Neuronal and behavioural pain processing

In our study “Neuronal and Behavioural Pain Processing: A Comparison Between a Strong Brand and a Generic Medication Placebo using the Example of Aspirin vs. 1A Pharma”, we investigated the expectation effects associated with brands by labelling two different placebo interventions. We tested the hypothesis, whether a strong brand can influence the impact of an inert substance. We studied the potential differences between the two placebos on a behavioural and neural level inducing the stimulus with noxious heat pain using Medoc. The research objective was to unveil, whether recipients can be influenced through expectations, verbal suggestions and the brand itself. We applied a two by two design with two identical placebo interventions that differed in their labelling. One group was told that they will receive 500 mg of “Aspirin” (original brand), while the other group was told that they will receive a popular ASA generic (“1A Pharma”). At the beginning, we established the individual pain levels of each subject with the numeric rating scale. Then we measured pain intensities before and after the intervention. The intervention was the administration of the placebo. We investigated behavioural as well as neural differences and looked for corresponding activated brain regions using functional magnetic resonance imaging (fMRI). Those participants, who were administered the original brand in the placebo intervention, showed a decrease in pain intensity. The generic group did not show any significant pain decrease. At the neuronal level, during the native condition, we observed activations of the anterior insula in both groups. After the intervention, the participants showed activations of the dorsomedial prefrontal cortex. The direct comparison of the two placebo conditions – the branded placebo vs. the generic – showed higher activations for the bilateral dorsolateral and dorsomedial prefrontal cortex. During the anticipation phase we observed activations of hippocampal, parahippocampal and adjacent brain areas for the generic group, only. These results suggest that only the original brand appears to evoke a behavioural response measured in terms of pain reduction. On a neuronal level, the activations were significant for the original brand only. Comparing the two placebo interventions, expectations seem to be significantly enhanced by the trusted brand, which appears to boost the placebo effect. Our results suggest that the underlying neural mechanisms of this placebo response are based on fronto-cortical neural networks

Developing advanced MR imaging to assess spinal cord function and tract integrity.

The overall purpose of this thesis is to develop a way to match diffusion and functional acquisition techniques in the spinal cord (SC) in order to offer a comprehensive assessment of factors responsible for functional and structural integrity. I began by optimising a pipeline to acquire and process spinal functional data and I finished by matching the functional information with that derived from diffusion imaging (DI) performed during the same scan session as fM RI. In order to characterize the interactions between local structural connections (derived from DI) and functional activation of the SC it has been necessary to develop an imaging protocol that acquires transverse SC images with both modalities, matching their spatial and geometrical characteristics. This is because transverse cord images possess the relevant anatomical information in terms of grey-white matter structure and allow better localisation of the functional response and structural properties within the spinal cord. My main contribution to the field has been: 1. To demonstrate that it is possible to use the “ZOOM” sequence for spinal fM RI 2. To characterize the signal obtained and the comparison of different image analysis approaches 3. To propose a final pipeline for acquisition and analysis of spinal fM RI 4. To demonstrate that there is a dependency of pathological functional and structural changes The same ZOOM-EPI sequence has been applied for all the functional studies reported in this thesis. The outcome of the optimisation for spinal fMRI has been matched by a DI protocol, using standard DI parameters for spinal microstructural characterization and constitutes the final MR protocol used in a pilot study including a group of healthy controls and a group of patients affected by multiple sclerosis (MS). Based on the gathered experience and results from data acquired and analysed over the years I have concluded with some recommendations for future studies and development strategies for structural and functional MRI of the spinal cor

Modulation of nociception and pain by attention and stress

Les facteurs psychologiques tels que l'hypnose, l'émotion, le stress et l’attention exercent un effet modulant puissant sur la nociception et la douleur. Toutefois, l’influence de l'attention sur la nociception et la douleur, ainsi que les mécanismes neuronaux sous-jacents, ne sont pas clairs. La littérature actuelle sur la modulation attentionnelle des réponses spinales nociceptives, telles que mesurées par le réflexe RIII, et de la perception de l’intensité de la douleur est discordante et souvent contradictoire. Ce mémoire fournit un nouveau cadre pour examiner la modulation du réflexe RIII et de la douleur par l’attention. Une tâche de discrimination sensorielle a été décomposée en trois composantes attentionnelles : la vigilance, l’orientation, et le contrôle exécutif. Auparavant, la nature multidimensionnelle de l’attention fut largement ignorée dans la littérature. Nous démontrons que les composantes attentionnelles ont des effets modulatoires distincts sur la nociception et la douleur et suggérons que ceci représente une partie de la confusion présente dans la littérature. En prenant compte du stress indépendamment, nous démontrons, pour la première fois, que le stress inhibe la modulation attentionnelle du réflexe RIII ce qui indique une interaction et dissociation de la modulation des réponses nociceptives par l’attention et le stress. Ces résultats importants clarifient, en grande partie, les contradictions dans la littérature, puisque les tâches cognitives produisent souvent des augmentations du stress ce qui confond l’interprétation des résultats. De plus, la tâche de discrimination inclut des stimuli visuels et somatosensoriels et révèle que l’influence de l'attention sur la douleur est spatialement spécifique tandis que la modulation attentionnelle de la nociception est spécifique à la modalité des stimuli, au moins en ce qui concerne les modalités examinées. A partir de ces résultats, un nouveau modèle de la modulation attentionnelle des processus de la douleur, basée sur les composantes attentionnelles, a été proposé. Celui-ci est appuyé par la littérature et fournit une explication systématique et intégratrice des résultats antérieurement contradictoires. De plus, à partir de ce modèle, plusieurs mécanismes neuronaux ont été proposés pour sous-tendre la modulation attentionnelle de la nociception et de la douleur.Psychological factors such as hypnosis, emotion, stress, and attention produce powerful modulatory effects on nociception and pain. However, the influence of attention on nociception and pain and the underlying neural mechanism responsible are unclear. The current literature on attentional modulation of spinal nociceptive responses, as measured by the RIII reflex, and pain perception (pain intensity) is inconsistent and often contradictory. The present thesis provides a new component-based framework for the examination of attentional modulation of the RIII reflex and pain. A delayed-discrimination task was decomposed into the three components of attention – namely alerting, orienting, and executive control (sensory working memory). Previously, the multidimensional nature of attention was largely ignored in the pain literature. We show that each component of attention exerts a distinct modulatory effect on nociception and pain and suggest that this accounts for some of the confusion in the literature. By considering stress separately, we demonstrate for the first time that stress blocks attentional modulation of the RIII reflex, indicating an interaction and dissociation of attention- and stress-mediated modulation of spinal nociceptive responses. This important finding clarifies much of the disagreement in the literature, since cognitive tasks often induce increases in stress that consequently confound interpretation. Additionally, both visual and somatosensory stimuli were included in the discrimination task, revealing that the influence of attention on pain intensity is spatially-specific whereas attentional modulation of nociception is modality-specific, at least for the modalities investigated. From these findings a component-based model for the attentional modulation of pain processes is proposed. This model is substantially supported by the literature and provides a meaningful and cohesive explanation of the seemingly contradictory results across studies. Moreover, this model suggests potential neural mechanisms underlying the attentional modulation of pain

Neuronal and behavioural pain processing

In our study “Neuronal and Behavioural Pain Processing: A Comparison Between a Strong Brand and a Generic Medication Placebo using the Example of Aspirin vs. 1A Pharma”, we investigated the expectation effects associated with brands by labelling two different placebo interventions. We tested the hypothesis, whether a strong brand can influence the impact of an inert substance. We studied the potential differences between the two placebos on a behavioural and neural level inducing the stimulus with noxious heat pain using Medoc. The research objective was to unveil, whether recipients can be influenced through expectations, verbal suggestions and the brand itself. We applied a two by two design with two identical placebo interventions that differed in their labelling. One group was told that they will receive 500 mg of “Aspirin” (original brand), while the other group was told that they will receive a popular ASA generic (“1A Pharma”). At the beginning, we established the individual pain levels of each subject with the numeric rating scale. Then we measured pain intensities before and after the intervention. The intervention was the administration of the placebo. We investigated behavioural as well as neural differences and looked for corresponding activated brain regions using functional magnetic resonance imaging (fMRI). Those participants, who were administered the original brand in the placebo intervention, showed a decrease in pain intensity. The generic group did not show any significant pain decrease. At the neuronal level, during the native condition, we observed activations of the anterior insula in both groups. After the intervention, the participants showed activations of the dorsomedial prefrontal cortex. The direct comparison of the two placebo conditions – the branded placebo vs. the generic – showed higher activations for the bilateral dorsolateral and dorsomedial prefrontal cortex. During the anticipation phase we observed activations of hippocampal, parahippocampal and adjacent brain areas for the generic group, only. These results suggest that only the original brand appears to evoke a behavioural response measured in terms of pain reduction. On a neuronal level, the activations were significant for the original brand only. Comparing the two placebo interventions, expectations seem to be significantly enhanced by the trusted brand, which appears to boost the placebo effect. Our results suggest that the underlying neural mechanisms of this placebo response are based on fronto-cortical neural networks