An Introduction to Contingent (Closed-Loop) Brain Electrical Stimulation for Seizure Blockage, to Ultra-short-term Clinical Trials, and to Multidimensional Statistical Analysis of Therapeutic Efficacy * † Ivan Osorio, † Mark G. Frei, ‡ Bryan F. J. Manly, † Sridhar Sunderam, † Naresh C. Bhavaraju, and †§ Steven B. Wilkinson *Comprehensive Epilepsy Center, § Department of Neurosurgery, University of Kansas Medical Center, Kansas City, Kansas; † Flint Hills Scientific, Lawrence, Kansas; ‡ Western EcoSystems Technology, Inc., Cheyenne, Wyoming, U.S.A. Summary: Automated seizure blockage is a top research priority of the American Epilepsy Society. This delivery modality (referred to herein as contingent or closed loop) requires for implementation a seizure detection algorithm for control of delivery of therapy via a suitable device. The authors address the many potential advantages of this modality over conventional alternatives (periodic or continuous), and the chal- lenges it poses in the design and analysis of trials to assess efficacy and safety—in the particular context of direct delivery of electrical stimulation to brain tissue. The experimental designs of closed-loop therapies are currently limited by ethical, techni- cal, medical, and practical considerations. One type of design that has been used successfully in an in-hospital “closed-loop” trial using subjects undergoing epilepsy surgery evaluation as their own controls is discussed in detail. This design performs a two-way comparison of seizure intensity, duration, and extent of spread between the control (surgery evaluation) versus the experimental phase, and, within the experi- mental phase, between treated versus untreated seizures. The proposed statistical analysis is based on a linear model that accounts for possible circadian effects, changes in treatment protocols, and other important factors such as change in seizure proba- bility. The analysis is illustrated using seizure intensity as one of several possible end points from one of the subjects who participated in this trial. In-hospital ultra-short- term trials to assess safety and efficacy of closed-loop delivery of electrical stimulation for seizure blockage are both feasible and valuable. Key Words: Ultra-Short-term— Closed-loop—Seizure blockage—Detection. INTRODUCTORY PERSPECTIVE Epilepsy is the most prevalent serious neurologic dis- order across all age groups. Approximately 1% of the United States population has the disorder (Hauser et al., 1996), and 25% of these patients do not respond to drug therapy and have disabling side effects (Dichter and Brodie, 1996). Furthermore, although surgery is a valu- able alternative to drugs in carefully selected cases, the majority of patients with uncontrolled epilepsy will not have access to surgical therapy because of (1) the marked limitation in availability of human and technical re- sources, (2) its inherent high technical complexity and cost, and (3) the inability, in a relatively large number of patients, to resect epileptogenic tissue either because of its ubiquity or the resulting disabling deficits. Given Address correspondence and reprint requests to Dr. Ivan Osorio, Comprehensive Epilepsy Center, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160. Journal of Clinical Neurophysiology 18(6):533–544, Lippincott Williams & Wilkins, Inc., Philadelphia © 2001 American Clinical Neurophysiology Society 533