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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Treatment preferences in fibromyalgia patients: A cross-sectional web-based survey.

BACKGROUND: Therapeutic approaches to fibromyalgia (FM) are shifting towards a combined multi-treatment approach to tackle the variety of symptoms experienced in FM. Importantly, little is known about FM patients' attitude towards the available treatments. METHODS: A cross-sectional web survey obtained responses from 464 individuals who satisfied diagnostic criteria for FM. Respondents were asked to report which treatments they adopted in their past, present and intend to adopt in the future. They also rated their level of well-being, depression, anxiety and pain catastrophizing. RESULTS: Data revealed a predominantly combined multi-treatment approach in a sample characterized by middle-aged, Caucasian women. Respondents reported pervasive use of pharmacological therapy but had also adopted non-pharmacological treatment in the past. Future intentions clustered on alternative treatment or no treatment. Regression analyses revealed that pharmacological treatment in the past was predictive of both pharmacological and non-pharmacological treatments in the present. However, use of non-pharmacological treatment in the past was uniquely predictive of its reuse in the present and future. This pattern was also accounted for by individual differences in pain magnification and well-being in the past. CONCLUSIONS: Treatment preferences of FM individuals reveal an ambivalent combination of heavy reliance on pharmacological treatment with lower but consistent reliance on non-pharmacological treatment for those individuals who used it in the past and present. This finding may inform longitudinal research into the relationship between pharmacological and non-pharmacological treatment preference in FM patients, which could in turn inform guidelines for individualized therapeutic plans for clinicians. SIGNIFICANCE: Individuals with fibromyalgia reported the use of non-pharmacological and pharmacological treatments in the past but a predominant use of a pharmacological approach overall. Patterns of treatment experienced in the past were differentially related to future preferences. Pharmacological treatment in the past was likely to lead to both pharmacological and non-pharmacological choices in the present. However, non-pharmacological treatment in the past was more likely to be chosen again in the present and future, but unlikely to lead to a pharmacological choice.

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.

Visual cues of threat elicit greater steady-state electroencephalographic responses than visual reminders of death.

Terror management theory (TMT) suggests that reminders of death activate an exclusive anxiety mechanism different from the one activated by other types of symbolic threats. This notion is supported by evidence showing how experimental participants verbally reflecting on their own death are then influenced in their opinions and behaviours. A previous study showed that magnitude of electroencephalography (EEG) activity is greater when images depicting death-related content are coupled with painful thermal stimuli compared to threat-related content. Here we expand on previous research by testing whether similar effects may be brought about by passive observation of generic visual reminders of death. More precisely, we hypothesised that fast periodic presentation of death-related vs. more generic threat-related images determine a preferential modulation of brain activity measured by means of EEG. In two experiments, we found that images depicting death content elicit lower frequency-tagged EEG response compared to more generic threat images. Visual evoked potentials revealed that a brief change of the scene from neutral to threat content elicits greater amplitude at the late latencies (compatible with a P300 potential), particularly at the parieto-occipital sites. Altogether, our findings suggest that, in a context where no reflection on death cues is allowed and no threatening stimuli in other modality occur, visual death cues trigger lower neural synchronisation than that elicited by similarly negative and arousing cues with divergent threatening meaning.

Visual reminders of death enhance nociceptive-related cortical responses and event-related alpha desynchronisation.

Previous research suggests that prompting individuals to think on their own mortality affects their perception of painful somatic stimuli and related brain activity. Grounded on the assumption that reminders of mortality may recruit threat-defence mechanisms similar to the ones activated by painful nociceptive stimuli, we hypothesize that the effects exerted by linguistic reminders of death on pain perception and brain activity would be elicited by passive observation of death-related pictures vs. more generic threat-related pictures. Results showed an increase of the laser evoked P2 amplitude and oscillatory theta activity when participants observed death-related images. However, no change in pain ratings was found. Moreover, observation of death-related content was linked to increased oscillatory alpha desynchronisation but not to variations of visual evoked potentials amplitude. Our findings indicate that pairing potentially noxious stimuli with death-related images exerts a preferential modulation of nociceptive and visual cortical representations.

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.

Seeing One's Own Painful Hand Positioned in the Contralateral Space Reduces Subjective Reports of Pain and Modulates Laser Evoked Potentials.

UNLABELLED: Studies report that viewing the body or keeping one's arms crossed while receiving painful stimuli may have an analgesic effect. Interestingly, changes in ratings of pain are accompanied by a reduction of brain metabolism or of laser evoked potentials amplitude. What remains unknown is the link between visual analgesia and crossed-arms related analgesia. Here, we investigated pain perception and laser evoked potentials in 3 visual contexts while participants kept their arms in a crossed or uncrossed position during vision of 1) one's own hand, 2) a neutral object in the same spatial location, and 3) a fixation cross placed in front of the participant. We found that having vision of the affected body part in the crossed-arms position was associated with a significant reduction in pain reports. However, no analgesic effect of having vision of the hand in an uncrossed position or of crossing the arms alone was found. The increase of the late vertex laser evoked potential P2 amplitude indexed a general effect of vision of the hand. Our results hint at a complex interaction between cross-modal input and body representation in different spatial frames of reference and at the same time question the effect of visual analgesia and crossed-arms analgesia alone. PERSPECTIVE: We found that nociceptive stimuli delivered to the hand in a crossed-arms position evoke less pain than in a canonical anatomic position. Yet we report no significant analgesic effect of vision or crossing the arms on their own. These findings foster the integration of visuospatial and proprioceptive information in rehabilitation protocols.

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.