### VOLUME 55 NUMBER 12

DECEMBER, 1984



## ScienceandTechnologyCommittee:1984~Selected ReviewPaper 

# A Review of Human Physiological and Performance Changes Associatedwith Desynchronosis of Biological Rhythms

CHARLESM. WINGET,B.A., PH.D., CHARLESW. DEROSHIA,B.S., M.A., CAROLL. MARKLEY,B.A., M.A., and DANIELC. HOLLEY,M.S., PH.D.

Biomedical Research Divison, NASA-Ames Research Center, Moffett Field, California, and Department of Biological Sciences, San Jose State University, San Jose, California

WINGETCM, DEROSHIACW, MARKLEY CL, HOLLEY

DC. A reviewofhumanphysiologicalandperformancechangesassociated withdesynchronosisofbiologicalrhythms. Aviat. SpaceEnviron. Med. 1984;55:1085-96. Thisreview discussesthe effects, inthe aerospace environment, of alterations in approximately 24-h periodicities (circadian rhythms) upon physiological and psychological functions and possible therapiesfordesynehronosis induced bysuchalterations. The consequences of circadian rhythm alteration resulting from shift work, transmeridian flight, or altered day lengths are known as desynchronosis, dysrhythmia, dyschrony, jet lag, or jet syndrome. Considerable attention is focused on the ability to operate jet aircraft and manned space vehicles. The importance of environmental cues, suchas light-dark cycles, which influence physiological and psychological rhythms is discussed. A section
on mathematical models is presented to enable selection and verification of appropriate preventive and corrective measures andto better understand the problem of dysrhythmia.


# A LTERATIONS OF CIRCADIAN rhythms, or approximately24-h periodicitiesinphysiological andpsychologicalfunctions,aswellaspossibletherapies for desynchronosis, are emphasized in this review. It focuses on the consequences for humans in the
aerospace environment of alterations of their daily cycles. These alterations are known as desynchronosis, dysrhythmia, dyschrony, jet-lag, or jet syndrome. In the last few decades, research concentrated on humans during tong-distance air and space travel. Considerable attention was focused on the ability to operate jet aircraft and manned space vehicles. The

Reprintrequeststo: CharlesM. Winget,BiomedicalResearch Division(239/7),NASA-AmesResearchCenter,MoffettField,CA 94035. C.L.MarkleyandD.C.HolleyarewithSanJoseStateUniversity. ThismanuscriptwasreceivedforreviewinApril, 1984. It was acceptedforpublicationasareviewarticleinMay,1984. importance of environmental cues, such as light-dark cycles, which influencephysiological and psychological rhythms,became apparent. Aerospace transportation exposes the traveler to environmental signals that are shifted in time. Flightrelated disturbances of both single biological rhythms andtheusualsynchronyamongseveral oftheserhythms

can be deleterious to physiological functioning and performance (9,44,47). Adverse effects on performance and well-being, includingdigestivedisturbancesandgeneralmalaise,were noted soon afterhumans began rapid transmeridian air travel. Although the normal oscillations in various physiological systems and performance tasks had been described in detail as early as 1931, it was Post and Gatty (76) who recognized physiological changes associated with transmeridian flight as a potential problem to aviators. A more scholarly treatment of thisphenomenonappeared about20yearslaterandwas published in thisjournal by Strughold (95). The desynchronizedindividualmayexperience states ofirritability, disorientation or confusion, distortion of time and distance, aches ofvarious types, digestiveupsets which include constipation, decrements ofphysical and mental efficiency, and disturbances in sleep habits (9,47). Although the primary consequence is fatigue (9,38,47), research has been plagued by problems of definition, measurement, and interpretation of fatigue (23,47). Ithasbeen suggestedthattheterm "fatigue"be replaced by more explicitphysiologicalcriteria, such as sleep loss or neural inhibition, by performance criteria such as performance decrement, or by psychological criteria such as impaired mood (23,47). The potential safety hazards of sleepiness and fatigue induced by circadian desynchronymay be of serious consequence

Aviation,Space,andEnvironmentalMedicine9 December,1984 1085HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

among airline pilots, astronauts, cosmonauts, and their supporting crews. Dysrhythmia is not considered a life-threatening illness (e.g. three females and over 150 males have survived periods up to 185 consecutive days in the space environment); however, dysrhythmia may

cause major bodily functions such as sleep onset, hunger, and defecation to occur at inappropriate times for variable periods. Such functions may become asynchronous in airline crews and millions of airline
passengers. Although definitive statements concerning the magnitude of aerospace effects on the human circadian systemcannot be made because ofthe paucity of actual flight data, disturbances ofbiological rhythms

are generally accepted as being responsible for the observed performance decrements. Rhythmic desynchronization among future Space Shuttle and Space Station crew members has the potential to create major problems for scheduling work and rest within the team. This is especially true if the shuttle can beretrofitted tocarryas many as 10persons,

as recently suggested by Rockwell International. In the present-day spaceflight environment, imposed 24- h schedules frequently conflict with physiological and psychological rhythms, altering work-rest periods from normal, ground-based sleep and wake cycles. The
consequencesofsuch conflictsare still largelyunknown. Biological rhythms are not to be confused with the discredited so-called biorhythms of a 23-d physical cycle, a 28-d emotional cycle, and a 33-d intellectual cycle (47,55), which have given rise to charts, books, and calculators to pinpoint propitious or unpropitious days according to the individual's date of birth. The biorhythm theory is much too simplistic to account for the complexities of everyday life, because it postulates that biorhythm cycle period lengths are constant from the moment of birth and are identical between individuals with the same birth date.



### ConceptsofBiological Rhythms Rhythmicity has been observed in all eukaryotes, from unicellular organisms to humans. Postulated

causes of rhythms are: 1) oscillations dependent

on rhythmic impulses received from the environment (exogenous), or 2) self-sustained oscillations (endogenous). The daily rise and fall of mammalian body temperature provides a classic example of the latter type. The interval of the oscillation to complete

one cycle is known as its period. The spectrum of biological periodicity includes ultradian rhythms with periodslessthan 20h, circadian rhythms withperiodsof about 24h, and infradian rhythms with aperiod greater than 28h (40). The rhythm waveform has many characteristics. The amplitude isthe distance from the mean value to either the peak or the trough. The phase refers to the time reference point on the cycle. Phase is sometimes expressed in degreeswith oneperiod equal to 360~
. The acrophase is the time to the maximal value (peak or crest) ofthe best fitting sine curve to the raw data. A phase shift means that a reference point of either the biological rhythm or the environmental cue has been somewhat advanced or delayed in time, while the period length remains relatively constant. Throughout this review references will be made both to shifts in the biological rhythms (dependent variable) and to the environmental cues (independent variable). In spaceflight and transmeridian flight, there is a phase shift in the rhythms of both the social and the environmental (e.g. daylight) factors. The groundbased time-shifted worker usually only experiences sustained changes in the environmental cues, whereas the predominant social cues (e.g. family activities) remain constant. Phase adjustment refers to the extent to which a physiologic parameter follows a phase shift of the synchronizer (environmental or internal cue). The largest possible phase shift is by a half a period (180~ Ifthe rhythm is symmetrical, the former maximum will correspond to the new minimum. This is described

as a reversal of phase. Perfect adjustment requires that the physiologicalparameter shiftsthe same number of hours as the synchronizer, retaining the original waveform and phase relationship. Early in the phase shiftprocesses, the circadian amplitude and waveshape
may significantly change. This commonly occurs during what is called the transient rephasal period. The acrophase isusually quicker to adjust than the through

or period length.



### Entrainment

Considerable experimental evidence indicates that circadian time measurement in multicellular systems is

a product ofself-sustaining oscillations generated within the organism (75). At leasttwomajoroscillatorscontrol bodyrhythms. They are normally coupled together and entrained byenvironmental cues. Circadian rhythms are thus endogenous and autonomous and are synchronized by external cues. Such synchronizers entrain the temporal position of the rhythm peak, establish the period, and influence the amplitude. Photoperiod, or the ratio oflight hours to darkness, is considered to be

a primary synchronizer, or Zeitgeber (the phase setter
or, literally, the time giver). However, in humans, other environmental factors (e.g..social interactions)
may override light and other secondary synchronizers (e.g. temperature) (110). In studies where all environmental conditions remain constant, humans have separate, individually synchronized, free-running circadian rhythms of body temperature, activity, urinary variables, and performance on various tasks. Even though the different rhythms are not always in phase, their periods are all approximately 25 h (110,113). The phase relationship between bodytemperature and activity differs dramatically in free-running and entrained conditions. In the 24-h day, when rhythms are entrained bythe light-dark cycles, temperature peaks near the end of the activity period; when night is indistinguishable from day bythe absence of environmental cues and rhythms are free running, temperature peaks about 90~(i.e. 6 h) earlier relative to activity (110). In vertebrates, the many physiological oscillating parameters are synchronized with one another as well

1086 Aviation, Space, and Environmental Medicine ~December, 1984HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

as with the Zeitgeber. It is not always clear, however, whether a particular rhythm is entrained by another rhythm within the organism or by the Zeitgeber. This complex of coupled circadian oscillations, with peaks occurring at different but well-defined times within the 24-h day, is referred to as the circadian phase
map. It is necessary to maintain a constancy of phase relation among the rhythms for optimal functioning by the various physiological systems. For example, acrophases of corticotropin-releasing hormone (CRH), ACTH, and adrenal glucocorticosteroids are temporally coupled starting with a CRH peak in the middle of the sleep period. This coupling increases the arousal level and stimulates metabolic processes, preparing the organism for the activities of the day. This pattern culminates with heart rate, locomotor activity, body temperature, and other metabolic rhythms peaking in afternoon to late evening.

Shift Work

Shift workers exhibit continual perturbation in their circadian phase relationships resulting from alterations in their sleep-wake cycles. These altered schedules often conflict with their relatively stable, prevailing social Zeitgebers. Circadian desynchronization in shift workers is often manifested by various psychosomatic complaints including fatigue, sleep disturbances, and gastrointestinal problems (9). In a study of 8,603 shift workers and former shift workers, Taylor and Pocock (100) found that shift workers exceeded dayworkers in death rates caused by atherosclerotic heart disease and hypertension, but not forvascular lesions ofthe central

nervous system. Work schedule satisfaction, health estimates, and work productivity improve when workrest schedules are designed to incorporate circadian principles (19).

PhysiologicalData Experiments reporting effectsoftransmeridian flights

on circadian rhythms have been published since the early fifties (95). Transmeridian flight results in

a phase shift between the circadian rhythms of the body, which are synchronized to departure time, and the Zeitgebers (external environmental synchronizers)
at the place of destination. Flights across time

zones involve a differential restructuring of the many oscillating body systems, resulting in internal circadian desynchronization and associated symptoms (9,47). Among flight crews, sleep disturbances were found in 59-78% ofthe personnel on the first night following transmeridian flight (61,79), falling to 25-30% with sleep disturbances on the third night postflight. Up to 41% of the crew members experienced gastrointestinal problems (61). Female flight attendants had a significantly higher incidence ofirregular menstrual cycles (78) and exacerbated dysmenorrhea (88). Physiological rhythms affected by external desynchronization include; the sleep-wake cycle; body temperature; pulse rate; respiration; arterial pressure; diuresis and excretion of K+, Na+, 17-hydroxycorticosteroids, and 17-ketosteroids in urine (92). Most flight experiments reported in the literature indicate that reentrainment and recovery usually occur at a faster rate following westerlyflights, which involve

a phase delay, than after eastward flight (phase advance) (8,40,44,55,92). For example, following a westbound flight from West Germany to the United States (52,55,83), 3 d were required to reach 95% resynchronization of the psychomotor performance rhythm, whereas 8 d were required following return flights in the easterly direction. If the measurements from seven flight studies (all involving flights in both directions) are averaged, then mean reentrainment shift
rate for all variables is 92min.d-~ after an eastbound flight, but only 57min.d-~ after a westbound flight (8,54). The actual rate of shift varies during the period of reentrainment. It is most rapid during the first 24 h and decreases thereafter exponentially (83,112). However,theproportion ofreentrainment which occurs during the first24h has been observedtobeup to 80% greater after a westbound flight (52,54). Relative flight direction (homeward vs. outgoing) and time of flight departure (day vs. night) have relatively little effect on reentrainment (52,83). The phenomenon in which the time necessary for reentrainment is different for advance and delay shifts is termed the "asymmetry effect" (6). The asymmetry of reentrainment time observed after eastward vs. westward transmeridian flight is opposite to the asymmetry observed in individuals under controlled laboratory conditions. In some isolation experiments, rephasal took longer after a phase delay than after a phase advance (111). The reason for this discrepancy is
notclear. Inherent differencesbetweenthetwotypesof experiments include isolation vs. socialcontact, artificial

vs. natural Zeitgebers, and uniformity ofthe Zeitgebers before and after the shift in the isolation chamber vs. possible differences in natural Zeitgebers before and afterthe flight. Finally, isolation experiments lack some ofthe stressorsandinduced sleepdeficitsassociatedwith flights (8,111). Another factor which influences reentrainment after phase shift of the Zeitgeber is the "preferred" period of the circadian system, as determined under constant conditions, i.e. constant light. In humans having a preferred period longer than 24 h, the asymmetry observed after flights in which reentrainment is faster followingdelayshiftsisatesssurprisingfindingthan that

seenintheisolation unit (8). In this instance, itiseasier
toreentrain bylengthening the circadian period than by shortening it. There is considerable variation in the rates of resynchronization of individual rhythms (44,55,110). After a time shift, all rhythms are phase shifted and the resynchronization processisnot completeuntil each rhythm has rephased. The different rates of rhythm readjustment lead to transient internal dissociation, in which the normal phase relationships between rhythms

are disrupted (4). For example, after a time shift of 6 h (easterly direction), performance returns to preflight levelsafter2dwhereasthesleep-wakecyclemayrequire 2-3 d, the bodytemperature 5 d, and cortisol excretion
up to 8 d to rephase (5).

Aviation, Space, and Environmental Medicine ~December, 1984 1087HUMAN CIRCADIAN RHYTHMS~WINGET ET AL.

The strength of new local Zeitgebers also influences rephasal of body rhythms after a phase shift has occurred. Social contact has been shown to be a powerful Zeitgeber in humans and one of particular importance in aviation (7,55,91). Klein and Wegmann (54) demonstrated that, when subjects were restricted
to relative isolation of indoor activity after transmeridian flight, resynchronization of performance and physiological functions took significantly longer than when subjects were allowed outdoor activity and social
contacts within the new environment. Recently, others (18) have maintained that Zeitgeber differences in strength between the indoor and outdoor environment
account for the different rates of resynchronization. Wever (110) found that some individuals exhibit freerunning circadian rhythms in isolation despite exposure to 24-h light-dark cycles. In addition, he found that subjects isolated in groups in constant light tended
to synchronize their circadian rhythms and exhibit longercircadian periods, withreducedperiod variability compared with the same subjects isolated singly (110). Winget, et al. (113) demonstrated that each group of three subjects exposed to constant light in isolation exhibited significantlydifferentcircadian period lengths, whichwereattributed tothe synchronizinginfluenceofa psychologicallydominant individual in each room. The evidence suggests that both light-dark cycles and social interaction are important factors in the synchronization ofcircadian rhythms. A common complaint after crossing time zones is the feeling of hunger at odd hours of the day. While an upset eating schedule may be reflected in disturbances of the cycles of waste elimination, blood amino acid levels, and other visceral activities, the timing ofmeals does not appear to act as a strong Zeitgeber in humans (3,39). Circadian rhythms persist in humans virtually without alteration, both in subjects who are fasted and those who receive constant amounts of food at short intervals (3). However, meal timing does affect some rhythmic variables. For example, the internal timing of blood hormones (insulin, glucagon, somatotropin, and cortisol), aswellasrhythms inbloodpressure andpulse,

can differon a regimen ofbreakfast onlyordinner only (36,39). However, changes in meal timing alone do not shift the rhythms for simple task performance, such as eye-hand coordination, adding speed, or grip strength (39). Following transmeridian flight, shiftwork scheduling,

or unusual work-rest scheduling, there is considerable variation intherate ofreadaptation betweenindividuals for a given rhythm and between rhythms in a given individual (8,41,55,110). For example, studies have shown that 25-30% oftransmeridian travelers have little

or no difficulty adjusting to the temporary circadian desynchronization; however, about an equal percentage do not adjust well at all (55). The individual factors associated with widely differing rates of rhythmic readaptation are directional asymmetry (advance vs. delay shift; 55,110,111), Zeitgeber strength (strong vs. weak; 56), rhythm stability (stable vs. labile; 94), rhythm amplitude (low vs. high; 1,110,11l), behavioral traits (extraversion/introversion, neuroticism; 15,46), rhythm chronotype (e. g. morning person vs. evening
person; 15), age (young vs. old; 43), motivation (high vs. low; 38), sleep habits (rigid vs. flexible; 30) and performance task type (simple vs. complex, high
memory load vs. low memory load; 29,38). Several researchers suggested that a small circadian amplitude for certain variables may serve as an index of an individual's abilitytophase shiftand adjusteasilytonew rest-activity schedules (4,81,110). Subjects with small amplitudes in the body temperature rhythm show less resistance to phase shift; the degree of acrophase shift is larger and the rate ofrephasal is more rapid in these individualsthan inthosewithlargecircadian amplitudes. Rhythm chronotypes include "larks" or "morning people," whose body temperatures rise and peak early in the day, and who typically have larger temperature amplitudes than "owls" or "evening people," whose temperatures peak later in the day (49). Because the body temperature rhythms of "larks" are phase advanced (peak earlier) compared to "owls" (phase delayed), the former tend to suffer from sleep disturbance asa result ofnight work and day sleep (99). Russian investigators are developing techniques by which overall "rhythm stabilities" can be assessed in individuals (93,94). Stepanova (94) stated that individuals can be classified into three groups--"inert," "intermediate," and "labile"--according tothe extentof the temporal fluctuations observed in various circadian parameters. Inert individuals typically exhibit circadian rhythm patterns which are more stationary in time than labile individuals. According to Stepanova (94), labile individuals would experience less difficulty adjusting to theunusual sleep-wakeschedulescommonin spaceflight and thus would make better candidates for space missions than inert or intermediate individuals. Thus, the state of internal rhythmic organization is complex and it is, then, an important area for further research to establish the specific types of rhythmically disorganized states associated with the most severe physiological and behavioral impairments. Such data

can be of use in selecting individuals most suited for resistance to phase shifts, e.g. astronauts or airline pilots. The data base for physiologic" rhythms following transmeridian flight has been expanded recently by Desir et al. (22). They investigated the hormonal changes underlying jet lag in a group offive volunteers after a transmeridian time zone change of 7 h (105~ including westward (phase delay) and then, 30 d later, eastward (phase advance) flights. Blood was sampled
at 15-rain intervals for 25 h on several days before and after each flight. In addition to the usual measurements of pituitary-adrenal cyclicity, the study included the changes in the rhythmic production of the pineal hormone, melatonin. Pineal melatonin production is of particular interest as a marker rhythm in circadian rhythm research. The pineal is linked in the rat (69), and probably also in humans, by neural pathways to the suprachiasmatic nucleus. In rats and monkeys
many of the biological rhythms so far studied can be eliminated by destroying the suprachiasmatic nuclei in the hypothalamus (85,86). These nuclei are likely

1088 Aviation, Space, and Environmental Medicine ~December, 1984HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

candidates as components of the hypothetical master biological clock in mammals which controls sleep-wake and associated rhythms (32,71). Melatonin rhythms are entrained by the light-dark cycle, in which melatonin levels are suppressed by light and stimulated by dark (108). The melatonin cycleis also remarkably resistant
to minor stresses, metabolic variations, and other manipulations of its rhythmic production. However, phase shifts in melatonin may influence sleep-wake cyclesin humans (22). In the Desir study (22), ACTH-Cortisol secretion took up to 3 weeks to adapt to local time after the westward flight, but only 11 d after the eastward flight. In contrast, and in line with most previous findings, there was greater subjective discomfort, perturbations of sleep, and disruption of the secretory rhythm of melatonin after the eastward flight. While the pattern of sleep disruption was highly correlated with psychological stress, assessed by ratings of anxiety and depression, there wasno correlation between subjective discomfort and ACTH-cortisol periodicity. In fact, normal sleep and lowratings of anxiety and depression

were observed with complete desynchronization of the ACTH-corisol rhythm. This study serves to underline the greater problems of adaptation associated with eastward flights, the possibly unrelated disturbance of pituitary-adrenal function, and the major contribution of sleep disturbance to the jet-lag effect. Our own research indicates that, after an eastward flight, more time is required for physiological adaptation (83). The significance of disruption of the melatonin secretion rhythm inthepsychologicaldisturbances associatedwith jet-lag isyetto beestablished. The surprising symmetry ofthe rate of adaptation ofmelatonin to either a phase advance or phase delay requires further investigation, butitmayberelated totheoverallphotoperiodiccontrol of its secretion and the strength of entrainment by natural light.

Performance

That transmeridian flight and the resulting internal rhythmic desynchronization also adversely affected performance has been well documented by Klein and his co-workers (52-55). Klein used both pilot and student populations as subjects, with tests designed for occupational realism (cockpit simulators). After crossing six time zones in the eastward direction, 24-h

mean performance levels decreased 3-4% compared
to preflight levels. Performance decrements in both simple tasks such as reaction time, and the complex sensorimotor skillsrequired tooperateflight simulators,

weremore severefollowingeasterlyflightsthan westerly flights. Simpler tasks recovered to baseline levels after 3 d, but decrements in complex tasks persisted for up to 5 d postflight. Followingwestwardflights, onlynonsignificant decrements wereobservedin simulator performance (56) and psychomotor performance (11). However, following eastward flights of6-9 time zones, significant decreases in efficiency, lasting from 1-5 d postflight, were found in flight simulator performance (9%, 56; 8.5%, 80), psychomotor performance (3.5%, 56; 1.8%, 11), and hand-eye coordination (8%, 62). A variety of performance tasks and indices of psychophysiological complaint were evaluated recentlyin military personnel followinga studyofeastwardtransatlantic flightthrough six time zones. Following the flight, 50% of the personnel reported fatigue and sleep difficulty and 40% reported subjective weakness. These symptoms diminished significantly by the fifth day postflight (115). Postflight performance deterioration was found in dynamic arm strength (6.1-10.8%), elbow flexor strength (13.3%), sprint times (8.4-12%), a lift and
carry task (9.5%) (115), logical reasoning (15%, 38), and encoding-decoding performance (16). The performancedeclinefollowingtransmeridian flightobservedin this study may have been underestimated since several individuals failed to complete the assigned tasks (115). Hauty and Adams (43) included north-south flights in addition to translongitudinal flights to determine whether fatigue or stress induced by the flight itself contributed to performance degradation. Effects of north-south flight were found to be insignificant compared to those imposed bytransmeridian flight. Performance levelswere also more adversely affected following phase advances (simulated eastward flight) than followingphase delays(simulated westwardflights) inground-based phase shift studies. Therefore, rephasal time is shorter but impairment is greater in the eastward direction. This probably results from the preferred period of 25 h which results in greater desynchronization and mayresultinrhythm partitioning in an eastward direction. Wever (111) found significant impairment in psychomotor performance following 6-h phase advances, but not after phase delays of the light-dark cycle. Subjects whose sleep-wake cycle was advanced 1.5 h every 5 d exhibited increased sleep disorders as well as decrements in psychomotor and calculation performance (64). Significant deterioration in vigilance, calculation proficiency, and mood was observed in subjects whose sleep-wake period was advanced 2-4 h (98). Female subjects advanced by 8 h exhibiteda 17-38% deterioration inshort-term memory, reaction time, and visual search performance (77). Student pilots whose sleep-wakeperiodswere advanced 2.5 h exhibited sleep impairment, a 35% increase in flight performance errors, and a 14-15% decrement in letter cancellation performance (117). Hawkins and Armstrong-Ester (45) found that significant decrements inshort-term memoryoccurredinnurses shiftedtonight duty. Time shifts of 2-3 h can result in performance impairment in athletes (63) and cosmonauts (63), and

eventhe 1-htime changebetween standard and daylight savings time may result in performance deterioration (66-68). Flight studies on aircrews working repeated 4/2, 4/4, 6/2, 10/10 and 16/16 hours duty-rest schedules indicated sleep rhythms considerably disrupted, leading
to sleep deficits with consequent subjective fatigue and reduced performance efficiency(10,31). ASSESS II was the second of two joint projects between NASA and ESA (European Space Agency) utilizing the CV-990 research aircraft for an extensive simulation of Spacelab operations. Payload specialists performed specialized astronomical and scientifictasks.

Aviation, Space, and Environmental Medicine ~December, 1984 1089HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

The actual mission consisted ofnine 6-h research flights carried out within a 10-d period with payload crew confined to the aircraft and contiguous living quarters. During the mission, most activities were performed

as night work and most sleep times were scheduled for daylight hours. In addition, flight periods were shifted several times, resulting in irregular work-rest schedules. This simulated Spacelab mission resulted in internal dissociation of circadian rhythms, sleep disturbances, and highly stressful operating conditions. The payload specialists stated that they required from 1-3 flightsbeforetheyhad reached the desirable degree ofeffectivenessin experiment operations (103,104). Thus, it is quite apparent that the crossing of time

zones or sleep-wake reversal, and the resulting phase shift of performance and physiological rhythms, often results in significant performance decrements. The etiology of these decrements may be the end result of
many factors underlying the desynchronosis syndrome, including sleep disturbances, workload, psychological and dietary factors, and specificindividual physiological characteristics. A large body of literature documents significant performance deterioration in response to sleep loss

or sleep disturbance (9,47,50). However, significant performance deterioration occurs following 2-4 h advances in the sleep-wake cycle despite normal sleep duration (98). These results indicate that performance deterioration can directly result from circadian rhythm disturbance and not solely from sleep loss. The recent discovery that sleep onset and duration depend upon circadian body temperature phase (17,119) provides a physiological basis for the performance deterioration observed in response to circadian desynchronization. Sleep is significantly impaired in subjects exposed to 23

or25-h light-dark cycles,in which thephase relationship between sleep onset and body temperature rhythm phase is altered (119). Pathology

The symptoms associated with acute desynchronization are similar to those noted in a wide variety of well-known clinical conditions. Among these clinical conditions may be included various fevers, reactions
to infection or viruses, alcohol hangover, some forms of migraine, old age, some mental disorders, and sleep deprivation. It is tempting to speculate that

some or all of these conditions may be manifestations of asynchrony of physiological rhythms. The sleepwake cycle is easily dissociated from the approximate 25-h endogenous circadian period in body temperature and also rapidly adjusts to a change in Zeitgeber input. In fact, hypnotics are frequently used to

overcome sleep-wake cycle disturbances but are not recommended for use in the aerospace environment becauseoftheir longbiologichalflifeand their tendency
to abolish rapid eye movement (REM) sleep. Other rhythms, however, such as cortisol secretion and body temperature, require a variable number of days to readjust; until all the systems have reestablished their initial phase relationships, the individual is in a state of desynchronization. A variety ofpathological conditions are associated with disturbances of internal circadian rhythmic phase relationships, or even disappearance of certain rhythms and the appearance of rhythms not normally present (82). Analysis of EEG recordings from subjects following a phase shift of the sleepwake cycle revealed disturbances of sleep resembling those seen in endogenously depressed patients, e.g. increased latencyofREM andmore awakenings atnight (107). The relationship between disturbed circadian rhythmicity and endogenous depression was further defined by Wehr et al. (105), who found in depressed patients that their circadian rhythm peaks are unusually phase advanced with respect to the sleep-wake cycle. These authors concluded that endogenous depression and chronic sleep disturbance may result from chronic, abnormal circadian phase relationships, in which the metabolicallyrelated rhythms, suchasbodytemperature and cortisol secretion, may peak too early with respect to the sleep-wake cycle. Kripke et al. (57) believe that bipolar manic-depressive cycles may result from beat phenomena between the vegetative rhythms, which are entrained to the light-dark cycle and have a shorter period length than the free-running hormonal rhythms. Profound physiological consequences are clearly the result of an inappropriate time of hormonal secretion,

as observed in time-zone displacement. For example, variation in the responses of plasma ACTH and blood cortisol to a stress, e.g. a cold pulse, at different times ofthe day may be significant in a hostile environment. A further area for concern is the effects of drugs

on the desynchronized human. Both pharmocokinetic and pharmacodynamic effects of drugs may vary dramatically according to the time of day (102). This much neglectedaspectofaerospacepharmacologycould have serious implications in the treatment of space travelers and time-zone travelers (I02).

Mathematical Models

In order to understand dysrhythmia and to enable selection of and verification of appropriate preventive and corrective measures, desynchronosis needs to be modeled mathematically. Dysrhythmia induced by

a mismatch between the body's biological clock and environmental Zeitgebers represents the attempt bythe bodytorestore initial homeostatic stabilityofindividual rhythms and also to restore the phase relationship
among rhythms. A number of models for predicting phase adjustment, and the time for adaptation in
response to the combination oftransmeridian flight and physiological duty load, have been developed. Some of these models were designed primarily to calculate appropriate rest times followingtransmeridian flight for traveling business executives, but have little application to aircrews or space station crews. Buley (13) developed a formula based upon flight duration, times ofdeparture and arrival, and travel through more than four time zones. Next, a pocket calculator for determining physiologicalrestperiodswasdevelopedby Gerathewohl (33). Gerathewohl's model, in addition
to certain components of Buley's model, includes
passenger age, flight direction, and total number of time zones crossed. An expanded model based on

1090 Aviation, Space, and Environmental Medicine~December, 1984HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

physiological load--defined by multiple flights, number of crossed time zones, and layover following evening arrival--was introduced by Mohler (65). It also takes into account multiple transits, day sleep, eastward flight direction, and duration of duty periods in establishing appropriate rest periods. Nicholson (73) developed a workload model based upon cumulated duty hours for days enroute. Workload is defined as the product of days on duty and average duty hours per day. It takes time zone changes into account only with respect to the progressivelyreduced workload experienced during flight. M. Winfree has developed a new model (personal communication) which simulates the interaction between duty schedules, sleep times, and times of local sunrise and sunset. The model assumes that sleep
onset will tend to commence following local sunset. Given times of local sunrise and sunset and duty hour scheduling, it predicts the times of occurrence and duration of sleep and napping episodes with respect to duty schedules, and provides an evaluation of the efficacyofrest periods. In general, these models are all limited because they donot take into account the large individual differences intimezonereentrainment observedbyKlein etal. (53),

orthey depend onverylimited data bases. The Winfree model, in particular, is based on limited duty schedule data and sleep-wake data. The Buley model of flight duration does not take into account potential rhythmic desynchronization and performance decrement which
mayoccur when fewerthan fourtime zones are crossed (35,64,68). Klein and Wegmann (55) evaluated all of the above models, except the Winfree model, in terms ofpredicted demand on various flight legs on a "round the world" and "eastern return" flight schedule. Their comparison revealed that there was little conformity in the relative demand predicted foreach flight leg. These differences were attributed to the complex variety of indices used in the models and the relative differences in emphasis on either aircrew or passenger schedules. A series of models, including those of Klein and Wegmann (55), Sasaki (87) and Winget et al. (112), have been developed to quantify the dynamics of the rephasal process. These models---essentially calculation of time constants from circadian rhythmic endpoints--

are used to fit exponential trajectories to the rhythmic reentrainment data. The Sasaki model additionally factors in variables for aircraft position and layover times. These models do not provide a priori predictive parameters forreentrainment and donottakeindividual differences into account, but do provide quantitative estimates of the rephasal process which are free of subjectivebias. Wever (109) developed a model, based primarily

on experimental work with birds, for predicting the
response of a rhythmic system to phase shifts as a function of Zeitgeber strength, direction of shift, and preferred period length of the individuals. The model is mathematically based upon solutions to the Van der Pol nonlinear differential equation. In general, it predicts a) that reentrainment duration is shorter in the westward than in eastward direction, given that the preferred period length exceeds 24 h, b) that reentrainment duration is shorter when dark time is extended than when light time is changed, and c) that reentrainment occurs by period lengthening following

a 6-h shift. This model is particularly advantageous with respect to the models previously discussed, since it takes into account specific individual circadian and environmental parameters in formulating preditions of reentrainment dynamics. Theresponsesofthe circadian systemofCebusmonkeys to 12-hphase shifts conforms
to the predictions of the Wever model (21). The model has limitations in potential application to human transmeridian flight because it does not take sleep timing, sleep duration, and physiological load into
account. In addition, Zeitgeber strength is more difficult to define in humans. Many investigators have found that the primary Zeitgeber in humans is social interaction, rather than the light-dark cycle(54,91,110), and the degree of social interaction is more difficult to quantify than light intensity. Recent work (17,59,69,110) indicates that the circadian system consists of a non-hierachically coupled, dual-oscillator mechanism which drives secondary oscillators responsible for the expression of circadian rhythms. The "stable" oscillator underlies body temperature circadian rhythms and canbe synchronized byenvironmental Zeitgebersonlywithin a narrowrange ofperiod lengths (23-27 h days in humans; 110). The "labile" oscillator underlies the sleep/wake and activity rhythms and isentrainable to a widerange ofZeitgeber period lengths (18.5-33.5 h days; 110). The body temperature oscillator interacts with the sleep/wake oscillator suchthat the duration ofsleep and the timing of sleep onset are dependent upon the phase of the body temperature circadian rhythm (17,119). The
onset and dynamics of circadian desynchronization are then dependent upon these coupling interactions. This picture ofthe circadian systemdoesnotprovide a direct relationship between circadian desynchronization and performance, but does provide a basis for predicting sleep onset and duration, based upon internal circadian phase relationships, which may have an impact on subsequent performance efficiency. The modelispresently limited by its data base, which includes only human isolation studies. Wever (111) has shown that rephasal dynamics and asymmetry differ between controlled isolation studies and transmeridian flight studies, which indicates that differences in relative Zeitgeber strength, physiological load, and other environmental factors
may directly influence adaptation to transmeridian flight. However, the model has significant potential forusein establishing a relationship between individual parameters of the circadian oscillatory mechanism and Zeitgeber effects, which could be used to predict circadian desynchronization, sleep disturbances, and their associatedperformance decrements. A newthreecomponent model postulates the existence of separate oscillators forbodytemperature, sleeponset, and wake
onset (51). Simulations performed using this model apparently confirm more accurately than the Kronauer

Aviation, Space, and Environmental Medicine9December, 1984 1091HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

model (59) the observed changes in sleep duration as

a function of different phases of the body temperature rhythm. 

### TherapyforDesynchronosis

There are several approaches to therapy, or prophylaxis, for desynchronosis; these include exercise, pre-adaptation by altering sleep-wake cycles, drug administration, altered meal timing and dietary constituents, relaxation techniques, electrosleep therapy, and even acupuncture (47). The relief of specific symptoms, such as constipation, headache, lack of sleep, etc.
, is one of several approaches. Secondly, chronobiotic drugs, which specifically alter rhythm period or phase without adversely affecting performance, might be considered. A reduction in amplitude of various rhythms during the rephasing period has been reported. Assuming this reduction in amplitude provides the means by which the body attempts to resynchronize, then drugs that reduce amplitude even further may be useful. For example, Enovid has been shown to reduce the amplitude ofthe activityrhythm in
rats. On the other hand, if a reduction in amplitude is the consequence of dysrhythmia, then drugs that increase amplitude should be sought. A number of putative chronobiotic drugs have been evaluated over the last decade. The reports of trials have indicated varying degrees of efficacy. For example, barbiturates have been commonly prescribed
to drivethe sleeprhythm onto a new schedule following transmeridian flight (90). Drugs such as alcohol and caffeine are commonly used by aircrews (44), in a non-chronobiotic application (not regulated by timed administration) to facilitate sleep or reduce symptoms offatigue and increase alertness. Quiadon, a serotonindepleting tranquilizer, and corticosteroids were tested forchronobiotic suitability in a human phase shift study (89) and transmeridian flight studies (14), but results

were inconsistent and inconclusive. Chronobiotic drugs influence the duration of reentrainment following phase shifts or transmeridian flights by two different means. In one way, the drug may act as a Zeitgeber forcing desynchronized physiological processes into phase, according to the Shock-Phase hypothesis of Richter (82). These "type a" drugs influence the circadian system by inducing a circadian response curve in which the subjects' own rhythms compare as phase-advanced or phase-delayed, depending upon which phase of the circadian rhythm the drug is administered. Administered early in the circadian phase, these drugs elicit a phase advance which facilitates rephasal in the eastward direction. "Type a" drugs include: ACTH, which rephases adrenal cycles in pulsed doses (2); nomifensine, an antidepressant, whichreducesphase shiftreentrainment in suprachiasmatic- nucleus-lesioned rats (40); theophylline, which facilitates phase shift by phase advance or delay, depending upon time of administration (25); Ldopa, which inhibits or promotes food-induced phase shiftsin rats (28); parachlorophenylalanine, which shifts the phase of brain temperature in macaques (74), and locomotor activity and plasma cortisol in rats (48); carbachol, a cholinergic agonist, which phase shifts pineal N-acetyltransferase activity in rats, implicating the role of acetycholine in rhythm entrainment (118); chlordiazepoxide (librium) in water, which produces dose-dependent lessening of the disruptive effects of phase shifts and promotes more rapid adaptation to 6-h phase shifts in rats (20); and, finally, implanted capsules of estradiol

, which have been found to phase advance the locomotor activity rhythm of entrained, ovariectomized hamsters (70). Drugs may also intensify the effect of other Zeitgebers, reflected in lengthening or shortening ofthe rhythm period to assist in resynchronization. These "type b" drugs which alter circadian period length, have not been studied in phase shift experiments but have thepotential toinfluence reentrainment byaltering circadian period length in the direction of the phase shift. Thus, period-lengthening drugs might facilitate reentrainment following westward flight and periodshortening drugs might shorten reentrainment following eastward direction phase shift or flight. Examples of drugs which lengthen the circadian period in
constant conditionsinclude: deuterium, which lengthens locomotor activity rhythms in deer mice (97) and laboratory mice (24); lithium, which lengthens period length of locomotor activity rhythm period length in
rats (58); amphetamine, which lengthens the locomotor activity rhythm period length in wood mice but not rats (12); clorgyline, which lengthens the locomotor activity rhythm period length in hamsters (114); and ethyl alcohol, which lengthens the locomotor activity rhythm in blind hamsters (84). Drugs which shorten the circadian period in constant conditions include the tricyclic antidepressives (desmethylimiprimine) in hamsters (106); melatonin in sparrows (101); and estradiol, which shortens theperiod length oflocomotor activity in ovariectomized hamsters (70). Certain food constituents showed Zeitgeber characteristics (26). Ehret, Groh, and Meinert (27) have developeda "dietplan for shiftworkers and transmeridian travelers" inwhichpreflight alteration oflight and heavy meals, alteration of proteins and carbohydrates, and the programmed intake of chronobiotics (agents with synchronizing properties) such as tea and coffee are used to speed resynchronization following a phase shift. These investigators claim that high-protein breakfasts and low-protein high-carbohydrate dinners facilitate rephasal in rats and humans following advance phase shifts. These effects are supposedly mediated through the synthesis of catecholamines from the high protein meal. Serotonin synthesis is enhanced following the high-carbohydrate meal bythe reduction in competitive inhibition by other amino acids of tryptophane uptake into the brain. On the basis of subjective results, trials with humans are reported to be highly successful (27). Graeber and his co-workers reported that subjectsfollowingthe diet plan experienced fewer sleep disturbances and reported less subjective fatigue on the first 2 d postflight than did control subjects. A more rapid phase adjustment ofthe bodytemperature rhythm

was also seen in test subjects over 30 years of age than in control subjects ofthe same age group (37,38).

1092 Aviation, Space, and Environmental Medicine • December, 1984HUMAN CIRCADIAN RHYTHMS--WINGET ET AL.

The use ofspecificdietary intake protocols are useful in the manipulation of circadian rhythms, particularly for individuals showing serious symptoms. For most individuals, such an approach is too complicated to be of practical value. In mice, however, controlled or restricted access to food can oppose or augment the effects of a lighting regimen. Diet is thereby claimed to
act as atrue Zeitgeberorrhythm synchronizer(72). Itis thought that some component ofthe ingested food may act directly or indirectly on circadian pacemakers, perhaps through plasma levels oftryptophane and choline, which influence brain levels of neurotransmitters (116). However, other research (34) indicates that restrictive feeding may not be a true Zeitgeber in the rat and that the observed entrainment of rhythms may instead be due to the masking effects of meals on the underlying circadian rhythms. However, cycles of feeding and fasting appear to be true Zeitgebers in the squirrel monkey (96) for urinary rhythms, but not for body temperature. In humans, the upset meal schedules resulting from transmeridian flight may be reflected in disturbances of the cycles of waste elimination, blood amino acids, and other visceral activities (9). The observed meal timing effects in humans upon blood hormones, blood pressure, and pulse (60) may be due
to masking effects of single meals upon the circadian rhythms observed. The multiple Zeitgeber (i.e. orthochronal) treatment is a recent approach to the resynchronization of physiological rhythms, which is necessary for the maintenance of good environmental synchronization and reentrainment followingphase shifts. Sulzman etal. (96) and Ehret et al. (27) found that application ofrestricted feeding or drugs as Zeitgebers at inappropriate phases of circadian rhythms with respect to the phase of the light-dark cycle, resulted in transient internal desynchronization in monkeys and rats, respectively. Conversely, Ehret et al. (27) found that optimal timing of food-fast cycles and theophylline administration, along with meal specific constituents, reduced the duration of reentrainment following phase shifts in
rats. Further research on the careful choice of foods, scheduling of meals, and dosage and administration time ofmedication appears toprovide a verypromising

means to combat desynchronosis.



### Summary
Significant deterioration in performance and wellbeing is most commonly found where circadian desynchronization is induced by shortening the workrest cycle or advancing the phase of the sleepwake cycle. The specific mechanism underlying circadian desynchronization, which leads to subsequent performance deterioration, has not been determined. Circadian desynchronization induced by phase advance is often associated with rhythm partitioning, in which different circadian rhythms shift in different directions (21,55) and body temperature levels are reduced (38,111). These phenomena are seldom observed following phase delay of the circadian system, so it is likely that they are somehow involved in the development of performance deterioration. Recent evidence suggests that circadian rhythmicityisregulated by a dual oscillatory system which underlies the sleepwake and body temperature-associated rhythms. The phaserelationship and couplinginteractionsbetween the bodytemperature and sleep-wake oscillators accountfor the dependence of sleep duration and the timing of sleep onset upon the phase of the body temperature rhythm. It also probably accounts for the large individual variability in circadian measures observed in
response to environmental phase shifts of the sleepwake cycle. This view ofcircadian rhythm organization provides a basis for predicting sleep onset and duration

as a function ofthe internal timing ofcircadian rhythm phases. Performance deterioration in response to sleep loss or disturbance is well documented. Therefore, performance decrements observed in response to alterationinhuman work-rest schedulesprobablyresults from sleep disturbances induced by alterations in the timing ofcircadian oscillatory systems. Considerably more flight- and ground-based experimentation will be necessary to ensure maximum performance in the aerospace environment. Such experimentation should assess the contribution offlight
stress to the severity of symptoms of dysrhythmia, social and emotional contributing factors, and the
rates of change of various rhythms in response to

new photoperiods and various light intensities and wavelengths. Means of controlling dysrhythmia would have practical application in medicine, pharmacology, civilaviation, and particularly in the shift-work scheduling of space stations and military aviation.

ACKNOWLEDGMENTS WethankDrs.L. C. Doroszand K. E. Hutton for theircritical reviewsofthismanuscript,andMr.NormanMartello,Ms.LindaK. Dillamanand Ms. JeanM. Kilcoursefor their technicalassistance. SupportforthisreviewwasprovidedinpartbyNationalAeronautics andSpaceAdministrationCooperativeAgreement @NCC2-197and NationalInstitutesofHealthgrant4~SO6RR0819204.

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