Within the past decade, deep brain stimulation that delivers microsecond duration electric pulses to specific brain regions via surgically implanted electrodes has become an established treatment for movement disorders (e.g., Parkinson's disease, tremor and dystonia) in patients who either do not respond to drug treatment or else experience unacceptable drug side effects. Other potential clinical applications of deep brain stimulation include treatment of epilepsy, pain and neurological disorders such as depression. My research builds on the growing clinical acceptance of electric stimulation for neuromodulation by focusing on a new type of electric stimulus, high intensity (> 1 megavolt-per-meter), nanosecond duration electric pulses, as an emerging technology for altering neural cell excitability. In a highly interdisciplinary collaborative effort that involves other researchers at the School of Medicine, the College of Engineering, and the Research Center for Bioelectrics at Old Dominion University (Norfolk, VA), I have been exploring the effectiveness of nanoelectropulses less than 10 ns in duration for evoking neurosecretion. Using adrenal chromaffin cells as a model of neural-type cells, we found that a 5 ns, 5-6 megavolt-per-meter electric pulse causes activation of voltage-gated calcium channels, which leads to calcium influx and the exocytotic release of the catecholamines epinephrine and norepinephrine. This secretory response not only mimics the stimulation of catecholamine release evoked in vivo by the neurotransmitter acetylcholine but also occurs in the absence of deleterious cellular effects. We are currently elucidating how such an ultra-short electric stimulus is capable of evoking neurosecretion via voltage-gated calcium channel activation. Preliminary evidence points to a novel mechanism, namely reversible membrane depolarization that depends on the transient formation of sodium-conducting nanopores in the plasma membrane lipid bilayer. Thus, our hypothesis is that a nanoelectropulse causes the plasma membrane lipid bilayer to assume a role typically ascribed to protein ion channels, ion conductance that leads to membrane depolarization. The research spans the disciplines of neurobiology, electrophysiology, biophysics, physics and engineering where experimental approaches, such as patch clamp and fluorescence imaging for monitoring cellular responses, are integrated with electro-physical computational approaches, in particular cell modeling and molecular dynamics simulations that can elucidate on a nanosecond time scale how the electric field interacts with the plasma membrane and how the membrane behaves under the influence of such an ultrashort, high intensity electric field. Another major goal of the research is to assess further the potential use of nanoelectropulses for modulating neurosecretion by establishing patterns of pulse delivery (pulse number versus pulse rate) that are effective for evoking reproducible effects on catecholamine release without causing adverse effects. The hope is that the research will be critical to the future development of an electrostimulation approach that is less invasive (does not require surgical implantation of electrodes) than the one currently used for neuromodulation, and that it will also result in new strategies for modulating the activity of other types of excitable cells.
Lecturer in the following graduate courses: