Neurophysiological mechanisms of longer-lasting experimental pain in humans

Pain serves the protection of the body. Consequently, noxious stimuli or, more precisely, the thereby induced neurophysiological processes commonly lead to pain perception. Identical noxious stimuli, however, do not always translate into the same pain experience depending on multiple factors. To acknowledge this variability, the distinction between nociception as the neural process elicited by noxious stimuli and pain as subjective multifactorial experience is essential. During longer-lasting experimental pain and chronic pain, nociception and pain can substantially dissociate. Moreover, longer-lasting experimental pain resembles chronic pain regarding certain perceptual features such as prolonged pain duration and intensity fluctuations. Thus, longer-lasting experimental pain offers the opportunity to gain new insights into both the differential neural representation of noxious stimuli and pain and the neuronal mechanisms associated with the state of longer- lasting pain. We applied 10 minutes of painful heat stimulation to the left and right hand of 39 healthy participants while we recorded continuous pain ratings, electroencephalography (EEG), and autonomic responses. Data were analyzed in three distinct projects aiming at different aspects of neuronal mechanisms underlying longer-lasting pain. Project 1 assessed whether stimulus intensity as proxy of nociception and pain intensity relate to distinct patterns of oscillatory brain activity. EEG recordings revealed that increases in stimulus intensity were reflected by suppressions of alpha and beta oscillations in sensorimotor areas contralateral to the stimulated hand. In contrast, increases in pain intensity were associated with enhanced gamma oscillations in the medial prefrontal cortex. More importantly, the encoding of stimulus intensity by alpha and beta oscillations in the sensorimotor areas was spatially specific, i.e. depended on the stimulus location, whereas the encoding of pain intensity by gamma oscillations in the medial prefrontal cortex was independent of stimulus location. Thus, prefrontal gamma oscillations might reflect higher- order aspects of noxious stimuli, such as salience, valence, and motivational aspects rather than precise sensory features. Project 2 investigated the relationship between stimulus intensity, pain intensity, autonomic responses, and brain activity. Skin conductance measures, as markers of sympathetic activity, co-varied more closely with stimulus intensity than with pain intensity. Correspondingly, skin conductance measures were related to suppressions of alpha and beta oscillations in the sensorimotor area contralateral to the stimulated hand. These finding suggest that skin conductance measures are in part directly elicited by nociceptive processes and, thus, at least partially independent of perceptual processes during longer-lasting pain. Hence, these observations corroborate concepts of pain in which sensory, motivational, and autonomic processes partially independently contribute to the experience of pain. Finally, project 3 incorporated the systematic and comprehensive assessment of oscillatory brain activity, functional connectivity, and graph- theory based network measures during the state of longer-lasting pain. Longer-lasting pain was associated with suppressions of oscillatory brain activity at alpha frequencies in addition to stronger connectivity at alpha and beta frequencies in sensorimotor areas. Furthermore, sensorimotor areas contralateral to stimulation showed increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies and built a sensorimotor-prefrontal network during longer-lasting pain. This network might be involved in the integration of sensory, cognitive, and motivational-affective information and, consequently, in the translation of a noxious stimulus into a subjective pain experience. All three projects contribute to a better understanding of neuronal mechanisms underlying longer-lasting experimental pain, which serves as an experimental model for chronic pain. Since the treatment of chronic pain has remained insufficient and unsatisfactory, the current results might provide EEG-based targets for urgently needed new treatment approaches, such as non-invasive brain stimulation and neurofeedback

Neurophysiological mechanisms of longer-lasting experimental pain in humans

Pain serves the protection of the body. Consequently, noxious stimuli or, more precisely, the thereby induced neurophysiological processes commonly lead to pain perception. Identical noxious stimuli, however, do not always translate into the same pain experience depending on multiple factors. To acknowledge this variability, the distinction between nociception as the neural process elicited by noxious stimuli and pain as subjective multifactorial experience is essential. During longer-lasting experimental pain and chronic pain, nociception and pain can substantially dissociate. Moreover, longer-lasting experimental pain resembles chronic pain regarding certain perceptual features such as prolonged pain duration and intensity fluctuations. Thus, longer-lasting experimental pain offers the opportunity to gain new insights into both the differential neural representation of noxious stimuli and pain and the neuronal mechanisms associated with the state of longer- lasting pain. We applied 10 minutes of painful heat stimulation to the left and right hand of 39 healthy participants while we recorded continuous pain ratings, electroencephalography (EEG), and autonomic responses. Data were analyzed in three distinct projects aiming at different aspects of neuronal mechanisms underlying longer-lasting pain. Project 1 assessed whether stimulus intensity as proxy of nociception and pain intensity relate to distinct patterns of oscillatory brain activity. EEG recordings revealed that increases in stimulus intensity were reflected by suppressions of alpha and beta oscillations in sensorimotor areas contralateral to the stimulated hand. In contrast, increases in pain intensity were associated with enhanced gamma oscillations in the medial prefrontal cortex. More importantly, the encoding of stimulus intensity by alpha and beta oscillations in the sensorimotor areas was spatially specific, i.e. depended on the stimulus location, whereas the encoding of pain intensity by gamma oscillations in the medial prefrontal cortex was independent of stimulus location. Thus, prefrontal gamma oscillations might reflect higher- order aspects of noxious stimuli, such as salience, valence, and motivational aspects rather than precise sensory features. Project 2 investigated the relationship between stimulus intensity, pain intensity, autonomic responses, and brain activity. Skin conductance measures, as markers of sympathetic activity, co-varied more closely with stimulus intensity than with pain intensity. Correspondingly, skin conductance measures were related to suppressions of alpha and beta oscillations in the sensorimotor area contralateral to the stimulated hand. These finding suggest that skin conductance measures are in part directly elicited by nociceptive processes and, thus, at least partially independent of perceptual processes during longer-lasting pain. Hence, these observations corroborate concepts of pain in which sensory, motivational, and autonomic processes partially independently contribute to the experience of pain. Finally, project 3 incorporated the systematic and comprehensive assessment of oscillatory brain activity, functional connectivity, and graph- theory based network measures during the state of longer-lasting pain. Longer-lasting pain was associated with suppressions of oscillatory brain activity at alpha frequencies in addition to stronger connectivity at alpha and beta frequencies in sensorimotor areas. Furthermore, sensorimotor areas contralateral to stimulation showed increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies and built a sensorimotor-prefrontal network during longer-lasting pain. This network might be involved in the integration of sensory, cognitive, and motivational-affective information and, consequently, in the translation of a noxious stimulus into a subjective pain experience. All three projects contribute to a better understanding of neuronal mechanisms underlying longer-lasting experimental pain, which serves as an experimental model for chronic pain. Since the treatment of chronic pain has remained insufficient and unsatisfactory, the current results might provide EEG-based targets for urgently needed new treatment approaches, such as non-invasive brain stimulation and neurofeedback

Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies

Several studies have used neuroimaging techniques to investigate brain correlates of the attentional modulation of pain. Although these studies have advanced the knowledge in the field, important confounding factors such as imprecise theoretical definitions of attention, incomplete operationalization of the construct under exam, and limitations of techniques relying on measuring regional changes in cerebral blood flow have hampered the potential relevance of the conclusions. Here, we first provide an overview of the major theories of attention and of attention in the study of pain to bridge theory and experimental results. We conclude that load and motivational/affective theories are particularly relevant to study the attentional modulation of pain and should be carefully integrated in functional neuroimaging studies. Then, we summarize previous findings and discuss the possible neural correlates of the attentional modulation of pain. We discuss whether classical functional neuroimaging techniques are suitable to measure the effect of a fluctuating process like attention, and in which circumstances functional neuroimaging can be reliably used to measure the attentional modulation of pain. Finally, we argue that the analysis of brain networks and spontaneous oscillations may be a crucial future development in the study of attentional modulation of pain, and why the interplay between attention and pain, as examined so far, may rely on neural mechanisms shared with other sensory modalities

Transcranial Alternating Current Stimulation at Alpha Frequency Reduces Pain When the Intensity of Pain is Uncertain

Alpha activity directly before pain onset has been implicated in pain experience with higher pre-stimulus alpha associated with lower reported pain. However, expectations about pain intensity also seem to affect pre-stimulus alpha activity. To date, evidence for a relationship between alpha activity and pain experience has been largely correlational. Transcranial alternating current stimulation at alpha frequency (alpha tACS) permits direct manipulation of alpha activity and therefore an examination of the potential causal relationship between alpha activity and pain. We investigated whether somatosensory alpha tACS could reduce pain experience and whether this was influenced by uncertainty about pain intensity. In a within-subjects design, perceived pain intensity and unpleasantness were assessed in 23 participants during alpha tACS and sham stimulation. Visual cues preceding the pain stimulus were used to manipulate uncertainty. A significant tACS * uncertainty * stimulus intensity interaction was found for reported pain intensity (F₂,₄₄ = 4.50; p = .017; Partial Eta² = .17) and unpleasantness (F₁,₂₂ = 4.78; p = .040; Partial Eta² = .18). Pain experience during the application of somatosensory alpha tACS was significantly lowered compared to sham stimulation, but only when the intensity of an upcoming stimulus was uncertain

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

Oscillatory dynamics in the perception of pain investigated using magnetoencephalography

This thesis investigates changes in the oscillatory dynamics in key areas of the pain matrix during different modalities of pain. Gamma oscillations were seen in the primary somatosensory cortex in response to somatic electrical stimulation at painful and non-painful intensities. The strength of the gamma oscillations was found to relate to the intensity of the stimulus. Gamma oscillations were not seen during distal oesophageal electrical stimulation or the cold pressor test. Gamma oscillations were not seen in all participants during somatic electrical stimulation, however clear evoked responses from SI were seen in everyone. During a train of electrical pulses to the median nerve and the digit, a decrease in the frequency of the gamma oscillations was seen across the duration of the train. During a train of electrical stimuli to the median nerve and the digit, gamma oscillations were seen at ~20-100ms following stimulus onset and at frequencies between 30-100Hz. This gamma response was found to have a strong evoked component. Following a single electrical pulse to the digit, gamma oscillations were seen at 100-250ms and between 60-95Hz and were not temporally coincident with the main components of the evoked response. These results suggest that gamma oscillations may have an important role in encoding different aspects of sensory stimuli within their characteristics such as strength and frequency. These findings help to elucidate how somatic stimuli are processed within the cortex which in turn may be used to understand abnormal cases of somatosensory processing

The role of expectations on affective sound processing: behavioural and neural correlates

Ph. D. Thesis.Theoretical frameworks and empirical evidence in the last two decades have shown that prior expectations about the upcoming stimulus can shape the perception when the stimulus arrives. How expectations influence emotional responses to the stimulus is, however, relatively less understood. In this thesis, using behavioural and neural measures of electroencephalography (EEG) and intracranially recorded local field potentials (LFPs) from human subjects, I explore the role of expectations on the processing of affective sounds. In Chapter 2, the neural basis of expectation is first established using EEG. Two visual cues were used to elicit the expectation of either neutral or aversive sounds. An event related potential just before the onset of upcoming stimuli, called Stimulus Preceding Negativity (SPN), is measured to index the expectation of an upcoming stimulus. Although a robust measure of SPN could be observed for the expectation of both aversive and neutral sounds, no difference between the two was observed indicating no relation between the magnitude of SPN and valence of sounds. Source localization of SPN, using multiple sparse priors algorithm revealed a network of brain areas including the anterior insula, inferior frontal gyrus, temporal cortex, supplementary motor area (SMA) and thalamus. A limitation of the first experiment was that no behavioural measure of expectation of valence was recorded. It is likely that there is variation across subjects in the expectation and perceived valence after the stimulus onset. The second experiment (Chapter 3), also a cued paradigm as above, addressed this limitation by using subjective measures of expectations before the sound onset and aversive ratings after sound offset as reported by the subjects. Mediation analysis between perceived ratings following sound onset and expectation ratings confirmed a mediator role of expectation/predictions in the aversive experience – an expectation for aversive sounds translated into a more aversive experience, and an expectation for less aversive sounds translated into a less aversive experience once the sound was heard. Exploratory analyses showed that subjects whose perceived aversiveness shifted in the direction of expectation displayed a stronger SPN. Moreover, this effect was seen for aversive but not for neutral sounds. Additionally, activity in the alpha-beta band during encoding of the predictive cues was associated with the precision of subjective expectancy. In summary, the data highlight the importance of measuring behavioural/subjective correlates of expectation and perceived aversiveness. This may be particularly important when the cues-contingencies are not explicitly disclosed and when using emotional (subjective) stimuli, as there is bound to be high inter-individual variability both in learning rates and stimulus appraisal. Expectations about the upcoming stimulus can be formed based on different sources. For example, it could be based on information from other people (that is, social source) or expectations can be formed based on personal experiences with the world (conditioned source). In the third and last experiment (Chapter 4), the behavioural, physiological and neural basis of social and conditioned expectations are measured. Using a cued paradigm, subjects formed expectations of the upcoming stimulus either based on social information or their own conditioning experiences. As in the experiment in Chapter 3, subjects rated their expectation prior to the stimulus onset and their perceived aversiveness following the onset of the stimulus. The data again show that the perceived aversiveness shifted in the direction of expectations for both the social and conditioned cues. Further, physiological and autonomic responses also shifted in the direction of expectations. Recordings from LFPs in a group of epileptic patients undergoing neurosurgical evaluations for the locations of their seizure foci show expectation-based changes during sound perception in a widespread network including temporal cortex, anterior cingulate and orbitofrontal cortices, inferior frontal gyrus, and insula. Collectively, the research presented in this doctoral thesis show expectations can and do alter the processing of aversive sounds at the behavioural, somatic, and neural levels.Newcastle Universit