Sleep disturbance and melatonin levels
following traumatic brain injury
J.A. Shekleton, BBNSc
D.L. Parcell, DPsych
J.R. Redman, PhD
J. Phipps-Nelson, BBSc
J.L. Ponsford, PhD
Objectives: Sleep disturbances commonly follow traumatic brain injury (TBI) and contribute to
ongoing disability. However, there are no conclusive findings regarding specific changes to sleep
quality and sleep architecture measured using polysomnography. Possible causes of the sleep
disturbances include disruption of circadian regulation of sleep-wakefulness, psychological dis-
tress, and a neuronal response to injury. We investigated sleep-wake disturbances and their un-
derlying mechanisms in a TBI patient sample.
Methods: This was an observational study comparing 23 patients with TBI (429.7 ? 287.6 days post
Results: Patients with TBI reported higher anxiety and depressive symptoms and sleep distur-
bance than controls. Patients with TBI showed decreased sleep efficiency (SE) and increased
wake after sleep onset (WASO). Although no significant group differences were found in sleep
architecture, when anxiety and depression scores were controlled, patients with TBI showed
higher amount of slow wave sleep. No differences in self-reported sleep timing or salivary DLMO
time were found. However, patients with TBI showed significantly lower levels of evening melato-
nin production. Melatonin level was significantly correlated with REM sleep but not SE or WASO.
Conclusions: Reduced evening melatonin production may indicate disruption to circadian regula-
tion of melatonin synthesis. The results suggest that there are at least 2 factors contributing to
sleep disturbances in patients with traumatic brain injury. We propose that elevated depression is
associated with reduced sleep quality, and increased slow wave sleep is attributed to the effects
of mechanical brain damage. Neurology®2010;74:1732–1738
AUC ? area under the curve; DLMO ? dim light melatonin onset; EOG ? electrooculogram; ESS ? Epworth Sleepiness Scale;
HADS ? Hospital Anxiety and Depression Scale; MEQ ? Morningness Eveningness Questionnaire; NREM ? non-REM;
PSQI ? Pittsburgh Sleep Quality Index; PTA ? posttraumatic amnesia; SE ? sleep efficiency; SOL ? sleep onset latency;
SWS ? slow wave sleep; TBI ? traumatic brain injury; WASO ? wake after sleep onset.
Sleep disturbances are common following traumatic brain injury (TBI), reported by 30%–75% of
individuals and contributing to ongoing disability.1-6Reported sleep complaints include insomnia,
hypersomnolence, and altered sleep-wake cycles.7Understanding of changes to sleep following TBI
is limited. Reduced sleep efficiency8and increased sleep fragmentation post-TBI9-11have been re-
no changes in patients with TBI,8increased slow wave sleep,11reduced REM sleep,11,13increased
REM in the second half of the night,14no change to REM,8or decreased REM onset latency.8,10
The mechanisms underlying sleep disturbances in patients with TBI are likely to be multi-
faceted. Injury-related damage to sleep-wake regulating centers and associated pathways or
neurotransmitter systems is implicated as the cause of such disturbances.5,11,14Anxiety and
depression that frequently follow TBI are also likely contributing factors.10,15
From the School of Psychology and Psychiatry (J.A.S., D.L.P., J.R.R., J.P.-N., J.L.P., S.M.W.R.), Monash University, Victoria; and Monash-Epworth
Rehabilitation Research Centre (J.L.P.), Epworth Hospital, Victoria, Australia.
Study funding: Supported by the National Health and Medical Research Council (334002).
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Shantha
M.W. Rajaratnam, School of
Psychology and Psychiatry,
Monash University, Building 17,
Clayton Campus, Victoria 3800,
Copyright © 2010 by AAN Enterprises, Inc.
The circadian (?24-hour) pacemaker in the
hypothalamic suprachiasmatic nuclei regulates
the timing of sleep and several physiologic pro-
cesses including pineal melatonin synthesis. En-
dogenous melatonin is involved in the circadian
regulation of sleep-wakefulness.16Circadian rhy-
thm sleep disorders and delayed circadian
rhythms have been reported in patients with
mild TBI with insomnia.17
This study aimed to characterize sleep-
wake disturbances following TBI and investi-
gate their underlying mechanisms by assessing
polysomnographic sleep, sleep quality, mela-
tonin rhythm, and mood.
METHODS Participants. ParticipantswererecruitedfromEp-
itation following TBI. Potential participants were approached at 6
months post-injury. See appendix e-1 on the Neurology®Web site at
Twenty-three patients with TBI and 23 age- and gender-
matched healthy volunteers were recruited (table 1). Duration of
posttraumatic amnesia (PTA), measured prospectively as an in-
dicator of injury severity, showed that the majority of patients
experienced a severe head injury.
Preliminary data from the study (n ? 10 per group) were
Standard protocol approvals, registrations, and patient
consents. The study was approved by the Monash University and
Epworth Hospital Human Research Ethics Committees. Written
informed consent was obtained from all participants.
Self-report measures. Participants completed the Pittsburgh
Sleep Quality Index (PSQI) to measure sleep quality, the Epworth
ness Eveningness Questionnaire (MEQ) to assess preferred sleep-wake
Procedure. Participants attended the Monash University Sleep
Laboratory for 2 overnight visits (?7 days apart). The laboratory
consisted of lightproof, sound-attenuated, and temperature-
controlled bedrooms each with ensuite and kitchen.
Visit 1: Saliva collection and habituation. On the first
laboratory visit, participants arrived at approximately 17:00
hours. From 17:30 hours, a modified constant routine protocol
was imposed19; participants remained in dim light (?10 lux;
light levels were measured using a Lumacolor J17 luxmeter [Tex-
tronix, USA] by placing the sensor on the forehead of the partic-
ipant in the angle of his or her gaze), posture and activity were
controlled, and food intake was standardized. From 18:00 to
00:30 hours, participants provided half-hourly saliva samples us-
ing polyester swab Salivettes (Sarstedt, Germany). Immediately
after collection samples were frozen (?20°C).
Radioimmunoassay of the saliva samples for melatonin con-
centration was conducted at the Department of Obstetrics and
Gynaecology, University of Adelaide, Australia. As previously
described,20saliva (200 ?L) was assayed in duplicate using re-
agents obtained from Buhlmann Laboratories (Allschwil Swit-
zerland). Sensitivity of the assay was 4.3 pM. Intraassay and
interassay coefficients of variation were ?10 and ?14%.
At approximately 19:00 hours, participants were fitted with
face and scalp electrodes to facilitate polysomnographic record-
ings (see appendix e-1). Following the final saliva sample at
00:30 hours, participants were provided with an 8-hour sleep
opportunity. The first laboratory visit served as an adaptation
night to the sleep laboratory environment and as such polysom-
nography data from the first recording were not analyzed.
Visit 2: Polysomnographic sleep recording. Participants
arrived at the sleep laboratory approximately 2 hours before their
habitual bedtime (determined by sleep-wake diary) for overnight
polysomnographic monitoring including EEG, electrooculo-
gram (EOG) (above and below cantomeatal plan), and EMG
(submentalis) (S-Series Sleep Monitoring System, Compumed-
ics Pty Ltd., Australia). Participants were instructed to get into
bed 15 minutes prior to scheduled lights-out time and to remain
in bed for approximately 8 hours.
Data analysis. Polysomnography data were scored visually ac-
cording to standard sleep staging criteria21by experienced techni-
cians blind to participant group. Awakenings were defined as any
epoch with greater than 50% ? or ? low voltage EEG activity.
Sleep recordings were evaluated for the following measures of
sleep continuity and architecture: total sleep time, non-REM
(NREM) stages (1, 2, slow wave sleep [SWS]) (%), REM (%),
wake after sleep onset (WASO) (min), sleep efficiency (%), and
sleep onset latency (min). Sleep efficiency was defined as the
total sleep time divided by the time in bed, and sleep onset was
defined as the first epoch of any stage other than awake.22
DLMO times were calculated for each participant according
to a standard method.20The mean of the first 3 saliva samples
(18:00 hours, 18:30 hours, and 19:00 hours) plus 2 standard
deviations was first calculated to give the threshold value. The
first timepoint where a participant’s salivary melatonin concen-
tration rose above this threshold and remained above the thresh-
old for 1 subsequent sample was taken as DLMO.
SPSS Statistics version 17.0 (SPSS Inc.) was used for all data
analysis. Group differences were analyzed using independent
group t tests, unless otherwise stated. Correlation analysis used
Pearson r. Adjustments for multiple comparisons were not made.
RESULTS Self-reported sleep-wake and psychologi-
cal characteristics. The TBI group reported higher
PSQI scores than controls, t (26.92) ? ?4.35, p ?
0.001, indicating poorer sleep quality, and more
symptoms on the HADS anxiety and HADS depres-
sion subscales, t (29.91) ? ?3.98, p ? 0.001, t
(28.79) ? ?4.72, p ? 0.001 (see table 2). After
Table 1Participant characteristics
ParameterTBI group Control group
Age, y, mean ? SD (range)
32.5 ? 12.0 (19–63)31.6 ? 11.6 (19–63)
Days postinjury, mean ? SD (range)
429.7 ? 287.6 (74–1,194)—
Duration of PTA, d, mean ? SD (range)
29.7 ? 29.9 (1–119)—
Glasgow Coma Scale, mean ? SD
8.8 ? 3.7 (3–14)—
Abbreviations: PTA ? posttraumatic amnesia; TBI ? traumatic brain injury.
Neurology 74May 25, 2010
adjusting for HADS anxiety scores (analysis of co-
variance), the patients with TBI were still found to
have elevated PSQI scores (F1,42? 7.96, p ? 0.007).
Likewise, after adjusting for HADS depression
scores, the patients with TBI were still found to have
elevated PSQI scores (F1,42? 8.04, p ? 0.007).
Although ESS scores were higher, on average, in
the TBI group this difference in self-reported day-
time sleepiness was not significant. The TBI and
control groups did not differ significantly on MEQ
scores, indicating no differences in preferred sleep
Dim light melatonin onset and melatonin production.
DLMO could not be determined for 9 patients and 9
controls due to sporadic levels or no apparent rise in
level, leaving a final sample size of 14 per group (see
figure). No significant difference was found in
DLMO times between groups.
Based on the observed difference in melatonin
levels between the 2 groups (see figure), we calculated
total melatonin production during the sampling pe-
riod for each participant, including those for whom
DLMO could not be assessed. Using the trapezoid
method, the area under each participant’s melatonin
curve (AUC) was calculated to estimate total melato-
nin production over the sampling period. The con-
trol group (AUC 361.7 ? 80.24) had higher
melatonin production than the TBI group (AUC
171.3 ? 22.98), t (25.58) ? 2.28, p ? 0.031.
Polysomnographic sleep measures. The TBI group
had lower sleep efficiency (t ?2.33, p ? 0.025)
and longer WASO (t [31.06] ? ?3.18, p ? 0.003)
(see table 3). Trends were found for the TBI group to
have less REM sleep (t ? 1.82, p ? 0.075) and
more SWS (t ? ?1.73, p ? 0.091). No group
differences were found on other measures of sleep
An association between injury severity and
WASO was found in the patients with TBI (r ?
0.56, n ? 23, p ? 0.006), with more severe injuries
associated with longer WASO. There was an associa-
tion between duration of PTA and sleep efficiency
(r ? ?0.49, n ? 23, p ? 0.017). No association
between duration of PTA and PSQI was found (r ?
?0.27, n ? 22, p ? 0.05).
Association between anxiety and depression and polysomno-
graphic sleep measures. Group differences in polysomno-
graphic measures that reached or approached significance
sion scores (analysis of covariance), with ? set at a more
After controlling for anxiety score, the TBI group
continued to show longer WASO (F1,42? 9.31, p ?
0.004) and lower sleep efficiency (F1,42? 7.37, p ?
0.01). When depression score was included as a
covariate, there was no group difference in WASO or
sleep efficiency (F1,42? 4.40, p ? 0.042; F1,42?
2.49, p ? 0.12). Depression score was associated
with WASO (r ? 0.338, n ? 45, p ? 0.023), with
depression score accounting for 6.5% of the variance
in WASO, but was not associated with sleep effi-
ciency (p ? 0.01).
The TBI group was found to have higher levels of
SWS after controlling for anxiety score (F1,42?
7.67, p ? 0.008) and depression score (F1,42? 6.90,
p ? 0.012). In contrast, no group difference in REM
sleep was found after controlling for anxiety or de-
pression scores (p ? 0.01).
Melatonin production and sleep measures, mood
symptoms. Melatonin level (AUC) was not associated
with sleep efficiency or WASO, nor was it associated
Figure Melatonin levels for traumatic brain injury (TBI) and control groups
Mean (?SE) salivary melatonin levels were calculated for patients with TBI and controls
every half hour during the sampling period (18:00 hours to 00:30 hours). The control group
had higher melatonin output across the sampling period than the TBI group (p ? 0.031).
mean ? SD
mean ? SD
9.2 ? 5.0a
4.3 ? 2.0
52.0 ? 13.0 54.3 ? 10.2
7.1 ? 4.15.1 ? 2.8
10.1 ? 6.2a
4.5 ? 3.2
7.0 ? 4.4a
2.3 ? 1.8
Abbreviations: ESS ? Epworth Sleepiness Scale; HADS ?
Hospital Anxiety and Depression Scale; MEQ ? Morningness-
Eveningness Questionnaire; PSQI ? Pittsburgh Sleep Quality
aGroup differences, p ? 0.001.
Neurology 74May 25, 2010
with anxiety or depression scores (p ? 0.05). Mela-
tonin level was associated with REM sleep (r ? 0.35,
n ? 45, p ? 0.017), accounting for 12% of the vari-
ance. Likewise, there was an association between
melatonin level and NREM stage 2 sleep (r ?
?0.32, n ? 25, p ? 0.03).
DISCUSSION TBI was associated with significant
self-reported and objective sleep disturbance in pa-
tients who were on average 14 months postinjury.
Specifically, patients with TBI reported lower sleep
quality, and were shown to have lower sleep effi-
ciency and increased WASO. These findings are con-
sistent with previous reports of sleep disturbance in
individuals with TBI.8-11Patients with TBI were also
found to have significantly elevated levels of depres-
sion and anxiety symptoms, consistent with previous
studies.24Importantly, the anxiety and depression
measures (HADS) used do not include items on
sleep, minimizing the possibility that these measures
are confounded by disturbed sleep.
When the influence of anxiety and depression
symptoms were statistically controlled the self-
reported sleep quality remained lower in patients
with TBI. This suggests that the subjective experi-
ence of poor sleep following TBI is associated with
factors beyond mood disturbance. In contrast, when
depression scores were controlled, the TBI group no
longer showed poorer quality sleep on polysomnog-
raphy measures. A significant association was ob-
served between depression symptoms and sleep
disturbance (WASO). These findings are consistent
with the established link between depressive disor-
ders and disturbed sleep,25,26and previous reports in
patients with TBI.15Elevated rates of psychological
symptoms and sleep disturbances are common in pa-
tients with TBI and do not appear to dissipate over
time.27We cannot rule out the possibility that pres-
ence of sleep disturbance leads to depression rather
than occurring as a consequence of it.
While we found no significant difference between
patients with TBI and controls in measures of sleep
architecture, when the effects of either anxiety or de-
pression scores were controlled, the TBI group
showed significantly higher SWS. Elevated symp-
toms of psychological distress may therefore mask
differences in sleep architecture. The higher level of
SWS may be attributed to the effects of the mechan-
ical brain damage caused by the injury. We speculate
that the TBI group experiences higher sleep pressure
due to endocrine imbalance, neural plasticity, global
reaction to trauma, and diffuse damage to the ho-
meostatic sleep system, which manifests as increased
Consistent with our previous findings,18the
present study found no group differences in the self-
reported sleep or DLMO times. When total produc-
tion of melatonin during the collection period was
assessed, the TBI group showed significantly lower
melatonin production than controls. To our knowl-
edge, melatonin production has not previously been
assessed in individuals with TBI beyond the days im-
mediately following injury, when melatonin is
thought to have a neuroprotective role as an antioxi-
dant in areas of damaged cerebral tissue.28Patients
with neurologically complete injuries to their lower
cervical spinal cord (i.e., tetraplegia) show no detect-
able melatonin in plasma and lower sleep efficiency.29
Furthermore, pharmacologic suppression of melato-
nin secretion results in increased wake time and
WASO.30Exogenous melatonin administration has
been shown to improve polysomnographic sleep
measures in older individuals with low endogenous
levels of melatonin.31Although we did not find sig-
nificant associations between melatonin level and
sleep disturbance, we propose that studies investigat-
ing the efficacy of exogenous melatonin to improve
sleep quality are warranted.
The present study also found a significant associ-
ation between percentage REM sleep and melatonin
production. REM sleep is strongly regulated by the
circadian system32and is temporally associated with
high circulating levels of endogenous melatonin.33
Furthermore, exogenous melatonin increases REM
sleep duration in healthy controls34and in patients
with abnormally lowered REM sleep.35The absence
of circulating levels of melatonin in tetraplegia pa-
tients is associated with increased latency to REM
sleep.36Based on these previous studies, it is hypoth-
esized that the observed trend toward lower REM
sleep in the TBI group is related to the reduced levels
of melatonin, the attenuated melatonin levels possi-
Table 3Polysomnographic sleep measures
mean ? SD
mean ? SD
Habitual bedtime, hh:mma
19, 2122:55 ? 1 h 40 min23:30 ? 1 h 16 min
Sleep onset latency, min
23, 2215.57 ? 13.96 16.59 ? 16.39
Total sleep time, h
23, 226.53 ? 1.22 6.87 ? 0.68
23, 2262.33 ? 43.76b
27.05 ? 17.00
Sleep efficiency, %
23, 2282.15 ? 9.79b
89.71 ? 5.80
Stage 1, %
23, 224.76 ? 2.893.31 ? 2.03
Stage 2, %
23, 2252.89 ? 10.98 55.19 ? 7.40
23, 22 23.80 ? 9.00c
19.61 ? 7.12
23, 2218.54 ? 7.48c
21.87 ? 6.28
Abbreviations: SWS ? slow wave sleep; TBI ? traumatic brain injury; WASO ? wake after
Group differences:bp ? 0.05,cp ? 0.10.
Neurology 74 May 25, 2010
bly weakening the circadian system’s ability to mod-
ulate REM sleep. Given that REM sleep is thought
to play an important role in learning and memory
consolidation,37future studies may examine the pos-
sible relationship between REM sleep and cognitive
deficits in the TBI population.
A somewhat paradoxical finding concerning sleep
disturbance in the TBI population has been reported
elsewhere: milder TBIs are associated with increased
self-reported sleep disturbance as well as other
postconcussional symptoms.7We found a nonsignif-
icant trend for those with milder injuries to self-
report greater levels of sleep disturbance. We also
found a significant relationship between objectively
measured sleep disturbance (WASO, sleep efficiency)
and injury severity. We suggest that people with
more severe TBI are experiencing significant sleep
disturbances, but they may underreport these
changes, perhaps because of impaired self-awareness
or because they do not perceive the sleep disturbance
to be problematic relative to other disabilities.
This study was designed to assess the phase of the
melatonin rhythm (DLMO) and not the 24-hour
melatonin profile. It is possible that at a subset of
patients with TBI show such profound circadian
phase abnormalities that their DLMO was not cap-
tured during the assessment period, notwithstanding
the fact that both groups reported average habitual
bedtime of between approximately 23:00 to 23:30
hours. The possibility that undiagnosed sleep disor-
ders may account for some of the observed differ-
ences in sleep cannot be ruled out, although
questionnaires were used to exclude patients with
high risk of obstructive sleep apnea.
Despite the widely accepted proposition that
structural damage to the cerebral structures regulat-
ing sleep may cause sleep disturbance in patients with
TBI, imaging studies have been unable to provide
supporting evidence. Several studies (some single
case) report no structural abnormalities on cerebral
imaging (MRI or CT) despite significant sleep dis-
turbance.12,17,38Others have been unable to show as-
sociations between location of injury on CT or MRI
scan with reports of sleep disturbance.3Our own
study indicates that cerebral damage associated with
TBI may disrupt the neural structures regulating
sleep-wakefulness, including synthesis of melatonin
by the pineal gland, which may not reliably be re-
vealed with nonfunctional imaging. Another possi-
bility is that disrupted sleep in patients with TBI may
impair neurogenesis and decrease cell proliferation
thought to occur in adult brains, increasing further
their susceptibility to cognitive impairment and
mood disorders.39A recent finding of reduced num-
ber of hypothalamic hypocretin (orexin) neurons of
patients who died after severe TBI raises the possibil-
ity that loss of this wake-promoting neuropeptide
may contribute to the hypersomnolence observed in
patients with TBI.40
This study demonstrates that the sleep distur-
bances reported following TBI are evident in poly-
somnographic measures, in particular increased
WASO and reduced sleep efficiency. Patients with
TBI showed lower levels of melatonin production in
the evening hours, indicating that the circadian regu-
lation of melatonin synthesis was disrupted. Elevated
levels of psychological distress, particularly depres-
sion, were found to be associated with reduced sleep
quality. We suggest that the observed increase in
SWS in patients with TBI (after controlling for anx-
iety and depression) may reflect the neural response
Statistical analysis was conducted by Julia Shekleton.
The authors acknowledge Athena Voultsios and Associate Professor David
Kennaway from the University of Adelaide, who assisted with the assaying
of melatonin samples. The authors also thank Dr. Tracey Sletten from
Monash University for her assistance analyzing the melatonin data. The
authors also thank Compumedics Pty Ltd., Australia, for providing the
J.A. Shekleton and Dr. Parcell report no disclosures. Dr. Redman has
received research support from the National Health and Medical Research
Council. J. Phipps-Nelson reports no disclosures. Dr. Ponsford has served
on the Scientific Advisory Committee of the Victorian Neurotrauma Ini-
tiative; serves on the editorial boards of the Journal of the International
Neuropsychological Society, Journal of Head Trauma Rehabilitation, Brain
Injury, Neuropsychological Rehabilitation, NeuroRehabilitation, and Brain
Impairment; receives royalties from the publication of Traumatic
Brain Injury: Rehabilitation for Everyday Adaptive Living (Psychology
Press, 1995) and Cognitive and Behavioral Rehabilitation: From Neurobiol-
ogy to Clinical Practice (Guilford Press, 2004); receives research support
from the NHMRC, the Victorian Neurotrauma Initiative, Monash Uni-
versity, and the Jack Brockhoff Foundation; and has provided medico-
legal reports to numerous legal firms in relation to clients sustaining
traumatic brain injury. Dr. Rajaratnam has received funding for travel
from and served as a consultant (in capacity as an employee of Monash
University) to Vanda Pharmaceuticals; has served as a paid expert witness
or consultant to industry and government organizations on issues related
to shift work, sleep, and/or circadian rhythms; and receives or has received
research support as principal investigator or coinvestigator from Vanda
Pharmaceuticals, Takeda Pharmaceutical Company Limited, ResMed
Foundation, Respironics Sleep and Respiratory Research Foundation,
Cephalon, Inc., Philips Lighting, the National Health and Medical Re-
search Council, the Department of Homeland Security–Federal Emer-
gency Management Agency (FEMA), Australia-India Council, NIH
(NHLBI) R01 HL093279, the Royal Australasian College of General
Practitioners/Centre of National Research on Disability and Rehabilita-
tion Medicine, Centers for Disease Control and Prevention, and the Na-
tional Institute of Justice; and has given expert testimony on behalf of
New South Wales Nurses Association.
Neurology 74May 25, 2010
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Editor’s Note to Authors and Readers: Levels of Evidence coming to Neurology®
Effective January 15, 2009, authors submitting Articles or Clinical/Scientific Notes to Neurology®that report on clinical
therapeutic studies must state the study type, the primary research question(s), and the classification of level of evidence assigned
to each question based on the classification scheme requirements shown below (left). While the authors will initially assign a
level of evidence, the final level will be adjudicated by an independent team prior to publication. Ultimately, these levels can be
translated into classes of recommendations for clinical care, as shown below (right). For more information, please access the
articles and the editorial on the use of classification of levels of evidence published in Neurology.1-3
1. French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634–1638.
2. Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology
3. Gross RA, Johnston KC. Levels of evidence: taking Neurology®to the next level. Neurology 2008;72:8–10.
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