The Hours of Changing Responsiveness or Susceptibility

THE HOURS OF CHANGING RESPONSIVENESS OR SUSCEPTIBILITY* ALAIN REINBERG, M.D., PkDj J During the last several years knowledge ofOrcadian rhythms in animals and in man has been marked by considerable progress which clearly indicates the fundamental importance of these rhythms for medicine and biology. Since the work ofBünning [?] on plant life and that ofPittendrigh [2, 3], Halberg [4-6], and Aschoff [7, 8] on animals and man, it is no longer possible to regard circadian rhythms, in particular, and biological rhythms, in general, as having an exclusively exogenous origin and, more precisely, as being reacquired by each individual in each generation. The results ofexperimental research suggest: (1) At aU levels oforganization , rhythmic activity appears as one ofthe fundamental characteristics of Uving [9, 10]. (2) Within certain limits, the period, amplitude, and timing ofcircadian rhythms can be influenced by the cycUc variations of certain environmental factors—the alternation ofday and night, hot and cold, noise and silence, and, in man, the hours ofwork and ofrepose tied up with the duties ofsocial life. These factors are caUed "synchronizers" by Halberg fu] and Halberg, Visscher, and Bittner [12], "entxainingagents " by Pittendrigh and Bruce [13], or "Zeitgeber" by Aschoff [14]. The three terms are synonymous: They are aU defined to indicate that the environment is a "clock or calendar time-giver" whüe physiologic timing * Lecture presented at the annual meeting ofthe American Association for the Advancement of Science (American Physiological Society), Washington, D.C, December 28, 1966. t Maitre de Recherches au Centre National de la Recherche Scientifique. Address: Laboratoire de Physiologie, Fondation A. de Rothschild, 29, Rue Masin, Paris íceme France. X The extension to man ofthe concept ofthe hours ofchanging resistance has been made under close scientific co-operation between the University of Minnesota and the Centre National de la Recherche Scientifique. I would like to express my deep gratitude to Dr. Franz Halberg, professor ofexperimental pathology. University ofMinnesota, Minneapolis, for his encouragement and advice. Special thanks are due to Dr. ConstantineJ. Falliers, director ofChildren's Asthma Research Institute and Hospital, Denver, and to Dr. Nathan S. Kline, director ofpsychiatric research, Rockland State Hospital, Orangeburg, New York, for their advice concerning parts ofthis text. Ill per seis given (persists) in the absence ofobvious external synchronization. Under the conditions ofour daily life, when the alternation ofactivity (in Ught) and rest (in darkness) is tied to relatively regular hourly imperatives , the period ofour circadian rhythms is, on the average, twenty-four hours. FoUowing certain manipulations ofthe organism, "average" circadian periods are found in body temperature, gross motor activity, and adrenal cortical hormone levels in blood that (a) differ from precisely twenty-four hours, (b) differ from one animal to the next, and for which (c) environmental cycles with the same frequency are not known. Such circadian periods that are desynchronized from the local twentyfour -hour clock time also have been found in children studied on "selfdemand " [15-17], in schizophrenic patients in a state of"regression" after electroshock [18], in men studied in an "isolator" speciaUy constructed to eUminate known synchronizers [19], and even during several months of Ufe in a cave in the absence ofknown time cues [20-24]. Under ordinary conditions of Ughting as well as in isolation without synchronizers, certain phase relations among the circadian rhythms themselves are consistently maintained; this finding ofa so-caUed internal synchronization with differences in phase leads to the concept of circadian systems [25]. This concept serves as the theoretical background for analyzing the responses of organisms as a function of the so-caUed circadian system phase, in order to coUert information ofpharmacologic, physiologic , and medical interest. The resistance ofan animal to a threat offixed kind and intensity varies dramaticaUy as a function ofthe time at which the organism is exposed to the stimulus. The threat can be ofa chemical nature, as an overdose ofdrugs, or it can be a toxic substance ofvegetable or bacterial origin. Alternatively, it can be a physical agent, such as the noise to which "(geneticaUy susceptible)" rodents are exposed. What seems more important to medicine, the reactivity of human beings to certain drugs and other substances has also been documented as being circadian-system phase dependent. A considerable...