Mechanisms of motivation and their disturbance in neurological disease

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.

Rewards drive us to perform well. Recently I have shown how motivation can incentivise us to be both accurate and fast, improving performance beyond its normal limits and breaking long-established concepts of speed-accuracy trade-off. Motivation is frequently disrupted in neurological conditions, ranging from Parkinson's disease (PD) and neurodegenerative disorders, to acquired brain injury. The consequence can be profound clinical apathy, or impulse control disorders, which have enormous individual, social and economic impacts on patients. Given their clinical importance, these syndromes remain under-recognised, poorly characterised, and only coarse nonspecific drug treatments are available.

One crucial question arises: If we can sometimes perform well, why not all the time? Building on my recent work, I will apply a unifying framework to quantitatively predict behavioural improvements by reward. These recent theoretical advances will then be translated to the clinical domain, applying them to symptoms of disease and neuromodulatory drugs.

This fellowship will allow me to combine my skills in computational methods, behavioural research and clinical practice to develop a unique and independent niche that is widely relevant and applicable.

First I will validate and test the generality of my framework in healthy people. Further studies will ask whether dopamine may be a key currency in which the brain "pays" for the cost of control, studying the effects of drugs in health, alterations seen in PD, and after focal isolated damage to the medial prefrontal cortex. Finally, in a highly novel study of cholinesterase inhibitors in PD, a treatment for cognitive dysfunction, I will explore the hypothesis that acetylcholine may also have noise-reduction functions, but in more posterior brain regions.

Together these basic science and clinical studies allow us to characterise and modulate motivation and its dysfunction, with broad potential clinical impact.

A. Short term beneficiaries:

1) Patients: treatment, assessment and prediction
A clear benefit of this project will improve quality of life for patients suffering from motivational changes, especially those with Parkinson's disease. They will benefit by
- improved explanations of how and why the deficits arise
- focused drug treatment harnessing our findings
- the possibility in future to predict which patients are likely to develop apathy, or impulsive side effects from dopaminergic therapy. Treatments could then be better tailored to individual patients.

2) Clinicians: diagnosis, monitoring and education
Clinicians would also benefit from this study, which will provide
a) a framework for thinking about motivation,
b) facilitating faster diagnosis in clinic
c) allowing earlier diagnosis in mild disease
d) providing more informative explanations to patients and their carers.
These benefits will be conveyed to clinicians through the Association of British Neurologists in year 3, and the Movement Disorders Society international meeting in year 4 of the fellowship.
e) It may also become possible to offer more specific and sensitive tests than the current questionnaire-based measures. After experimentally dissociating aspects of motivation differentially affected by disease, I would plan to produce a computer-based test that probes these aspects of motivation. Such a test could be used in clinic to quantify disorders and provide finer grained diagnostics. This may be especially useful since apathy can predate memory symptoms in some neurodegenerative conditions. I already have extensive experience with designing such tablet-based clinical tests, and translating them to patient environments.
f) Although these advances would primarily benefit neurologists and dementia specialists, there is also a need to educate GPs about scientific improvements and how they apply to patients. Detecting motivational disturbances early and at a primary care level could speed up impact from this project.

3) Researchers: testing predictions and causality
Researchers in many other domains may find this work of great value.
a) Neurophysiological studies in non-human animals are dependent upon this work to demonstrate that proposed neural functions are valid and applicable to humans.
b) Imaging studies in healthy individuals also rely on pharmacological and lesion studies to demonstrate a causal role for the neural representations they uncover.
The proposed studies therefore fit an essential and translational niche in current neuroscience.

4) Charities: raising awareness, information, counselling
Patient and carer support in neurology is often partly devolved to charities such as
a) Young Dementia UK,
b) Parkinsons UK.
These charities can benefit from this research by having more systematic understanding of what constitutes motivation, how it can go wrong, and what patients and their families can expect.

B. Long term beneficiaries:

1) Patients: extend to many other conditions
As the principles underlying motivation are elucidated, it will become possible to use the findings from this research in other conditions that are known to produce apathy and impulsivity. These include neurological diseases such as
a) dementia,
b) multiple sclerosis,
c) strokes and
d) head injury.
However, it will also be applicable to
e) depression,
f) schizophrenia and
g) addiction,
in which apathy and impulsivity play a key role.

2) Pharmaceuticals: more sensitive outcome measures

3) Society: motivation in the healthy, and enhancement
Could this project have benefits outside of clinical medicine and neuroscience? The study will answer fundamental questions about the nature of motivation. Reduced motivation may contribute to unemployment and poverty. An ability to understand, predict, or modulate this aspect of human behaviour will have profound implications on society.