Memory and motivation in human health and disease (360G-Wellcome-206330_Z_17_Z)

Many brain diseases are associated with disabling cognitive and behavioural syndromes, which are currently poorly understood and have few effective treatments. Here, I propose that we need a systems level account to develop new therapies which target syndromes at the systems or network level, across diseases – regardless of underlying pathology. To test this transdiagnostic approach, I focus on two model syndromes: one cognitive (short-term memory deficits) and the other behavioural (apathy or lack of motivation). My aim is first to deconstruct the cognitive and behavioural components underlying these syndromes using carefully designed, sensitive behavioural measures. Then to relate behavioural performance to brain networks using a multimodal neuroimaging approach, including structural and functional connectivity measures. To identify whether there are robust brain imaging signatures of component deficits that are common to different diseases, we shall examine patients with Alzheimer’s disease, Parkinson’s disease, stroke and small vessel cerebrovascular disease. To determine whether we can detect these signatures at the earliest stages of disease (in their preclinical phase) we shall apply these methods also to groups at high risk of developing neurodegenerative disorders. Finally, we shall examine whether it is possible to modulate component deficits using cholinergic and dopaminergic drugs.