Mechanisms of motivation and their disturbance in neurological disease

奖励驱使我们做得更好。这种激励我们的能力是人类生活中熟悉和重要的一部分。然而，在许多神经系统疾病中，动力被打乱，导致冷漠或冲动。这些变化在帕金森氏病(PD)和中风中尤其常见，但人们对它们知之甚少。这在一定程度上是因为我们只有非常粗略、主观的方法来量化动机。冷漠的特征是未能采取行动，尽管其目标是高度重视的，而且很容易实现。大约60%的帕金森病患者和中风患者会出现临床冷漠。相比之下，冲动可以被认为是未能对奖励驱动的行为施加控制，大约14%的帕金森氏症患者存在这种情况。有这些问题的患者可能会颠覆他们的生活，失去他们的朋友和利益，或者陷入巨额债务。他们给照顾者带来了沉重的负担，他们发现自己改变后的行为很难理解和接受。我提出了一个解决这个问题的研究计划。首先，我将通过研究奖励和惩罚的前景如何改变健康人的决策和行动来检验一些理论预测。其次，我会问，影响多巴胺的药物是否会改变人们对激励的反应。多巴胺是大脑中的一个关键奖励信号。最后，我将通过研究帕金森氏症和中风这两种重要的大脑疾病患者的动机是如何被打乱的，将这些措施应用于疾病。根据对动物的研究，化学物质多巴胺很可能在人类的动机中发挥核心作用。我的研究将准确地描述它的作用，因为它可能提供治疗的基本把手。另一种化学信号，乙酰胆碱，也可能产生类似的效果。这是一个新的和未被探索的途径，最近在动物研究中积累了支持。利瓦斯明是一种公认的增加乙酰胆碱的药物，对帕金森病患者的认知问题有很强的积极作用。在一组开始服用这种药物的患者中，我计划测量药物对动力的影响。这些研究将建立在我最近的工作基础上，结合了理论、行为和临床研究。我的关键问题是：1)决定和行动是否都受单一的动机法则支配？2)惩罚和奖励是否具有类似的激励作用？3)大脑化学物质多巴胺是否可以微调这些影响？4)帕金森氏症患者的动机是否会因奖励、惩罚或这两个因素而改变？5)与多巴胺相关的药物能否扭转这种缺陷？6)另一种大脑化学物质--乙酰胆碱是否也能改变动机？7)大脑中的特定区域对产生动机至关重要吗？因此，拟议的研究将把理论从基础神经科学转化为临床领域，提高我们对临床认知障碍的理解，并最终促进其诊断和治疗。这项研究的结果将传达给患者，并传播给临床医生和神经学家。虽然我的建议集中在帕金森病和局灶性脑损伤上，但这个项目的最终目标是研究一般的动机障碍。现在人们意识到，动机障碍会给各种诊断带来大规模的社会、个人和经济问题，例如，导致痴呆症(50%的阿尔茨海默病患者会表现出冷漠)、多发性硬化症和头部损伤的多种原因。但还有更广泛的应用。同时患有抑郁症和精神分裂症的患者特别容易受到临床冷漠的影响，而动力不足的频谱可能也是健康人的共同特征。因此，我的工作也对药物如何调节健康个体的动机产生了影响。了解动机的生物学，包括毒品效应，将与更广泛的社会背景高度相关。

Rewards drive us to perform well. This ability of incentives to motivate us is a familiar and important part of human life. However in many neurological diseases, motivation is disrupted, leading to apathy or impulsivity. These changes are especially common in Parkinson's disease (PD) and stroke, yet they are very poorly understood. This is in part because we have only very coarse, subjective ways to quantify motivation. Apathy is characterised by failure to engage in an action even though its goal is highly valued and can be easily obtained. About 60% of PD and stroke patients will develop clinical apathy. Impulsivity, in contrast, can be thought of as a failure to exert control over reward-driven behaviours, and is present in about 14% of individuals with PD. Patients with these problems can have their lives overturned, losing their friends and interests, or running into vast debt. They pose a heavy burden to their carers, who find their changed behaviours difficult to understand and accept. I propose a programme of research that will address this problem. First, I will test some theoretical predictions by examining how the prospect of rewards and penalties alter decision-making and action in healthy people. Second, I will ask whether drugs influencing dopamine, a key reward signal in the brain, alter how people respond to incentives. Finally, I will bring these measures to bear on disease, by studying how motivation is disrupted in patients with PD and stroke - two important brain disorders. Based on work in animals, the chemical dopamine is likely to play a central role in human motivation. My studies will precisely characterise its role, because it may provide an essential handle on treatment. Another chemical signal, acetylcholine, may also produce similar effects. This is a novel and underexplored avenue which has recently accumulated support in animal studies. Rivastigmine, a well-established drug that increases acetylcholine, has strong positive effects on cognitive problems in PD. In a group of patients who are commencing this medication, I plan to measure the drug's effects on motivation. These studies will build upon my recent work that combines theory, behaviour and clinical studies. My key questions are 1) Are both decisions and actions governed by a single law of motivation?2) Do penalties and rewards have similar motivating effects?3) Does the brain chemical dopamine fine-tune these effects?4) Is motivation in Parkinson's disease altered by rewards, penalties or both these factors? 5) Can deficits be reversed by dopamine-related medication? 6) Can another brain chemical, acetylcholine, also alter motivation?7) Are specific brain regions critical to generating motivation in humans? The proposed studies will therefore translate theory from basic neuroscience to a clinical domain, improving our understanding of clinical disorders of cognition, and ultimately facilitating their diagnosis and treatment. The results from the study will be communicated to patients and disseminated to clinicians and neuroscientists. Although my proposal focuses on PD and focal brain damage, the ultimate goal of this programme is to study motivational disorders in general. It is now appreciated that motivational disturbances bring large-scale social, personal and economic issues across a wide range of diagnoses, including for example many causes of dementia (apathy occurs in 50% of patients with Alzheimer's disease), multiple sclerosis and head injury. But there are even wider applications. Patients with both depression and schizophrenia are especially vulnerable to clinical apathy, and a spectrum of low motivation may also be a common feature in healthy people. Thus my work also has ramifications in how motivation in healthy individuals can be modulated by drugs. Understanding the biology of motivation, including drug effects, would be highly relevant to the wider context of society.