Negative symptoms, striatal dopamine and model-free reward decision-making in schizophrenia

• Published in: Brain (London, England : 1878) Vol. 146; no. 2; pp. 767 - 777
• Main Authors: Brandl, Felix, Knolle, Franziska, Avram, Mihai, Leucht, Claudia, Yakushev, Igor, Priller, Josef, Leucht, Stefan, Ziegler, Sibylle, Wunderlich, Klaus, Sorg, Christian
• Format: Journal Article
• Language: English
• Published: England 13.02.2023
• Subjects: Dopamine; Humans; Psychotic Disorders - diagnostic imaging; Reward; Schizophrenia - diagnostic imaging; Tomography, X-Ray Computed; executive dysfunction; schizophrenia; dopamine; model-based decision making; negative symptoms
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awac268

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making (‘reward prediction influence’, RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms.