Daniel S. Barth - US grants

Because of a number of unique properties of neuromagnetic fields, magnetoencephalography (MEG) promises to be a valuable tool for the non-invasive study of epileptic phenomena in man and animals. Neuromagnetic measures have recently been applied to the practical localization of epileptic foci in the three dimensional cranial space of patients with focal seizure disorders. Yet, the capacity of MEG to measure intracellular currents, and to record both rapid and extremely slow changes of these currents, make MEG not just a practical localization tool but a means of noninvasively studying the cellular mechanisms of epilepsy. To realize this potential, we propose to study penicillin epilepsy in the rat. Three initial experiments are proposed to establish an empirical foundation for the neurogenesis of neuromagnetic fields in epilepsy. In these studies, the relationship between magnetic field strength and the size of the epileptic focus, the orientation of magnetic fields and cells within the focus, and possible contributions of secondary sources will be examined. The fourth experiment examines the relationship between magnetic field patterns and known intracellular currents produced by direct cortical stimulation, for comparison to the fields of penicillin epilepsy. The remaining experiments draw upon this empirical data to explore the intracellular currents of interictal spiking, rapid seizure spiking, slow ictal field shifts, and possible interictal standing fields. This work will introduce an entirely new area of biomagnetism, animal magnetometry. The empirical foundation for the neurogenesis of neuromagnetic fields established in this work will substantiate the interpretation of all studies in the growing field of neuromagnetism. Exploratory studies in the magnetic fields of penicillin epilepsy will serve as a necessary starting point for future neuromagnetic studies of the cellular mechanisms of epilepsy. Finally, the investigation of slow and standing fields in the rat may introduce a powerful new method of localizing and studying seizure foci in patients with focal seizure disorders.

The magnetoencephalogram (MEG) is a recently developed method of noninvasively localizing and studying the summed intracellular currents of epileptic paroxysms in animal and man by mapping the extracranial magnetic fields that they produce. The long-term goal of this project is to use models of epilepsy in animal cortex to establish an empirical basis for the neurogenesis of epileptiform magnetic fields in man, and to combine MEG with detailed electrical recording to obtain information about the intra and extracellular currents produced by excitability changes in the in vivo epileptic neocortex. The present project will study a more complex cobalt focus in the more realistic gyrencephalic cortex of miniature swine. Our goal is to reduce the ambiguity and increase the realism of analytical solutions derived from physiological modeling of noninvasively recorded epilepsy data. We will approach this problem in three ways. First, we will combine information from both MEG and electroencephalogram (EEG) in all modeling procedures. Second, instead of simply comparing the results of modeling to the geometry of underlying anatomy, we will incorporate information about the location and shape of gyri and sulci into the modeling solutions directly. Finally, we will selectively filter data in both space and time to isolate contributions to the total system variance from sharp versus slow wave activity, and from focal versus regional activity respectively. We will evaluate and improve the accuracy of these modeling solutions by comparing them to detailed quantitative information about the intracranial distribution of cellular currents, information obtainable only invasively from an animal preparation. The results of this work will not only provide insights into membrane excitability changes that result in epileptic seizures, but will also be directly relevant to the interpretation of extracranial magnetic fields measured from normal and epileptic human neocortex.

DESCRIPTION (provided by applicant): While there has been increasing recognition of the importance of microglial and astrocyte activation in the creation & maintenance of diverse enhanced pain states, an important aspect of glial functioning that has not yet been explored in the context of pain enhancement is the effect of a sensitized, or primed, microglial response. Evidence has accrued from outside of the pain field that the past history of microglial activation can dramatically alter their response to new challenges. Microglia can reach a primed state via a variety of challenges, including peripheral or central trauma/inflammation, stress, prior pain, and exposure to opioids, which strikingly are known co-morbidities for the transition of acute to chronic pain, including neuropathic pain. While in such a primed state, microglia now dramatically over-respond to new challenges, stronger and longer than before. We believe such prior challenges that result in glial priming can set the stage for the transition of acute to chronic pain following peripheral & central neural damage, resulting in chronic neuropathic pain. Re-activation of primed microglia may lead to a transition from acute pain to chronic pain as a result of a neuroinflammatory response that is greatly amplified in both magnitude and duration. Goals. (1) In accordance with the specified goals of this RFA, develop new rat models to study the transition from acute to chronic neuropathic pain, based on the premise that a first challenge (Hit 1: peripheral or central trauma/inflammation, stress, prior pain, exposure to opioids) will markedly enhance pain induced by a subsequent (second) challenge (Hit 2: peripheral or central neural inflammation/injury). (2) Utilize the refined robust models to test the potential of non-opioid, non-addictive blood-brain barrier permeable glial activation inhibitors & resolvins to prevent the transition of acute to chronic pain. (3) Given the remarkably powerful positive effects produced by chronic voluntary exercise in creating resiliency to a multitude of negative outcomes (including constraining glial/immune reactivity), chronic voluntary exercise will also be tested for its ability to prevent the transition from acute to chronic pain, an approach enabled by teaming with an expert from outside the pain field (M. Fleshner). (4) Discover intracellular changes that differentiate rats which do vs. do not transition from acute to chronic neuropathic pain, & define how these potential cellular markers of impending chronic pain are affected by successful interventions (glial inhibitors, voluntary exercise). This will lay the groundwork for identifying and targeting changes reliably predictive of the transition of acute to chronic neuropathic pain.