Fine-grained nociceptive maps in primary somatosensory cortex

Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded fMRI analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the timecourse and the spatial pattern of plastic changes in cortical organization involved in chronic pain

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

CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH DISORDER PATIENTS: AN fMRI STUDY

Functional magnetic resonance imaging (fMRI) has been widely used to study cortical and subcortical mechanisms related to pain. The pathophysiology of burning mouth disorder (BMD) is not clearly understood. Central neuropathic mechanisms are thought to be main players in BMD. This study aimed to compare the location and extension of brain activation following thermal stimulation of the trigeminal nerve with fMRI blood oxygenation level dependent (BOLD) signal. This study included 8 female patients with BMD and 8 matched pain-free volunteers. Qualitative and quantitative differences in brain activation patterns between the two study groups were demonstrated. There were differences in the activation maps regarding the location of activation, with patients displaying greater BOLD signal changes in the right anterior cingulate cortex (ACC BA 32/24) and bilateral precuneus (pandlt;0.005). The control group showed larger BOLD signal changes in the bilateral thalamus, right middle frontal gyrus, right pre-central gyrus, left lingual gyrus and cerebellum (pandlt;0.005). It was also demonstrated that patients had far less volumetric activation throughout the entire brain compared to the control group. These data are discussed in light of recent findings suggesting brain hypofunction as a key player in chronic neuropathic pain conditions

Pain perception and migraine

Background: It is well-known that both inter-and intra-individual differences exist in the perception of pain; this is especially true in migraine, an elusive pain disorder of the head. Although electrophysiology and neuroimaging techniques have greatly contributed to a better understanding of the mechanisms involved in migraine during recent decades, the exact characteristics of pain threshold and pain intensity perception remain to be determined, and continue to be a matter of debate.Objective: The aim of this review is to provide a comprehensive overview of clinical, electrophysiological, and functional neuroimaging studies investigating changes during various phases of the so-called "migraine cycle" and in different migraine phenotypes, using pain threshold and pain intensity perception assessments.Methods: A systematic search for qualitative studies was conducted using search terms "migraine," "pain," "headache," "temporal summation," "quantitative sensory testing," and "threshold," alone and in combination (subject headings and keywords). The literature search was updated using the additional keywords "pain intensity," and "neuroimaging"to identify full-text papers written in English and published in peer-reviewed journals, using PubMed and Google Scholar databases. In addition, we manually searched the reference lists of all research articles and review articles.Conclusion: Consistent data indicate that pain threshold is lower during the ictal phase than during the interictal phase of migraine or healthy controls in response to pressure, cold and heat stimuli. There is evidence for preictal sub-allodynia, whereas interictal results are conflicting due to either reduced or no observed difference in pain threshold. On the other hand, despite methodological limitations, converging observations support the concept that migraine attacks may be characterized by an increased pain intensity perception, which normalizes between episodes. Nevertheless, future studies are required to longitudinally evaluate a large group of patients before and after pharmacological and non-pharmacological interventions to investigate phases of the migraine cycle, clinical parameters of disease severity and chronic medication usage

Alternatives for Analgesiometric Tests in Animals: The Feasibility to Reduce Discomfort by Anaesthesia

Animal pain and nociception studies have greatly contributed to our understanding of acute and chronic  pain processing and thereby contributed to the reduction of suffering of patients in pain. In classic analgesiometric  tests in conscious animals, animal suffering is inevitable as pain behaviour is the primary outcome.  Therefore, the feasibility of refining analgesiometric tests by anaesthesia is reviewed. The influence  on analgesiometric tests of different anaesthetics is described. Other objective primary outcome measures  than pain behaviour, including quantification of neural activation with c-fos and functional MRI (fMRI), are  suggested to reduce animal discomfort for pain testing. In conclusion, reflex analgesiometric tests may be  refined by choosing the right anaesthetics and alternative outcome measures such as c-fos or fMRI. Complex,  higher order pain behaviour testing still requires conscious animals and can currently not be refined  by the use of anaesthetics.

Cortical pain processing in the infant brain.

Premature infants are exposed to multiple invasive procedures as part of their essential medical care. It is not known, however, if nociceptive information is processed by the cortex at this age. The fundamental question to be addressed by this thesis is whether premature infants display cortical responses to noxious stimulation. This thesis describes a series of studies where the question of cortical pain processing is addressed by directly measuring cortical responses to noxious stimulation using near-infrared spectroscopy (NIRS) and electroencephalography (EEG). The NIRS results show that, following an acute noxious event, the contralateral somatosensory cortex is functionally activated in infants from 25 weeks postmenstrual age (PMA). Awake infants have a larger cortical response than asleep infants and, in the awake group, the size of the response increases with PMA. The magnitude of the haemodynamic response correlates with pain scores calculated using the premature infant pain profile (PIPP), although infants who do not display a change in facial expression can still process noxious stimuli at the cortical level. Latency to response is longest in the youngest infants using either the haemodynamic response or change in facial expression as an output measure. The underlying pain-related neuronal activity in the cortex has been investigated using EEG. Nociceptive-specific event related potentials have been observed in infants from 31-42 weeks PMA, with a recognisable N-P complex visible in the contralateral somatosensory cortex in 82% of studies. Noxious stimulation can evoke specific patterns of neural activity within the cortex of preterm and term infants that can be observed on a single-trial basis. The studies represent the first measurements of cortical activation in the immature preterm cortex following a noxious event. The fact that noxious information is transmitted to higher levels of the central nervous system highlights the importance of developing a systematic approach to reduce pain and improve analgesic strategies in this vulnerable population

The Application of Functional Magnetic Resonance Imaging in Neuropathic Pain

In the past, neuropathic pain has been lacking in ideal imaging research methods, which not only limits our research on the pathogenesis of neuropathic pain but also seriously affects the prognosis of treatments. With the rapid development of fMRI technology, more and more scholars have begun to use fMRI technology in the study of neuropathic pain in recent years. This provides a new idea for revealing the underlining mechanisms of neuropathic pain and improving the clinical treatment concepts. In this chapter, we summarized the recent studies of fMRI in neuropathic pain so that readers can better understand the research status and future research directions