Orientadores: Leonilda Maria Barbosa Santos, Benito Pereira Damasceno / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T05:17:45Z (GMT). No. of bitstreams: 1 Brandao_CarlosOtavio.pdf: 12100017 bytes, checksum: 1f85472f37234586b0f2737319179e3d (MD5) Previous issue date: 2009 / Resumo: Esclerose múltipla é uma doença inflamatória crônica, desmielinizante e neurodegenerativa do sistema nervoso central (SNC) que apresenta intensa variabilidade clínica e prognóstico imprevisível. Este é um estudo prospectivo com o objetivo de investigar o perfil da resposta inflamatória e a neurodegeneração em uma amostra de pacientes brasileiros com esclerose múltipla, comparando marcadores no líquido cefalorraquiano (LCR) e na imagem por ressonância magnética (IRM) quantitativa. Um grupo de 54 pacientes com esclerose múltipla remitente-recorrente (EMRR) foi recrutado para este estudo, de acordo com os critérios diagnósticos de Poser. Os exames de IRM foram processados e as amostras de LCR coletadas durante o processo diagnóstico e após tratamento com imunomodulador (beta-interferona ou acetato de glatirâmer). IgG e albumina no LCR e soro foram analisadas pelo método da nefelometria e a pesquisa de bandas IgG oligoclonais (BO) pela focalização isoelétrica. Citocinas, anticorpos para o vírus Epstein-Barr (EBV) e proteínas Tau foram quantificados através de kits comerciais pelo método ELISA. Os exames de IRM foram realizados com a utilização de um programa semi-automático. Os resultados demonstraram que pacientes com EMRR, mesmo na fase de remissão, apresentam aumento na secreção de citocinas pró-inflamatórias no soro e LCR associados à síntese intratecal de IgG e ao aumento do número de leucócitos no LCR. Na IRM foram detectadas lesões desmielinizantes em 94.4% e a presença de bandas oligoclonais foi demonstrada em 83% dos pacientes. Durante a evolução da doença foi possível observar uma correlação positiva do índice IgG com o volume total de lesões na IRM e com o número de leucócitos no LCR. Os níveis de T-tau estavam elevados quando comparados com os indivíduos controle e atrofia cerebral foi observada desde o diagnóstico. A taxa anual de surtos e o nível de proteína T-tau no LCR foram reduzidos após o tratamento com imunomodulador, mas aumento da EDSS foi demonstrado em grande parte dos pacientes. Com base em todas as análises, nós podemos concluir que a avaliação da IRM quantitativa e dos biomarcadores de inflamação pode ser muito útil na monitorização dos pacientes com EM, mesmo nos períodos clinicamente estáveis / Abstract: Quantitative MRI and CSF inflammatory mediators in a sample of brazilian multiple sclerosis population: a prospective study. Multiple sclerosis (MS) is referred to as a chronic inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS), with a highly variable clinical course and prognosis. This is a prospective study to investigate the profile of inflammatory response and neurodegeneration in brazilian MS population by comparing cerebrospinal fluid (CSF) markers and quantitative magnetic resonance imaging (MRI). A total of 54 patients with relapsing-remitting MS (RRMS) were included in this study according to Poser criteria. MRIs were performed and CSF samples were collected both during the diagnostic process and after immunomodulator treatment (beta interferon and glatiramer acetate). IgG and albumin in the CSF and serum were measured by nephelometry and oligoclonal IgG bands were identified by isoelectrofocusing. Cytokines, Epstein-Barr virus (EBV) antibodies and Tau proteins were quantified using commercial kits by ELISA. Brain MRI examinations were performed using a semi-automated local lesion threshold technique. The results demonstrated that patients with RRMS in stable phase of the disease reveal increase in the secretion of pro-inflamatory cytokines in both serum and CSF associated with the intrathecal synthesis of IgG and the number of leucocytes in the CSF. Demyelinating brain lesions were detected by MRI in 94.4% and the presence of oligoclonal bands were observed in 83% of patients. During the evolution of the disease, it was possible to establish a positive correlation of IgG index with total lesion volume and total leukocytes count. Increased CSF T-tau levels were found in MS as compared to controls and brain atrophy was observed since the diagnosis of disease. The both annual relapse rate and the level T-tau protein were significantly reduced after the treatment with IFNß, although many of the patients had presented an increased at EDSS. Taken together, we provide evidence that the study of MRI and the inflammatory parameters is an useful tool for monitorizing MS patients even in the stable form of the disease / Universidade Estadual de Campi / Neurologia / Doutor em Ciências Médicas

INTRODUÇÃO: O Doppler Transcraniano funcional pode avaliar mudanças na velocidade do fluxo sanguíneo encefálico associadas a tarefas cognitivas e/ou sensitivo-motoras. Mede de maneira indireta a atividade metabólica de regiões cerebrais, segundo o princípio do acoplamento neurovascular. Os objetivos deste estudo foram: desenvolver um novo método de análise de Doppler transcraniano funcional para análise da lateralização hemisférica e verificar a capacidade deste novo método em diferenciar a lateralização hemisférica durante a execução de uma tarefa motora unimanual por indivíduos saudáveis. Adicionalmente, a lateralização hemisférica foi correlacionada com a preferência manual nestes indivíduos. MÉTODOS: Treze indivíduos saudáveis foram submetidos a um exame de Doppler transcraniano funcional durante uma prova de ativação motora manual (oposição de dedos). As sessões de Doppler transcraniano funcional foram realizadas com aparelho Doppler-Box Transcranial Doppler Unit. A prova manual compreendeu uma sequência de movimentos de oposição do primeiro e segundo dedos (thumb-tofinger opposition movement) realizado por uma mão e depois pela outra, em uma frequência de 1 movimento por segundo (1Hz) fornecida por um metrônomo digital. Durante a execução dos movimentos, foram insonadas simultaneamente as artérias cerebrais médias direita e esquerda. Para interpretação dos dados de Doppler transcraniano funcional desenvolvemos um novo programa de análise denominado FDAT, que tem vantagens de sofrer mínima influência de artefatos de ruído no sinal e de não assumir um formato pré-determinado da resposta hemodinâmica cerebral. Foi calculado um índice de lateralização (IL) como a diferença entre a velocidade relativa média da época de ativação e a velocidade relativa média da época de repouso para cada prova motora. Foi calculada a diferença dos valores de IL (ILe - ILd) provenientes da análise com cada método, obtendo-se um índice de ativação, próprio de cada sujeito. A comparação do índice de ativação durante a movimentação da mão direita, e durante a movimentação da mão esquerda, foi feita com o teste de Wilcoxon. A correlação entre o índice de ativação e a preferência manual avaliada pelo Inventário de Edimburgo foi avaliada pelo coeficiente rho de Spearman. RESULTADOS: Houve uma diferença estatisticamente significante entre o IA obtido durante a movimentação da mão direita ou da mão esquerda (p=0,02). Houve correlação estatisticamente significante entre a preferência manual e a assimetria na lateralização hemisférica identificada pelo Doppler Transcraniano funcional (rho = 0.85, p < 0.001). CONCLUSÕES: A análise do Doppler Transcraniano funcional mostrou-se viável pelo método proposto, capaz de avaliar o grau de lateralização hemisférica em uma prova de ativação motora, com boa correlação com a preferência manual. Trata-se de uma ferramenta prática, não invasiva e de baixo custo para a avaliação da lateralização hemisférica em determinadas provas funcionais / INTRODUCTION: Functional transcranial Doppler is a method for the assessment of changes in blood flow velocity of the middle cerebral artery. An asymmetric increase in blood flow velocity is a marker of hemispheric lateralization during unimanual motor task performance. The aims of this study were to propose a novel and efficient method for functional transcranial Doppler analysis based on cubic smoothing splines, and to verify the ability of this method to identify hemispheric lateralization during unimanual motor task performance in healthy subjects. In addition, hemispheric lateralization was correlated with handedness in these subjects. METHODS: Thirteen healthy subjects participated in the study. Blood flow velocities in the right and left middle cerebral arteries were recorded using functional transcranial Doppler during a finger-tapping task with either the right or left hand. Data were analyzed with a multi-step new method that included: baseline determination, raw data normalization, smoothing, lateralization Index calculation, definition of rest and motor task epochs and activation Index calculation. A positive activation Index reflects right-hemisphere lateralization and a negative activation index, left hemisphere lateralization. RESULTS: There was a statistically significant difference between the activation index obtained during right or left hand movements (p=0.02). Hand dominance was significantly correlated with asymmetry in hemispheric lateralization assessed with functional transcranial Doppler (rho = 0.85, p<0.001). CONCLUSIONS: This novel method for functional transcranial Doppler analysis was capable to assess the hemispheric lateralization during motor task performance, and correlated well with handedness. It is a practical, non-invasive and unexpensive tool for the assessment of hemispheric lateralization.

Introdução: Déficits de memória episódica constituem o marcador cognitivo mais frequente em pacientes com Comprometimento Cognitivo Leve (CCL).Estudos prévios mostram que déficits de memória episódica podem ser minimizados nestes pacientes por intervenções comportamentais. Entretanto, os mecanismos cerebrais envolvidos nos efeitos do treino cognitivo ainda são pouco explorados. O objetivo deste estudo foi avaliar o correlato neural por ressonância magnética funcional de um treino breve de memória em pacientes com CCL e compará-los com os achados em idosos saudáveis. Foram avaliados 18 pacientes com CCL e 19 idosos controles com a utilização de ressonância magnética funcional (RMf) em uma tarefa de codificação de listas de palavras com diferentes graus de relação semântica antes e após uma sessão de treino de estratégias de memória. Na sessão pré-treino, os participantes foram instruídos a memorizar as palavras durante a sessão de RMf sem qualquer orientação sobre o uso de estratégias de codificação. Após um treino breve no qual estratégias específicas de organização e agrupamento semântico foram exercitadas, os sujeitos foram reconduzidos ao aparelho de ressonância magnética e realizaram a sessão pós-treino, na qual foram instruídos a utilizar a estratégia treinada durante o paradigma de codificação de palavras. Os resultados dos exames de ressonância magnética funcional foram processados e analisados com o programa FSL versão 4.1. Ambos os grupos apresentaram aumento no número de palavras evocadas associado ao uso da estratégia treinada. Em ambos os grupos foi observado um aumento do sinal BOLD após o treino em regiões do córtex pré-frontal dorsolateral esquerdo e do córtex parietal bilateral. No grupo de idosos controles, entretanto, foi observada também uma redução da ativação em regiões do córtex parietal posterior esquerdo e cíngulo posterior bilateral, do córtex pré-frontal medial e cíngulo anterior direitos, do lóbulo parietal inferior e do córtex temporal superior direitos, do córtex pré-frontal dorsolateral direiro e do córtex óribito-frontal bilateral. A interação grupo x tempo foi significativa em áreas do córtex pré-frontal dorsolateral e ventromedial direitos. Estes resultado indicam que existem diferenças no recrutamento de regiões pré-frontais em resposta ao uso de estratégias de codificação em paradigmas de codificação de palavras entre pacientes com CCL e idosos cognitivamente saudáveis / The present studyinvestigated the effects of different applicationsof verbal learning strategies duringepisodicmemory encoding in patients with Mild Cognitive Impairment (MCI) (n=18) and normal controls (n=17) using functional magnetic resonance imaging (fMRI).The main goal of this study was to verify whether externally guided increases in verbal learning strategy application during episodic memory encoding modulate brain activity in memory-related networks in the same level in MCI as in controls. Participantswerescanned twice, using a word-list encoding fMRI paradigm.In the first session, self-initiated encoding strategies were used to intentionally memorize words during encoding. In the second session, participants received an explicit instruction to apply a semantic organization strategy (i.e. semantic clustering)to perform the task. The fMRI word list learning paradigm consisted of alternating blocks of encoding and resting baseline conditions. To perform the spontaneous fMRI session, participants were not instructed about the semantic organization of the words in the lists beforehand or given any practice with related lists. Therefore, any grouping by category observed in the subsequent free recall at the end of this fMRI acquisition was presumed to be self-initiated by the subject. At the end of the spontaneous session, each subject received a brief period of guidance or instructions to apply semantic strategies and organize words in terms of semantic categories during encoding, using a new set of word lists. Immediately after practicing the application of the strategy, participants were scanned again using the same type of paradigm as in the first session, except for the use of new set of word lists and the explicit instruction to apply semantic clustering.Free recall and strategic index scores were assessedafter each session. fMRI brain activation and deactivation during encoding of word lists in memory-related networks were examined across sessions. Results from the fMRI analysis revealed that after the explicit orientation to apply the verbal learning strategy, greater recruitment of frontoparietal network regions were observed in both MCI and control groups in relation to the unconstrained encoding condition. Group-differences in functional deactivations, however, were observed in the medial prefrontal (mPFC) cortex and in the right superior frontal gyrus, two critical nodes of the default mode network, related to the absence of modulation in the activity of the mPFC, along with a lack of suppression of the right superior frontal gyrus in MCI, in response to the increased use of the encoding strategy. A different association between improvement in strategy use and session-related changes in activation of the medial orbitalfrontal cortex between groups was also confirmed. That is, improvements in strategy use in controls contribute to a great extent in the amount of deactivation in OFC, whereas in patients, only a small portion of the increase in activation in this region was predicted by increases in strategy application

Orientadores: Marilisa Mantovani Guerreiro, Maria Augusta Santos Montenegro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T12:19:41Z (GMT). No. of bitstreams: 1 Teixeira_KarineCoutoSarmento_D.pdf: 1935380 bytes, checksum: f49a9408e7247c9252440fae53c691c3 (MD5) Previous issue date: 2013 / Resumo: A cefaléia é uma condição extremamente prevalente em crianças e gera transtorno na vida familiar e escolar do seu portador. O objetivo geral do presente estudo foi caracterizar a frequência e tipos de cefaléia na infância, além de responder a algumas perguntas organizadas em subprojetos expostos abaixo. Foi realizada avaliação retrospectiva de prontuários, visando analisar os dados clínicos e de neuroimagem. As informações obtidas por análise de prontuários e complementadas em visitas de rotina. Os 674 pacientes estudados integraram um banco de dados, a partir do qual os resultados foram analisados e distribuídos em subprojetos. No subprojeto 1, verificamos o papel da investigação por neuroimagem nas cefaléias na infância. Foram incluídos 646 pacientes que apresentavam queixa de cefaléia e exame neurológico normal, a fim de avaliar o benefício da neuroimagem no diagnóstico e tratamento dessa patologia. Achados anormais de neuroimagem foram encontrados em 60 pacientes, classificados em três grupos: a) 9 pacientes com alterações relacionadas à patologia de base; b) 43 pacientes com alterações radiológicas benignas; e c) 8 pacientes com alterações radiológicas que mudaram a conduta médica. Desse último grupo, quatro pacientes tiveram lesões potencialmente cirúrgicas: hematoma subdural, tumor temporal de baixo grau, cisto colóide do terceiro ventrículo e papiloma do plexo coróide. No subprojeto 2, analisamos o papel da sinusopatia diagnosticada por imagem como etiologia das cefaléias. Os pacientes foram incluídos de forma prospectiva, comparando-se um grupo de 62 pacientes com cefaléia com um grupo controle de 41 pacientes, todos sem sintomas agudos de sinusite. Não encontramos diferença significativa entre os dois grupos em relação ao diagnóstico de sinusopatia por neuroimagem. No subprojeto 3, foram estudadas as características das síndromes periódicas da infância em 38 pacientes: 2 pacientes com torcicolo paroxístico benigno da infância; 12 com vertigem paroxística benigna da infância; 15 com migrânea abdominal; 1 com vômitos cíclicos; 3 com auras em migrânea; e 5 pacientes com migrânea confusional. Todos tinham exame neurológico normal e 25 pacientes tinham história familiar de migrânea. Os dois subtipos mais prevalentes na infância foram vertigem paroxística benigna da infância e migrânea abdominal. A profilaxia foi instituída em 23 pacientes (13 com ciproeptadina e 10 com flunarizina), todos tiveram boa evolução. No subprojeto 4 foi avaliado qual porcentagem dos pacientes com migrânea necessita de profilaxia e qual a sua eficácia. Dos 430 pacientes com migrânea, a terapia profilática foi instituída em 168 pacientes e 90% destes obtiveram boa resposta terapêutica. A droga mais utilizada foi a flunarizina em 90 pacientes, seguida pela ciproheptadina em 34 pacientes. Com os dados acima descritos foi possível concluir que: A história clínica de pacientes pediátricos não permite boa caracterização do tipo de cefaléia em muitas crianças, a maioria dos pacientes com cefaléia apresenta exame neurológico normal; migrânea sem aura é o tipo de cefaléia mais prevalente entre os pacientes acompanhados em nosso serviço; exame neurológico normal em pacientes pediátricos com cefaléia primária do tipo migrânea e tensional não exclui alteração de neuroimagem; cefaléia secundária mais frequentemente está associada a exame neurológico e neuroimagem alterados; este estudo sugere que a neuroimagem seja indicada na infância, após atendimento de serviço terciário, pois pode alterar conduta; sinusopatia diagnosticada pela neuroimagem em pacientes com cefaléia não exclui o diagnóstico de cefaléias primárias; os equivalentes de migrânea apresentam exame neurológico normal e boa resposta ao tratamento profilático; sugerimos que flunarizina e ciproheptadina são eficazes na profilaxia medicamentosa da migrânea / Abstract: Headache is an extremely prevalent condition in children and causes distress in their families and school life. The general aim of this study was to characterize the frequency and types of headache in childhood. This was a retrospective study conducted at an outpatient pediatric neurology clinic. Our database included 674 patients. Our data showed that most patients with headache had a normal neurological examination and migraine without aura was the most prevalent type of headache. Further results were subdivided in four subprojects. In subproject 1, we verified the role of neuroimaging in the diagnosis and treatment of headache in childhood. We included 646 patients with headache as a main complain and normal neurological examination. The findings were subdivided into three groups: 9 patients had abnormalities related to an underlying disease; 43 had radiological benign findings; and, eight had radiological findings that influenced clinical care. Of this latter group, four patients had potentially surgical lesions: subdural hematoma, low-grade temporal lobe tumor, colloid cyst of the third ventricle and choroid plexus papilloma. In subproject 2, we verified the role of sinus disease as a cause of headache when sinus disease is diagnosed by neuroimaging. Patients were included prospectively, comparing the group of 62 patients with headache with a control group of 41 patients with other neurological conditions and without headache, all without symptoms of acute sinusitis. There was no significant difference among them. In subproject 3, we included 38 patients with childhood periodic syndromes: 15 children had abdominal migraine, 12 had benign paroxysmal vertigo of childhood, five had confusional migraine, three had aura without migraine, two had benign paroxysmal torticollis of infancy, and one had cyclic vomiting. All had normal neurological examination and 25 patients had a family history of migraine. The two most prevalent subtypes in childhood were benign paroxysmal vertigo of infancy and abdominal migraine. Prophylaxis was recommended to 23 patients (13 cyproheptadine and 10 flunarizine), all had a good outcome. In subgroup 4, we verified the percentage of patients with migraine that need prophylaxis and its effectiveness. The prophylactic therapy was introduced in 168 patients and was effective in 90% of them. Flunarizine was the most used drug in 90 patients, followed by cyproheptadine in 34 patients. Our data allowed the following conclusions: clinical history of pediatric patients does not allow a good characterization of type headache in many children, most patients present with headache normal neurological examination; migraine without aura is the most prevalent type of headache among patients followed in our service; normal neurological examination in pediatric patients with primary headache of migraine and tension-type does not exclude changes in neuroimaging, secondary headache is most often associated with neurological examination and neuroimaging changed, this study suggests that neuroimaging is indicated in childhood after tertiary care, as it can alter conduct; sinusitis diagnosed by neuroimaging in patients with headache does not exclude the diagnosis of primary headaches, migraine equivalents have normal neurological examination and a good response to prophylactic treatment, we suggest that flunarizine and cyproheptadine are effective in the prophylaxis of migraine medication / Doutorado / Neurologia / Doutora em Ciências Médicas

Plusieurs fonctions cognitives sont latéralisées dans le cerveau humain adulte. Nous avons étudié l’origine des asymétries fonctionnelles chez les nourrissons, en évaluant les substrats neuronaux de reconnaissance des visages et des traitements du langage imbriqués dans les réseaux visuels et auditifs, grâce à la neuroimagerie non invasive (EEG et l’IRM de diffusion). Pour cela, nous avons étudié le développement fonctionnel et structurel de ces deux systèmes cérébraux au cours des six premiers mois postnataux. Nous avons observé que la vitesse des réponses visuelles était liée à la maturation des faisceaux de fibres de la matière blanche conduisant ces réponses, plus que l’âge des bébés, alors que la vitesse des réponses auditives doit dépendre d’un réseau de faisceaux de fibres et de régions corticales plus vaste. Parallèlement, nous avons étudié la latéralisation de la reconnaissance des visages grâce à un paradigme de discrimination des visages présentés dans chaque hémichamp. Nous avons observé que seul l'hémisphère droit pouvait discriminer les visages et que les informations pertinentes étaient transférées entre les deux hémisphères. Pour cibler la latéralisation du traitement du langage, nous avons étudié les réponses à des stimuli de la parole présentés de manière monaurale. Une comparaison entre un groupe de nourrissons avec une agénésie du corps calleux et un groupe contrôle a montré que les réponses à ces stimuli étaient transférées de façon asymétrique via le corps calleux. Cette asymétrie, facilitée vers l’hémisphère gauche, intervient probablement dans la latéralisation précoce du réseau du langage. L’ensemble de ces études mettent bien en évidence le potentiel de la neuroimagerie pour étudier le développement du cerveau et ces asymétries précoces. / Several cognitive functions such as face and speech processing are lateralized in the adult human brain. The ontogeny of these functional asymmetries is yet poorly understood. We aimed to evaluate the neural substrates of face and speech processing, nested in the visual and auditory networks using non-invasive neuroimaging techniques in infants. First, we studied how the functional and structural characteristics of these two brain systems change over the first postnatal semester. With EEG, we showed age-related decreases in the latency of brain responses and demonstrated that the speed of early visual responses is related to the maturation of underlying white matter tracts conducting them, as assessed with diffusion MRI. For the auditory system, our results suggested that the speed of responses may rely on maturation of more pathways and cortical regions. In parallel, we studied face processing lateralization using a discrimination paradigm of faces presented in each hemifield and observed that only the right hemisphere was able to discriminate between faces. Further evidence also suggested a transfer of face-relevant information across hemispheres. To study speech processing lateralization, we used a paradigm with monaural presentation of speech stimuli. A comparison between typical infants and infants with callosal agenesis, suggested an asymmetric transfer of auditory information across hemispheres, facilitated toward the left hemisphere, that might contribute to the lateralization of language early on. This thesis highlights the potential of neuroimaging techniques for the study of brain’s structural and functional development and of hemispheric asymmetries early on.

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings.

Visuomotor behaviour – from handling simple objects to operating complex devices – is of fundamental importance in our everyday lives, yet there is relatively little evidence as to how healthy ageing affects these processes. A central role is played by the human capacity for reaching and grasping. Grasping an object requires complex visuomotor transformations, including processing of the object’s extrinsic features (it’s spatial location) and intrinsic features (such as size and shape). It has been documented that action relevant intrinsic object properties automatically facilitate specific motor actions despite being task-irrelevant, the so-called object affordance effect. These effects have been demonstrated for (1) grasp type (precision and power grips being facilitated by small and large objects) and (2) object-orientation (whereby right and left handed grasps are facilitated by object-orientation), and might underlie the effortlessness with which humans can interact with objects. Yet, these paradigms have not previously been employed in the study of healthy ageing, and little is known concerning how these processes change over the life span. Elucidating these changes is of particular importance as age-related degeneration of white matter integrity is well documented. Consequently, if successful visuomotor behaviour relies on white matter integrity, age-related reductions in affordance effects should be observed. This prediction was tested in a series of experiments. Experiment 1 investigated age-differences in object-size compatibility effects, and results corroborated our prediction of age-related reductions in object-size effects. Experiment 2 investigated age-differences in (1) spatial compatibility effects versus object-orientation effects, and (2) the locus of the effects (facilitation versus interference effects). Results revealed (1) some evidence of larger affordance than spatial effects in both age-groups, and (2) interference effects in the younger group and both facilitation and interference effects in the older group, showing a potential change in processing modes or strategies. Experiments 3 and 4 addressed the main competing account, the attention-directing hypothesis (according to which attentional shifts are responsible for the generation of automatic response codes, rather than the affects arising from afforded actions), by using a novel stimulus set in which such attentional differences can be ruled out. Results provided strong evidence in favour of the object-size affordance hypothesis. A final neuroimaging experiment investigated age-differences in the object-size effect and its neural correlates by combining behavioural, functional MRI and diffusion tensor imaging (DTI) data. Results revealed evidence of age-differences, both on the behavioural and functional level. For the DTI data, we investigated all four diffusion metrics (something which is not frequently reported in the healthy ageing literature), and found widespread age-related differences in white matter integrity. The empirical findings presented in this thesis offer a significant contribution to ageing research, by further elucidating the relationship between age-related neurophysiological changes and visuomotor behaviour. The overall picture which emerged from this series of experiments was consistent with our prediction of age-related reductions in affordance effects. Furthermore, it is likely that these age-differences may have, at least in part, a neurophysiological basis.

There is growing evidence to suggest that vascular disease plays an important role in late life depressive disorder. The aim of this study was to characterize vascular impairment in late life depression. Assessment of endothelial function, arterial stiffness, and atherosclerosis in a variety of vessel beds was carried out in 25 subjects with late life depression and 21 nondepressed control subjects. All study subjects underwent wave velocity, pulse wave analysis, carotid intima media thickness analysis, and magnetic resonance imaging of the brain and a subset gluteal fat biopsy and direct assessment of small artery endothelial function. There were no baseline differences in demographics or a range of vascular risk factors between the groups. There was a generalised vascular dysfunction in depressed subjects with significantly more atherosclerosis, poorer endothelial function and increased arterial stiffness. On neuroimaging, depressed subjects had significantly more dilated Virchow-Robin spaces in the basal ganglia. White matter lesion volumes in all regions were higher in depressed subjects but not significantly so. Furthermore, subjects with late onset depression (onset >60years) had greater vascular impairment when compared to those with early onset illness. Lastly, depressed subjects who did not respond to antidepressant monotherapy showed more vascular dysfunction compared to responders. The study has a number of limitations including the small sample size and as the study was cross sectional, the observed relationship between vascular dysfunction and depression is associative rather than causal. Further research in larger samples is required to address the methodological limitations of this study. If the study results are confirmed, the use of vasoprotective drugs to improve vascular function or retard atherosclerosis as diasease modifying agents in late life depression would be a rational development.

Les travaux en psychologie ont mis en évidence que les jeunes et âgés utilisent différentes stratégies pour accomplir des tâches cognitives. La question qui se pose alors est comment nous choisissons une stratégie parmi plusieurs stratégies disponibles. Afin de mieux comprendre la sélection stratégique, l’objectif de cette thèse était d’étudier le phénomène de changement stratégique intra-item et son évolution au cours du vieillissement, d’une part, et de mettre en évidence les mécanismes impliqués lors du choix d’une stratégie, d’autre part. Nos données montrent que différentes variables, intrinsèques et extrinsèques aux problèmes, influencent la capacité de changement stratégique intra-item au cours du vieillissement. Les jeunes et les âgés interrompent une stratégie en cours d’exécution et choisissent une stratégie différente que celle précédemment exécutée. Les participants changeaient plus fréquemment de stratégies afin de choisir la meilleure stratégie, et ce d’autant plus que la stratégie était facile à exécuter. Les âgés avaient de plus difficultés que les jeunes à changer de stratégies et par conséquent, ils choisissaient moins fréquemment la meilleure stratégie. Nous montrons aussi que la sélection stratégique est associée à une augmentation de l’activité cérébrale dans des régions préfrontales bien connues pour être le siège des fonctions exécutives. Enfin, nous discutons en quoi ces résultats ont d’importantes implications concernant, les modèles théoriques de la sélection stratégique, et concernant le vieillissement cognitif. / Psychology research has shown that young and older adults used different strategies to accomplish a cognitive task. Thus, the issue of how we choose a strategy among several available strategies is raised. In order to further understand strategy selection, the goal of this thesis was to investigate the within-item strategy switching and its evolution with age, on one hand, and to highlight mechanisms involved in the selection strategy, on other hand. Our data show that different variables, intrinsic and extrinsic to the problems, affect the ability of switching strategies within item during aging. Young and older adults interrupt a mid-execution strategy and choose a different strategy than previously executed. Participants switched strategies more frequently to choose the best strategy, and especially when the strategy was easy to execute. Older adults had more difficulties than young adults to switch strategies and therefore, they chose less frequently the best strategy. We also show that the strategy selection is associated with increased brain activities in prefrontal regions, well known to be the seat of executive functions. Finally, we discuss how these results have important implications for theoretical models of strategy selection, and for cognitive aging.

Le langage demeure préservé des effets du vieillissement mais précocement atteint dans la Maladie d'Alzheimer (MA). Le discours, en mobilisant l'ensemble des fonctions cognitives, pourrait mettre en évidence davantage de difficultés. Ce travail vise à analyser des productions de patients et de participants âgés typiques en lien avec les changements cognitifs et cérébraux. Une étude s'est intéressée à la production de discours portant sur des événements personnellement vécus. Une deuxième visait à comparer ce type de discours à un discours sur support imagé. Les résultats montrent que les difficultés rencontrées lors d'un discours d'événements vécus seraient corrélées à l'atteinte mnésique des patients. A l'inverse, elles seraient associées à l'atteinte exécutive et lexicale dans un discours imagé. Une dernière étude s'est focalisée sur la variabilité existant chez les participants âgés "typiques". Une analyse en cluster a montré quatre profils de locuteurs, dont un profil "hors-sujet" qui pourrait refléter une zone ambiguë entre vieillissement normal et pathologique. Ce travail pointe des marqueurs de MA prodromale, en lien avec les modifications cognitives et cérébrales. Certaines difficultés seraient liées à une atteinte mnésique ou exécutive indépendamment de l'altération langagière. / Language is the most preserved cognitive function from the effects of aging. Unlike typical aging, Alzheimer's disease (AD) is characterized by an early impairment. Analysis of discourse may reveal more difficulties than other tests since it mobilizes a large set of cognitive functions. This work aims to analyze various discourses in AD patients and participants with typical aging, in relation to various cognitive tests as well as neuroimaging data. One study focused on a memory-based discourse. A second study compared a memory-based and in a picture-based discourse. Patients' difficulties were correlated on one hand with memory impairment in the memory-based discourse and on the second hand with lexical-executive impairment in the picture-based discourse. A final study focused on discourse variability in the general aging population. A cluster analysis revealed four profiles of speakers. Among them, an "off-topic" profile could reflect a grey zone between normal and pathological aging. This work allowed us to shed light on deficit markers and compensatory strategies in prodromal AD, in relation with cognitive and cerebral changes. In particular, many difficulties may actually be related to memory or executive impairment, regardless of a language alteration.