Ventral striatal fMRI in affective and psychotic disorders: a transdiagnostic approach using resting state and task functional resonance imaging, clinical and genetic data

Eberle, Christopher (2021): Ventral striatal fMRI in affective and psychotic disorders: a transdiagnostic approach using resting state and task functional resonance imaging, clinical and genetic data. Dissertation, LMU München: Medizinische Fakultät

Abstract

The effective clinical management of psychotic and affective disorders still represents a major challenge in psychiatry. Due to the high prevalence of these disorders and the subjective suffering, they cause a massive burden for the health system and society, and improvement in diagnostic and treatment strategies is urgently sought. In consideration of the literature, there are two promising avenues for this endeavour: On the one hand, particularly regarding schizophrenia (SCZ), early detection of high risk states or disease manifestation is crucial for the eventual treatment success. On the other hand, the heterogeneity of psychotic and affective disorders as well as blurry boundaries between the associated clinical syndromes often leave the diagnosis, which is the foundation of an evidence based treatment selection, on shaky ground. At the neurobiological level, several lines of evidence underline the role of the ventral striatum, particularly the nucleus accumbens (NAcc), for the pathophysiology of psychosis and more generally reward processing. Disturbed reward processing in turn is related to anhedonia, a core symptom of major depressive disorder (MDD), bipolar disorder (BD) and also SCZ. Against this background, this thesis aimed to unravel the potential of ventral striatal brain circuits as a source of biomarkers of psychotic and affective disorders. For this purpose, two sub-studies were performed: Firstly, we studied the impact of a validated polygenic risk score (PGRS) for SCZ, childhood adversity (CA) as widespread environmental factor and their interaction on resting state (RS) fMRI measures and NAcc seed connectivity in 253 healthy controls (HC) and compared these patterns with fully expressed disease in 23 patients with SCZ. Consistent with previous reports, SCZ patients showed strong regional functional connectivity density (FCD) increases in subcortical nuclei, particularly in the NAcc, compared with HC. Furthermore, in the HC sample, a a positive association between the FCD of the NAcc and both the PGRS and the interaction between PGRS and CA was found. Fine-mapping exhibited increased connectivity between the NAcc and visual association cortices for high levels of both PGRS and the PGRS-by-CA interaction. Taken together, this study showed that in HC, high PGRS for SCZ affects both global and regionally specific connectivity of the NAcc in a similar pattern as observed in SCZ patients, and that this effect was already amplified even by a history of very mild CA. This latter observation strengthened the notion that environmental factors need consideration in imaging genetics studies. Secondly, we examined the neural underpinnings of reward anticipation (RA) in MDD, BD and SCZ as studied by fMRI. This study revealed that aberrantly low striatal activation during RA is typical of SCZ, whereas the response of this network appeared to be preserved in MDD and BD. Interestingly, two further large-scale brain networks involved in RA – the salience network and the default mode network showed both transdiagnostic and further disease-specific alterations: While the salience network was found to be impaired primarily in SCZ patients, all patient groups revealed deficits in the suppression of the default mode network. Among hub regions of all three networks that were further differentiated in an early and a late response period, levels of anhedonia were correlated with the extent of the (early) hippocampal deactivation failure across diagnostic boundaries. In sum, both investigations confirm the possibility to use fMRI to probe the functional status of the ventral striatum. The first study underlines the centrality of striatal regions in the pahophysiology of psychosis as these alterations already emerged in healthy individuals at high genetic risk for developing SCZ, particularly when including unspecific environmental risk to the model. Hyperconnectivity of this region in SCZ during the resting state matched with a blunted response during the RA task. The latter studyshowed that at least two further large-scale brain networks are impaired in both psychotic and affective disorders during RA, indicating a potential of reward processing as a source of imaging phenotypes or biomarkers to characterize patients of the respective disease spectrum.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 7. Oktober 2021
• 1. Bericht­erstatter:in: Koutsouleris, Nikolaos