Apathy is a common and disabling complication of Parkinson’s disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action, or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesised that apathy in Parkinson’s disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision making in 75 volunteers; 53 patients with Parkinson’s Disease, with and without clinical apathy, and 22 age matched healthy controls. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient’s apathy severity measured using the Lille Apathy Rating scale (R = -0.46, p<0.001). Computational modelling of the patient’s choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration which also correlated with apathy scores (R = -0.5, p<0.001). We went on to acquire fMRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age matched controls performing the restless bandit task. Analysis of the fMRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson’s disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorisation of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson’s patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched controls, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson’s disease.

中文翻译：

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帕金森病冷漠患者基于价值的决策受损

冷漠是帕金森病的一种常见且致残的并发症，其特征是目标导向行为减少。一些研究报告了前额皮质区域的功能障碍和脑干核的投射，其神经调节剂包括多巴胺、血清素和去甲肾上腺素。动物和人类神经科学的工作已经证实了这些神经调节剂在动机性决策方面的贡献。具体来说，这些神经调节剂对编码决策价值有重叠的贡献，并影响是否探索替代行动方案，或坚持现有策略以实现奖励目标。基于这项工作，我们假设帕金森病的冷漠应该与基于价值的学习受损有关。我们使用四臂不安强强盗强化学习任务，研究了 75 名志愿者的决策过程； 53 名患有帕金森病（有或没有临床冷漠）的患者以及 22 名年龄匹配的健康对照者。冷漠的患者表现出选择最高价值老虎机的能力受损。任务表现预测个体患者的冷漠严重程度，使用里尔冷漠评定量表测量（R=-0.46，p＜0.001）。患者选择的计算模型证实，冷漠组做出的决定与选项的学习价值无关，这与之前关于奖励不敏感的报告一致。进一步的分析表明，人们不再利用最高价值的选择，而且坚持不懈的程度也有所下降，这也与冷漠得分相关（R = -0.5，p＜0.001）。我们继续对 59 名志愿者进行了功能磁共振成像检查；一组由 19 名患有冷漠症的患者和 20 名没有冷漠症的患者以及 20 名年龄匹配的对照组组成，执行不安分的强盗任务。对奖励反馈点的功能磁共振成像信号的分析证实了帕金森病患者腹内侧前额叶皮层内的信号减弱，这种信号在冷漠中更为明显，但不能预测他们个体冷漠的严重程度。使用基于模型的选择类型分类，冷漠组中探索较低价值强盗的决定激活前额皮质的程度与年龄匹配的对照组相似。相比之下，没有冷漠的帕金森病患者的分布式丘脑皮质网络的激活显着增加。丘脑活动的增强预测了两个患者组个体冷漠的严重程度，并表现出与背侧前扣带皮层和前岛叶的功能连接。鉴于没有冷漠的患者的任务表现与年龄匹配的对照组没有什么不同，我们将这个网络的招募解释为一种可能的补偿机制，它可以补偿帕金森病中冷漠的症状表现。