Unveiling the Role of Contingent Negative Variation (CNV) in Migraine: A Review of Electrophysiological Studies in Adults and Children.

Migraine has been considered a chronic neuronal-based pain disorder characterized by the presence of cortical hyperexcitability. The Contingent Negative Variation (CNV) is the most explored electrophysiological index in migraine. However, the findings show inconsistencies regarding its functional significance. To address this, we conducted a review in both adults and children with migraine without aura to gain a deeper understanding of it and to derive clinical implications. The literature search was conducted in the PubMed, SCOPUS and PsycINFO databases until September 2022m and 34 articles were retrieved and considered relevant for further analysis. The main results in adults showed higher CNV amplitudes (with no habituation) in migraine patients. Electrophysiological abnormalities, particularly focused on the early CNV subcomponent (eCNV), were especially prominent a few days before the onset of a migraine attack, normalizing during and after the attack. We also explored various modulatory factors, including pharmacological treatments-CNV amplitude was lower after the intake of drugs targeting neural hyperexcitability-and other factors such as psychological, hormonal or genetic/familial influences on CNV. Although similar patterns were found in children, the evidence is particularly scarce and less consistent, likely due to the brain's maturation process during childhood. As the first review exploring the relationship between CNV and migraine, this study supports the role of the CNV as a potential neural marker for migraine pathophysiology and the prediction of pain attacks. The importance of further exploring the relationship between this neurophysiological index and childhood migraine is critical for identifying potential therapeutic targets for managing migraine symptoms during its development.

Pain E-motion Faces Database (PEMF): Pain-related micro-clips for emotion research.

A large number of publications have focused on the study of pain expressions. Despite the growing knowledge, the availability of pain-related face databases is still very scarce compared with other emotional facial expressions. The Pain E-Motion Faces Database (PEMF) is a new open-access database currently consisting of 272 micro-clips of 68 different identities. Each model displays one neutral expression and three pain-related facial expressions: posed, spontaneous-algometer and spontaneous-CO2 laser. Normative ratings of pain intensity, valence and arousal were provided by students of three different European universities. Six independent coders carried out a coding process on the facial stimuli based on the Facial Action Coding System (FACS), in which ratings of intensity of pain, valence and arousal were computed for each type of facial expression. Gender and age effects of models across each type of micro-clip were also analysed. Additionally, participants' ability to discriminate the veracity of pain-related facial expressions (i.e., spontaneous vs posed) was explored. Finally, a series of ANOVAs were carried out to test the presence of other basic emotions and common facial action unit (AU) patterns. The main results revealed that posed facial expressions received higher ratings of pain intensity, more negative valence and higher arousal compared with spontaneous pain-related and neutral faces. No differential effects of model gender were found. Participants were unable to accurately discriminate whether a given pain-related face represented spontaneous or posed pain. PEMF thus constitutes a large open-source and reliable set of dynamic pain expressions useful for designing experimental studies focused on pain processes.

Working memory dysfunction in fibromyalgia is associated with genotypes of the catechol- O-methyltransferase gene: an event-related potential study.

Recent findings have associated different COMT genotypes with working memory capacity in patients with fibromyalgia. Although it is thought that the COMT gene may influence neural correlates (P2 and P3 ERP components) underlying working memory impairment in this chronic-pain syndrome, it has not yet been explored. Therefore, the aim of the present research was to investigate the potential effect of the COMT gene in fibromyalgia patients on ERP working memory indices (P2 and P3 components). For this purpose, 102 participants (51 patients and 51 healthy control participants) took part in the experiment. Event-related potentials and behavioral responses were recorded while participants performed a spatial n-back task. Participants had to decide if the stimulus coincided or not in the same location as the one presented one (1-back condition) or two (2-back condition) trials before. Genotypes of the COMT gene were determined through a saliva sample from all participants. Present results significantly showed lower working memory performance (p < 0.05) in patients with fibromyalgia as compared to control participants (higher rate of errors and slower reaction times). At neural level, we found that patients exhibited enhanced frontocentral and parieto-occipital P2 amplitudes compared to control participants (p < 0.05). Interestingly, we also observed that only fibromyalgia patients carrying the Val/Val genotype of the COMT gene showed higher frontocentral P2 amplitudes than control participants (p < 0.05). Current results (behavioral outcomes and P2 amplitudes) confirmed the presence of an alteration in working memory functioning in fibromyalgia. The enhancement of frontocentral P2 could be reflecting that these patients would manifest an inefficient way of activating executive attention processes, in carriers of the Val/Val genotype of COMT. To our knowledge, the present findings are the first linking neural indices of working memory dysfunctions and COMT genotypes in fibromyalgia. Applying a subgroup of patient's strategy based on this genetic marker could be useful to establish more tailored therapeutical approaches.

Electrophysiological indices of pain expectation abnormalities in fibromyalgia patients.

Fibromyalgia is a chronic pain syndrome characterized by dysfunctional processing of nociceptive stimulation. Neuroimaging studies have pointed out that pain-related network functioning seems to be altered in these patients. It is thought that this clinical symptomatology may be maintained or even strengthened because of an enhanced expectancy for painful stimuli or its forthcoming appearance. However, neural electrophysiological correlates associated with such attentional mechanisms have been scarcely explored. In the current study, expectancy processes of upcoming laser stimulation (painful and non-painful) and its further processing were explored by event-related potentials (ERPs). Nineteen fibromyalgia patients and twenty healthy control volunteers took part in the experiment. Behavioral measures (reaction times and subjective pain perception) were also collected. We manipulated the pain/no pain expectancy through an S1-S2 paradigm (cue-target). S1 (image: triangle or square) predicted the S2 appearance (laser stimulation: warmth or pinprick sensation). Laser stimuli were delivered using a CO2 laser device. Temporal and spatial principal component analyses were employed to define and quantify the ERP component reliability. Statistical analyses revealed the existence of an abnormal pattern of pain expectancy in patients with fibromyalgia. Specifically, our results showed attenuated amplitudes at posterior lCNV component in anticipation of painful stimulation that was not found in healthy participants. In contrast, although larger P2 amplitudes to painful compared to innocuous events were shown, patients did not show any amplitude change in this laser-evoked response as a function of pain predictive cues (as occurred in the healthy control group). Additionally, analyses of the subjective perception of pain and reaction time indicated that laser stimuli preceded by pain cues were rated as more painful than those signaling non-pain expectancy and were associated with faster responses. Differences between groups were not found. The present findings suggest the presence of dysfunction in pain expectation mechanisms in fibromyalgia that eventually may make it difficult for patients to correctly interpret signs that prevent pain symptoms. Furthermore, the abnormal pattern in pain expectancy displayed by fibromyalgia patients could result in ineffective pain coping strategies. Understanding the neural correlates of pain processing and its modulatory factors is crucial to identify treatments for chronic pain syndromes.

Neural correlates of the attentional bias towards pain-related faces in fibromyalgia patients: An ERP study using a dot-probe task.

BACKGROUND: One of the major cognitive deficits in fibromyalgia has been linked to the hypervigilance phenomenon. It is mainly reflected as a negative bias for allocating attentional resources towards both threatening and pain-related information. Although the interest in its study has recently grown, the neural temporal dynamics of the attentional bias in fibromyalgia still remains an open question. METHOD: Fifty participants (25 fibromyalgia patients and 25 healthy control subjects) performed a dot-probe task. Two types of facial expressions (pain-related and neutral) were employed as signal stimuli. Then, as a target stimulus, a single dot replaced the location of one of these two faces. Event-related potentials (ERP) in response to facial expressions and target stimulation (i.e., dot) were recorded. Reaction time (RT) and accuracy measures in the experimental task were collected as behavioural outcomes. RESULTS: Temporal dynamics of brain electrical activity were analysed on two ERP components (P2 and N2a) sensitive to the facial expressions meaning. Pain-related faces elicited higher frontal P2 amplitudes than neutral faces for the whole sample. Interestingly, an interaction effect between group and facial expressions was also found showing that pain-related faces elicited enhanced P2 amplitudes (at fronto-central regions, in this case) compared to neutral faces only when the group of patients was considered. Furthermore, higher P2 amplitudes were observed in response to pain-related faces in patients with fibromyalgia compared to healthy control participants. Additionally, a shorter latency of P2 (at centro-parietal regions) was also detected for pain-related facial expressions compared to neutral faces. Regarding the amplitude of N2a, it was lower for patients as compared to the control group. Non-relevant effects of the target stimulation on the ERPs were found. However, patients with fibromyalgia exhibited slower RT to locate the single dot for incongruent trials as compared to congruent and neutral trials. CONCLUSIONS: Data suggest the presence of an attentional bias in fibromyalgia that it would be followed by a deficit in the allocation of attentional resources to further process pain-related information. Altogether the current results suggest that attentional biases in fibromyalgia might be explained by automatic attentional mechanisms, which seem to be accompanied by an alteration of more strategic or controlled attentional components.

Altered Subprocesses of Working Memory in Patients with Fibromyalgia: An Event-Related Potential Study Using N-Back Task.

OBJECTIVE: Cognitive dysfunction in fibromyalgia has become a key symptom considered by patients as more disabling than pain itself. Experimental evidence from neuropsychological and neuroimaging studies indicates that such cognitive impairments are especially robust when patients need to set in motion working memory processes, suggesting the existence of an altered functioning underlying the cerebral cortices of the frontoparietal memory network. However, the temporal dynamics of working memory subprocesses have not yet been explored in fibromyalgia. SUBJECTS: Thirty-six right-handed women participated in the experiment, comprising 18 patients with fibromyalgia and 18 healthy controls. METHODS: Event-related potentials (ERPs) and behavioral responses were recorded while participants were engaged in a two-back working memory task. Principal component analyses were used to define and quantify the ERP components associated with working memory processes. RESULTS: Patients with fibromyalgia exhibited worse performance than the control group, as revealed by their number of errors in the working memory task. Moreover, both scalp parieto-occipital P2 and parieto-occipital P3 amplitudes were lower for patients than for healthy control participants. Regression analyses revealed that lower P3 amplitudes were observed in those patients with fibromyalgia reporting higher pain ratings. CONCLUSIONS: The present results suggest that both encoding of information (as reflected by P2) and subsequently context updating and replacement (as seen in lower P3 amplitudes), as a part of working memory subprocesses, are impaired in fibromyalgia. Studying the temporal dynamics of working memory through the use of ERP methodology is a helpful approach to detect specific impaired cognitive mechanisms in this chronic pain syndrome. These new data could be used to develop more specific treatments adapted for each patient.

Fear of pain moderates the relationship between self-reported fatigue and methionine allele of catechol-O-methyltransferase gene in patients with fibromyalgia.

Previous research has shown a consistent association among genetic factors, psychological symptoms and pain associated with fibromyalgia. However, how these symptoms interact to moderate genetic factors in fibromyalgia has rarely been studied to date. The present research investigates whether psychological symptoms can moderate the effects of catechol-O-methyltransferase on pain and fatigue. A total of 108 women diagnosed with fibromyalgia and 77 healthy control participants took part in the study. Pain, fatigue, and psychological symptoms (anxiety, depression, pain catastrophizing, fear of pain and fear of movement) were measured by self-report questionnaires. Two types of statistical analyses were performed; the first was undertaken to explore the influences of COMT genotypes on clinical symptoms by comparing patients with fibromyalgia and healthy controls. In the second analysis, moderation analyses to explore the role of psychological symptoms as potential factors that moderate the relationship between pain/fatigue and COMT genotypes were performed. The main results indicated that patients carrying the Met/Met genotype reported significantly higher levels of fatigue than heterozygote carriers (i.e., Met/Val genotype) and higher levels of fatigue, but not significantly different, than Val homozygote carriers. Among patients with fibromyalgia carrying methionine alleles (i.e., Met/Met + Met/Val carriers), only those who scored high on medical fear of pain, experienced an intensified feeling of fatigue. Thus, the present research suggests that fear of pain, as a psychological symptom frequently described in fibromyalgia may act as a moderating factor in the relationship between the Met allele of the COMT gene and the increase or decrease in self-reported fatigue. Although further research with wider patient samples is needed to confirm the present findings, these results point out that the use of psychological interventions focused on affective symptomatology might be a useful tool to reduce the severity of fibromyalgia.

Effects of COMT Genotypes on Working Memory Performance in Fibromyalgia Patients.

Growing research has reported the presence of a clear impairment of working memory functioning in fibromyalgia. Although different genetic factors involving dopamine availability (i.e, the COMT gene) have been associated with the more severe presentation of key symptoms in fibromyalgia, scientific evidence regarding the influence of COMT genotypes on cognitive impairment in these patients is still lacking. To this end, 167 participants took part in the present investigation. Working memory performance was assessed by the application of the SST (Spatial Span Test) and LNST (Letter and Number Sequence Test) belonging to the Weschler Memory Scale III. Significant working memory impairment was shown by the fibromyalgia patients. Remarkably, our results suggest that performance according to different working memory measures might be influenced by different genotypes of the COMT gene. Specifically, fibromyalgia patients carrying the Val/Val genotype exhibited significantly worse outcomes for the span of SST backward, SST backward score, SST total score and the Working Memory Index (WMI) than the Val/Val healthy carriers. Furthermore, the Val/Val patients performed worse on the SST backward and SST score than heterozygotes. Our findings are the first to show a link between the COMT gene and working memory dysfunction in fibromyalgia, supporting the idea that higher COMT enzyme activity would contribute to more severe working memory impairment in fibromyalgia.

Subliminal emotional pictures are capable of modulating early cerebral responses to pain in fibromyalgia.

Pain experience involves a complex relationship between sensory and both emotional and cognitive factors, which appear to be mediated by different neural pathways. Previous evidence has shown that whereas conscious processing of unpleasant stimuli enhances pain perception, the influence of emotions on pain under unaware conditions is much less known. The need to better characterise the relationship between pain processing and emotional factors is crucial for dealing with chronic pain conditions. Therefore, the present study aimed to explore the neural correlates relating to the influence of visual masking emotional stimulation on the processing of painful stimuli in chronic pain patients suffering from fibromyalgia (FM). Twenty FM and 22 healthy control (HC) women participated in the study. The experimental masking paradigm consisted of a rapid succession of two types of stimuli, where a masked picture (neutral, negative or pain-related) was followed by a laser stimulus (painful or not painful). LEP activity was recorded at sixty scalp electrodes. An LEP-amplitude approach was used to quantify the main cerebral waves linked to pain response. ANOVAs indicated that the posterior regions of the P1 component were sensitive to experimental manipulation (p<0.05). Specifically, FM patients showed higher amplitudes to painful stimuli preceded by pain-related pictures compared with painful trials preceded by other emotional pictures. The FM group also showed greater amplitudes than those in the HC group in P2a and P2b waves. In addition to the scalp data, at the neural level the posterior cingulate cortex, lingual gyrus and insular cortex showed higher activation in the FM group than in the HC group. Our findings show an early cerebral modulation of pain (as reflected by the P1) in FM patients, suggesting that only pain-related information, even when it is unconsciously perceived, is capable to enhance exogenous (automatic) attention, increasing the neural activity involved in processing painful stimulation. Further research is needed to fully understand unconscious emotional influences on pain in fibromyalgia.

Corrigendum: Decreased Pain Perception by Unconscious Emotional Pictures.

[This corrects the article DOI: 10.3389/fpsyg.2016.01636.].

Decreased Pain Perception by Unconscious Emotional Pictures.

Pain perception arises from a complex interaction between a nociceptive stimulus and different emotional and cognitive factors, which appear to be mediated by both automatic and controlled systems. Previous evidence has shown that whereas conscious processing of unpleasant stimuli enhances pain perception, emotional influences on pain under unaware conditions are much less known. The aim of the present study was to investigate the modulation of pain perception by unconscious emotional pictures through an emotional masking paradigm. Two kinds of both somatosensory (painful and non-painful) and emotional stimulation (negative and neutral pictures) were employed. Fifty pain-free participants were asked to rate the perception of pain they were feeling in response to laser-induced somatosensory stimuli as faster as they can. Data from pain intensity and reaction times were measured. Statistical analyses revealed a significant effect for the interaction between pain and emotional stimulation, but surprisingly this relationship was opposite to expected. In particular, lower pain intensity scores and longer reaction times were found in response to negative images being strengthened this effect for painful stimulation. Present findings suggest a clear pain perception modulation by unconscious emotional contexts. Attentional capture mechanisms triggered by unaware negative stimulation could explain this phenomenon leading to a withdrawal of processing resources from pain.

Neural correlates of an early attentional capture by positive distractor words.

Exogenous or automatic attention to emotional distractors has been observed for emotional scenes and faces. In the language domain, however, automatic attention capture by emotional words has been scarcely investigated. In the current event-related potentials study we explored distractor effects elicited by positive, negative and neutral words in a concurrent but distinct target distractor paradigm. Specifically, participants performed a digit categorization task in which task-irrelevant words were flanked by numbers. The results of both temporo-spatial principal component and source location analyses revealed the existence of early distractor effects that were specifically triggered by positive words. At the scalp level, task-irrelevant positive compared to neutral and negative words elicited larger amplitudes in an anterior negative component that peaked around 120 ms. Also, at the voxel level, positive distractor words increased activity in orbitofrontal regions compared to negative words. These results suggest that positive distractor words quickly and automatically capture attentional resources diverting them from the task where attention was voluntarily directed.

Changes in clinical pain in fibromyalgia patients correlate with changes in brain activation in the cingulate cortex in a response inhibition task.

OBJECTIVE: The primary symptom of fibromyalgia is chronic, widespread pain; however, patients report additional symptoms including decreased concentration and memory. Performance-based deficits are seen mainly in tests of working memory and executive functioning. It has been hypothesized that pain interferes with cognitive performance; however, the neural correlates of this interference are still a matter of debate. In a previous, cross-sectional study, we reported that fibromyalgia patients (as compared with healthy controls) showed a decreased blood oxygen level dependent (BOLD) response related to response inhibition (in a simple Go/No-Go task) in the anterior/mid cingulate cortex, supplementary motor area, and right premotor cortex. METHODS: Here in this longitudinal study, neural activation elicited by response inhibition was assessed again in the same cohort of fibromyalgia patients and healthy controls using the same Go/No-Go paradigm. RESULTS: A decrease in percentage of body pain distribution was associated with an increase in BOLD signal in the anterior/mid cingulate cortex and the supplementary motor area, regions that have previously been shown to be "hyporeactive" in this cohort. CONCLUSIONS: Our results suggest that the clinical distribution of pain is associated with the BOLD response elicited by a cognitive task. The cingulate cortex and the supplementary motor area are critically involved in both the pain system as well as the response inhibition network. We hypothesize that increases in the spatial distribution of pain might engage greater neural resources, thereby reducing their availability for other networks. Our data also point to the potential for, at least partial, reversibility of these changes.

Brain correlates of cognitive inhibition in fibromyalgia: emotional intrusion of symptom-related words.

Evidence coming from neuropsychological studies has showed the presence of cognitive alterations in fibromyalgia. Such dysfunctions are especially remarkable when the set in motion of executive control processes, such as inhibition, is required to perform successfully; however, neural data related to these mechanisms are very scarce. Present study tried to characterize cognitive inhibition mechanisms, as part of the attentional control functions, in patients with fibromyalgia. Participants (two groups: fibromyalgia patients and healthy control participants) were asked to perform in an emotional Stroop task while event-related potentials (ERP) were recorded. Four different emotional interference conditions were created: fibromyalgia symptom-related words, arousing-negative, arousing-positive and neutral words. Brain activity and behavioral data were analyzed. Principal component analyses were employed to reliably define ERP components along with a source-estimation technique. Symptom-related words elicited greater frontal P450 amplitudes and enhanced activation within right inferior frontal gyrus as compared to the rest of stimuli. This effect was only true for the fibromyalgia group. Behavioral contrasts, however, did not produce significant differences. Scalp and source estimation findings suggest the presence of a specific difficulty in cognitive inhibition in fibromyalgia patients (under conditions intimately linked with the core concerns of their disease). Data point to the involvement of right inferior frontal cortices in this inefficient mechanism, which might cause an enhanced and dysfunctional effort of processing to achieve only a comparable performance to healthy people. Implications of these results are discussed. Nevertheless, further investigations are needed to better understand dysfunctional cognition in fibromyalgia.

Executive function in chronic pain patients and healthy controls: different cortical activation during response inhibition in fibromyalgia.

UNLABELLED: The primary symptom of fibromyalgia (FM) is chronic, widespread pain; however, patients report additional symptoms including decreased concentration and memory. Performance-based deficits are seen mainly in tests of working memory and executive function. Neural correlates of executive function were investigated in 18 FM patients and 14 age-matched healthy controls during a simple Go/No-Go task (response inhibition) while they underwent functional magnetic resonance imaging (fMRI). Performance was not different between FM and healthy control, in either reaction time or accuracy. However, fMRI revealed that FM patients had lower activation in the right premotor cortex, supplementary motor area, midcingulate cortex, putamen and, after controlling for anxiety, in the right insular cortex and right inferior frontal gyrus. A hyperactivation in FM patients was seen in the right inferior temporal gyrus/fusiform gyrus. Despite the same reaction times and accuracy, FM patients show less brain activation in cortical structures in the inhibition network (specifically in areas involved in response selection/motor preparation) and the attention network along with increased activation in brain areas not normally part of the inhibition network. We hypothesize that response inhibition and pain perception may rely on partially overlapping networks, and that in chronic pain patients, resources taken up by pain processing may not be available for executive functioning tasks such as response inhibition. Compensatory cortical plasticity may be required to achieve performance on a par with control groups. PERSPECTIVE: Neural activation (fMRI) during response inhibition was measured in fibromyalgia patients and controls. FM patients show lower activation in the inhibition and attention networks and increased activation in other areas. Inhibition and pain perception may use overlapping networks: resources taken up by pain processing may be unavailable for other processes.

Generalized hypervigilance in fibromyalgia patients: an experimental analysis with the emotional Stroop paradigm.

OBJECTIVE: In recent years, a good deal of serious research has been carried out on the hypothesized presence of generalized hypervigilance to sensory stimulation in fibromyalgia (FM). However, there are no studies which, following an operationalization of generalized hypervigilance as a propensity to attend to any task-irrelevant stimuli presented, make use of interference paradigms as the most appropriate experimental models for its analysis. The purpose of this study was to test the hypothesis of generalized hypervigilance in FM using the emotional modification of the Stroop task and to explore the possible mediating role of anxiety. METHODS: To this end, 25 women diagnosed with fibromyalgia and 25 matched controls were shown 32 stimulus words equally distributed in four categories: fibromyalgia symptoms, arousing-negative (A-), arousing-positive (A+), and neutral (N). These words had been selected on the basis of the results of an independent study. In addition to the emotional Stroop task, measures of trait and state anxiety were included. RESULTS: The results showed the possible presence of a generalized hypervigilance response in fibromyalgia patients based on significant slowness in the color-naming. This effect was mediated by the degree of perceived unpleasantness of the A-stimuli. However, the expected mediation effect of anxiety was not found. CONCLUSIONS: These results suggest the presence of a generalized hypervigilance response in FM patients that is not mediated by anxiety. Implications for the correct functioning of controlled self-regulatory processes in fibromyalgia and similar pathologies are discussed.