In this thesis the neurocognitive deficits in adult ADHD and the effects of ADHD medication have been investigated in animals and in humans. Firstly, by utilising a translational behavioural paradigm we have characterised of a novel animal model of the core symptoms of adult ADHD. In the first study, the 5-choice continuous performance task (5C-CPT) was used to examine different forms of attention and impulsivity in female Lister-hooded adult rats. Subsequently rats were separated into subgroups according to their baseline levels of attention and impulsivity in the 5C-CPT. The low-attentive; LA subgroup and the high-attentive; HA subgroup were selected based on levels of sustained attention and vigilance. The second subgroups include animals with varying levels of motor impulsivity and response inhibition (high-impulsive; HI and low-impulsive; LI subgroups). This allowed for examination of the effects of ADHD medication (methylphenidate and atomoxetine) on attention and impulsivity in the subgroups of animals modeling the inattentive subtype (ADHD-I), and the impulsive symptoms in the combined (ADHD-C) and impulsive-hyperactive (ADHD-IH) subtypes. Both drugs significantly improved sustained attention and vigilance in LA animals only. In HI animals methylphenidate decreased motor impulsivity, however in LI also increased motor impulsivity. Atomoxetine decreased motor impulsivity and response disinhibition in HI animals only. The second animal study extended this by selecting a group of animals with combined deficits in both attention and impulsivity (ADHD-C group). This separation (ADHD-C) allowed for the investigation of potential novel therapeutic targets, revealing the cognitive effects of tolcapone and A-412997. Tolcapone increased vigilance and sustained attention and reduced response disinhibition in ADHD-C animals only, while A-412997 increased vigilance and reduced response disinhibition also in ADHD-C animals only. The first clinical study evaluated the core neurocognitive deficits, including emotion recognition abilities in medicated and unmedicated adult ADHD patients, compared with a group of healthy controls. The back-translational cognitive tasks used for the evaluation were taken from the Cambridge Automated Neuropsychological Test Battery (CANTAB). Unmedicated adults with ADHD showed core deficits in sustained attention, attentional set-shifting, response inhibition and spatial working memory. Medicated patients showed no impairments compared with controls; highlighting the importance of ADHD medication for improving these cognitive deficits in ADHD. In the second study, the emotion recognition ability of each group was assessed and compared to each other. The second study also examined if the emotion recognition impairments were as a result of a general cognitive dysfunction or are a specific impairment in social perception. The unmedicated ADHD patients showed deficits in the correct recognition of the negative emotions including; fear, anger, sadness and disgust compared with controls. The group of patients followed-up after starting treatment with methylphenidate showed significant improvements in the recognition of all four negative emotions. This improvement was improved to a level comparable to healthy controls. Interestingly, in the unmedicated ADHD group, anger recognition proved to be a specific deficit in social perception whereas sadness, disgust and fear were influenced by deficits in attention and working memory. Following treatment with methylphenidate, improvements in attention accounted for the improvements in sadness, fear and disgust recognition but not anger recognition. In conclusion the animal studies have shown that animals from within a normal population could be selected according to variations in levels of attention and impulsivity. The ADHD drugs had different effects on attention and impulsivity depending on the natural baseline levels of behaviour of the adult rats. These findings highlight the need for a patient stratification approach in adult ADHD; as different responses are dependent of differences in symptom expression. They also show some potential new therapeutic targets in the animal model, which warrant further exploration. The clinical studies highlight the range of neurocognitive deficits, including emotion recognition deficits in adult ADHD. Together these results highlight the importance of pharmacotherapy in ADHD, not only to treat the core symptoms of ADHD (inattention, impulsivity and hyperactivity) but also to improve the disabling emotion recognition deficits of this disorder.

Yes / Background: The study aim was to determine if state and trait intra-individual measures of everyday affect predict cognitive functioning in healthy older community dwelling European adults (n = 387), aged 55-87 years. Methods: Participants were recruited from centres in France, Italy and Northern Ireland. Trait level and variability in positive and negative affect (PA and NA) were assessed using self-administered PANAS scales, four times a day for four days. State mood was assessed by one PANAS scale prior to assessment of recognition memory, spatial working memory, reaction time and sustained attention using the CANTAB computerized test battery. Results: A series of hierarchical regression analyses were carried out, one for each measure of cognitive function as the dependent variable, and socio-demographic variables (age, sex and social class), state and trait mood measures as the predictors. State PA and NA were both predictive of spatial working memory prior to looking at the contribution of trait mood. Trait PA and its variability were predictive of sustained attention. In the final step of the regression analyses, trait PA variability predicted greater sustained attention, whereas state NA predicted fewer spatial working memory errors, accounting for a very small percentage of the variance (1-2%) in the respective tests. Conclusion: Moods, by and large, have a small transient effect on cognition in this older sample.

A neuropsicologia infantil e uma area distinta dentro da neuropsicologia clinica e o seu surgimento e uma consequencia do reconhecimento de que as relacoes cerebrocomportamento na crianca diferem significativamente dessas relacoes no adulto. Diversos testes neuropsicologicos tem sido desenvolvidos especialmente para administracao em computador, incluindo a bateria CANTAB que tem sido amplamente utilizada em pesquisas com diferentes grupos de idade e patologias. Em relacao ao desenvolvimento, alguns aspectos da atencao estao presentes no inicio da infancia enquanto outros continuam a se desenvolver ao longo da infancia e adolescencia. A memoria sofre inumeras alteracoes ao longo da vida, especialmente na idade pre-escolar. E as funcoes executivas demoram mais tempo para se desenvolver por completo e estudos apontam que alguns componentes ja estao presentes de forma imatura em criancas entre os 6 e 12 anos de idade, mas a completa maturacao acontece com a idade. O objetivo dessa pesquisa foi investigar o desenvolvimento da atencao, memoria e funcoes executivas em criancas e adolescentes dos 6 aos 12 anos de idade com o CANTAB, buscando padroes especificos de desenvolvimento para os componente dessas funcoes. Foram avaliados 85 criancas e adolescentes (43 masculino) entre 6 e 12 anos de idade, sem historico de disturbios neurologicos e/ou psiquiatricos, exposicao cronica a agentes toxicos, lesao ou cirurgia cerebral e problemas de desenvolvimento. Foram utilizados o teste Matrizes Progressiva Coloridas de Raven e os seguintes subtestes do CANTAB: Choice Reaction Time, Rapid Visual Information Processing, Pattern Recognition Memory, Delayed Matching to Sample, Spatial Recognition Memory, Spatial Span, Stockings of Cambridge, Intra-Extra Dimensional Set Shift, Stop Signal Task e Information Sampling Task. Os resultados indicaram que a atencao, a memoria e as funcoes executivas apresentam melhora no desenvolvimento nas idades avaliadas. A atencao visual simples, percepcao visual e capacidade de conceituacao ja estao desenvolvidas aos 6 anos. A amplitude atencional, memoria visual, memoria espacial, flexibilidade mental e controle mental estao em desenvolvimento nas idades avaliadas e apresentam um bom desempenho aos 12 anos. O planejamento e atencao sustentada apresentaram melhoras, mas ainda nao alcancaram o pleno desenvolvimento. A, tomada de decisao e controle inibitorio nao apresentaram aprimoramentos significativos e sua maturacao deve ocorrer apos os 12 anos. A bateria CANTAB se mostrou eficaz na avaliacao de criancas e adolescentes brasileiros de 6 a 12 anos de idade com alta aplicabilidade nessa amostra e resultados compativeis com a literatura. A comparacao entre os nossos resultados e aqueles encontrados nos estudos internacionais com o CANTAB indica compatibilidade entre boa parte dos grupos etarios avaliados, independentemente das diferencas culturais existentes / Child neuropsychology is a distinct area in the clinical neuropsychology and its emergence is a consequence of the acknowledgment that the brain-behavior relationships in child differ significantly from those in adult. Several neuropsychology tests have been developed to be administered in computers, including the CANTAB that has been widely used by researchers concerning different ages and pathologies groups. In regard to the development, some aspects of attention are present in the beginning of childhood while others continue to develop along the childhood and youth. Memory processes undergo many changes throughout life, especially in preschool age. Executive functions take longer to fully develop and researches indicate that some components are present in immature form on child between 6 to 12 years old, but the complete ripening occurs with age increase. The aim of this work was to investigate the development of attention, memory and executive functions in children and teenagers from 6 to 12 years old using the CANTAB, and verify if there are specific patterns of development for the components of these functions. There were evaluated 85 children and teenagers (43 male) between 6 to 12 years old with no history of neurological and/or psychiatric disorders, chronic exposures to toxic agents, injury or brain surgery and development disorders. They were submitted to the Ravens progressive matrices and the following CANTABs subtests: Choice Reaction Time, Rapid Visual Information Processing, Pattern Recognition Memory, Delayed Matching to Sample, Spatial Recognition Memory, Spatial Span, Stockings of Cambridge, Intra-Extra Dimensional Set Shift, Stop Signal Task e Information Sampling Task. The results indicated improvements in attention, memory and executive functions in the development in the age groups evaluated. Simple visual attention, visual perception and conceptualization capacity seem to be developed at 6 years old. Attentional span, visual memory, spatial memory, mental flexibility and mental control are in ongoing development in the age groups evaluated, and a good performance is reached at 12 years old. Planning ability and sustained attention showed improvements in age groups evaluated but they have not reached fully development. Decision making and inhibitory control do not showed significant improvement and their ripening should occur after the 12 years old. The CANTAB battery was effective to evaluate Brazilians children and teenagers from 6 to 12 years old with high applicability in this sample and results consistent with the literature. The comparison between our results and those found in the international studies with CANTAB indicates compatibility in almost all age evaluated, regardless cultural differences

A neuropsicologia infantil e uma area distinta dentro da neuropsicologia clinica e o seu surgimento e uma consequencia do reconhecimento de que as relacoes cerebrocomportamento na crianca diferem significativamente dessas relacoes no adulto. Diversos testes neuropsicologicos tem sido desenvolvidos especialmente para administracao em computador, incluindo a bateria CANTAB que tem sido amplamente utilizada em pesquisas com diferentes grupos de idade e patologias. Em relacao ao desenvolvimento, alguns aspectos da atencao estao presentes no inicio da infancia enquanto outros continuam a se desenvolver ao longo da infancia e adolescencia. A memoria sofre inumeras alteracoes ao longo da vida, especialmente na idade pre-escolar. E as funcoes executivas demoram mais tempo para se desenvolver por completo e estudos apontam que alguns componentes ja estao presentes de forma imatura em criancas entre os 6 e 12 anos de idade, mas a completa maturacao acontece com a idade. O objetivo dessa pesquisa foi investigar o desenvolvimento da atencao, memoria e funcoes executivas em criancas e adolescentes dos 6 aos 12 anos de idade com o CANTAB, buscando padroes especificos de desenvolvimento para os componente dessas funcoes. Foram avaliados 85 criancas e adolescentes (43 masculino) entre 6 e 12 anos de idade, sem historico de disturbios neurologicos e/ou psiquiatricos, exposicao cronica a agentes toxicos, lesao ou cirurgia cerebral e problemas de desenvolvimento. Foram utilizados o teste Matrizes Progressiva Coloridas de Raven e os seguintes subtestes do CANTAB: Choice Reaction Time, Rapid Visual Information Processing, Pattern Recognition Memory, Delayed Matching to Sample, Spatial Recognition Memory, Spatial Span, Stockings of Cambridge, Intra-Extra Dimensional Set Shift, Stop Signal Task e Information Sampling Task. Os resultados indicaram que a atencao, a memoria e as funcoes executivas apresentam melhora no desenvolvimento nas idades avaliadas. A atencao visual simples, percepcao visual e capacidade de conceituacao ja estao desenvolvidas aos 6 anos. A amplitude atencional, memoria visual, memoria espacial, flexibilidade mental e controle mental estao em desenvolvimento nas idades avaliadas e apresentam um bom desempenho aos 12 anos. O planejamento e atencao sustentada apresentaram melhoras, mas ainda nao alcancaram o pleno desenvolvimento. A, tomada de decisao e controle inibitorio nao apresentaram aprimoramentos significativos e sua maturacao deve ocorrer apos os 12 anos. A bateria CANTAB se mostrou eficaz na avaliacao de criancas e adolescentes brasileiros de 6 a 12 anos de idade com alta aplicabilidade nessa amostra e resultados compativeis com a literatura. A comparacao entre os nossos resultados e aqueles encontrados nos estudos internacionais com o CANTAB indica compatibilidade entre boa parte dos grupos etarios avaliados, independentemente das diferencas culturais existentes / Child neuropsychology is a distinct area in the clinical neuropsychology and its emergence is a consequence of the acknowledgment that the brain-behavior relationships in child differ significantly from those in adult. Several neuropsychology tests have been developed to be administered in computers, including the CANTAB that has been widely used by researchers concerning different ages and pathologies groups. In regard to the development, some aspects of attention are present in the beginning of childhood while others continue to develop along the childhood and youth. Memory processes undergo many changes throughout life, especially in preschool age. Executive functions take longer to fully develop and researches indicate that some components are present in immature form on child between 6 to 12 years old, but the complete ripening occurs with age increase. The aim of this work was to investigate the development of attention, memory and executive functions in children and teenagers from 6 to 12 years old using the CANTAB, and verify if there are specific patterns of development for the components of these functions. There were evaluated 85 children and teenagers (43 male) between 6 to 12 years old with no history of neurological and/or psychiatric disorders, chronic exposures to toxic agents, injury or brain surgery and development disorders. They were submitted to the Ravens progressive matrices and the following CANTABs subtests: Choice Reaction Time, Rapid Visual Information Processing, Pattern Recognition Memory, Delayed Matching to Sample, Spatial Recognition Memory, Spatial Span, Stockings of Cambridge, Intra-Extra Dimensional Set Shift, Stop Signal Task e Information Sampling Task. The results indicated improvements in attention, memory and executive functions in the development in the age groups evaluated. Simple visual attention, visual perception and conceptualization capacity seem to be developed at 6 years old. Attentional span, visual memory, spatial memory, mental flexibility and mental control are in ongoing development in the age groups evaluated, and a good performance is reached at 12 years old. Planning ability and sustained attention showed improvements in age groups evaluated but they have not reached fully development. Decision making and inhibitory control do not showed significant improvement and their ripening should occur after the 12 years old. The CANTAB battery was effective to evaluate Brazilians children and teenagers from 6 to 12 years old with high applicability in this sample and results consistent with the literature. The comparison between our results and those found in the international studies with CANTAB indicates compatibility in almost all age evaluated, regardless cultural differences

Background: Cognitive deficits are a core symptom of schizophrenia, severely debilitating and untreated by current medication. However, to date there is limited research focusing on the precise nature of the cognitive disturbances at first episode in ethnic populations. Improved understanding of this will allow improved approaches to therapy. The aim of this study was to investigate cognitive function with a first episode of psychosis South Asian patients. Methods: Twenty South Asian first episode psychosis patients and 15 healthy South Asian matched controls were recruited. All were second generation South Asian people living in the UK. Subjects who took part in the study completed the Positive and Negative Syndrome Scale (patient group), the Wechsler Test of Adult Reading and a battery of neuropsychological assessments to assess specific domains of cognition of relevance to Measurement and Treatment Research to Improve Cognition in Schizophrenia using the Cambridge Neuropsychological Test Automated Battery (CANTAB) (all groups). Results: Results show that first episode patients performed significantly worse than controls across all cognitive domains tested using CANTAB. Significant impairments were found in tests of visual and spatial memory, executive function, working memory, spatial planning and attention. Importantly, a number of cognitive performance indices (visual memory, spatial memory, executive function) were positively correlated with the severity of negative symptoms. Conclusion: We demonstrate that first episode South Asian patients display significant and specific cognitive deficits with evidence to support an association between negative symptoms and certain cognitive domains at first episode in this patient population.

no / Significant changes in endogenous plasma hormone levels are required to sustain pregnancy which provides a unique opportunity to study their effect on cognitive function. Four carefully selected tests from the Cambridge Neuropsychological Automated Test Battery (CANTAB) were administered to assess the cognitive function of a group of 23 women during each trimester of pregnancy and at three months following birth. Test scores were compared with a control group of 24 non-pregnant women. The Edinburgh Postnatal Depression Scale was administered to assess anxiety and risk of depression. The National Adult Reading Test (NART) was used as a measure of verbal intelligence. Plasma hormone levels were measured at each time-point. The pregnant group scored significantly lower than the control group on the Spatial Recognition Memory (SRM) test at the second trimester and postpartum assessments (p ⩽ 0.004). A significant pregnant group-time interaction (p = 0.005) for SRM performance was demonstrated. Compared to their first trimester assessment, the pregnant group scored on average 11.7% less on each subsequent SRM test. The pregnant group reported more symptoms of anxiety and depression compared to the control group (EPDS-4 point increase in mean score at each assessment, p = 0.002). There were no plasma hormone levels and test score associations identified.

Darbo tikslas: įvertinti ankstyva Parkinsono liga (PL) be demencijos sergančių asmenų pažinimo funkcijas naudojant Kembridžo kompiuterinės neuropsichologinio ištyrimo sistemos testų rinkinį, palyginti rezultatus su kontrolinės grupės asmenų duomenimis bei nustatyti kognityvinių rodiklių ryšius su biologiniais žymenimis ir klinikiniais nekognityviniais PL simptomais. Darbo uždaviniai: ištirti ankstyva PL sergančių asmenų dėmesio, atminties, regos erdvinę ir vykdomąsias funkcijas, naudojant kompiuterizuotų testų rinkinį CANTAB eclipse 3.0.0, ir palyginti juos su kontrolinių asmenų duomenimis; nustatyti pacientų kognityvinių funkcijų ryšį su UPLVS skale įvertintu ligos sunkumu, transkranijinės sonografijos (TKS) metodu nustatytu juodosios medžiagos (JM) echogeniškumu, presinapsinio dopamine transporterio koncentracija dryžuotame kūne, nustatyta radionuklidinės kompiuterinės tomografijos (RKT) su I¹²³-FP-CIT būdu, miego, nuovargio bei demografiniais veiksniais, gyvenimo kokybės rodikliais, PL gydyti skiriamų vaistų vartojimu; išanalizuoti kompiuterizuotais testais įvertintų kognityvinių funkcijų diagnostinę vertę sergant ankstyva PL. Metodai. Tyrimas atliktas Vilniaus universiteto ligoninės Santariškių klinikų Neurologijos centre. Atrinkta 115 pacientų, sergančių ankstyva kliniškai tikėtina PL, kurie atitiko įtraukimo kriterijus bei nebuvo neįtraukimo kriterijų, ir 42 pagal amžių, lytį, mokymosi trukmę atrinkti kontroliniai tiriamieji, kurie nesirgo PL ar kitomis... [toliau žr. visą tekstą] / The aim of the study: to evaluate the cognitive functions of patients with early-stage Parkinson‘s disease (PD) without dementia using Cambridge Neuropsychological Test Automated Battery (CANTAB Eclipse 3.0.0), to compare the obtained results with the data of control subjects, to determine the associations of the variables of cognitive testing with biological markers and clinical non-cognitive symptoms of PD. Objectives: to examine attention, memory, visuospatial and executive functions of patients with early-stage PD without dementia using CANTAB Eclipse 3.0.0 and to compare the obtained results with the data of control subjects; to investigate the relationship between the cognitive functions of patients with early-stage PD and the severity of disease measured by UPDRS score, the echogenic properties of brainstem nigral substance (SN) examined by transcranial sonography (TCS), the striatal binding of presinaptic dopamine transporter determined by single-photon emission computed tomography (SPECT) with I¹²³-FP-CIT, sleep, fatigue, demographic factors and quality of life scores, the usage of medications for early-stage PD; to analize the diagnostic characteristics of particular computerised tests for evaluation of cognitive function in patients with early-stage PD. Methods. The study was performed at the Department of Neurology of Vilnius University Hospital Santariškių Klinikos. 115 patients diagnosed with clinically probable early-stage PD who met inclusion criteria and... [to full text]

The aim of the study: to evaluate the cognitive functions of patients with early-stage Parkinson‘s disease (PD) without dementia using Cambridge Neuropsychological Test Automated Battery (CANTAB Eclipse 3.0.0), to compare the obtained results with the data of control subjects, to determine the associations of the variables of cognitive testing with biological markers and clinical non-cognitive symptoms of PD. Objectives: to examine attention, memory, visuospatial and executive functions of patients with early-stage PD without dementia using CANTAB Eclipse 3.0.0 and to compare the obtained results with the data of control subjects; to investigate the relationship between the cognitive functions of patients with early-stage PD and the severity of disease measured by UPDRS score, the echogenic properties of brainstem nigral substance (SN) examined by transcranial sonography (TCS), the striatal binding of presinaptic dopamine transporter determined by single-photon emission computed tomography (SPECT) with I¹²³-FP-CIT, sleep, fatigue, demographic factors and quality of life scores, the usage of medications for early-stage PD; to analize the diagnostic characteristics of particular computerised tests for evaluation of cognitive function in patients with early-stage PD. Methods. The study was performed at the Department of Neurology of Vilnius University Hospital Santariškių Klinikos. 115 patients diagnosed with clinically probable early-stage PD who met inclusion criteria and... [to full text] / Darbo tikslas: įvertinti ankstyva Parkinsono liga (PL) be demencijos sergančių asmenų pažinimo funkcijas naudojant Kembridžo kompiuterinės neuropsichologinio ištyrimo sistemos testų rinkinį, palyginti rezultatus su kontrolinės grupės asmenų duomenimis bei nustatyti kognityvinių rodiklių ryšius su biologiniais žymenimis ir klinikiniais nekognityviniais PL simptomais. Darbo uždaviniai: ištirti ankstyva PL sergančių asmenų dėmesio, atminties, regos erdvinę ir vykdomąsias funkcijas, naudojant kompiuterizuotų testų rinkinį CANTAB eclipse 3.0.0, ir palyginti juos su kontrolinių asmenų duomenimis; nustatyti pacientų kognityvinių funkcijų ryšį su UPLVS skale įvertintu ligos sunkumu, transkranijinės sonografijos (TKS) metodu nustatytu juodosios medžiagos (JM) echogeniškumu, presinapsinio dopamine transporterio koncentracija dryžuotame kūne, nustatyta radionuklidinės kompiuterinės tomografijos (RKT) su I¹²³-FP-CIT būdu, miego, nuovargio bei demografiniais veiksniais, gyvenimo kokybės rodikliais, PL gydyti skiriamų vaistų vartojimu; išanalizuoti kompiuterizuotais testais įvertintų kognityvinių funkcijų diagnostinę vertę sergant ankstyva PL. Metodai. Tyrimas atliktas Vilniaus universiteto ligoninės Santariškių klinikų Neurologijos centre. Atrinkta 115 pacientų, sergančių ankstyva kliniškai tikėtina PL, kurie atitiko įtraukimo kriterijus bei nebuvo neįtraukimo kriterijų, ir 42 pagal amžių, lytį, mokymosi trukmę atrinkti kontroliniai tiriamieji, kurie nesirgo PL ar kitomis... [toliau žr. visą tekstą]

Rationale Cognitive deficits are now recognised as a major symptom of schizophrenia with a number of studies reporting profound deficits in cognitive function in both chronic and first episode patients. Recent advances in cognitive remediation therapy have provided the opportunity for patients to improve their cognitive function and therefore improve their functional outcome. Aim The aim of the present study was to investigate cognitive deficits using the Cambridge Neuropsychological Test Automated Battery (CANTAB®) in first episode psychosis and chronic schizophrenia patients. In the first episode population the effect of ethnicity on cognition was also examined. In the chronic schizophrenia study comparisons between severity of deficits with first episode psychosis patients were also made. The effects of cognitive remediation therapy were also examined in a sample of first episode patients. Methods A total of 35 patients and 30 healthy controls were recruited into the first episode study, 17 patients and 17 controls into the chronic schizophrenia study and 11 patients into the cognitive remediation study. The first episode psychosis patients were recruited from the Bradford and Airedale Early Intervention Service and the chronic patients from the Leeds Partnership NHS Foundation Trust. The control subjects were matched as closely as possible in terms of intelligence and demographics to the patient groups. The Wechsler Test of Adult Reading (WTAR) was used to estimate subjects pre-morbid IQ. The severity of symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). All subjects who took part in the study completed a comprehensive battery of neuropsychological tests from the CANTAB®. Patients in the cognitive remediation study participated in group therapy sessions using X-cog®. Results There were no significant differences found between There were no significant differences found between patients and controls in relation to intelligence or demographics in all studies. The effect of ethnicity was shown to be not significant in the first episode study. Results show that patients performed significantly worse than controls across all iv cognitive domains tested in all studies. A correlation between negative symptoms and executive function was found in both first episode and chronic schizophrenia patients. Comparisons between first episode psychosis and chronic schizophrenia patients in cognition showed no significant differences, however significant differences were found in levels of negative symptoms and age between the two groups with chronic patients scoring higher on negative symptoms and being older. In the cognitive remediation study a significant improvement was observed in patients in the domain of executive function and a reduction in negative symptoms following completion of the intervention. Conclusion First episode and chronic schizophrenia patients display significant cognitive deficits across all domains when tested using the CANTAB®. Some of these deficits appear to be independent of the length of the illness but dependent on negative symptoms. This study demonstrates that cognitive deficits exist across all patient groups regardless of age, gender, pre-morbid IQ, years in education and ethnicity. Cognitive remediation therapy has also been shown to be effective in improving cognitive functioning in patients.

Les cytokines, produites lors de l’activation du système immunitaire, ont la capacité d’agir au niveau du système nerveux central et d’induire diverses altérations comportementales. Lorsque l’activation du système de l’immunité innée devient chronique, ces altérations comportementales peuvent évoluer en véritables symptômes neuropsychiatriques. La physiopathologie des symptômes neuropsychiatriques qui se développent dans un contexte d’inflammation chronique à bas bruit, c’est-à-dire caractérisé par une activation chronique des processus immunitaires mais à un niveau relativement faible, est peu connue et reste à déterminer. L’implication de l’inflammation chronique à bas bruit dans les symptômes de fatigue et les altérations cognitives constitue l’élément d’étude principal de ce travail de thèse. Les troubles métaboliques, tels que l’obésité et le diabète de type 2, sont de bons modèles pour une telle étude. Ces deux pathologies sont en effet caractérisées par une inflammation chronique à bas bruit qui proviendrait, au moins en partie, du tissu adipeux. De plus, la fatigue et les altérations cognitives sont fréquentes chez les patients souffrant de troubles métaboliques. Compte tenu du rôle connu de l’inflammation dans la physiopathologie de ces altérations comportementales, leur développement dans des contextes de troubles métaboliques pourrait également être lié à l’activation chronique à bas bruit de processus inflammatoires. Différents objectifs ont été définis pour tester cette hypothèse : 1) caractériser et spécifier les symptômes de fatigue et les altérations cognitives chez des patients diabétiques ou obèses ; 2) évaluer la relation entre inflammation systémique et état inflammatoire du tissu adipeux ; 3) étudier l’association de l’inflammation chronique à bas bruit avec les symptômes de fatigue et les altérations cognitives des patients souffrant de troubles métaboliques. Nos résultats indiquent que la fatigue, en particulier la fatigue générale et physique, représente une caractéristique fondamentale des troubles métaboliques. Des perturbations cognitives, se traduisant par un ralentissement psychomoteur dans un test de temps de réaction ainsi qu’une altération de performance dans une tâche de planification spatiale, ont également été décelées chez les patients diabétiques de type 2, particulièrement ceux sous insulinothérapie, et chez les patients obèses. Des altérations mineures étaient également mesurées dans une tâche d’empan spatial rétrograde chez les patients obèses. En ce qui concerne les données biologiques, nos résultats indiquent diverses associations entre l’inflammation systémique et l’expression des marqueurs inflammatoires (cytokines inflammatoires, dont le MCP1, et marqueurs des cellules T) dans le tissu adipeux viscéral des patients obèses. De façon intéressante, l’inflammation systémique à bas bruit était associée aux dimensions de fatigue (générale, mentale, réduction des activités et de la motivation) et aux altérations de performance dans les tests ciblant les fonctions exécutives. Dans l’ensemble, ces résultats supportent l’hypothèse de l’implication des macrophages et des lymphocytes T du tissu adipeux dans l’état inflammatoire systémique associé à l’obésité. Il suggère en outre que l’inflammation systémique à bas bruit pourrait participer au développement de la fatigue et des altérations cognitives chez les patients souffrant de troubles métaboliques. Ce travail de thèse offre une caractérisation précise des symptômes de fatigue et des altérations cognitives associées aux troubles métaboliques. En outre, ce travail apporte d’importantes informations sur les relations de l’inflammation chronique à bas bruit avec ces symptômes, et permet d’affiner les hypothèses relatives à l’implication de processus inflammatoires dans la physiopathologie de ces altérations. / Cytokines produced during the activation of the immune system have the ability to act within the central nervous system and to induce a large number of behavioral alterations. When the activation of immune system becomes chronic and unregulated, these behavioral alterations may lead to the development of neuropsychiatric symptoms. The pathophysiology of neuropsychiatric symptoms that develop in conditions of chronic low-grade inflammation context (i.e., characterized by a chronic but low activation of inflammatory processes), remains unknown. The main aim of this thesis was to investigate the involvement of low-grade inflammation in the development of fatigue symptoms and cognitive alterations in patients with metabolic disorders including obesity and type 2 diabetes. These conditions are characterized by a chronic low-grade inflammatory state, manifesting by higher blood concentrations of inflammatory factors. This inflammatory state would originate, at least partially, from the adipose tissue. Moreover, fatigue symptoms and cognitive alterations are common in metabolic disorders. Given the role of inflammation in the physiopathology of these symptoms, their development could also rely on chronic low-grade inflammatory processes. Several objectives were defined to test this hypothesis: 1) to characterize fatigue symptoms and cognitive alterations in obese and diabetic patients; 2) to assess the relationship of systemic inflammation with the inflammatory state of the adipose tissue; and 3) to investigate the association of low-grade inflammation with fatigue symptoms and cognitive alterations in patients with metabolic disorders. Fatigue symptoms and cognitive function were respectively assessed using the multidimensional fatigue inventory (MFI) and the neuropsychological tests automated battery CANTAB in diabetic patients (type 1 and type 2) and in obese patients before and after bariatric surgery. A control group was included for each model (obesity and type 2 diabetes). Circulating concentrations of inflammatory markers, as well as expression of inflammatory markers in the visceral adipose tissue of obese patients, were measured. Our results indicate that fatigue symptoms, especially in the dimensions of general and physical fatigue, represent fundamental characteristics of patients suffering from metabolic disorders. In addition, cognitive alterations (psychomotor slowing and alterations in spatial planning performance) were measured in type 2 diabetic patients, more particularly those under insulin treatment, and in obese patients. Slight alterations in the test of backward spatial span were measured in obese patients. With respect to biological data, our results indicate significant relationships between systemic inflammation and inflammatory markers (inflammatory cytokines, including MCP1, and T-cell markers) in the visceral adipose tissue of obese patients. Interestingly, chronic low-grade inflammation was associated with fatigue symptoms (general fatigue, mental fatigue, reduced activity and motivation) and performance alterations in tests assessing executive functions. Altogether, these data support the hypothesis of the involvement of the adipose macrophages and T lymphocytes in the systemic inflammatory state associated with obesity. Moreover, these results suggest that systemic low-grade inflammation associated with metabolic disorders may contribute to the physiopathology of fatigue and cognitive alterations in these conditions. In conclusion, these studies provide a precise characterization of fatigue symptoms and cognitive alterations associated with metabolic disorders, such as obesity or type 2 diabetes. In addition, this thesis work gives interesting information about the relationships of chronic low-grade inflammation and fatigue and cognitive symptoms, and refines hypotheses regarding the involvement of inflammatory processes in the physiopathology of these symptoms in patients with diabetes or obesity.