Convection Enhanced Delivery to Study the Pathophysiology Underlying the Clinical Features of Human Parkinson's disease

Objective/Rationale: 
Infusion of neuroactive drugs into targeted nuclei of the basal ganglia involved in Parkinson’s disease should provide critical insight into the role of neurotransmitters in these anatomic structures and should help improve strategies to better treat the disease. Convection-enhanced delivery bypasses the blood-brain barrier and permits for precise targeting of anatomic regions with a variety of molecules in a safe homogeneous manner. Moreover, recent studies have shown that surrogate imaging tracers can be co-infused with therapeutic agents to accurately determine drug distribution in real-time.
Project Description: 
We will study distribution and correlate it with clinical effects using convection of a small molecule, muscimol (a temporary neuronal inhibitor), into the subthalamic nucleus of PD patients before deep brain stimulation surgery. In the first experiment, volunteers will undergo stereotactic insertion of microcatheters into the subthalamic nucleus and real-time MRI will be used to monitor the time course and anatomic distribution of muscimol co-infused with an MR-imaging tracer (gadolinium). In the second experiment, a continuous infusion of muscimol into the subthalamic nucleus will be performed over 48 hours to monitor the clinical effects of PD symptoms. Standard PD rating scales will be used to compare the effects of intracerebral muscimol, oral dopamine replacement therapy and deep brain stimulation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: 
A critical next advance in the treatment of Parkinson’s disease and other neurodegenerative conditions is the precise therapeutic delivery of neuroactive and neuroprotective compounds to specific regions of the brain. This project utilizes the expertise of 2 institutions to better understand the distributive properties for an intracerebral infusion of a compound into the human basal ganglia using convection.
Anticipated Outcome: 
This project will:
1. Establish the capacity to precisely distribute a small molecule within discrete central nervous system nuclei in humans.
2. Determine the feasibility of selective pharmacologic manipulation of diseased neuronal circuits in PD.
3. Provide direct insight into the mechanisms underlying PD pathophysiology and clinical symptomatology.