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.

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.

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.

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.