Дисертації з теми "Neurological soft sign"

This dissertation describes a series of studies addressing the prevalence, correlates and longitudinal changes in soft neurological signs (SNS) in schizophrenia. SNS are found to be increased in schizophrenia. The increase appeared to have both a genetic and a non-genetic component. It has been proposed that SNS could be considered as one of the biological markers expressing a mediating risk for schizophrenia. In order to clarify the role of SNS in this perspective it is important to understand factors that affect the expression of SNS in a given population. Previous studies have identified possible relationships between SNS on one hand, and age, ethnicity, intelligence as well as education levels on the other. Associations with clinical features as well as cognitive function impairment have also been suggested. Antipsychotic medication side-effects appear not to be directly related to SNS, nevertheless their impacts cannot be entirely ruled out. Inconsistencies have also emerged as a result of sampling and methodological variations. The potential change of SNS with time in different phases of the disorder is another important issue that has not been adequately addressed with longitudinal studies. This dissertation describes works that addressed some of these issues in different samples using the same assessment methodology. A relatively extensive cross-sectional study addresses the relationship of SNS with demographic, educational, clinical and cognitive factors. The level of SNS in a Chinese sample is also compared with that obtained in a Caucasian sample to investigate effects of ethnicity. Data from the cross-sectional study also allow a limited analysis addressing the contributions of age and illness duration across a wider time range. Two longitudinal studies then focus on specific phases of the disorder. The first study investigates changes in SNS amongst chronic patients approaching old age (the fifth decade). The second study addresses changes in SNS following first episode psychosis. In the first chapter a broad introduction to methodological issues is presented. Chapter 2 continues with a more detailed review of the existing data about SNS in schizophrenia. Chapter 3 presents the core methodology and assessment instruments used in the studies. In Chapter 4 the recruitment procedures and the characteristics of the samples are described. Data analysis and results are presented in Chapters 5 to 8. In Chapter 5 important correlates of SNS are explored using data from a larger crosssectional sample of Chinese patients and controls. These include age, gender, education level, intelligence, as well as symptom correlates of SNS. The potential effects of ethnicity were further explored by comparison between Chinese and Caucasian control samples. Additional analyses were carried out to attempt to address the relative importance of age and illness duration for SNS in patients. Chapter 6 describes in more detail the relationship between SNS and cognitive functions in this cross-sectional sample. Chapters 7 and 8 describe two longitudinal studies. Chapter 7 deals with a 3-year follow-up study for stable chronic patients. Chapter 8 addresses a 2-year follow-up study of SNS in first episode patients. In Chapter 9 the dissertation ends with a general discussion of the current findings and suggestions for key areas for future research.

La esquizofrenia es un trastorno psiquiátrico grave, un síndrome complejo y heterogéneo originado por la alteración del desarrollo del cerebro por factor genéticos o ambientales. Las bases genéticas pueden estar presentes en individuos sin enfermedad como en hermanos de pacientes y pueden ser identificadas a través de marcadores biológicos. Los signos neurológicos menores son discretas alteraciones sensitivo-motoras asociadas con un desarrollo cerebral alterado que se han propuesto como un endofenotipo de la esquizofrenia. Un perfil específico de temperamento y carácter así como la presencia de rasgos de personalidad esquizotípicos también se han relacionado con rasgos de personalidad esquizotípicos se han propuesto como un marcador de vulnerabilidad a la esquizofrenia. La etiopatogénesis de la esquizofrenia sugiere que puede haber una “alteración progresiva del neurodesarrollo”. Esta visión aboga por una alteración en los circuitos funcionales que implican áreas de asociación heteromodal más que alteraciones específicas en un área concreta del cerebro. El objetivo de este estudio es explorar las anomalías de conectividad funcional en el Default Mode Network relacionados con la asociación entre signos neurológicos menores y rasgos de personalidad en la esquizofrenia. Para investigar esta asociación se plantea un estudio transversal comparando un grupo de pacientes con esquizofrenia, un grupo de parientes no afectos de pacientes y un grupo de sujetos sanos, para explorar la asociación de estos posibles marcadores biológicos de esquizofrenia se estudio: a) Asociación entre signos neurológicos menores y rasgos de personalidad : Inventario de temperamento y carácter TCI, Cuestionario de personalidad esquizotípica SPQ) y una evaluación de los signos neurológicos menores. b) Asociación entre cambios en la conectividad cerebral en el default mode network con la presencia de signos neurológicos: fMRI en estado de reposo.. El principal hallazgo de este estudio es que los pacientes con esquizofrenia y los parientes no afectos presentan un perfil específico de temperamento y carácter con más rasgos de personalidad esquizotípicos que se correlacionan con una mayor presencia se signos neurológicos menores. Los resultados revelan que la asociación entre estos posibles biomarcadores a nivel teórico como el temperamento (especialmente la evitación del daño, la búsqueda de recompensa y la persistencia) y el carácter (especialmente la autodirección y la cooperación) que se correlaciona con la presencia de signos neurológicos menores en toda la muestra. También los rasgos esquizotípicos de personalidad mostraron una fuerte correlación con la presencia de signos neurológicos menores en toda la muestra. Los resultados muestran la susceptibilidad a los signos neurológicos menores y a la esquizofrenia está relacionada en ambos casos con diferencias individuales en aspectos de personalidad en parientes no psicóticos de pacientes con esquizofrenia. Estos hallazgos subrayan el valor de usar ambos parámetros para el estudio de poblaciones de riesgo. Los resultados de neuroimagen mostraron cambios en la conectividad de las redes neuronales por defecto posiblemente asociados a la presencia de signos neurológicos menores. Estos hallazgos apoyan la teoría de la dismetría cognitiva como una posible disfunción en las conexiones córtico-tálamo-cerebelares. Este modelo también podría explicar la diversidad de síntomas de la esquizofrenia y sus asociaciones (como en este estudio que incluye personalidad y funciones sensitivo-motoras).
Schizophrenia is a severe psychiatric disorder that has a profound effect on both the individuals affected and society. This common mental illness is a complex, heterogeneous behavioural and cognitive syndrome that seems to originate from disruption of brain development caused by genetic or environmental factors, or both. The genetic basis may be present in individuals without disease, as in the case of relatives of patients, being detectable through biological markers. Neurological soft signs (NSS) are discrete sensorimotor impairments associated with deviant brain development that were postulate as an endophenotype of schizophrenic spectrum disorder. Also the personality traits have been proposed as a vulnerability marker in schizophrenia. A specific profile of temperament and character and the schizotypal personality traits have also been correlated with schizotypal personality traits. These traits and some neurological abnormalities have been shown to aggregate in the relatives of schizophrenia patients. The etiopathogenesis of schizophrenia suggests it may be a "progressive neurodevelopmental disorder". This view postulates a disruption in functional circuits involving hetero modal association areas rather than a specific abnormality in a single brain region. The aim of this study is to explore the abnormalities in the functional connectivity of the default mode network related to the association between neurological soft signs and personality in schizophrenia. To investigate this a cross-sectional study is proposed, comparing a group of patients with schizophrenia, a group of unaffected relatives and a group of healthy controls. In order to explore the association of these potential biomarkers of schizophrenia the study was composed of two parts: a) To explore the association between neurological soft signs and personality traits in schizophrenia, two personality examinations (Temperament and Character Inventory and the Schizotypal Personality Questionnaire) and an evaluation of Neurological Soft Signs were performed. b) To explore the association between cerebral connectivity changes in the default mode network with the presence of neurological soft signs in schizophrenia a functional magnetic resonance scan was performed on participants in a resting state. The major finding in this study was that patients with schizophrenia and non-psychotic relatives display a unique profile of temperament and character and more schizotypal traits that correlate with higher presence of NSS. Our results reveal an association between these hypothesized vulnerability markers, as temperament (especially harm avoidance, reward dependence and persistence) and character (especially self-directedness and cooperativeness) correlated with the presence of NSS in the entire sample. Also the schizotypal traits (total scores and subscores) showed a very strong correlation with the presence of NSS in the entire sample. The results showed that susceptibility to NSS and to schizophrenia are both related to individual differences in personality features in non-psychotic relatives of patients with schizophrenia. These findings highlight the value of using both assessments to study high risk populations. The neuroimaging results showed connectivity changes in the default mode network with a possible association with the presence of neurological soft signs. These findings support the theory of cognitive dysmetria as a possible dysfunction in cortical-thalamic-cerebellar connectivity. This model also could explain the diversity of symptoms in schizophrenia and their associations (like this study that includes personality and sensory and motor functions). One strength of the study is that the relatives of patients with schizophrenia had no familial ties to the patients used, thus decreasing the possibility that similar upbringing would confound the results.

Background: The challenges of research in economically stunted countries’ settings remains a profound concern and is linked to socioeconomic development of these countries. More research is needed regarding psychiatric morbidity in rural areas of the developing and poverty stricken countries. The present studies were undertaken within the framework of a broader ongoing community-based project on the course and outcome of major psychiatric disorders in the rural Butajira district located in Ethiopia. This thesis treats the course and outcome of bipolar I disorder in the district. Objectives: Through appraising mental health and population based research in a rural Ethiopian district, to evaluate the utility of modern research instruments, and to obtain baseline information relating to bipolar I disorder in the poverty stricken rural Butajira district of Ethiopia. The specific objectives were: 1. Evaluating and comparing two different screening methods of case detection and identification for schizophrenia and bipolar I disorder in the adult population of Butajira district. 2. Assesing the prevalence and clinical characteristics of of bipolar I disorder in Butajira at the community level. 3. Evaluating short-term outcome at follow-up of bipolar I disorder in the Butajira district. 4. Determining Neurological Soft Signs in community-identified cases of bipolar I disorder in Butajira district in comparison with healthy controls. 5. Assessing the burden of care among caregivers of those affected by bipolar I disorder identified in the Butajira Study. Methods: The district’s entire adult population aged 15-49 was identified through a double-sampling design. In the first stage of screening, door-to-door interviews were conducted by lay trained high school completed individuals who knew the culture of the people. Females interviewed females whereas males interviewed males. Additionally, the key-informants method was used to identify cases that would be missed by the CIDI or otherwise. The final confirmatory diagnostic interview was conducted by clinicians using the SCAN on door-to-door basis as well. The probable cases that fulfilled the lifetime DSM-IV diagnosis of bipolar I disorder were assigned for assessment by other baseline research instruments such as Neurological Evaluation vii Scale (NES), Young Mania Rating Scale, Hamilton Rating Scale for Depression, LCSS, PANS and SANS, BISS, BII, FIS and so on. Cases so identified with bipolar I disorder were subject to a follow-up for upto 2.5 years on the average (range 1 to 4 years). Two of the main clinical outcomes assessed were relapse to a mood episode, and remission from a mood episode. Outcomes were assessed annually by the instruments, and were further assessed monthly by trained psychiatric nurses. We also did a cross-sectional study of caregivers of bipolar I disorder cases, and assessed objective burden on the caregivers as considered from social, family strain, occupational and financial domains. Results: Information provided by the key informants was better at detecting schizophrenia or chronic psychiatric disease, whereas the CIDI was better at detecting affective disorders. Of the around 100 000 adults living in Butajira, 83.3% were found by the project’s census, of which 82% (68,378 subjects) were successfully screened by the CIDI, yielding 2,161 CIDI positive. These, together with 719 cases identified by the key informants, were invited for the SCAN interview, of which 74.7% agreed. This yielded 315 SCAN positive cases for bipolar I disorder, and complete information could be collected on 295 of these. Lifetime prevalence was estimated as 0.6% for males and 0.3% for females. The mean age of onset of the manic phase was 22.0 years and that of the depressive phase was 23.4 years. For 22.7% of the cases the illness started with a depressive episode and for the remaining 77.3% it started with a manic episode. Over half of the cases (55.9%) had never sought help from modern health care sector, and only 13.2% had ever been admitted to psychiatric hospital. At follow-up, 65.9% had exprerienced a relapse and 31.1% had persistent illness, while only 5% of the patients were in remission for most of the follow-up time. The bipolar I cases, as compared with healthy controls, performed worse on several items of NES, thus having more neurological dysfunction compared to controls. Caregives were largely (80.3%) first-degree relatives and spouses. Overall, 84% of the caregivers reported difficulties in at least one of the domains of family burden. Of these, 58.7% reported a severe degree of difficulties. Caregivers reported a high level of difficulties in intrafamilial relationships and social restrictions, disruption in earning a livelihood, and financial difficulties. Conclusions: The prevalence of bipolar I disorder is comparable to the prevalences reported from other countries, and our findings support the cross-cultural validity of the concept of bipolar I disorder. Majority of the cases are not treated in contrast to that in the developed countries. The burden of care for the caregivers is substantial in the population studied.

While multiple Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans suffer from mild Traumatic Brain Injury (mTBI), Post-traumatic Stress Disorder (PTSD), and co-morbid mTBI and PTSD, there remains difficulty disentangling the specific symptoms associated with each disorder using self-report and neurocognitive assessments. We propose that neurological soft signs (NSS), which are tasks associated with general neurologic compromise, may prove useful in this regard. Based on our review of the literature we hypothesized that individuals with PTSD would present with a greater number of NSS than controls or individuals with mTBI. Further, we hypothesized a synergistic effect, such that individuals with mTBI + PTSD would present with the greatest number of NSS. To test these hypotheses, we analyzed a subset of individuals (N=238) taken from a larger study of neurocognitive functioning in veterans. Participants completed a battery of neuropsychological measures, which included the Behavioral Dyscontrol Scale (BDS), the current study’s measure of NSS. A subset of other neuropsychological measures were also included to examine the utility of NSS over and above traditional neuropsychological measures. Individuals were removed from the study if they sustained a moderate/severe TBI or did not meet validity criteria on the Green’s Word Memory Test or the Negative Impression Management subscale of the Personality Assessment Inventory. Binomial logistic and multinomial logistic regression were used to examine the ability of NSS to discriminate between the study groups, first by themselves and then after the variance explained by the traditional neuropsychological measures was accounted for. Exploratory cluster analyses were performed on neuropsychological measures and NSS to identify profiles of cognitive performance in the data set. Results indicated that individuals in the mTBI and/or PTSD group had more NSS compared to controls. Of the individual NSS items only a go/no-go task of the BDS discriminated between groups, with worse performance among individuals in the mTBI, PTSD, and mTBI + PTSD group compared to controls. In contrast, the overall BDS score and individual NSS, in general, did not discriminate between the mTBI, PTSD, and mTBI + PTSD group. Overall, the current study suggests that, when eliminating participants who do not meet validity criteria, NSS do not aid in discriminating between individuals with mTBI, PTSD, and mTBI + PTSD.

Le terme de neurodéveloppement dans son acception la plus large renvoie à l'ensemble des processus permettant le développement du système nerveux depuis les étapes les plus précoces de sa formation in utero jusqu'aux étapes plus tardives de maturation à l'adolescence aboutissant au système nerveux adulte. Les travaux de ces quarante dernières années ont conduit à proposer un modèle neurodéveloppemental des troubles psychiatriques, notamment schizophréniques, sur la base d'arguments génétiques, épidémiologiques et d'imagerie. Ce modèle propose que l'apparition de la maladie soit liée à une/des anomalie(s) dans les processus de formation (neurodéveloppement précoce) et de maturation (neurodéveloppement tardif) du système nerveux, sous l'effet combiné de facteurs génétiques et environnementaux. Dans ce contexte, ce travail de thèse vise à préciser les effets des anomalies neurodéveloppementales sur les troubles psychiatriques, notamment schizophréniques à travers l'étude de différents marqueurs. La première étude a pour objectif d'étudier les corrélations entre deux marqueurs du développement cérébral précoce : un marqueur clinique (les signes neurologiques mineurs) et un marqueur en imagerie (la sulcation du cortex cérébral) dans une population de sujets atteints de schizophrénie. Une corrélation entre ces deux marqueurs est mise en évidence : l'index de sulcation est d'autant plus faible que les sujets présentent des signes neurologiques mineurs significatifs. Notre conclusion est que l'étude combinée de différents marqueurs peut permettre d'isoler des sous-groupes de patients ayant eu des atteintes neurodéveloppementales précoces plus marquées. La deuxième étude a pour objectif de caractériser l'effet de différents marqueurs d'anomalies neurodéveloppementales précoces sur le fonctionnement cognitif de sujets atteints de schizophrénie. L'effet sur le contrôle exécutif (mesuré par la tâche du Trail Making Test) de marqueurs cliniques (signes neurologiques mineurs, latéralisation manuelle) et en imagerie (sulcation du cortex cingulaire antérieur et élargissement des ventricules ventraux) est mesuré en recherchant les effets principaux et les interactions entre chaque marqueur. Nous trouvons des interactions entre différents marqueurs, avec principalement un effet de sommation non-linéaire. Notre interprétation est que les différents marqueurs reflètent des atteintes distinctes, bien que toutes précoces, du développement cérébral avec un effet final commun sur les fonctions exécutives. La troisième étude a pour objectif de préciser la spécificité de la sulcation comme marqueur d'anomalies neurodéveloppementales précoces à travers son étude dans une population de sujets adultes présentant un trouble du spectre autistique (TSA), pathologie débutant dès la petite enfance, en lien évident avec des atteintes neurodéveloppementales précoces. Des anomalies de sulcation du cortex cingulaire antérieur, similaires à celles observées chez les patients atteints de troubles schizophréniques, sont détectées chez les patients présentant un TSA. Ces résultats sont en faveur d'anomalies neurodéveloppementales précoces partagées entre différentes pathologies psychiatriques : les modifications de la sulcation corticale sont spécifiques non pas d'un trouble donné mais de la précocité des atteintes. En conclusion, nous proposons que l'étude des anomalies neurodéveloppementales soit intégrée dans une approche dimensionnelle en psychiatrie
The term neurodevelopment in its broadest sense refers to all of the processes encompassing development of the nervous system from the earliest stages of formation in utero to later stages of maturation during adolescence to produce the fully functional adult nervous system. Work over the last thirty years has led to a neurodevelopmental model of human psychiatric disorders, including schizophrenia, based on genetic, epidemiological and imaging evidence. This model asserts that disease is fundamentally linked to or develops from abnormality(s) in the formation processes (early neurodevelopment) and maturation (late neurodevelopment) of the nervous system due to a combination of genetic and environmental factors. In this context this thesis aims to clarify the effects of neurodevelopmental abnormalities on psychiatric disorders, including schizophrenia, through the study of different markers. The first study aims to investigate correlations between markers of early brain development: a clinical marker (neurological soft signs) and an imaging marker (sulcation of the cerebral cortex) in a population of subjects with schizophrenia. A correlation between these two markers is presented: the sulcation index was found to be lower in subjects that had significant neurological soft signs. We concluded that the combined study of different markers may help to isolate subgroups of patients with greater early neurodevelopmental damage. The second study aims to characterize effects of different markers of early neurodevelopmental abnormalities on cognitive functioning in patients with schizophrenia. Effects on executive control (as measured by the Trail Making Test) were correlated with clinical markers (neurological soft signs, handedness) and imaging (sulcation of the anterior cingulate cortex and enlargment of the ventricles). We found interactions between different markers with a mainly non-linear summation effect. Our interpretation is that different markers reflect separate insults, though all early, on brain development with a common final effect on executive function. The third study aims to clarify the specificity of sulcation as a marker of early neurodevelopmental abnormalities by studying a population of adult subjects with autism spectrum disorder (ASD), a patholody beginning in early childhood and linked with evidence of early neurodevelopmental damage. Sulcation abnormalities of the anterior cingulate cortex, similar to those observed in patients with schizophrenia are detected in patients with ASD. These results suggest early neurodevelopmental abnormalities are shared by different psychiatric disorders and that changes in cortical sulcation are not specific to a given disorder but the early damage. In conclusion, we suggest that the study of neurodevelopmental abnormalities should be integrated into a dimensional approach in psychiatry

Los Signos Neurológicos Menores (SNM), entendidos como alteraciones neurológicas que no tienen una localización específica a nivel cerebral, presentan una mayor prevalencia en los pacientes con esquizofrenia que en la población sana. También se ha descrito una mayor frecuencia de los mismos en los familiares de los pacientes con esquizofrenia (aunque en menor medida que en los pacientes). Algunos aspectos de la asociación de los SNM con el cuadro clínico de la esquizofrenia permanecen sin esclarecer. Otros temas de interés en la literatura se dirigen hacia la relación entre los SNM y los déficits neuropsicológicos observados en la esquizofrenia y su asociación con los cambios estructurales que caracterizan el trastorno. El objetivo general de esta tesis fue el de estudiar la relación entre los SNM y diversos aspectos de la esquizofrenia en una muestra relativamente amplia de pacientes. El primer estudio examinó los correlatos con: a) los síntomas de la enfermedad organizados en los síntomas positivos (delirios y alucinaciones), el síndrome de desorganización (principalmente trastorno formal del pensamiento) y los síntomas negativos, y b) con el deterioro cognitivo, específicamente con dos aspectos concretos del déficit neuropsicológico observados en la esquizofrenia como son la función ejecutiva y la memoria. El segundo estudio evaluó la relación de los SNM con las estructuras cerebrales, específicamente con los cambios en la sustancia gris. Los SNM fueron valorados en ambos estudios a través de una escala detallada y estructurada, la NES de Buchanan y Heinrichs, que ofrece una puntuación total y tres subescalas: integración sensorial, coordinación motora, secuenciación de actos motores complejos. En el primer estudio se examinó la prevalencia de los SNM en una muestra de 78 sujetos con esquizofrenia crónica. También se exploró un grupo de 36 sujetos controles sanos para su comparación. Los síntomas clínicos fueron evaluados utilizando la escala de síntomas positivos y negativos (PANSS) a través de la cual se calcularon las puntuaciones para los síntomas positivos, de desorganización y los síntomas negativos. La función ejecutiva y la memoria fueron evaluadas utilizando dos baterías de pruebas, la BADSy el RBMT. El Coeficiente Intelectual (CI) actual se utilizó como una medida de función intelectual general. Tal y como se esperaba, se encontró que los pacientes esquizofrénicos presentaron una mayor frecuencia de SNM que los sujetos controles. En cuanto a los síntomas clínicos de la enfermedad no se encontró relación entre los SNM y la clínica positiva ni tampoco con la clínica negativa; tan solo hubo evidencia equívoca en la correlación con el síndrome de desorganización. Las puntuaciones de los SNM correlacionaron de forma inversa y fuertemente con todas las puntuaciones de las pruebas cognitivas administradas. Las correlaciones con las puntuaciones de la memoria y de la función ejecutiva se mantuvieron significativas tras controlar la correlación con el deterioro general intelectual. El segundo estudio se llevó a cabo con una muestra de 83 pacientes y un grupo de 60 sujetos controles sanos. Para medir el volumen de la sustancia gris se usó la resonancia magnética y se analizaron las imágenes mediante el análisis de morfometría basada en vóxeles de todo el cerebro. Los pacientes con esquizofrenia mostraron un patrón de reducción de volumen extendido por la corteza que también comprendía diversas estructuras subcorticales. Además, se observó un incremento de volumen de la sustancia gris en el tronco cerebral y mesencéfalo y una pequeña región del cerebelo izquierdo. No se pudieron encontrar clústeres de correlación significativa con la puntuación total de los SNM ni con las subescalas en el grupo de pacientes con esquizofrenia. La discusión de los hallazgos de esta tesis se realizará haciendo particular referencia al fallo en la replicación de los hallazgos previos y la evidencia encontrada en muchos de los estudios revisados. También se discute acerca de las potenciales implicaciones: la hipótesis de la dismetría cognitiva de Andreasen y la idea de que representen un marcador de rasgo o endofenotipo para la enfermedad.
Neurological soft signs (NSS), defined as minor neurological abnormalities that do not have localizing value, are established as being present at a higher frequency in patients with schizophrenia than in the healthy population. They are also present at a higher than normal frequency in the relatives of patients with schizophrenia, although at a lower rate than in the patients themselves, leading to considerable interest in their potential role as a marker of vulnerability or predisposition to the disorder. Nevertheless, some aspects of the association of NSS with the clinical features of schizophrenia remain unclear. Other relevant issues concern the relationship between NSS and the cognitive impairment and brain structural changes that also characterize the disorder. The general aim of this thesis was to examine the relationship between NSS and selected aspects of schizophrenia in a relatively large sample of patients. The first study examined a) their association with the symptoms of the disorder, as classified into positive symptoms (delusions and hallucinations), the disorganization syndrome (mainly formal thought disorder) and negative symptoms; and b) with the cognitive impairment seen in the disorder, specifically two major specific deficits, executive function and memory. The second study evaluated the relationship of NSS with brain structural abnormality, specifically changes in grey matter. NSS were assessed in both studies using a detailed scale, the Neurological Evaluation Scale (NES) of Buchanan and co-workers, which provides a total score and three subscale scores: sensory integration, motor coordination, and sequencing of complex motor acts. In the first study, the frequency of NSS was rated in a sample of 78 subjects with chronic schizophrenia. A comparison sample of 36 healthy control subjects was also employed. Clinical symptoms were rated using the Positive and Negative Symptom Scale (PANSS). The Behavioural Assessment of the Dysexecutive Syndrome (BADS) and the Rivermead Behavioral Memory Test (RBMT) were used to measure executive function and memory, respectively; current WAIS IQ was used as a measure of general intellectual function. As expected, the schizophrenic patients showed a higher frequency of NSS than the control subjects. With respect to symptoms, no relationship was found between NSS total or subscale scores and positive or negative symptoms; there was only equivocal evidence for a correlation with the disorganization syndrome. NSS scores correlated inversely and strongly with scores on all the cognitive measures. The correlations with memory and executive function scores remained significant after controlling for the correlation with general intellectual impairment. The second study was carried out on a sample of 83 patients with schizophrenia and a group of 60 healthy controls. Grey matter volume was measured using MRI, and the images were analyzed using whole-brain voxel-based morphometry. The patients with schizophrenia showed a pattern of widespread volume reduction in the cortex, and also in several subcortical structures. They also showed significantly increased grey matter volume in the brainstem and midbrain and in a small region of the left cerebellum. No clusters of significant correlation between NSS total or subscale scores were observed in the patients. The findings are discussed with particular reference to the failure to replicate previous findings of associations between NSS and negative symptoms, as well as the second study’s failure to find an association with structural cerebral changes in schizophrenia, something that has been reported in almost all previous MRI studies. The potential implications of the findings for two current theories of NSS in schizophrenia are also discussed: Andreasen’s hypothesis of cognitive dysmetria and the proposal that they represent a trait marker or endophenotype for the disorder.

Autisme et schizophrénie sont deux troubles psychiatriques neuro-développementaux. L’étude des formes précoces de schizophrénie, fréquemment associées aux troubles du spectre de l’autisme (TSA), a suggéré un possible continuum développemental entre ces troubles. Des arguments cliniques et épidémiologiques, et issus des études en génétique moléculaire ou en imagerie cérébrale, sont progressivement venus étayer cette hypothèse. Dans ce contexte, l’étude de la cognition sociale a fait l’objet d’un intérêt particulier, des altérations étant rapportées dans les deux troubles avec toutefois des résultats contrastés, révélant autant de points communs que de différences. Les relations entre altération de la cognition sociale et charge neuro-développementale ont par ailleurs été peu explorées. A travers nos trois études, nous avons confirmé l’existence d’altérations de la cognition sociale dans les TSA et la schizophrénie. Le MASC (Movie for the Assessment of Social Cognition), épreuve mixte et originale dont nous avons validé la version française, a permis de montrer une altération globale des capacités de mentalisation plus importante dans les TSA que dans la schizophrénie. Les Triangles Animés (épreuve d’attribution d’intention reposant sur un matériel non verbal) ont permis de révéler des différences qualitatives : tandis que l’hypomentalisation est commune aux deux troubles, l’hypermentalisation apparaît plus marquée dans la schizophrénie. Par ailleurs, à travers un continuum autisme-schizophrénie, l’altération de la cognition sociale était liée à la désorganisation de la pensée et du langage, et à l’importance des signes neurologiques mineurs (marqueur de vulnérabilité neurodéveloppementale). En outre, chez les sujets avec schizophrénie, l’hypermentalisation était corrélée à la précocité d’installation du trouble. Nos résultats soulignent l’intérêt de pouvoir repérer chez des patients adultes un trouble du développement. En ce sens, nous avons présenté les premiers éléments de validation d’un autoquestionnaire de dépistage des troubles du développement, permettant en population adulte un repérage rétrospectif des signes et symptômes d’autisme présents dans l’enfance. En conclusion, nos résultats apportent des arguments en faveur du continuum autisme-schizophrénie, en montrant l’existence d’une altération de la cognition sociale, dans ces deux troubles, corrélée à la charge neuro-développementale de façon trans-nosographique. Il existe toutefois des différences qualitatives. Un sous-groupe de sujets avec schizophrénie dont le trouble a débuté précocement semble par ailleurs se dessiner, caractérisé par une tendance à hyper-mentaliser et présentant une désorganisation plus marquée
Autism and schizophrenia are both neurodevelopmental psychiatric disorders. Research on early-onset schizophrenia, commonly associated to autism spectrum disorders (ASD), suggested a possible developmental continuum between both of these disorders. Clinical and epidemiological evidence, and research from molecular genetics or brain imaging, come to support this hypothesis. In this context, social cognition is a matter of special interest. Impairments are reported both in the two disorders, but with inconsistent results, revealing common features as well as differences. Otherwise, links between social cognition impairments and neurodevelopmental burden have been until now poorly explored. Through the contribution of our three studies, we confirmed the importance of social cognition impairment in autism and schizophrenia. The MASC test (Movie for the Assessment of Social Cognition), an original tool which was by our findings validated in a French version, revealed higher overall impairment of mentalizing capabilities in ASD than in schizophrenia. Animated Shapes (non verbal test of attribution of intentions) revealed qualitative differences: whereas hypomentalizing is common both to ASD and schizophrenia, overmentalizing seemed to be more important in schizophrenia. Furthermore, along a continuum between autism and schizophrenia, social cognition impairment was linked to thought and language disorganization, and to neurological soft signs (a marker for neurodevelopmental load). In addition, in subjects with schizophrenia, overmentalizing was correlated to the precocity of onset of the disease. Altogether, our results highlight the need to screen developmental feature in adulthood. In that way, we presented preliminary results in order to validate a developmental disorders screening self-rated questionnaire. As a conclusion, our results bring evidence in favour of a hypothesis of a continuum between autism and schizophrenia, showing a social cognition impairment in both disorders, correlated to the neurodevelopmental load existing in both of them in a transnosographic way. We contributed to emphasize the sub-group of subjects with schizophrenia with early-onset of disease, characterized by a tendency to overmentalizing and presenting a marked disorganization. Our work provides avenue to further studies, integrating neuroimaging and genetic data, that will help to advance in a deeper comprehension of the pathophysiology of autism and schizophrenia. Furthermore, we used and validated in this work promising tools to improve finely psychopathological evaluation and differential diagnosis in adults suffering from autism and from schizophrenia

Le Trouble de Stress Post-Traumatique (TSPT) se développe suite à une confrontation traumatique. Il se caractérise par une tétrade clinique : conduites d'évitement, hypervigilance, reviviscences et troubles cognitivo-émotionnels. Le TSPT a une prévalence de 1 à 7 % en Europe (vie entière), et de 20% en milieu militaire selon les missions. L’évolution clinique quelle que soit la prise en charge, montre que plus de 20 % des sujets résistent aux prises en charge et qu’environ 40% des sujets qui se rétablissent présentent des rechutes à plus ou moins long termes. Ainsi, pour une partie non négligeable des patientsle TSPT se pose comme une maladie chronique. Ce constat interroge les mécanismes du rétablissement chez ces patients qui permettent une réinsertion socio-professionnelle satisfaisante. Se rétablir d’une pathologie chronique met en jeu des ressources psychologiques, cognitives et sociales. Les données disponibles chez des patients souffrant de maladie chronique pointent l’importance de ressources psychologiques permettant une capacité d’autonomie et d’engagement social. Force est de constater que dans le cadre du TSPT, les ressources psychologiques soutenant le rétablissement ont peu été étudiées. Sur un plan neurocognitif, le TSPT s’accompagne d’atteintes cognitives exécutives touchant en particulier la mémoire souvent associées à des plaintes neurologiques encore peu explorées. Ces troubles neurocognitifs sont des facteurs de risque de chronicisation du TSPT impactant non seulement la qualité de vie des patients et mais aussi leurs possibilités de réinsertion socioprofessionnelles. Enfin, sur le plan social, le chemin du rétablissement et de la réinsertion, implique une socialisation satisfaisante. La socialisation n’est pas un processus linéaire mais elle est soumise à des changements constants perpétuels dans lesquels la qualité des interactions sociales jouent un rôle majeur. Si l’hypothèse d’un impact des symptômes cliniques du TSPT dans la socialisation de ces est licite, les données disponibles sont rares. Cette question est d’autant plus important pour les militaires souffrant de TSPT chronique, qui le plus souvent vont devoir quitter le milieu militaire et se resocialiser dans un monde civil. Ce travail doctoral ambitionne de mieux appréhender les mécanismes psychoneurosociologiques de la trajectoire de rétablissement chez les patients souffrant d’un TSPT chronique. Plus précisément, il s’attache à répondre à 4 questions. La première question est théorique. Elle vise à analyser les données de la littérature portant sur le rétablissement, et ses dimensions, dans les maladies chroniques psychiques pour proposer un cadre théorique du rétablissement et des interventions d’intérêt à évaluer pour le TSPT (article 1). Trois questions ont fait l’objet d’études de terrain : a) quelles sont les ressources psychologiques importantes pour le rétablissement et la réinsertion des TSPT ? ; b) Quels sont les signes neurologiques d’intérêt pour mieux appréhender la trajectoire évolutive du patient souffrant de TSPT ? ; et c) Quels sont les obstacles et leviers de socialisation pour les patients souffrant de TSPT ? Au terme de ce travail exploratoire, réalisé principalement chez des militaires souffrant de TSPT chronique, nous proposons des pistes de travail et des recommandations d’intervention pour améliorer le cheminement de ces patients vers un rétablissement permettant la réinsertion socio-professionnel
Post-Traumatic Stress Disorder (PTSD) develops following a traumatic confrontation. It is characterized by a clinical tetrad: avoidance behaviors, hypervigilance, revivals and cognitivo- emotional impairments. PTSD has a prevalence of 1 to 7% in Europe (lifetime), and 20% in the military depending on the missions. The clinical course, regardless of the care, shows that more than 20% of subjects are resistant to treatment and that about 40% of subjects who recover relapse at some point. Thus, for a significant part of PTSD patients arise as a chronic disease. This finding questions the recovery mechanisms in these patients that could allow satisfactory socio-professional reintegration.Recovering process from this chronic pathology involves the interplay of psychological, cognitive and social resources. The data available in patients suffering from chronic illness point to the importance of psychological resources which allow a capacity for autonomy and social commitment. It is clear that in the context of PTSD, the psychological resources supporting recovery need further investigation. On a neurocognitive level, PTSD is characterized by executive cognitive impairment affecting in particular the memory, often associated with neurological complaints that are still little explored. These neurocognitive disorders are risk factors for chronic PTSD, impacting not only the patients' quality of life and also their socio-professional reintegration possibilities. Finally, on the social level, the course of recovery and reintegration involves satisfactory socialization. Socialization is not a linear process but it is subject to constant perpetual changes in the quality of social interactions, a key feature in this process. While the hypothesis of an impact of clinical symptoms of PTSD in the socialization of these is legitimate, the available data are scarce. This issue is all the more important for soldiers with chronic PTSD, since most of them will have to leave the military environment and re-socialize in civilian world. This doctoral work aims to better understand the psychoneurosociological mechanisms of the recovery trajectory in patients suffering from chronic PTSD. More specifically, it focuses on 4 issues. The first one is theoretical. It aims to analyze the data in the literature on recovery, and its dimensions, in chronic mental illnesses in order to propose a theoretical framework for recovery and interventionsthat could be assessed in PTSD (article 1). Three issues on the subject of field studies: a) What are the important psychological resources for the recovery and reintegration of PTSD? ; b) What are the neurological signs of interest for better understanding the evolutionary trajectory of the patient suffering from PTSD? ; and c) What are the core characteristics (pro and cons) of socialization for patients suffering from PTSD? At the end of this exploratory work, carried out mainly on soldiers suffering from chronic PTSD, we propose lines of work/evidence and recommendations for intervention to improve course of their socio-professional reintegration

Les maladies mentales représentent un ensemble catégoriel très hétérogène, même au sein d’une entité nosographique. L’approche multifactorielle rend compte de l’hétérogénéité clinique des troubles mentaux et du continuum entre certaines dimensions cliniques, voire entre le normal et le pathologique. Parmi ces dimensions, le phénotype psychotique constitue une dimension essentielle du trouble schizophrénique. L’approche dimensionnelle permet d’envisager la recherche d’expériences psychotiques dans la plupart des troubles mentaux ainsi qu’en population générale. Nous faisons l’hypothèse générale que certains troubles psychiatriques avec symptômes psychotiques pourraient être la résultante de l’interaction entre certains facteurs environnementaux précoces (traumatismes obstétricaux par exemple) et tardifs (consommation de toxiques, traumatismes) et le neurodéveloppement de l’individu. Un travail initial a été de rappeler les concepts de vulnérabilité en psychiatrie, et de prendre l’exemple du trouble schizophrénique pour réaliser une revue de la littérature sur les facteurs de risque en fonction de leur interaction précoce ou tardive avec le neurodéveloppement. Ensuite, dans le premier axe de recherche de la thèse, nous évaluons certains marqueurs neurodéveloppementaux précoces (signes neurologiques mineurs, latéralité, cognition). Notre premier travail, concerne la caractérisation clinique, neurologique et cognitive de 64 patients souffrant de trouble schizophrénique, en fonction de leur consommation de cannabis ou pas avant le début des troubles. Il apporte des éléments en faveur d’une charge neurodéveloppementale moins lourde chez les patients ayant consommé du cannabis, et de l’impact potentiel de cette substance chez des sujets vulnérables. Notre second travail, préliminaire, concerne l’impact clinique et cognitif de la latéralité chez les patients souffrant de schizophrénie (n=667) et de trouble bipolaire (n=2445). Nous apportons des arguments pour un poids neurodéveloppemental (mesuré avec cet indice) plus important dans la schizophrénie. Notre deuxième axe de recherche se concentre sur le tabagisme comme facteur environnemental tardif dans le trouble schizophrénique et le phénotype psychotique. Nous montrons dans deux travaux sur la cohorte FACE-SZ (n=361 ; n=474), que ces patients consomment presque deux fois plus qu’en population générale et qu’ils pourraient représenter un sous-groupe présentant des caractéristiques spécifiques d’un point de vue socio-démographique, clinique et thérapeutique. Dans un troisième travail préliminaire, nous comparons les fonctions cognitives de ces patients (n=785) et montrons que l’hypothèse d’automédication ne peut pas rendre compte à elle seule, de la forte prévalence du tabagisme chez ces patients. Dans un quatrième travail, nous étudions l’impact du tabagisme sur le phénotype psychotique dans une approche dimensionnelle, et montrons une association entre le tabagisme et certaines expériences de type psychotique dans un échantillon représentatif de la population générale américaine (NESARC, n=34653). Enfin dans un dernier axe de recherche nous nous intéressons au phénotype psychotique dans une population d’adolescents et jeunes adultes hospitalisés pour un premier épisode psychiatrique (n=50). Dans une étude préliminaire, nous montrons une forte prévalence des expériences de type psychotique chez ces jeunes adultes, quel que soit le diagnostic posé six mois à postériori, soulignant le caractère trans-nosographique du phénotype psychotique lors de l’émergence des troubles. L’ensemble de ce travail reflète l’hétérogénéité clinique des maladies mentales et l’importance de l’approche dimensionnelle et trajectorielle pour identifier des facteurs de risque (ou de protection). Les enjeux sont une meilleure compréhension étiopathogénique, des perspectives de prévention, et une prise en charge personnalisée des patients
Mental diseases represent a very heterogeneous categorical group, even within a given nosographic entity. Multifactorial approaches allow accounting for the clinical heterogeneity of mental disorders, the continuum between certain clinical dimensions, and even between the normal and the pathological. Among such dimensions, the psychotic phenotype constitutes an essential dimension of schizophrenic disorder. The dimensional approach allows for the search of psychotic experiences in most mental disorders as well as in the general population. We make the general hypothesis that certain psychiatric disorders with psychotic symptoms could be the result of the interaction between early- (obstetric traumas for example) and late- environmental factors (toxics, traumatisms) and the neurodevelopment of the individual. The initial step in this thesis work was to better define the concepts of vulnerability in psychiatry, and, based on the example of schizophrenia, to conduct a review of the literature on risk factors according to their early or late interaction with neurodevelopment. Subsequently, the first axis of research of the present thesis was to evaluate early neurodevelopmental markers (neurological soft signs, laterality, cognition). Our first work concerned the clinical, neurological and cognitive characterization of 64 patients suffering from schizophrenia, according to their cannabis use (or not) prior to psychosis. It provided evidence for a lower burden of neurodevelopment in cannabis users, and the potential impact of this substance on vulnerable individuals. Our second work concerns the clinical and cognitive impact of lateralization in patients with schizophrenia (n = 667) and bipolar disorder (n = 2445). We bring arguments for a neurodevelopmental weight (measured with this lateralization index) that is more important in schizophrenia. Our second axis of research focused on tobacco smoking as a late environmental factor in schizophrenia and psychotic phenotype. We showed in two studies on the FACE-SZ cohort (n = 361, n = 474) that SZ patients consumed almost twice as much as the general population and that they could represent a SZ subgroup with specific socio-demographic and clinical characteristics. In a third study, we compare the cognitive functions of these patients (n = 785) and show that the self-medication hypothesis alone cannot account for the high prevalence of their smoking. In a fourth work, we studied the impact of smoking on the psychotic phenotype with a dimensional approach, and showed an association between smoking and certain psychotic-type experiences in a representative sample of the US general population (NESARC, n = 34653). Finally, in a last line of research, we evaluated the psychotic phenotype in a population of adolescents and young adults hospitalized for a first psychiatric episode (n = 50). In a preliminary study, we show a high prevalence of psychotic-like experiences in these young adults, regardless of the diagnosis made six months afterwards, highlighting the trans-nosographic character of the psychotic phenotype during the emergence of different mental disorders. Overall, the present thesis underscores the clinical heterogeneity of mental illnesses and the importance of dimensional and trajectory approaches in identifying risk (or protective) factors, towards a better etiopathogenic understanding, better prevention opportunities, and a personalized patient care

BACKGROUND: Soft neurological signs (SNS) are subtle, nonspecific neurological abnormalities that are present in first episode psychosis (FEP) patients. SNS are associated with clinical variables such as poor long term psychosocial functioning, executive functioning, and positive and negative symptomology. However, few studies have evaluated treatment responsiveness with respect to SNS. OBJECTIVE: To investigate whether SNS show: 1.) baseline and longitudinal differences between both diagnostic groups (schizophrenia (FEP-SZ), non-schizophrenia FEP-NSZ, and healthy controls (HC)) and treatment outcome (week 26 and year 1); 2.) relationships to clinical measures; 3.) predictive characteristics of treatment response. METHODS: SNS scores (Neurological Evaluation Scale) were obtained for 312 FEP (236 FEP-SZ and 76 FEP-NSZ subjects and 169 HC subjects and for subjects classified as treatment responsive and non-responsive at week 26 (N=105, N=105) and year 1 (N=101, N=97), respectively. Diagnostic group and treatment responsiveness group comparisons were assessed with ANCOVA and logistic regression models and both were co-varied for age, sex, race, and handedness. Baseline and longitudinal SNS relationships to clinical variables were determined using Spearman correlations and repeated measures correlations, and both were corrected by False Discovery Rate. Linear mixed effects model was utilized to analyze the data longitudinally. RESULTS: Baseline cognitive perceptual SNS measures had the greatest effect size differences, were predictive of group membership, and differentiated the two proband groups with FEP-SZ having worse SNS scores. Baseline cognitive perceptual SNS did not significantly predict treatment response at week 26 or year 1, but changes in cognitive perceptual at week 26 was predictive of treatment responsiveness at week 26 and year 1. Longitudinally, SNS scores drop in both FEP groups and treatment groups. The FEP-SZ group showed greater longitudinal within subject correlations than FEP-NSZ. SNS scores were only differentiated between year 1 outcome groups at week 8. There were greater longitudinal within subject correlations for the responsive group. CONCLUSION: Our findings indicate that there are baseline group differences and that changes in cognitive perceptual SNS scores at week 26 are predictive of treatment responsiveness at week 26 and year 1.
2019-07-03T00:00:00Z

BACKGROUND: Gli Endofenotipi sono componenti stabili ed ereditabili dei disturbi psicotici, misurabili in laboratorio con metodi quantitativi di analisi. I marker di risonanza magnetica, i deficit neuropsicologici, la prepulse inhibition del riflesso di startle (PPI) e i neurological soft signs (NSS) sono alcuni tra gli endofenotipi più studiati per la schizofrenia. Un’evoluzione del concetto di endofenotipo è quella di “endofenotipo esteso” che definisce l'unione tra più endofenotipi funzionalmente associati tra loro. OBIETTIVI: Il presente progetto di Dottorato si pone lo scopo di: 1) condurre per la prima volta una revisione sistematica allo scopo di individuare potenziali "endofenotipi estesi", formati da deficit neuropsicologici e alterazioni cerebrali strutturali, associati al polimorfismo Val158Met del gene COMT; 2) testare per la prima volta, in una coorte di pazienti affetti da psicosi, l'ipotesi che i pazienti con alti livelli di NSS (sensory integration and sequencing of complex motor act), rilevati da una valutazione neurologica, hanno più elevati deficit di PPI e che i pazienti con elevati deficit di PPI e elevati livelli di NSS hanno maggiori sintomi negativi; 3) valutare per la prima volta, in una coorte di pazienti affetti da psicosi se i pazienti con il genotipo Val/Val del polimorfismo Val158Met del gene COMT hanno più elevati livelli di NSS (sensory integration and sequencing of complex motor act) e una minore prestazione nelle funzioni esecutive. E' stata inoltre valutata l'ipotesi di un'associazione tra elevati livelli di NSS e basse funzioni esecutive. Infine è stato ipotizzata un'associazione tra il genotipo Val/Val della COMT e contemporaneamente elevati livelli di NSS (sensory integration and sequencing of complex motor act) e basse prestazioni nelle funzioni cognitive. METODI: Per il primo obiettivo è stata condotta una revisione sistematica sui database Medline e PubMed per individuare i test neuropsicologici e le alterazioni cerebrali strutturali legati al polimorfimso Val158Met del gene COMT e per verificare se gli endofenotipi cerebrali strutturali e neuropsicologici individuati sono associati tra loro. Infine sono stati proposti alcuni "endofenotipi estesi". Per il secondo obiettivo è stata reclutata una coorte di pazienti psicotici in contatto con il Servizio di Salute Mentale di Verona Sud (Italia) ed è stata sottoposta alle valutazioni della PPI e dei NSS. Inoltre è stato reclutato un gruppo di controllo. Per il terzo obiettivo, è stata reclutata una coorte di pazienti affetti da psicosi, che hanno donato il loro DNA e sono stati sottoposti alla valutazione dei NSS e a una valutazione neuropsicologica. I dati sono stati raccolti nell'ambito di tre studi epidemiologici multicentrici, condotti rispettivamente in Veneto (Italia) e a Londra Sud, Nottingham e Bristol (Regno Unito): il "Psychosis Incident Cohort Outcome Study" (PICOS), l'"Aetiology and Ethnicity in Schizophrenia and Other Psychoses study (AESOP) " and il "Genetics and Psychotic Illness study (GAP)". Inoltre è stata inclusa una coorte di pazienti psicotici in contatto con il Servizio di Salute Mentale di Verona Sud, Italia. RISULTATI: Rispetto al primo obiettivo, sono stati proposti tre "endofenotipi estesi" associati al polimorfismo Val158Met del gene COMT; un endofenotipo caratterizzato da: 1) la performance all'N-back e il volume della corteccia prefrontale, 2) la performance all'N-back e il volume del lobo mediale temporale, 3) la performance al CPT e il volume della corteccia prefrontale. Rispetto al secondo obiettivo, sono stati sottoposti alle valutazioni della PPI e dei NSS quindici pazienti affetti da psicosi con una durata di malattia uguale o inferiore a cinque anni e quindici soggetti di controllo. I risultati hanno dimostrato che nei pazienti non erano evidenziabili maggiori livelli di deficit di PPI ma solo più elevati livelli di NSS (p<0.01), rispetto ai soggetti controllo. Più elevati livelli di NSS non erano associati a deficit di PPI. I deficit di PPI non erano correlati con nessuna caratteristica clinica; al contrario i NSS sensory integration signs erano correlati positivamente ai sintomi negativi (p<0,01). Rispetto al terzo obiettivo, sono stati inclusi nel nostro studio quattrocentonovantotto pazienti affetti da psicosi. I risultati hanno evidenziato che il genotipo Met/Met era associato ad alti livelli di NSS sequencing of complex motor acts (p=0,034) e a basse prestazioni nelle funzioni esecutive (p<0,01) nei soggetti Caucasici ma non negli Africani e Afro-caraibici. I pazienti Caucasici con NSS sequencing of complex motor acts più elevati dimostravano anche peggiori funzioni esecutive (p<0,05). Tra i pazienti Caucasici che presentavano sia alti livelli di NSS sequencing of complex motor acts sia basse funzioni esecutive è stata riscontrata una più elevata percentuale del genotipo Met/Met, mentre il genotipo Val/Val era maggiormente presente nei pazienti che presentavano sia bassi livelli di NSS sequencing of complex motor acts sia alte funzioni cognitive e il genotipo Val/Met era più frequenti tra i pazienti che presentavano o alti livelli di NSS sequencing of complex o basse funzioni esecutive (Chi quadrato p=0,016). CONCLUSIONI: Concludendo, lo scopo di questo progetto è quello di contribuire a chiarire i potenziali meccanismi sottostanti l'esordio della psicosi, al fine di migliorare l'assessment e contribuire a definire nuove strategie di prevenzione e migliori trattamenti per tale disturbo.
BACKGROUND: Endophenotypes are defined as heritable and stable components of the psychotic disorder, with the advantage of being measurable with quantitative methods and amenable to laboratory assessment. Examples of currently investigated endophenotypes in schizophrenia are neuroimaging markers, neuropsychological deficit, prepulse inhibition of the startle reflex (PPI), and neurological soft signs (NSS). In multigenerational families with schizophrenia, a co-segregation between some endophenotypes, such as magnetic resonance imaging (MRI) and neuropsychological measures, has been found. Moving from this observation, some authors have recently introduced the concept of “extended endophenotype”, referring to the proposal of combining multiple endophenotypes functionally associated with each other. AIMS: The present PhD project aims at: 1) performing for the first time a systematic review of the potential role of neuropsychological impairments and brain structural abnormalities in relation to the COMT Val158Met polymorphism as potential “extended endophenotypes” in psychosis; 2) testing for the first time, in a cohort of patients with psychosis that patients with higher levels of NSS sensory integration and NSS motor sequencing signs elicited by a neurological evaluation show higher PPI deficits and that patients with PPI deficits and high NSS scores have high level of negative symptoms. 3) investigating for the first time, in cohort of patients with psychosis, that patients with the Val/Val genotype of the COMT Val158Met polymorphism have higher score of NSS (sensory integration and sequencing of complex motor acts) and lower executive function. The hypothesis of an association between high NSS and lower executive function was also tested. Moreover, we hypothesized that the COMT Val/Val genotype would be associated with both higher NSS (sensory integration and sequencing of complex motor acts) and poorer executive function. METHODS: For the Aim 1, we searched the PubMed and Medline databases to systematically identify the neuropsychological tasks and brain structural variations related to COMT Val158Met across psychosis spectrum disorders and to verify if the neuropsychological and the brain structural endophenotypes identified were associated with each other. Finally we propose some "extended endophenotypes". For the Aim 2 a cohort of psychotic patients in contact with the South Verona Community-based Mental Health Service (CMHS), Italy, during a period of three years, was recruited and underwent PPI and NSS evaluations. Moreover a group of matched healthy controls was recruited. For the Aim 3, 4 cohort of subjects with psychosis were recruited, gave their DNA, underwent NSS and neuropsychological evaluation. The data were collected within the framework of three multisite epidemiological studies of first episode psychosis, conducted respectively in Veneto (Italy) and South London, Nottingham and Bristol (UK): the Psychosis Incident Cohort Outcome Study (PICOS), the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP) study and the Genetics and Psychotic Illness study (GAP). Moreover a cohort of psychotic patients in contact with the South Verona Community-based Mental Health Service (CMHS), Italy, was included. RESULTS: Regarding the 1st aim, three proposals of extended endophenotypes associated with COMT Val158Met polymorphism were identified; an extended endophenotype characterised by: 1) N-back performance and prefrontal cortex volumes, 2) N-back performance and medial temporal lobe volumes and 3) CPT performance, prefrontal volumes. Regarding the 2nd aim fifteen subjects affected by psychosis with a duration of illness equal or less than 5 years and fifteen healthy controls underwent PPI and NSS evaluations. Results showed that the patients did not exhibit higher levels of PPI deficits but only higher levels of NSS (p<0.01), as compared to healthy controls. Higher NSS rates were not associated with PPI deficits. PPI deficits did not correlate with any clinical characteristic; inversely, NSS sensory integration signs correlated positively with negative symptoms (p<0.01). Regarding the 3rd aim, four hundred ninety eight patients with psychosis were included in our study. We found that the Met/Met genotype is associated with higher sequencing of complex motor acts signs (p=0,034) and with lower executive function (p<0,01) in Caucasian but not in African and African-Caribbean individuals. Patients with higher sequencing of complex motor acts signs exhibited also lower executive function in Caucasians (p<0,05). Caucasian patients with both higher sequencing of complex motor acts signs and poorer executive function showed an higher percentage of Met/Met genotype, whereas the percentage of Val/Val individuals was higher in patients with both lower sequencing of complex motor acts signs and higher executive function and the Val/Met genotype was more frequent among patients with either higher sequencing of complex motor acts signs or poorer executive function (Chi Square, p=0,016). CONCLUSION: In conclusion, the purpose of this project is to contribute to clarifying the potential mechanisms underlying the onset of psychosis, in order to improve the assessment of the illness and to contribute to defining new prevention strategies and better treatment interventions for psychosis.