John D. Rolston, M.D./Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Epilepsy is a debilitating disorder for millions of Americans, and many are not helped with medications or resective surgery. New therapies are needed. The laboratory of Dr. Steve Potter has recently shown that epileptic activity in neuronal cultures is completely blocked by low-current, low-frequency stimulation from an array of small electrodes. Simultaneously recording neural activity and using it to modify stimulation voltages-that is, using closed-loop feedback to control stimulation-allowed even lower voltages and slower frequencies to block the seizure-like events. The current proposal will extend these findings to live rodents with chronic, spontaneous seizures. Specifically, it is proposed to investigate parameters for effective microstimulation in vivo (using a custom-built stimulator and recording suite), in both normal and epileptic brains, and attempt to suppress epileptiform activity in vivo with both distributed stimulation and closed-loop stimulation. Lastly, since the proposed method relies on recorded action potentials from multiple individual cells, it is proposed to investigate the relation of this single cell activity to the classical seizure measure, the electroencephalogram (EEC), along with local field potentials recorded from high impedance microwires. The methodology uses 32-channel microwire arrays, chronically implanted in the hippocampi or sensorimotor cortex of adult rats, made epileptic with microinjections of tetanus toxin in the same region. The arrays record both cellular action potentials and EEG-like field potentials during the chronic, spontaneous seizures the rodents exhibit. A custom-built stimulator allows simultaneous recording and stimulation from the same implanted set of electrodes. [unreadable] PUBLIC HEALTH RELEVANCE: Many patients with epilepsy continue to experience seizures despite our best medical therapies. Our lab has shown that small arrays of electrodes, recording and stimulating with a state-control algorithm, can completely suppress epileptic activity in cultured brain tissue. This proposal will investigate this treatment in animal models of epilepsy, to validate its safety and efficacy, before beginning clinical trials. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Only a few parts of the brain appear utterly essential for human speech. Damage to these few, unique areas is therefore devastating. When patients develop focal lesions like brain tumors or epileptic foci that must be surgically removed, great care must be taken to avoid injuring nearby, normally functioning speech areas. The gold-standard technique by which speech areas are preserved during neurosurgical procedures is direct electrical stimulation of the brain. Essentially, a small probe is slowly advanced over the brain surface, delivering brief trains of electrical stimulation, while an awake patient speaks. Areas where stimulation stops speech-that is, causes speech arrest-are deemed essential for speech and left intact. Other quiet areas are thought safely removed. Yet despite how often this technique is used, we do not understand how it works. Speech arrest sites are highly variable from person to person. Their size, shape, and distribution are irregular. Yet their existence offers an important clue for the physiology underlying normal speech. Why are speech arrest sites special? Why are they located where they are? What role do they serve in normal speech production? Our research aims to answer these questions. We will use novel, high-density electrocorticography (ECoG) to record brain activity during normal speech production in patients undergoing epilepsy surgery. We have already used similar arrays to find maps of speech articulation in the human brain. We hypothesize that speech arrest sites will be found within these same articulation maps. We also hypothesize that speech arrest sites will be privileged in their functional connectivity to other speech-producing regions. Both aims will be achieved by first identifying the location of speech arrest sites in awake, behaving patients, and then determining the sites' role in articulation maps and determining their functional connectivity with other sites within the same maps. This work uses new technology to answer longstanding questions about speech. Ultimately, this work will not only help us understand the physiology of speech, but will also enable improved prediction of surgical morbidity and improved mapping of eloquent cortex prior to surgical resection. Such improvements will directly benefit patients with brain tumors, epilepsy, and disorders of language.

The most common burden of epilepsy, reported by epilepsy patients themselves, is the lack of predictability of their seizures. While seizures occur infrequently and are unpredictable, interictal epileptiform discharges (IEDs) are isolated epileptiform discharges between seizures that can occur relatively frequently; up to several times per second. While IEDs are associated with epilepsy, little is known about the underlying physiology of IEDs and the relationship between IEDs and seizures remains a mystery. The overall goal of our research proposal is to understand the spatial propagation of IEDs and their relationship to the seizure core with the potential for evaluating spatial and neuronal properties of IEDs as predictive tools for localizing when and where a seizure happens. The significant barriers to studying the relationship between IEDs and seizures in humans stem from the low resolution of clinical recordings, which also makes these recordings difficult to compare to more mechanistic studies of IEDs in animals. We will address this gap by examining thousands of IEDs recorded from microelectrode arrays in 11 human epilepsy patients. These arrays subsample approximately the same area recorded by a standard clinical electrode with 96 penetrating microelectrodes. The density of these arrays and their ability to record single unit activity will allow us to translate between clinical intracranial EEG and single human neuron activity. We propose to understand IED neurophysiology relative to the seizure onset zone via the following three Specific Aims. Aim 1 will elucidate how IEDs travel across the cortex, relative to the location of the seizure onset zone. We hypothesize that IEDs will propagate towards the seizure onset zone and will become more consistent as a seizure approaches. Aim 2 will focus on understanding neuronal firing and high frequency LFP correlates of IEDs in order to determine a correlate of distance from the seizure onset zone. Together, these aims will improve our understanding of the neurophysiology of IEDs and how physiological features of IEDs relate to the seizure onset zone. Any reduction in uncertainty that can be gleaned about seizure occurrence from IEDs will be highly valuable for epilepsy patients? everyday lives. These experiments will therefore be important for understanding the neuronal and spatial properties of IEDs, which will aid in the diagnosis and treatment of medically refractory epilepsy.

PROJECT SUMMARY/ABSTRACT Direct cortical stimulation of the brain is used to treat epilepsy and map brain function during surgery. Yet few patients are free of seizures with this treatment, and morbidity occurs despite ostensibly adequate mapping. When cortical stimulation is used, it is assumed that the area nearby the electrode, within a few centimeters, is most affected. But our prior work shows that stimulation evokes widespread effects in distant regions of the brain. Understanding these network effects will be key in improving our use of brain stimulation. Using patients with electrodes implanted in the brain for epilepsy treatment, I will investigate cortical stimulation by 1) using resting-state functional connectivity to predict evoked potential characteristics, 2) using detailed computer models of patient brains to predict the responses of stimulation, and 3) correlating the networks activated by stimulation with patient outcomes following NeuroPace Responsive Neurostimulator placement. I am a practicing neurosurgeon and neuroscientist with a career devoted to understanding electrical stimulation of the brain. I was trained as a computer scientist and have relied heavily on this skillset during my PhD and post-doctoral training. For my PhD, I designed the hardware and software for a closed-loop neurostimulator, and applied this system to epilepsy research. During my post-doc and residency in neurosurgery, I studied the basis of electrical stimulation mapping using high-density electrocorticography. While in industry, I worked as lead software engineer for a company designing closed-loop stimulation/recording technology for multielectrode arrays. Now, as a functional neurosurgeon, I use multielectrode stimulation and recording daily in my patients. Network imaging and computer modeling of stimulation will provide new ways to understand and restore brain function. Such modeling goes beyond the empirical data that most researchers collect, and that most of my prior research has focused on. To develop these models, I will work with an expert in neuromodulation modeling, Dr. Christopher Butson, at the University of Utah. I will acquire these skills through hands-on training, didactic coursework, and intensive mentoring. At the end of my training, my hope is to create an independent research program to further link brain stimulation with an understanding of brain networks, and use these insights to improve the safety and efficacy of the direct cortical stimulation I use in my patients.