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

Brain imaging of chronic pain

Acute pain has substantial survival value because of its protective function in the everyday environment. Instead, chronic pain lacks survival and adaptive function, causes great amount of individual suffering, and consumes the resources of the society due to the treatment costs and loss of production. The treatment of chronic pain has remained challenging because of inadequate understanding of mechanisms working at different levels of the nervous system in the development, modulation, and maintenance of chronic pain. Especially in unclear chronic pain conditions the treatment may be suboptimal because it can not be targeted to the underlying mechanisms. Noninvasive neuroimaging techniques have greatly contributed to our understanding of brain activity associated with pain in healthy individuals. Many previous studies, focusing on brain activations to acute experimental pain in healthy individuals, have consistently demonstrated a widely-distributed network of brain regions that participate in the processing of acute pain. The aim of the present thesis was to employ non-invasive brain imaging to better understand the brain mechanisms in patients suffering from chronic pain. In Study I, we used magnetoencephalography (MEG) to measure cortical responses to painful laser stimulation in healthy individuals for optimization of the stimulus parameters for patient studies. In Studies II and III, we monitored with MEG the cortical processing of touch and acute pain in patients with complex regional pain syndrome (CRPS). We found persisting plastic changes in the hand representation area of the primary somatosensory (SI) cortex, suggesting that chronic pain causes cortical reorganization. Responses in the posterior parietal cortex to both tactile and painful laser stimulation were attenuated, which could be associated with neglect-like symptoms of the patients. The primary motor cortex reactivity to acute pain was reduced in patients who had stronger spontaneous pain and weaker grip strength in the painful hand. The tight coupling between spontaneous pain and motor dysfunction supports the idea that motor rehabilitation is important in CRPS. In Studies IV and V we used MEG and functional magnetic resonance imaging (fMRI) to investigate the central processing of touch and acute pain in patients who suffered from recurrent herpes simplex virus infections and from chronic widespread pain in one side of the body. With MEG, we found plastic changes in the SI cortex, suggesting that many different types of chronic pain may be associated with similar cortical reorganization. With fMRI, we found functional and morphological changes in the central pain circuitry, as an indication of central contribution for the pain. These results show that chronic pain is associated with morphological and functional changes in the brain, and that such changes can be measured with functional imaging.Akuutti kipu toimii terveellä ihmisellä elämää ylläpitäväna varoitussignaalina, joka syntyy vahingollisen ärsykkeen vaikutuksesta. Kivun muuttuessa krooniseksi se menettää normaalin varoitusfunktionsa, eikä enää edesauta selviytymistä. Krooninen kipu aiheuttaa yksilötasolla suurta kärsimystä ja huonontaa elämänlaatua, ja sen yhteiskunnalliset ja taloudelliset vaikutukset ovat mittavat hoitokulujen ja työkyvyttömyyden vuoksi. Kaikentyyppisessä kroonisessa kivussa keskushermostolliset mekanismit osallistuvat kivun kehittymiseen, säätelyyn ja ylläpitoon. Toistaiseksi näitä mekanismeja on ymmärretty huonosti, joten kroonisen kivun tehokas hoito on vaikeaa. Erityisesti silloin kun kroonisen kivun syntymekanismia ei tunneta, diagnostiikka, hoito ja kuntoutus ovat erityisen haasteellisia. Uudet aivokuvantamismenetelmät kuten magnetoenkefalografia (MEG) ja toiminnallinen magneettikuvaus (fMRI), joilla kipuun liittyviä aivoaktivaatioita voidaan havaita hyvällä aika- ja paikkatarkkuudella ovat tuoneet runsaasti tietoa akuutin kivun keskushermostollisesta käsittelystä terveillä ihmisillä. Tämän väitöskirjan tarkoituksena oli näitä menetelmiä käyttäen tutkia krooniseen kipuun liittyviä aivomekanismeja kahdella potilasryhmällä, jotka kärsivät kroonisesta kivusta. Tutkimuksiin osallistui kahdeksan monimuotoisesta paikallisesta kipuoireyhtymästä (CRPS) kärsivää potilasta, joilla krooninen kipu paikantui toiseen yläraajaan, sekä kahdeksan potilasta, jotka kärsivät toistuviin virusinfektioihin liittyvästä koko toisen kehonpuoliskon käsittävästä kroonisesta kiputilasta. Kipupotilaitten aivoaktivaatiota verrattiin terveiden verrokkihenkilöiden vastaaviin aivoaktivaatioihin. Tutkimuksissamme selvitimme ensin MEG:llä terveiden koehenkilöiden aivokuorivasteita kivuliaille lasersärsykkeille optimoidaksemme mittausparametreja ennen siirtymistämme varsinaisiin potilasmittauksiin. Seuraavaksi tarkastelimme MEG:llä CRPS-potilaiden aivokuorivasteita kosketukseen ja akuuttiin kipuun, sekä mittasimme liikeaivokuoren reaktiivisuutta akuuttiin kipuun. Osoitimme että käden edustustalue primaarilla tuntoaivokuorella (SI) oli kutistunut, viitaten siihen että krooninen kipu voi muovata aivoja ja jättää niihin pysyvät jäljet. Liikeaivokuori reagoi akuuttiin kipuun sitä huonommin, mitä voimakkaammasta kivusta potilaat kärsivät ja mitä huonompi puristusvoima kädessä oli. On mahdollista että potilaitten krooninen kipu johtaa liikeaivokuoren huonontuneeseen toimintaan ja sen välityksellä puristusvoiman heikkouteen. Lopulta käytimme MEG:tä ja fMRI:tä tutkiaksemme kosketuksen ja kivun käsittelyä potilailla, jotka kärsivät toistuviin virusinfektioihin liittyvästä kroonisesta kivusta. Havaitsimme käden edustusalueen kutistumisen SI:lla, viitaten siihen että useasta eri syystä johtuva krooninen kipu voi jättää samanlaiset jäljet aivoihin. fMRI:llä löysimme sekä toiminnallisia että rakenteellisia muutoksia aivojen kivunkäsittelyalueilla. Nämä muutokset viittaavat siihen että toistuviin virusinfektioihin liittyvillä keskushermostollisilla mekanismeilla voi olla osuutta kroonisen kivun kehittymisessä näillä potilailla. Tutkimuksen tulokset osoittavat, että krooniseen kipuun liittyy sekä rakenteellisia että toiminnallisia muutoksia aivoissa, ja että tällaiset muutokset ovat mitattavissa moderneilla aivokuvantamismenetelmillä

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

Modulation ascendante et descendante de l'intégration supraspinale d'inputs nociceptifs bilatéraux

La nociception est un système d’alarme spécialisé dans la détection d’évènements potentiellement nocifs pour l’organisme. Les informations nociceptives sont traitées en priorité par le cerveau et captent l’attention involontairement (un mécanisme ascendant). Cependant, l’information sensorielle à laquelle nous portons attention volontairement est sélectionnée pour être priorisée (un mécanisme descendant). Ainsi, le traitement de l’information nociceptive est déterminé par une balance attentionnelle résultant de la compétition entre les signaux ascendants et descendants. Or, des situations où plusieurs stimuli nociceptifs ont lieu simultanément se produisent couramment. Mais quels mécanismes permettent au système nerveux central de s’adapter à de telles situations? Cela demeure méconnu à ce jour. L’objectif principal de cette thèse était de mieux comprendre les mécanismes d’intégration cérébrale de l’information nociceptive. Cette thèse inclut quatre études examinant l’intégration cérébrale de l’information nociceptive bilatérale dans différentes conditions expérimentales. Dans ces études, nous avons investigué comment l’intégration de l’information nociceptive est affectée par 1) la latéralisation hémisphérique présumée distincte entre les droitiers et les gauchers, 2) la modalité utilisée pour induire la douleur (stimuli laser sélectifs aux nocicepteurs et stimuli électriques non spécifiques), 3) l’attention spatiale et 4) la proximité des régions corporelles stimulées. Dans chaque étude, au moins vingt participants furent recrutés et reçurent soit des stimuli électriques (étude 1 et 3) ou lasers (étude 2 à 4) douloureux. L’activité du cerveau fut enregistrée avec l’électroencéphalographie. Les stimulations unilatérales et bilatérales furent appliquées sur les chevilles (étude 1) et sur les mains (études 2 à 4). Les variables d’intérêts étaient la perception de la douleur, les potentiels évoqués, et les oscillations cérébrales évoquées entre 2 et 100 Hz. Nos résultats indiquent que l’effet le plus reproductible lors d’une stimulation laser ou électrique bilatérale comparée à une stimulation unilatérale, est une augmentation de l’amplitude des réponses cérébrales (potentiels évoqués et oscillations cérébrales dans certaines bandes de fréquences). De plus, la comparaison entre les gauchers et les droitiers indique que ces effets sont comparables malgré la latéralisation hémisphérique présumée. Par ailleurs, l’augmentation des réponses cérébrales est modulée par la proximité des régions corporelles stimulées. Quant à la perception de la douleur, elle augmente pour les stimuli bilatéraux lorsque ces derniers sont appliqués sur les chevilles ou les mains. Pour les mains, cet effet dépend toutefois de la distance entre les mains et de l’attention spatiale, étant observé seulement lorsque les mains sont rapprochées l’une de l’autre ou lorsque l’attention spatiale est dirigée vers les deux mains plutôt qu’une seule. Ces résultats montrent que l’intégration cérébrale de l’information nociceptive bilatérale est modulable, et nous proposons que l’augmentation des réponses cérébrales lors d’une stimulation bilatérale reflète une augmentation de la saillance et de la capture attentionnelle. Cette intégration et sa modulation par différents facteurs permettraient au système nerveux central de produire des réponses adaptées selon les sources de nociception et la balance attentionnelle.Nociception is an alarm system specialized in the detection of events that are potentially harmful to the body. Nociceptive processing is prioritized in the brain and is particularly adept at capturing attention automatically and involuntarily (i.e., a bottom-up mechanism). However, the sensory information to which we voluntarily pay attention (a top-down mechanism) is also prioritized. Thus, the processing of nociceptive information is subject to a bottom-up and top-down attentional balance. However, situations where several nociceptive stimuli take place simultaneously are common. The mechanisms that allow the nervous system to manage this attentional balance in such situations remain poorly understood. The main objective of this thesis was to better understand the integration of nociceptive information. This thesis presents four studies examining the cortical integration of bilateral nociceptive stimuli. These studies investigated the role of 1) the hemispherical lateralization of pain that is presumed to be different between left- and right-handed individuals, 2) the modality (a bottom-up mechanism) used to induce pain, 3) spatial attention (a top-down mechanism), and 4) between-limb proximity in the integration of bilateral painful stimuli. In each study, at least twenty participants were recruited and received either painful but tolerable electrical (Studies 1 and 3) or laser (Studies 2 to 4) stimulation. Brain activity was recorded via electroencephalography. Unilateral and bilateral stimulations were delivered to the ankles (Study 1) and to the hands (Studies 2 to 4). The variables of interest were pain perception, evoked potentials (ERP), and event-related spectral perturbations (ERSP) from 2 to 100 Hz. In the first study, the impact of the hemispherical lateralization of pain processing (located mainly in the right hemisphere) on the integration of pain stimuli was examined by comparing left-handed and right-handed participants. In the second study, lasers selectively activating nociceptors were used to study the integration of bilateral nociceptive stimuli specifically. The third study sought to explain the observed discrepancies between laser and electrical modalities in Studies 1 and 2 by comparing these modalities in the same participants and in two separate experiments. The fourth study explored the role of spatial attention and limb proximity in the integration of bilateral nociceptive stimuli. The results show that bilateral painful stimuli led to increases in ERP and some ERSP frequencies compared to unilateral stimuli. These results were similar between left-handed and right-handed people. More variability was noted for laser compared to electrical stimuli with the most reproducible response being an increase in ERP and ERSP. Finally, this increase was modulated by limb proximity. Pain perception was increased for bilateral stimuli to the ankles. It was also increased for bilateral stimuli to the hands, but only when the limbs were in close proximity or when spatial attention was global. These results suggest that bilateral painful stimuli are integrated, which possibly reflects an increase in salience and attentional capture. This would allow the central nervous system to produce adapted responses in the face of increased danger