Background. Impaired insight, or unawareness of illness, is a common symptom of schizophrenia. Clinical insight is awareness of having a mental disorder; cognitive insight is ability to self-reflect (self­reflectiveness) and certainty in cognitions (self­certainty). In schizophrenia insight is associated with brain function and improving insight is a potential early intervention point. This study investigated whether insight is impaired in youth at ultra high-risk (UHR) for psychosis, and if it is related to major brain networks. Methods. Data from a larger UHR study was used, including 55 UHR adolescents and 55 controls assessed with the Structured Interview of Prodromal Symptoms, MATRICS Consensus Cognitive Battery, Scale to Assess Unawareness of Mental Disorder, and Beck Cognitive Insight Scale, as well as resting state functional MRI scans. UHR and control groups were tested for differences in self-reflectiveness and self-certainty, and correlations between insight dimensions and clinical and cognitive measures. Functional connectivity was calculated for the default mode, the cingulo-opercular, and central executive networks and regressed on participants’ reported clinical and cognitive insight, while covarying for head motion. Results. Self-reflectiveness was higher in the UHR group (d = 1.28), but the groups did not differ in self-certainty (d = 0.28). Among UHR, poorer clinical insight was related to greater symptom severity. Default mode connectivity was negatively correlated with self-reflectiveness (R2 = .091) and clinical insight (R2 = .399) in UHR, but no such correlations were found in controls. Cerebello-prefrontal cortex connectivity was negatively associated with self-certainty in the UHR group (R2 = .089 - .138). Conclusions. Default mode connectivity appears to be associated with the facets of insight concerning self-awareness, whereas cerebello-prefrontal connectivity appears to be associated specifically with self-certainty. This is the first study to relate major brain networks to insight before the onset of psychosis, and is consistent with models proposing that different facets of insight are related to self-awareness and executive functioning through networks associated with these processes.

The findings of this PhD provide a significant contribution to early intervention research. The ability to detect those at ultra-high risk for psychosis (UHR) has been made possible in recent years. It is well known that people with serious mental illness have poor physical health, yet prior to this PhD little was known about the physical health of UHR individuals. This PhD explores the physical health and lifestyle of the UHR group, and makes recommendations for the development of a physical health intervention. A range of methods have been used including quantitative and qualitative methods, systematic reviews and meta-analyses, and a clinical audit. Therefore, a multifaceted approach to investigate the physical health and lifestyle of UHR individuals has been taken. Papers 1-3 suggest UHR individuals are more likely to live an unhealthy lifestyle than their peers. This includes lower levels of physical activity, and higher levels of substance use (generally cannabis, tobacco and alcohol). Paper 4 contains a clinical audit showing physical health and lifestyle factors are not monitored routinely in early detection services, despite the UHR phase being an ideal opportunity to intervene. Living an unhealthy lifestyle can have a detrimental effect on physical and mental health. Papers 1-4 emphasise the need to intervene to promote a healthy lifestyle for the UHR group. In line with the Medical Research Guidelines for the development of complex interventions, a theoretical model is applied in Paper 5. The final paper presents a qualitative study with UHR individuals, their parents and clinicians to explore barriers and facilitators to living a healthy lifestyle and inform the development of a physical health intervention. A final evidence synthesis includes recommendations for future work and the clinical implications of this thesis. The findings of this PhD provide an important and timely contribution to early intervention research. Prior to this work, the physical health of UHR individuals had been largely under researched. For the first time, this PhD presents evidence to suggest individuals at ultra-high risk for psychosis experience cardiovascular risk, and there is an opportunity to intervene to promote physical health. Although not all UHR individuals will develop psychosis, many will continue to experience difficulties with their mental health. Given that this group are also more likely to live an unhealthy lifestyle, it is important to take a holistic approach to treating those at imminent risk for psychosis, considering both mental and physical health.

A modern conceptualization of psychotic disorders is as neurodevelopmental disorders, with different stages characterized by discrete clusters of symptoms. This conceptualization includes a stage of pre-psychotic prodrome, a target of contemporary research as an attempt to intervene before the development of psychosis. However, these at-risk individuals rarely present to the mental health services before transitioning into psychosis, even more so for male patients. In this study, a method of inductive thematic analysis has been employed to inquire into the pathways to care for young men at Ultra-High Risk (UHR) for psychosis to gain knowledge of- and generate hypotheses about pathways to care for this group. Data was collected using semi-structured interviews (n = 9) over video conference or telephone. Three core-themes were developed as “Willingness to Disclose Distress”, “The Gatekeeping Confidant”, and “The Boiler”, with “Openness” as a core organizing category permeating the core-themes. Together, the themes represent findings on both the importance of relations in help-seeking, as well as how the young men commonly employ non-disclosure, and how this lack of openness delays pathways to care, often resulting in adversities for the participants. Findings provide implications for further inquiry into how to increase the likelihood of young men to disclose distress, as well as providing additional rationale for the development of Mental Health Literacy in the public to make peers as well as participants more able to recognize symptoms of the pre-psychotic prodrome, when, where and how to seek help.

Two main psychopathology-based approaches to detection of the prodrome have emerged; the Ultra High Risk (UHR) and Basic Symptom approaches. Conversion risk varies between studies using these approaches and in one centre conversion rates are reported to be decreasing year on year. There is a need examine the conversion risk across studies to establish a pooled estimate of risk for instruments designed to detect the prodrome of psychosis. To maximise the detection of those thought to present a risk of psychosis the Lancashire Early Assessment and Detection (LEAD) clinic uses an UHR instrument, the Comprehensive Assessment of at Risk Mental States (CAARMS) and A Basic Symptom instrument, the Schizophrenia Proneness Instrument (SPI-A). The thesis had two broad aims 1) to conduct a systematic review with meta-analysis of the research field to date and identify areas for further research, 2) to establish the accuracy of the LEAD clinic predictions. The meta-analysis involved a systematic search of MEDLINE, EMBASE, PsychINFO and CINHAL identifying studies of psychopathology-based instruments for the detection of the psychosis prodrome. The service evaluation examined for conversion to psychosis in patients examined for Basic Symptoms (SPI-A), attenuated positive symptoms (CAARMS), schizotypy (SPQ-A) and social functioning (SOFAS).The meta-analysis found that both the UHR and Basic Symptom approaches yield similar results. The differences in the positive predictive values (PPV) of the two approaches were not significant (Basic Symptoms, 0.34, UHR 0.25). The service evaluation found over a third (n=58) of referrals to the LEAD clinic to be psychotic at baseline and sixty-four patients to have an at risk mental state (ARMS). Conversion risk for CAARMS was 36.67%. and was 28.57% for SPI-A. The COGDIS criterion of SPI-A was found to be the most predictive with a PPV of 0.43, a sensitivity of 0.80. When patients met a combination of both COGDIS and CAARMS the likelihood ratio increased to 5.25 although the sensitivity was low (0.47).Overall, the findings of the thesis indicate that both the Basic Symptom and UHR approaches are valid for use in routine clinical settings for the assessment of psychosis risk. The thesis found that a combination of both approaches could provide future opportunities research. The SPQ-A schizotypy assessment was found to correlate with the attenuated symptom criterion of CAARMS and evidence suggests that the SPQ-A score increases closer to transition. The SPQ-A could offer opportunities for developing efficient methods of monitoring progression of prodromal symptoms.

La mémoire autobiographique est vue comme un ensemble d'informations et de souvenirs personnels permettant de construire un sentiment d'identité. Elle se développe progressivement et apparaît très sensible aux pathologies neurodéveloppementales. La mémoire autobiographique est intimement liée au Soi lui permettant d'encoder et de récupérer toutes ses représentations et expériences. Ainsi, le Soi se constitue d'aspects explicites comprenant la mémoire autobiographique mais également d'aspects plus implicites relatifs aux expériences corporelles du sujet. L'atteinte des aspects implicites et explicites du Soi pourrait rendre compte de certains symptômes psychotiques et des difficultés d'adaptation des patients atteints de schizophrénie. La schizophrénie est une pathologie neurodéveloppementale qui débute à la fin de l'adolescence mais qui pourrait puiser son émergence dans des stades bien plus précoces. Le premier épisode psychotique qui signe l'entrée dans la phase active de la maladie est généralement précédé par une phase « prodromique » où des symptômes cliniques sont présents à un niveau infraliminaire du seuil de psychose. Ces sujets sont qualifiés de sujets à ultra haut risque de psychose (UHR). Les troubles du Soi sont bien documentés dans la schizophrénie, néanmoins très peu de données sont disponibles concernant les sujets UHR. Le but de cette thèse est multiple : (i) mesurer l'impact des anomalies neurodéveloppementales sur la mémoire autobiographique, (ii) objectiver des déficits de la mémoire autobiographique dès la phase prodromique, (iii) évaluer l'ensemble des composantes du Soi afin d'investiguer leurs interactions et l'impact des anomalies développementales sur celles-ci. Nous avons ainsi effectué trois études. Notre première étude a investigué le lien entre le poids des anomalies neurodéveloppementales et la mémoire autobiographique en comparant deux pathologies neurodéveloppementales, une à début tardif : la schizophrénie, et l'autre à début précoce : les troubles du spectre autistique. Nous avons pu mettre en évidence un pattern de performances similaires entre les deux populations bien que les mécanismes responsables des troubles en mémoire autobiographique apparaissent distincts. Dans notre deuxième étude, nous avons comparé les performances autobiographiques de patients atteints de schizophrénie par rapport à celles de sujets UHR. Nos résultats révèlent un déficit de la mémoire autobiographique aussi sévère chez les sujets UHR que chez les patients atteints de schizophrénie mettant ainsi en évidence une atteinte de cette fonction en amont du premier épisode psychotique. Dans la lignée de ces résultats, nous avons conduit une troisième étude. Le but étant de situer la mémoire autobiographique dans un contexte plus large, celui du Soi, tout en intégrant une composante développementale. Nous avons élaboré et proposé une batterie d'investigation examinant différents aspects du Soi implicites et explicites, combiné à l'évaluation d'anomalies du neurodéveloppement. Celle-ci a été administrée chez des sujets UHR en comparaison à des patients atteints de schizophrénie. Au final, nos résultats révèlent un impact de la charge neurodéveloppementale sur les différents aspects du Soi, la pertinence d'investiguer au sein d'un même protocole ces différents aspects et la présence d'anomalies du Soi déjà présents chez les sujets UHR, constituant potentiellement des marqueurs prédicteurs de transition psychotique et permettant d'améliorer la détection précoce de ces sujets et leur prise en charge. / Autobiographical memory is delineated as a set of personal information and experiences to build a sense of identity. It develops gradually and appears very sensitive to neurodevelopmental disorders. Autobiographical memory is intimately linked to the self, enabling it to encode and retrieve all its representations and experiences. Thus, the self is constituted of explicit aspects including autobiographical memory but also by more implicit aspects relating to the subject's body. Implicit and explicit self-aspects alterations may account for certain psychotic symptoms and adaptation difficulties in patients with schizophrenia. Schizophrenia is a neurodevelopmental disorder that begins at the end of adolescence but which could emerge in much earlier stages. The first psychotic episode that signs the beginning of the active phase of schizophrenia is usually preceded by a "prodromal phase" during which clinical signs are present at a sub-threshold level. Individuals experiencing these signs are considering as Ultra High Risk of psychosis (UHR). Self-disorders are well documented in schizophrenia, however very little is known regarding UHR subjects. The aim of this thesis is multiple: (i) to measure the impact of neurodevelopmental anomalies on autobiographical memory, (ii) to objectify autobiographical memory deficits in the prodromal phase, (iii) to evaluate all the self-components in order to investigate their interactions and the impact of developmental anomalies. We have conducted three studies. Our first study investigated the relationship between neurodevelopmental anomalies and autobiographical memory by comparing two neurodevelopmental disorders, one with late onset: schizophrenia and the other with early onset: autism spectrum disorders. Results revealed a pattern of similar performances between the two populations although the mechanisms responsible for autobiographical memory impairment do not appear the same. In our second study, we compared the autobiographical performances of patients with schizophrenia compared to those of UHR subjects. Our results highlighted a deficit of autobiographical memory as severe in UHR subjects as in patients with schizophrenia, thus revealing an impairment of this function upstream of the first psychotic episode. In line with these results, we conducted a third study. The aim was to situate the autobiographical memory in a wider context, the multi-componential Self, while integrating a developmental component. We developed and proposed a battery investigating different self-components, combined with the assessment of neurodevelopmental anomalies. This battery was administered in UHR subjects compared to patients with schizophrenia. Finally, our results reveal an impact of neurodevelopmental abnormalities on the different self-aspects, the relevance of investigating these different self-aspects within the same protocol and the presence of self-abnormalities already present in the UHR subjects, constituting potentially predictive marker of psychotic transition and improving the early detection of these subjects and the development of healthcare and reinsertion programs.

La psychose est un syndrome apparaissant progressivement à l’adolescence chez des individus à risque selon un processus dynamique appelé transition psychotique. Ces individus à risque sont repérables cliniquement mais les données biologiques actuelles sont insuffisantes pour expliquer l’apparition de la psychose. Au cours de cette thèse, nous avons cherché à identifier les facteurs biologiques responsables de ce processus. Les hypothèses permettant d’expliquer la transition psychotique privilégient l’interaction gène x environnement, sous-tendue par des mécanismes épigénétiques. Nous avons mené une étude des modifications de la méthylation de l’ADN et de la transcription à l’aide de techniques de biologie moléculaire et de bio-informatique à l’échelle pan-génomique. La transition psychotique semble être liée à des modifications de méthylation et de transcription de gènes impliqués dans des mécanismes comme le guidage axonal ou la régulation du stress oxydatif. Ces modifications longitudinales pourraient refléter l’influence de l’environnement. Les facteurs environnementaux pourraient déréguler l’axe biologique du stress dès les phases précoces de la maladie, comme le suggère l’augmentation de la sécrétion de cortisol basal que nous avons montré chez les individus à risque. En outre, il est probable que des spécificités au niveau des gènes et des processus régulant l’épigénome soient également impliquées dans cette réponse individuelle à l’environnement. Nous avons montré l’importance du métabolisme mono-carboné au moins dans un sous-groupe spécifique de patients. Ces résultats doivent être répliqués et étendus dans d’autres paradigmes pour valider l’implication de ces processus dans la transition psychotique. En cas de confirmation, ces voies biologiques pourraient s’avérer être des pistes intéressantes pour développer des thérapeutiques ciblées et relever le défi de la prévention de la psychose chez des individus à risque. / Psychosis is a progressive mental disorder which normally occurs during adolescence in at-risk subjects following a dynamic process termed “psychotic transition”. These at-risk subjects are clinically identifiable but biological data are still insufficient in explaining the onset of psychosis. Throughout this thesis, we aim to identify biological factors implicated in this pathophysiological process. Current hypotheses explaining the psychotic transition favor the interaction between genes and the environment mediated by epigenetic mechanisms. We conducted studies examining methylomic and transcriptomic changes during psychotic transition using molecular biology and bioinformatics techniques at a whole genome scale. Our results suggest that psychotic transition may be linked to methylomic and transcriptomic changes in genes implicated in axon guidance or oxidative stress. These longitudinal changes could be related to environmental factors. Some of these factors could deregulate the hormonal stress response at the earliest phases of psychosis. Indeed, our results show that secretion of basal cortisol is increased in prodromal individuals. Moreover, it is likely that genes and processes regulating epigenetic modifications are also implicated in the individual response to the environment. We have shown the importance of the one-carbon metabolism for at least one sub-group of patients affected by psychosis. Our results should be replicated using other paradigms in order to definitively validate the implication of these various actors in the psychotic transition. If confirmed, knowledge of these biological mechanisms could lead to the development of targeted therapeutics to prevent psychosis in at-risk individuals.