Motivational processing, Mesolimbic and Mesostriatal Function in Neuropsychiatric Disease

Motivation and the response to rewarding events are adversely affected in many psychiatric and neurological illnesses: many patients with psychosis or Parkinson‘s Disease (PD) are de-motivated and experience apathy. Also, patients with some illnesses, such young adults with psychosis, seem to be over motivated by irrelevant information, which they seem to find captivating. This can also happen in patients with PD, possibly secondary to medication. But very little is known about the precise cause of these motivational abnormalities at the brain level. One reason is why few studies have even tried to investigate these processes in patients is because, until very recently, the techniques and methods to study brain motivational processes in patients were underdeveloped. Recent advances in (a) MRI brain imaging, and (b) basic understanding of reward and motivational processing, have meant that the time is now ripe to study how these processes are affected in psychiatric and neurological illness. I will study patients with psychosis, and PD, and examine to what extent their apathy and psychotic symptoms can be related to abnormalities in motivational and reward processing systems. Greater understanding will be helpful to patients, will enable better use of existing treatments and could help develop new treatments.

Whilst a wealth of studies in animals and healthy humans have recently characterized brain responses whilst learning about or anticipating reward (and strongly implicating dopamine neurons in these processes, as well as in the related construct of incentive salience), this progress has yet to be translated into advances in understanding deficits in motivation, reward and salience processing in patients. This is in spite of the fact that disrupted motivation and abnormal responses to rewards are strongly implicated in a number of neurological and psychiatric disorders, including Parkinson‘s Disease (PD) and psychotic illness. However, recent neuroimaging experiments (by myself and others) have shown that it is possible and instructive to study brain activity in patients whilst they learn about, and respond to, rewards, indicating that there is now a opportunity for a translational approach to further the understanding of how incentive salience and reward prediction are be disturbed in illness.

I will study the emergence of psychosis through complementary studies extending my previous work on reward prediction and salience processing in psychotic illness. I will characterize brain responses to reward in unmedicated patients with mild psychotic symptoms (young adults with attenuated psychotic symptoms or prodromal symptoms). I anticipate they will show similar pathophysiological disruptions whilst learning about salient events as do patients with established psychotic illness. I will use the same psychological paradigms to study PD patients with and without psychotic symptoms (between 20-40% of PD patients report some level of psychotic symptoms), to see if the same pattern of brain activity is tied to psychosis in a different clinical context. I will also study motivational deficits in PD and attenuated psychosis using specific tasks, and I will relate functional brain abnormalities here to severity of symptoms such as apathy; in this way I will examine if there are common brain deficits in reward related regions in patients with differing conditions, each of which involve motivational deficits.

These experiments will demonstrate how reward and salience signals affect choice behaviour and brain response, and how this differs in health and in disease. The results will show whether there are abnormalities in brain or behavioural responses to salient stimuli in psychosis and Parkinson‘s Disease, and how these relate to symptoms. Such increased understanding will be of direct benefit to patients and their families in terms of patient education, could lead to better use of existing treatments and will help in developing new treatments.