Network mechanisms of motor and motivational impairments in Parkinson's disease

Parkinson's disease (PD) is a common and incurable neurological illness that affects 1% of the population over the age of 60, leading to progressive impairments of movement, memory, and behaviour. The symptoms of PD are thought to be the result of the death of brain cells that produce a chemical called dopamine. Medications that replace dopamine are a mainstay of treatment for PD. In certain cases, electrical stimulation of deep brain areas via surgically implanted electrodes - a technique known as Deep Brain Stimulation (DBS) - can also be highly effective. PD is a heterogeneous condition, meaning that one patient can experience very different symptoms to another. I will study the mechanisms by which PD can result in different symptoms for different patients. Specifically, I will look at impairments of action in PD. Some patients suffer predominantly with difficulty performing actions such as movement, whilst others suffer from a lack of motivation to engage in action - a condition known as apathy. Using brain imaging techniques, I will discover how dopamine loss in PD impacts communication within brain networks responsible for movement and motivation. Making a link between specific symptoms and corresponding brain networks is likely to lead to an improved classification of PD on an individual patient basis and my hold the key to unlocking new treatments. I will also study patients with REM sleep behaviour disorder (RBD), which is a condition that is commonly associated with apathy and often precedes the onset of PD. RBD is thought to represent one of the earliest stages of PD and could be a critical point at which therapies designed to prevent disease progression are trialled. Patients with RBD are likely to exhibit the earliest network abnormalities underpinning action impairments. This proposal will address the following questions regarding movement and motivational brain networks in PD and RBD. Movement Networks Recent evidence suggests that short lived 'bursts' of activity have the ability to jam normal communication within the brain's movement network, in turn leading to the movement impairments observed in PD. DBS approaches that are selectively turned on in response to the occurrence of such bursts ('reactive DBS') may be more effective than conventional continuous DBS, whilst also minimising stimulation related side effects. Stimulation related side effects are not uncommon and can occur in up to 50% of patients. I will use artificial intelligence (AI) techniques to predict when bursts resulting in movement impairments occur. This predictive capability will allow for the development of improved DBS devices that are capable of preventing the onset of bursts, by stimulating in a specific manner in advance of their onset ('predictive DBS'). Motivation Networks Memories corresponding to rewarding experiences are reactivated (or replayed) by the brain during rest and sleep. This process contributes to decision making and motivating engagement in rewarding actions. Dopamine may play an important role in initiating memory replay. By studying patients with PD on and off their usual dopamine containing medication, I will establish how dopamine influences brain networks that are responsible for replay. Memory replay will be established using state of the art brain imaging and AI techniques. Importantly, I aim to establish whether apathy in PD and RBD is the result of impaired replay resulting from dopamine deficiency. Apathy is a debilitating, poorly understood and often inadequately treated symptom that commonly occurs in many neurological illnesses. Linking apathy to memory replay in PD is therefore likely to carry broader relevance for the improved characterisation and treatment of other neurological conditions (e.g., Alzheimer's disease and other dementias).