Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Eur J Neurosci. 2023 Dec;58(12):4523-4544. doi: 10.1111/ejn.15875. Epub 2022 Dec 20.
Decision-making during mixed-strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed-strategy decision-making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty-six PD patients (ages 49-85, Hoehn and Yahr Stages 1-3) and 22 healthy controls (ages 54-75) competed in a mixed-strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed-strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within-subject, multi-centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val Met), rs6277 (C957T) and rs907094 (encoding DARPP-32). PD and control participants displayed comparable mixed-strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow-up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD.
在混合策略游戏中进行决策需要灵活地根据他人的行为调整选择策略，并动态跟踪结果。这些决策涉及多种认知过程，包括强化学习，而这些过程会受到纹状体多巴胺系统的干扰。因此，我们研究了多巴胺功能的遗传变异如何影响帕金森病（PD）患者的混合策略决策，而 PD 涉及纹状体多巴胺病理学。66 名 PD 患者（年龄 49-85 岁，Hoehn 和 Yahr 分期 1-3 期）和 22 名健康对照者（年龄 54-75 岁）参与了一项混合策略游戏，成功表现取决于最小化选择偏差（即，灵活地根据每次试验的结果调整选择）。参与者还完成了一项固定策略任务，该任务在感官输入、运动输出和整体奖励率方面与混合策略任务相匹配。因子分析用于区分两个任务中的认知和运动方面。使用一项基于个体的、多中心设计，患者在接受和不接受多巴胺能治疗时接受检查，并通过代表三种影响多巴胺传递的单核苷酸多态性（SNP）的加性效应的多基因谱评分来检查遗传变异：rs4680（COMT Val Met）、rs6277（C957T）和 rs907094（编码 DARPP-32）。PD 和对照组参与者表现出相似的混合策略选择行为（整体）；然而，具有较高多巴胺传递遗传谱评分的 PD 患者的表现优于具有较低评分的患者。对个体 SNP 的探索性后续测试显示，具有 C957T 多态性的个体表现更好，反映了较高的纹状体 D2/D3 受体密度。重要的是，遗传变异调节了认知方面的表现，超越了运动功能，表明多巴胺信号转导的遗传变异可能是 PD 患者认知功能个体差异的基础。
