VOLUME 55 NUMBER 12 

DECEMBER, 1984 

Science and Technology Committee: 1984~Selected Review Paper 

A Review of Human Physiological and 

Performance Changes Associated with 

Desynchronosis of Biological Rhythms 

CHARLES M. WINGET, B.A., PH.D., CHARLES W. 

DEROSHIA, B.S., M.A., CAROL L. MARKLEY, B.A., M.A., 

and DANIEL C. 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 

WINGET CM, DEROSHIA CW, MARKLEY CL, HOLLEY DC. A 

review of human physiological and performance changes associated 

with desynchronosis of biological rhythms. Aviat. Space Environ. 

Med. 1984;55:1085-96. 

This review discusses the effects, in the aerospace environment, 

of alterations in approximately 24-h periodicities (circadian 

rhythms) upon physiological and psychological functions and 

possible therapies for desynehronosis induced by such alterations. 

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, such as 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 

and to better understand the problem of dysrhythmia. 

A LTERATIONS OF CIRCADIAN rhythms, or 

approximately 24-h periodicities in physiological 

and psychological functions, as well as possible therapies 

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 

Reprint requests to: Charles M. Winget, Biomedical Research 

Division (239/7), NASA-Ames Research Center, Moffett Field, CA 

94035. 

C. L. Markley and D. C. Holley are with San Jose State University. 

This manuscript was received for review in April, 1984. It was 

accepted for publication as a review article in May, 1984. 

importance of environmental cues, such as light-dark 

cycles, which influence physiological 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 

and the usual synchrony among several of these rhythms 

can be deleterious to physiological functioning and 

performance (9,44,47). 

Adverse effects on performance and well-being, including digestive disturbances and general malaise, were 

noted soon after humans 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 

this phenomenon appeared about 20 years later and was 

published in this journal by Strughold (95). 

The desynchronized individual may experience states 

of irritability, disorientation or confusion, distortion of 

time and distance, aches of various types, digestive upsets which include constipation, decrements of physical 

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). It has been suggested that the term "fatigue" be 

replaced by more explicit physiological criteria, 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 desynchrony may be of serious consequence 

Aviation, Space, and Environmental Medicine 9 December, 1984 1085 
HUMAN 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 system cannot be made because of the paucity 

of actual flight data, disturbances of biological 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 be retrofitted to carry as many as 10 persons, 

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 

consequences of such conflicts are still largely unknown. 

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. 

Concepts of Biological 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 

periods less than 20 h, circadian rhythms with periods of 

about 24 h, and infradian rhythms with a period greater 

than 28 h (40). 

The rhythm waveform has many characteristics. The 

amplitude is the 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 degrees with one period equal to 360 ~ . The 

acrophase is the time to the maximal value (peak or 

crest) of the 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~ 

If the 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 physiological parameter shifts the same number 

of hours as the synchronizer, retaining the original 

waveform and phase relationship. Early in the phase 

shift processes, the circadian amplitude and wave shape 

may significantly change. This commonly occurs during 

what is called the transient rephasal period. The 

acrophase is usually quicker to adjust than the through 

or period length. 

Entrainment 

Considerable experimental evidence indicates that 

circadian time measurement in multicellular systems is 

a product of self-sustaining oscillations generated within 

the organism (75). At least two major oscillators control 

body rhythms. They are normally coupled together and 

entrained by environmental 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 of light 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 body temperature and activity differs dramatically in free-running and entrained conditions. In the 

24-h day, when rhythms are entrained by the light-dark 

cycles, temperature peaks near the end of the activity 

period; when night is indistinguishable from day by the 

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, 1984 
HUMAN 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 day workers in 

death rates caused by atherosclerotic heart disease and 

hypertension, but not for vascular lesions of the central 

nervous system. Work schedule satisfaction, health 

estimates, and work productivity improve when workrest schedules are designed to incorporate circadian 

principles (19). 

Physiological Data 

Experiments reporting effects of transmeridian 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% of the 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 of irregular 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 westerly flights, 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, the proportion of reentrainment which occurs 

during the first 24 h has been observed to be up 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 

not clear. Inherent differences between the two types of 

experiments include isolation vs. social contact, artificial 

vs. natural Zeitgebers, and uniformity of the Zeitgebers 

before and after the shift in the isolation chamber vs. 

possible differences in natural Zeitgebers before and 

after the flight. Finally, isolation experiments lack some 

of the stressors and induced sleep deficits associated with 

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 

following delay shifts is a tess surprising finding than that 

seen in the isolation unit (8). In this instance, it is easier 

to reentrain by lengthening 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 process is not complete until 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 

levels after 2 d whereas the sleep-wake cycle may require 

2-3 d, the body temperature 5 d, and cortisol excretion 

up to 8 d to rephase (5). 

Aviation, Space, and Environmental Medicine ~ December, 1984 1087 
HUMAN 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 

longer circadian periods, with reduced period 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 significantly different circadian period lengths, 

which were attributed to the synchronizing influence of a 

psychologically dominant individual in each room. The 

evidence suggests that both light-dark cycles and social 

interaction are important factors in the synchronization 

of circadian 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 of meals 

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), as well as rhythms in blood pressure and pulse, 

can differ on a regimen of breakfast only or dinner 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 in the rate of readaptation between individuals 

for a given rhythm and between rhythms in a given 

individual (8,41,55,110). For example, studies have 

shown that 25-30% of transmeridian 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 ability to phase shift and adjust easily to new 

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 of rephasal is more rapid in these 

individuals than in those with large circadian 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 as a result of night 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 to the extent of 

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 

the unusual sleep-wake schedules common in 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 of five 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, 1984 
HUMAN 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 cycle is also remarkably resistant 

to minor stresses, metabolic variations, and other 

manipulations of its rhythmic production. However, 

phase shifts in melatonin may influence sleep-wake 

cycles in 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 was no correlation between subjective 

discomfort and ACTH-cortisol periodicity. In fact, 

normal sleep and low ratings 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 in the psychological disturbances associated with 

jet-lag is yet to be established. The surprising symmetry 

of the rate of adaptation of melatonin to either a phase 

advance or phase delay requires further investigation, 

but it may be related to the overall photoperiodic control 

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 skills required to operate flight simulators, 

were more severe following easterly flights than westerly 

flights. Simpler tasks recovered to baseline levels after 

3 d, but decrements in complex tasks persisted for up 

to 5 d postflight. 

Following westward flights, only nonsignificant decrements were observed in simulator performance (56) and 

psychomotor performance (11). However, following 

eastward flights of 6-9 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 recently in military personnel 

following a study of eastward transatlantic flight through 

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 performance decline following transmeridian flight observed in 

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 by transmeridian flight. 

Performance levels were also more adversely affected 

following phase advances (simulated eastward flight) 

than following phase delays (simulated westward flights) 

in ground-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 may result in rhythm 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 

exhibited a 17-38% deterioration in short-term memory, 

reaction time, and visual search performance (77). 

Student pilots whose sleep-wake periods were 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 

in short-term memory occurred in nurses shifted to night 

duty. Time shifts of 2-3 h can result in performance 

impairment in athletes (63) and cosmonauts (63), and 

even the 1-h time change between 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 scientific tasks. 

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

The actual mission consisted of nine 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 flights before they had reached the desirable degree 

of effectiveness in 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 specific individual 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 

or 25-h light-dark cycles, in which the phase 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 

because of their long biologic halflife and 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 of pathological 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 latency of REM and more awakenings at night 

(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 

metabolically related rhythms, such as body temperature 

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 

of the 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 neglected aspect of aerospace pharmacology could 

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 by the 

body to restore initial homeostatic stability of individual 

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 of transmeridian flight and 

physiological duty load, have been developed. 

Some of these models were designed primarily to 

calculate appropriate rest times following transmeridian 

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 of departure and arrival, and travel through more 

than four time zones. Next, a pocket calculator for 

determining physiological rest periods was developed by 

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, 1984 
HUMAN 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 progressively reduced 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 

efficacy of rest periods. 

In general, these models are all limited because they 

do not take into account the large individual differences 

in time zone reentrainment observed by Klein et al. (53), 

or they depend on very limited 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 

may occur when fewer than four time zones are crossed 

(35,64,68). Klein and Wegmann (55) evaluated all of 

the above models, except the Winfree model, in terms 

of predicted 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 for each 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 for reentrainment and do not take individual 

differences into account, but do provide quantitative 

estimates of the rephasal process which are free of 

subjective bias. 

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. The responses of the circadian 

system of Cebus monkeys to 12-h phase 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 can be synchronized 

by environmental Zeitgebers only within a narrow range 

of period lengths (23-27 h days in humans; 110). The 

"labile" oscillator underlies the sleep/wake and activity 

rhythms and is entrainable to a wide range of Zeitgeber 

period lengths (18.5-33.5 h days; 110). The body 

temperature oscillator interacts with the sleep/wake 

oscillator such that the duration of sleep 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 of the circadian system does not provide 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 model is presently 

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 

for use in 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 associated performance decrements. A new threecomponent model postulates the existence of separate 

oscillators for body temperature, sleep onset, and wake 

onset (51). Simulations performed using this model 

apparently confirm more accurately than the Kronauer 

Aviation, Space, and Environmental Medicine 9 December, 1984 1091 
HUMAN CIRCADIAN RHYTHMS--WINGET ET AL. 

model (59) the observed changes in sleep duration as 

a function of different phases of the body temperature 

rhythm. 

Therapy for Desynchronosis 

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 of the activity rhythm 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 drive the sleep rhythm 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 

of fatigue and increase alertness. Quiadon, a serotonindepleting tranquilizer, and corticosteroids were tested 

for chronobiotic 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, which reduces phase shift reentrainment 

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 

shifts in 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 of the 

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 the potential to influence reentrainment by altering 

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 conditions include: 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 the period length of locomotor 

activity in ovariectomized hamsters (70). 

Certain food constituents showed Zeitgeber characteristics (26). Ehret, Groh, and Meinert (27) have developed a "diet plan for shift workers and transmeridian 

travelers" in which preflight alteration of light 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 by the 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 

subjects following the 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 of the body temperature rhythm 

was also seen in test subjects over 30 years of age than 

in control subjects of the same age group (37,38). 

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

The use of specific dietary 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 a true Zeitgeber or rhythm synchronizer (72). It is 

thought that some component of the ingested food may 

act directly or indirectly on circadian pacemakers, perhaps through plasma levels of tryptophane 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 following phase shifts. Sulzman et al. (96) 

and Ehret et al. (27) found that application of restricted 

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 of medication appears to provide a very promising 

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 rhythmicity is regulated 

by a dual oscillatory system which underlies the sleepwake and body temperature-associated rhythms. The 

phase relationship and coupling interactions between the 

body temperature and sleep-wake oscillators account for 

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 of circadian rhythm organization 

provides a basis for predicting sleep onset and duration 

as a function of the internal timing of circadian rhythm 

phases. Performance deterioration in response to sleep 

loss or disturbance is well documented. Therefore, 

performance decrements observed in response to 

alteration in human work-rest schedules probably results 

from sleep disturbances induced by alterations in the 

timing of circadian 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 of flight 

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, 

civil aviation, and particularly in the shift-work scheduling of space stations and military aviation. 

ACKNOWLEDGMENTS 

We thank Drs. L. C. Dorosz and K. E. Hutton for their critical 

reviews of this manuscript, and Mr. Norman Martello, Ms. Linda K. 

Dillaman and Ms. Jean M. Kilcourse for their technical assistance. 

Support for this review was provided in part by National Aeronautics 

and Space Administration Cooperative Agreement @NCC 2-197 and 

National Institutes of Health grant 4~SO6RR0819204. 

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