Helen M. Bronte-Stewart - US grants

disease /therapy duration; nervous system disorder therapy; human therapy evaluation; Parkinson's disease; brain electronic stimulator; electrostimulus; thalamic nuclei; subthalamus; clinical research; human subject;

PROJECT SUMMARY Freezing of gait (FOG) in Parkinson?s disease (PD) results in unpredictable episodes of gait cessation, which may lead to falls, injury, a loss of independent living, and even death19. The treatment of FOG is inconsistent with either dopaminergic medication or with current open loop, continuous high frequency deep brain stimulation (cDBS)15, 25. Emerging technology using non-continuous, closed loop or adaptive DBS (aDBS), has the potential to improve treatment for FOG. Adaptive DBS can sense patient specific neural and/or kinematic signals and respond by adjusting DBS parameters to provide more efficacious therapy while reducing adverse side effects known to occur with cDBS. The critical barriers of using aDBS for FOG are the lack of knowledge of: the neural features of FOG that could be ?sensed? by aDBS to trigger stimulation, the optimal, patient specific DBS parameters for the treatment of FOG, and whether aDBS for FOG is safe and tolerable in human PD patients. In the Bronte-Stewart Lab, we have the technology, the regulatory approvals and the research experience collecting synchronized neural and quantitative kinematic signals, applying different DBS parameters for FOG, performing the first aDBS experiments in freely moving PD subjects. The Bronte-Stewart Lab was the first group and Stanford was the first site in the United States to implant a sensing neurostimulator for PD, the Activa® PC+S (Medtronic Inc., FDA IDE/Stanford IRB approval, October 2013). This comprised the FDA approved neurostimulator (Activa PC®, Medtronic Inc.) with additional software that enabled recording of brain signals via telemetry from the neurostimulator itself. We have implanted twenty PD patients (largest cohort in the world), from whom we have been collecting synchronized neural and computerized kinematic signals for over thirty months without adverse events. We will use this new technology in conjunction with our expertise in quantitative kinematics and validated measure of FOG to begin understanding the neural features associated with FOG. In addition, we will use quantitative measures of FOG to accurately determine the efficacy of patient specific stimulation parameters for effective and consistent treatment of FOG. No center has had the technological capability to test the safety and feasibility of aDBS for FOG in freely moving PD patients. Whether patients can tolerate aDBS, which continually adjusts output to control a time-varying patient-specific neural signal as they are walking and moving freely is completely unknown and will be assessed in a pilot study in this proposal. This project is expected to signal the beginning of a new era of precise medicine: the possibility to treat FOG in PD in a customized, adaptive manner, while minimizing adverse effects and complementing the treatment of other disabling motor features of PD such as tremor.

Gait impairment and Freezing of gait (FOG), lead to falls, injury (even death), loss of independent living, and are common in neurodegenerative diseases such as Parkinson?s Disease (PD), affecting over 7 million people worldwide. The incidence of neurodegenerative diseases increases with age and as the population lives longer, the societal consequences of FOG, will be very significant. Gait impairment and FOG have a partial response to medication and subthalamic nucleus (STN) open loop deep brain stimulation (olDBS), which cannot adjust therapy in response to underlying brain signals or motor symptoms such as FOG. One reason is that FOG may respond to different parameters of DBS, such as lower frequency, than that needed for tremor and most patients do not tolerate 60 Hz DBS for long periods of time. Emerging technology using sensing neurostimulators and Bluetooth enabled wearable sensors has allowed research into closed loop or adaptive (a)DBS using neural or behavioral control variables. FOG is episodic and usually occurs in predictable environments, so it is well suited for ?on demand? aDBS. ADBS, responding to markers of gait impairment and intermittent FOG, with changes in DBS intensity or frequency, could then prevent FOG, falls and injury, while still treating other motor signs of PD. From over four years of research and regulatory experience in an academic-industry collaboration with Medtronic, we have provided design inputs for the next generation aDBS devices, and have determined that aDBS for tremor and bradykinesia is safe and tolerable in the largest freely-moving PD cohort implanted with a Medtronic investigative neurostimulation/sensing system (Activa® PC+S-Nexus D/D3/E). We have discovered neural and behavioral markers of gait impairment and FOG using synchronized neural and kinematic recordings during gait tasks that elicit FOG. Our research findings and the technological advances embedded in the Medtronic Summit® RC+S-system now enable the next step: the first clinical studies of lateralized, independent, bilateral STN aDBS control algorithms for FOG in PD, driven by subject-specific neural (Aim 1) or behavioral (Aim 2) control variables, and in response to medication (Aim 3). The project will translate stepwise in a ?bench to bedside? manner, testing aDBS during the stepping in place (SIP) task, where the subject is in a harness and steps in place on dual force-plates. Then aDBS will be tested during the forward walking Turning and Barrier Course, which mimics environments known to trigger FOG in the real world, and then how aDBS responds to subject-specific doses of medication, while freely moving. The outcome of these experiments will provide critical next-steps for safety and feasibility of testing aDBS for gait impairment and FOG in the subject?s home environment, and on their normal medication. Patient safety, tolerability, adverse effects, gait parameters, and the number and duration of freezing episodes (FEs), during no DBS, olDBS, aDBS and a control, intermittent (i)olDBS will provide inputs for future devices and novel algorithms applicable to NaDBS or KaDBS for gait impairment and FOG in other neurological diseases.