BACKGROUND: Cognitive deficits are a core component of schizophrenia and among the strongest determinants of functional disability in psychotic illnesses. In particular, impairment in information processing speed has been demonstrated to be among the most significant in patients. Poor processing speed not only frequently occurs prior to psychosis onset during the prodromal or clinical high risk phase of psychotic illness, it has also been found to be a strong predictor of conversion to psychosis. However, the neurobiological basis of impaired processing speed in the clinical high risk population is not well understood. Functional connectivity during resting state fMRI provides useful insights into the organization and communication between brain regions that may elucidate the brain circuit basis underlying processing speed. OBJECTIVE: To identify the strongest link between brain functional connectivity and a measure of information processing speed in individuals at clinical high risk for conversion to psychosis by utilizing a data-driven analysis. METHODS: Cognitive and resting state fMRI data were collected from 198 clinical high risk participants and 123 neurotypical controls in the second phase of the North American Prodromal Longitudinal Study. Processing speed was measured by the Brief Assessment of Cognition in Schizophrenia Symbol Coding task. A multivariate pattern analysis was used to identify, at the individual voxel level, how functional connectivity correlates with information processing speed. RESULTS: Clinical high risk participants demonstrated significantly reduced processing speed, relative to neurotypical controls. Similarly, at risk patients who later converted to psychosis (n=17) also showed poorer performance on the BACS Symbol Coding task compared to non-converters. The strongest whole-brain link between connectivity and processing speed within the clinical high risk population was the bilateral amygdala. Specifically, connectivity between the bilateral amygdala and a functional brain network known as the salience network correlated with processing speed. CONCLUSIONS: Functional connectivity between the bilateral amygdala and the salience network was linked to individual variation in processing speed in the clinical high risk population. This affirmed a growing literature that implicates amygdala involvement in cognitive function and provides a potential biomarker for psychosis risk prior to diagnosis.

BACKGROUND: Schizophrenia is a diverse disorder comprising positive, negative, and cognitive symptoms. While several cognitive domains have been alleged to influence symptom severity and quality of life, impaired information processing speed (IPS) is the most profoundly affected and is present even before a diagnosis of a psychotic disorder. Although extensively studied, reliable and reproducible pathological neural circuitry leading to cognitive dysfunction has yet to be fully identified or understood. OBJECTIVE: Our study seeks to identify the neurobiological connections responsible for diminished processing speed in a group of patients with psychotic disorders and a group of individuals at risk to develop a psychotic disorder. METHODS: This data-driven evaluation of resting-state fMRI data and cognitive testing considers two populations: one cohort of adults diagnosed with psychotic disorders and another cohort of individuals identified as being at risk for developing psychotic disorders (ShangHai At-Risk for Psychosis). The images were processed and evaluated using multivariate pattern analysis (MVPA) to compare brain connectivity to information processing speed. The MVPA calculations generated a map to determine the regions where brain connectivity has the strongest correlation to information processing speed as measured by the Brief Assessment in Cognition for Schizophrenia (BACS). RESULTS: The results of the cognitive assessments demonstrate that information processing speed (IPS) is the most impaired domain of cognition in adults with psychotic disorders. Multivariate distance matrix regression (MDMR) was used to identify the cerebellum as the specific brain location where connectivity was most strongly correlated to information processing speed. Specifically, the cerebellar (CBM) connectivity to the dorsal medial prefrontal cortex (dmPFC) exhibited the strongest positive correlation with IPS. The cohort of individuals diagnosed with a psychotic disorder (n = 103) exhibited a moderately strong relationship (r = 0.396, p = 0.000036) between the CBM-dmPFC coactivation and IPS. This finding was then replicated in the SHARP dataset. The clinical high risk sample (n = 137) also identified the CBM-dmPFC circuit as the strongest correlation to information processing speed (r=0.39, p = 0.000002057). Furthermore, the CBM-dmPFC circuit relationship to IPS became stronger as we considered the most impaired subjects. Individuals who would go on to be diagnosed with a psychotic disorder (converters, n = 19) exhibited the strongest relationship between CBM-dmPFC and information processing speed (r = 0.56, p = 0.01). CONCLUSIONS: The reduction in functional connectivity between cerebellum and dmPFC appears to be critically related to the generalized decrease in information processing speed in patients with psychotic disorders and patients at risk of developing a psychotic disorder in the future. The finding is reproduced in two culturally, linguistically, and geographically disparate populations. Interestingly, the finding demonstrates a link between the functional dysconnectivity and cognitive dysfunction in the years before and during the onset of a diagnosis of a psychotic disorder. The research indicates a diagnostic role for assessing information processing speed to identify prodromal patients at risk of developing a psychotic disorder. Finally, the identification of a specific neurological circuit related to impaired cognition would provide a therapeutic target to alleviate cognitive deficits in patients with psychotic disorders in the future.

No description available.

No description available.

La sclérose en plaques (SEP) est la maladie chronique la plus fréquente parmi les pathologies neurologiques invalidantes non-traumatiques de l’adulte jeune en France. Le phénotype le plus fréquent est la SEP récurrente-rémittente (SEP-RR). Le diagnostic de SEP-RR est fondé sur la démonstration de la dissémination des lésions dans l'espace et dans le temps après un premier événement clinique démyélinisant dénommé syndrome clinique isolé (SCI). Les 2 principaux objectifs de cette thèse étaient de déterminer des marqueurs prédictifs d'un diagnostic précoce de la SEP après un SCI typique, et de démontrer que l’atteinte cognitive pouvait être utilisée comme un marqueur pronostique dès les stades précoces de la maladie. Le premier article décrit les résultats d’une étude rétrospective de 114 patients atteints d'un SCI médullaire. Le diagnostic de la SEP a été prédit par 3 facteurs indépendants: âge ≤40 ans, présence de bandes oligoclonales surnuméraires dans le liquide céphalo-rachidien ou une élévation de l’index IgG, et ≥3 lésions périventriculaires lors du SCI. Ces 3 facteurs prédictifs ont été validés dans une étude prospective de 652 patients avec différentes topographies de SCI (article 2). Il a été retrouvé des performances égales ou supérieures à celles des critères de dissémination spatiale proposés par McDonald et coll. pour la prédiction du diagnostic de la SEP après un SCI. Une fois le diagnostic de SEP établi, le principal défi consiste à évaluer la gravité de la maladie. Il manque de marqueurs prédictifs du handicap à long-terme. La perte axonale représente le substrat anatomique du handicap accumulé dans la SEP. Par ailleurs, les troubles cognitifs sont fréquents dans la SEP, ont été détectés dès les stades précoces de la maladie, et ont été associés à des marqueurs d’imagerie reflétant l’atteinte diffuse cérébrale. Par conséquent, l’atteinte cognitive semble être un candidat intéressant comme marqueur pronostique aux stades précoces de la SEP. Dans le troisième article, la relation entre les troubles cognitifs et les paramètres d’IRM reflétant l’atteinte diffuse cérébrale a été confirmé dans une étude longitudinale sur 7 ans de 44 patients ayant une SEP-RR nouvellement diagnostiquée. Dans le quatrième article, il a été montré la capacité de l’atteinte cognitive détectée après le diagnostic de SEP-RR à prédire la progression du handicap physique au cours du temps, étayant la valeur pronostique des déficits cognitifs dans la SEP. Dans le cinquième article, les évaluations cognitives ont été effectuées chez des patients présentant 2 phénotypes cliniques de SEP aux pronostics différents: SEP-RR et SEP progressive primaire (SEP-PP). L'étendue et la sévérité des déficits cognitifs étaient plus élevées chez les 41 patients ayant une SEP-PP par rapport aux 60 patients atteints de SEP-RR. Dans le sixième article, la valeur pronostique de l’atteinte cognitive dans la SEP a été illustrée par les effets négatifs des déficits cognitifs sur la qualité de la vie et les statuts professionnels de 48 patients atteints de SEP suivis pendant 7 ans. Après avoir montré que les déficits cognitifs pouvaient prédire l'invalidité précoce chez les patients atteints de SEP, et sachant que le handicap précoce est un marqueur prédictif de l’invalidité à long terme, la détection des déficits cognitifs apparaît comme une priorité dans la gestion des patients ayant une SEP. Par ailleurs, la vitesse de traitement de l'information (VTI) est le principal domaine cognitif altéré dans la SEP. Dans le septième article, un nouvel outil cognitif développé dans notre unité de recherche appelé «computerised speed cognitive test» a été utilisé pour détecter un ralentissement de la VTI dans un échantillon de 101 patients atteints de SEP et 415 sujets sains. Ce test a été associé à une excellente fiabilité, une bonne validité écologique, et de bonnes performances pour détecter un ralentissement de la VTI chez les patients atteints de SEP. / Multiple sclerosis (MS) is the most frequent chronic, disabling, non-traumatic neurologic disease of young adults in France. Relapsing-remitting MS (RRMS) is the most frequent phenotype of this disease. The diagnosis of RRMS is based on the demonstration of the dissemination of lesions in space and time after a first typical clinical event, which is called a clinically isolated syndrome (CIS). The 2 main objectives of this thesis were, first, to investigate predictors of an early diagnosis of MS after a typical CIS and, second, to provide support for cognitive impairment as a potentially useful prognostic marker in the early stages of MS. The first article reported the results obtained in a retrospective study that included a homogeneous sample of 114 patients with a spinal cord CIS. The diagnosis of MS was predicted by 3 independent factors: ≤40 years of age, positive for oligoclonal bands in the cerebrospinal fluid or a raised IgG index, and ≥3 periventricular lesions at the time of the CIS. In the second article, a confirmation of the validity of these 3 predictive factors was provided through a large prospective study that included 652 patients with a CIS, regardless of the anatomical location of the lesions. Notably, these predictive factors achieved the same accuracy as the dissemination in space criteria which were proposed in the McDonald criteria for the prediction of the diagnosis of MS. Once an MS diagnosis is established, the main challenge is to assess the severity of the disease, and early clinical predictors of long-term disability are still lacking. The anatomical substrate of the disabilities that are accumulated in MS appears primarily to be cumulative axonal loss. Cognitive impairment is frequent in MS, even at the early stages of the disease, and has been associated with MRI markers of diffuse brain damage. Therefore, cognitive impairment appears to be an interesting candidate as a prognostic factor in the early stages of MS. In the third article, the relationship between cognitive impairment and MRI parameters reflecting early diffuse brain damage was confirmed in a 7-year longitudinal study of 44 newly diagnosed RRMS patients. In the fourth article, the ability of the cognitive impairment detected after RRMS diagnosis in this sample of patients to predict the progression of disability over time supported the prognostic value of cognitive deficits in early MS. In the fifth article, cognitive assessments were performed on patients with 2 clinical phenotypes of MS with different prognoses: RRMS and primary progressive MS (PPMS). The extent and the severity of cognitive deficits were greater in the 41 PPMS patients compared to the 60 RRMS patients; this finding supports the relationship between cognitive impairment and widespread brain damage. In the sixth article, the prognostic value of cognitive dysfunction in MS was illustrated through the negative impacts of cognitive deficits on the qualities of life and vocational statuses of 48 patients living with MS who were followed for 7 years. Finally, as cognitive deficits were shown to have the potential to predict early disability in patients with MS, and early disability is known to be relevant to predict long-term disability in MS, the detection of cognitive deficits appears to be a priority in managing patients with MS and adapting early-stage therapeutic strategies. Information processing speed (IPS) is the main cognitive domain impaired in MS that has clinical implications. In the seventh article, the ability of a new, in-house cognitive tool called the computerised speed cognitive test to detect lowered processing speed was assessed in a validation study using samples obtained from 101 patients with MS and 415 healthy subjects. This test was clinically relevant, and had excellent reliability, ecological validity, and predictive value for detecting IPS impairment in patients with MS.

Muitas operações cognitivas requerem velocidade de processamento de informação (VPI) suficiente para serem executadas dentro do prazo permitido, sendo que VPI retardada geralmente está subjacente a déficits atencionais. A desaceleração no tempo de resposta é particularmente evidente em pacientes com traumatismo crânio-encefálico, doença de Parkinson, depressão, demência e esclerose múltipla (EM). A importância de compreender os déficits de VPI e o desenvolvimento de programas efetivos de reabilitação é, portanto, crítico. Devido à sua alta validade preditiva e à sua fácil administração, o Symbol Digit Modalities Test (SDMT) é um dos testes clínicos mais amplamente utilizados para a avaliação cognitiva de pacientes com menor VPI. No entanto, além de avaliar a presença e gravidade de seus déficits, é interessante determinar as regiões cerebrais responsáveis por essa função e sua integração. Devido à sua não invasividade e ao seu bom nível de confiabilidade, a técnica de Imagem de Ressonância Magnética Funcional Dependente do Nível de Oxigenação no Sangue (BOLD-fMRI) é a ferramenta mais apropriada para esse fim. Logo, o objetivo do presente estudo foi o mapeamento funcional cerebral de VPI durante o desempenho de uma tarefa (SDMT) adaptada para o ambiente da ressonância em um grupo de voluntários saudáveis jovens. 16 controles saudáveis destros foram recrutados e submetidos à avaliação cognitiva com a versão oral do SDMT antes da aquisição de imagens. IRM foi adquirida em um sistema de 3T (Philips Achieva). Imagens funcionais (BOLD) foram adquiridas com uma sequência EPI. O experimento consistiu de seis blocos de 30 s de controle intercalados com cinco blocos de 30 segundos de tarefa (SDMT). Durante os blocos de tarefa, um símbolo foi apresentado a cada 2 segundos e ao participante foi requerido que associasse o número correspondente ao símbolo apresentado baseando-se em uma chave de resposta. Durante os blocos de controle, um número foi apresentado a cada 2 segundos e ao participante foi requerido que lesse silenciosamente o número em questão. Mapas paramétricos estatísticos foram obtidos para estudo de localização funcional utilizando o Modelo Linear Geral com um regressor boxcar convoluído com uma função de resposta hemodinâmica canônica (p-FDR < 0,01). Foi realizada a correlação bivariada entre as séries temporais médias das regiões associadas à tarefa para estudo de integração funcional (p-FDR < 0.0001). As informações de localização e integração funcionais foram inseridas em analise de conectividade efetiva. Ativações foram observadas na rede frontoparietal e no córtex occipital para análises individual e em grupo. Análise de conectividade efetiva para a arquitetura do sistema revelou o declive em posição serial com o giro lingual, o cúneo e duas regiões paralelas (pré-cúneo e lóbulo parietal superior), a partir do qual a informação converge para o giro frontal inferior e se bifurca para os giros frontais médios esquerdo e direito. Um modelo de rede envolvendo áreas relacionadas à VPI foi obtido e pode servir como referência para investigações futuras deste processo cognitivo em grupos clínicos, combinadas com estudos de neuroplasticidade cerebral. / Many cognitive operations require sufficient information processing speed (IPS) to be executed within the allowed time frame, with delayed IPS often underlining attentional deficits. The deceleration in response time is particularly evident in patients with traumatic brain injury, Parkinson\'s disease, depression, dementia and multiple sclerosis (MS). The importance of understanding IPS deficits and developing effective rehabilitation programs is therefore critical. Because of its high predictive validity and easy administration, the Symbol Digit Modalities Test (SDMT) is one of the most widely used clinical tests for the cognitive assessment of patients with lower IPS. However, in addition to evaluating the presence and severity of its deficits, it is interesting to determine the brain regions responsible for this function and its integration. Because of its non-invasiveness and its good level of reliability, the BOLD-fMRI technique is the most appropriate tool for this purpose. Therefore, the aim of the present study was the functional brain function mapping of IPS during the performance of a task (SDMT) adapted to the resonance environment in a group of healthy young volunteers. 16 healthy right controls were recruited and submitted to cognitive assessment with the oral version of SDMT prior to image acquisition. MRI was acquired in a 3T system (Philips Achieva). Functional images (BOLD) were acquired with an EPI sequence. The experiment consisted of six blocks of 30 s of control intercalated with five blocks of 30 seconds of task (SDMT). During the task blocks, a symbol was displayed every 2 seconds and the participant was required to associate the number corresponding to the displayed symbol based on a response key. During the control blocks, a number was displayed every 2 seconds and the participant was required to silently read the number in question. Statistical parametric maps were obtained for functional localization study using the General Linear Model with a boxcar regressor convolved with a canonical hemodynamic response function (p-FDR <0.01). The bivariate correlation between the mean time series of the regions associated with the task for functional integration study (p-FDR <0.0001) was performed. The functional location and integration information was inserted into effective connectivity analysis. Activations were observed in the frontoparietal network and in the occipital cortex for individual and group analyzes. Effective connectivity analysis for the system architecture revealed the declive in serial position with the lingual gyrus, the cuneus and two parallel regions (precuneus and superior parietal lobule), from which the information converges to the inferior frontal gyrus and bifurcates to the left and right middle turns. A network model involving areas related to IPS has been obtained and may serve as a reference for future investigations of this cognitive process in clinical groups, combined with studies of cerebral neuroplasticity.

Muitas operações cognitivas requerem velocidade de processamento de informação (VPI) suficiente para serem executadas dentro do prazo permitido, sendo que VPI retardada geralmente está subjacente a déficits atencionais. A desaceleração no tempo de resposta é particularmente evidente em pacientes com traumatismo crânio-encefálico, doença de Parkinson, depressão, demência e esclerose múltipla (EM). A importância de compreender os déficits de VPI e o desenvolvimento de programas efetivos de reabilitação é, portanto, crítico. Devido à sua alta validade preditiva e à sua fácil administração, o Symbol Digit Modalities Test (SDMT) é um dos testes clínicos mais amplamente utilizados para a avaliação cognitiva de pacientes com menor VPI. No entanto, além de avaliar a presença e gravidade de seus déficits, é interessante determinar as regiões cerebrais responsáveis por essa função e sua integração. Devido à sua não invasividade e ao seu bom nível de confiabilidade, a técnica de Imagem de Ressonância Magnética Funcional Dependente do Nível de Oxigenação no Sangue (BOLD-fMRI) é a ferramenta mais apropriada para esse fim. Logo, o objetivo do presente estudo foi o mapeamento funcional cerebral de VPI durante o desempenho de uma tarefa (SDMT) adaptada para o ambiente da ressonância em um grupo de voluntários saudáveis jovens. 16 controles saudáveis destros foram recrutados e submetidos à avaliação cognitiva com a versão oral do SDMT antes da aquisição de imagens. IRM foi adquirida em um sistema de 3T (Philips Achieva). Imagens funcionais (BOLD) foram adquiridas com uma sequência EPI. O experimento consistiu de seis blocos de 30 s de controle intercalados com cinco blocos de 30 segundos de tarefa (SDMT). Durante os blocos de tarefa, um símbolo foi apresentado a cada 2 segundos e ao participante foi requerido que associasse o número correspondente ao símbolo apresentado baseando-se em uma chave de resposta. Durante os blocos de controle, um número foi apresentado a cada 2 segundos e ao participante foi requerido que lesse silenciosamente o número em questão. Mapas paramétricos estatísticos foram obtidos para estudo de localização funcional utilizando o Modelo Linear Geral com um regressor boxcar convoluído com uma função de resposta hemodinâmica canônica (p-FDR < 0,01). Foi realizada a correlação bivariada entre as séries temporais médias das regiões associadas à tarefa para estudo de integração funcional (p-FDR < 0.0001). As informações de localização e integração funcionais foram inseridas em analise de conectividade efetiva. Ativações foram observadas na rede frontoparietal e no córtex occipital para análises individual e em grupo. Análise de conectividade efetiva para a arquitetura do sistema revelou o declive em posição serial com o giro lingual, o cúneo e duas regiões paralelas (pré-cúneo e lóbulo parietal superior), a partir do qual a informação converge para o giro frontal inferior e se bifurca para os giros frontais médios esquerdo e direito. Um modelo de rede envolvendo áreas relacionadas à VPI foi obtido e pode servir como referência para investigações futuras deste processo cognitivo em grupos clínicos, combinadas com estudos de neuroplasticidade cerebral. / Many cognitive operations require sufficient information processing speed (IPS) to be executed within the allowed time frame, with delayed IPS often underlining attentional deficits. The deceleration in response time is particularly evident in patients with traumatic brain injury, Parkinson\'s disease, depression, dementia and multiple sclerosis (MS). The importance of understanding IPS deficits and developing effective rehabilitation programs is therefore critical. Because of its high predictive validity and easy administration, the Symbol Digit Modalities Test (SDMT) is one of the most widely used clinical tests for the cognitive assessment of patients with lower IPS. However, in addition to evaluating the presence and severity of its deficits, it is interesting to determine the brain regions responsible for this function and its integration. Because of its non-invasiveness and its good level of reliability, the BOLD-fMRI technique is the most appropriate tool for this purpose. Therefore, the aim of the present study was the functional brain function mapping of IPS during the performance of a task (SDMT) adapted to the resonance environment in a group of healthy young volunteers. 16 healthy right controls were recruited and submitted to cognitive assessment with the oral version of SDMT prior to image acquisition. MRI was acquired in a 3T system (Philips Achieva). Functional images (BOLD) were acquired with an EPI sequence. The experiment consisted of six blocks of 30 s of control intercalated with five blocks of 30 seconds of task (SDMT). During the task blocks, a symbol was displayed every 2 seconds and the participant was required to associate the number corresponding to the displayed symbol based on a response key. During the control blocks, a number was displayed every 2 seconds and the participant was required to silently read the number in question. Statistical parametric maps were obtained for functional localization study using the General Linear Model with a boxcar regressor convolved with a canonical hemodynamic response function (p-FDR <0.01). The bivariate correlation between the mean time series of the regions associated with the task for functional integration study (p-FDR <0.0001) was performed. The functional location and integration information was inserted into effective connectivity analysis. Activations were observed in the frontoparietal network and in the occipital cortex for individual and group analyzes. Effective connectivity analysis for the system architecture revealed the declive in serial position with the lingual gyrus, the cuneus and two parallel regions (precuneus and superior parietal lobule), from which the information converges to the inferior frontal gyrus and bifurcates to the left and right middle turns. A network model involving areas related to IPS has been obtained and may serve as a reference for future investigations of this cognitive process in clinical groups, combined with studies of cerebral neuroplasticity.