Dokument

Summary:
For a long time, traditional classification systems have been used to categorize mental disorders into strict classes based on a set of specific and standardized criteria. Such classifications assume a clear cut off between disorders. However, research using these classification systems fail to identify transdiagnostic markers and “points of rarity” separating mental disorders. Categorical approaches are limited by the large neurobiological overlapping of phenomenology as well as molecular genetics, neuro-anatomy and function, and environmental risk across disorders. Moreover, categorical approaches merely consider characteristics above and below the given categorical thresholds using not otherwise specified diagnoses, not fitting to other officially specified categories. Given the limitations of categorical approaches, dimensional factor models can be used as a valuable framework providing significant progress for the understanding of the neurobiology of the major psychiatric disorders (major depressive disorder, bipolar disorder, schizophrenia spectrum disorder). Previous studies show a range of different factor models, indicating that descriptive psychopathology might be organized in a bifactorial or hierarchical framework. However, there is still a lack of comprehensive factorial models comprising a broad range of symptoms across the major psychiatric disorders. Moreover, the neuro-anatomical and neuro-cognitive correlates of transdiagnostic psychopathological factors remain largely elusive. Categorical studies on overlapping gray matter volume alterations across disorders compared to a healthy control group show paralimbic and heteromodal regions to be commonly altered across disorders. In addition, the transdiagnostic investigation of neuro-cognitive measures shows large overlaps and comparable results across disorders and domains with motor speed being the only domain separating disorders. To overcome the reported obstacles, the studies underlying this dissertation investigate the factorial structure of a broad range of psychopathological symptoms across affective and psychotic disorders. Further, dimensional factors are used to determine the underlying neuro-anatomical and neuro-cognitive correlates of descriptive psychopathology. STUDY I demonstrates a cross-validated factor model comprising five first order and two second order factors, supporting the use of hierarchical models. The extracted first order factors (depression, negative syndrome, positive formal thought disorder, paranoid-hallucinatory syndrome, increased appetite) are present in all diagnostic categories, suggesting a diagnosis-shared phenomenology. STUDY II examines the brain structural correlates of the factors derived from STUDY I. Results include a negative association of the negative syndrome with the bilateral frontal opercula. Positive formal thought disorder is negatively associated with the right middle frontal gyrus and with the left amygdala-hippocampus-complex. The paranoid-hallucinatory syndrome is negatively associated with two whole brain clusters (right fusiform gyrus and left middle frontal gyrus) as well as regions-of-interest including the left angular gyrus, bilateral thalami, left postcentral gyrus and left posterior cingulate gyrus. Investigating the neuro-cognitive correlates of psychopathological factors, STUDY III indicates state of illness-dependent associations in almost all cognitive domains. While positive formal thought disorder and the negative syndrome show most pronounced correlations, no or only weak correlations emerge for the other factors. Finally, STUDY IV investigates formal thought disorder in more detail. Results indicate a three factor model (verbosity, emptiness, disorganization) that is differentially associated with gray and white matter brain structure. The verbosity factor is negatively associated with gray matter volume of the temporo-occipital language junction and positively with the white matter microstructure of the inferior longitudinal fascicle and the posterior part of the cingulum bundle. Emptiness is negatively associated with the gray matter volume of the left hippocampus and thalamus but not with white matter. The disorganization factor associates with the white matter structure of the bilateral anterior thalamic radiation and with the hippocampal part of the right cingulum bundle. In conclusion, this dissertation can be interpreted as a first effort overcoming the limitations given by previous categorical approaches. The psychopathological factor models reported are linked to brain structural and neuro-cognitive measures, supporting the view of diagnosis shared and independent biological mechanisms. The studies of this dissertation open up completely new approaches for pathogenic and etiological research. Dimensional methods as applied in this dissertation constitute the basis for a new taxonomy that can in a next step be used to improve prediction, treatment and therapy of the major psychiatric disorders.

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