Am J Physiol Regul Integr Comp Physiol 277:R1152-R1163, 1999.

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20-h day

and neurobehavioral function in humans living on a 

Circadian temperature and melatonin rhythms, sleep,

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Circadian temperature and melatonin rhythms, sleep, and

neurobehavioral function in humans living on a 20-h day

JAMES K. WYATT, ANGELA RITZ-DE CECCO, CHARLES A. CZEISLER, AND DERK-JAN DIJK

Circadian, Neuroendocrine and Sleep Disorders Section, Division of Endocrinology,

Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School,

Boston, Massachusetts 02115

Wyatt, James K., Angela Ritz-De Cecco, Charles A.

Czeisler, and Derk-Jan Dijk. Circadian temperature and

melatonin rhythms, sleep, and neurobehavioral function in

humans living on a 20-h day. Am. J. Physiol. 277 (Regulatory

Integrative Comp. Physiol. 46): R1152–R1163, 1999.—The

interaction of homeostatic and circadian processes in the

regulation of waking neurobehavioral functions and sleep

was studied in six healthy young subjects. Subjects were

scheduled to 15–24 repetitions of a 20-h rest/activity cycle,

resulting in desynchrony between the sleep-wake cycle and

the circadian rhythms of body temperature and melatonin.

The circadian components of cognitive throughput, shortterm memory, alertness, psychomotor vigilance, and sleep

disruption were at peak levels near the temperature maximum, shortly before melatonin secretion onset. These measures exhibited their circadian nadir at or shortly after the

temperature minimum, which in turn was shortly after the

melatonin maximum. Neurobehavioral measures showed impairment toward the end of the 13-h 20-min scheduled wake

episodes. This wake-dependent deterioration of neurobehavioral functions can be offset by the circadian drive for

wakefulness, which peaks in the latter half of the habitual

waking day during entrainment. The data demonstrate the

exquisite sensitivity of many neurobehavioral functions to

circadian phase and the accumulation of homeostatic drive

for sleep.

circadian rhythms; performance; body temperature; alertness; memory

IT IS GENERALLY ACCEPTED that the endogenous circadian pacemaker, located in the suprachiasmatic nucleus

of the hypothalamus, plays a pivotal role in the regulation of sleep propensity, sleep structure, and waking

neurobehavioral function. It has been established that

in addition to this circadian process, a homeostatic

process that tracks the duration of wakefulness and

sleep contributes significantly to sleep propensity and

waking neurobehavioral function (15, 18). Many protocols have been applied in the effort to measure the

interaction of the circadian and homeostatic processes

and their contribution to the variability of human sleep

and waking neurobehavioral performance, with the

ultimate goal of constructing sufficiently accurate predictive models (1, 5, 15, 33). Quantification of this

interaction requires that measurements of sleep propensity and waking neurobehavioral function be obtained

for a wide range of the two independent variables, i.e.

circadian phase and duration of prior wakefulness.

Sleep fragmentation (4), partial or selective sleep

deprivation (28, 51), total sleep deprivation (3, 24, 27,

30), and constant-routine protocols (34) have the benefit of varying levels of homeostatic sleep pressure.

However, in these protocols there was a fixed phase

relationship between the sleep homeostat and the

circadian pacemaker, which prevented analysis of the

interaction of the two processes. Measures of the homeostat and/or the pacemaker were also contaminated by

masking effects (e.g., effects of uncontrolled motor

activity, access to caffeine, and/or exposure to light

except for constant routine studies). Finally, in some of

those protocols, neurobehavioral assessments were

given infrequently, resulting in temporal resolutions

far too low to allow for estimation of circadian variation

in performance.

High-frequency sleep/wake schedule studies, in which

sleep/wake cycles were scheduled in a 1:2 time ratio

with periods such as 20 min (e.g., Ref. 43), 90 min (e.g.,

Ref. 9), or 180 min (e.g., Ref. 49), have been used to

demonstrate differences in sleep onset propensity and

subjective alertness at different circadian phases, with

the positive attribute that the protocols could be as

short as a few days. However, most of these protocols

had wake episodes that were too short to allow for

accumulation of substantial homeostatic sleep pressure, lighting conditions that were uncontrolled, absent

or marginal markers of circadian phase, cumulative

sleep deprivation, and 28 h of enforced sleep deprivation before the experiment in most of the 20-min

protocols.

Kleitman (36) first described a forced desynchrony

protocol, which has subsequently been used by a number of investigators (12, 17, 18, 29, 32, 34, 42, 50). With

the use of this protocol, subjects were studied in our

laboratory on an imposed sleep/wake schedule with a

28-h period to force a desynchronization of the sleep/

wake cycle from the endogenous circadian cycle (12,

17–19, 34, 42). Under these conditions, the endogenous

circadian periods of temperature, melatonin, and cortisol averaged 24.18 h (12). With the imposition of the

28-h sleep/wake schedule, subjects were placed on a

routine of bedtimes and waketimes that were 4 h later

each sleep/wake cycle. Thus over the course of the

1-mo-long protocol, subjects were scheduled to bedtimes at many different circadian phases. Similarly,

cognitive throughput and subjective alertness testing

occurred at all possible ranges of circadian phase, with

varying amounts of elapsed time since scheduled wakeThe costs of publication of this article were defrayed in part by the

payment of page charges. The article must therefore be hereby

marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734

solely to indicate this fact.

R1152 0363-6119/99 $5.00 Copyright r 1999 the American Physiological Society

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time (up to 18 h 40 min) occurring at each of these

circadian phases. Data from this 28-h protocol demonstrated a nonadditive interaction of the two processes

in the modulation of subjective alertness and cognitive

throughput (19), wakefulness within sleep episodes

(17, 20), and sleep structure, slow wave, and sleep

spindle activity (18). Recent analyses of these data

have shown a circadian modulation of low-frequency

sleep spindles during non-rapid eye movement (NREM)

sleep and of alpha frequency electroencephalogram

(EEG) activity during rapid eye movement (REM) sleep

(21).

The findings from the 28-h forced desynchrony protocol of circadian modulation of REM sleep and paradoxical timing of the sleep propensity rhythm were in good

agreement with previous findings (as reviewed in Ref.

18). Other findings from this protocol, such as the near

24-h intrinsic period of the endogenous body temperature and melatonin rhythms and the nonadditive interaction of the circadian and homeostatic processes in the

regulation of waking neurobehavioral function, were

new. The close phase relationship between high plasma

melatonin levels and optimal sleep consolidation remains a provisional finding.

On the basis of prior experience with a 28-h forced

desynchrony protocol, which produced greater than

normal sleep homeostatic drive due to its 18-h 40-min

scheduled wake and 9-h 20-min scheduled sleep episodes, we constructed a comparison protocol with a

20-h forced rest/activity and sleep/wake cycle. Thus

with only 13-h 20-min scheduled wake and 6-h 40-min

scheduled sleep episodes, sleep homeostatic drive was

lower than under normal (16-h wake and 8-h sleep)

conditions. Also, rather than delaying the sleep episodes, subjects in the current protocol were required to

undergo 4-h advances of their bedtimes and waketimes

each rest/activity cycle. Blood samples were obtained

each hour throughout the protocol for melatonin assay.

Neurobehavioral functions were assessed using an

entirely computerized assessment battery, which included additional testing of short-term memory, visual

vigilance and reaction time, and another test of cognitive throughput.

METHODS

Subject Selection

Potential volunteers were recruited via poster, newspaper,

and radio advertisement in the New England area. After

passing a telephone screening interview, potential subjects

gave informed consent and completed the following screening

questionnaires: the Beck Depression Inventory, the Minnesota Multiphasic Personality Inventory-II, the Horne-O ̈ stberg Morningness-Eveningness Questionnaire, and a questionnaire covering sleep habits and physical health. Subjects

showing no evidence of psychopathology or symptoms of a

primary sleep disorder (e.g., insomnia, sleep apnea) on these

screening instruments were scheduled for a physical examination, routine blood and urine chemistries, and a 12-lead

electrocardiogram. Exclusion criteria included any probable

or documented chronic or current major medical illness or

injury. They also received a screening interview with a

licensed clinical psychologist to rule out personal or familial

history of major psychopathology and to determine their

comprehension of and ability to comply with the investigational procedures. Finally, potential volunteers were interviewed by an investigator, and written informed consent was

obtained for the protocol, which was approved by the Brigham

and Women’s Hospital’s Human Research Committee.

Subjects were required to telephone the laboratory immediately prior to their scheduled bedtimes and immediately after

their scheduled waketimes for at least 3 wk before the study

to document adherence to an 8-h sleep episode, with bedtimes

and waketimes fixed at their reported habitual times. All

subjects completed at least 1 wk of wrist actigraphic monitoring (AMI-32, Ambulatory Monitoring, Ardsley, NY) of rest/

activity patterns to verify compliance with the prestudy sleep

schedule. Subjects were also instructed to abstain from

intake of alcohol, caffeine, nicotine, over-the-counter or prescription medications, health food or vitamin supplements, or

illicit substances for at least 2 wk before study. A urinary

comprehensive toxicological analysis was conducted to verify

that the subjects were drug-free on admission. Female subjects were given a blood pregnancy test both during screening

and on admission to verify absence of pregnancy. Self-report

data were collected on the timing of the menstrual cycle

relative to admission date.

Data reported in this paper represent subjects found to

have received placebo capsules only from an interim unblinding of our between-groups clinical trial of the efficacy of oral

Table 1. Subject demographics and estimated intrinsic period and amplitude of simultaneously estimated

intrinsic and evoked components of core body temperature and plasma melatonin

Subjects Study

Duration,

days

20-h Cycles

Completed, no.

Core Body Temperature Data Endogenous Melatonin Data

Code

Age,

yr Gender

Intrinsic

circadian

period, h:min

Endogenous

amplitude,

°C

Evoked

amplitude,

°C

Intrinsic

circadian

period, h:min

Endogenous

amplitude,

pmol/l

Evoked

amplitude,

pmol/l

a 25 M 27 24 24:15 0.24 0.13 24:15 97.7 25.9

b 25 M 27 24 23:58 0.21 0.25 24:01 249.4 25.0

c 24 M 18 17 * 0.24 0.17 24:00 43.6 7.0

d 19 M 17 15 * 0.20 0.10 24:02 151.1 38.5

e 19 M 27 24 24:17 0.27 0.36 24:15 196.6 47.7

f 27 F 27 24 24:10 0.21 0.18 24:09 123.3 15.3

Mean 23.2 — — — 24:10 0.23 0.20 24:07 143.6 26.6

SD 0:09 0.03 0.09 0:07 72.9 14.8

*Study duration insufficient to allow precise estimation of intrinsic circadian period from temperature data. M, male; F, female.

HOMEOSTATIC AND CIRCADIAN MODULATION R1153

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melatonin administration as a hypnotic (see Table 1 for

subject demographics).

Study Admission

Six subjects, one female and five male (age 19–27 yr, mean

23.2 yr), were studied in the Environmental Scheduling

Facility or the Intensive Physiological Monitoring Unit of the

General Clinical Research Center at Brigham and Women’s

Hospital. They were oriented to the study procedures and

systems in their suite. They received ,3 h of training on the

computerized neurobehavioral assessment battery, including

feedback from an investigator on their performance during

the first three baseline wake episodes. For all performance

tasks, subjects were instructed to perform as quickly as

possible, but without sacrificing accuracy.

Sleep/Wake and Light/Dark Cycle

In this 27-day protocol, subjects were scheduled to an

initial baseline segment consisting of three wake/sleep and

light/dark repetitions of 24-h cycles with 16-h wake episodes

and 8-h sleep episodes. The sleep schedule during the baseline segment was based on the bedtimes and waketimes

reported by the subject during the prestudy screening week

immediately before admission. Subjects arrived at the laboratory in the middle of the afternoon during that first 16-h wake

episode. Following three baseline cycles, they were scheduled

to 24 repetitions of a 20-h cycle, with 13-h 20-min wake

episodes and 6-h 40-min sleep episodes. After this forced

desynchrony segment, subjects were again scheduled to the

24-h cycle for three repetitions for a postdesynchrony baseline segment (see Fig. 1). The forced desynchrony segment

was thus similar to traveling eastward four time zones per

day, with bedtimes and waketimes advanced by 4 h per cycle.

Ambient lighting in the subject’s living area and bathroom

was verified to be ,15 lx (angle of gaze) during wake episodes

and ,0.03 lx during sleep episodes. We selected a relatively

dim lighting level during scheduled wake to minimize both

the possibility of relative coordination of circadian pacemaker

to the light/dark cycle (37) and the direct arousing effect seen

with brighter light (as reviewed in Ref. 8). From admission to

end of study, subjects were kept in an environment free of

time cues, with no access to timepieces of any type or any

information about time or calendar day from the nursing or

technical staff or from the investigators. Two subjects were

disempaneled midway through the protocol for minor illnesses. Their data are included in this report, because they

completed sufficient 20-h cycles to allow for analysis of

endogenous circadian phase and period (subject c was disempaneled due to tooth pain, after completing 17 20-h cycles;

subject d was disempaneled due to forearm dermal irritation

related to intravenous catheter use after completing 15 20-h

cycles).

Circadian Parameters

Core body temperature was recorded continuously from a

rectal temperature thermistor (Yellow Springs Instrument

Company, Yellow Springs, OH), with data stored in 1-min

epochs. Hourly blood plasma samples were obtained from an

indwelling catheter in a forearm vein for analysis of melatonin. Immediately after collection, each whole blood sample

was placed in a Vacutainer tube with EDTA, centrifuged at

2°C for 10 min at 2,200–2,800 rpm, and the separated plasma

was placed in an aliquot tube and frozen at 225°C. Plasma

samples were assayed by radioimmunoassay for melatonin

(assay sensitivity 10.1 pmol/l; DiagnosTech, Osceola, WI).

Separate nonorthogonal spectral analyses of the core body

temperature and plasma melatonin data collected during the

forced desynchrony portion of the protocol were used to

simultaneously estimate the evoked effect of the sleep/wake

cycle and the modulation from intrinsic circadian oscillation

(12). For both the core body temperature and plasma melatonin data, the regression model was fit with one fundamental

and one additional harmonic for the intrinsic circadian

component and a fundamental and seven additional harmonics for the evoked component. For core body temperature only,

the model included a parameter for serially correlated noise.

Estimations for the intrinsic amplitude of the temperature

and plasma melatonin rhythms were derived from composite

measures of a fundamental component plus one harmonic.

Estimations of evoked amplitude in these measures were

derived from composite measures of a fundamental component plus seven additional harmonics.

In addition to yielding an estimation of intrinsic period, the

regression analysis also yielded an estimated clock time for

the first core body temperature nadir. Thus each minute of an

individual subject’s forced desynchrony protocol could be

assigned a circadian phase varying from 0 to 360 degrees,

based on the offset from the first core body temperature

minimum (circadian phase 0) and the circadian period estimate given by the regression analysis (47).

Fig. 1. Double-raster plot of 27-day forced desynchrony protocol.

Each successive 24-h period is plotted to right and below preceding

24-h period. In this example from 1 subject (ID 1684), habitual

bedtime was 2400 and habitual waketime was 0800. After 3 baseline

cycles of 24 h, subject was placed on a 20-h sleep/wake and light/dark

cycle (sleep episodes indicated with horizontal boxes). All 5-min

epochs of the polysomnogram comprised of $50% wakefulness are

also shown (vertical bars within horizontal boxes indicating sleep

episodes). Two sleep episodes for which complete data were not

available are indicated with an ‘‘M.’’ Fitted peak of endogenous

plasma melatonin levels (dashed line) and trough of core body

temperature (solid line) drift to a later phase position relative to clock

time in this subject, both indicating a circadian period of 24 h 15 min.

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For each subject, plasma melatonin data were folded at the

circadian periods of the core body temperature data. They

were then analyzed with a bin width of 40 degrees for the

circadian component (,2.67 h) and a bin width of 30 degrees

for the sleep-wake dependent component (,1.67 h) referenced to the circadian phase and period data from the body

temperature, as outlined above.

Sleep Recordings

Referential electrooculogram (EOG) and scalp EEG, and

chin electromyogram were acquired during all sleep episodes

with a caplike sensor array (Sleep*Net, Physiometrix, North

Billerica, MA). Sleep data were collected using the Nicolet

UltraSom (Nicolet Biomedical, Madison, WI) or the Vitaport 2

Digital Sleep Recorder (Temec Instruments, Kerkrade, Netherlands). Data were acquired on both systems via amplification and analog-to-digital conversion (low-pass filter 5 35 Hz

and high-pass filter 5 0.3 Hz for UltraSom and low-pass

filter 5 70 Hz and high-pass time constant 5 0.33 s for

Vitaport 2). Sleep data were scored in 30-s epochs in accordance with standard criteria (41) by a polysomnographic

technician or an investigator, each with .7 years of experience with polysomnography. Each 30-s epoch of the sleep

recordings was assigned a circadian phase based on the core

body temperature data (as described above) and an elapsed

time-into-sleep episode. Sleep latency, defined as the elapsed

time from lights out to the first epoch of any sleep stage and

latency from sleep onset to REM sleep were log transformed

due to the skewed distributions of raw scores.

Neurobehavioral Assessment

At 2-h intervals beginning 2 h after scheduled awakening,

subjects were administered a 30-min computerized neurobehavioral assessment battery consisting of short-term memory

[Probed Recall Memory test (PRM); Ref. 22], simple reaction

time and visual vigilance [Psychomotor Vigilance Task (PVT);

Ref. 23], and two cognitive throughput tasks [Addition/

Calculation test (ADD); Refs. 19 and 34, Digit Symbol Substitution Test (DSST)]. At 30-min intervals beginning 30 min

after scheduled awakening, subjects were administered computerized tests of alertness/sleepiness [Karolinska Sleepiness

Scale (KSS); Ref. 26] and mood. Waking EEG and EOG were

recorded from 3 h after scheduled waketime until 1 h before

lights out each wake episode to document that wakefulness

was maintained in each scheduled wake episode. Technicians

awakened subjects whenever they noted that the EEG indicated the subject had fallen asleep.

Data Reduction and Statistical Procedures

In all results reported below, individual data points were

assigned a circadian phase and either 1) an elapsed time into

the wake episode (neurobehavioral measures); 2) an elapsed

time into the sleep episode (polysomnographic data); or 3) an

elapsed time into the 20-h cycle measured from scheduled

waketime (endogenous plasma melatonin data). Mean performance scores during the entire forced desynchrony segment

of the protocol were used to calculate deviation-from-mean

scores for all neurobehavioral measures collected during

forced desynchrony. Data reduction was accomplished by

averaging, within subjects and within measures, all data

points assigned the same circadian phase and elapsed time.

Thus each subject contributed equally to subsequent analyses. For analysis of circadian modulation of sleep structure, a

bin width of 60 degrees (,4 h) was selected. Neurobehavioral

data were analyzed with bin widths of 40 degrees for the

circadian component (,2.67 h) and 40 degrees for the wakedependent component (,2.22 h). Due to more frequent administration, the KSS data were analyzed with 30-degree bins for

both components.

Repeated-measures analyses of variance procedures were

used with the SAS software for Windows (version 6.12 for PC,

SAS Institute, Cary, NC). All P values are reported with

Huynh-Feldt correction for sphericity, but the original degrees of freedom are reported.

RESULTS

Intrinsic Period of Temperature and Melatonin

The intrinsic circadian periods estimated from the

core body temperature and plasma melatonin data

were on average slightly longer than 24 h, although

subjects were observed to have intrinsic circadian

periods both shorter and longer than 24 h (see Table 1).

Thus, in the 20-h forced desynchrony protocol, the

circadian pacemaker oscillated at a close to 24-h period

and desynchronized from the scheduled sleep/wake and

light/dark cycle period of 20 h.

Endogenous Plasma Melatonin

There was a significant effect of elapsed time into the

20-h day [F(8,24) 5 9.35, P , 0.0004]. There was also a

significant effect of circadian temperature phase

[F(8,24) 5 23.80, P , 0.0058]. The interaction between

elapsed cycle time and circadian phase was also significant [F(84,192) 5 2.84, P , 0.0372]. Melatonin levels

declined during elapsed hours of the wake episode,

rising coincident with the onset of the sleep episode

(Fig. 2, right). Average melatonin levels reached a peak

shortly before the core body temperature minimum (Fig. 2,

left). The melatonin data suggest greater circadian than

activity/rest cycle modulation of this hormone (Fig. 2).

Sleep Structure

In separate repeated-measures analyses of variance,

there were significant effects of circadian phase at the

beginning of the sleep episode on sleep latency [F(5,25) 5

4.28, P 5 0.0066] and latency from sleep onset to REM

sleep [F(5,25) 5 3.06, P 5 0.0341]. Sleep latency and

REM sleep latency were shortest near or shortly after 0

degrees and longest at 240 degrees of core body temperature (see Fig. 2).

With regard to sleep continuity, there was a significant effect of circadian phase on sleep efficiency

[F(5,25) 5 5.45, P 5 0.0016], minutes of total sleep time

[F(5,25) 5 5.69, P 5 0.0012], and minutes of wake after

sleep onset [F(5,25) 5 5.58, P 5 0.0023]. In all cases,

sleep continuity was highest in sleep episodes centered

at 0 degrees and lowest at 240 degrees (see Fig. 2).

Evidence of the effect of circadian phase of the sleep

episodes on sleep continuity can be seen in a double

raster plot of each sleep episode from a single subject

(Fig. 1). It is evident that in sleep episodes centered

around 240 degrees, significant sleep disruption occurs,

particularly in the last third of the sleep episodes.

For a more detailed inspection of sleep architecture,

data were assigned both a circadian phase relative to

the middle of the sleep episode and divided by third of

the 6-h 40-min sleep episode (see Table 2). With

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regard to sleep continuity, there were significant main

effects of both circadian phase and third of the sleep

episode, as well as significant two-way interactions for

the variables of sleep efficiency, minutes of total sleep

time, and percent of epochs scored as wakefulness. The

degree of circadian modulation of sleep continuity

increased in the last third of the sleep episodes, showing maximal circadian drive for sleep and minimal

intrusion of wakefulness in sleep episodes centered at 0

degrees (Fig. 3). Sleep continuity was also lowest

during the last third of the sleep episodes. Similarly,

the lowest percentage of stage 1 NREM sleep was seen

in the first third of the sleep episodes or, during the

later parts of the night, near the circadian temperature

Fig. 2. Double plots of body temperature, endogenous

plasma melatonin, and sleep parameters. Except for G,

all data in left panels are plotted with data folded at

endogenous circadian period as determined by core body

temperature for each subject. Data in all right panels are

folded at forced 20-h sleep-wake cycle. All data were

averaged first within each subject across all sleep episodes (sleep data) and sleep/wake cycles (melatonin and

temperature data), then averaged across subjects, with

plotted points reflecting mean values and their respective SE. Sleep latency is expressed in minutes, plotted on

a logarithmic scale (A). Sleep efficiency is expressed as a

percentage of time in bed (B). Slow-wave sleep (SWS; C)

and rapid eye movement (REM) sleep (D) are expressed

as a percentage of total sleep time. REM latency (E) was

expressed as minutes from sleep onset to first epoch of

REM sleep. Melatonin data are depicted with raw plasma

levels folded either at endogenous circadian period as

determined by temperature (F, left) or at forced 20-h

sleep-wake cycle (F, right). Core body temperature was

also determined by simultaneously estimated intrinsic

circadian variation (G, left) and evoked effect of sleep/

wake cycle (G, right). W, wake; S, sleep.

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nadir. Percentage of stage 2 NREM sleep increased

across the sleep episodes, concurrent with a decrease in

slow-wave sleep (SWS). However, of the two stages,

only stage 2 sleep showed a significant circadian modulation as well. Finally, REM sleep showed a significant

effect of circadian phase and trend for third of the sleep

episode, and a significant interaction of the two effects.

The highest percentage of time spent in REM sleep was

seen just after the circadian temperature nadir.

Waking Neurobehavioral Assessment

For the ADD task, there were significant main effects

of elapsed wake and circadian phase. For the DSST,

there was a trend in the main effect of elapsed wake

and a significant effect of circadian phase. For the PRM

task, there was a significant main effect of elapsed

wake, but not a significant effect of circadian phase. For

the PVT, there were significant main effects of elapsed

wake for median reaction time and lapses (lapses

defined as reaction times $500 ms) and circadian

phase. In none of these tasks were there significant

interactions of elapsed wake and circadian phase.

However, for all tasks, performance worsened with

increased hours of wakefulness and near the circadian

temperature nadir. During the first 3 h 20 min of

wakefulness, performance across the test battery remained better than the mean level from the entire

forced desynchrony portion of the protocol. Also within

this time bin, there was little circadian variation

evident in the tasks, except for the ADD task. In

marked contrast, during the last bin of elapsed wakefulness (from 10 h to 13 h 20 min), performance levels

were worse than the mean level. Also, with increased

hours of elapsed wakefulness, and hence increased

sleep homeostatic pressure, the degree of circadian

modulation became greater, although not reaching

statistical significance (see Figs. 4 and 5 and Table 3).

With regard to subjective sleepiness/alertness, there

were significant main effects of elapsed wake and

circadian phase. There was also a significant interaction of the two factors; the degree of circadian modulation increased with hours of elapsed wakefulness (Fig. 5).

DISCUSSION

General Findings

In this forced desynchrony protocol with 20-h light/

dark and activity/rest cycles, we found that the intrinTable 2. Analysis of sleep architecture by third of sleep

episode and circadian phase

Variable

Third of Sleep Episode Circadian Phase Interaction

F(2,10) P F(5,25) P F(10,50) P

TST, min 10.63 0.0071 6.61 0.0005 2.76 0.0191

SE, % 10.52 0.0072 6.56 0.0005 2.76 0.0191

Wake, % 10.47 0.0073 6.66 0.0005 2.78 0.0187

Stage 1, % 13.04 0.0016 3.12 0.0383 1.69 NS

Stage 2, % 17.41 0.0006 4.12 0.0508 1.56 NS

SWS, % 29.15 ,0.0001 0.70 NS 0.81 NS

REM, % 2.94 0.1425 9.86 0.0002 4.28 0.0003

TST, total sleep time; SE, sleep efficiency; SWS, slow-wave sleep;

REM, rapid eye movement; NS, not significant.

Fig. 3. Depiction of interaction of time into each sleep episode (rows) and circadian phase (abscissa of each plot,

determined as circadian phase position of each 30-s epoch of sleep relative to core body temperature minimum) on

sleep efficiency and architecture. Plotted points show mean values and their respective SE. Sleep efficiency (A) is

expressed as a percentage of time in bed. Sleep stages (B-E) are expressed as a percentage of total sleep time.

CBTmin, core body temperature minimum.

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sic period of the circadian pacemaker averaged 24.1–

24.2 h. Also, even with only 13 h 20 min of scheduled

wakefulness preceding each sleep episode, there was

still significant homeostatic and circadian modulation

of sleep structure, with the highest sleep efficiency

occurring in sleep episodes bracketing the melatonin

maximum and core body temperature minimum. However, at these same circadian phases and toward the

end of each wake episode, maximal impairment of

neurobehavioral functioning was observed across all

subjective and objective measures. The results make

clear the importance of the sleep/wake homeostatic

system, the endogenous circadian system, and their

interaction in the modulation of sleep and neurobehavioral functions in healthy young adults.

Intrinsic Period: Melatonin and Core Body

Temperature

In this study, we found that under a forced desynchrony protocol with a 20-h light/dark and activity/rest

cycle, the intrinsic period of the circadian pacemaker as

derived from core temperature and plasma melatonin

averaged much closer to 24 h than earlier reported in a

variety of studies (e.g., Refs. 2, 35, 50), but consistent

with more recent estimations (e.g., Refs. 7, 10, 12, 29,

39). The period estimations appeared quite stable in

the subjects who completed the entire protocol, and

were nearly identical when estimated based on either

continuous recordings of core body temperature or

hourly plasma melatonin samples. Importantly, the

variability of our estimations of intrinsic circadian

period was quite small both within and across subjects,

in contrast to the report of a very short duration (5 day)

20-h forced desynchrony protocol (29), which found

higher intra- and intersubject variability in estimations of period. In addition, our estimations of intrinsic

period were not confounded by exposure to potential

nonphotic synchronizers (e.g., access to time information, direct contact with other subjects, activity recurring at the same circadian phase) and potential interactions between self-selected sleeping times and melatonin

secretion (39).

Fig. 4. Double plots of main effects of circadian phase

relative to minimum of core body temperature (left) and

duration of prior scheduled wakefulness (right) on

neurobehavioral measures. Plotted points show deviation from mean values during forced desynchrony section of protocol and their respective SE. For all panels,

values plotted lower in panel represent impairment on

that neurobehavioral measure.Addition/Calculation test

(ADD; A), Digit Symbol Substitution Test (DSST; B),

and Probed Recall Memory test (PRM; C) scores are

derived from total number of correct responses. Psychomotor Vigilance Task (PVT) results represent median

reaction time (D) and total number of lapses (E, reaction

times .500 ms). Karolinska Sleepiness Scale (KSS)

scores (F) represent responses on this 1–9 Likert-type

scale.

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Furthermore, we found a stable phase relationship

between melatonin and core body temperature, with

the onset of melatonin secretion and the initial decline

in core body temperature occurring at a circadian phase

normally encountered a few hours before habitual

bedtime. Peak melatonin levels were reached just

before the core body temperature minimum at a circadian phase value normally encountered a few hours

before the habitual waketime.

Homeostatic and Circadian Modulation of Sleep

Propensity and Sleep Structure

Sleep initiation and continuity. In the analyses of the

sleep episodes as a whole, the sleep latency data point

to the temperature nadir (0 circadian degrees) as a time

of maximal circadian drive for sleep and approximately

240 degrees as a time of maximal circadian drive for

wakefulness or minimal circadian drive for sleep. These

data are consistent with the earlier observations from

high-frequency sleep/wake schedules (9, 38, 49), freerunning studies (13, 44, 47, 53), and 28-h forced desynchrony studies (17, 18). However, it was somewhat

surprising that even with phase advances of the sleep/

wake episodes that placed scheduled bedtime near

what has been called the ‘‘forbidden zone for sleep’’ (38)

Fig. 5. Depiction of interaction of duration of prior scheduled wakefulness (rows) and circadian phase (abscissa of

each plot, determined as circadian phase position of time of each individual test administration relative to core body

temperature minimum) on neurobehavioral measures. Plotted points show deviation from mean values during

forced desynchrony section of protocol and their respective SE. For all panels, values plotted lower in panel

represent impairment on that neurobehavioral measure. As in Fig. 4, ADD (A), DSST (B), and PRM (C) scores are

derived from total number of correct responses. PVT results represent median reaction time (RT; D) and total

number of lapses (E, reaction times .500 ms). KSS scores (F) represent responses on this 1–9 Likert-type scale.

Table 3. Analysis of neurobehavioral measures by

elapsed time into wake episode and circadian phase

Variable

Duration of Prior

Scheduled

Wakefulness Circadian Phase Interaction

F(3,15) P F(5,25) P F(15,75) P

ADD 12.07 0.0003 5.23 0.0051 1.45 NS

DSST 2.79 0.0910 3.51 0.0220 1.33 NS

PRM 5.77 0.0079 1.82 NS 0.84 NS

PVT: median RT 5.21 0.0553 4.60 0.0545 1.27 NS

PVT: lapses 9.94 0.0066 8.59 0.0013 1.51 NS

KSS 4.94 0.0045 12.20 0.0002 1.82 0.0590

ADD, Addition/Calculation test; DSST, Digit Symbol Substitution

Test; PRM, Probed Recall Memory test; PVT, Psychomotor Vigilance

Task; KSS, Karolinska Sleepiness Scale.

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or the ‘‘wake maintenance zone’’ (45), we did not

observe pathologically long sleep latencies. These data

suggest that with at least 13 h 20 min of wakefulness

preceding each sleep attempt, healthy, young normalsleeping individuals do not exhibit sleep-onset insomnia in this protocol, even with sleep scheduled at a

phase corresponding to late in the habitual waking day.

The word ‘‘forbidden’’ is thus perhaps a bit too strong.

In fact, in the ultrashort sleep studies, subjects were

given only 7 min to fall asleep in each attempt. Our

data indicate that at the circadian phase associated

with the wake maintenance zone (45), sleep latencies

were at their peak, averaging nearly 20 min. Hence, our

data are consistent with those of Lavie (38) and with

the concept of a wake maintenance zone. Psychophysiological insomniacs studied on this protocol might

exhibit an even more impressive variability of sleep

latencies when bedtimes are varied over the range of

the circadian cycle.

We also observed significant effects of circadian phase

on several measures of sleep continuity: minutes of

total sleep time, sleep efficiency, and percentage of

wakefulness. Across these highly related measures,

sleep episodes centered at the phase of 0 circadian

degrees had the highest sleep continuity and the lowest

percentage of wakefulness. Conversely, sleep episodes

centered around the 240 degree circadian temperature

phase had the lowest sleep continuity and the greatest

amount of wakefulness. These data are also consistent

with findings from both free-running studies (14, 53)

and 28-h forced desynchrony protocols (17, 18). The

data are also consistent with the observations that the

duration and termination of self-selected sleep episodes

in free-running subjects were highly related to the

phase of the core body temperature rhythm, such that

subjects tended to wake up on the rising phase of the

temperature rhythm (13, 53). Taken together, the sleep

initiation and continuity data suggest that in normal

healthy adults without sleep complaints, the greatest

sleep propensity and hence the most efficient, consolidated sleep would be obtained under conditions seen in

normal entrainment, with the habitual bed- and waketimes bracketing the endogenous circadian temperature nadir and melatonin maximum.

Sleep architecture. The analyses of sleep episodes by

third of sleep episode and by midsleep circadian phase

address the combined effects of the sleep/wake homeostat and the circadian pacemaker on sleep continuity

and structure. Sleep fragmentation was worst during

the last third of the sleep episode, indicating that with

low homeostatic pressure for sleep, circadian modulation of sleep fragmentation becomes impressively evident. This is consistent with our findings from the 28-h

forced desynchrony protocol (18). Also, as described

elsewhere (16, 18), we observed a sleep-dependent

disinhibition of REM sleep. In addition to showing

profound circadian modulation of REM percentage and

latency from sleep onset to REM sleep, as has been

shown in free-running studies (13, 14), there was

suggestive evidence of a trend increase in REM sleep

percentage as homeostatic pressure for sleep abated.

Finally, we observed a dominant homeostatic modulation of SWS, with the amount of SWS declining across

successive thirds of the individual sleep episode regardless of circadian phase position of the sleep episode, as

has also been shown in free-running studies and forced

desynchrony protocols (18, 48). Thus these analyses

confirm that SWS is a simple but informative indicator

of both overall homeostatic sleep pressure built up

before sleep and the satiation of homeostatic sleep

pressure brought about by continued time spent sleeping, as proposed by Webb and Agnew (46).

Temporal Relation of Melatonin, Core Body

Temperature, and Sleep

The close correspondence between the phase of the

rhythms of core body temperature, endogenous plasma

melatonin, and sleep propensity was consistent with

our previous findings (18, 21). With regard to possible

effects of body temperature on sleep, melatonin has

been reported to be a hypothermic agent when given

exogenously (25, 31), but it remains unclear whether

melatonin levels in the true physiological range produce significant declines in body temperature (reviewed in Ref. 6). We found a small but significant

evoked effect of the imposed 20-h routine on the plasma

melatonin levels consistent with our report from the

28-h day (42). Whether this effect is evoked by the

timing of the sleep/wake cycle or the associated changes

in lighting (although very dim throughout the protocol

during wake) or posture cannot be determined from

this protocol. In general, it remains unclear the extent

to which melatonin and core body temperature may

have been causally related in this protocol and the

extent to which melatonin and/or core body temperature may have been causally related to sleep propensity.

Homeostatic and Circadian Modulation of

Neurobehavioral Functions

This protocol used a broader range of neurobehavioral measures than has previously been reported in

studies examining both sleep/wake homeostatic and

circadian modulation of alertness and cognitive performance. Across all measures, we observed homeostatic

modulation of performance, with impairments in subjective sleepiness and cognitive performance increasing

with duration of elapsed wakefulness. This is impressive, given that the scheduled wake episodes were

several hours shorter than the duration of a habitual

waking day, and hence there was less time for homeostatic sleep pressure to build.

In addition, we noted significant circadian modulation of these measures. Across all measures, neurobehavioral functioning was best at ,240 circadian degrees and showed maximal impairment at or just after

0 circadian degrees. In terms of the physiology, maximal circadian promotion of neurobehavioral functioning was seen near the core body temperature maximum

and just before the release of melatonin, and maximal

circadian impairment was seen just after the nadir of

core body temperature and the maximum of melatonin

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secretion. Under conditions of entrainment, this maximal circadian drive for wakefulness would occur near

the end of the habitual waking day. Similarly, maximal

circadian drive for sleep and, hence, maximal impairment of waking neurobehavioral functioning, would

occur near the end of the habitual sleep episode. All of

these findings are consistent with the subjective alertness and cognitive throughput results reported from

the 28-h forced desynchrony protocol (19).

Only the subjective alertness measure showed statistically significant interaction between the homeostatic

and circadian processes. However, visual inspection of

the data (Fig. 5) suggested interesting potential differences between the tasks. For example, it appeared that

there was circadian modulation of the two cognitive

throughput tasks regardless of the level of homeostatic

sleep pressure. These two tasks have heavy attentional

and short-term memory loading, which may make

them more sensitive to circadian modulation than the

other tasks. For the PRM task and the two indexes of

the PVT, the amplitude of circadian modulation appeared to increase with increasing hours of wakefulness. Furthermore, studies on a larger data set will be

required to determine whether these intriguing intertask differences in the extent of circadian-homeostatic

interaction are upheld.

A possible explanation for the failure to find a

significant interaction between the homeostatic and

circadian factors in these analyses lies in the fact that

the absolute level of homeostatic pressure was never

very great in this protocol; none of the subjects reported

great difficulty remaining awake during the wake

episodes, and the duration of enforced wakefulness was

limited to 13 h 20 min. In other reports of a nonlinear

interaction of the pacemaker and the homeostat in the

modulation of waking neurobehavioral performance

(19, 52), wake episodes were scheduled to between 18 h

40 min and 28 h 34 min. Thus it may not have been

possible to find significant interactions in the present

protocol due to an insufficient physiological challenge

to the sleep homeostatic system. Finally, limited statistical power associated with this small sample size may

have contributed to the lack of significance in these

interactions, except as demonstrated for subjective

alertness.

Implications

In this 20-h forced desynchrony protocol, we found

patterns of sleep and neurobehavioral regulation similar to those found in a 28-h forced desynchrony protocol

(19). In both the sleep and neurobehavioral data, we

found further evidence to support the conclusion that

the endogenous circadian pacemaker actively promotes

both sleep initiation and sleep consolidation, the latter

being particularly critical when homeostatic pressure

for sleep is nearly satiated toward the end of a sleep

episode. In contrast, during wake episodes scheduled to

occur during the normal circadian time of wakefulness

(60–240 degrees), the pacemaker has an active role in

the promotion of wakefulness, which is particularly

useful in offsetting the decline in alertness and performance resulting from homeostatic sleep pressure shown

with increased hours of wakefulness (11). If not for

these active modulations from the circadian pacemaker, sleep would become very fragmented after the

first few hours and it would be difficult to maintain

optimal alertness during even a normal, 16-h duration

of desired wake. Taken together, when an optimal

relationship exists between the sleep/wake schedule

and the phase of the endogenous circadian system, the

modulatory influences of the sleep/wake homeostat and

the pacemaker combine in this complementary manner

to allow for a relatively long (7–9 h) consolidated sleep

episode and a stable level of waking neurobehavioral

function across the habitual waking day (15–17 h; Refs.

11, 17). Although these findings are clear in this

population of healthy young adults, it could be the case

that differences may be found between these young

adults and older adults (20) or adults with sleep

complaints.

In addition to providing additional information about

the basic, yet critically important, interaction of the

sleep/wake homeostatic and the endogenous circadian

processes, data from the forced desynchrony protocol

allow us to make testable predictions for sleep and

waking functioning in individuals with sleep/wake

schedules other than the traditional 8:16-h pattern. In

jobs requiring high levels of attention and performance

over extended durations of time (e.g., long-haul aircrews or truck drivers, medical house staff, nuclear

power plant operators), medical advisers or supervisors

using computerized models that include this nonlinear

interaction of the sleep homeostat and the circadian

pacemaker could warn workers of times of performance

vulnerability and inadvertent sleep onset, as well as

advise optimal timing of sleep or other countermeasures against neurobehavioral deficit (see Ref. 40). The

forced desynchrony protocol itself also provides a singular opportunity to quantify the homeostatic- and circadian-dependent properties of various medications, including stimulants and hypnotics, medications with a

desired time of action (e.g., antihypertensives), and

medications with variable side-effect profiles (e.g., anticancer medications). Additionally, awareness of the

relationship between the sleep homeostat and the

endogenous circadian pacemaker may increase our

understanding of the most prevalent sleep disorder,

insomnia.

In summary, we found that healthy young subjects on

a 20-h forced desynchrony protocol exhibited significant modulation of sleep structure and waking neurobehavioral functions from the sleep/wake homeostatic

and endogenous circadian systems. We saw progressive

impairment on multiple neurobehavioral tasks with

increasing duration of prior wakefulness, suggesting

the powerful impact of accumulating homeostatic sleep

pressure even with scheduled wake episodes several

hours shorter than the habitual 16- to 17-h duration.

Relative to clock hours observed during conditions of

normal entrainment and given the average intrinsic

circadian period of 24.1–24.2 h found in this protocol,

the timing of maximal circadian drive for wakefulness

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occurred just before the habitual bedtime, and the

maximal drive for sleep occurred just before habitual

waketime. These data support the concept that under

normal conditions, the paradoxical interaction of the

homeostatic and circadian systems serves to consolidate both sleep and wakefulness in healthy young

adults.

The authors thank Wendy Campanella and Sara DenBesten for

subject recruitment; Karen Smith, RPsgT, and Jason Sullivan for

assistance with sleep scoring; Joseph M. Ronda, MS, for software

development in support of the temperature and neurobehavioral

measures; David F. Dinges, PhD, and John Powell for providing three

neurobehavioral tasks (PRM, PVT, and DSST) and advice on their

interpretation; the staff of the General Clinical Research Center at

Brigham and Women’s Hospital for subject monitoring and data

collection; and Jeanne F. Duffy, PhD, for helpful comments on the

manuscript.

This research was supported by National Institute on Aging Grant

U01-AG12642 and National Academy of Sciences National Aeronautics and Space Administration Grant NAS9-19435. The studies were

carried out in a General Clinical Research Center supported by

National Institutes of Health Division of Research Resources Grant

RR-02635.

Address for reprint requests and other correspondence: J. K.

Wyatt, Department of Psychology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612-3833 (E-mail: jwyatt@rush.edu).

Received 9 February 1999; accepted in final form 10 June 1999.

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