Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, 81675, Germany.
Department of Neuroradiology, School of Medicine, Technical University of Munich, Munich, 81675, Germany.
Brain. 2023 Feb 13;146(2):767-777. 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.
阴性症状，如缺乏动力或社会退缩，在精神分裂症患者中非常普遍且具有致残性。阴性症状的潜在机制尚未完全了解，从而阻止了靶向治疗的发展。我们假设在精神分裂症患者精神缓解期，基于模型和无模型的奖励预测对决策的影响（“奖励预测影响”，RPI）受损，是阴性症状的基础。我们专注于精神缓解期，因为精神病症状可能会干扰基于奖励的决策。此外，我们假设受损的基于模型/无模型 RPI 取决于关联纹状体多巴胺合成和储存（DSS）以及执行功能的改变。这两个因素都影响健康受试者的 RPI，并且在精神分裂症中通常会受损。研究纳入了 25 名在精神缓解期出现明显阴性症状的精神分裂症患者和 24 名健康对照者。阴性症状严重程度通过阳性和阴性综合征量表阴性子量表进行测量，基于模型/无模型 RPI 通过两阶段决策任务进行测量，关联纹状体 DSS 通过 18F-DOPA 正电子发射断层扫描进行测量，执行功能通过符号编码任务进行测量。与健康对照组相比，患者的无模型 RPI 选择性降低，与阴性症状严重程度以及关联纹状体 DSS 减少（仅在患者中）和执行功能降低（在患者和对照组中）相关。相比之下，患者的基于模型的 RPI 没有改变。研究结果为精神分裂症阴性症状的无模型奖励预测影响受损提供了证据，以及关联纹状体多巴胺和执行功能降低作为相关因素提供了证据。数据表明，对于有明显阴性症状的精神分裂症患者，可能有潜在的治疗靶点。
