Attentional modulations of pain perception: evidence from laser evoked potentials

This thesis aims to provide a contribution to the current neurophysiological and psychophysiological understanding of nociception and pain processing in humans. The introduction of high-power, radiant heat stimulators (lasers) in sensory physiology has revolutionised the study of the nociceptive system. Laser pulses activate Aδ and/or C skin nociceptors selectively, i.e. without coactivating deeper, tactile mechanoreceptors, and elicit brain responses that can be detected using electroencephalography, and are called laser-evoked potentials (LEP). This was the technique applied in the two experimental studies reported in the present thesis work. The doctoral dissertation is organized in five chapters. Chapter 1 – Introduction - defines the concepts of nociception and pain. It also provides an introduction to the event related potential technique (ERP), a description of basic biophysics and neurophysiology related to LEP recording, followed by a literature review of its related cortical generators. In addition, the Chapter attempts to draw an elementary parallel between LEPs and other EPs elicited by stimuli belonging to other sensory modalities. Chapter 2 – Determinants of vertex potentials – describes the determinants of neural processes of pain perception and support their interpretation through a neurocognitive model of attention. The mechanism of attention allows allocating resources for selection and integration of this process with working memory requirements. More in detail, cognitive science suggested that the attention mechanism can be divided into two categories: stimulus-driven (or ‘bottom-up’) and goal-directed (or ‘top-down’). ‘Top-down’ and ‘bottom-up’ are treated as key interpretative categories to explain the findings reported in this thesis. Infact, they are metaphors which are used to represent information processing in a hierarchical fashion, where lower levels of processing would rely on the physical features of the stimulus while higher levels would involve comparisons with information stored in memory, selection of relevant information in competition and response to the stimulus. A review of selected literature in the field or ERP studies of sensory processing is provided and interpreted within this framework. The thesis aims to contribute to the understanding of both ‘bottom-up’ and ‘top-down’ mechanisms of attention during nociceptive processing, with two distinct experiments. Chapter 3 – Contribution to the analysis of ‘bottom-up features: “Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus modality” - presents a study where the hypothesis that a change of modality (from auditory to nociceptive and vicerversa, rather than no change at all) can significantly modulate brain responses (no matter the subjects expectation of this change) has been tested. The results of this study bring support for a determinant role of saliency (here modulated by the novelty introduced by a change in the stimulus modality) in affecting brain responses to the sensory input. Chapter 4 - Hypnotic modulation of sensory and affective dimensions of pain: a top-down signature on pain experience - introduces a study where hypnotic suggestions were used to draw subject’s attention either on intensity or on unpleasantness of pain perception. Thus, the study aimed to investigate whether this manipulation could induce a dissociation between this two measure of subjective experience and whether LEP could reflect the role of focused attention and expectation in indexing changes of subjective feeling. The results are discussed according to previous literature and to a neurocognitive model of pain processing as observed during an altered state of consciousness known to heighten the fronto-parietal network of sustained attention. In Chapter 5 - General discussion - the findings related to these two different research lines are integrated and discussed considering the existing theoretical accounts. The critical assumption is that the understanding of pain processing would largely benefit from the application of an attention-driven interpretative framework within which can be included different theoretical-epistemological views concerning (II) the Bayesian inference in perception, (III) the motivational account of pain monitoring and control, (IV) the neuroanatomy of homeostatic feeling of body integrity and self-regulation. As conclusive remark, the work presented in this thesis wish to highlight the importance of a renewed concept of ‘pain matrix’, based on its function of potential threat detector and action planner, in order to preserve the integrity of the body. In addition, the interpretation of pain as homeostatic-motivational force naturally carries us to consider the ‘pain matrix’ not as a sensory-specific cortical network but rather as an action-specific network, representing the activity by which the individual identifies and responds purposefully to a sudden, potential threat inside or outside of the body

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

Neurological Markers of Maladaptive Brain Activity in Fibromyalgia and their Relationship with Treatment Effectiveness

Chronic pain (CP) is estimated to affect at least one-third of the population in the United Kingdom. Fibromyalgia (FM) is one of the most disabling CP conditions. Epidemiological research suggests its global prevalence to be between 2-8%. The unknown pathogenesis, lack of biological markers to monitor its development, and lack of successful treatment make FM a crucial target of pre-clinical research.The goal of this project is twofold. The project aims to 1) identify robust neurological markers (i.e., electrochemical brain activity) by applying a combination of advanced electroencephalography (EEG) signal processing (i.e., functional connectivity of oscillatory activity) and neuroinflammatory (NI) responses (i.e., estimation of pro-inflammatory cytokines intake), through which 2) characterizing successfully and unsuccessfully treated FM patients (compared to age-matched healthy controls). These measures, seldom combined, have been successfully applied to the study of psychiatric conditions and sleep. Crucially, the identification of neurological markers at rest and during arousing sensory stimulation will allow us to estimate the relationship between these neurological markers and treatment effectiveness. This proposal is important because it aims to generate a robust pre-clinical neurological tool to identify FM and its relationship with measures of treatment effectiveness. The successful identification of neurological markers will improve the assessment of the development of maladaptive changes in FM and will kick-start further research on treatment effectiveness.This project is of great medical relevance as it will identify pathological signatures of FM that can then inform research on etiology and treatment of this condition

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

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

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

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

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

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