mixed modelling disclosed the greater effects of MS directed at one's romantic partner on pain perception (as opposed to the participant's own mortality). The theta event-related oscillatory activity measured at the vertex of the scalp was significantly lower compared to the control condition. We suggest that MS aimed at one's romantic partner can result in increased effects on perceptual experience; however, the underlying neural activities are not reflected by a classical measure of cortical arousal.

Validation of Cross-Individual Pain Assessment with Individual Recognition Model from Electroencephalogram.

Cross-individual pain assessment models based on electroencephalography (EEG) allow pain assessment in individuals who cannot report pain (e.g., unresponsive patients). The main obstacle to the generalisation of pain assessment models is the individual variation of brain responses to pain. Hence, we took the individual variation into account in cross-individual model development. We developed two convolutional neural networks (CNN) sharing an encoder architecture. One CNN predicts pain, while the other predicts the identity of an individual. We performed a leave-one-out (LOO) test with the exclusion of each subject and applied evidence accumulation to it for validating the pain prediction model's performance, where the binary classifier involves the states of pain (Hot) and resting state (Eyes-open). The mean accuracy produced by the LOO tests was 57.81% (max: 73.33%), and the mean accuracy of evidence accumulation achieved 69.75% (max: 100.00%). The individual recognition model achieved an accuracy of 99.63%. Nevertheless, when we acquired the most similar subject to a novel subject using the individual recognition model, where the most similar subject was used to train a subject-wise pain prediction model. The accuracy of predicting the pain-related conditions of the novel subject by the subject-wise model was only 53.73% (max: 79.50%). Therefore, the approach to utilising the features related to individual variation extracted by the CNN model needs more investigation for improving cross-individual pain assessment.Clinical relevance- This model can be applied to assess pain from EEG signals at the bedside with future improvement, which can help caretakers of unresponsive patients.

Should I trust you? Investigating trustworthiness judgements of painful facial expressions.

Past research indicates that patients' reports of pain are often met with skepticism and that observers tend to underestimate patients' pain. The mechanisms behind these biases are not yet fully understood. One relevant domain of inquiry is the interaction between the emotional valence of a stranger's expression and the onlooker's trustworthiness judgment. The emotion overgeneralization hypothesis posits that when facial cues of valence are clear, individuals displaying negative expressions (e.g., disgust) are perceived as less trustworthy than those showing positive facial expressions (e.g., happiness). Accordingly, we hypothesized that facial expressions of pain (like disgust) would be judged more untrustworthy than facial expressions of happiness. In two separate studies, we measured trustworthiness judgments of four different facial expressions (i.e., neutral, happiness, pain, and disgust), displayed by both computer-generated and real faces, via both explicit self-reported ratings (Study 1) and implicit motor trajectories in a trustworthiness categorization task (Study 2). Ratings and categorization findings partly support our hypotheses. Our results reveal for the first time that when judging strangers' facial expressions, both negative expressions were perceived as more untrustworthy than happy expressions. They also indicate that facial expressions of pain are perceived as untrustworthy as disgust expressions, at least for computer-generated faces. These findings are relevant to the clinical setting because they highlight how overgeneralization of emotional facial expressions may subtend an early perceptual bias exerted by the patient's emotional facial cues onto the clinician's cognitive appraisal process.

Fine-grained analysis of shared neural circuits between perceived and observed pain: implications for the study of empathy for pain.

Feeling pain and seeing it in others activates largely overlapping neural substrates. A recent study (Corradi-Dell'Acqua C, Hofstetter C, Vuilleumier P. J Neurosci 31: 17996-18006, 2011) for the first time raises the question of whether shared neural activations specifically code pain-related contents or merely their negative-aversive implication. The authors conclude that mid-insula and mid-cingulate share information specific to the presence of pain, whereas anterior insula shares information about its aversive content. We suggest that, together with valence and arousal, the control of saliency and threat may have an important heuristic potential in the study of empathy for pain.

Seeing touch and pain in a stranger modulates the cortical responses elicited by somatosensory but not auditory stimulation.

Viewing other's pain inhibits the excitability of the motor cortex and also modulates the neural activity elicited by a concomitantly delivered nociceptive somatosensory stimulus. As the neural activity elicited by a transient nociceptive stimulus largely reflects non nociceptive-specific, multimodal neural processes, here we tested, for the first time, whether the observation of other's pain preferentially affects the brain responses elicited by nociceptive stimulation, or instead similarly modulates those elicited by stimuli belonging to a different sensory modality. Using 58-channel electroencephalography (EEG), we recorded the cortical responses elicited by laser and auditory stimulation during the observation of videoclips showing either noxious or non-noxious stimulation of a stranger's hand. We found that the observation of other's pain modulated the cortical activity consisting in an event-related desynchronization in the ß band (ß ERD), and elicited by nociceptive laser stimuli, but not by auditory stimuli. Using three different source analysis approaches, we provide converging evidence that such modulation affected neural activity in the contralateral primary sensorimotor cortex. The magnitude of this modulation correlated well with a subjective measure of similarity between the model's hand and the onlooker's representation of the hand. Altogether, these findings demonstrate that the observation of other's pain modulates, in a somatosensory-specific fashion, the cortical responses elicited by nociceptive stimuli in the sensorimotor cortex contralateral to the stimulated hand.

Classification of Tonic Pain Experience based on Phase Connectivity in the Alpha Frequency Band of the Electroencephalogram using Convolutional Neural Networks.

The complexity of brain activity involved in the generation of the experience of pain makes it hard to identify neural markers able to predict pain states. The within and between subjects variability of pain hinders the predictive potential of machine learning models trained across participants. This challenge can be tackled by implementing deep learning classifiers based on convolutional neural networks (CNNs). We targeted phase-based connectivity in the alpha band recorded with electroencephalography (EEG) during resting states and sensory conditions (eyes open [O] and closed [C] as resting states, and warm [W] and hot [H] water as sensory conditions). Connectivity features were extracted and re-organized as square matrices, because CNNs are effective in detecting the patterns from 2D data. To assess the classifier performance we implemented two complementary approaches: we 1) trained and tested the classifier with data from all participants, and 2) using a leave-one-out approach, that is excluding one participant at a time during training while using their data as a test set. The accuracy of binary classification between pain condition (H) and eyes open resting state (O) was 94.16% with the first approach, and 61.01 % with the leave-one-out approach. Clinical relevance-Further validation of the CNN classifier may help caregivers track the rehabilitation of chronic pain patients and dynamically modify the therapy. Further refinement of the model may allow its application in critical care setting with unresponsive patients to identify pain-like states otherwise incommunicable to medical personnel.

The biospheric emergency calls for scientists to change tactics.

Our current economic and political structures have an increasingly devastating impact on the Earth's climate and ecosystems: we are facing a biospheric emergency, with catastrophic consequences for both humans and the natural world on which we depend. Life scientists - including biologists, medical scientists, psychologists and public health experts - have had a crucial role in documenting the impacts of this emergency, but they have failed to drive governments to take action in order to prevent the situation from getting worse. Here we, as members of the movement Scientist Rebellion, call on life scientists to re-embrace advocacy and activism - which were once hallmarks of academia - in order to highlight the urgency and necessity of systemic change across our societies. We particularly emphasise the need for scientists to engage in nonviolent civil resistance, a form of public engagement which has proven to be highly effective in social struggles throughout history.

Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus modality.

The repetition of nociceptive stimuli of identical modality, intensity, and location at short and constant interstimulus intervals (ISIs) determines a strong habituation of the corresponding EEG responses, without affecting the subjective perception of pain. To understand what determines this response habituation, we (i) examined the effect of introducing a change in the modality of the repeated stimulus, and (ii) dissected the relative contribution of bottom-up, stimulus-driven changes in modality and top-down, cognitive expectations of such a change, on both laser-evoked and auditory-evoked EEG responses. Multichannel EEG was recorded while participants received trains of three stimuli (S1-S2-S3, a triplet) delivered to the hand dorsum at 1-sec ISI. S3 belonged either to the same modality as S1 and S2 or to the other modality. In addition, participants were either explicitly informed or not informed of the modality of S3. We found that introducing a change in stimulus modality produced a significant dishabituation of the laser-evoked N1, N2, and P2 waves; the auditory N1 and P2 waves; and the laser- and auditory-induced event-related synchronization and desynchronization. In contrast, the lack of explicit knowledge of a possible change in the sensory modality of the stimulus (i.e., uncertainty) only increased the ascending portion of the laser-evoked and auditory-evoked P2 wave. Altogether, these results indicate that bottom-up novelty resulting from the change of stimulus modality, and not top-down cognitive expectations, plays a major role in determining the habituation of these brain responses.

Republished review: systematic review and meta-analysis of psychomotor effects of mobile phone electromagnetic fields.

OBJECTIVES Over the past 10 years there has been increasing concern about the possible behavioural effects of mobile phone use. This systematic review and meta-analysis focuses on studies published since 1999 on the human cognitive and performance effects of mobile phone-related electromagnetic fields (EMF). METHODS PubMed, Biomed, Medline, Biological Sciences, PsychInfo, PsycARTICLES, Environmental Sciences and Pollution Management, Neurosciences Abstracts and Web of Science professional databases were searched and 24 studies selected for meta-analysis. Each study had to have at least one psychomotor measurement result as a main outcome. Data were analysed using standardised mean difference (SMD) as the effect size measure. RESULTS Only three tasks (2-back, 3-back and simple reaction time (SRT)) displayed significant heterogeneity, but after studies with extreme SMD were excluded using sensitivity analysis, the statistical significance disappeared (χ(2)(7)=1.63, p=0.20; χ(2)(6)=1.00, p=0.32; χ(2)(10)=14.04, p=0.17, respectively). Following sensitivity analysis, the effect of sponsorship and publication bias were assessed. Meta-regression indicated a significant effect (b1/40.12, p<0.05) only for the 2-back task with mixed funding (industry and public/charity). Funnel plot inspection revealed a significant publication bias only for two cognitive tasks: SRT (Begg's rank correlation r=0.443; Egger's test b=-0.652) and the subtraction task (Egger's test b=-0.687). CONCLUSIONS Mobile phone-like EMF do not seem to induce cognitive and psychomotor effects. Nonetheless, the existence of sponsorship and publication biases should encourage WHO intervention to develop official research standards and guidelines. In addition, future research should address critical and neglected issues such as investigation of repeated, intensive and chronic exposures, especially in highly sensitive populations such as children.

A novel tool for the removal of muscle artefacts from EEG: Improving data quality in the gamma frequency range.

BACKGROUND: The past two decades have seen a particular focus towards high-frequency neural activity in the gamma band (>30 Hz). However, gamma band activity shares frequency range with unwanted artefacts from muscular activity. NEW METHOD: We developed a novel approach to remove muscle artefacts from neurophysiological data. We re-analysed existing EEG data that were decomposed by a blind source separation method (independent component analysis, ICA), which helped to better spatially and temporally separate single muscle spikes. We then applied an adapting algorithm that detects these singled-out muscle spikes. RESULTS: We obtained data almost free from muscle artefacts; we needed to remove significantly fewer artefact components from the ICA and we included more trials for the statistical analysis compared to standard ICA artefact removal. All pain-related cortical effects in the gamma band have been preserved, which underlines the high efficacy and precision of this algorithm. CONCLUSIONS: Our results show a significant improvement of data quality by preserving task-relevant gamma oscillations of presumed cortical origin. We were able to precisely detect, gauge, and carve out single muscle spikes from the time course of neurophysiological measures without perturbing cortical gamma. We advocate the application of the tool for studies investigating gamma activity that contain a rather low number of trials, as well as for data that are highly contaminated with muscle artefacts. This validation of our tool allows for the application on event-free continuous EEG, for which the artefact removal is more challenging.

Seeming confines: Electrophysiological evidence of peripersonal space remapping following tool-use in humans.

The peripersonal space (PPS) is a special portion of space immediately surrounding the body, where the integration between tactile stimuli delivered on the body and auditory or visual events emanating from the environment occurs. Interestingly, PPS can widen if a tool is employed to interact with objects in the far space. However, electrophysiological evidence of such tool-use dependent plasticity in the human brain is scarce. Here, in a series of three experiments, participants were asked to respond to tactile stimuli, delivered to their right hand, either in isolation (unimodal condition) or combined with auditory stimulation, which could occur near (bimodal-near) or far from the stimulated hand (bimodal-far). According to multisensory integration spatial rule, when bimodal stimuli are presented at the same location, we expected a response enhancement (response time - RT - facilitation and event-related potential - ERP - super-additivity). In Experiment 1, we verified that RT facilitation was driven by bimodal input spatial congruency, independently from auditory stimulus intensity. In Experiment 2, we showed that our bimodal task was effective in eliciting the magnification of ERPs in bimodal conditions, with significantly larger responses in the near as compared to far condition. In Experiment 3 (main experiment), we explored tool-use driven PPS plasticity. Our audio-tactile task was performed either following tool-use (a 20-min reaching task, performed using a 145 cm-long rake) or after a control cognitive training (a 20-min visual discrimination task) performed in the far space. Following the control training, faster RTs and greater super-additive ERPs were found in bimodal-near as compared to bimodal-far condition (replicating Experiment 2 results). Crucially, this far-near differential response was significantly reduced after tool-use. Altogether our results indicate a selective effect of tool-use remapping in extending the boundaries of PPS. The present finding might be considered as an electrophysiological evidence of tool-use dependent plasticity in the human brain.

The role of anterior insula and anterior cingulate in empathy for pain.

The understanding of others' feelings and emotional states is commonly defined by the term empathy. Here, I discuss recent findings regarding the differential contribution of anterior insula and anterior cingulate cortices to this function. For the first time, Gu and colleagues (2010) showed no direct involvement of the anterior cingulate during observation of another's pain and proposed the anterior insula as the main neural substrate for the mental representation of empathy.