Am J Physiol Regulatory Integrative Comp Physiol

279: R1574R1579, 2000.

Dynamic resetting of the human circadian pacemaker by

intermittent bright light
DAVID W. RIMMER,1 DIANE B. BOIVIN,1 THERESA L. SHANAHAN,1
RICHARD
E. KRONAUER,2 JEANNE F. DUFFY,1 AND CHARLES A. CZEISLER1
1
Circadian, Neuroendocrine and Sleep Disorders Section, Division of Endocrinology, Department of
Medicine, Harvard Medical School, Brigham and Womens Hospital, Boston 02115; and 2Division of
Engineering and Applied Sciences, Harvard University, Cambridge, Massachussets 02138
Received 15 March 2000; accepted in final form 16 June 2000

Rimmer, David W., Diane B. Boivin, Theresa L.

Shanahan, Richard E. Kronauer, Jeanne F. Duffy, and
Charles A. Czeisler. Dynamic resetting of the human circadian pacemaker by intermittent bright light. Am J Physiol
Regulatory Integrative Comp Physiol 279: R1574R1579,
2000.In humans, experimental studies of circadian resetting typically have been limited to lengthy episodes of exposure to continuous bright light. To evaluate the time course of
the human endogenous circadian pacemakers resetting response to brief episodes of intermittent bright light, we studied 16 subjects assigned to one of two intermittent lighting
conditions in which the subjects were presented with intermittent episodes of bright-light exposure at 25- or 90-min
intervals. The effective duration of bright-light exposure was
31% or 63% compared with a continuous 5-h bright-light
stimulus. Exposure to intermittent bright light elicited almost as great a resetting response compared with 5 h of
continuous bright light. We conclude that exposure to intermittent bright light produces robust phase shifts of the endogenous circadian pacemaker. Furthermore, these results
demonstrate that humans, like other species, exhibit an
enhanced sensitivity to the initial minutes of bright-light
exposure.

in understanding photic
resetting of the human circadian pacemaker since it
was initially recognized that light is the principal circadian synchronizer in humans (9, 12, 14, 18, 27, 34,
41). Photic induction of circadian phase shifts has been
characterized extensively and is known to depend on
several variables including the timing, duration, and
intensity of retinal light exposure. Techniques of bright
light administration gleaned from these principles
have been implemented successfully not only in the
laboratory setting but also in the treatment of a variety
of disorders including maladaptation to night shift
work, delayed and advanced sleep phase syndrome,
circadian rhythm sleep disorders, dyssomnia associated with transmeridian travel and spaceflight, as well
as age-related early morning awakening (3, 4, 7, 8, 10,

13, 17, 23, 34, 38, 40, 41). However, the use of brightlight therapy in these settings typically has consisted
of 2- to 8-h continuous exposures. The imposition of
time constraints involved in such extended exposures
obviates the need to develop, on the one hand, more
efficient means of delivering bright-light therapy,
whereas on the other hand, retaining the ability to
induce phase shifts of comparable magnitude to those
obtained through extended exposures.
Much of the evidence supporting the notion that the
endogenous circadian pacemaker may be sensitive to
shorter durations of light exposure comes from animal
models. In 1991, Nelson and Takahashi (35) demonstrated that the action of light as a synchronizer of the
circadian clock in the golden hamster Mesocricetus
auratus was most efficient during the first few minutes
of the application and that further extension of the
stimulus produced little additional phase shift. This
finding was consistent with photic resetting properties
observed in the mosquito (37). Furthermore, it has
been reported that the circadian system of mice can
integrate a chain of 60 very brief (2 ms) light pulses to
cause circadian phase shifts of up to 2 h (42). Yet, the
temporal dynamics of the circadian phase resetting
response to light in humans remains unquantified.
This is particularly notable because exposure to bright
light is typically intermittent in everyday life (21, 26,
36, 39). Therefore, to characterize whether humans,
like rodents and mosquitoes, have enhanced sensitivity
to the initial minutes of intermittent light exposure, we
undertook experiments to examine whether repeated
brief exposures to 9,500 lx of light produce robust
phase shifts of the circadian timing system. We compared the phase shifts produced by those brief, repeated light exposures to those elicited by continuous
light exposure and by darkness to estimate the temporal dynamics of the human circadian response to light.
Our results reveal that the endogenous circadian timing system of humans is far more sensitive to shorterduration light exposure than was previously recognized.

Address for reprint requests and other correspondence: C. A.

Czeisler, Circadian, Neuroendocrine and Sleep Disorders Section,
Div. of Endocrinology, Harvard Medical School, Brigham and Womens Hospital, 221 Longwood Ave., Boston, MA 021155817.

The 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.

circadian rhythms; core body temperature; phototherapy

MANY ADVANCES HAVE BEEN MADE

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0363-6119/00 $5.00 Copyright 2000 the American Physiological Society

http://www.ajpregu.org

INTERMITTENT LIGHT RESETS THE HUMAN CIRCADIAN PACEMAKER

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MATERIALS AND METHODS

Subjects. Sixteen healthy men (24 2.1 yr, means SD)

were recruited for study using newspaper advertisements
and billboard flyers. All subjects were free from any acute or
chronic physical or psychiatric disorders. Medical suitability
was determined on the basis of medical history, physical
examination, ophthalmologic examination, and blood and
urine chemistries. Psychological screening questionnaires,
including the Minnesota Multiphasic Personality Inventory
and the Beck Depression Inventory and State Anxiety Scale
were used to exclude subjects with evidence of psychopathology from participation in the study. Individuals with a history of drug dependency, psychiatric illness, or affective disorder such as major depression or manic-depressive illness,
were excluded from study. Subjects were asked to refrain
from using alcohol, nicotine, prescription drugs, dietary supplements, and caffeine throughout the course of the study;
urinary toxicological analysis was performed to ensure that
subjects were drug free on admission to the laboratory. All
subjects studied reported no recent history of regular nightshift work, and none reported crossing more than one time
zone in the previous 3 mo. Subjects were asked to maintain a
regular sleep-wake schedule for 3 wk at home before the
study, such that their habitual bedtimes and wake times
occurred at the same time (30 min) each day and were 8 h
apart. Compliance was verified by sleep-wake logs and wrist
actigraphy monitoring for the week before the study. The
protocols used were reviewed and approved by the Human
Research Committee at the Brigham and Womens Hospital,
and each subject gave written informed consent before the
start of the inpatient portion of the protocol.
Experimental protocol. Subjects underwent an experimental protocol designed to measure the phase-shifting effects of
intermittent light on the endogenous core body temperature
cycle. All studies were performed in the Environmental
Scheduling Facility of the General Clinical Research Center
of the Brigham and Womens Hospital.
On empanelment in the 2-wk study, each subject underwent 3 adaptation days, with the time of their 8-h sleep
episode schedule based on their habitual bedtime and wake
time obtained from the prestudy sleep-wake logs. Beginning
at wake time on the fourth day, subjects underwent a constant-routine (CR) procedure (detailed below) that consisted
of 3033 h of enforced wakefulness to assess the phase of the
endogenous circadian core body temperature rhythm. The
CR continued until 9.5 h after the fitted minimum of the core
body temperature rhythm on day 5, at which time subjects
were allowed to sleep for 8 h. For the next 3 consecutive days,
subjects were then scheduled to undergo one of two intermittent bright-light conditions (detailed below) followed by a
final CR assessment of endogenous circadian phase that
lasted 4050 h (Fig. 1).
From admission to the laboratory until 1.5 h before bedtime
on day 3, subjects lived in 150 lx of light during waking hours.
From that point forward, room light intensity was lowered to
1015 lx during waking hours (except during bright lightexposure episodes) for the remainder of the study. All sleep
episodes were conducted in 0.02 lx (all reported light intensities were measured in the angle of gaze).
CR. We used the CR procedure to reveal the endogenous
component of the circadian core body temperature rhythm.
This methodology is a modification of the original technique
used by Mills et al. (32) and has been successfully used to
minimize or distribute evenly the potential masking effects
associated with changes in activity, posture, sleep-wake
state, diet, and ambient temperature across the circadian

Fig. 1. Double raster plot of study protocol. Successive days are

plotted both beneath each other as well as side by side. Solid bars
indicate scheduled sleep episodes, open bars represent the constant
routines (CR), and open circles represent the estimated endogenous
circadian phase of the core body temperature minimum (CBTmin).
Open boxes (sun) represent the 3-cycle, 5-h/day bright-light stimuli.
For the first 3 days, subjects 8-h sleep episodes were scheduled to
occur at their habitual bedtimes and were conducted in darkness
(0.03 lx). Ambient light intensity during waking hours was 150 lx
until 1.5 h before bedtime on day 3. Thereafter, all waking hours
were conducted in 1015 lx for the remainder of the study (gray
area). Bright-light stimuli were centered 1.5 h after the CBTmin
determined during the first CR. Subsequent sleep episodes were
scheduled to begin 9.5 h after the initial CBTmin, the midpoint of
which corresponded to 12 h opposite the midpoint of the bright-light
stimuli. The phase-shifting effect of the bright-light treatments was
assessed during the second CR.

cycle (9, 12, 15, 33). When successfully employed, this technique affords an assessment of the output of endogenous
circadian pacemaker, as reflected by the core body temperature rhythm. The CR procedure in these studies consisted of
a regimen of enforced semirecumbent wakefulness with activity restricted to prevent changes in body posture. Daily
caloric intake was calculated using the Wilmore nomogram
(44) that was adjusted upward by an activity factor of 10% to
maintain a consistent metabolic state across circadian
phases. Sustenance was provided in the form of hourly
snacks and liquid aliquots containing 150 mmol of sodium
and 100 mmol of potassium per 24-h period. A technician was
present throughout the CRs to ensure compliance with the
posture, activity level, and constant wakefulness aspects of
the protocol.
Lighting regimen. Subjects were assigned to one of two
intermittent lighting conditions that consisted of a threecycle, 5-h episode of exposure to bright light (9,500 lx in the
angle of gaze) interrupted by episodes of complete darkness.
This episode was centered on average 1.51 0.08 h (means
SD) after the initial endogenous temperature minimum and
administered against a background of dim light (1015 lx).
Within each 5-h episode, darkness episodes were repeated at
90- or 25-min intervals (duty cycle; Fig. 2, c and d ). Subject
comfort required that the light-dark transitions be effected
with moderate stepwise changes that were spaced uniformly
in time. As a result, the subjects were in darkness for 44
min of the 90-min duty cycle or 19.7 min of the 25-min duty
cycle. The effective duration of bright-light exposure for each
5-h intermittent stimulus together with the 25-min transitions before and after the 5-h stimulus was 63% or 31%,
respectively, compared with the continuous bright-light protocol (see below). Results obtained from these two groups of
subjects were compared with historical data from 15 volunteers (21.67 3.54 yr, mean SD) who participated in the

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INTERMITTENT LIGHT RESETS THE HUMAN CIRCADIAN PACEMAKER

Fig. 2. Lighting regimen used to study the phase-shifting effect of 3

cycles of 5-h bright-light exposures on the endogenous circadian
pacemaker. Exposures were centered 1.5 h after the endogenous
circadian core body temperature minimum (time 0 on axis) to induce
phase advances of the endogenous circadian pacemaker (a). Each
stimulus consisted of exposure to either 3 cycles of 5 h of continuous
bright (10,000 lx) light (100% stimulus; b), 3 cycles of 5 h of bright
light consisting of 46 min of light within each 90-min duty cycle
(63% stiumulus; c), 3 cycles of 5 h of bright light consisting of 5.3
min of bright light within each 25-min duty cycle (31% stimulus; d),
or complete darkness (0% stimulus; e). Each 5-h stimulus was preceded and followed by 25-min transitions during which the intensities were increased and decreased in 5-min intervals. Similarly,
within the 90- and 25-min duty cycles, light intensities were progressively increased and decreased in 1-min intervals and 10-s intervals,
respectively. The effective duration of bright-light exposure producing drive on the endogenous pacemaker for all transitions are represented by the dashed lines (28).

same experimental protocol but were exposed to a 5-h stimulus consisting of either continuous (100%) bright light (Fig.
2b) or continuous (0%) darkness (control; Fig. 2e) (16).
Physiological monitoring. The bright-light stimuli were
administered using ceiling-mounted cool-white fluorescent
lamps (North American Philips Lighting, Bloomfield, NJ).
Light measurements were performed using a research photometer [model 1700 and SED (SEL) 038/Y 7859/W 3339
detector; International Light, Newburyport, MA] held at the
forehead and directed in the line of gaze. Subjects were
outfitted with clear goggles throughout the 5-h intermittent
light episodes (model #S379; Uvex Safety, Smithfield, RI) to
exclude ultraviolet exposure.
Throughout the entire study, subjects were maintained in
an environment free from time cues, and social contact was
limited to the laboratory personnel who were specially
trained to apply the physiological monitoring devices, administer light stimuli, ensure wakefulness, and shield the subjects from temporal information.
Core body temperature was recorded via disposable rectal
thermistors (Yellow Springs Instrument, Yellow Springs,
OH), and room temperature was recorded by a surface thermistor and maintained at 29.6 0.9C (mean SD). Both
the core body temperature and room temperature were recorded at 1-min intervals by means of a real-time, online
data-acquisition system using IBM PC-compatible, Pentiumbased computers.
Statistical analysis. Circadian phase was estimated from
the core body temperature data derived from the CRs by a

dual-harmonic regression plus correlated noise model fit to

the data by a nonlinear least-squares procedure (6). The first
5 h of CR temperature data were excluded from analysis to
minimize the masking effects resulting from the transition
from sleep to wake and postural changes associated with
beginning the CR. Phase shifts were calculated as the difference (in hours) in the time of the fitted core body temperature
minima between the first and second CRs. By convention,
phase advances (to an earlier hour) are represented as positive phase shifts, whereas phase delays (to a later hour) are
negative phase shifts. An ANOVA, with planned tests for
linear and quadratic trends, as well as post hoc pairwise
comparisons using Tukeys method, were used to evaluate
the effect of the intervention regimen on phase shifts between groups of subjects. In addition, the data were compared with the resetting responses predicted for the intermittent light stimulus by a mathematical model of the effect
of light on the human circadian pacemaker (22), in which it
was presumed that any given duration of light exposure
exerts an intensity-dependent direct drive on the pacemaker,
independent of the duration of prior light exposure (30).
RESULTS

As previously reported at that phase of light administration (12), all light-exposed groups demonstrated
phase advances of their endogenous circadian rhythm
of core body temperature. The median phase-advance
shift observed was 2.87 h in the group of subjects
exposed to the intermittent 31% bright-light duty
schedule; 3.90 h in the group exposed to the intermittent 63% bright-light duty schedule; and 4.52 h in the
group exposed to the 100% continuous bright-light
stimulus, respectively (Fig. 3). A median phase delay of
0.97 h was observed in the 0% group of subjects
exposed to continuous darkness, consistent with the
slightly longer-than-24-h period of the endogenous circadian pacemaker (11, 16). Thus, compared with the

Fig. 3. Resetting responses of 31 individual subjects to the 0%

(continuous darkness), 31% (5-min bright light, 20-min darkness
duty cycle), 63% (46-min bright light, 44-min darkness duty
cycle), and 100% (continuous bright light) conditions. Phase-advance
shifts are plotted as positive values, whereas phase-delay shifts are
plotted as negative values. Horizontal bars represent the median
phase shifts observed in each condition. For clarity, resetting responses of similar magnitude have been slightly offset horizontally.
Data from the continuous darkness and continuous bright-light
groups from Duffy et al. (16).

INTERMITTENT LIGHT RESETS THE HUMAN CIRCADIAN PACEMAKER

control 0% condition (darkness), the 31% intermittent

bright-light duty schedule, the 63% intermittent
bright-light duty schedule, and the 100% continuous
bright-light stimulus duty schedule produced median
phase shifts of 3.84, 4.87, and 5.51 h (individual
phase shifts are reported in Table 1). The planned
ANOVA revealed both a significant linear trend (P
0.0001) and a significant quadratic trend (P 0.0104),
indicating that there was a significant nonlinear relationship between the relative duration of the brightlight exposure and the resetting response. The post hoc
ANOVA for pairwise comparisons using Tukeys
method revealed that 1) the phase advance shifts in all
light-exposed groups were significantly different from
the change in phase observed for the 0% control group
of subjects exposed to darkness (P 0.01 in all cases);
2) the phase advances observed for the 63% intermittent bright-light group were not significantly different
from those observed in the group exposed to 100%
continuous bright light; and 3) the phase-advances
observed for the 31% intermittent bright-light group
were significantly less than from those of the 100%
continuous bright-light group (P 0.05) but were not
significantly different from the 63% bright-light group.
Figure 4 illustrates how these resetting responses
compare with those predicted for the intermittent light
stimulus by the direct drive model of the effect of light
on the human circadian pacemaker (22).

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Fig. 4. Fractional median resetting responses of the circadian phaseshifting effect in response to 3 cycles of exposure to 2 different
regimen of 5 h intermittent bright-light stimuli on the output of the
endogenous circadian pacemaker. The relative duration of brightlight exposure for each nominal 5-h stimulus represents the percentage of the 5-h episode that subjects were exposed to bright light in
each of the intermittent light groups. The response fractions represent the ratios of the resetting responses observed in the endogenous
circadian rhythm of core body temperature in each of the intermittent light groups (solid black bars) to the resetting response of
subjects in the continuous light group. The response fractions predicted by the direct-drive model of the effect of the bright light on the
endogenous circadian pacemaker for the intermittent light conditions are plotted in open bars (22).

DISCUSSION

This is the first laboratory-based study designed to

quantify the temporal dynamics of circadian phase
resetting by intermittent bright light in humans. Our
findings demonstrate that the response of the human
Table 1. Individual and mean phase shifts of the
endogenous circadian temperature rhythm
in the intermittent light groups
Subject Code

Phase Shift, h

63% Bright-Light Group

1341
1343
1347
1324
1328
1329
1321
1338
Mean
SE

3.55
3.51
0.07
3.57
4.67
5.14
5.72
4.22
3.81
0.07
31% Bright-Light Group

1251
1384
14a4
1502
1506
1517
1518
1521
Mean
SE

2.87
1.06
3.15
0.36
0.27
4.19
2.86
4.79
2.44
0.65

circadian pacemaker to short-duration light pulses is

not different from those observed in other organisms
(35, 37, 42) and necessitate the refinement of previous
models describing human sensitivity to light.
Our results suggest that an intermittent bright-light
stimulus, interrupted by intervals of complete darkness that substantially exceed the duration of the light
exposure, can significantly phase shift the human circadian pacemaker. Surprisingly, when the bright-light
exposure occupied only 31% of the stimulus, 70% of the
median resetting response was preserved compared
with the continuous stimulus. Furthermore, when the
bright-light exposure occupied only 63% of the stimulus, nearly 90% of the median resetting response was
preserved compared with the continuous stimulus (Fig.
4). The results from the latter group are especially
revealing. Although 37% of light was eliminated, only a
10% price was paid in the phase-shifting response.
Such results are inconsistent with the direct-drive
model that we had proposed, in which the effectiveness
of bright light in phase shifting the endogenous circadian pacemaker was homogenous throughout the duration of the stimulus.
We have thus now proposed two alternative modifications to the direct-drive model to reconcile these new
findings. The first alternative is the maintained-drive
model, which embodies two rate constants, representing the turn-on process (when the lights are turned
on) and representing the persistence after the turnoff process (when the lights are turned off) (28, 29).
This model postulates that light produces a drive on

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INTERMITTENT LIGHT RESETS THE HUMAN CIRCADIAN PACEMAKER

the endogenous pacemaker that persists or is maintained for a period of time after it is turned off, decaying only gradually with an extended time course. Similarly, when a light stimulus is initiated, a period of
time elapses before full phase-shifting strength is attained. The second alternative, the dynamic-stimulus
model, postulates that during dark episodes, a potential for photic drive is stored and that this potential is
tapped at the start of light exposure with rate constant
and is reconstituted (restored) with a rate constant
(28, 29). During an extended light episode, the phaseshifting drive potential declines (with a time constant
of 20 min) to a low asymptotic level (/) corresponding to a balance between utilization and reconstitution. That is, the drive rate onto the circadian
pacemaker is limited by the restoration process. Thus,
when light is turned off, the phase-shifting drive stops
completely, but the restoration of drive potential continues at the rate, thereby priming the system for the
next light episode.
We have shown mathematically (28, 29) that the
temporal pattern of drive for the maintained-drive
model can be determined by passing the drive pattern
from the dynamic-stimulus model through a leaky
integrator of time constant 1. Thus, in the sense of
cumulative drive, the two new models are equivalent,
but important distinctions remain. Compared with the
dynamic-stimulus temporal-drive pattern, the pattern
of the maintained-drive model is significantly delayed
by the time 1 2.2 h, too long to account for the
initial strong phase-shifting response presently observed (29). Because the dynamic-stimulus model is
more consistent with the prompt biochemical responses (Fos protein) (20) to light observed in mammalian suprachiasmatic nuclei, it is the one we adopted.
The current results, as anticipated by the dynamicstimulus model, demonstrate that the initial strength
of the photic drive produced by the bright-light stimulus is very strong after several hours of dim light
exposure. As the bright-light exposure is maintained,
the drive strength declines (with a time constant of
20 min) to an asymptotic level of only about one-sixth
of its initial value. Thus the initial strength of the drive
after several hours of dim light is approximately six
times the strength of the drive after 1 h of bright-light
exposure (28, 29). These results suggest that, as in the
golden hamster and mosquito, there is a strong phaseresetting response to the initial minutes of a light
stimulus followed by a much weaker continuing response as the light duration is increased. This concept
is supported by both Brainard et al. (5), who demonstrated that intermittent bright light, which is conveyed to the pineal gland through the circadian pacemaker (25, 31), is capable of inducing significant
suppression of plasma melatonin levels in humans and
by Baehr et al. (1), who in a lab/field study reported
significant phase-delay shifts in groups exposed to intermittent bright light during simulated night shifts
compared with those exposed to dim light.

Perspectives
Our findings demonstrate that humans are much
more sensitive to the phase-resetting effects of brief
intermittent exposures to light than was previously
recognized (26, 43) and reinforce the concept that the
mechanisms by which human circadian rhythms are
entrained by light are not qualitatively different from
those of other mammals (14). Our study provides evidence that intermittent light exposure, even to as little
as repeated 5-min intervals of bright light, can produce
circadian resetting effects nearly as great as those
observed with a continuous 5-h bright-light exposure.
These findings, together with the recognition that humans are sensitive to the phase-resetting effects of
light throughout the subjective day (24), indicate that
the brief intermittent exposures to bright light that we
typically experience in everyday life (21, 36, 39) may
have a much greater impact on circadian entrainment
than was previously recognized (19, 26, 36, 39, 43).
Given that photic resetting responses can also be
achieved in humans at much lower light intensities (3,
45), these data suggest that sporadic nocturnal light
exposure, such as that which occurs to a wide variety of
people ranging from hospitalized patients to astronauts orbiting the Earth, may have more of an adverse
circadian phase-shifting effect than previously anticipated. These data also have practical implications and
suggest that a less-restrictive bright-light treatment
regimen can be used to reset the circadian pacemaker
in populations such as night workers or transmeridian
travelers and to treat patients with seasonal affective
disorders or circadian rhythm sleep disorders.
The authors acknowledge the contribution of B. Vu to the initial
protocol development, implementation, and supervision of studies in
the 63% intermittent light condition. We also thank the subject
volunteers, research technicians, dieticians, and nurses at the General Clinical Research Center; J. Kao, K. Foote, and G. Jayne for
subject recruitment and technical supervision; L. Rosenthal for illustrations; S. Hurwitz for consultation on the statistical analyses;
and D.-J. Dijk for critical review of the manuscript.
This research was supported in part by Grants NAGW-4033 and
NAG53952 from the National Aeronautics and Space Administration, 1-R01-AG06072 from the National Institute on Aging, 1-R01MH-45130 from the National Institute of Mental Health, and
F49620940398 from the Air Force Office of Scientific Research.
These studies were performed in a General Clinical Research Center
supported by National Center for Research Resources Grant M01RR-02635.
This work was presented, in part, at the Second International
Congress of the World Federation of Sleep Research Societies, Nassau, Bahamas 1995.
Present address of D. W. Rimmer: Dept. of Kinesiology, Pennsylvania State University, University Park, PA 16802; present address
for D. B. Boivin: Douglas Hospital Research Centre, Verdun, Quebec
H4H 1R3, Canada.
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