Metacognitive deficits in patients with at risk mental states for schizophrenia and their interaction with psychopathology, cognitive dysfunction and functional imaging

• Applicants: Professor Dr. Peter Kirsch; Professor Dr. Andreas Meyer-Lindenberg; Professor Dr. Mathias Zink
• Subject Area: Biological Psychiatry
• Term: from 2011 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 192623319

Schizophrenia patients suffer from cognitive deficits and specifically show dysfunctions in monitoring and controlling their own thoughts. These so called metacognitive biases are associated with delusional ideation. So far, it is unclear whether deficits in metacognition precede the onset of psychosis and might be present in at risk mental states (ARMS). The relation to other cognitive dysfunctions and the associated functional alterations are also insufficiently understood. We applied for a comprehensive investigation of ARMS-patients regarding metacognition, neuropsychological performance and neuronal activation in sensitive functional magnetic resonance imaging (fMRI) tasks. In accordance with the recommendations of the DFG-reviewers to this application (ZI1253/3-1), we validated this investigational programme in a proof of principle study. We recruited samples of 24 schizophrenia patients and 28 control subjects matched for age, sex and education. Our newly developed fMRI-paradigm jumping to conclusion (JTC) revealed the expected broad cortical activation pattern in the whole sample when applying a block design analysis of the entire task. When analysing the final decision in an event related approach, we observed specific activations in nucleus accumbens (NACC) and ventral tegmental area (VTA). Interestingly, schizophrenia patients showed a significant deficit in activating these dopaminergic brain regions. Subgroups were investigated with additional fMRI tasks as well as comprehensive neuropsychological (MATRICS) and metacognitive testing. Here, we detected significant deficits in all neuropsychological and several metacognitive domains. After successfully completing the proof of principle study, this renewal proposal aims at investigating the early pathogenesis of psychosis in ARMS patients. For this task, we are able to contact and recruit 63 ARMS patients defined according to the instruments CAARMS (Comprehensive Assessment of At Risk Mental States) and ERIraos (Early Recognition Inventory based on IRAOS). These patients have been characterised in our specific outpatient service dedicated to the early detection and treatment of psychosis: FAPS (Head MZ). In addition, we established a data base of 192 control subjects. The primary endpoint of the planned study will be the cross-sectional comparison of the NACC- and VTA-activation in the JTC-fMRI paradigm. Secondary endpoints will be comparisons of behavioural neuropsychological and metacognitive domains, as well as additional fMRI-paradigms (theory of mind, monetary reward anticipation, working memory). Follow-up-investigations after 12 and 24 months aim at investigating the interactions of these parameters with each other and with the general course of illness (e.g. transition to psychosis). This project will foster the knowledge on the cognitive and neurobiological pathogenesis of schizophrenia and might provide new targets for innovative treatment interventions.

• DFG Programme: Research Grants