Is touch gating due to sensory or cognitive interference? An investigation using repeated testing

The present study was conducted to determine whether touch gating, in which pain decreases tactile sensitivity, is the result of sensory or cognitive interference. Touch gating was repeatedly produced by delivering a co-localized painful heat stimulus (45 C) during measurements of vibration threshold on the palm. Pain significantly increased thresholds compared to those measured at normal skin temperature and this interference did not decline over the course of the experiments, despite the fact that perceived pain significantly habituated. For comparison, Stroop interference was also measured repeatedly; this cognitive interference declined significantly across sessions and bore no resemblance to touch gating interference. Touch gating was not correlated with measures of distractibility, fear of pain, hypervigilance, or anxiety - variables previously found to contribute to pain's ability to cause cognitive interference. Taken together, the results suggest that touch gating is a sensory phenomenon, one that cannot be explained by pain's capability to distract.Master of Art

Functional Imaging of Central Mechanisms Underlying Human Pain Perception

Investigations of human somatosensory perception have demonstrated robust interactions between the submodalities of pain and touch, and there is increasing recognition that the systematic assessment of somatosensory perception in disorders characterized by persistent pain such as Temporomandibular Disorder (TMD) would greatly aid diagnosis and evaluation of treatment efficacy. To better understand the pathophysiological mechanisms underlying TMD, we investigated cortical processing interactions that occur between innocuous and noxious cutaneous input using functional magnetic resonance imaging (fMRI). Innocuous vibrotactile stimulation and noxious skin heating were delivered separately and concurrently to the hand of women with TMD and to pain-free, gender-matched controls (HC). Cortical responses evoked by innocuous vibrotactile stimulation alone differentiated TMDs from HCs, and the differences between the groups suggest cortical plasticity in TMD which primes areas to respond to innocuous vibrotactile input that normally would not, including parts of the pain matrix and auditory cortex. In contrast, pain ratings and cortical responses to noxious heat alone did not differ significantly between TMDs and HCs. However, additional group differences emerged in the cortical patterns characterizing interactions between somatosensory submodalities in subjects with and without TMD during concurrent stimulation that could not be explained exclusively by group differences in the response to innocuous vibrotactile stimulation. Some of these differences in the interaction of innocuous and noxious somatosensory inputs were correlated with the severity of the TMD patients' clinical pain despite the fact that no significant correlations were observed between TMD pain and responses to vibrotactile or noxious heat stimulation alone. This suggests that cortical processing interactions between somatosensory submodalities more closely reflect individual experiences of persistent clinical pain than does the unimodal processing of innocuous vibrotactile or noxious heat input alone

Developing and characterising imaging biomarkers for pain and analgesia

There is a need to improve translation of novel pain treatments from pre-clinical to clinical research, and the development of objective standardised biomarkers to verify target engagement is a vital step towards this goal. Features of chronic pain conditions, such as central sensitisation, can be experimentally induced in healthy humans. Functional magnetic resonance imaging (fMRI) is a highly valuable method to explore the neural basis for pain and also analgesic activity. This thesis combines these two research tools to develop and characterise neuroimaging biomarkers for pain and analgesia. The first chapter consists of a systematic literature review, evidencing that this combination of techniques has provided a wealth of information about brain activity during pain states and analgesia. Co-ordinate based meta-analysis conducted to summarise results for a simple comparison between the neural responses during experimental hyperalgesia compared to control showed activation clusters in the insula cortex and thalamus. Next, exploratory analysis of early 7 Tesla MRI data was conducted to investigate the neural changes that occur during the onset of central sensitisation. Conclusions were limited due to a low sample size, but there were interesting results showing increased blood oxygen-level dependent (BOLD) response in the insula and in the nucleus cuneiformis, a brainstem region shown to be specific to maintenance of central sensitisation. The remaining three chapters comprise primary results and exploratory analysis from the IMI- PainCare BioPain RCT4 trial. The trial utilises the high frequency stimulation (HFS) model to induce central sensitisation, the neural basis for which had not previously been studied using fMRI. Comparison between pre-HFS and post-HFS data showed that the neural basis for HFS-induced central sensitisation was aligned to that seen with the well-characterised capsaicin model in imaging studies. Subsequently, analysis of the main trial endpoints was conducted, to investigate the effects of lacosamide, pregabalin and tapentadol on biomarkers of pain processing observed by fMRI. Pregabalin reduced the punctate-evoked BOLD response in the posterior insula cortex. Lacosamide modulated resting state functional connectivity between the thalamus and secondary somatosensory cortex. In whole-brain analyses, tapentadol modulated responses in areas relevant to pain processing such as the anterior insula cortex. Finally, exploratory analysis was conducted to characterise the placebo effect in the trial, showing that during placebo analgesia changes in brain activity were observed in regions associated with pain perception, including the insula and anterior cingulate cortices, and regions involved in affective and cognitive aspects of pain processing, such as the amygdala and dorsolateral prefrontal cortex. Overall, this work comprises a valuable contribution to increase the utility and standardisation of applying experimental models in conjunction with fMRI in the assessment of novel analgesics prior to large scale clinical trials. As evidenced in the systematic review, individual fMRI studies are highly informative, but lack of standardisation makes comparison between studies difficult. The BioPain work addresses this challenge, providing a standardised assessment of multiple drugs across many pain biomarkers, demonstrating how these biomarkers can be valuably employed in drug development

Periphere und zenralnervöse Mechanismen bei Postherpetischer Neuralgie: Hinweise aus Quantitativen Sensorischen Tests und EEG-Untersuchungen

Postherpetische Neuralgie (PHN) ist eine chronische Schmerzerkrankung, die nach Herpes Zoster auftreten kann und besonders Personen im höheren Lebensalter betrifft. Auf Grund des ansteigenden mittleren Lebensalters in den Industrienationen stellt PHN ein hoch relevantes Problem dar. Die vorliegende Dissertation hatte zum Ziel, somatosensorische Symptome mittels einer umfassenden Quantitativen Sensorischen Testung (QST) des derzeit bestmöglichen Standards zu beschreiben. Zusätzlich wurden EEG-Registrierungen bei selektiver Stimulation nozizeptiver Fasern durchgeführt. Es wurden 23 Patientinnen und Patienten mit PHN mit 23 alters- und geschlechtsparallelisierten Kontrollpersonen in vier Testarealen verglichen. Die Ergebnisse der Dissertation zeigen, dass vermutlich eine Kombination aus einer verringerten Wahrnehmung taktiler Reize („taktile Hypästhesie“) und dynamisch mechanischer Allodynie (Schmerz bei leichter Berührung mit einem sich bewegenden Stimulus) für die Entstehung und Aufrechterhaltung Postherpetischer Neuralgie eine Rolle spielt. Diese Kombination ist bisher noch nicht als charakteristisches Merkmal von PHN berichtet worden und kann daher genutzt werden, um neue Impulse in der Entwicklung zukünftiger PHN-Therapien zu setzen. Zusätzlich wurden Hinweise auf zentralnervöse Sensitivierungsprozesse bei PHN (erhöhte Sensibilität des kontralateralen Areals und entfernter Areale der betroffenen Körperseite) gefunden. Ergebnisse der EEG-Analyse zeigten, dass ein bei PHN stattfindender Verlust bzw. eine verringerte Sensibilität nozizeptiver Aδ-Fasern eine bedeutsame Rolle spielen könnte. Da Ergebnisse, die auf eine verringerte Sensibilität dieser Nervenfasern hindeuten, in der QST nicht berichtet werden konnten, kann dies auf eine erhöhte Sensitivität der EEG-Untersuchung für Verluste peripherer Nervenfasern hinweisen. Eine Ergänzung von EEG und QST kann daher dazu dienen, frühzeitig Veränderungen bei PHN zu erfassen und Therapiemöglichkeiten zu entwickeln

The roles of the somatosensory cortices in the perception of noxious and innocuous stimuli

Résumé Les premières études électrophysiologiques et anatomiques ont établi le rôle crucial du cortex somatosensoriel primaire et secondaire (SI et SII) dans le traitement de l'information somatosensorielle. Toutefois, les récentes avancées en techniques d’imagerie cérébrale ont mis en question leur rôle dans la perception somatosensorielle. La réorganisation du cortex somatosensoriel est un phénomène qui a été proposé comme cause de la douleur du membre fantôme chez les individus amputés. Comme la plupart des études se sont concentrées sur le rôle du SI, une étude plus approfondie est nécessaire. La présente série d'expériences implique une exploration du rôle des régions somatosensorielles dans la perception des stimuli douleureux et non-douleureux chez des volontaires sains et patients avec des douleurs de membre fantôme. La première étude expérimentale présentée dans le chapitre 3 est une méta-analyse des études de neuro-imagerie employant des stimuli nociceptifs chez des volontaires sains. En comparaison aux précédentes, la présente étude permet la génération de cartes quantitatives probabilistes permettant la localisation des régions activées en réponse à des stimuli nociceptifs. Le rôle du cortex somatosensoriel dans la perception consciente de stimuli chauds a été étudié dans le chapitre 4 grâce à une étude d'imagerie par résonance magnétique fonctionnelle, dans laquelle des stimuli thermiques douloureux et non-douloureux ont été administrés de manière contrebalancée. Grâce à cette procédure, la perception de la chaleur fut atténuée par les stimuli douloureux, ce qui permit la comparaison des stimuli consciemment perçus avec ceux qui ne le furent pas. Les résultats ont montrés que les stimulations chaudes perçues ont engendré l’activation de l’aire SI controlatérale, ainsi que de la région SII. Grâce à l’évaluation clinique de patients amputés présentant une altération de leurs perceptions somatosensorielles, il est également possible de dessiner un aperçu des régions corticales qui sous-tendent ces modifications perceptuelles. Dans le chapitre 5 nous avons émis l'hypothèse proposant que les sensations du membre fantôme représentent un corrélat perceptuel de la réorganisation somatotopique des représentations sensorielles corticales. En effet, la réorganisation des sensations peut donner des indices sur les régions impliquées dans la genèse des sensations référées. Ainsi, un protocole d’évaluation sensoriel a été administré à un groupe de patients affligés de douleur au niveau du membre fantôme. Les résultats ont montré que, contrairement aux études précédentes, les sensations diffèrent grandement selon le type et l'intensité des stimuli tactiles, sans évidence de la présence d’un modèle spatialement localisé. Toutefois, les résultats actuels suggèrent que les régions corticales à champs récepteurs bilatéraux présentent également des modifications en réponse à une déafférentation. Ces études présentent une nouvelle image des régions corticales impliquées dans la perception des stimuli somatosensoriels, lesquelles comprennent les aires SI et SII, ainsi que l'insula. Les résultats sont pertinents à notre compréhension des corrélats neurologiques de la perception somatosensorielle consciente.Abstract Early anatomical and single-unit recording studies established a crucial role for the primary and secondary somatosensory cortices (SI & SII) in processing somatosensory information. However, recent advances in brain imaging and analysis techniques have called into question their role in somatosensation. Findings from this recent research are relevant to the study of the reorganizational changes occurring in the somatosensory cortices that have been causally linked to the genesis of pain in amputee patients. These patients continue to perceive and experience pain in the absent limb, which is usually referred to as phantom-limb pain; but little research on this phenomenon has focused on other regions outside SI, and further study is needed. The present series of experiments involve an exploration of the roles of the somatosensory cortices in the perception of noxious and innocuous tactile stimuli in healthy volunteers and patients with phantom-limb pain. The first experimental study in Chapter 3 is a meta-analytic review of neuroimaging studies examining noxious stimuli evoked activation in healthy volunteers. In comparison to previous reviews that have merely reported the prevalence of pain-related activation, the present study yields quantitative probabilistic maps that permit localization of the likelihood of obtaining activation in response to noxious stimuli within any brain region. The role of the somatosensory cortices in the conscious perception of brief warm stimuli was explored in Chapter 4 using functional magnetic resonance imaging, where noxious and innocuous thermal stimuli were counterbalanced within the experimental protocol. This procedure allowed a gating of the somatosensory system in which the perception of warm stimuli was attenuated by painful stimuli, thus permitting the comparison of detected with undetected stimuli. Results showed that detected warm stimuli significantly activated SI and SII. It is also possible to draw insight regarding which cortical regions subserve somatosensory processing and its organization by clinical assessment of amputee patients, who demonstrate altered somatosensation. To date, few studies have explored the relationship between referred sensations to the phantom and cortical reorganization. In Chapter 5 we hypothesized that referred sensations to phantom limbs are a perceptual correlates of a somatotopic reorganization of sensory representations. Derangements in referred sensations can give clues to the regions involved in referred sensations genesis. Thus, a quantitative sensory testing protocol was administered to a group of phantom-limb pain patients. Results showed that, contrary to previous reports, referred sensations to the phantom differed greatly based on the type and intensity of the tactile stimuli applied to the body, with no evidence of a spatially localized pattern. Previous reports of referred sensations have solely focused on plastic changes in SI. However, the present results suggest that other cortical regions with bilateral receptive fields also undergo reorganizational changes in response to deafferentation. These studies present an emerging picture of the cortical regions involved in the perception of somatosensory stimuli, which include SI and SII, as well as the insula. Findings are relevant to our understanding of the neural correlates of conscious perception of somatosensation and the formation of the mental representation of stimuli applied to the body

Mécanismes cérébraux de la régulation de la douleur : perception de la douleur et hypoalgésie induite psychologiquement

Objectif : Cette thèse a pour but de préciser les mécanismes neuropsychologiques de la douleur, de la régulation endogène de la douleur et de l'hypoalgésie induite psychologiquement (HIP) par la synthèse de près de trente ans de recherche imagerie cérébrale fonctionnelle. Méthodologie : Étant donné l'abondance des études sur le sujet et le manque d'intégration de leurs résultats, la technique de métaanalyse quantitative basée sur les coordonnées d'activation cérébrale fut privilégiée dans cette thèse, telle qu’implémentée dans l'algorithme ALE (Activation Likelyhood Estimate). Une force supplémentaire de cette thèse repose sur la rigueur du processus de sélection des articles. En effet, les études incluses dans les métaanalyses devaient satisfaire des critères stricts d'inclusion, ceci dans le but de favoriser la précision et la validité des conclusions subséquentes. Étude 1 : Le premier article visait à identifier les aires cérébrales impliquées dans la réduction de la douleur par des méthodes psychologiques d'interventions. Les articles retenus portent sur une variété de méthodes d'intervention, telles que le placebo, l'hypnose, la méditation, la perception de contrôle sur la stimulation douloureuse et l'induction d'émotions. Les résultats indiquent que l'HIP implique un vaste réseau d'activation qui comprend le cortex cingulaire antérieur, l'insula antérieure, les zones orbitofrontale et préfrontale latérale, ainsi que les régions pariétale, temporale et souscorticales. Ces activations reflèteraient l'implication des mécanismes neuropsychologiques cognitifs et émotionnels sous-tendent les interventions psychologiques ciblées par ces études, incluant la conscience de soi et la motivation. De plus, les divergences de patron d'activation entre les approches ont été explorées, notamment pour le placebo et la distraction. Étude 2 : Le deuxième article a identifié des patrons d'activations préférentiellement associés à la perception de la douleur, à l'HIP, ainsi que des activations communément associées à la douleur et l'HIP. Les résultats indiquent que 1) la perception de la douleur est associée à l'activation d'aires somatosensorielles et motrices, ce qui pourrait être le reflet de la préparation d'une action adaptative, 2) l'HIP est liée à l'engagement de régions préfrontales antéromédianes et orbitales, possiblement en lien avec des processus motivationnels et émotionnels, et 3) la douleur et l'HIP sont associés à l'activation d'aires préfrontales dorsolatérales, de l'insula antérieure et du cortex cingulaire moyen, ce qui pourrait refléter l'engagement spontané pendant la douleur de mécanismes endogènes de régulation descendante. Conclusion : Par ces études, cette thèse fait le point sur les mécanismes cérébraux impliqués différentiellement dans la perception de la douleur, dans sa régulation endogène et dans l'hypoalgésie induite psychologiquement.Objective: This thesis aims to clarify the neuropsychological mechanisms of pain, of the endogenous regulation of pain and of psychologically induced hypoalgesia (PIH), through the synthesis of almost thirty years of functional brain imaging research. Methodology: Given the abundance of studies in this domain and the lack of integration of their results, we used the quantitative meta-analysis technique based on brain activation using the ALE (Activation likelihood Estimate) statistic. The strength of this thesis lies in the globalized perspective of the litterature, and in the rigor of the article selection process from which results were extracted. Indeed, the studies included in the meta-analyses needed to meet strict inclusion criteria in order to strengthen the accuracy and the validity of subsequent conclusions. Study 1: The first article is aimed at identifying brain areas involved in pain reduction through psychological methods of intervention. Chosen articles that covered a variety of approaches, such as placebo, hypnosis, meditation, perception of control over the stimulation, and induction of emotions. Analysis across these various studies indicated that PIH involves a broad network of activation that includes the anterior cingulate cortex, anterior insulae, orbital and lateral prefrontal and frontal areas, as well as parietal, temporal and subcortical regions. This activation network may reflect the involvement of diverse neuropsychological mechanisms in the various affective, self-awareness, cognitive and motivational processes underlying the psychological interventions targeted by these studies. In addition, we explored some specific patterns of brain activity related to placebo and distraction, in comparison to other approaches. We propose several hypotheses regarding the distinctive neuropsychological processes underlying these approaches. Study 2: The second article aimed at investigating patterns of brain activity preferentially associated with pain perception or with PIH. First we assessed patterns of increased and decreased activity during experimental pain in healthy volunteers. Second we determined the brain regions preferentially activated during pain perception or during PIH with subtraction analyses. Using a conjunction analysis, we also determined a set of brain regions possibly involved in regulatory processes activated spontaneously during acute of pain. Our results indicate that 1) somatosensory and motor areas are preferentially related to pain perception, which may reflect the preparation of a motor response, 2) dorsolateral prefrontal areas, anterior insula and the anterior midcingulate cortex were associated with both pain and PIH and may reflect the spontaneous activation of top-down regulation mechanisms during pain, and 3) antero-medial and orbital prefrontal regions were preferentially associated with PIH, which may indicate motivational and emotional processes associated with the engagement of an externally driven hypoalgesic procedure