京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19889号 / 医博第4138号 / 新制||医||1016(附属図書館) / 32966 / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 髙橋 良輔, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Objective: To examine the hypothesis that the “natural” combination of delusions and hallucinations in psychotic disorders in fact represents a selection of early subclinical hallucinatory experiences associated with delusional ideation, resulting in need for care and mental health service use. Methods: In the Early Developmental Stages of Psychopathology study, a prospective, 10-year follow-up of a representative cohort of adolescents and young adults in Munich, Germany (n = 2524), clinical psychologists assessed hallucinations and delusions at 2 time points (T2 and T3). Analyses compared differences in psychopathology, familial liability for nonpsychotic disorder, nongenetic risk factors, persistence, and clinical outcome between groups characterized by: (1) absence of positive psychotic symptoms, (2) presence of isolated hallucinations, (3) isolated delusions, and (4) both hallucinations and delusions. Results: Delusions and hallucinations occurred together much more often (T2: 3.1%; T3: 2.0%) than predicted by chance (T2: 1.0%; T3: 0.4%; OR = 11.0; 95% CI: 8.1, 15.1). Content of delusions was contingent on presence of hallucinations but modality of hallucinations was not contingent on presence of delusions. The group with both hallucinations and delusions, compared to groups with either delusions or hallucinations in isolation, displayed the strongest associations with familial affective liability and nongenetic risk factors, as well as with persistence of psychotic symptoms, comorbidity with negative symptoms, affective psychopathology, and clinical need. Conclusions: The early stages of psychosis may involve hallucinatory experiences that, if complicated by delusional ideation under the influence of environmental risks and (liability for) affective dysregulation, give rise to a poor prognosis hallucinatory–delusional syndrome.

Background The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. Method A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. Results Six cohorts were identified with a 3–24-year follow-up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose–response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. Conclusions Subthreshold self-reported psychotic experiences in epidemiological non-help-seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra-high risk, for whom much higher transition rates have been indicated.

Computational modelling has been gaining an increasing amount of support from the neuroscience community as a tool to assay cognition and computational processes in the brain. Lately, scientists have started to apply computational methods from neuroscience to the study of psychiatry to gain further insight into the mechanisms leading to mental disorders. In fact, only recently has psychiatry started to move away from categorising illnesses using behavioural symptoms in an attempt for a more biologically driven diagnosis. To date, several neurobiological anomalies have been found in schizophrenia and led to a multitude of conceptual framework attempting to link the biology to the patients’ symptoms. Computational modelling can be applied to formalise these conceptual frameworks in an effort to test the validity or likelihood of each hypothesis. Recently, a novel conceptual model has been proposed to describe how positive symptoms (delusions, hallucinations and thought disorder) and cognitive symptoms (poor decision-making, i.e. “executive functioning”) might arise in schizophrenia. This framework however, has not been tested experimentally or against computational models. The focus of this thesis was to use a combination of behavioural experiments and computational models to independently assess the validity of each component that make up this framework. The first study of this thesis focused on the computational analysis of a disrupted prediction-error signalling and its implications for decision-making performances in complex tasks. Briefly, we used a reinforcement-learning model of a gambling task in rodents and disrupted the prediction-error signal known to be critical for learning. We found that this disruption can account for poor performances in decision-making due to an incorrect acquisition of the model of the world. This study illustrates how disruptions in prediction-error signalling (known to be present in schizophrenia) can lead to the acquisition of an incorrect world model which can lead to poor executive functioning or false beliefs (delusions) as seen in patients. The second study presented in this thesis addressed spatial working memory performances in chronic schizophrenia, bipolar disorder, first episode psychosis and family relatives of DISC1 translocation carriers. We build a probabilistic inference model to solve the working memory task optimally and then implemented various alterations of this model to test commonly debated hypotheses of cognitive deficiency in schizophrenia. Our goal was to find which of these hypotheses accounts best for the poor performance observed in patients. We found that while the performance at the task was significantly different for most patients groups in comparison to controls, this effect disappeared after controlling for IQ in one group. The models were nonetheless fitted to the experimental data and suggest that working memory maintenance is most likely to account for the poor performances observed in patients. We propose that the maintenance of information in working memory might have indirect implications for measures of general cognitive performance, as these rely on a correct filtering of information against distractions and cortical noise. Finally the third study presented in this thesis assessed the performance of medicated chronic schizophrenia patients in a statistical learning task of visual stimuli and measured how the acquired statistics influenced their perception. We find that patient with chronic schizophrenia appear to be unimpaired at statistical learning of visual stimuli. The acquired statistics however appear to induce less expectation-driven ‘hallucinations’ of the stimuli in the patients group than in controls. We find that this is in line with previous literature showing that patients are less susceptible to expectation-driven illusions than controls. This study highlights however the idea that perceptual processes during sensory integration diverge from this of healthy controls. In conclusion, this thesis suggests that impairments in reinforcement learning and Bayesian inference appear to be able to account for the positive and cognitive symptoms observed in schizophrenia, but that further work is required to merge these findings. Specifically, while our studies addressed individual components such as associative learning, working memory, implicit learning & perceptual inference, we cannot conclude that deficits of reinforcement learning and Bayesian inference can collectively account for symptoms in schizophrenia. We argue however that the studies presented in this thesis provided evidence that impairments of reinforcement learning and Bayesian inference are compatible with the emergence of positive and cognitive symptoms in schizophrenia.

Objective: To examine the hypothesis that the “natural” combination of delusions and hallucinations in psychotic disorders in fact represents a selection of early subclinical hallucinatory experiences associated with delusional ideation, resulting in need for care and mental health service use. Methods: In the Early Developmental Stages of Psychopathology study, a prospective, 10-year follow-up of a representative cohort of adolescents and young adults in Munich, Germany (n = 2524), clinical psychologists assessed hallucinations and delusions at 2 time points (T2 and T3). Analyses compared differences in psychopathology, familial liability for nonpsychotic disorder, nongenetic risk factors, persistence, and clinical outcome between groups characterized by: (1) absence of positive psychotic symptoms, (2) presence of isolated hallucinations, (3) isolated delusions, and (4) both hallucinations and delusions. Results: Delusions and hallucinations occurred together much more often (T2: 3.1%; T3: 2.0%) than predicted by chance (T2: 1.0%; T3: 0.4%; OR = 11.0; 95% CI: 8.1, 15.1). Content of delusions was contingent on presence of hallucinations but modality of hallucinations was not contingent on presence of delusions. The group with both hallucinations and delusions, compared to groups with either delusions or hallucinations in isolation, displayed the strongest associations with familial affective liability and nongenetic risk factors, as well as with persistence of psychotic symptoms, comorbidity with negative symptoms, affective psychopathology, and clinical need. Conclusions: The early stages of psychosis may involve hallucinatory experiences that, if complicated by delusional ideation under the influence of environmental risks and (liability for) affective dysregulation, give rise to a poor prognosis hallucinatory–delusional syndrome.

This thesis examines attentional and cognitive biases for particular facial expressions in delusion-prone and deluded individuals. The exploration of cognitive biases in delusion-prone individuals provides one means of elucidating psychological processes that might be involved in the genesis of delusions. Chapter 1 provides a brief review of the continuum approach to schizophrenia, and outlines recent theoretical conceptualisations of delusions. The study of schizophrenia phenomena at the symptom level has become a popular method of inquiry, given the heterogeneous phenotypic expression of schizophrenia, and the uncertainty surrounding the existence of a core neuropathology. Delusions are one of the most commonly experienced symptoms of schizophrenia, and have traditionally been regarded as fixed, false beliefs that are pathognomonic of an organic disease process. However, recent phenomenological evidence of delusional ideation in the general population has led to the conceptualisation of delusions as multi-dimensional entities, lying at the extreme end of a continuum from normal through to maladaptive beliefs. Recent investigations of the information processing abnormalities in deluded individuals are reviewed in Chapter 2. This strand of research has revealed evidence of various biases in social cognition, particularly in relation to threat-related material, in deluded individuals. These biases are evident in probabilistic reasoning, attribution style, and attention, but there has been relatively little investigation of cognitive aberrations in delusion-prone individuals. In the present thesis, social-cognitive biases were examined in relation to a standard series of faces that included threat-related (anger, fear) and non-threatening (happy, sad) expressions, in both delusion-prone and clinically deluded individuals. Chapters 3 and 4 present the results of behavioural (RT, affect recognition accuracy) and visual scanpath investigations in healthy participants assessed for level of delusion- proneness. The results indicate that delusion-prone individuals are slower at processing angry faces, and show a general (rather than emotion-specific) impairment in facial affect recognition, compared to non-prone healthy controls. Visual scanpath studies show that healthy individuals tend to direct more foveal fixations to the feature areas (eyes, nose, mouth) of threat-related facial expressions (anger, fear). By contrast, delusion-prone individuals exhibit reduced foveal attention to threat-related faces, combined with �extended� scanpaths, that may be interpreted as an attentional pattern of �vigilance-avoidance� for social threat. Chapters 5 and 6 extend the work presented in Chapters 3 and 4, by investigating the presence of similar behavioural and attentional biases in deluded schizophrenia, compared to healthy control and non-deluded schizophrenia groups. Deluded schizophrenia subjects exhibited a similar delay in processing angry faces, compared to non-prone control participants, while both deluded and non-deluded schizophrenia groups displayed a generalised affect recognition deficit. Visual scanpath investigations revealed a similar style of avoiding a broader range of negative (anger, fear, sad) faces in deluded schizophrenia, as well as a common pattern of fewer fixations with shorter duration, and reduced attention to facial features of all faces in both deluded and non-deluded schizophrenia. The examination of inferential biases for emotions displayed in facial expressions is presented in Chapter 7 in a study of causal attributional style. The results of this study provide some support for a �self-serving� bias in deluded schizophrenia, as well as evidence for an inability to appreciate situational cues when making causal judgements in both delusion-prone and deluded schizophrenia. A theoretical integration of the current findings is presented in Chapter 8, with regard to the implications for cognitive theories of delusions, and neurobiological models of schizophrenia phenomena, more generally. Visual attention biases for threat-related facial expressions in delusion-prone and deluded schizophrenia are consistent with proposals of neural dysconnectivity between frontal-limbic networks, while attributional biases and impaired facial expression perception may reflect dysfunction in a broader �social brain� network encompassing these and medial temporal lobe regions. Strong evidence for attentional biases and affect recognition deficits in delusion-prone individuals implicates their role in the development of delusional beliefs, but the weaker evidence for attributional biases in delusion-prone individuals suggests that inferential biases about others� emotions may be relevant only to the maintenance of delusional beliefs (or that attributional biases for others� emotional states may reflect other, trait-linked difficulties related to mentalising ability). In summary, the work presented in this thesis demonstrates the utility of adopting a single-symptom approach to schizophrenia within the continuum framework, and attests to the importance of further investigations of aberrant social cognition in relation to the development of delusions.

This thesis examines attentional and cognitive biases for particular facial expressions in delusion-prone and deluded individuals. The exploration of cognitive biases in delusion-prone individuals provides one means of elucidating psychological processes that might be involved in the genesis of delusions. Chapter 1 provides a brief review of the continuum approach to schizophrenia, and outlines recent theoretical conceptualisations of delusions. The study of schizophrenia phenomena at the symptom level has become a popular method of inquiry, given the heterogeneous phenotypic expression of schizophrenia, and the uncertainty surrounding the existence of a core neuropathology. Delusions are one of the most commonly experienced symptoms of schizophrenia, and have traditionally been regarded as fixed, false beliefs that are pathognomonic of an organic disease process. However, recent phenomenological evidence of delusional ideation in the general population has led to the conceptualisation of delusions as multi-dimensional entities, lying at the extreme end of a continuum from normal through to maladaptive beliefs. Recent investigations of the information processing abnormalities in deluded individuals are reviewed in Chapter 2. This strand of research has revealed evidence of various biases in social cognition, particularly in relation to threat-related material, in deluded individuals. These biases are evident in probabilistic reasoning, attribution style, and attention, but there has been relatively little investigation of cognitive aberrations in delusion-prone individuals. In the present thesis, social-cognitive biases were examined in relation to a standard series of faces that included threat-related (anger, fear) and non-threatening (happy, sad) expressions, in both delusion-prone and clinically deluded individuals. Chapters 3 and 4 present the results of behavioural (RT, affect recognition accuracy) and visual scanpath investigations in healthy participants assessed for level of delusion- proneness. The results indicate that delusion-prone individuals are slower at processing angry faces, and show a general (rather than emotion-specific) impairment in facial affect recognition, compared to non-prone healthy controls. Visual scanpath studies show that healthy individuals tend to direct more foveal fixations to the feature areas (eyes, nose, mouth) of threat-related facial expressions (anger, fear). By contrast, delusion-prone individuals exhibit reduced foveal attention to threat-related faces, combined with �extended� scanpaths, that may be interpreted as an attentional pattern of �vigilance-avoidance� for social threat. Chapters 5 and 6 extend the work presented in Chapters 3 and 4, by investigating the presence of similar behavioural and attentional biases in deluded schizophrenia, compared to healthy control and non-deluded schizophrenia groups. Deluded schizophrenia subjects exhibited a similar delay in processing angry faces, compared to non-prone control participants, while both deluded and non-deluded schizophrenia groups displayed a generalised affect recognition deficit. Visual scanpath investigations revealed a similar style of avoiding a broader range of negative (anger, fear, sad) faces in deluded schizophrenia, as well as a common pattern of fewer fixations with shorter duration, and reduced attention to facial features of all faces in both deluded and non-deluded schizophrenia. The examination of inferential biases for emotions displayed in facial expressions is presented in Chapter 7 in a study of causal attributional style. The results of this study provide some support for a �self-serving� bias in deluded schizophrenia, as well as evidence for an inability to appreciate situational cues when making causal judgements in both delusion-prone and deluded schizophrenia. A theoretical integration of the current findings is presented in Chapter 8, with regard to the implications for cognitive theories of delusions, and neurobiological models of schizophrenia phenomena, more generally. Visual attention biases for threat-related facial expressions in delusion-prone and deluded schizophrenia are consistent with proposals of neural dysconnectivity between frontal-limbic networks, while attributional biases and impaired facial expression perception may reflect dysfunction in a broader �social brain� network encompassing these and medial temporal lobe regions. Strong evidence for attentional biases and affect recognition deficits in delusion-prone individuals implicates their role in the development of delusional beliefs, but the weaker evidence for attributional biases in delusion-prone individuals suggests that inferential biases about others� emotions may be relevant only to the maintenance of delusional beliefs (or that attributional biases for others� emotional states may reflect other, trait-linked difficulties related to mentalising ability). In summary, the work presented in this thesis demonstrates the utility of adopting a single-symptom approach to schizophrenia within the continuum framework, and attests to the importance of further investigations of aberrant social cognition in relation to the development of delusions.

The work deals with the lives of people with mental illness - schizophrenia and opportunities that contribute to improving or maintaining their current health status. The theoretical part includes the characteristics of psychotic illness, legal protection of patients, possible treatment and aftercare. The practical part describes and compares three selected services or facilities. This is the Horizon Zlín, therapeutic workshops Kotva Strážnice and day service center Uherské Hradiště - Jarošov. It also includes assessment of the importance of individual therapeutic activities with clients focusing on the reduction of recurrent symptoms of schizophrenia and pointing out the importance of aftercare services and improving the facilities that this follow-up care for people with schizophrenic disorders are provided. A major benefit would be the establishment of other centers, care centers and therapeutic workshops offering services already mentioned, which would benefit not only for patients, their families, but also for the general public.

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This thesis forms a valuable tool of analysis, as well as an important reference guide to anyone interested in communicating, expressing, representing, simulating and or imagining what it is like to experience psychotic phenomena. Understanding what it is like to experience psychotic phenomena is difficult. Those who have experience with it find it hard to describe, and those who do not have that experience find it hard to envision. Yet, the ability to understand is crucial to the interaction with a person struggling with psychotic experiences, and for this help is needed. In recent years, the psychosis simulation projects Mindstorm, Paved with Fear, Virtual Hallucinations and Living With Schizophrenia have been developed as teaching and awareness tools for mental health workers, police, students and family members, so that they can better understand psychotic phenomena. These multimedia projects aim to improve understanding of what a person in psychosis is going through. This thesis represents a journey into taking a closer look at their designs and comparing them to biographical and professional literature. In doing so, throughout the chapters, a set of considerations and design challenges have been created that need to be taken into account when simulating psychosis. After a series of artistic case study labyrinths, Suicide Pigeon, Intruder, and Intruder 2.0, two final ‘do-it-yourself-psychosis’ projects have been created that have taken the aspects collected into account: The Labyrinth and The Wearable. Together these two projects form experiences that may be considered analogous to psychotic experiences. My original contribution to knowledge lies, on the one hand, within the function that both The Labyrinth and The Wearable have on a person’s ability to gain a better understanding of what it feels like to be in psychosis, and on the other hand within the background information provided on the context and urgency of psychosis simulation, how the existing simulations may be improved, and how labyrinthine installation art may contribute to these improvements.