Kip A. Ludwig, Doctorate - US grants

PROJECT SUMMARY Subthalamic nucleus (STN) deep brain stimulation (DBS) is a common surgical treatment for Parkinson?s disease (PD). Despite over 20 years of clinical success, the therapeutic mechanisms of STN DBS remain elusive. However, it has become clear that DBS acts at the molecular, cellular, and systems levels in complex and sometimes contradictory ways. Current techniques such as electrophysiology, electrochemistry, and functional imaging commonly used to study pieces of this puzzle are limited in either resolution or behavioral paradigms these can be applied to, and have thus not provided all the information needed to parse out the complicated relationships between stimulation and evoked effects. Here, we propose the use of fluorescence calcium microscopy in GCaMP6f-expressing rats using a head-mounted miniature single photon system as a novel tool to bridge the gap between cellular and system level understanding of DBS in awake behaving animal models of PD. To this end, we will analyze neural activity changes in motor cortex evoked by stimulation of the STN during open field, stepping, cylinder tests, and apomorphine-induced rotations, all of which are stereotypical tests that have shown predictive validity for evaluation of movement and therapeutic efficacy in parkinsonian animals. The techniques proposed here provide a unique approach for answering questions about DBS mechanisms such as whether DBS-induced activation or pharmacologic inhibition of excitatory STN glutamatergic neuronal projections to the globus pallidus internus / substantia nigra reticulata produces detectable changes in motor cortex activity associated with changes in behavioral outcomes (e.g., open field, kinematic assessment of stepping, cylinder, and apomorphine-induced rotation tests).

Project Summary/Abstract: Clinical trials targeting the reduction of amyloid-? and hyperphosphorylated tau load have been largely unsuccessful against neurodegenerative diseases including Alzheimer?s (AD) and AD-related dementias (ADRD). This may be due to the relatively late stage at which they are deployed, wherein cognitive symptoms are already manifest and the underlying inflammatory and degenerative processes are well underway. Conversely, prophylactic intervention aims to prevent or mitigate initiation of harmful, self-propagating disease processes before they become uncontrollable. For a treatment to be used prophylactically, ie before the presence of significant symptoms, it must be ?trivially invasive?, simple to use, and inexpensive. This is critical for the expected benefits when deployed before symptoms to outweigh the potential risks. In this supplement, we propose a novel application of the minimally invasive InjectrodeTM technology outlined in the parent award to treat pain, to target brain waste clearance and cerebral hemodynamics through cranial nerve stimulation as a potential prophylactic strategy to combat AD. The Injectrode consists of a polymer matrix which is liquid in a syringe but quickly cures into a solid form when injected into the body. This technology offers many advantages over traditionally made electrodes amenable to prophylactic use including minimally invasive implantation (a simple injection). The successful completion of these aims would provide pilot data demonstrating the Injectrode concept can be utilized to improve the clearance of molecules within the brain, while identifying likely physiological components driving CSF/ISF interchange for future optimization.