Philip Starr - US grants

DESCRIPTION (provided by applicant: Dystonia is a movement disorder defined as a syndrome of sustained muscle contractions, causing twisting and repetitive movements, and abnormal postures. It is often devastating and its pathophysiology is poorly understood. Recently, attempts have been made to understand movement disorders in terms of alterations in a loop circuit involving the cortex, basal ganglia and thalamus. The globus pallidus internus (GPi) occupies a critical position in this circuit since it is the major output structure of the basal ganglia. Another movement disorder, Parkinson's disease (PD), has been found to be associated with excessive and abnormally patterned GPi activity. This finding has led to improved surgical treatments for PD by pallidal inactivation. In contrast to PD, a better understanding of dystonia has been hampered by a lack of data on the physiology of the basal ganglia in this condition, and by the lack of a well-characterized nonhuman primate model of dystonia. Both problems are addressed in this ongoing study. In the initial three years, we recorded and analyzed 283 pallidal units in 14 patients with dystonia, 74 units in a normal Rhesus macaque, and 75 units from four patients with Parkinson's disease. Human patients undergo electrophysiologic mapping as a routine part of pallidal surgery for movement disorders. We showed that, in comparison with normal macaque, dystonia is associated with reduced neuronal activity in the GPi in most but not all cases, increased bursting activity in GPi, and a slight reduction in activity in the external pallidum. These data lend support to a model of dystonia in which both direct and indirect pathways of the basal ganglia are overactive. However, some cases show little abnormality in discharge rate or pattern, motivating a continued search for a "signature" abnormality in dystonia. In addition, we began development of a model of focal arm dystonia in the Rhesus macaque, in which dystonia is generated by repetitive performance of a skilled motor task. In the proposed continuation, spontaneous and movement-related discharge in GPi will be studied in ten additional dystonia patients, with a new emphasis on neuronal responses to sensory feedback and cross correlation of simultaneously recorded cells. In the macaque model of dystonia, the effect on motor performance of lesioning the globus pallidus will be analyzed. The experiments test the following hypotheses: 1) Idiopathic dystonia in humans is associated with abnormal neuronal synchrony and abnormal responses to somatosensory examination in the GPi. 2) In non-human primates, dystonia induced by a repetitive arm movement task can be ameliorated by lesions of the GPi, establishing the relevance of this model to human idiopathic dystonias. These experiments should allow refinement of existing theories of the pathophysiology of dystonia, and provide a better rationale for pallidal surgery in dystonia. Development of an animal model in a large nonhuman primate will open the possibility for further detailed investigations of basal ganglia physiology in dystonia, beyond those which are possible during human surgery.

DESCRIPTION (provided by applicant): The goal of this project is to advance the understanding of movement disorders pathophysiology through studies of basal ganglia and cortical local field potentials (LFPs) in humans. The LFP represents synchronized sub- and supra-threshold activity in presynaptic terminals and postsynaptic neurons. Recent studies of subthalamic nucleus (STN) LFPs in Parkinson's disease (PD) produced a novel hypothesis: that parkinsonian bradykinesia is due to excessive basal ganglia synchronized oscillatory activity in the beta frequency range (13-30 Hz), and that suppression of beta oscillations is the mechanism for the effectiveness of STN deep brain stimulation (DBS). However, this framework leaves unanswered questions. Can the beta oscillation hypothesis be confirmed by comparison to subjects without movement disorders? Are excessive beta oscillations unique to PD, or are they associated with other movement disorders of basal ganglia origin? Are abnormal beta oscillations present in motor cortex as well, reflecting a network property of the basal ganglia-thalamocortical (BGTC) circuit? Here, we address these questions by comparing primary motor (M1) and primary sensory (S1) cortex LFPs in patients with a basal ganglia disorder (PD and primary dystonia), with two comparison groups without basal ganglia pathology (essential tremor (ET) and epilepsy). Movement disorders patients are studied while undergoing awake placement of DBS electrodes. Epilepsy patients are studied while undergoing inpatient video monitoring. We hypothesize that PD and dystonia both are characterized by broad beta band cortical activity which distinguishes these disorders from ET and from subjects without movement disorders. Our second major goal is to understand BGTC oscillations in primary dystonia, which has been less studied than PD. Our approach is simultaneous recording of STN and cortical LFPs in M1 and S1. We hypothesize: (1) Dystonic patients have an excess of high beta (21-30) and low gamma (30-55 Hz) oscillations in the STN during voluntary movement, while PD patients have predominant low beta (13- 20 Hz) activity, particularly at rest. 2.) Similar patterns are seen in M1 and S1, and in STN-cortical coherence. 3.) Movement related abnormalities in dystonia will be reproduced under conditions in which sensory feedback is activated. The novel features of this proposal are the use of electrocorticography in movement disorders, the introduction of a new target, STN, into the study of dystonia, and the analysis of cortex-basal ganglia interactions through simultaneous LFP recording in both areas. The proposed work should expand the framework for the "oscillation hypothesis" of PD to include the other major movement disorders, improve the rationale for choice of stimulation frequencies in DBS and could provide a basis for cortically based therapies for PD and dystonia. PUBLIC HEALTH RELEVANCE: The goal of this study is to improve the understanding of abnormal brain electrical activity in persons with movement disorders such as Parkinson's disease and dystonia. Patients are studied while undergoing routine neurosurgical treatment of their disorder by implantation of brain stimulators. Knowledge gained in this study may lead to simpler surgical therapies than those now available, and may help neurologists improve existing treatments by understanding how to program implanted brain stimulators more effectively.

? DESCRIPTION (provided by applicant): Our goal is to understand the motor network in movement disorders and the mechanism of therapeutic interventions in humans, at very fast time scales. Over the past five years we introduced the novel technique of combining subdural electrocorticography (ECoG) with basal ganglia recording and stimulation in persons undergoing neurosurgical treatment. From ECoG potentials, we can extract information about low frequency rhythms (such as the motor beta rhythm), or about population spiking activity (from high frequency broadband activity). Our prior work in acute intraoperative recording showed that: 1) a major abnormality of the motor cortex in Parkinson's disease (PD) is the excessive coupling of population spiking to the motor beta rhythm; and 2) acute therapeutic deep brain stimulation (DBS) reversibly alleviates this pattern of excessive synchrony. These findings provide a new foundation for understanding the cortical basis for impaired movement and the network mechanisms of antiparkinsonian therapies. However, critical questions remain that cannot readily be studied in the intraoperative setting: Does the mechanism of chronic therapeutic stimulation differ from that of acute stimulation? How do mechanisms of stimulation and levodopa compare? What are the network characteristics underlying dyskinesias? Here, we address these questions using a novel, totally implantable bidirectional neural interface that both delivers DBS and therapy and senses/stores ECoG or local field potentials (Aims 1 and 2). We record and download basal ganglia and cortical potentials at regular intervals in our outpatient clinic under well-defined behavioral conditions with expert characterization of motor function by movement disorders neurologists. In November 2013, we implanted the first such device for multisite (cortex and basal ganglia) recording in a Parkinson's disease patient, under a physician-sponsored protocol. Recording via ECoG has the advantage of excellent signal:noise characteristics and superb spatial and temporal resolution, but given its invasiveness is not amenable to normal controls. Therefore, in Aim 3 we address similar questions using a complementary, noninvasive technique, scalp electroencephalograph (EEG), based on our recent finding that measures of cortical population synchrony unique to PD are detectable by EEG and modulated by both oral levodopa and DBS. This approach allows us to study a large number of subjects and to include normal controls. The impact of these studies will be to: 1) Provide a more detailed understanding of abnormal network synchronization in PD, informing new models that better incorporate cortical function than past models. 2) Provide a mechanistic understanding of the effects of therapeutic DBS on cortical function. 3) Create a foundation for the development of closed loop deep brain stimulation, which could utilize a clinically practical cortical signal for automated control of stimulation parameters. Mechanisms elucidated in this study may be applicable to other network brain disorders where subcortical stimulation shows therapeutic promise.

Abstract Deep brain stimulation (DBS) has a major role in the management of movement disorders, and is under investigation for the treatment of disorders of mood and memory. In Parkinson's disease (PD), DBS of basal ganglia nuclei can improve motor signs and reduce medication-induced motor fluctuations and dyskinesia, characterized by frequent transitions between a hypokinetic state (too little movement) and a hyperkinetic state (too much movement). However, since the introduction of DBS for PD 25 years ago, there have been no major improvements in this therapy. Existing DBS devices deliver ?open loop? stimulation, continuously stimulating their target structures regardless of changes in the brain circuits related to disease expression. Device programming is a labor-intensive process based on ?trial and error? requiring significant clinical expertise, which is a barrier to widespread application. In PD, continuous open-loop stimulation may result in suboptimal control of fluctuating motor signs, stimulation-induced adverse effects, and short battery life. DBS could be significantly improved by delivering ?closed-loop? stimulation, in which stimulation parameters are automatically adjusted based on brain signals that reflect the patient's clinical state. Using both intraoperative and chronic invasive recording techniques, we and others have identified abnormal patterns of oscillatory activity that may provide physiological signatures or ?biomarkers? of hypokinetic and hyperkinetic states in PD. Here, we plan to develop closed-loop DBS algorithms based on these brain signals, using an investigational neural interface (Medtronic Activa RC+S) that can sense and store brain activity as well as delivering DBS. We will determine which brain signals are the most appropriate to optimize DBS therapy and answer critical questions including the site of control signal detection (cortical versus subcortical) and the required complexity of control signals (single frequency power versus cross frequency interactions). Ten PD patients with motor fluctuations and dyskinesia will be implanted bilaterally with Activa RC+S attached to a subthalamic nucleus (STN) DBS lead and an electrocorticography (ECoG) lead placed over motor cortex. We will collect ECoG and subcortical local field potential (LFP) recordings to characterize ?personalized? physiological signatures for each subject and prototype stimulation paradigms by data streaming through an external computer in a clinical setting (Aims 1 and 2). We will then embed algorithms in the pulse generator to implement chronic and fully closed-loop DBS in a small double-blinded clinical trial (Aim 3). Motor function will be assessed by wearable automated detectors as well as rating scales from videotapes and self-report instruments. The study will define the technical characteristics required for the design of future DBS devices. ?Self programming? DBS devices offer the potential to simplify the therapy and allow many more patients to receive DBS. As electrophysiological signatures of abnormal circuit function in other disorders are identified, this new generation of closed-loop devices will facilitate the introduction of novel DBS therapies in other brain diseases. .

Summary Invasive neurostimulation is an established technique in the therapy of movement disorders and epilepsy, and shows promise for amelioration of psychiatric and cognitive disorders. Recently, several implantable neurostimulation hardware platforms have begun to incorporate sensing of cortical and subcortical field potential activity, with the capability for wireless streaming from the internal device to external computers over years. These high temporal and spatial resolution signals may be used for discovering the circuit basis of brain disorders, developing new therapies rationally derived from circuit analysis, and developing adaptive (feedback controlled) neurostimulation paradigms in which the device auto-adjusts according to changing brain needs. The most recent ?second generation? implantable devices, such as Summit RC+S (Medtronic), have substantially improved capabilities and offer great flexibility for novel uses, at the expense of increased complexity. However, effective use of this and related platforms requires academic investigators to develop previously unfamiliar capabilities, including programming of the desired device functions using an ?application programming interface?, and documenting the performance and validation of software according to FDA device regulations. While many BRAIN Initiative funded grants intend to use these second generation bidirectional interfaces, the four institutions on this proposal, working together, are the only groups that have surmounted the technical and regulatory barriers to launching clinical protocols with second generation sensing devices. We have formed the ?Open Mind? neural communications consortium to share technical and regulatory infrastructure with each other and with new investigators, and begun to disseminate this knowledge at open meetings for new investigators, at the April 2018 and 2019 Brain Initiative Meetings. Through this proposal, we will greatly expand these technology dissemination activities, to provide investigators with elements critical to the launch of their own clinical studies: A ?turnkey? user interface to get started that includes open source software elements for neural sensing at home and for adaptive stimulation, and a streamlined regulatory pathway for FDA approval of investigational protocols, which we call the ?Open Source Quality Management System?. We will disseminate education and resources through biannual workshops and a web-based library of regulatory documents, software, and the Quality Management System. Our team represents the major clinical areas of interest in neuromodulation: movement disorders (UCSF), epilepsy (Mayo Clinic), and psychiatry (Brown/Baylor), and includes experts in the design and dissemination of implantable devices (Oxford). This consortium will facilitate already funded proposals, as well as entry of new investigators, in the rapidly evolving ecosystem of implantable wireless neural interfaces. Two new clinical teams have already begun to work with our neural sensing interface in preparation for their own clinical trials of adaptive stimulation, demonstrating readiness of tools for dissemination.

Invasive neurostimulation is a promising therapy for psychiatric disease, but with contemporary neurostimulation techniques, many patients in recent clinical trials have been nonresponders. For improved efficacy, invasive therapies in psychiatry may require a more advanced circuit-level understanding of these disorders, so as to target specific patterns of abnormal neural activity. In support of this concept, short term invasive recordings have revealed potential physiological biomarkers of specific psychiatric symptoms such as depression and anxiety. Signal discovery and circuit analysis will be further facilitated by newly available, chronically implantable, neural interfaces that can both deliver neurostimulation and wirelessly stream sensed electrical activity to external computers. These devices ? such as the responsive neurostimulaor (RNS, Neuropace) or Summit RC+S (Medtronic) have great potential for longitudinal correlations of psychiatric symptoms with neural activity. However, the permanently implantable cortical leads currently available to attach to these interfaces pose technical barriers to easy, safe surgical placement and signal discovery. Available cortical recording leads have a low channel count (4 contacts) low spatial resolution (1 cm), and are mechanically inflexible, precluding access to many cortical areas. Here, we address this problem by designing, fabricating, and testing cortical leads with mechanical properties favorable for the passage of leads through minimally invasive exposures. Testing will involve both benchtop tests and short term intraoperative human testing. Two lead designs will be fabricated and tested, one with lower channel count for multisite cortical recording, another with double the currently available channel count (8 contacts) and improved spatial resolution. These leads are designed to attach to Summit RC+S, under collaborative agreement with the neural interface manufacturer. The PIs bring complementary expertise to this project: electrical engineering with a specialty in brain lead fabrication; and neurosurgery/neurophysiology with a specialty in acute and chronic cortical recording (electrocorticography) for detection of physiological signatures of brain disorders. After this 2 year grant period, we expect to pursue biocompatibility testing and FDA approval for permanent implantation, and commercialization. The proposed work will facilitate the deployment of newly available neural interfaces, both for circuit analysis and for the development of ?adaptive stimuluation?, in which neural signals are used to autoregulate stimulation parameters, to respond to changing brain needs and reduce stimulation- induced adverse effects.

PROJECT SUMMARY Many pain syndromes are notoriously refractory to almost all treatment and pose significant costs to patients and society. Deep brain stimulation (DBS) for refractory pain disorders showed early promise but demonstration of long-term efficacy is lacking. Current DBS devices provide ?open-loop? continuous stimulation and thus are prone to loss of effect owing to nervous system adaptation and a failure to accommodate natural fluctuations in chronic pain states. DBS could be significantly improved if neural biomarkers for relevant disease states could be used as feedback signals in ?closed-loop? DBS algorithms that would selectively provide stimulation when it is needed. This approach may help avert the development of tolerance over time and enable the dynamic features of chronic pain to be targeted in a personalized fashion. Optimizing the brain targets for both biomarker detection and stimulation delivery may also markedly impact efficacy. Recent imaging studies in humans point to the key role of frontal cortical regions in supporting the affective and cognitive dimensions of pain, which may be more effective DBS targets than previous targets involved in basic somatosensory processing. Pathological activity in the anterior cingulate (ACC) and orbitofrontal cortex (OFC) is correlated with the higher-order processing of pain, and recent clinical trials have identified ACC as a promising stimulation target for the neuromodulation of pain. In this study we will target ACC and OFC for biomarker discovery and closed-loop stimulation. We will develop data-driven stimulation control algorithms to treat chronic pain using a novel neural interface device (Medtronic Activa PC+S) that allows longitudinal intracranial signal recording in an ambulatory setting. By building and validating this technological capacity in an implanted device, we will empower DBS for chronic pain indications and advance personalized, precision methods for DBS more generally. We will enroll ten patients with post-stroke pain, phantom limb syndrome and spinal cord injury pain in our three-phase clinical trial. We will first identify biomarkers of low and high pain states to define optimal neural signals for pain prediction in individuals (Aim 1). We will then use these pain biomarkers to develop closed-loop algorithms for DBS and test the feasibility and efficacy of performing closed-loop DBS for chronic pain in a single-blinded, sham controlled clinical trial (Aim 2). Our main outcome measures will be a combination of pain, mood and functional scores together with quantitative sensory testing. In the last phase, we will assess the efficacy of closed-loop DBS algorithms against traditional open-loop DBS (Aim 3) and assess mechanisms of DBS tolerance in response to chronic stimulation. Successful completion of this study would result in the first algorithms to predict real-time fluctuations in chronic pain states for the delivery of analgesic stimulation and would prove the feasibility of closed-loop DBS for pain-relief by advancing implantable device technology.