Mechanisms of motivation and their disturbance in neurological disease

神经系统疾病中的动机及其干扰机制

• 批准号: MR/P00878X/1
• 负责人: Sanjay Manohar
• 金额: $ 133.33万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP00878X%2F1
• 关键词: Mechanisms; motivation; their; disturbance; neurological

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.

奖励促使我们表现得更好。这种激励我们的能力是人类生活中熟悉而重要的一部分。然而，在许多神经系统疾病中，动机被破坏，导致冷漠或冲动。这些变化在帕金森病（PD）和中风中尤为常见，但对它们的了解甚少。这在一定程度上是因为我们只有非常粗糙、主观的方法来量化动机。冷漠的特点是，即使目标很有价值，而且很容易实现，也不能参与其中。约60%的帕金森病和中风患者会发展为临床冷漠。相比之下，冲动性可以被认为是无法控制奖励驱动的行为，大约14%的PD患者存在冲动性。有这些问题的患者可能会改变他们的生活，失去朋友和兴趣，或者陷入巨额债务。他们给照顾者带来了沉重的负担，照顾者很难理解和接受他们改变了的行为。我提出一个研究计划来解决这个问题。首先，我将检验一些理论预测，通过研究奖惩的前景如何改变健康人的决策和行动。其次，我会问影响多巴胺（大脑中一个关键的奖励信号）的药物是否会改变人们对激励的反应。最后，我将通过研究PD和中风（两种重要的脑部疾病）患者的动机是如何被破坏的，将这些措施应用于疾病。基于对动物的研究，化学物质多巴胺可能在人类动机中起着核心作用。我的研究将精确地描述它的作用，因为它可能提供治疗的基本方法。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充分探索的途径，最近在动物研究中积累了支持。利瓦斯汀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病人中，我计划测量这种药物对动机的影响。这些研究将建立在我最近结合理论、行为和临床研究的工作基础上。我的关键问题是：1)决策和行动是否都受到单一动机法则的支配？2)惩罚和奖励是否具有相似的激励效果？3)大脑中的化学物质多巴胺会微调这些效果吗？4)帕金森病患者的动机是否会因奖励、惩罚或这两种因素而改变？5)多巴胺相关药物能逆转缺陷吗？另一种大脑化学物质乙酰胆碱也能改变动机吗？7)特定的大脑区域对人类产生动机至关重要吗？因此，拟议的研究将把基础神经科学理论转化为临床领域，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。研究结果将传达给患者，并传播给临床医生和神经科学家。虽然我的建议侧重于PD和局灶性脑损伤，但这个项目的最终目标是研究一般的动机障碍。现在人们认识到，动机性干扰会在广泛的诊断范围内带来大规模的社会、个人和经济问题，例如包括痴呆症的许多原因（50%的阿尔茨海默病患者会出现冷漠）、多发性硬化症和头部损伤。但还有更广泛的应用。抑郁症和精神分裂症患者特别容易出现临床冷漠，而一系列低动机也可能是健康人的共同特征。因此，我的工作也涉及到健康个体的动机如何被药物调节。理解动机的生物学，包括药物效应，将与更广泛的社会背景高度相关。

项目成果

4789Non-invasive imaging of myocardial disarray associates with ventricular arrhythmia in hypertrophic cardiomyopathy

4789 心肌紊乱的无创成像与肥厚型心肌病的室性心律失常相关

• DOI: 10.1093/eurheartj/ehx493.4789
• 发表时间: 2017
• 期刊: European Heart Journal
• 影响因子: 39.3
• 作者: Ariga R

A common neural network architecture for visual search and working memory

用于视觉搜索和工作记忆的通用神经网络架构

• DOI: 10.1080/13506285.2020.1825142
• 发表时间: 2020
• 期刊: Visual Cognition
• 影响因子: 2
• 作者: Bocincova A

6 Diffusion tensor magnetic resonance imaging of myocardial disarray in hypertrophic cardiomyopathy

图6 肥厚型心肌病心肌紊乱的弥散张量磁共振成像

• DOI: 10.1136/heartjnl-2018-bcvi.21
• 发表时间: 2018
• 作者: Ariga R

Neural signature of flexible coding in prefrontal cortex.

• DOI: 10.1073/pnas.2200400119
• 发表时间: 2022-10-04
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Reward-based improvements in motor control are driven by multiple error-reducing mechanisms

基于奖励的电机控制改进是由多种误差减少机制驱动的

• DOI: 10.1101/792598
• 发表时间: 2019
• 作者: Codol O