PFC circuits and systems in human intraoperative neurophysiology

摘要

Abstract Parkinson's disease (PD) is an increasingly prevalent progressive neurodegenerative disorder that in most patients eventually leads to disabling non-motor symptoms including significant speech, and cognitive dysfunction. These impairments can dramatically reduce quality of life for patients and their families. Importantly, few treatments exist that can effectively treat these non-motor effects. Furthermore, treatments like dopaminergic medications and deep brain stimulation (DBS) that are generally effective at improving the motor function of people with PD, are very often ineffective at improving speech and cognition. In many cases, these treatments can even worsen those functions. Prefrontal cortex (PFC) is known to be key to effective human speech and cognitive function. However, many questions remain about how human PFC is affected by PD, and how these disease-specific effects result in disrupted speech and cognitive function. To address these knowledge gaps and in order to optimize and develop better treatments for those living with PD, it is necessary to better understand the role of PFC in speech and cognition. Here we study 20 PD patients who have chosen to undergo bilateral subthalamic nucleus (STN) DBS implantation surgery to leverage this special opportunity to directly record from PFC sites during speech and cognitive tasks during surgery. In addition, we will simultaneously record from STN, as it is known to be connected to PFC and modulated by those brain regions. To complement the detailed anatomical and temporal resolution of direct PFC and STN brain recordings and effective connectivity measures between these cortical and subcortical regions, participants will also be assessed with detailed structural, functional, and connectivity MRI imaging studies. Scans will be obtained before and three months after surgery so all areas of PFC, in both cerebral hemispheres can be assessed with speech and cognitive tasks. In addition, we will collect PFC tissue samples in these participants during their surgery to examine gene expression. Gene expression profiles related to dopamine and cholinergic pathways and language will be quantified. To our knowledge, this feasibility data will be the first of its kind to evaluate participants with PD before, during, and after surgery with the goals of defining the role of PFC and its interactions with STN in speech and cognitive function. Such knowledge will provide mechanistic insights that cannot be obtained using other techniques and will guide development of new studies and hopefully eventually treatments of impaired speech and cognition in PD.