A new systems approach to therapeutic target selection in degenerative neurological disease. (360G-Wellcome-089603_Z_09_Z)

We will develop a new approach to selecting and verifying novel therapeutic targets in degenerative neurological diseases, piloting this innovation in Parkinson s disease (PD). To this end, we will use dynamic causal models (DCMs) that allow electrophysiological data to be fitted by biologically plausible (conductance-based), neural-mass models of coupled sources. Data will be derived from simultaneous electrophysiological recordings of neuronal network activity at multiple sites in the basal ga nglia and cortex in dopamine-intact (control) rats and 6-hydroxydopamine-lesioned (Parkinsonian) rats, as well as from simultaneous recordings from more restricted sites in patients undergoing functional neurosurgery. Bayesian inversion will then be used to derive estimates of extrinsic parameters (internuclear connectivities) and intrinsic parameters (intranuclear connectivities and conductances) in the DCMs. We will focus on those parameters that are similar in Parkinsonian rodents and PD pati ents, but differ in control rodents and in patients without PD. The importance of candidate differences will then be confirmed using techniques drawn from neuroeconomics and finally targeted in the Parkonsonian rodents to confirm their utility as candidate therapeutic approaches. Importantly, we will not restrict ourselves to the modeling and testing of pharmacological interventions, but also exploit the potential for surgical intervention through lesioning and deep brain stimulation.