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Serum brain-derived neurotrophic factor (BDNF) in sleep-disordered patients: Relation to sleep stage N3 and rapid eye movement (REM) sleep across diagnostic entities

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Experimental and clinical evidence suggests an association between neuroplasticity, brain-derived neurotrophic factor and sleep. We aimed at testing the hypotheses that brain-derived neurotrophic factor is associated with specific aspects of sleep architecture or sleep stages in patients with sleep disorders. We included 35 patients with primary insomnia, 31 patients with restless legs syndrome, 17 patients with idiopathic hypersomnia, 10 patients with narcolepsy and 37 healthy controls. Morning serum brain-derived neurotrophic factor concentrations were measured in patients and controls. In patients, blood sampling was followed by polysomnographic sleep investigation. Low brain-derived neurotrophic factor levels were associated with a low percentage of sleep stage N3 and rapid eye movement sleep across diagnostic entities. However, there was no difference in brain-derived neurotrophic factor levels between diagnostic groups. Our data indicate that serum levels of brain-derived neurotrophic factor, independent of a specific sleep disorder, are related to the proportion of sleep stage N3 and REM sleep. This preliminary observation is in accordance with the assumption that sleep stage N3 is involved in the regulation of neuroplasticity.
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Serum brain-derived neurotrophic factor (BDNF) in
sleep-disordered patients: relation to sleep stage N3 and rapid
eye movement (REM) sleep across diagnostic entities
MICHAEL DEUSCHLE
1
, MICHAEL SCHREDL
1
, CHRISTIAN WISCH
1
,
CLAUDIA SCHILLING
1
, MARIA GILLES
1
, OLGA GEISEL
2
and
RAINER HELLWEG
2
1
Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, University of Heidelberg,
Mannheim, Germany;
2
Department of Psychiatry and Psychotherapy, Charit
e, Berlin, Germany
Keywords
neuroplasticity, synaptic homeostasis theory,
neurotrophic factors
Correspondence
Michael Deuschle, MD, Central Institute of
Mental Health, J5, 68159 Mannheim, Germany.
Tel.: 0049 621 1703 2331;
fax: 0049 621 1703 2325
e-mail: michael.deuschle@zi-mannheim.de
Registration: German Clinical Trials
Registration: DRKS00008902
Accepted in revised form 18 May 2017; received
14 February 2017
DOI: 10.1111/jsr.12577
SUMMARY
Experimental and clinical evidence suggests an association between
neuroplasticity, brain-derived neurotrophic factor and sleep. We aimed at
testing the hypotheses that brain-derived neurotrophic factor is associ-
ated with specic aspects of sleep architecture or sleep stages in
patients with sleep disorders. We included 35 patients with primary
insomnia, 31 patients with restless legs syndrome, 17 patients with
idiopathic hypersomnia, 10 patients with narcolepsy and 37 healthy
controls. Morning serum brain-derived neurotrophic factor concentrations
were measured in patients and controls. In patients, blood sampling was
followed by polysomnographic sleep investigation. Low brain-derived
neurotrophic factor levels were associated with a low percentage of sleep
stage N3 and rapid eye movement sleep across diagnostic entities.
However, there was no difference in brain-derived neurotrophic factor
levels between diagnostic groups. Our data indicate that serum levels of
brain-derived neurotrophic factor, independent of a specic sleep
disorder, are related to the proportion of sleep stage N3 and REM
sleep. This preliminary observation is in accordance with the assumption
that sleep stage N3 is involved in the regulation of neuroplasticity.
INTRODUCTION
There is evidence from rodent research that neuroplasticity
and sleep are intertwined phenomena. Especially, sleep
stage N3, or slow-wave sleep, is assumed to be a sensitive
marker of cortical synaptic strength and network synchro-
nization (Esser et al., 2007). Moreover, it has been shown
that cortical brain-derived neurotrophic factor (BDNF), a
modulator of neuroplasticity, induces sleep stage N3 in the
subsequent sleep period (Faraguna et al., 2008). From
ndings in adolescent mice it could be concluded that sleep
is associated with neuronal spine loss (Maret et al., 2012).
Tononis synaptic homeostasis hypothesis proposes that
sleep is the price the brain pays for plasticity: synaptic
potentiation may occur primarily in the awake stage, when
the individual interacts with the environment, while renormal-
ization of synaptic strength and neuronal spine loss may
happen mainly during sleep (Tononi and Cirelli, 2014). This
hypothesis is based on rodent research, but may provide a
framework for understanding the relationship between sleep,
neuroplasticity and learning in healthy subjects and patients
with neuropsychiatric disorders.
In humans, there are several sources of evidence asso-
ciating neurotrophic factors with sleep. First, the BDNF
Val66Met genotype is related to polysomnographic features,
with Met carriers showing decreased spectral power in the
alpha band in N1 stage and decreased theta power in N2 and
sleep stage N3 (Guindalini et al., 2014). In contrast, homozy-
gous Val carriers had higher sleep stage N3 intensity
compared with Val/Met carriers (Bachmann et al., 2012).
Second, in healthy controls and patients with a lifetime
diagnosis of restless legs syndrome (RLS) or periodic limb
movement (Giese et al., 2013), as well as in female patients
with disturbed sleep (Nishich et al., 2013), sleep distur-
bances are related to low BDNF. In contrast, in patients with
narcolepsy being characterized by daytime sleepiness and
increased rapid eye movement (REM) sleep, serum BDNF
was found to be increased (Klein et al., 2013).
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J Sleep Res. (2017) Regular Research Paper
Next to these epidemiological and clinical observations, the
association of sleep with BDNF has mainly been examined in
pharmacological studies in depressed patients, as it is widely
accepted that the expression of BDNF is reduced in the brain
and blood of patients with affective disorders (Lee et al.,
2007). First, it was shown that in depressed patients, sleep
disturbance is related to low plasma levels of BDNF
(DellOsso et al., 2010). In addition, ketamine has been
identied to regulate sleep stage N3 and brain BDNF levels in
depressed patients in a coordinated manner (Duncan et al.,
2014). Lastly, it has repeatedly been shown that antidepres-
sants acting on monoamines may increase BDNF concen-
trations in animals and depressed patients (Brunoni et al.,
2008; Nibuya et al., 1995). Within this context, however, a
considerable heterogeneity was observed with some antide-
pressants having strong effects, while others may hardly
change BDNF concentrations (Molendijk et al., 2011). Our
research showed the effect of various antidepressants on
serum BDNF to differ (amitriptyline > paroxetine; mirtazapine
> venlafaxine; Deuschle et al., 2013; Hellweg et al., 2008).
Based on these data, it may be hypothesized that antide-
pressants with sleep-promoting properties (amitriptyline,
mirtazapine) have stronger effects on serum BDNF than
antidepressants without major effects on sleep (paroxetine,
venlafaxine). These ndings contributed to the neurotrophin
hypothesis of depression (Duman and Monteggia, 2006),
with stress and neuroplasticity being considered key ele-
ments in the pathophysiology of affective disorders (MacQu-
een and Frodl, 2011). In contrast to depression, BDNF levels
in sleep disorders received less attention.
Taken together, substantial experimental and clinical
evidence suggests an association between daytime neuro-
plasticity and BDNF on the one hand and nighttime sleep on
the other. However, it is not clear whether BDNF, as a
presumable marker of neuroplasticity, is related to sleep
efciency or duration per se or rather to a specic sleep
stage. Our study tested the hypotheses that morning BDNF is
related to: (1) specic sleep disorders; or (2) sleep efciency
or specic sleep stages in the following night. We investi-
gated a heterogeneous group of patients with sleep disorders
rather than a homogenous group of healthy controls in order
to cover more variance of sleep variables.
MATERIALS AND METHODS
Subjects
This study was approved by the local ethics committee of the
Medical Faculty Mannheim, University of Heidelberg, regis-
tered at German Clinical Trials Register (DRKS00008902),
and all subjects gave fully informed written consent prior to
the investigation. Thirty-ve patients with primary insomnia,
31 patients with RLS, 17 patients with idiopathic hypersom-
nia, 10 patients with narcolepsy and 37 healthy controls were
included (Table 1). In our patient sample, 19 subjects were
smokers and 74 were non-smokers. Except in the RLS
group, we included only subjects with periodic limb move-
ment with arousal index (PLMI) <5h
1
(all subjects: PLMI
with arousals 04.8 h
1
). Also, we excluded all subjects with
an apneahypopnea index (AHI) of 5 or more per hour (all
subjects, except one narcolepsy patient: AHI: 04.5 h
1
). In
line with their rather young age, there were only a few
patients suffering from physical disorders, which were all
considered not to be related to the sleep disorder: hypothy-
roidism (three RLS, seven insomnia, one hypersomnia);
hypertension (six RLS, six insomnia); arthrosis; lumbago or
pain (six RLS, two insomnia, one narcolepsy); type 2
diabetes (one RLS, one insomnia, one narcolepsy); airway
disorders [one asthma bronchiale (insomnia); one chronic
obstructive pulmonary disease (RLS)]; mostly with adequate
treatments. Four patients had psychiatric diagnoses and
suffered from current mild to moderate depression (one
Table 1 BDNF serum concentrations as well as sleep parameters of patients with sleep disorders and healthy controls
Primary insomnia
(n=35)
RLS
(n=31)
Idiopathic
hypersomnia
(n=17)
Narcolepsy
(n=10)
Healthy
controls
(n=37)
ANCOVA: effect of
diagnosis (covariates:
age, nicotine)
Sex (f/m) 22/13 15/16 6/11 5/5 24/13
Age (years) 47.2 11.4 45.8 15.5 29.2 10.1 37.3 16.6 49.2 11.3 F
4,125
=8.66; P=0.001
BMI (kg m
2
) 24.8 3.5 25.1 4.8 24.9 4.0 26.2 2.3 24.8 3.5 n.s.
Polysomnography
Total sleep time (min) 365 57 342 66 385 38 362 52 n.a. F
3,89
=2.21; P=0.092
Sleep latency (min) 15.5 11.1 27.0 38.9 13.3 8.7 15.0 9.9 n.a. n.s.
WASO (min) 71 47 59 47 38 28 65 42 F
3,89
=2.26; P=0.087
Sleep efciency (%) 80.0 11.7 78.0 12.6 87.6 6.8 76.9 20.4 n.a. F
3,89
=2.56; P=0.060
N1 stage (%) 10.1 4.3 12.1 7.6 9.0 4.3 18.0 11.0 n.a. F
3,89
=4.84; P=0.004
N2 stage (%) 51.0 9.7 47.0 10.3 52.8 4.7 40.4 15.0 n.a. F
3,89
=4.25; P=0.007
N3 stage (%) 7.6 7.5 10.9 11.8 12.3 7.8 5.1 8.5 n.a. n.s.
REM (%) 14.8 6.1 15.4 5.9 16.9 4.9 21.4 9.2 n.a. F
3,89
=3.22; P=0.026
BDNF (pg L
1
) 4352 1403 4217 1256 3804 1329 3651 1671 4139 1359 n.s.
BDNF, brain-derived neurotrophic factor; BMI, body mass index; REM, rapid eye movement; RLS, restless legs syndrome; WASO, wake after
sleep onset.
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2M. Deuschle et al.
narcolepsy) or major depressive disorder in remission (two
RLS) or obsessive compulsive disorder (one insomnia).
Some patients had been using Z-drugs, benzodiazepines or
sedating antidepressants that had been discontinued at least
6 days before polysomnography (18 insomnia, eight RLS).
All other drug treatments were continued.
Diagnostic and study procedures
Our sleep laboratory is a referral centre for patients with
probable neuropsychiatric sleep disorders. Patients were
recruited consecutively from our clinical outpatient depart-
ment for inclusion in the study. All diagnostics were
performed within routine diagnostic procedures according to
ICSD-2 criteria. Organic, substance-related or psychiatric
causes of sleep disorders were excluded by means of clinical
interview, physical examination, electrocardiogram (ECG)
and laboratory investigations. Blood was drawn after the
adaptation night at 08:30 hours, and serum was immediately
frozen and stored at 80°C. Similar to sleep laboratory
patients, healthy controls underwent physical examination
and clinical interview to exclude psychiatric disorders and
physical disorders that may affect sleep or BDNF in serum. In
healthy controls we found no clinical evidence for sleep
disorders by examination or interview, and blood was drawn
using the same procedures as in patients.
Polysomnography
In patients, but not in controls, polysomnography was
performed using a standard polysomnography montage
according to the criteria of the American Academy of Sleep
Medicine (AASM). This included electroencephalography
(EEG) in seven derivations (F4-A1, C4-A1, O2-A1, Cz-A1,
F3-A2, C3-A2 and O1-A2), left and right electrooculography,
chin electromyography, surface electromyography of both
tibialis anterior muscles, and recording of ECG and respira-
tory variables. The EEG sampling rate was 256 s
1
. Sleep
stage scoring and detection of arousals for each 30-s epoch
was performed visually according to standard AASM proce-
dures (Berry et al., 2015). All patients were investigated by
polysomnography for two consecutive nights, with the rst
night being considered an adaptation night. During the
second night, we determined sleep latency and efciency
as well as percentage of sleep stages N1, N2 and N3 and
REM sleep.
BDNF
Blood was drawn, centrifuged (800 gfor 15 min) and serum
samples stored at 80°C until concentrations of BDNF were
determined. BDNF serum concentrations were quantied by
a modied enzyme immunoassay (Promega, Madison, WI,
USA), as described previously (Deuschle et al., 2013; Hell-
weg et al., 2008). This assay has a detection limit of
0.7 pg mL
1
serum BDNF, the coefcients of inter- and
intra-assay variation are 34.1% and 6.7%, respectively
(Hellweg et al., 2006, 2008; Ziegenhorn et al., 2007).
Statistics
First, we tested the association of age, body mass index
(BMI), sex and smoking status (Giese et al., 2014) with
BDNF using ANCOVA in order to identify confounders. Age
(F
1,87
=2.3; P=0.12; r=0.19; P=0.07) and nicotine use
(F
1,87
=3.7; P=0.059) were related, by trend, with BDNF
and were considered covariates in the next steps of analysis,
while BMI and sex were not related to BDNF. In the second
step, we used ANCOVA with age and nicotine use as covariates
to test the association of sleep disorder diagnoses with
BDNF. In the third step, we used univariate ANOVA and
multiple linear regression with sleep parameters (sleep
efciency; percentage of REM, N3 and combined stage N1
and N2 sleep) as independent parameters, age and nicotine
use as covariates, and BDNF as dependent parameter. In a
fourth and explorative step, we added the latency of the rst
REM period or arousal index in total sleep time or wakeful-
ness after sleep onset to the model. Because the Kol-
mogorovSmirnov test rejected the hypothesis of normal
distribution for all relevant sleep variables (sleep-onset
latency, sleep efciency, combined stage N1 and N2 sleep,
sleep stage N3 sleep, REM sleep), we used ln-transformed
variables. Statistical signicance was assumed at the alpha
level of 0.05.
RESULTS
Sleep disorders and polysomnography
Controlling for age and nicotine use, we found signicant
differences with regard to stage N1 and stage N2 and REM
sleep between the groups of patients with sleep disorders. All
polysomnography sleep parameters showed a pattern that
was in accordance with the clinical diagnoses (Table 1).
BDNF and sleep disorders
Age differed signicantly between groups of patients with
sleep disorders and healthy controls (t-test: P=0.013), as
well as within diagnostic subgroups (ANOVA:F
3,89
=8.33;
P=0.001). Especially, patients with primary hypersomnia
were signicantly younger than healthy controls. Also, age
was related to BDNF and, therefore, controlled for as a
potential confounder. Using ANCOVA, controlled for age and
nicotine use, we did not nd signicant group differences in
BDNF levels between sleep disorder patients and healthy
controls (Table 1).
BDNF and sleep parameters
Controlling for age and nicotine use, our model (independent
variables: sleep efciency; percentage of REM, N3 and
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BDNF is related to sleep stage N3 and REM sleep 3
combined stage N1 and N2 sleep) was of signicance with
regard to BDNF (F
6,79
=2.57; P=0.025): the covariate age
(F
1,79
=4.03, b=0.28; P=0.061), but not nicotine use, was
related by trend with BDNF. Regarding the sleep variables,
we found signicant associations of sleep stage N3
(F
1,78
=5.37; P=0.023) and REM sleep (F
1,79
=5.31;
P=0.024) with BDNF. There was no association of stage
1 and 2 sleep or sleep efciency (all F<2.1) with BDNF.
Accordingly, a multiple linear regression model with BDNF as
dependent variable and sleep stage N3 (b=0.40;
P=0.007), REM (b=0.31; P=0.020), sleep efciency
(n.s.), stage N1 and N2 sleep (n.s.) and age (b=0.29;
P=0.021) as independent variables was of signicance
(F
5,80
=2.88; P=0.019).
BDNF and latency of rst REM episode, arousal index,
wakefulness after sleep onset
In an explorative approach we added other sleep variables to
the above-mentioned model. Adding the latency of the rst
REM episode showed a signicant association with BDNF
(F
1,75
=6.02; P=0.016) without changing the effects of N3
(F
1,75
=4.78; P=0.032) or REM sleep (F
1,75
=10.56;
P=0.002). Adding wake after sleep onset (WASO) to the
model revealed a trend association (F
1,78
=3.65; P=0.060)
and diminished the effects of sleep stage N3 (F
1,78
=2.25;
n.s.) and REM sleep (F
1,78
=3.95; P=0.050). Adding
arousal index in total sleep time (F
1,78
=0.005; n.s.) or total
sleep time (F
1,78
=0.041; n.s.) to the model did not reveal
additional effects.
DISCUSSION
We tested the hypotheses that morning BDNF is related to:
(1) specic sleep disorders; or (2) specic sleep stages in the
following night and, to the best of our knowledge, this is the
rst study using polysomnography to investigate a potential
association between BDNF in serum and specic sleep
stages in patients with sleep disorders. First, our data
indicate that BDNF in serum is not signicantly related to a
specic sleep disorder. Second, independent of the nature of
a specic sleep disorder, low percentage of sleep stage N3
sleep as well as low percentage of REM sleep are related to
low serum BDNF.
With regard to our rst observation, there is evidence that
narcolepsy is related to increased BDNF (Klein et al., 2013)
and insomnia to low BDNF (Giese et al., 2014). However,
this is the rst systematic study including and comparing
various sleep disorders. Our data do not conrm the
assumption that a specic sleep disorder or diagnosis is
related to BDNF and, thus, BDNF may not be considered a
diagnostic markerfor a specic sleep disorder.
Regarding our second observation of BDNF being posi-
tively associated to stage N3 sleep and REM sleep latency
and duration, we are not aware of other studies relating
BDNF to specic sleep stages. The association of stage N3
with BDNF lost signicance after adding WASO to the model,
which might be due to the strong interaction of these
variables. Several psychiatric and sleep disorders are show-
ing both specic changes of sleep stages and BDNF.
Depression, for example, is related to low BDNF (Brunoni
et al., 2008) as well as impaired sleep stage N3 (Riemann
et al., 2001). Also, narcolepsy is related to both increased
REM sleep and BDNF (Klein et al., 2013). Moreover, there is
limited evidence that REM sleep deprivation inhibits BDNF
expression in the rat brain (Sei et al., 2000; Shaffery and
Lopez, 2013). Thus, our ndings are in accordance with
independent clinical and experimental observations.
Of course, due to the non-interventional nature of our data,
we may only speculate about the direction of this association.
However, there is some evidence for BDNF to be involved in
the regulation of sleep stage N3 sleep. For example, slow-
wave activity in recovery sleep after sleep deprivation was
found to be higher in BDNF Val/Val compared with Val/Met
genotype (Bachmann et al., 2012). Moreover, BDNF was
shown to have direct effects on rodentssleep stage N3
regulation: intracerebroventricular BDNF application during
waking state was found to increase slow-wave activity in
subsequent sleep in rats (Faraguna et al., 2008), but also
REM sleep in rabbits (Sei et al., 2000). Our ndings are in
accordance with these reports and show BDNF to be
positively related to sleep stage N3 sleep and REM. With
regard to the clinical example of major depressive disorder,
some antidepressants may induce BDNF thereby potentially
leading to improved sleep (Deuschle et al., 2013).
Finally, we consider it a limitation that our healthy controls
could not be investigated with polysomnography. However,
the inclusion of healthy controls did allow us to show that
patients with sleep disorders do not have a general deviation
of BDNF in serum. Also, the heterogeneity, especially with
regard to age, may be considered a limitation for our
analyses. Ideally, future studies should provide information
on power in the delta range.
Taken together, our data indicate that low sleep stage N3
and REM sleep, independent of a specic sleep disorder, are
related to low BDNF. These ndings extend the increasingly
acknowledged impact of an interplay between stress and
sleep on BDNF levels (Schmitt et al., 2016).
ACKNOWLEDGEMENTS
The expert technical assistance of Mrs S. Saft, H. Stender
and S. Laubender is appreciated.
AUTHOR CONTRIBUTORSHIP
MD and MS designed the study; MS and CS were respon-
sible for polysomnography and sleep analysis; CW organized
the data bank and was (together with MD and MG) respon-
sible for the statistical analysis; OG and RH did the laboratory
work; MD wrote the rst draft of the paper; and all authors
contributed to the discussion.
ª2017 European Sleep Research Society
4M. Deuschle et al.
CONFLICT OF INTEREST
None of the authors reports any conict of interest.
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14361445.
ª2017 European Sleep Research Society
BDNF is related to sleep stage N3 and REM sleep 5
... The relationship between human sleep and BDNF levels is complex. Low BDNF levels have been reported in adults with a low percentage of N3 and REM stages during polysomnography [16]. Similarly, a declining neurotrophin trend in patients suffering from J o u r n a l P r e -p r o o f narcolepsy [17] and short sleep insomnia (<6 hours) [18], and in women with poor sleep quality [19] has been observed. ...
... However, no significant differences were found in BDNF levels between groups. A significant positive correlation was observed with N3 and REM in a sample of individuals with sleep disorders [16] only when the sleep variables (efficiency, percentage of REM, N3, and combined N1 and N2 sleep stages) were analyzed as independent and BDNF as the outcome. ...
... Subjective instruments to measure sleep quality and EDS may not accurately express these phenomena. Further, the literature reports a possible bidirectional relationship between BDNF and NGF with sleep, further complicating the analyses [16,76,77]. Finally, the collection of blood samples performed at different times of the day may have increased the results' variability. ...
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Introduction The brain-derived neurotrophic factor (BDNF) and neural growth factor (NGF) are widely expressed in the brain and play an important role in neuroplasticity, neurogenesis, and increased neuronal connections. Previous studies have shown that reduced serum levels of these proteins are associated with disorders in human sleep. Objective Current study evaluates the prevalence in adolescents of excessive daytime sleepiness (EDS) and sleep quality, and analyzes the influence of these factors on BDNF and NGF serum levels. Methods A cross-section population-based study was conducted with data from a Brazilian birth cohort, with a sample of five hundred and thirteen 18-19-year-old adolescents. Sleep quality was assessed by the Pittsburgh Sleep Quality Index and EDS by Epworth Sleepiness Scale. Neurotrophins serum levels were measured by Luminex™ technology kits. Analysis consisted of marginal structural models which compared people who were exposed and not exposed to sleep quality and EDS. Results Poor sleep quality and EDS were detected in 62.57% and 36.35% of the sample. Adolescents with poor sleep quality and EDS had -0.39 (p-value=0.049) and -0.51 pg/ml in NGF (p-value=0.009). Individuals with self-reported sleep disorder had lower serum levels of NGF (Coef. -0.41, p-value = 0.045). Conclusion High prevalence of EDS and low sleep quality in a population of adolescents were evidenced. Poor sleep quality and EDS were associated with lower NGF levels, whilst adolescents with self-reported sleep disorder had lower serum levels of NGF.
... It remains unclear whether an increase in brain BDNF accounts for the sleep-deepening effects of exercise in humans. For instance, a study including a group of participants with heterogeneous sleep problems found that those with higher basal serum BDNF concentrations have lower SWS and REM sleep [52]. Of note, serum BDNF levels are increased two-to three-fold after acute exercise compared to resting conditions [53]. ...
... Of note, serum BDNF levels are increased two-to three-fold after acute exercise compared to resting conditions [53]. Thus, it remains unclear whether exercise-induced increases in blood and brain BDNF concentrations would show similar negative associations with time spent in SWS and REM sleep as described under rest conditions in [52]. ...
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Background Recurrently disrupted sleep is a widespread phenomenon in our society. This is worrisome as chronically impaired sleep increases the risk of numerous diseases that place a heavy burden on health services worldwide, including type 2 diabetes, obesity, depression, cardiovascular disease, and dementia. Therefore, strategies mitigating the current societal sleep crisis are needed. Scope of review Observational and interventional studies have found that regular moderate to intensive exercise is associated with better subjective and objective sleep in humans, with and without pre-existing sleep disturbances. Here, we summarize recent findings from clinical studies in humans and animal experiments suggesting that molecules that are expressed, produced, and released by the skeletal muscle in response to exercise may contribute to the sleep-improving effects of exercise. Major conclusions Exercise-induced skeletal muscle recruitment increases blood concentrations of signaling molecules, such as the myokine brain-derived neurotrophic factor (BDNF), which has been shown to increase the depth of sleep in animals. As reviewed herein, BDNF and other muscle-induced factors are likely to contribute to the sleep-promoting effects of exercise. Despite progress in the field, however, several fundamental questions remain. For example, one central question concerns the optimal time window for exercise to promote sleep. It is also unknown whether the production of muscle-induced peripheral factors promoting sleep is altered by acute and chronic sleep disturbances, which has become increasingly common in the modern 24/7 lifestyle.
... One major confounding parameter we did not consider in our study was the quality of sleep, which has been shown to influence BDNF [33]. Deuschle et al. [34] showed that independent of a specific sleep disorder, serum BDNF levels are related to the proportion of specific sleep stages. Though we did not find differences monitoring serum BDNF levels in our setup, it would be an interesting topic of future research to evaluate long-term effects with regular therapy dog over at least 1 month. ...
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Background: Animal-assisted intervention has become a common therapeutic practice used for patients with dementia in home-dwelling and institutions. The most established procedure is a visiting service by specially trained dogs and their owners to improve social interactions and reduce symptoms of agitation. Objectives: The study aims to investigate the effects of a therapy dog on agitation of inpatients with dementia in a gerontopsychiatric ward. Materials and methods: The severity of agitation was assessed by a rater blinded for the presence of the dog via the Overt Agitation Severity Scale (OASS). The scale was conducted on 1 day with the dog and his handler present (resident doctor on the ward) and on another day with only the handler present. Each patient was his/her own control. Heart rate variability (HRV) and serum level of brain-derived neurotrophic factor (BDNF) of the patients were measured on both days. 26 patients with the Mini-Mental Status Examination (MMSE) score <21 and the diagnosis of dementia were included in the study. Results: A significant reduction of agitation in the OASS could be shown when the dog was present (p = 0.006). The data neither demonstrated a difference in the HRV for the parameters mean heart rate (p = 0.65), root mean square of successive differences (p = 0.63), and high frequencies (p = 0.27) nor in serum BDNF concentrations (p = 0.42). Discussion: Therapy dogs can be implemented as a therapeutic tool in a gerontopsychiatric ward to reduce symptoms of agitation in patients with dementia. The study was registered in the German Clinical Trials Register (DRKS00024093).
... [10][11][12] Acute SD in patients with primary and secondary sleep disorders was associated with decreased serum BDNF levels. 13,14 In cultured hippocampal neurons and slices, application of exogenous BDNF activated tyrosine receptor kinase (Trk)B signaling and led to the recruitment of downstream signaling molecules such as mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (Erk). 15 In vivo studies demonstrated that BDNF induced long-lasting synaptic strengthening in the rodent hippocampus via MAPK/Erk activation. ...
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Aims: This study aimed to investigate whether electroacupuncture (EA) promotes the survival and synaptic plasticity of hippocampal neurons by activating brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TrkB)/extracellular signal-regulated kinase (Erk) signaling, thereby improving spatial memory deficits in rats under SD. Methods: In vivo, Morris water maze (MWM) was used to detect the effect of EA on learning and memory, at the same time Western blotting (WB), immunofluorescence (IF), and transmission electron microscopy (TEM) were used to explore the plasticity of hippocampal neurons and synapses, and the expression of BDNF/TrkB/Erk signaling. In vitro, cultured hippocampal neurons were treated with exogenous BDNF and the TrkB inhibitor K252a to confirm the relationship between BDNF/TrkB/Erk signaling and synaptic plasticity. Results: Our results showed that EA mitigated the loss of hippocampal neurons and synapses, stimulated hippocampal neurogenesis, and improved learning and memory of rats under SD accompanied by upregulation of BDNF and increased phosphorylation of TrkB and Erk. In cultured hippocampal neurons, exogenous BDNF enhanced the expression of synaptic proteins, the frequency of the postsynaptic currents, and the phosphorylation of TrkB and Erk; these effects were reversed by treatment with K252a. Conclusions: Electroacupuncture alleviates SD-induced spatial memory impairment by promoting hippocampal neurogenesis and synaptic plasticity via activation of BDNF/TrkB/Erk signaling, which provided evidence for EA as a therapeutic strategy for countering the adverse effects of SD on cognition.
... For example, intracerebroventricular injection of BDNF was found to induce NREM sleep in rats and NREM and REM sleep in rabbits [171]. Studies in humans also report that lower levels of BDNF associate with shorter sleep duration or with decreased amount of deep NREM and REM sleep [172,173]. Interestingly, TrkB KO mice have more REM sleep, reduced REM sleep latency, and shorter bouts of wake and NREM sleep [174]. Secondly, the BDNF/TrkB pathway was found to impact the sleep EEG. ...
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Uncaria rhynchophylla is a plant highly used in the traditional Chinese and Japanese medicines. It has numerous health benefits, which are often attributed to its alkaloid components. Recent studies in humans show that drugs containing Uncaria ameliorate sleep quality and increase sleep time, both in physiological and pathological conditions. Rhynchophylline (Rhy) is one of the principal alkaloids in Uncaria species. Although treatment with Rhy alone has not been tested in humans, observations in rodents show that Rhy increases sleep time. However, the mechanisms by which Rhy could modulate sleep have not been comprehensively described. In this review, we are highlighting cellular pathways that are shown to be targeted by Rhy and which are also known for their implications in the regulation of wakefulness and sleep. We conclude that Rhy can impact sleep through mechanisms involving ion channels, N-methyl-d-aspartate (NMDA) receptors, tyrosine kinase receptors, extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/RAC serine/threonine-protein kinase (AKT), and nuclear factor-kappa B (NF-κB) pathways. In modulating multiple cellular responses, Rhy impacts neuronal communication in a way that could have substantial effects on sleep phenotypes. Thus, understanding the mechanisms of action of Rhy will have implications for sleep pharmacology.
... Infusion DEX could also increase the N3 sleep in a dose-dependent manner, which is associated with improved cognition and synaptic plasticity. 37,38 This suggested biomimetic N3 sleep may beneficial to cognition improvement. ...
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In this article, we conduct a systematic review of the literature to explore the specific role of dexmedetomidine (DEX) on postoperative sleep and its associated mechanisms at present. The electronic database Embase, MEDLINE/PubMed, the Cochrane Library, Web of Science, and Google Scholar were searched. The restriction terms included "dexmedetomidine", "sleep" and "surgery". The inclusion criteria were as following: 1) patients 18 years old or older; 2) DEX used in the perioperative period not just for critically ill patients in the intensive care unit (ICU); 3) prospective or retrospective studies. The review articles, conference abstracts, and animal studies were excluded. Out of the 22 articles which met the above criteria, 20 of them were randomized controlled studies and 2 of them were retrospective cohort studies. Infusion of DEX including during the surgery and after surgery at a low or high dose was shown to improve subjective and objective sleep quality, although 2 studies showed there is no evidence that the use of DEX improves sleep quality and 1 showed less sleep efficiency and shorter total sleep time in the DEX group. Other postoperative outcomes evaluated postoperative nausea and vomiting, pain, postoperative delirium bradycardia and hypotension. Outcomes of our systematic review showed that DEX has advantages in improving patients' postoperative sleep quality. Combined with the use of general anesthetic, DEX provides a reliable choice for procedural sedation.
... There is a need to investigate other astrocyte-related markers, such as glial fibrillary acidic protein (GFAP), 23 brain-derived neurotrophic factor (BDNF), 24 and glial cell line-derived neurotrophic factor (GDNF), 25 and study their role in CID. The aim of this study was to determine whether astrocyte-specific biomarker levels in patients with CID could serve as objective and accurate complementary diagnostic tools for the detection and assessment of insomnia severity. ...
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Purpose: The objective of this study was to investigate whether the serum biomarkers S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) change in patients with chronic insomnia disorder (CID), and if this is the case, whether the altered levels of these serum biomarkers are associated with poor sleep quality and cognitive decline in CID. Patients and methods: Fifty-seven CID outpatients constituted the CID group; thirty healthy controls (HC) were also enrolled. Questionnaires, polysomnography, Chinese-Beijing Version of Montreal Cognitive Assessment (MoCA-C) and Nine Box Maze Test (NBMT) were used to assess their sleep and neuropsychological function. Serum S100B, GFAP, BDNF, and GDNF were evaluated using enzyme-linked immunosorbent assay. Results: The CID group had higher levels of S100B and GFAP and lower levels of BDNF and GDNF than the HC group. Spearman correlation analysis revealed that poor sleep quality, assessed by subjective and objective measures, was positively correlated with S100B level and negatively correlated with BDNF level. GFAP level correlated positively with poor subjective sleep quality. Moreover, S100B and GFAP levels correlated negatively with general cognitive function assessed using MoCA-C. GFAP level correlated positively with poor spatial working memory (SWM) in the NBMT; BDNF level was linked to poor SWM and object recognition memory (ORcM) in the NBMT. However, principal component analysis revealed that serum S100B level was positively linked to the errors in object working memories, BDNF and GDNF concentrations were negatively linked with errors in ORcM, and GFAP concentration was positively correlated with the errors in the SWM and spatial reference memories. Conclusion: Serum S100B, GFAP, BDNF, and GDNF levels were altered in patients with CID, indicating astrocyte damage, and were associated with insomnia severity or/and cognitive dysfunction.
... 9 On the other hand, sleep deprivation increased BDNF level. 10 Moreover, BDNF has been shown to be involved in circadian regulation via the tropomyosin receptor kinase B. 11 Pain and sleep problems are also common in CD patients. ...
Article
Background Brain‐derived neurotrophic factor (BDNF) is associated with depression, pain, or sleep disorders, factors that are thought to be involved in the pathogenesis and clinical course of Crohn's disease (CD). Therefore, the study aimed at assessing the BDNF serum level in patients with CD and evaluates the effect of anti‐TNF‐α therapy on the BDNF level and its impact on sleep, mood, and pain parameters. Methods Fifty‐eight CD patients and 26 healthy controls (HC) were included in the study. The severity of insomnia symptoms was assessed by the Athens Insomnia Scale (AIS). Subjective pain intensity was estimated by the Visual Analogue Scale (VAS) and Laitinen Pain Scale. Mood level was measured using the Beck Depression Inventory (BDI). Seventeen patients were treated with anti‐TNF‐α therapy for 14 weeks and were re‐examined after treatment. Key Results CD patients had a higher serum BDNF level than HC (P = .010). No correlation between clinical severity and BDNF was found. There were positive correlations between the BDNF level and the results of AIS (r = 0.253, P = .020), the severity of pain measured using the VAS (r = 0.251, P = .021) and the Laitinen Pain Scale (r = 0.218, P = .047), but not BDI. No differences were observed in the BDNF level before and after 14 weeks of anti‐TNF‐α therapy. Conclusions and Inferences Increased BDNF level in CD patients suggests that it may be involved in the pathogenesis and clinical course of the disease. Further research into BDNF might contribute to a better understanding of the effects of sleep and pain on the course of CD.
... Exercise stimulates serotonergic and gamma-aminobutyric-acid (GABA) releasing neurons, which have shown modulate sleep regulation mechanisms [3,88]. Furthermore, exercise up-regulates brain-derived neurotrophic factor (BDNF) [89], which has been shown to contribute to increase slow wave sleep activity during slow wave (N3) sleep [90,91]. Reductions in chronic inflammation and oxidative stress with exercise [92], could in principle slow the neurodegenerative progression of the disease and improve sleep quality in persons with PD [88,93]. ...
Article
We conducted a systematic review with meta-analysis to determine the evidence in support of exercise to improve sleep quality assessed subjectively and objectively in Parkinson’s Disease (PD). Standardized mean differences (SMD) comparing the effects of exercise and control interventions on sleep quality with 95% confidence intervals (CI) were calculated. Data from 10 randomized and 2 non-randomized controlled trials, including a total of 690 persons with PD were included. Exercise had a significant positive effect on sleep quality assessed subjectively (SMD=0.53; 95% CI=0.16−0.90; p=0.005). However, the methodological quality of the studies showing positive effects on sleep quality was significantly poorer than the studies showing no effects. Only one study assessed the impact of exercise on objective sleep quality, showing improvements in sleep efficiency assessed with polysomnography (SMD=0.94; 95% CI=0.38−1.50; p=0.001). Exercise performed at moderate to maximal intensities (SMD=0.46; 95% CI=0.05−0.87; p=0.03) had significant effects on subjective sleep quality. In contrast, exercise performed at mild to moderate intensities showed non-significant effects (SMD=0.76; 95% CI= -0.24−1.76; p=0.14). These results support the use of exercise to improve sleep quality in persons with PD and reinforce the importance of achieving vigorous exercise intensities. Biases, limitations, practice points and directions for future research are discussed.
Article
Background Millions of Americans experience traumatic orthopaedic injuries (TOIs) annually. Post-injury symptoms of acute stress disorder (ASD), anxiety, depression, pain, and sleep disturbance are common. Symptoms often present in clusters. Symptom cluster profiles phenotypically characterize TOI survivors’ experiences with clustered symptoms. Expression of brain-derived neurotrophic factor (BDNF) may contribute to the biological underpinnings of symptom cluster profile membership. Methods We recruited hospitalized TOI survivors within 72 hours of injury. We measured symptoms of ASD with the Acute Stress Disorder Scale and symptoms of anxiety, depression, pain, and sleep disturbance with Patient-Reported Outcomes Measurement Information System (PROMIS) short forms. We measured serum BDNF concentrations with enzyme-linked immunosorbent assay (ELISA) and identified rs6265 genotypes with TaqMan real-time PCR. We performed latent profile analysis to identify the symptom cluster profiles. We identified the variables associated with symptom cluster profile membership with unadjusted and adjusted multinomial logistic regression. Results We identified 4 symptom cluster profiles characterized by symptom severity that we labelled Physical Symptoms Only, and Mild, Moderate, and Severe Psychological Distress. Age, self-identified Black race, resilience, and serum BDNF concentrations were associated with lower odds, and female sex with higher odds, of being in the Psychological Distress clusters. Clinical characteristics and rs6265 genotypes were not associated with symptom cluster profile membership. Conclusion TOI survivors experience distinct symptom cluster profiles. Sociodemographic characteristics and serum BDNF concentrations, not clinical characteristics, were associated with symptom cluster profile membership. These findings support comprehensive symptom screening and treatment for all TOI survivors and further evaluating BDNF as a biomarker of post-injury symptom burden.
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The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic-pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase.
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Sleep is universal, tightly regulated, and its loss impairs cognition. But why does the brain need to disconnect from the environment for hours every day? The synaptic homeostasis hypothesis (SHY) proposes that sleep is the price the brain pays for plasticity. During a waking episode, learning statistical regularities about the current environment requires strengthening connections throughout the brain. This increases cellular needs for energy and supplies, decreases signal-to-noise ratios, and saturates learning. During sleep, spontaneous activity renormalizes net synaptic strength and restores cellular homeostasis. Activity-dependent down-selection of synapses can also explain the benefits of sleep on memory acquisition, consolidation, and integration. This happens through the offline, comprehensive sampling of statistical regularities incorporated in neuronal circuits over a lifetime. This Perspective considers the rationale and evidence for SHY and points to open issues related to sleep and plasticity.
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Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF. Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels. This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a mental disorder.
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The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
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The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
Article
Previous studies have suggested that brain-derived neurotrophic factor (BDNF) participates in the homeostatic regulation of sleep. The objective of this study was to investigate the influence of the Val66Met functional polymorphism of the BDNF gene on sleep and sleep EEG parameters in a large population-based sample. In total 337 individuals participating in the São Paulo Epidemiologic Sleep Study were selected for analysis. None of the participants had indications of a sleep disorder, as measured by full-night polysomnography and questionnaire. Spectral analysis of the EEG was carried out in all individuals using fast Fourier transformation of the oscillatory signals for each EEG electrode. Sleep and sleep EEG parameters in individuals with the Val/Val genotype were compared with those in Met carriers (Val/Met and Met/Met genotypes). After correction for multiple comparisons and for potential confounding factors, Met carriers showed decreased spectral power in the alpha band in stage one and decreased theta power in stages two and three of nonrapid-eye-movement sleep, at the central recording electrode. No significant influence on sleep macrostructure was observed among the genotype groups. Thus, the Val66Met polymorphism seems to modulate the electrical activity of the brain, predicting interindividual variation of sleep EEG parameters. Further studies of this and other polymorphic variants in potential candidate genes will help the characterization of the molecular basis of sleep. © 2014 Wiley Periodicals, Inc.
Article
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that promote the growth and survival of neurons. Recent evidence suggests that BDNF is a sleep regulatory substance that contributes to sleep behavior. However, no studies have examined the association between the serum BDNF levels and dyssomnia. The present study was conducted to clarify the association between the serum BDNF levels and dyssomnia. A total of 344 workers (age: 40.1 ± 10.5 years, male: 204, female: 140) were included in the study. The serum BDNF levels were categorized into tertiles according to sex. The prevalence of dyssomnia was 35.1% in males and 30.0% in females. In the females, the BDNF levels were found to be negatively associated with dyssomnia after adjusting for age, body mass index, hypertension, dyslipidemia, hyperglycemia, depression, smoking, alcohol intake, and regular exercise. Compared with the females in the high BDNF group, the multivariate odds ratio (95% CI) of dyssomnia was 2.08 (0.62-6.98) in females in the moderate BDNF group and 8.41 (2.05-27.14) in females in the low BDNF group. No such relationships were found in the males. The serum BDNF levels are associated with dyssomnia in Japanese female, but not male, workers. Nishichi R; Nufuji Y; Washio M; Shuzo Kumagai S. Serum brain-derived neurotrophic factor levels are associated with dyssomnia in females, but not males, among Japanese workers. J Clin Sleep Med 2013;9(7):649-654.
Article
Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction in hypocretin neurons in hypothalamus in post-mortem tissue. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are important for activity-dependent neuronal function and synaptic modulation and it is considered that these mechanisms are important in sleep regulation. We hypothesised that serum levels of these factors are altered in patients with narcolepsy compared to healthy controls without sleep disturbances. Polysomnography data was obtained and serum BDNF and NGF levels measured using ELISA, while hypocretin was measured using RIA. Serum BDNF levels were significantly higher in narcolepsy patients than in healthy controls (64.2±3.9ng/ml vs 47.3±2.6ng/ml, P<0.01), while there were no significant differences in NGF levels. As expected, narcolepsy patients had higher BMI compared to controls, but BMI did not correlate with the serum BDNF levels. The change in BDNF levels was not related to disease duration and sleep parameters did not correlate with BDNF in narcolepsy patients. The mechanisms behind the marked increase in BDNF levels in narcolepsy patients remain unknown.
Article
Introduction: Depression, stress and antidepressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF). Recent research suggests that serum BDNF concentration is reduced in depression and that antidepressant treatment leads to an increase in serum BDNF concentration. Methods: We studied depressed patients receiving a randomized antidepressant treatment with either mirtazapine (n=29) or venlafaxine (n=27) for 28 days in a prospective design. Changes in the concentrations of serum neurotrophins in response to antidepressant treatment were assessed. Results: There was a significant "treatment" by "medication" interaction effect on BDNF serum concentrations that indicated a decline of BDNF in venlafaxine-treated patients (7.82±3.75-7.18±5.64 ng/mL), while there was an increase in mirtazapine-treated patients (7.64±6.23-8.50±5.37 ng/mL). There was a trend for a "treatment" by "remission" interaction with a favourable clinical course being related to increasing serum BDNF. Discussion: Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant and potentially on the clinical course.