Aysegul Gunduz - US grants

The human brain consists of numerous networks distributed over space and connected over time to orchestrate meaningful interaction with the external world. Neurological disorders disrupt this interaction, as well as our control over our bodies. Deep brain stimulation (DBS) has emerged in the nineties as a neurosurgical intervention for the treatment of movement disorders. The principle behind DBS is to implant electrodes into deep brain structures and to inject electrical pulses to suppress pathological brain activity. The clinical personnel that perform programming of stimulation settings however, base their decisions on the observable patient responses rather than a scientific understanding of the underlying pathology, or the physiological response to stimulation. The PI's proposed effort includes studying the neural signatures of movement disorders, and the aftereffects of stimulation to provide insight into treatment options that can be tailored to the current clinical condition of the patient. Responsive DBS is expected to provide improved symptom suppression, reduce adverse effects of continuous stimulation, and prolong battery life of DBS implants. This project will also provide students in the PI's lab with an environment that promotes learning in the design of neural engineering systems, data collection in clinical settings, and analysis of large-scale datasets. All of these skills are prolific to the development of translational medicine applications for those suffering from disabilities, and to the education of the next generation of biomedical engineers.

The overall research goal of this project is to study the electrophysiological underpinnings of neurological disorders using next generation DBS devices capable of recording brain signals in humans, in order to responsively deliver stimulation to the current pathological state of the brain. To this end, the PI is investigating the neurophysiology of Tourette syndrome, which affects an estimated 3 to 9 school-age children in 1000, and to develop responsive DBS systems for its improved and targeted treatment in humans. Online classifieres will be built to detect involuntary tics that characterize Tourette syndrome from neural activity in the centromedian nucleus of the thalamus and the motor cortex. The input-output relationship between DBS parameters and neural activity will be studied to build inverse adaptive controllers that will yield optimal stimulation parameters. The knowledge gained from this project and the established platform can be extended to other movement disorders. The overall objective of the educational plan is to increase interest and engagement in STEM fields and to proliferate the study of engineering through a series of focused educational activities at the K-12, undergraduate, and graduate education levels.

The project will be co-funded by the Activation and Modulation Programs in the Neural Systems cluster of MCB and, therefore, is eligible for BioMaps co-funding.

PROJECT SUMMARY Essential tremor (ET) is an incurable, degenerative brain disorder that results in increasingly debilitating tremor, and afflicts an estimated 7 million people in the US (2.2% of the population). While the economic impact of ET is indeterminate, it is surely quite substantial. In one study, 25% of ET patients were forced to change jobs or take early retirement because of tremor. ET is directly linked to progressive functional impairment, social embarrassment, and even depression. The tremor associated with ET is typically slow (~5 Hz), involves the hands (and sometimes the head and voice), worsens with intentional movements, and is insidiously progressive over many years. Deep Brain Stimulation (DBS) has emerged as a highly effective treatment for intractable, debilitating ET. However, since the intention tremor of ET is typically intermittent, and commonly absent at rest, the currently available continuous DBS may be delivering unnecessary current to the brain that increases undesirable side effects such as slurred speech and walking difficulty, and hastens the depletion of device batteries, necessitating more frequent surgical procedures to replace spent pulse generators. The overall objective of this early feasibility study is to provide preliminary data on the safety and efficacy of ?closed-loop? DBS for intention tremor using novel DBS devices capable of continuously sensing brain activity and delivering therapeutic stimulation only when necessary to suppress tremor. We will measure and compare the power usage and the assessment of side-effects with adaptive (closed-loop) vs. continuous (open-loop) DBS. In Aim 1, we will identify the neural correlates of movement intention in local field potential (LFP) recordings from subdural electrode arrays implanted over the premotor hand cortex. In Aim 2, we will first determine the neural correlates of hand tremor from the primary motor hand cortex and in the ventral intermediate (Vim) nucleus LFPs. We will then use these markers to actuate therapeutic DBS when intention and/or tremor is detected, and terminate DBS when absence of tremor is detected. These aims will be achieved using first generation Medtronic Activa PC+S devices, which are capable stimulation and recording simultaneously. The proposed project is expected to provide proof-of-concept for the first chronic closed-loop DBS system for the treatment of a debilitating movement disorder in humans. We expect that this project will also lead the way for future closed-loop adaptive DBS systems designed for other movement disorders.

? DESCRIPTION (provided by applicant): Tourette syndrome (TS) and disorders involving tic are highly prevalent and socially embarrassing. There are a group of TS sufferers with motor and vocal tics that are resistant to medication and behavioral intervention. Deep brain stimulation (DBS) has emerged as a highly efficacious treatment option for addressing motor and vocal tics in a select group of appropriately screened cases. The proposed research will directly address the important knowledge gaps in TS physiology and TS DBS. These gaps include a need to characterize the pathophysiological signals related to tics and the modulation of physiology by DBS therapy. In Aim 1, we will correlate individual tic expression with local fiel potential (LFP) activity in the human centromedian (CM) thalamic nucleus region and precentral gyrus (motor cortex) using next generation DBS devices capable of chronic LFP recordings. We will also study thalamocortical network interactions leading to tics. Our preliminary data from two subjects have revealed that low-frequency activity in the CM thalamus and beta rhythm suppression in the motor cortex correlate with the occurrence of tics, and that these features can be differentiated from the neural correlates of voluntary movements. In Aim 2, we will determine how LFP physiology changes following DBS therapy and clinical improvement. Our preliminary data from five subjects, treated with bilateral centromedian (CM) thalamic region DBS, (from recently completed NIH R34 and R21 grants) demonstrated the presence of both a measurable clinical effect and quantifiable physiological changes (decreases in low frequency power). Understanding how DBS modulates brain activity to reduce TS symptoms, could provide a neuromarker to guide clinical programming and potentially facilitate faster clinical relief. The overarching goal of the proposed project will be to generate the physiological dataset required to fill these knowledge gaps and to move the field toward responsive stimulation.

PROJECT SUMMARY Tourette syndrome (TS) is a continuous lifelong condition that is highly prevalent, socially disabling, and in some severe cases, physically injurious. DBS has emerged as a promising treatment option for addressing uncontrollable tics in medically resistant and severe cases of TS frequently involving self-injurious behavior. We have undertaken a major informatics initiative by establishing the International TS DBS Registry and Database, a multi-country consortium that has captured long term outcomes of 277 TS DBS patients representing 50-75% of all TS DBS cases worldwide. From these outcomes, two deep brain targets have emerged as potentially effective: the centromedian nucleus region (CM) of the thalamus, and the anterior globus pallidus internus (aGPi). However, our current understanding of tic generation is limited by many factors including a lack of animal models for TS, apparently normal brain structure on structural imaging, and the impracticality of studying involuntary motor tics with functional imaging. Next generation closed-loop DBS systems can record brain activity in patients with TS and identify the neurophysiological correlates of tics. Moreover, these devices can deliver stimulation in response to a patient's symptomatic state. Our overall goal is to develop neurophysiology driven and connectivity-guided closed-loop DBS systems for the improved treatment of TS. To this end, we will implant 8 medically resistant TS patients with bilateral leads in the CM and aGPi. In Aim 1, we will identify structural network projections from CM and aGPi to guide pre-operative surgical planning and post-operative selection of stimulation parameters. In Aim 2, we will identify neurophysiologic correlates of tic genesis in the CM and aGPi. We will also study thalamo-pallidal network interactions leading to and during tics. In Aim 3, we will test the feasibility, safety, and efficacy of closed-loop TS DBS. We expect that closed-loop stimulation will provide more effective and personalized treatment options with longer battery life and fewer adverse effects.