Our goal is to advance the understanding of movement disorders pathophysiology, and therapeutic mechanisms, through studies of cortical and basal ganglia local field potentials (LFPs) in humans undergoing neurosurgical treatment. The LFP represents synchronized sub- and supra-threshold activity in presynaptic terminals and postsynaptic neurons. The current model of Parkinson's disease (PD) posits that the critical circuit-level abnormality is excessive synchronization of basal ganglia neuronal activity, especially at beta (13- 30 Hz) frequencies. In the initial period of this grant (2010-2013), we utilized intraoperative recordings to show that in PD, there is exaggerated coupling of the phase of the cortical beta rhythm to the amplitude of gamma activity (50-250 Hz). This "phase amplitude coupling" (PAC) is already known as an important mechanism for the cortical control of cognitive and motor function. Since cortical gamma activity reflects local population spiking, we interpret excessive PAC is a cortical manifestation of increased neuronal synchronization. We propose that this constrains motor cortex to an inflexible pattern of activity, leading to a paucity of movement. Here, we further investigate aspects of network synchronization in two movement disorders, PD and primary dystonia, using both invasive intraoperative recording and noninvasive scalp electroencephalography (EEG) methods. First, in what part of a movement sequence (holding a position, movement preparation, or action) are cortical and basal ganglia oscillatory activity most disrupted, and what is the anatomic localization (at 4 mm resolution) of the most important cortical abnormalities? Second, how does deep brain stimulation (DBS) in movement disorders disrupt cortical synchronization and what is the time course of this disruption and its behavioral sequelae? Third, can effects of acute and chronic DBS on cortical function be studied non- invasively? To address these, in intraoperative recordings we utilize a touch screen based binary choice task that separates movement planning from movement execution. We introduce high spatial resolution subdural recording grids (28 channel), to ask where are the cortical "hot spots" of greatest physiologic abnormality. To address effects of DBS on cortical synchronization noninvasively, we will utilize scalp EEG at several time points in the outpatient setting, based on the surprising and novel finding that cortical PAC is detectable in scalp EEG. Cortical physiology is a primary focus of these studies, since in the prior grant period we found that cortical signals are more sensitive to disease state than basal ganglia LFPs. The impact of these studies will be to: 1) Provide a more detailed understanding of abnormal cortical synchronization in PD and dystonia, informing new models of network abnormalities in these disorders. 2) Provide a mechanistic understanding of the effects of therapeutic DBS on cortical and basal ganglia function. 3) Create a foundation for the development of a closed loop deep brain stimulation, which could utilize a clinically practical cortical signal for automated control of stimulation parameters.

Public Health Relevance

How do basal ganglia diseases affect the cortex, and how do therapies such as deep brain stimulation improve cortical function? Here, we address these questions by recording brain activity in patients undergoing placement of brain stimulators for Parkinson's disease and dystonia. A better understanding of the circuit abnormalities and circuit effects of therapy in these disorders will lead to improvements in brain stimulation therapy, such as devices that automatically suppress abnormal brain activity using a cortical sensor for feedback control.

National Institute of Health (NIH)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Sieber, Beth-Anne
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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