Neural Substrates of Switching in Parkinson's Disease

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The focus of the proposed work is to determine the underlying neural substrates of task switching deficits in Parkinson's disease (PD) and to link these dysfunctions with behavioral impairments in everyday life. Although PD was initially considered a motor disorder, deficits in cognitive function contribute significantly to the hallmark signs of PD. However, there is a lack of consensus regarding the pathophysiology of these deficits primarily because of the diversity of tasks previously studied and the challenge of separating the cognitive aspects, such as task switching, from motor execution. Task switching is the ability to make a change in the plan (switching from one response option to another, e.g. pressing one button vs. another) and switching can be externally generated, based on environmental stimuli, or internally or self-generated. We have chosen to study motor planning, specifically switching, because it is a critical part of normal motor behavior and is intimately intertwined with the motor deficits associated with PD. Our HYPOTHESIS is that the planning of these aspects of switching behavior relies on separate basal ganglia (BG)-thalamocortical circuits that are differentially affected by PD. SPECIFIC AIM 1 is to test the prediction that PD-related behavioral deficits in internally generated and externally cued switching are correlated with individual BG-thalamocortical circuits that are differentially affected by PD. SPECIFIC AIM 2 is to determine if parkinsonian switching deficits and related abnormalities in BG-thalamocortical activity are correlated with the hallmark signs of PD such as bradykinesia, as well as impairments in daily activities including verbal fluency and gait initiation. We have designed a behavioral task that will allow us to dissociate not only motor planning from execution, but also internally vs. externally generated switching. We will measure patterns of cortical activation and synchronization with functional magnetic resonance imaging and magnetoencephalography, respectively, to obtain complimentary anatomic and physiologic views of switching dysfunctions in PD. Further, we propose to provide a link between the abnormal brain activity of PD and difficulties in everyday life. SIGNIFICANCE: While cognitive abilities are an integral part of normal motor behavior, our developing appreciation of cognitive dysfunction in PD has not yet been incorporated into standard clinical practice. Cognitive symptoms differ among parkinsonian patients, change over the course of the disease, and may be differentially affected by dopamine replacement, yet the treatment across patients is similar. Our results can be used to inform target-specific drug development, direct tailored cognitive neuro-rehabilitation, and evaluate emerging PD treatment options. 2.