Les tumeurs de la fosse postérieure (PFT) représentent les deux tiers des tumeurs cérébrales pédiatriques. Les PFT malignes les plus fréquentes sont le médulloblastome (40%), suivie de l'épendymome (10%). La chirurgie, la radiothérapie et/ou la chimiothérapie sont les approches thérapeutiques utilisées à l’heure actuelle. En raison de l'amélioration des traitements, la survie a augmenté de façon significative. Cependant, ces enfants souffrent de déficiences cognitives variées en partie attribuées à la radiothérapie et ce d’autant plus qu’ils sont jeunes. Atténuer les séquelles neurocognitives est devenu ces dernières années un des enjeux majeurs de l'oncologie pédiatrique. Dans cette optique, ce travail examine chez des enfants traités pour une PFT, les relations entre doses de radiothérapie reçues et performances neuropsychologiques en fonction de l’âge, au moyen d’une approche associant la neuroimagerie et la neuropsychologie. La contribution expérimentale s’articule autour de deux principaux axes. Le 1er axe utilise une approche exploratoire pour rendre compte des relations entre l’irradiation des régions cérébrales et le déclin cognitif chez les enfants traités pour une PFT. L’analyse des données met en relation des patterns spatiaux de répartition des doses dans le cerveau avec la variation des scores neuropsychologiques dans le temps (Mémoire de travail, vitesse de traitement, QI). Nos principaux résultats suggèrent une association entre la diminution des capacités en mémoire de travail et l’augmentation des doses (Dose uniforme équivalente, EUD) délivrées aux régions orbitofrontales ; alors qu’un ralentissement de la vitesse de traitement semble être lié à une dose élevée dans les lobes temporaux et la fosse postérieure. Le 2nd axe utilise une approche a priori pour déterminer l’impact de la maladie et des traitements sur le développement de la mémoire épisodique (ME) et des hippocampes, chez de jeunes enfants (2-13 ans). Cette partie se structure autour d’une part de l’analyse des performances des patients lors d’une tâche expérimentale mesurant la ME et d’autre part, d’une analyse longitudinale des volumes hippocampiques de ces enfants pendant le traitement. Nous avons a mis en évidence chez les enfants avec PFT une altération de la ME dépendant de l’âge : Chez les patients plus jeunes (<7 ans), l'altération était globale tandis que chez les plus âgés, elle ne concernait que la reconnaissance à long terme des détails temporels (c'est-à-dire «quand»). L’analyse des données volumiques hippocampiques n’a pas pu être achevée dans le temps de cette thèse, compte tenu de plusieurs difficultés méthodologiques liées notamment au recalage longitudinal des cerveaux en croissance. Ce travail apporte des connaissances nouvelles sur le rôle de certains facteurs dans l’émergence de difficultés cognitives spécifiques. La prévention des séquelles à long terme de ces enfants reste un défi pour les années à venir. / Pediatric posterior fossa tumors (PFT) account for two-thirds of all pediatric brain tumors. The most common malignant PFT is medulloblastoma (40%), followed by ependymoma (10%). Surgery, radiotherapy and/or chemotherapy are the current therapeutic approaches. As a result of the progress of treatment, event-free survival has significantly improved. Unfortunately, these children suffer from many cognitive impairments partly attributed to radiotherapy, especially in young children. Alleviating neurocognitive impairments has become one of the major challenges of pediatric oncology. Using an approach combining neuroimaging and neuropsychology, this work examines the relationship between treatments and neuropsychological performances as a function of age in children treated for PFT. The experimental contribution is based on two main axes. The first axis uses an exploratory approach to investigate the relationship between the decline of intellectual functioning and radiation dose distribution. For this purpose, we analyze, with a whole brain analysis, the relation between regional biological dose and changes over time of different cognitive scores (IQ, processing speed and working memory). Our results suggest a positive association between working memory decline and high dose (Equivalent Uniform Dose, EUD) delivered to the orbitofrontal regions, whereas decline of processing speed seems more related to EUD in the temporal lobes and posterior fossa. The 2nd axis uses a hypothesis-driven approach to determine the susceptibility of episodic memory (EM) impairment and hippocampal alteration in young child PFT patients (2-13yo). This part is structured around two aims: First, the assessment of PFT EM performances, thanks to an EM task, in comparison to Controls; second, the exploration of longitudinal patterns of hippocampal volume as a potential neural substrate underlying EM performance. The main results support the evidence of EM impairment in the PFT condition, which varied according to age: in the younger patients (<7yo) impairment was global while in the older it involved only the long term recognition of temporal details (i.e. ‘When’). However, at this stage of the work, several methodological difficulties mainly related to the registration parameters of the segmentation algorithm prevent us from achieving hippocampal volume analysis. This work brings new knowledge about the role of some risk factors on specific cognitive difficulties. Preventing long-term impairments of these children remains a challenge for years to come.

Introdução: A memória prospectiva (MP) refere-se a um conjunto de habilidades cognitivas que permitem lembrar-se de uma intenção a desempenhar no futuro, no momento adequado. Essa função é pouco avaliada em baterias neuropsicológicas que avaliam pessoas com epilepsia. Objetivo: Estudamos o impacto da cirurgia para epilepsia sobre a MP, componente prospectivo, em pessoas submetidas a lobectomia temporal unilateral para controle de epilepsia refratária ao tratamento clínico. Métodos: Comparamos o desempenho de MP em pessoas com epilepsia associada à esclerose mesial temporal à esquerda (EMTE) ou direita (EMTD) com dois grupos controles. Um grupo foi composto por indivíduos sem epilepsia (controles normais), e o outro por pessoas com epilepsia secundária à EMT, submetidos a avaliação e reavaliação neuropsicológica, sem intervenção cirúrgica (grupo clínico para controle teste/reteste). Resultados: Avaliamos 42 indivíduos sem epilepsia, 20 do grupo clínico (controle teste/reteste) e 39 do grupo cirúrgico (pré e pósoperatório). Comparamos o desempenho entre grupos e também a variação de desempenho individual, pelo índice de mudança confiável. Os grupos não diferiram em idade, escolaridade e quociente de inteligência. Na avaliação inicial, observou-se rebaixamento no desempenho em MP nos grupos clínico e cirúrgico (p < 0,01) (efeito lesão), sem diferença entre os grupos EMTE ou EMTD (efeito lateralidade). Para o grupo cirúrgico, observamos acentuada (p < 0,01) redução de crises e leve, porém significativa, redução de carga de drogas antiepilépticas pós-operatória. Observamos estabilidade em reteste de MP, declínio de memória verbal para o grupo EMTE e estabilidade de memória verbal e visual para o grupo EMTD. Conclusão: Embora exista um sistema de evocação compartilhado entre a MP e a memória episódica, a ressecção de estruturas temporais mesiais acometidas patologicamente não provoca declínio adicional em MP, mesmo quando se observou declínio de memória verbal no grupo EMTE. O comportamento dissociado de declínio de memória verbal para o grupo EMTE e preservação de MP após cirurgia de epilepsia sugere diferentes papeis das estruturas temporais mesiais nestes sistemas de memória. O papel do acometimento de estruturas extratemporais e de estruturas temporais não mesiais na MP em pacientes com EMT deverá ser melhor elucidado em estudos futuros / Introduction: Prospective memory (PM) refers to a set of cognitive abilities that allow recall of a previous intention to perform in the future, in the appropriate setting. This function is not usually evaluated in neuropsychological batteries used to evaluate people with epilepsy. Objective: We evaluated the impact of epilepsy surgery on the prospective component of PM, in people undergoing unilateral temporal lobectomy to treat medically refractory epilepsy. Methods: We compared performance in PM in people with left or right mesial temporal sclerosis (MTS) in the pre and postoperative periods with that of two control groups. One group was composed of people without epilepsy (normal controls), and another group was composed of people with epilepsy associated with mesial temporal sclerosis that underwent neuropsychological testing and retesting without undergoing surgery (clinical test/retest control group). Results: We studied 42 people without epilepsy, 20 clinical controls (test/retest group), and 39 patients that underwent epilepsy surgery (pre and postoperative testing). We compared groups performances and changes in individual performances with the reliable change index. Groups did not differ in age, education, and intelligence quotient. We found decreased preoperative PM performance for the clinical and surgical groups (p < 0.01) (lesion effect), without a difference between right and left groups (laterality effect). Postoperatively, there was a significant (p < 0.01) decrease in number of seizures, a small, but significant reduction in antiepileptic drug load, stable prospective memory, verbal and visual memory for right mesial temporal sclerosis, and decreased verbal memory in the left mesial temporal sclerosis group. Conclusion: In spite of a shared evocation system for episodic and prospective memory, resection of pathologically involved mesial temporal structures does not impact on prospective memory performance, even in the setting verbal memory decline in the left MTS group.The finding of dissociated verbal memory decline and PM stability after epilepsy surgery suggests a different role of mesial temporal lobe structures in these memory systems. The role of extratemporal and nonmesial temporal lobe structures in prospective memory in MTS patients should be evaluated in future studies

INTRODUÇÃO: As bases neurofisiológicas do declínio cognitivo associado ao envelhecimento normal ainda não são adequadamente conhecidas. Estudos sobre conectividade funcional cerebral estimada através de imagens por ressonância magnética funcional durante o repouso têm identificado diminuições de conectividade dentro da rede de modo padrão (default mode network) em idosos e correlações entre desempenho cognitivo e conectividade funcional. Há evidências de que idosos apresentam maior dificuldade em recuperar informações episódicas de eventos autobiográficos mas não existem investigações sobre a relação entre tal função cognitiva e conectividade de repouso. Além disso, estudos desta área geralmente não têm utilizado entrevista psiquiátrica para seleção da amostra, apesar de transtornos psiquiátricos apresentarem alta prevalência, serem subdiagnosticados e afetarem o funcionamento cerebral. OBJETIVOS: caracterizar as mudanças de conectividade funcional de repouso associadas a idade e a desempenho cognitivo, em especial à função de memória autobiográfica, em uma amostra de adultos de diferentes idades e livres de deficiências cognitivas e de transtornos psiquiátricos. MÉTODOS: adultos jovens, de meia idade e idosos sem transtornos cognitivos ou psiquiátricos foram selecionados através de avaliação neuropsicológica e entrevista psiquiátrica estruturada. Quantificamos o desempenho em recuperar informações episódicas de eventos autobiográficos. Conectividade funcional cerebral foi estimada a partir de imagens de ressonância magnética funcional adquiridas durante o repouso vigil, utilizando um atlas de 278 regiões englobando todo o cérebro. As relações entre conectividade e idade e conectividade e desempenho cognitivo foram avaliadas através do método dos quadrados parciais mínimos. RESULTADOS: em uma amostra de 59 adultos (19 jovens, 20 de meia idade e 20 idosos), idade apresentou correlação negativa com desempenho cognitivo geral, mas sua relação com memória autobiográfica não foi significativa. Caracterizamos um padrão de conectividade associado ao envelhecimento caracterizado por aumento difuso de magnitude de correlações positivas entre diferentes circuitarias, diminuições de magnitude de anticorrelação envolvendo principalmente as conexões entre a rede de modo padrão e as redes atencionais e uma perda de correlações positivas intra-circuitarias, especialmente dentro do sistema visual e da rede de modo padrão. Não identificamos um padrão de conectividade associado a desempenho cognitivo geral ou autobiográfico. DISCUSSÃO: idade mostrou-se negativamente correlacionada com desempenho cognitivo geral. Os resultados sugerem que o efeito do envelhecimento sobre memória autobiográfica seja de menor tamanho e/ou sujeito a maiores variações entre estudos. O padrão de mudanças de conectividade associado ao envelhecimento que encontramos inclui os achados mais comumente descritos na literatura (diminuições de conectividade intra-circuitaria) mas também abrange mudanças funcionais mais amplas (aumentos difusos de correlação positiva e ! ! xii perdas de anticorrelação). Estes achados estão em linha com a hipótese de que o cérebro sofre um processo de desdiferenciação durante o envelhecimento no qual há perda de diversidade funcional. CONCLUSÃO: Na presente amostra não identificamos relação entre desempenho em memória autobiográfica e idade. Envelhecimento normal, inclusive em voluntários sem transtornos mentais, está associado a um aumento difuso de correlações positivas entre diferentes circuitarias, a perdas focais de anticorrelação, especialmente entre a rede de modo padrão e as redes atencionais e a uma redução de conectividade dentro da rede de modo padrão e da rede visual / INTRODUCTION: The neurophysiological basis of the cognitive decline associated with aging is not yet known. Brain functional connectivity studies using functional magnetic resonance images acquired during rest have shown that aging is associated with decreases in connectivity within the default mode network. Moreover, cognitive performance has been associated with resting functional connectivity. There is evidence that older adults present worse performance during retrieval of episodic information from autobiographical events but there is no investigation regarding the relationship between functional connectivity at rest and this cognitive function. Moreover, studies in this field have not applied a structured psychiatric interview to select the sample, although it is known that psychiatric disorders present high prevalence, are underdiagnosed and are associated with functional abnormalities. OBJECTIVES: to characterize changes in resting-state functional connectivity associated with age and cognitive performance, especially with autobiographical memory, in adults from different ages, free of cognitive deficits and psychiatric disorders. METHODS: using a neuropsychological evaluation and a structured psychiatric interview we selected a sample of young, middle aged and elderly adults free of cognitive and psychiatric disorders. We measured the performance to recover episodic information from autobiographical events. Brain functional connectivity was estimated from resting-state functional magnetic resonance images acquired during rest, using a whole-brain 278-region atlas. We used partial least squares to characterize the relationships between connectivity and age and connectivity and cognitive performance. RESULTS: in a sample of 59 adults (19 young, 20 middle aged and 20 elderly), age was negatively correlated with general cognitive performance but its relationship with autobiographical memory was not statistically significant. The pattern of connectivity changes associated with aging was characterized by a diffuse increase in the magnitude of positive correlations between different networks, decreases in magnitude of anticorrelations (especially between the default mode network and the attentional networks) and a loss of within-network positive correlations (mainly within the visual system and the default mode network). We did not find a pattern of connectivity associated with general cognitive performance or with autobiographical memory. DISCUSSION: age was negatively correlated with general cognitive performance. The results suggest that the effect of age on autobiographical memory is smaller and/or present greater between-study variability. The age-related pattern of changes in connectivity found in this study includes the most commonly reported findings in the literature (decreases in withinnetwork connectivity) but it also contains broader functional changes (diffuse increases in positive correlations and losses of anticorrelations). These findings are in accordance with the hypothesis that the brain undergoes dedifferentiation processes during aging with loss of functional diversity. CONCLUSION: in our sample, we could not identify a significant relationship between age and autobiographical memory. Normal aging, even in individuals with no mental disorder, is associated with an increase in positive correlations between different brain networks, focal losses of anticorrelations (especially between the default mode network and the attentional networks) and reductions in connectivity within the default mode network and the visual system

Establishing appropriate animal models for the study of human memory is paramount to the development of memory disorder treatments. Damage to the hippocampus, a medial temporal lobe brain structure, has been implicated in the memory loss associated with Alzheimer’s disease and other dementias. In humans, the role of the hippocampus is largely defined; yet, its role in rodents is much less clear due to conflicting findings. To investigate these discrepancies, an extensive review of the rodent literature was conducted, with a focus on studies that used the Novel Object Recognition (NOR) paradigm for testing. The total amount of time the objects were explored during training and the delay imposed between training and testing seemed to determine hippocampal recruitment in rodents. Male C57BL/6J mice were implanted with bilateral dorsal CA1 guide cannulae to allow for the inactivation of the hippocampus at discrete time points in the task. The results suggest that the rodent hippocampus is crucial to the encoding, consolidation and retrieval of object memory. Next, it was determined that there is a delay-dependent involvement of the hippocampus in object memory, implying that other structures may be supporting the memory prior to the recruitment of hippocampus. In addition, when the context memory and object memory could be further dissociated, by altering the task design, the results imply a necessary role for the hippocampus in the object memory, irrespective of context. Also, making the task more perceptually demanding, by requiring the mice to perform a two-dimensional to three-dimensional association between stimuli, engaged the hippocampus. Then, in the traditional NOR task, long and short training exploration times were imposed to determine brain region activity for weak and strong object memory. The inactivation and immunohistochemistry findings imply weak object memory is perirhinal cortex dependent, while strong object memory is hippocampal-dependent. Taken together, the findings suggest that mice, like humans, process object memory on a continuum from weak to strong, recruiting the hippocampus conditionally for strong familiarity. Confirming this functional similarity between the rodent and human object memory systems could be beneficial for future studies investigating memory disorders. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

La mémoire épisodique lie différents éléments dans un contexte spatial et temporel particulier. Il a été proposé que lors de la récupération d‟un épisode, la ré-instanciation d‟une cohérence entre les éléments néocorticaux soit opérée grâce à une représentation spatiale allocentrée stockée au niveau de la structure hippocampique (i.e., codage de la position des objets entre eux, indépendamment de la position de l‟individu, Burgess, Becker, King, & O'Keefe, 2001; Nadel & Moscovitch, 1998). Ce travail de thèse propose de traiter la mémoire épisodique et le sentiment de projection dans son passé (i.e., conscience autonoétique) comme une qualité attribuée à une dextérité relative dans le traitement spatial égocentré mis à jour (i.e., la position, orientation et le déplacement de son corps dans l‟environnement). Le rôle des traitements spatiaux allocentrés et égocentrés mis à jour dans la mémoire épisodique a été évalué expérimentalement. Les résultats suggèrent l‟existence d‟un lien causal entre le traitement de la mise à jour égocentré et les performances de mémoire épisodique. De plus, les études ont mis en évidence l‟existence de spécificités cérébrales et comportementales de la mise à jour égocentrée confirmant l‟adéquation de ce traitement au modèle théorique proposé. Par ailleurs, en référence à cette dissociation entre l‟information égocentrée mis à jour et allocentrée, des études neuropsychologiques ont révélé la présence de déficits de la mise à jour égocentrée, et d‟une préservation allocentrée dans l‟amnésie bihippocampique qu‟elle soit acquise ou développementale. Enfin, l‟évaluation des conséquences cérébrales lors de la récupération épisodique d‟un encodage maximisant le traitement égocentré mis à jour a permis de révéler une implication spécifique des structures temporo-pariétales. Ce travail de thèse a été organisé autour d‟un modèle théorique original du fonctionnement de la mémoire épisodique proposant de nouvelles prédictions expérimentales. Les approches comportementale, neuropsychologique et en imagerie fonctionnelle soulèvent à leur tour de nouvelles pistes de recherche sur le lien entre conscience de son corps et mémoire épisodique. / Episodic memory binds various elements in a specific spatial and temporal context. During retrieval, disparate neocortical elements can be re-associated into a coherent episode due to an allocentric spatial context maintained within the hippocampal formation (ie, coding for object-to-object relations, independently of the individual‟s position, Burgess, Becker, King, & O‟Keefe, 2001, Nadel & Moscovitch, 1998). Phenomenological experience is characteristic of episodic memory. In this thesis, it is described as an individual‟s attribution to a fluency in processing egocentric-updating spatial information (i.e., the position, orientation and movement of one‟s body) during retrieval. The function of egocentric-updating and of allocentric spatial processing in episodic memory was assessed experimentally. Results demonstrate the presence of a causal link between egocentric-updating and episodic memory performance. Moreover, experiments showed cerebral and behavioural specificities of egocentric-updating spatial processing supporting its involvement in episodic memory. Additionally, in line with this distinction between allocentric and egocentric-updating spatial processing, neuropsychological experiments revealed deficits in egocentric-updating with a preservation of allocentric spatial processing in both acquired and developemental bi-hippocampal amnesia. Finally, the assessment of cerebral consequences of encoding an episode while maximizing egocentric-updating processes revealed a higher involvement of temporo-parietal regions during the subsequent episodic retrieval. This thesis work was structured over an original theoretical model on episodic memory functioning allowing new experimental predictions. Combining behavioural, neuropsychological and neuroimaging approaches raised in turn new questions concerning links between episodic memory and self-consciousness.

In dieser Dissertation zeige ich anhand einer Reihe von Beispielen, wie das Langzeitgedächtnis die perzeptuelle Verarbeitung beeinflussen kann. Anhand einer Aufgabe zur visuellen Aufmerksamkeit verdeutliche ich, inwiefern episodische Erinnerungen perzeptuelle Distrakoreffekte reduzieren können. In Experiment 1 sollten Versuchspersonen zuvor gelernte Worte entweder ins Gedächtnis zu rufen oder die Erinnerung an die Worte zu unterdrücken. Anschließend mussten sie unter Zeitdruck neue, bisher nicht präsentierte Worte semantisch einordnen, wobei die Zielworte von den zuvor abgerufenen oder unterdrückten Worten flankiert waren. Da die flankierenden Worte für die semantische Entscheidungsaufgabe irrelevant und die Versuchspersonen instruiert worden waren, diese zu ignorieren, kann von einem perzeptuellen Distraktoreffekt ausgegangen werden. Distraktoreffekte waren für zuvor unterdrückte Gedächtnisinhalte im Vergleich zur abgerufenen Gedächtnisinhalten deutlich reduziert, was nahelegt, dass episodische Gedächtnisinhalte die Wahrnehmung beeinflussen. Auf dieser Erkenntnis aufbauend zeige ich in Experiment 2, wie die suppressionsinduzierte Reduktion der Verarbeitung von Distraktorreizen durch individuelle Differenzen maskiert werden kann. Schließlich wurden den Versuchspersonen in Experiment 3 in einer „Attentional-Blink“-Aufgabe unbekannte Objekte als zweites von zwei aufeinander folgenden Zielobjekten dargeboten. Versuchspersonen konnten Objekte, die mit einer neu gelernten semantischen Information assoziiert waren, besser erkennen als Objekte, die mit minimaler Information assoziiert waren. Dieser Effekt ging mit einer Modulation der ereigniskorrelierten Potenziale 100ms nach Erscheinen des Reizes einher. Diese Ergebnisse zeigen, dass Inhalte aus dem Langzeitgedächtnis Wahrnehmungsprozesse beeinflussen können und leisten damit einen weiteren Beitrag zur Erkenntnis, dass die Wahrnehmung gegenüber höheren Kognitionen nicht unabhängig ist. / Numerous studies are emerging which suggest that long-term memories can influence early perceptual processing. Notwithstanding, these finding have come under fire from critics who view perceptual processing as independent of cognition. In this dissertation I demonstrate novel instances of long-term memory effects on perceptual processing, both in the context of an attentional task where I look at the extent to which episodic memory can reduce perceptual distraction and in a conscious detection task where I assess the effect of semantic knowledge on peoples ability to consciously detect briefly presented objects. In experiment one, participants retrieved or suppressed previously memorised words. Following this task, participants made speeded semantic judgments on novel target words that were flanked by the words that had previously undergone suppression or retrieval. Because the flanking words were irrelevant to the semantic judgment and were supposed to be ignored, any influence of their presence on semantic judgment speed can be taken as a marker of perceptual distraction. Results showed that the tendency for flankers to distract from target processing was markedly reduced if those flankers had undergone suppression. In experiment two, I expanded upon this finding by showing how this suppression-induced reduction in distractor processing can be masked by individual differences. Finally, in experiment three, I presented pictures of novel objects to participants as the second of two targets in an attentional blink paradigm. Results showed that participants were able to perceive objects associated with newly acquired semantic knowledge better than objects associated with minimal knowledge, a finding that was associated with a modulation of event-related brain potentials 100 msec after stimulus onset. Taken together, these experiments contribute to the growing body of evidence showing that information from long-term memory can influence perceptual processing.

The aim of this doctoral thesis was to study the influence of memory, pain, age and education on the regional cerebral blood flow (rCBF), i.e. brain function, in early Alzheimer's disease (AD) and in chronic neck pain patients in comparison to healthy controls and in healthy elderly per se. This was done by optimizing single photon emission computed tomography (SPECT) as a method to study rCBF with the tracer Technetium-99m (99mTc) hexamethylpropyleneamine oxime (HMPAO) and by matching all image data to a brain atlas before evaluation. The rCBF-SPECT was evaluated and developed to obtain higher diagnostic accuracy in AD and in chronic neck pain patients it was used to study basic pain related cerebral processes in chronic pain of different origin. A new semimanual registration method, based on fiducial marker, suitable for investigations with low spatial resolution was developed. The method was used to reconstruct images with an improved attenuation and scatter correction by using an attenuation-map calculated from the patients' previously acquired CT images. The influence of age and education on rCBF was evaluated with statistical parametric mapping, SPM in healthy elderly. The main findings were age related changes in rCBF in regions close to interlobar and interhemispheric space but not in regions typically affected in early AD, except for the medial temporal lobe. The theory of a 'cognitive reserve' in individuals with a longer education was supported with findings in the lateral temporal lobe, a region related to semantic memory, and in the frontal lobe. A cross-sectional study of chronic neck pain patients showed extensive rCBF changes in coping related regions in a non-traumatic pain patients compared to both healthy and a pain group with a traumatic origin, i.e. whiplash syndrome. The whiplash group displayed no significant differences in rCBF in comparison with the healthy controls. This suggests different pain mechanisms in these groups. The AD-patients showed a significantly lower rCBF in temporoparietal regions including left hippocampus. These changes were associated to episodic memory performance, and especially to face recognition. The diagnostic sensitivity for AD was high. The face recognition test (episodic memory) was used in AD patients to improve the sensitivity of method, i.e. memory-provoked rCBF-SPECT (MP-SPECT). The results were compared to healthy controls and the reductions of rCBF in temporoparietal regions were more pronounced in mild AD during provocation. Memory provocation increased the sensitivity of AD-related rCBF changes at group level. If a higher sensitivity for AD at the individual level is verified in future studies, a single MP-SPECT study might then be of help to set diagnosis earlier. In conclusion rCBF in temporoparietal regions are associated to an impaired episodic memory in early AD. Changes in these regions do not have a strong connection to chronological age. The diagnostic sensitivity of rCBF-SPECT in AD is high and there is a potentially higher sensitivity if memory provoked investigations are used. The findings in this thesis have given an increased knowledge of underlying cerebral pain processing in non-traumatic and traumatic (whiplash) neck pain. Preliminary results supporting the theory of 'cognitive reserve' by showing a correlation between long education and preserved rCBF was found in healthy elderly.

Ovarian steroid hormones are neuroactive steroids with widespread actions in the brain, and are thus able to influence mood, behavior and cognition. In this thesis the effects of progesterone withdrawal and the direct effects of the progesterone metabolite allopregnanolone are evaluated. Allopregnanolone, through binding to the GABAA receptor complex, enhances inhibitory neurotransmission, thus exerting anxiolytic, sedative and antiepileptic effects. The acoustic startle response (ASR) is a withdrawal reflex evoked by sudden or noxious auditory stimuli, and can be measured in humans as an eye blink. ASR is significantly increased in several anxiety disorders, and notably also during progesterone withdrawal. Sensorimotor gating can be assessed by measuring prepulse inhibition of the startle response (PPI). The CNS circuits regulating PPI are sensitive to hormone fluctuations. GABAergic drugs are involved in cognitive impairment and animal studies have indicated that allopregnanolone may inhibit learning. The main purpose of this research was to evaluate the behavioral effects of progesterone withdrawal on the startle response and sensorimotor gating in PMDD patients and healthy controls, in healthy third trimester pregnant women and healthy postpartum women. A second aim was to evaluate allopregnanolone effects on memory and cognition in healthy women and also on the startle response and PPI. We found that PMDD patients have an increased startle response across the menstrual cycle and a deficiency in sensorimotor gating during the late luteal phase. Ovarian steroids affect sensorimotor gating; pregnant women have lower levels of PPI than late postpartum women. Acutely administered allopregnanolone did not affect the ASR or PPI. Allopregnanolone impairs episodic memory in healthy women. In conclusion, our studies suggest that ovarian steroids, including allopregnanolone, do not influence the startle response. Ovarian steroids affect sensorimotor gating; pregnancy, a condition with high levels of ovarian steroids, suppresses PPI. Theoretically, the variability in PPI across reproductive events is due to effects mediated by the progesterone or estradiol receptors but is not mediated by allopregnanolone. PMDD patients display decreased PPI during the late luteal phase, suggesting underlying pathophysiology in common with other anxiety disorders. The most vulnerable memory system, the episodic memory, is impaired by the allopregnanolone in healthy women.

Recent proposals have attributed a key role to novelty in the formation of new episodic memories. These proposals are based on evidence of enhanced memory and greater metabolic activity in the hippocampus in response to novel relative to familiar materials. However, such novelty effects are incongruous with long-standing observations that familiar items and lists are associated with better memory than novel ones. In four experiments, I explored possible reasons for this apparent discrepancy. In Experiment 1, I directly tested whether previously observed novelty effects were the result of novelty, discrimination demands, or both. I used linguistic materials (proverbs) to replicate the novelty effect but found it occurred only when familiar items were subject to source confusion. In Experiment 2, to examine better how novelty influences episodic memory, I used experimentally familiar, pre-experimentally familiar, and novel proverbs in a paradigm designed to overcome discrimination demand confounds. Memory was better for both types of familiar proverbs. These cognitive results indicate that familiarity, not novelty, leads to better episodic memory for studied items, regardless of whether familiarity is experimentally induced or based on prior knowledge. I also conducted two fMRI experiments to evaluate the neural correlates of the encoding of novel and familiar forms of information. In Experiment 3, I compared the neural encoding correlates of source memory for novel and familiar visual scenes using fMRI. Replicating previous neuroimaging studies, I observed an anterior novelty-sensitive region of the hippocampus specialized in novelty encoding. Unlike past studies, I also probed for familiarity-encoding regions and identified such regions in the posterior hippocampus. I replicated this pattern in Experiment 4 using proverbs as stimuli. As in Experiment 2, I found the effect held whether familiarity was based on prior knowledge or experimental induction. In both fMRI experiments, anterior and posterior hippocampal regions were functionally connected with different large-scale networks, helping to explain local variation in hippocampal functional specialization in terms of different neural contexts. Together, these experiments show that stimulus familiarity enhances episodic memory for materials, and that novelty is processed differently, not preferentially, in the hippocampus. A new model of hippocampal novelty processing is proposed.

Recent proposals have attributed a key role to novelty in the formation of new episodic memories. These proposals are based on evidence of enhanced memory and greater metabolic activity in the hippocampus in response to novel relative to familiar materials. However, such novelty effects are incongruous with long-standing observations that familiar items and lists are associated with better memory than novel ones. In four experiments, I explored possible reasons for this apparent discrepancy. In Experiment 1, I directly tested whether previously observed novelty effects were the result of novelty, discrimination demands, or both. I used linguistic materials (proverbs) to replicate the novelty effect but found it occurred only when familiar items were subject to source confusion. In Experiment 2, to examine better how novelty influences episodic memory, I used experimentally familiar, pre-experimentally familiar, and novel proverbs in a paradigm designed to overcome discrimination demand confounds. Memory was better for both types of familiar proverbs. These cognitive results indicate that familiarity, not novelty, leads to better episodic memory for studied items, regardless of whether familiarity is experimentally induced or based on prior knowledge. I also conducted two fMRI experiments to evaluate the neural correlates of the encoding of novel and familiar forms of information. In Experiment 3, I compared the neural encoding correlates of source memory for novel and familiar visual scenes using fMRI. Replicating previous neuroimaging studies, I observed an anterior novelty-sensitive region of the hippocampus specialized in novelty encoding. Unlike past studies, I also probed for familiarity-encoding regions and identified such regions in the posterior hippocampus. I replicated this pattern in Experiment 4 using proverbs as stimuli. As in Experiment 2, I found the effect held whether familiarity was based on prior knowledge or experimental induction. In both fMRI experiments, anterior and posterior hippocampal regions were functionally connected with different large-scale networks, helping to explain local variation in hippocampal functional specialization in terms of different neural contexts. Together, these experiments show that stimulus familiarity enhances episodic memory for materials, and that novelty is processed differently, not preferentially, in the hippocampus. A new model of hippocampal novelty processing is proposed.