Study Rationale: Activity changes in nerve cells in the brain’s cerebral cortex are central to Parkinson’s disease (PD). However, which specific cell types are affected, and how and when their activity changes during the development of parkinsonism, it unknown. We study these questions in preclinical models of progressive parkinsonism, so that we can correlate the timing of the identified changes with the appearance and evolution of behavioral abnormalities. Based on our recent results, we also study whether drugs with antiparkinsonian effects change the morphology of cortical neurons and examine the effectiveness of a new approach to treating parkinsonism.
Hypothesis: We hypothesize that specific groups of cortical neurons that send fibers to the spinal cord show abnormal activity and undergo morphological changes as parkinsonism develops and that reversal of the activity changes by local cortical interventions can improve parkinsonian signs.
Study Design: We will measure the anatomical and functional characteristics of motor cortical neurons in preclinical models of slowly progressive parkinsonism. Before and during the development of parkinsonism, we will measure activity patterns of large groups of cortical neurons, carry out anatomical studies to identify the reshaping of connections between these cells and use the resulting data in computer simulations to help with the interpretation of the results. As a direct consequence of our ongoing work, we will also study the effectiveness of a new potential antiparkinsonian strategy which alters the activity of a specific class of cortical neurons.
Impact on Diagnosis/Treatment of Parkinson’s disease: Understanding how movement problems in PD develop is key to developing more effective methods to control them. Characterizing the abnormalities in specific types of cortical neurons may allow us to develop new therapies that target the affected circuits through deep-brain stimulation, pharmacologic or genetic methods.
Next Steps for Development: The results of these studies will guide the development of new therapeutic strategies and optimization of deep-brain stimulation methods to disrupt abnormal cortical activity. Establishing the time course of anatomical changes, relative to disease progression, may provide insight into the appropriate timing for applying these strategies