Dopaminergic mechanisms of reinforcement learning and working memory deficits in schizophrenia patients

• Applicant: Professor Dr. Florian Schlagenhauf, since 10/2018
• Subject Area: Biological Psychiatry
• Term: from 2012 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 204208448

• Final Report Year: 2023

Final Report Abstract

We utilized a multimodal imaging approach to examine fundamental cognitive functions, including reward learning, belief updating, and working memory, in patients with schizophrenia versus controls. During reward learning, unmedicated schizophrenia patients exhibited diminished signaling in the ventral striatal reward prediction error (RPE) compared to controls, which correlated with increased negative symptoms. While dopamine synthesis capacity was not significantly different between groups in our sample, its levels in the associative striatum correlated with the intensity of positive symptoms in the patient group. This suggested that reward learning mechanisms are connected to negative symptoms, whereas a heightened striatal dopaminergic activity might be linked to positive symptoms. Computational modeling using Hierarchical Bayesian learning models was used to describe belief updating processes. We found that schizophrenia patients misinterpreted environmental changes, which was related to executive functioning. In an online study, we found that individuals with mild psychotic tendencies formed less accurate beliefs based on fewer past experiences. Schizophrenia patients displayed reduced working memory function and reduced DLPFC activation. The relationship between DLPFC activation and glutamate levels was contingent upon medication, with unmedicated patients revealing a positive correlation. Meta-analytic evidence suggested that glutamate levels in the DLPFC may be affected by medication status with elevated levels in drug-naïve patients, hinting at a potential compensatory response for NMDAR dysfunction. Accessible and economical markers of dopaminergic neurotransmission, such as neuromelanin-sensitive Magnetic Resonance Imaging (NMRI), displayed increased signals in psychosis spectrum patients. This may help to further investigate associations between dopaminergic dysfunction in patients and cognitive functions.

Publications

• Towards a Unifying Cognitive, Neurophysiological, and Computational Neuroscience Account of Schizophrenia. Schizophrenia Bulletin, 45(5), 1092-1100.
  Heinz, Andreas; Murray, Graham K.; Schlagenhauf, Florian; Sterzer, Philipp; Grace, Anthony A. & Waltz, James A.
  
• Decision-making in schizophrenia: A predictive-coding perspective. NeuroImage, 190(2019, 4), 133-143.
  Sterzer, Philipp; Voss, Martin; Schlagenhauf, Florian & Heinz, Andreas
  
• Reduced parietofrontal effective connectivity during a working-memory task in people with high delusional ideation. Journal of Psychiatry and Neuroscience, 44(3), 195-204.
  Fukuda, Yu; Katthagen, Teresa; Deserno, Lorenz; Shayegan, Leila; Kaminski, Jakob; Heinz, Andreas & Schlagenhauf, Florian
  
• Association of Cortical Glutamate and Working Memory Activation in Patients With Schizophrenia: A Multimodal Proton Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study. Biological Psychiatry, 87(3), 225-233.
  Kaminski, Jakob; Gleich, Tobias; Fukuda, Yu; Katthagen, Teresa; Gallinat, Jürgen; Heinz, Andreas & Schlagenhauf, Florian
  
• Striatal Dopamine and Reward Prediction Error Signaling in Unmedicated Schizophrenia Patients. Schizophrenia Bulletin, 46(6), 1535-1546.
  Katthagen, Teresa; Kaminski, Jakob; Heinz, Andreas; Buchert, Ralph & Schlagenhauf, Florian
  
• Volatility Estimates Increase Choice Switching and Relate to Prefrontal Activity in Schizophrenia. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 5(2), 173-183.
  Deserno, Lorenz; Boehme, Rebecca; Mathys, Christoph; Katthagen, Teresa; Kaminski, Jakob; Stephan, Klaas Enno; Heinz, Andreas & Schlagenhauf, Florian
  
• Glutamate in the Dorsolateral Prefrontal Cortex in Patients With Schizophrenia: A Meta-analysis of 1H-Magnetic Resonance Spectroscopy Studies. Biological Psychiatry, 89(3), 270-277.
  Kaminski, Jakob; Mascarell-Maricic, Lea; Fukuda, Yu; Katthagen, Teresa; Heinz, Andreas & Schlagenhauf, Florian
  
• Neuromelanin-Sensitive Magnetic Resonance Imaging in Schizophrenia: A Meta-Analysis of Case-Control Studies. Frontiers in Psychiatry, 12.
  Wieland, Lara; Fromm, Sophie; Hetzer, Stefan; Schlagenhauf, Florian & Kaminski, Jakob
  
• Belief Updating in Subclinical and Clinical Delusions. Schizophrenia Bulletin Open, 4(1).
  Fromm, Sophie; Katthagen, Teresa; Deserno, Lorenz; Heinz, Andreas; Kaminski, Jakob & Schlagenhauf, Florian
  
• Models of Dynamic Belief Updating in Psychosis—A Review Across Different Computational Approaches. Frontiers in Psychiatry, 13(2022, 4, 12).
  Katthagen, Teresa; Fromm, Sophie; Wieland, Lara & Schlagenhauf, Florian
  
• Acute stress alters probabilistic reversal learning in healthy male adults. European Journal of Neuroscience, 57(5), 824-839.
  Wieland, Lara; Ebrahimi, Claudia; Katthagen, Teresa; Panitz, Martin; Luettgau, Lennart; Heinz, Andreas; Schlagenhauf, Florian & Sjoerds, Zsuzsika
  
• Computational mechanisms of belief updating in relation to psychotic-like experiences. Frontiers in Psychiatry, 14(2023, 5, 5).
  Fromm, Sophie Pauline; Wieland, Lara; Klettke, Arne; Nassar, Matthew R.; Katthagen, Teresa; Markett, Sebastian; Heinz, Andreas & Schlagenhauf, Florian