Mechanisms of motivation and their disturbance in neurological disease

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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.