Prefrontal Cortex, Cognition, and Speech Symptoms in PD (PRECIS-PD)

Abstract Parkinson’s disease (PD) impairs not only movement, but also cognition and speech. As PD progresses, cognitive and speech symptoms become increasingly prevalent, heavily compromising quality of life and often leading to loss of independence and placement in nursing homes. Few interventions improve these dehumanizing aspects of PD, and current therapies for motor symptoms, such as levodopa and deep brain stimulation (DBS), do not improve, and can even worsen cognition and speech. To mitigate these deficits, a better understanding of the basic mechanisms leading to abnormal cognition and speech in PD is needed. The prefrontal cortex (PFC) is critical for goal-directed planning of temporally sensitive behavioral sequences essential for cognition and speech. In PD patients, the PFC is thinned, and our published work demonstrates that PFC 4 Hz rhythms are decreased. Furthermore, PD involves diverse pathophysiological processes such as disrupted dopamine, acetylcholine, and synuclein. There is a critical need to understand how PD disrupts the PFC and leads to cognitive and speech symptoms. This knowledge will inspire new biomarkers and targeted treatments for non-motor symptoms of PD. The goal of the proposed Exploratory Grant is to catalyze novel collaborations that will lead to an Udall Center of Excellence. We will test the overall hypothesis that decreased dopamine-dependent PFC 4 Hz activity impairs cognition and speech in PD. We will identify cellular and circuit mechanisms underlying PFC function and dysfunction in preclinical rodent models and in human PD patients. We will harness complementary and convergent cutting-edge techniques, such as cell-type-specific 2-photon imaging of the PFC in behaving animals, human intraoperative neurophysiology, brain imaging, and brain connectivity. Common research themes focus on the PFC in cognitive and speech symptoms of PD, neuronal oscillations, and neuronal circuits. Specific synergies among projects include our molecularly- defined circuits, shared analytic tools, and the temporal organization of cognitive and speech functions disrupted in PD. We propose an Exploratory Grant. Project 1 will focus on cellular and circuit mechanisms of PFC 4 Hz rhythms in rodents. Project 2 will focus on PFC circuits and systems in human intraoperative neurophysiology. Project 3 will focus on Multi-modal analysis of human PFC in cognition and speech in PD. The proposed research plan leverages our world-class clinical infrastructure at The University of Iowa Parkinson’s Foundation Center of Excellence and catalyzes new synergies around cognition and speech, which are greatly understudied facets of PD. Our work will lead to new targeted therapies for those suffering from PD.