Brain, Behavior, and Immunity 25 (2011) 16–24

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Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

Benefits of napping and an extended duration of recovery sleep on alertness

and immune cells after acute sleep restriction q
Brice Faraut a,b, Karim Zouaoui Boudjeltia b, Michal Dyzma a,b, Alexandre Rousseau b, Elodie David a,
Patricia Stenuit a, Thierry Franck c, Pierre Van Antwerpen d, Michel Vanhaeverbeek b, Myriam Kerkhofs a,b,*
a
Sleep Laboratory, (ULB 222 Unit), CHU de Charleroi, A. Vésale Hospital, Université Libre de Bruxelles, Montigny-le-Tilleul, Belgium
b
Laboratory of Experimental Medicine, (ULB 222 Unit), CHU de Charleroi, A. Vésale Hospital, Université Libre de Bruxelles, Montigny-le-Tilleul, Belgium
c
Anesthésiologie et Pathologie Chirurgicale des Grands Animaux, Université de Liège, Liège, Belgium
d
Laboratory of Pharmaceutical Chemistry, Université Libre de Bruxelles, Brussels, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Understanding the interactions between sleep and the immune system may offer insight into why short
Received 27 April 2010 sleep duration has been linked to negative health outcomes. We, therefore, investigated the effects of
Received in revised form 16 July 2010 napping and extended recovery sleep after sleep restriction on the immune and inflammatory systems
Accepted 3 August 2010
and sleepiness. After a baseline night, healthy young men slept for a 2-h night followed by either a stan-
Available online 8 August 2010
dard 8-h recovery night (n = 12), a 30-min nap (at 1 p.m.) in addition to an 8-h recovery night (n = 10), or
a 10-h extended recovery night (n = 9). A control group slept 3 consecutive 8-h nights (n = 9). Subjects
Keywords:
underwent continuous electroencephalogram polysomnography and blood was sampled every day at
Sleep restriction
Extended sleep recovery
7 a.m. Leukocytes, inflammatory and atherogenesis biomarkers (high-sensitivity C-reactive protein,
Nap interleukin-8, myeloperoxidase, fibrinogen and apolipoproteins ApoB/ApoA), sleep patterns and sleepi-
Immune cells ness were investigated. All parameters remained unchanged in the control group. After sleep restriction,
Inflammation leukocyte and – among leukocyte subsets – neutrophil counts were increased, an effect that persisted
Alertness after the 8-h recovery sleep, but, in subjects who had a nap or a 10-h recovery sleep, these values
Myeloperoxidase returned nearly to baseline. Inflammatory and atherogenesis biomarkers were unchanged except for
higher myeloperoxidase levels after sleep restriction. The increased sleepiness after sleep restriction
was reversed better in the nap and extended sleep recovery conditions. Saliva cortisol decreased imme-
diately after the nap. Our results indicate that additional recovery sleep after sleep restriction provided by
a midday nap prior to recovery sleep or a sleep extended night can improve alertness and return leuko-
cyte counts to baseline values.
Ó 2010 Elsevier Inc. All rights reserved.

1. Introduction
Sleep deprivation is widely described as being associated with
sleepiness and impaired neurobehavioral performance. Moreover,
accumulating evidence from experimental studies links sleep loss
to alterations in the immune and inflammatory systems that may
have clinical relevance. It is not clearly established how these
post-sleep-deprivation changes in immune and inflammatory
functions – mediated via the neuroendocrine system – can affect
health. However, epidemiological surveys implicate poor sleep as
a predictor of cardiovascular risk, and meta-analyses have reported
that shorter sleep duration, an emerging condition in the western
population, is associated with a higher incidence of cardiovascular
q
Please see Brief Commentary by Tanja Lange and Born in this issue.
* Corresponding author at: Sleep Laboratory, CHU A. Vésale, Université Libre de
Bruxelles, Unit 222, Rue de Gozée 706, 6110 Montigny-le-Tilleul, Belgium. Fax: +32
71 921469.
E-mail address: mykerkho@ulb.ac.be (M. Kerkhofs).
events (Heslop et al., 2002; King et al., 2008; Ferrie et al., 2007; Na-
tional Sleep Foundation, 2009). Increased peripheral circulation of
leukocytes (Dinges et al., 1994; Born et al., 1997; Kerkhofs et al.,
2007) and elevated levels of C-reactive protein (CRP) and inflam-
matory cytokines (Meier-Ewert et al., 2004; Vgontzas et al.,
2004; Irwin et al., 2006) have been reported in healthy humans
after experimental sleep deprivation. CRP, leukocyte count, fibrin-
ogen, and emerging biomarkers, such as myeloperoxidase (MPO),
interleukin-8 (IL-8), and apolipoproteins (Apo), are all associated
with the inflammatory and atherogenesis pathways that lead to
cardiovascular disease (Danesh et al., 1998; Inoue et al., 2008; Rug-
giero et al., 2007; Zhang et al., 2008; Sniderman et al., 2003). Inter-
estingly, several sleep deprivation studies have indicated that one
8-h night of recovery sleep is not sufficient to normalize alertness
and performance or cardiovascular risk markers, such as leuko-
cytes and CRP (Lamond et al., 2007; Belenky et al., 2003; Dinges
et al., 1994; Meier-Ewert et al., 2004).
To our knowledge, the effects of a short nap in addition to
recovery sleep or an extended duration of recovery sleep as

0889-1591/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbi.2010.08.001
 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24
countermeasures to acute sleep restriction have never been inves-
tigated in an integrated design on sleepiness and immune and
cardiovascular risk markers. We hypothesized that following a
sleep-restricted night of 2 h, a 30-min midday nap prior to a normal
8-h recovery sleep or an extended 10-h recovery sleep would im-
prove restoration of these parameters. We, therefore, examined
peripheral blood immune cells, inflammatory and atherogenesis
biomarkers (CRP, IL-8, MPO, ApoB/ApoA, and fibrinogen) together
with sleep patterns, sleepiness and saliva cortisol in young healthy
adults.
2. Methods
2.1. Subjects
All volunteers were non-smokers, not regular nappers, had a
body mass index between 19 and 25, and were aged between 18
and 27 years. They were free of any disease and/or sleep com-
plaints and slept regular nights of 7–9 h as indicated by a rigorous
medical evaluation that included psychiatric and medical histories,
screening laboratory tests, sleep questionnaires and one adapta-
tion night of polysomnography monitoring.
2.2. Experimental design and procedure
The protocol was approved by the Ethic’s Committee of the hos-
pital. All volunteers gave their written informed consent and re-
ceived financial compensation. During the week preceding their
admission to the Sleep Laboratory, the participants followed
1 week of regular sleep-wake behavior of 8 h in bed (11:00 p.m.–
7:00 a.m.) documented by actigraphic recordings and sleep diaries.
Before admission, ongoing infection was excluded based on the
CRP concentration and the leukocyte count. The protocol included
a control group and three groups with distinct recovery conditions.
In the control group, nine healthy young men underwent three
consecutive nights of 8 h sleep (in bed from 11:00 p.m. to
7:00 a.m.). In the first recovery condition group, 12 healthy young
men underwent one baseline night of 8 h (in bed from 11:00 p.m.
to 7:00 a.m.), one restricted night of 2 h (in bed from 2:00 a.m. to
4:00 a.m.), and one recovery night of 8 h (in bed from 11:00 p.m.
to 7:00 a.m.). In the second recovery condition group, 10 healthy
young men underwent one baseline night of 8 h (in bed from
11:00 p.m. to 7:00 a.m.), one restricted night of 2 h (in bed from
2:00 a.m. to 4:00 a.m.), a nap from 1:00 p.m. to 1:30 p.m. after
the restricted night, and one recovery night of 8 h (in bed from
11:00 p.m. to 7:00 a.m.). In the third recovery condition group, 9
healthy young men underwent one baseline night of 8 h (in bed
from 11:00 p.m. to 7:00 a.m.), one restricted night of 2 h (in bed
from 2:00 a.m. to 4:00 a.m.), and one extended recovery night of
10 h (in bed from 9:00 p.m. to 7:00 a.m.).
To control the state of alertness of the subjects and to avoid
sleep episodes outside the permitted hours, continuous electroen-
cephalogram (EEG), electrooculogram and electromyogram record-
ings were taken using an ambulatory device (DreamÒ, Medatec,
Brussels, Belgium) with the following EEG derivations (C4/A1, C3/
A2, O2/A1, O1/A2 F4/A1, F3/A2), which were also used for sleep
recordings. During the study, volunteers were free to move within
the unit carrying this ambulatory device. Subjects received stan-
dard hospital meals of a maximum of 2500 cal/day with a balanced
proportion of nutrients (protein, fat, carbohydrates). Intake of any
medication, alcohol, or xanthine derivatives (coffee, tea, chocolate
and cola) was prohibited throughout the study period. Controlled
drinks and snacks were available during the sleep-restricted nights
until 11 p.m. Sleep recordings were scored visually in all subjects
according to the 2007 American Academy of Sleep Medicine crite-
ria (Silber et al., 2007). Fasting blood samples were obtained from
17
an antecubital vein at 7:00 a.m. each day of the experiment. To as-
sess the effects of the nap on cortisol, saliva samples were taken for
cortisol measurement every 2 h from 9:30 a.m. to 5:30 p.m. on the
three study days in the 8 h-sleep recovery and 30-min nap + 8 h-
sleep recovery groups.
2.3. Sleepiness evaluation
Objective and subjective sleepiness were assessed at 1:00 and
3:00 p.m. on the three study days using the Maintenance of Wake-
fulness Test (MWT; Mitler et al., 1982) and the Stanford Sleepiness
Scale (Hoddes et al., 1985), respectively, as previously described
(Stenuit and Kerkhofs, 2005). Briefly, the MWT assessed the ability
to sustain wakefulness and was performed during 20 min. During
the test, the subjects were comfortably installed in a chair in a
dimly light room and instructed to remain awake while polysom-
nographic recordings were performed. The test was interrupted at
the onset of sleep (stage 1) and the subject was immediately awak-
ened. In the absence of sleep, the test ended after 20 min.
2.4. Assays and measurements
Fasting blood samples were obtained from an antecubital vein
by a needle stick at 7:00 a.m. each morning. Serum samples were
collected in vacuum tubes without anticoagulant (VenojectÒ). Plas-
ma samples were harvested in citrated vacuum tubes (Buffer So-
dium Citrate, 0.109 mol/L:3.2 W/V%, VenojectÒ), immediately
processed and put on melting ice. Whole blood was collected in
EDTA-treated tubes (K3EDTA, VenosafeÒ). High sensitivity CRP
(Hs-CRP), Apolipoproteins A and B were evaluated by antibody-
binding and turbidity measurement on SYNCHRON LXÒ. Leukocyte
counts and subsets were determined on a CELL-DYN4000Ò hemo-
cytometer (Abbott, Abbott Park, IL). Fibrinogen was determined
by thrombin time on a STAÒ automate (Stago, Parsippany, NJ). Plas-
ma MPO was determined by ELISA (ZentechÒ, Angleur, Belgium).
MPO activity was determined by the SIEFED method as previously
described (Franck et al., 2009). Serum IL-8 concentrations were
quantified using an ELISA test (Becton DickinsonÒ, Franklin Lakes,
NJ). Saliva samples for cortisol analysis were stored at 20 °C until
assayed. After thawing, samples were mixed well prior to assay
and cortisol concentrations measured by radioimmunoassay
(Stockgrand Ltd., Guildford, UK).
2.5. Statistics
Data were analyzed using the SigmaStatÒ 3.5 software (SystatÒ,
San Jose, CA). Values are expressed as mean values (SEM). We per-
formed two types of comparisons with the objectives of testing the
effects of sleep restriction and of the distinct recovery modalities.
The first comparisons were between experimental points within
each experimental group using a within-subjects one-way re-
peated measure ANOVA completed by a pairwise comparisons post
hoc test (Student–Newman–Keuls’ test). The second comparisons
involved the 3 sleep-restricted groups with distinct recovery con-
ditions. We first tested whether the effects of sleep restriction were
similar in each sleep-restricted group by comparing the normal-
ized differences observed between sleep restriction and baseline
values for each sleep-restricted group (normalized d = (Restric-
tion–Baseline)/Baseline). There were no significant differences in
the normalized d scores, indicating that the physiological effects
of sleep restriction were similar for the 3 sleep-restricted groups.
To increase the sample size, we therefore pooled the results for
all subjects from the 3 sleep-restricted groups together and com-
pared sleep restriction to baseline values. Comparisons between
the different sleep recovery conditions were made using normal-
ized d scores for each recovery condition, i.e., (recovery 8 h –
18 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24

restriction)/restriction; (nap + recovery 8 h – restriction)/restric-

tion); and (recovery 10 h – restriction)/restriction). For sleep anal-
yses, comparisons among groups were performed for each sleep
stage for baseline, sleep restriction, and recovery nights. Additional
analyses to compare cortisol values between no-nap and nap con-
ditions were performed for each time point. All these comparisons
were performed using a one way ANOVA completed by a pairwise
comparisons post hoc test (Student–Newman–Keuls’ test). A prob-
ability level of p < 0.05 was considered as statistically significant.

3. Results

3.1. Within-group comparisons

3.1.1. Peripheral blood leukocytes

There were no significant changes in leukocyte counts in the
control group during the three consecutive baseline nights (F (2,
8) = 0.07, p = 0.93; Fig. 1A). Changes in leukocyte count were signif-
icant over time in the 8-h recovery group (F (2, 11) = 6.03,
p = 0.009), the nap + 8-h recovery group (F (2, 9) = 21.09, p <
0.001), and the 10-h recovery group (F (2, 8) = 7.85, p = 0.005). Pair-
wise comparisons showed that after the sleep-restricted night, leu-
kocyte counts increased significantly compared to baseline in the
three study groups. After recovery sleep, this increase in leukocyte
count persisted in the 8 h-recovery condition but not in the
nap + 8 h-recovery or the 10 h-recovery conditions. Among the
leukocyte subtypes, changes in neutrophil count were significant
over the three study days in the 8-h recovery group (F (2, 11) =
6.27, p = 0.008), the nap + 8-h recovery group (F (2, 9) = 16.26,
p < 0.001), and the 10-h recovery group (F (2, 8) = 15.25,
p < 0.001) (Fig. 1B). Pairwise comparisons indicated that after sleep
restriction, neutrophil counts increased significantly in each of the
three study groups compared to baseline. After the recovery night,
the neutrophil increase persisted in the 8 h-recovery group but
there was a significant reduction in neutrophil count in the
nap + 8-h recovery and 10-h recovery groups. Sleep restriction
did not significantly affect lymphocyte levels in any of the groups.
In the 8-h recovery group (F (2, 11) = 4.27, p = 0.027) and the
nap + 8-h recovery group (F (2, 9) = 6.56, p = 0.007), pairwise com-
parisons showed that the lymphocyte level was significantly re-
duced after 8 h of recovery sleep and nap + 8 h of recovery sleep
but not after extended recovery sleep (Fig. 1C). Monocyte counts
were not significantly altered in any of the groups (Fig. 1D).

3.1.2. Peripheral blood inflammatory and atherogenesis biomarkers

MPO levels did not change significantly over the three days in
the control group. The MPO level tended to increase after the
sleep-restricted night and the increase was significant compared
to baseline in the 8-h recovery group (F (2, 9) = 4.60, p = 0.02;
Fig. 2A). The concentrations of Hs-CRP, IL-8, fibrinogen and the
ApoB/ApoA ratio did not change significantly in any of the groups
(Fig. 2B–E).

3.1.3. Subjective and objective sleepiness

Stanford Sleepiness Scale scores did not change significantly in
the control group with no onsets of sleep detected with the MWT.
As expected, Stanford Sleepiness Scale scores indicated that after
sleep restriction volunteers felt sleepier at 1 p.m. in the 8-h recov-
ery group (F (2, 11) = 13.90, p < 0.001), the nap + 8-h recovery
group (F (2, 9) = 5.28, p = 0.016) and the 10-h recovery group (F Fig. 1. Mean (SEM) counts of peripheral blood leukocytes (A), neutrophils (B),
(2, 8) = 9.64, p = 0.002 (Fig. 3A). Pairwise comparisons indicated lymphocytes (C) and monocytes (D) at baseline (Bas), after sleep restriction (Res) and
significantly higher sleepiness values in the three study groups after 8-h recovery (Rec 8 h), 30 min-nap + 8-h recovery (Nap + Rec 8 h), or 10-h
recovery (Rec 10 h).  indicates p < 0.05 between conditions.
compared to respective baseline. At 3 p.m., Stanford Sleepiness
Scale scores indicated that volunteers also felt sleepier after sleep and the 10-h recovery group (F (2, 8) = 11.64, p < 0.001) but not
restriction in the 8-h recovery group (F (2, 11) = 26.90, p < 0.001) in the nap + 8-h recovery group (Fig. 3C). Interestingly, while sleep-
 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24
Fig. 2. Myeloperoxidase (A), C-reactive protein (B), interleukin-8 (C), fibrinogen (D)
and ApoB/ApoA ratio (E) at baseline (Bas), after sleep restriction (Res) and after 8-h
recovery (Rec 8 h), 30 min-nap + 8-h recovery (Nap + Rec 8 h), or 10-h recovery (Rec
10 h). Values are expressed as mean (SEM).  indicates p < 0.05 between conditions.
19
iness returned to baseline values in the groups with extended
recovery sleep or with a nap before recovery sleep, the group with
just 8 h of recovery sleep had sleepiness scores that were still sig-
nificantly higher than baseline.
3.1.4. Sleep architecture
Pairwise comparisons with the corresponding baseline values
indicated that the rebound in slow-wave sleep (SWS) observed
during the 8-h recovery night (F (1, 11) = 9.16, p = 0.01) was no
longer significant in the group who took a nap (Table 1). The 30-
min midday nap was mainly composed of SWS. Significant in-
creases in stage 2 (F (1, 8) = 23.56, p = 0.005), slow-wave (F (1,
8) = 55.42, p < 0.001) and rapid eye movement (REM) (F (1,
11) = 14.93, p = 0.01) sleep were noted during the extended recov-
ery night. There were no significant variations in the distribution of
sleep stages during the three nights in the control group. Analysis
of the continuous EEG recordings showed only two short sleep epi-
sodes (7 and 8 min of stage 2 sleep, respectively) outside the per-
mitted hours, demonstrating the success of the sleep restriction
procedure.
3.2. Between-group comparisons
3.2.1. Peripheral blood leukocytes
The increases in leukocyte count after sleep restriction were
comparable in the 3 sleep-restricted groups (F (2, 28) = 0.12,
p = 0.886), so we pooled the values for the three groups to increase
the sample size and confirmed a significant increase in leukocytes
after sleep restriction (F (1, 60) = 11.35, p = 0.001). The effects of
sleep recovery on leukocyte counts were different in the three
recovery conditions (F (2, 28) = 4.53, p = 0.021). Pairwise be-
tween-group comparisons showed a significant difference between
the ‘‘8-h recovery group” and both the ‘‘nap + 8-h recovery group”
and the ‘‘10-h recovery group” indicating a higher reduction in
leukocyte count in these two groups (Fig. 4A). The neutrophil in-
creases after sleep restriction were comparable in the 3 sleep-
restricted groups (F (2, 28) = 0.05, p = 0.947), so we pooled the
values and noted a significantly higher neutrophil count after sleep
restriction compared to controls (F (1, 60) = 11.35, p = 0.001). The
effects of sleep recovery on neutrophil counts varied according to
the recovery condition (F (2, 28) = 4.20, p = 0.028). Pairwise be-
tween-group comparisons showed a significant difference between
the ‘‘8-h recovery group” and both the ‘‘nap + 8-h recovery group”
and the ‘‘10-h recovery group” indicating a greater reduction in
neutrophil counts in the subjects who had a nap and in those
who had extended recovery sleep (Fig. 4B). There were no signifi-
cant differences in the recovery of lymphocyte (F (2, 28) = 0.31,
p = 0.733); Fig. 4C) or monocyte (F (2, 28) = 0.75, p = 0.48;
Fig. 4D) counts.
3.2.2. Peripheral blood inflammatory and atherogenesis biomarkers
The increases in MPO level after sleep restriction were similar in
the 3 sleep-restricted groups (F (2, 28) = 0.73, p = 0.491), so we
pooled the values and noted a significantly higher level of MPO
after sleep restriction (F (1, 60) = 5.63, p = 0.02). Between-group
comparisons did not show significant differences in MPO levels
after the recovery night (F (2, 28) = 0.01, p = 0.98; Fig. 5A). The ef-
fects of sleep restriction on Hs-CRP, IL-8, fibrinogen and ApoB/
ApoA ratio were not significant when the values for all subjects
were pooled and between-group comparisons did not show signif-
icant differences after the recovery night for the three recovery
conditions (Fig. 5B–E).
3.2.3. Subjective and objective sleepiness
The increases in sleepiness at 1 p.m. after sleep restriction were
comparable in the 3 sleep-restricted groups (F (2, 28) = 1.05,
20 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24
Fig. 3. Stanford Sleepiness Scale scores and number of sleep onsets as assessed by
the Maintenance of Wakefulness Test at baseline (Bas), after sleep restriction (Res)
and after 8-h recovery (Rec 8 h), 30 min-nap + 8-h recovery (Nap + Rec 8 h), or 10-h
recovery (Rec 10 h). Values are shown at 1 p.m. (A and B) and 3 p.m. (C and D) and
are expressed as mean (SEM).  indicates a p < 0.05 between conditions.
p = 0.362) so we pooled the values for the three groups and con-
firmed a significantly higher level of sleepiness after sleep restric-
tion (F (1, 60) = 40.83, p < 0.001). Between-group comparisons did
not show significant differences in sleepiness at 1 p.m. after the
recovery night (F (2, 28) = 0.40, p = 0.67, Fig. 6A). The increases in
sleepiness at 3 p.m. after sleep restriction were similar in the 8-h
recovery group and the 10-h recovery group but different in sub-
jects who had had a nap (F (2, 28) = 5.01, p = 0.01). When values
for the subjects in the 8-h recovery group and the 10-h recovery
group were pooled, sleepiness was higher than baseline values (F
(1, 39) = 40.94, p < 0.001). Between-group comparisons showed
significant differences in sleepiness at 3 p.m., which was greater
with 8 h of recovery sleep than with 10 h of recovery sleep (F (1,
19) = 7.41, p = 0.014, Fig. 6B).
These subjective evaluations were confirmed by the objective
findings with the MWT. Indeed, only one sleep onset (sleep latency
18 min) was recorded at 3 p.m. in the subjects who had a nap while
in subjects who had no nap, 4 sleep onsets (sleep latency
13.57 ± 2.07 min) were recorded in the 8-h recovery group and 6
sleep onsets (sleep latency 9.25 ± 3.00 min) in the 10-h recovery
group (Fig. 4D). During the recovery day, 2 sleep onsets (one at
1 p.m., sleep latency 19 min and one at 3 p.m., sleep latency
9 min.) were observed in the 8-h recovery group while 1 sleep on-
set (sleep latency 12.5 min) was recorded in the extended recovery
group, similar to baseline, and none in the nap + 8-h recovery
group (Fig. 6B and D).
3.2.4. Sleep architecture
The durations of each sleep stage during baseline and sleep-re-
stricted nights were not significantly different between groups.
SWS (F (2, 28) = 1.88, p = 0.17), and the duration of stage 1 sleep
(F (2, 28) = 2.94, p = 0.07) during the recovery night was not signif-
icantly different in the 3 recovery conditions. Pairwise between-
group comparisons indicated a higher amount of Stage 2 sleep dur-
ing the 10-h recovery night compared to the 8-h recovery night (F
(2, 28) = 4.85, p = 0.01) and a greater amount of REM sleep com-
pared to the 8-h recovery night and the nap + 8-h recovery night
(F (2, 28) = 4.92, p = 0.01).
3.2.5. Saliva cortisol
To assess the effects of the nap on cortisol levels, we quantified
cortisol values in saliva as shown in Fig. 7. There was no significant
effect of sleep restriction or recovery on cortisol levels. However,
there was a significant decrease in saliva cortisol at 1.30 p.m. in
subjects who had a nap compared to the same time point in sub-
jects who did not (F (1, 20) = 18.93, p < 0.001).
4. Discussion
Our results provide confirmation of the interactions between
sleep and the immune system. An increase in peripheral blood leu-
kocytes was observed after a night restricted to 2 h of sleep, an in-
crease which persisted after the recovery night. Interestingly, both
a short midday nap prior to the recovery night and an extended
night of recovery sleep normalized this increase. Analysis of the
leukocyte subsets indicated that neutrophils were the most sensi-
tive subtype to our sleep restriction and recovery protocols. There
were no significant correlations between the changes in neutrophil
count after recovery sleep and the time spent in a particular stage
of sleep during the recovery night. Polysomnography analysis indi-
cated that the 30-min nap was sufficient to reduce the rebound in
SWS observed after sleep restriction, suggesting that even a short
episode of SWS during a nap can reduce the homeostatic pressure
of sleep.
 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24
Table 1
Sleep stages of baseline, sleep restriction, and 8-h recovery, 30 min-nap + 8-h recovery, or 10-h recovery nights. Values are expressed as mean (SEM).  indicates p < 0.05 versus
within-group corresponding baseline nights. a and b indicate p < 0.05 versus 8-h recovery sleep and nap + 8-h recovery sleep conditions, respectively.
Stage 1 (min)
Baseline 1 9.12 ± 4.65
Baseline 2 9.0 ± 2.0
Baseline 3 14.0 ± 9.33
Baseline 9.55 ± 0.94
Restriction 1.09 ± 0.39
Recovery 8 h 5.5* ± 1.38
Baseline 14.14 ± 10.33
Restriction 4.00 ± 1.73
Nap 4.22 ± 0.79
Recovery 8 h 10.33 ± 1.52
Baseline 10.33 ± 1.76
Restriction 3.62 ± 0.82
Recovery 10 h 7.37 ± 1.14
As expected, there was an increase in objective and subjective
sleepiness after sleep restriction. These increases were reversed
during the post-nap period and, interestingly, returned to baseline
during the recovery day only in the nap and extended sleep condi-
tions. The same trend was observed at 9 a.m. and 5 p.m. of the
recovery day with better alertness in subjects who took a nap than
in those who just had 8 h of recovery sleep (data not shown). A
short nap, especially during the post-noon nap zone, has been
shown to restore alertness and promote performance without the
inconvenience of sleep inertia that is associated with longer naps
(Takahashi and Arito, 2000; Mednick et al., 2003; Brooks and Lack,
2006; Milner and Cote, 2009). Similar to our findings, less overall
fatigue and reduced subjective sleepiness were observed when res-
ident interns sleeping 2–3 h during extended work shifts were as-
signed to a short nap schedule (Arora et al., 2006). Lamond et al.
(2007) also reported that subjective sleepiness and psychomotor
vigilance performance recovered better with an extended 9-h com-
pared to a 6-h recovery sleep following sleep deprivation. How-
ever, although the effects of nap and extended sleep recovery on
neurobehavioral performance and alertness have previously been
examined after sleep deprivation, these previous studies did not
simultaneously evaluate the effects on immune parameters.
Our multi-parameter integrated study has some limitations but
also certain strengths. For the nap group, we cannot determine at
which time the effect took place after the nap, i.e., before or after
the recovery night. We chose not to perform multiple blood sam-
plings to avoid local inflammation from the blood drawing proce-
dure as has previously been reported (Haack et al., 2002). The
effectiveness of our sleep restriction procedure was confirmed by
the continuous EEG recordings. All subjects had leukocytosis and
neutrophilia after sleep restriction. After the recovery night, a de-
crease in leukocyte and neutrophil counts was observed for all par-
ticipants who had taken a nap and all subjects who had the
extended recovery sleep, but in the group with a standard recovery
night, the effect was heterogeneous. Total sleep deprivation has
been shown to affect hematocrit (Goldman et al., 1990) which
could also affect leukocyte subset counts. However, we found no
significant hematocrit changes after partial sleep deprivation (data
not shown).
Several studies have indicated that sleep deprivation can lead to
an inflammatory response that may trigger the development of
cardiovascular disease processes (Meier-Ewert et al., 2004; Vgont-
zas et al., 2004; Irwin et al., 2006, 2010; Frey et al., 2007; van Leeu-
wen et al., 2009; Mullington et al., 2009). We did not note any
significant changes in the stable inflammatory marker CRP, the
pro-inflammatory IL-8, or fibrinogen after sleep restriction. Be-
cause CRP has been shown to induce IL-8 gene expression in hu-
man peripheral blood monocytes, the lack of change in IL-8
levels could in part be the result of the unaltered CRP level (Xie
21
Stage 2 (min) SWS (min) REM (min)
205.4 ± 17.92 107.4 ± 21.68 87.62 ± 13.62
199.25 ± 26.62 100.5 ± 18.0 90.57 ± 20.04
196.14 ± 20.04 107.83 ± 18.55 106.88 ± 15.45
216.77 ± 12.61 97.00 ± 10.95 92.88 ± 8.66
30.27 ± 4.86 62.54 ± 5.42 16.45 ± 3.67
190.60 ± 12.27 130.10* ± 10.81 116.55 ± 8.16
213.14 ± 10.59 91.62 ± 8.59 104.71 ± 11.02
33.66 ± 5.45 61.11 ± 3.40 12.00 ± 3.18
10.55 ± 1.44 14.77 ± 1.73 3.1 ± 2.50
211.33 ± 11.68 113.00 ± 11.68 113.83 ± 8.38
199.50 ± 7.96 94.16 ± 8.34 87 ± 6.07
30.62 ± 4.7 65.25 ± 4.14 10.75 ± 2.34
241.0*a ± 7.49 144.0* ± 9.10 151.5*ab ± 11.1
et al., 2005). Elevated concentrations of CRP and of pro-inflamma-
tory cytokines, such as IL-6 or tumor necrosis factor (TNF)-a, have
been reported following chronic partial or total sleep deprivation.
(Meier-Ewert et al., 2004; Vgontzas et al., 2004; van Leeuwen
et al., 2009). However, decreased or unchanged concentrations of
CRP and reduced levels of IL-6 have also been reported after one
night of total sleep loss (Frey et al., 2007; Dimitrov et al., 2006). De-
creases in habitual sleep duration were associated with reduced
CRP and IL-6 concentrations but elevated TNF-a levels in a large
sample of 614 subjects (Patel et al., 2009). In a cohort of 210
healthy men and women, poor sleep quality was associated with
higher fibrinogen and CRP concentrations but only for women,
and a laboratory study reported that increases in IL-6 and TNF-a
were still present in the evening following partial sleep deprivation
in women but not in men (Suarez, 2008; Irwin et al., 2010).
The increased leukocyte and neutrophil counts observed in our
study are consistent with previous studies showing similar effects
in healthy young adults after sleep restriction or deprivation
(Zouaoui-Boudjeltia et al., 2008; Dinges et al., 1994). These in-
creases have not yet been linked with any clinically significant ef-
fect on cardiovascular pathology. However, leukocyte count, which
is mainly determined by neutrophil count in healthy humans, is
also important in the absence of acute medical events. Increased
leukocyte counts have long been associated with increased all-
cause mortality and are considered a biomarker of inflammatory
processes that contribute to vascular injury and atherosclerosis
(Loimaala et al., 2006). Increased leukocyte and neutrophil counts
have been shown to be an independent risk factor for cardiovascu-
lar mortality in numerous studies and meta-analyses (Brown et al.,
2004, Wheeler et al., 2004, Horne et al., 2005; Danesh et al., 1998).
In a prospective study that was conducted over 44 years, higher
leukocyte counts, even within the normal range (mainly neutro-
phils), were associated with higher mortality (Ruggiero et al.,
2007). Interestingly, this study found that leukocyte counts
(mostly neutrophils) increased progressively, starting several years
before death, in participants who died during follow-up, although
leukocyte counts remained stable over time in those who survived.
Hence, we suggest that repetitive acute sleep restriction, as com-
monly observed in extended workshifts or in individuals with
sleep disorders, could result in progressively elevated leukocyte
and neutrophil levels over time, with potentially negative long-
term effects on mortality. Neutrophils can provoke oxidative and
proteolytic damage to coronary arteries and may influence the
development of cardiovascular diseases. We noted an increase in
MPO – mainly released by neutrophils – after sleep restriction,
which has potential negative consequences because of its role in
catalyzing the formation of oxidizing agents that can convert LDL
into an atherogenic form (Podrez et al., 1999; Zouaoui Boudjeltia
et al., 2004). The same profile was also observed for MPO activity
22 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24

Fig. 4. Changes (normalized d) in leukocyte (A), neutrophil (B), lymphocyte (C) and Fig. 5. Changes (normalized d) in myeloperoxidase (A), C-reactive protein (B),
monocyte (D) counts after 8-h recovery sleep, 30 min-nap + 8-h recovery sleep, or interleukin-8 (C), fibrinogen (D) and ApoB/ApoA ratio (E) after 8-h recovery sleep,
10-h recovery sleep. Values are expressed as mean (SEM).  indicates p < 0.05 30 min-nap + 8-h recovery sleep, or 10-h recovery sleep. Values are expressed as
between conditions. mean (SEM).  indicates p < 0.05 between conditions.
 B. Faraut et al. / Brain, Behavior, and Immunity 25 (2011) 16–24
Fig. 6. Changes (normalized d) in Standford sleepiness scores after 8-h recovery
sleep, 30 min-nap + 8-h recovery sleep, or 10-h recovery sleep at 1 p.m. (A) and
after 8-h recovery sleep and 10-h recovery sleep at 3 p.m. (B). Values are expressed
as mean (SEM).  indicates p < 0.05 between conditions.
Fig. 7. Saliva cortisol concentrations at baseline, after sleep restriction, and after 8-
h recovery sleep in the no-nap and nap conditions. The solid black line on the
abscissa indicates the nap period. Values are expressed as mean (SEM).  indicates
p < 0.05 between no-nap and nap conditions.
(data not shown). Accordingly, measurement of objective sleep
duration by actimetry has been investigated in relation to the level
23
of artery calcification, a marker of the atheromatous plaque, the
main process involved in the development of cardiovascular dis-
eases. Results reported that shorter measured sleep length was
associated with a higher incidence of coronary artery calcification
in a healthy middle-aged population of 495 participants (King
et al., 2008). Our data suggest that leukocyte recovery can be im-
proved by having a nap prior to recovery sleep; this has a stress-
releasing effect as shown by the decrease in cortisol levels imme-
diately after the nap and could explain why midday napping in
healthy individuals has been reported to be inversely associated
with coronary mortality, particularly among working men, after
controlling for potential confounders, e.g., physical activity, diet,
co morbidity (Naska et al., 2007). Similarly, longer recovery sleep
may also have a stress-reducing effect. This would suggest that
the increase in leukocyte count is secondary to autonomic activa-
tion and not a direct effect of sleep restriction on the immune sys-
tem. However, it is difficult to determine whether the immune
alterations are associated with activation of a non-specific immune
response or a stress response that occurs post-sleep deprivation
(Meerlo et al., 2008). To our knowledge, other sleep restriction
studies have not reported cortisol variations during the period
we assessed, i.e., the end of the morning and afternoon. However,
several studies have reported increased cortisol levels during the
evening and the early morning after total or partial sleep depriva-
tion (Leproult et al., 1997; Vgontzas et al., 2004). With regard to
the effect of napping on cortisol release, one could hypothesize
that SWS within the nap could inhibit the hypothalamic-pituary-
adrenal axis and cortisol release as previously described as well
as the elevated release of catecholamines by the sympathoadrenal
system observed following partial sleep deprivation (Späth-Schw-
albe et al., 1993; Vgontzas et al., 2007; Irwin et al., 1999). Indeed,
catecholamines could contribute to vascular neutrophil mobiliza-
tion because neutrophils and leukocyte subsets with cytotoxic
effector functions can be swept into the circulation after epineph-
rine administration (Brohee et al., 1990; Davis et al., 1991; Dimit-
rov et al., 2010). Further experiments are needed to better
understand the mechanism(s) involved in the effect of additional
sleep on immune cells and its relation to the neuroendocrine
system.
In summary, the current study reports for the first time that
when young healthy subjects are sleep deprived, modulating sleep
recovery by having a short nap during the day before the recovery
night or by extending the duration of the recovery night can im-
prove alertness and aid the return of normal cellular immune func-
tion. However, larger samples of subjects need to be investigated to
better understand whether leukocytosis induced by sleep restric-
tion – and its reversal by sleep extension – are involved in cardio-
vascular disease pathogenesis.
Acknowledgments
We would like to thank Geneviève Turci (CHU Charleroi), the
study nurse, Benita Middleton (University of Surrey) for cortisol as-
says, Karen Pickett for English-language editing and also Alain Bos-
seloir (Zentech), Didier Serteijn and Ginette Deby-Dupont
(Université de Liège). Sources of Funding: European Union Grant
MCRTN-CT-2004-512362 and Scientific Research Fund of the
ISPPC-CHU de Charleroi and Institut de Recherche en Pathologie
et en Génétique (IRSPG), Gosselies.
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