Deep Brain Stimulation (DBS) is a surgical procedure that is used to treat the debilitating symptoms of Parkinson's Disease (PD). In the process of surgically implanting the stimulating electrodes, surgeons and researchers have a unique opportunity to measure and manipulate the activity of individual neurons while the awake PD patient performs a perceptual, cognitive, or other kind of relatively simple task. These studies are important because they far surpass the spatial and temporal resolution of state-of-the-art human imaging techniques and can yield insights into the basic building blocks of higher brain function, and how those building blocks may be disrupted in PD. Our proposed studies take advantage of this opportunity to establish a novel and sustainable research program to identify mechanisms of decision-making at the single-neuron level. We target the Substantia Nigra, Pars Reticulata (SNr), an output nucleus of the basal ganglia (BG) that acts as a gating mechanism that suppresses unwanted eye movements but allows wanted ones. Because goal-directed eye movements are used to select and attend to features of the visual scene for further processing, their underlying mechanisms must incorporate rapid and sophisticated decision-making. Ours will be the first research program to systematically test the SNr's role in these decision processes. These studies will have a major impact because of our use of: 1) our established and high-volume infrastructure and clinical program to obtain reliable SNr recordings and apply microstimulation in awake, behaving patients undergoing DBS surgery; 2) a visual motion-saccadic decision (?dots?) task that has been used with PD patients and is amenable to the kinds of quantitative modeling approaches that we use regularly; 3) task manipulations that are differentially sensitive to PD-related deficits, allowing us to gain insights into normal and abnormal BG function; 4) complementary studies in non-human primates that act as critical, healthy controls; and 5) electrical microstimulation to test if and how the SNr can play a causal role in the decision process, even with the BG in a pathological state. The proposed project has three Specific Aims.
Aim 1 is to identify single-unit correlates of evidence accumulation and commitment in SNr of PD patients and monkeys.
Aim 2 is to identify single-unit correlates of speed-accuracy and choice-bias instructions in SNr of PD patients.
Aim 3 is to use electrical microstimulation to test for a causal role of the SNr in oculomotor decisions. Together, these Aims will form a solid foundation for a long-term program to understand how the dynamic response properties of individual neurons in the SNr and BG contribute to flexible decision-making. The use of complementary monkey studies is particularly noteworthy, allowing us to firmly establish the quantitative rigor and reproducibility of the human work. We will then build on this solid foundation to better understand the neuronal basis of normal decision-making, decision-making deficits associated with BG malfunction, and potential causes of and remedies to the cognitive side effects associated with DBS.

Public Health Relevance

Parkinson's Disease (PD) is one of several debilitating illnesses that attack brain mechanisms responsible for some of the basic building blocks of higher brain function, including some forms of decision-making. Our studies will take advantage of unique opportunities provided by Deep Brain Stimulation (DBS) surgery in PD patients to study these mechanisms at an extraordinarily fine scale. In the long run, these studies will yield new insights into the neuronal basis of normal decision-making, decision-making deficits associated with PD and other diseases, and potential causes of and remedies to the cognitive side effects associated with DBS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1)
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Gnadt, James W
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University of Pennsylvania
Schools of Medicine
United States
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