Le développement de la représentation de l'espace auditif dans le collicule supérieur du rat

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

L’effet du stress sur la douleur aiguë et chronique

Objectif : Cette thèse a pour objectif de mieux comprendre l’effet du stress sur la douleur aiguë et chronique. Devis expérimental : 16 patients souffrant de douleur chronique lombalgique et 18 sujets contrôles ont participé à une étude d’imagerie par résonance magnétique (IRM) et ont collecté des échantillons de salive afin de quantifier les niveaux d’hormone de stress (i.e. cortisol) la journée de l’étude (réponse réactive) et durant les sept jours consécutifs suivants (réponse basale). Étude 1 : Une première étude a examiné le lien entre les niveaux de cortisol basal, le volume de l’hippocampe et l’activité cérébrale évoquée par la douleur thermique chez des patients souffrant de douleur chronique et les sujets contrôles. Les résultats révèlent que les patients souffrant de douleur chronique avaient des niveaux de cortisol plus élevés que ceux des sujets contrôles. Chez ces patients, un niveau élevé de cortisol était associé à un plus petit volume de l'hippocampe et à davantage d’activation dans le gyrus parahippocampique antérieure (une région impliquée dans l'anxiété anticipatoire et l'apprentissage associatif). De plus, une analyse de médiation a montré que le niveau de cortisol basal et la force de la réponse parahippocampique explique statistiquement l’association négative entre le volume de l'hippocampe et l'intensité de la douleur chronique. Ces résultats suggèrent que l’activité endocrinienne plus élevée chez les patients ayant un plus petit hippocampe modifie le fonctionnement du complexe hippocampique et contribue à l’intensité de la douleur chronique. Étude 2 : La deuxième étude a évalué la contribution de la réponse de stress réactif aux différences interindividuelles dans la perception de la douleur aiguë chez des patients souffrant de douleur chronique et chez des sujets normaux. Les deux groupes ont montré des augmentations significatives du niveau de cortisol en réponse à des stimulations nocives administrées dans un contexte d’IRM suggérant ainsi que la réactivité de l’axe hypothalamo-hypophyso-surrénalien est préservée chez les patients lombalgiques. De plus, les individus présentant une réponse hormonale de stress plus forte ont rapporté moins de douleur et ont montré une réduction de l'activation cérébrale dans le noyau accumbens, dans le cortex cingulaire antérieur (CCA), le cortex somatosensoriel primaire, et l'insula postérieure. Des analyses de médiation ont indiqué que la douleur liée à l'activité du CCA explique statistiquement la relation entre la réponse de stress et le désagrément de la douleur rapportée par les participants. Enfin, des analyses complémentaires ont révélé que le stress réduit la connectivité fonctionnelle entre le CCA et le tronc cérébral pendant la douleur aiguë. Ces résultats indiquent que le stress réactif module la douleur et contribue à la variabilité interindividuelle de l'activité cérébrale et la réponse affective à la douleur. Discussion : Conjointement, ces études suggèrent dans un premier temps que la douleur chronique peut être exacerbée par une réponse physiologique inadéquate de l'organisme exposé à un stress récurrent, et en un second temps, que le CCA contribuerait à l'analgésie induite par le stress. Sur le plan conceptuel, ces études renforcent le point de vue prédominant suggérant que la douleur chronique induit des changements dans les systèmes cérébraux régissant les fonctions motivationnelles et affective de la douleur.Goal : This thesis aimed at better understanding the impact of stress on acute and chronic pain. Experimental design: 16 patients with chronic low back pain pain and 18 control subjects participated in a functional magnetic resonance imaging (fMRI) study and collected saliva samples to quantify the levels of stress hormone (ie cortisol) the day of study (reactive response) and during the following 7 consecutive days (basal response). Study 1: The first study examined the associations between basal levels of cortisol, the hippocampal volumes, and brain activation to thermal stimulations in the low back pain patients and the healthy controls. Results showed that CBP patients have higher levels of cortisol than controls. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus (PHG), a region involved in anticipatory-anxiety and associative learning. Importantly, the results revealed that the cortisol levels and phasic pain responses in the PHG of the patients mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the higher levels of endocrine activity observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states. Study 2: The second study assessed the magnitude of the acute stress response to the noxious thermal stimulations administered in a MRI environment and tested its possible contribution to individual differences in pain perception. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared to their basal levels, suggesting normal hypothalamic–pituitary–adrenal axis reactivity to painful stressors in chronic back pain patients. Critically, individuals with stronger cortisol responses reported less pain unpleasantness and showed a reduction of BOLD activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula during heat pain. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness reported by the participants. Psychophysiological interaction further revealed that stress reduced functional connectivity between the aMCC and the brainstem during pain. These findings indicate that acute stress responses modulate pain in humans and contribute to individual variability in pain affect and pain-related brain activity. Discussion: Taken together, these studies firstly support recent theories suggesting that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor and secondly revealed the neural correlates of stress-induced analgesia. On a conceptual level, these findings are important because they strengthen the predominant view that chronic pain does not disrupt the acute response to stress and the sensory dimension of pain, but rather induces long-term changes in neural systems underlying affective-motivational functions

The modulation of somatosensory resonance by psychopathic traits and empathy

A large number of neuroimaging studies have shown neural overlaps between first-hand experiences of pain and the perception of pain in others. This shared neural representation of vicarious pain is thought to involve both affective and sensorimotor systems. A number of individual factors are thought to modulate the cerebral response to other's pain. The goal of this study was to investigate the impact of psychopathic traits on the relation between sensorimotor resonance to other's pain and self-reported empathy. Our group has previously shown that a steady-state response to non-painful stimulation is modulated by the observation of other people's bodily pain. This change in somatosensory response was interpreted as a form of somatosensory gating (SG). Here, using the same technique, SG was compared between two groups of 15 young adult males: one scoring very high on a self-reported measure of psychopathic traits [60.8 ± 4.98; Levenson's Self-Report Psychopathy Scale (LSRP)] and one scoring very low (42.7 ± 2.94). The results showed a significantly greater reduction of SG to pain observation for the high psychopathic traits group compared to the low psychopathic traits group. SG to pain observation was positively correlated with affective and interpersonal facet of psychopathy in the whole sample. The high psychopathic traits group also reported lower empathic concern (EC) scores than the low psychopathic traits group. Importantly, primary psychopathy, as assessed by the LSRP, mediated the relation between EC and SG to pain observation. Together, these results suggest that increase somatosensory resonance to other's pain is not exclusively explained by trait empathy and may be linked to other personality dimensions, such as psychopathic traits

Imaging Pain Relief in Osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome

Introduction: Osteoarthritis (OA) pain is a major cause of long-term disability and chronic pain in the adult population. One in five patients does not receive satisfactory pain relief, which reflects the complexity of chronic pain and the current lack of understanding of mechanisms of chronic pain. Recently, duloxetine has demonstrated clinically relevant pain relief, but only in half of treated patients with OA. Here the aim is to investigate the neural mechanisms of pain relief and neural signatures that may predict treatment response to duloxetine in chronic knee OA pain. Methods and analysis: This is an ongoing single-centre randomised placebo-controlled mechanistic study (2:1 [placebo] allocation), using a multi-modal neuroimaging approach, together with psychophysiological [quantitative sensory testing], genetics and questionnaire assessments. Eighty-one subjects with chronic knee OA pain are planned to power for between group comparisons (placebo, duloxetine-responder, and duloxetine-non-responder). Participants have a baseline assessment and, following six weeks of duloxetine (30mg for two weeks, then 60mg for four weeks), a follow-up evaluation. Brain imaging is performed at 3T with blood-oxygen-level dependent functional magnetic resonance imaging at rest and during pin-prick nociceptive stimulation for main outcome assessment; arterial spin labelling and structural imaging (T1- weighted) for secondary outcome assessment. Questionnaires evaluate pain, negative affect, quality of sleep and cognition. Ethics and dissemination: The study has been approved by the East Midlands – Nottingham 2 research ethics committee (18/EM/0189) and is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. Results will be disseminated in peer-reviewed journals and at scientific conferences

Accelerated functional brain aging in pre-clinical familial Alzheimer's disease

Alzheimer's disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer's disease. Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (A beta) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant A beta pathology

¿Afecta el dolor al volumen local del cerebro? Aportaciones desde un modelo clínico de dolor agudo

Background/Objective:To study pain-brain morphometry associations as a function of post-surgery stages (anesthesia, pain and analgesia) in an acute pain model. Method:Impacted mandible third molar were extracted. Before surgery, an anatomical T1 scan was obtained. Regional brain volumen and subcortical nuclei shapes were obtained. Statistical analyses were done using multiple regression, being pain scores the predictors and voxel volumes, subcortical nuclei volumes and subcortical nuclei shapes, the outcomes. Results:Pain was significantly larger at pain than at anesthesia and analgesia stages, and was higher during anesthesia than during analgesia. Pain intensity was related to grey matter in several cortical (Insula, Mid Frontal and Temporal Gyruses, Precuneus, Anterior Cingulate), and subcortical nuclei (Hippocampus, Thalamus, Putamen, Amygdala), depending of the post-surgical stage. A larger number of brain areas showed significance at pain that at anesthesia and analgesia stages. Conclusions:The relationships of regional brain volumes and subcortical nuclei shapes with pain scores seemed to be unsteady, as they changed with the patient’s actual pain stage.Antecedentes/Objetivo: Se trata de determinar la asociación entre dolor percibido y morfometría cerebral en tres etapas postquirúrgicas (anestesia, dolor y analgesia), en un modelo de dolor agudo. Método: Se obtuvo una imagen cerebral estructural de alta resolución y posteriormente se extrajeron los terceros molares mandibulares impactados. Se realizó un análisis morfométrico para determinar volumen cerebral y forma de núcleos subcorticales. Se realizaron análisis de regresión múltiple, siendo la intensidad del dolor el predictor, y el volumen y la forma de los núcleos subcorticales, medidos pre-cirugía, las variables dependientes.Resultados:El dolor experimentado fue mayor en la etapa de dolor que en las de anestesia y analgesia, y mayor en anestesia que en analgesia. El dolor se asoció con el volumen de materiagris en áreas corticales (insula, giros frontal medial y temporal, precuneus y cingulado anterior) y subcorticales (hipocampo, tálamo, putamen y amígdala). El número de áreas asociadasal dolor experimentado fue mayor en la etapa de dolor que en las de anestesia y analgesia. Conclusiones: La relación entre volumen cerebral regional y forma de núcleos subcorticales con la intensidad del dolor no es fijo, sino que varía en función de la etapa post-quirúrgica (magnitud del dolor).This investigation was partially supported by Research Groups #CTS-138, #CTS-176 and #CTS-1028. (Junta de Andalucía, Spain)

Negative emotional responses elicited by the anticipation of pain in others: Psychophysiological evidence

Limited evidence is available about factors influencing observers' anticipatory emotional responses to another's pain. We investigated fear and distress towards the threat of pain in others, and the moderating role of observers' psychopathic traits and catastrophizing about their own or others' pain. Thirty-six dyads of healthy participants were randomly assigned to either the role of observer or observed participant. Both participants were instructed that 1 colored slide (blue or yellow) signalled that a pain stimulus could possibly be delivered to the observed participant (=pain signal), whereas no pain stimulus would be delivered when a differently colored slide was presented (=safety signal). Observers' self-reported fear, fear-potentiated startle, and corrugator electromyography activity during pain and safety signals were measured. Furthermore, observers rated the presence of pain after each trial allowing assessment of observers' perceptual sensitivity to others' pain. Results indicated that self-reported fear, fear-potentiated startle, and corrugator electromyography activity were augmented during pain signals compared to safety signals. Moreover, these negative emotional responses were heightened in observers highly catastrophizing about others' pain, but reduced in observers with heightened psychopathic traits. Psychopathic traits were also related with a diminished perceptual sensitivity to others' pain. The results are discussed in light of affective-motivational perspectives on pain. Perspective: This study investigated observers' negative emotional responses in anticipation of pain in another, and the moderating role of observers' psychopathic traits and pain catastrophizing. Knowledge about characteristics influencing observers' emotional response to others' pain may provide insight into why observers engage in particular behaviors when faced with another in pain. © 2012 by the American Pain Society

Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology

Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer's Disease

Background: Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods: A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results: In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions: In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression