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Photo of Mark Stewart

Mark Stewart, M.D., Ph.D.

Professor

Physiology and Pharmacology, Neurology

Dean, School of Graduate Studies, Vice Dean for Research

Tel: (718) 270-1167 • e-mail: mark.stewart@downstate.edu


Seizure activity in the limbic cortices and its spread through brain to impact systemic physiology

We use a number of approaches to address questions about how seizures can occur, how they spread through cortical and sub-cortical brain areas, and what the ultimate impact on the other body organs may be. The most serious consequence is sudden death.

Our lab has two broad research emphases related to the causes and consequences of seizures. One approach uses brain slices to study cellular and circuit mechanisms of seizure generation, and the other approach uses in vivo methods (animals, humans) to study seizure spread and systemic consequences of seizures.

Over the last several years, we have developed a rat model that mirrors features of seizures and systemic pathology found in temporal lobe epilepsy patients and has permitted us to explore and define the cardiovascular and respiratory consequences of acute and chronic seizures, including the mechanisms for death in epilepsy. Our use of peripheral nerve recordings together with blood pressure, ECG, echocardiography, laryngoscopy, plethysmography, and EEG recordings during seizure activity has enabled us to define peripheral autonomic nerve activity and the extremes of activity that can cause severe brady- or tachyarrhythmias, and central or obstructive apnea.

Our rat model is unique in that we can elicit acute limbic cortical seizures during a battery of neural, cardiovascular, and respiratory recordings and measurements. The result of this body of work is that we have defined the mechanism for sudden death in epilepsy (SUDEP) to be seizure induced laryngospasm that causes obstructive apnea, rapid hypoxemia, respiratory arrest, cardiac arrest, and death. We also have demonstrated that this sequence includes biomarkers that link the human data and our model precisely.

Our work has enabled the development of tools and strategies to prevent death. In addition to biomarkers that can be used to signal the "death sequence" has started, we have derived other interventional devices from our work is the vagus nerve stimulation-based cardioverter/defibrillator. It is an example of how our work can drive practical therapeutic applications as one means for translating research from bench to bedside.


Selected Publications

Sakamoto, K., Saito, T., Orman, R., Koizumi, K., Lazar, J., Salciccioli, L., and Stewart, M. (2008). Autonomic consequences of kainic acid-induced limbic cortical seizures in rats: peripheral autonomic nerve activity, acute cardiovascular changes, and death. Epilepsia 49, 982-996, 2008.

Hotta, H., Koizumi, K., and Stewart, M. (2009). Cardiac sympathetic nerve activity during kainic acid-induced limbic cortical seizures in rats. Epilepsia 50, 923-927.

Hotta, H., Lazar, J., Orman, R., Koizumi, K., Shiba, K., Kamran, H., and Stewart, M. (2009) Vagus nerve stimulation-induced bradyarrhythmias in rats. Auton. Neurosci. 151, 98-105.

Hotta, H., Watanabe, N., Orman, R., and Stewart, M. (2010). Efferent and afferent vagal actions on cortical blood flow and kainic acid-induced seizure activity in urethane anesthetized rats. Auton. Neurosci. 156, 144-148.

Naggar, I., Uchida, S., Kamran, H., Lazar, J., and Stewart, M. (2012). Autonomic boundary conditions for ventricular fibrillation and their implications for a novel defibrillation technique. J. Physiol. Sci. 62: 479-492.

Naggar, I., Nakase, K., Lazar, J., Salciccioli, L., Selesnick, I., and Stewart, M. (2014). Vagal control of cardiac electrical activity and wall motion during ventricular fibrillation in large animals. Auton. Neurosci. 183, 12-22.

Naggar, I., Lazar, J., Kamran, H., Orman, R., and Stewart, M. (2014). Relation of autonomic and cardiac abnormalities to ventricular fibrillation in a rat model of epilepsy. Epilepsy Res. 108, 44-56.

Nakase, K., Kollmar, R., Lazar, J., Arjomandi, H., Sundaram, K., Silverman, J., Orman, R., Weedon, J., Stefanov, D., Savoca, E., Tordjman, L., Stiles, K., Ihsan, M., Nunez, A., Guzman, L., and Stewart, M. (2016). Laryngospasm, central and obstructive apnea during seizures: defining pathophysiology for sudden death in a rat model. Epilepsy Res. 128, 126-139.

Villiere, S., Nakase, K., Kollmar, R., Silverman, J., Sundaram, K., and Stewart, M. (2017). Seizure-associated central apnea in a rat model: evidence for resetting the respiratory rhythm and activation of the diving reflex. Neurobiol. Dis. 101, 8-15.

Stewart, M., Kollmar, R., Nakase, K., Silverman, J., Sundaram, K., Orman, R., and Lazar, J. (2017). Obstructive apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones. Epilepsia, in press.

List of Publications (Pub Med)


Personnel

Rena Orman, Ph.D., Research Assistant Professor


Service Functions

Co-director, Program in Nanomedicine (a joint program with the College of Nanoscale Science and Engineering, Albany, NY)

Co-director, Program in Developmental Neuroscience (a joint program with the Institute for Basic Research, Staten Island, NY)



E-mail: mark.stewart@downstate.edu

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