ABSTRACTParkinson's disease (PD) is the 2nd most common neurodegenerative disorder affecting over 1 million people inthe United States. PD causes difficulties with movements such as walking and speaking that occur because ofloss of the brain chemical dopamine. Current symptomatic PD treatments are based largely on dopaminereplacement therapies with L-DOPA; however these treatments have many long-term side effects which led tointerest in non-dopaminergic therapies. The most severe side effect is the development of L-DODA-induceddyskinesia (LID) involuntary movements that can be as or even more debilitating than the disease itself. Anyadjunct therapy extending the time frame where L-DOPA can be used without LID would be a major advance. Recent publications showed that low-dose ketamine infusion paradigms were safe and well tolerated inclinical trials for pain states (including migraine headaches) treatment-resistant depression and posttraumaticstress disorder (PTSD). Low-dose ketamine has led to a long-term reduction of pain states treatment-resistantdepression it also reduced PTSD symptom severity and comorbid depression. One commonality betweenmigraine headaches depression PTSD PD and LID is that electric activity in the brain is overly synchronizedand maladaptive plastic changes occur in the brain including in an area that is of interest in PD and LID calledthe basal ganglia (BG). Therefore we investigated the use of low-dose sub-anesthetic ketamine in the treatmentof PD and LID. We have evidence of a therapeutic effect of low-dose ketamine infusion from preclinical data ina rat model of LID (dose-dependent reduction of abnormal involuntary movements; long-term effects after asingle infusion-treatment) and from 5 PD patient case studies (reduced dyskinesia and reduced depression).In the rat LID model this effect was only seen when low-dose ketamine was given for 10 hours and not with justa single acute low-dose ketamine injection. The premise of the proposed studies to define mechanisms of thenovel use of low-dose ketamine is true bench to bedside science will provide the foundation for controlledclinical trials of low-dose ketamine treatment for LID and could identify new more specific therapeutic drugtargets to treat LID and depression two critical problems for many PD patients. Our main hypothesis is that alow-dose sub-anesthetic ketamine infusion desynchronizes overly synchronous oscillatory activity in nerve cellsinvolved in LID sufficiently to induce a lasting anti-dyskinetic effect working as a chemical deep brain stimulation(DBS). We hypothesize that ketamine works on the molecular level via 2 types of receptor molecules in the BGand cortex NMDA receptors and opioid receptors and that the long-term effect includes changes in nerve cellconnections called dendritic spines. A multidisciplinary team of researchers and a clinician with the necessaryexpertise will fill a critical gap in knowledge by investigating the mechanisms of this long-term effect of low-doseketamine infusion on the molecular and cellular level. They will study effects on receptors and changes in spinesize and density (Aim 1) and on the systems level investigate synchrony of oscillatory neural activity (Aim 2).