General Methodologies Utilized

For animal experiments, the first choice an investigator must make is the experimental animal model. The majority of epilepsy studies are conducted in rodents,

TABLE 12.2

Selected Organizations and University Research Centers Devoted to Rhythms Research

Name and address Brief description

Society for Research into Biological Rhythms University of Virginia Department of Biology Gilmer Hall

Charlottesville, VA 22903

Society for Light Treatment and Biological Rhythms

10200 W. 44th Avenue, Suite 304

Wheat Ridge, CO 80033-2840

Biological Rhythm Research

Department of Physiology

University of Leiden

2300 RC Leiden The Netherlands San Diego Sleep and Rhythms Society Research Service 151 Veterans Affairs Medical Center 3350 La Jolla Village Drive San Diego, CA 92161

Chronotherapeutics

Searle Corporation

5200 Old Orchard Road

Skokie, IL 60077

NSF Center for Biological Timing

Department of Biology

University of Virginia

Charlottesville, VA 22903

Center for Circadian Biology & Medicine

Northwestern University

Evanston, IL 60208

Medical Chronobiology Lab Stratton Veteran's Medical Center 113 Holland Avenue Albany, NY 12208

Chronobiology Research Department of Biology Texas A&M University College Station, TX 77840

Major society organized to investigate research on rhythms from unicellular organisms to humans; Journal of Biological Rhythms is a bimonthly publication of the society

Society primarily devoted to understanding rhythms research in humans

Journal for European Society for Chronobiology

Local society to coordinate rhythms research in the San Diego area

Information on circadian effectiveness of pharmaceuticals

A regional center established by the National Science Foundation for the study of biological rhythms

Midwestern center for the study of circadian biology

Veteran's center chronobiology group

Chronobiology research at Texas A&M University is highlighted

Note: The majority of these groups have internet sites that can be accessed using available search engines.

with rats and gerbils predominating.183839 Other species, including cats and primates, are also used in epilepsy studies.40 When the specific animal model is chosen, the animals are acquired and allowed to acclimate to the housing conditions. As mentioned earlier, the housing conditions must remain constant throughout any experiment that attempts to investigate rhythmic processes. If a rhythm in seizure severity is under investigation, the researchers would place all of the animals in the same conditions and produce the seizures at specific times throughout the light:dark cycle, usually at intervals of 4 h or less.38 The time points that occur in the dark portion of the light:dark cycle are conducted in the dark with the aid of a dim red light (Kodak, Safelight, Rochester, NY) or the use of infrared night vision goggles (IR Goggles, Electrophysics, Nutley, NJ). The investigators must determine whether the same animals can receive multiple seizures throughout a 24-h period (a within-animal design) or whether different animals should be used for each seizure induction (a between-animal design). It is recommended that a between-animal design be used, due to the long-term postictal refractory period that may affect subsequent seizure responses. The results from studies of this type would determine if a diurnal rhythm in seizure severity exists, but would not indicate whether this rhythm is endogenous to the animal or is controlled by exogenous factors, such as the light:dark cycle.

A second experiment is necessary to determine if the rhythm is endogenous and circadian. The same species of animals would be placed in constant darkness and another rhythm, such as activity, would be measured to determine that the subjects were not entrained to any outside influences, but were free running. After a free running rhythm is established, the animals would receive the seizure stimulus at 4-h intervals throughout a 24- to 48-h period. Again, a 24-h curve to seizure induction can be generated. The rhythm in seizure severity found in both experiments can be compared and correlated to determine if the seizure rhythm is endogenous and circadian.

Utilizing the rhythm of seizure severity, the time of peak seizure production can be determined. This time point could be of interest to researchers exploring cellular mechanisms of seizure production and propagation by providing the proper time to examine these mechanisms (providing the largest window of response to experimental treatments). Conversely, the time of least seizure production could also be used to investigate the endogenous processes that limit seizure severity.

This same methodology can be used to investigate diurnal/circadian differences in anticonvulsant effectiveness. The results from studies of this type allow the administration of anticonvulsant compounds at the proper time for optimal control of seizures. It should be stressed that any treatments that increase or decrease seizure expression may have rhythmic components and that conclusions reached on the efficacy of these treatments may only be true at specific times of the day.

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