Biological oscillators, of which neurons are a special class, generate oscillations with characteristic frequencies and phases. These oscillations can be investigated from a topological perspective to identify regions (""""""""null spaces"""""""") into which they can be """"""""pushed"""""""" (or their phases reset), using DC stimuli delivered at a """"""""critical"""""""" time during their cycle. Conventional AC stimulation pulses are unsuitable for this purpose. Oscillations pushed into the """"""""null space"""""""" are annihilated, but phase resetting of """"""""finite magnitude"""""""" (phase delays or advances) are a common occurrence. The existence of this phenomenon has been convincingly demonstrated in neuronal and axonal preparations. The cathodal or anodal depolarization blocks and the recently described """"""""delayed responses"""""""" to single cathodal pulses delivered to human epileptogenic cortex, may in fact be examples of phase resetting. Preliminary results in our lab suggest that seizure onset may be consistently delayed, blocked or annihilated, but also precipitated, using DC stimulation, as a function of when in the cycle they are delivered. This proposal will investigate phase resetting as a tool for control of abnormal oscillations such as seizures, using: 1. Single DC (monophasic) pulses delivered automatically (in response to seizure detections) and directly to a discrete cortical region in rabbits that has been made epileptogenic with topical penicillin; 2. Transcranial continuous DC stimulation of rats with 3-MPA-induced generalized seizures; and, 3. Histopathologic effects of single DC pulses delivered to epileptogenic cortex, for which there is no literature. Electrical cortical activity will be recorded with high-precision DC amplifiers, since the long time constant of DC oscillations associated with seizures (several seconds to minutes) provide a unique opportunity to systematically and thoroughly scan their """"""""phase space"""""""", increasing the probability of locating the """"""""null space."""""""" The potential contributions of this study will be substantive: 1. It will provide insight into a phenomenon that plays a fundamental role in the pathophysiology of disorders of neuronal synchronization such as epilepsy and movement disorders; 2. It will provide scientific bases for developing successful therapies; 3. It will improve quality of life of those with these disorders and in the case of epilepsy it may decrease annual costs of care by $4.3B. The significant advances made in the control of fatal arrhythmias are in part attributable to the use by cardiologists of phase resetting as an investigative and therapeutic tool. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-BDCN-K (10))
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Jacobs, Margaret
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University of Kansas
Schools of Medicine
Kansas City
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Osorio, Ivan; Frei, Mark G; Sornette, Didier et al. (2010) Epileptic seizures: Quakes of the brain? Phys Rev E Stat Nonlin Soft Matter Phys 82:021919
Osorio, I; Manly, B; Sunderam, S (2010) Toward a quantitative multivariate analysis of the efficacy of antiseizure therapies. Epilepsy Behav 18:335-43
Osorio, Ivan; Frei, Mark G; Sornette, Didier et al. (2009) Pharmaco-resistant seizures: self-triggering capacity, scale-free properties and predictability? Eur J Neurosci 30:1554-8
Osorio, Ivan; Frei, M G (2009) Seizure abatement with single dc pulses: is phase resetting at play? Int J Neural Syst 19:149-56