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DOI 10.1007/s11910-015-0527-3
Abstract Insomnia is one of the most prevalent health complaints afflicting approximately 10 % of the population in
Western industrialized countries at a clinical level. Despite
the proposition that both biological and psychological factors
play a role in the experience of insomnia, the field continues to
puzzle over so-called Bdiscrepancies^ between objective and
subjective measurements of sleep and daytime functioning.
The promise of neuroimaging is to uncover physiological processes that may readily explain patient reports. However,
while there has been an explosion in the number of studies
investigating the neural correlates of insomnia with neuroimaging technologies, there appears to be little consistency in
findings across studies. We suggest a number of methodological reasons which may, at least partially, explain variability in
findings across neuroimaging studies in insomnia.
Introduction
Prevalence and Associated Morbidity
W. Regen
e-mail: Wolfram.Regen@uniklinik-freiburg.de
C. Baglioni
e-mail: Chiara.Baglioni@uniklinik-freiburg.de
C. Nissen
e-mail: Christoph.Nissen@uniklinik-freiburg.de
D. Riemann
e-mail: Dieter.Riemann@uniklinik-freiburg.de
K. Spiegelhalder : S. D. Kyle
School of Psychological Sciences, University of Manchester,
Manchester, UK
S. D. Kyle
e-mail: simon.kyle@manchester.ac.uk
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Fig. 1 Effect sizes in cross-sectional insomnia research. Effect size estimates for subjective sleep were obtained by calculating the standardized
mean effect size for Pittsburgh Sleep Quality Index scores from five
cross-sectional studies [2023, 24] and by presenting sleep diary-based
group differences in sleep efficiency and sleep-onset latency from a recent
meta-analysis [25]. Effect sizes for polysomnographically determined
sleep were taken from the same meta-analysis [25]. With respect to
physiological variables, standardized mean effect sizes were calculated
for NREM EEG beta activity [22, 2633] and resting heart rate [3440] as
Functional Neuroimaging
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been used to investigate insomnia patients brain function during sleep [4346].
In the most frequently cited neuroimaging study, Nofzinger
et al. observed elevated (or attenuated decrease in) cerebral
metabolism from wake to NREM sleep in insomnia patients
relative to healthy controls [45]. More specifically, the findings suggest an involvement of the general arousal system
(ascending reticular activating system, hypothalamus), the
emotion-regulating system (hippocampus, amygdala, anterior
cingulate cortex), and the cognitive system (reduced metabolism in prefrontal cortex during the day) in the pathophysiology of insomnia. This has contributed to the conceptualization
of insomnia as a disorder of corticolimbic overactivity that
interferes with sleep-promoting brain structures [47]. However, Nofzinger et al. [45] investigated a very small sample (seven insomnia patients), and, to our knowledge, the results have
never been replicated. Moreover, results from this single PET
study are somewhat inconsistent with the SPECT investigation by Smith et al. [43] which showed hypoperfusion in insomnia patients (n=5), particularly in the basal ganglia.
To date, functional magnetic resonance imaging (fMRI), due
to its inherent limitations, was primarily used to investigate neurobiological correlates of daytime performance in patients with
insomnia. These studies revealed that the performance of insomnia patients in neuropsychological tasks is associated with a
hypoactivation of task-related areas, especially in fronto-striatal
networks [48, 49, 50]. Most notably, the study of Stoffers et al.
showed an impaired recruitment of the head of the left caudate
nucleusa candidate structure for arousal regulationduring an
executive task in 24 patients with primary insomnia compared to
13 healthy good sleepers [50]. In a recent own fMRI study, 22
insomnia patients showed an increased cue-induced amygdala
reactivity to sleep-related pictorial stimuli in comparison with 38
healthy good sleepers [51], which is in line with previous literature on the phenomenon called sleep-related attentional bias
[20, 52, 53]. While cognitive-behavioral therapy for insomnia
had an effect on the observed prefrontal hypoactivation during
category and letter fluency tasks [48], it did not alter caudate
hypoactivation during executive task performance [50]. To
date, it has yet to be investigated whether one can directly improve the voluntary regulation of altered localized brain activity
in insomnia patients. This may be a potential target of future
studies using real-time fMRI, an emerging method that has been
used for neurofeedback in different patient populations [54, 55].
Four fMRI studies investigated the resting-state in insomnia
patients targeting functional connectivity in various brain networks [5658, 59]. This method is used for analyzing temporal
correlations between spontaneous fMRI signal oscillations of
different brain areas while participants rest quietly in the MRI
scanner. In the most comprehensive study, Chen et al. reported
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Chemical Neuroimaging
Magnetic resonance spectroscopy (MRS) can be used to measure chemical metabolite concentrations across selected regions
of interest within the living brain [63]. In insomnia, spectroscopic studies have mainly focused on the assessment of cortical -aminobutyric acid (GABA), the most important inhibitory
neurotransmitter. In the first published study, 16 patients with
primary insomnia and 16 healthy good sleepers were compared
using proton magnetic resonance spectroscopy [23]. In line
with the hyperarousal account of insomnia, findings indicated
that insomnia patients had almost 30 % lower global GABA
levels in comparison to healthy controls. In a second study,
conducted by the same research group, Plante et al. investigated
regional GABA levels in 20 patients with primary insomnia
and 20 healthy good sleepers [64]. Consistent with
Winkelman et al. [23], lower GABA levels were reported in
insomnia patients, specifically in the occipital cortex (33 %
reduction) and the anterior cingulate cortex (21 % reduction),
with no between-group difference in the thalamus. In contrast to
these findings, Morgan et al. reported increased occipital
GABA levels (by 12 %) in 16 primary insomnia patients, relative to 17 healthy controls [65]. The differences between the
studies of the two groups with respect to sample characteristics
as well as specific methods for spectroscopic data collection
and analysis were outlined by Plante et al. [66].
The most recent spectroscopic publication on insomnia was
provided by Harper et al. [67]. Reporting on the same sample as
studied in Winkelman et al. [23], the authors analyzed data collected with phosphorous magnetic resonance spectroscopy. Primary insomnia patients demonstrated lower phosphocreatine
levels in the gray matter reflecting increased energy demand, thus
also being consistent with the hyperarousal account.
Structural Neuroimaging
Frontal Cortex
Several morphometric brain imaging studies suggest gray matter
loss in the frontal cortex of insomnia patients. In the first of these
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studies, voxel-based morphometry (VBM) revealed a gray matter reduction in the left orbitofrontal cortex in 24 primary insomnia patients in comparison with 13 healthy good sleepers [68].
Using the peak voxel coordinates of this finding, Stoffers et al.,
in an independent validation study recruiting 65 healthy good
sleepers, reported a negative correlation between subjective complaints of early morning awakening and gray matter density in
the left orbitofrontal cortex [69]. Moreover, a further VBM study
in 27 patients with primary insomnia and an equal number of
healthy good sleepers reported gray matter reductions in several
frontal areas including the left orbitofrontal cortex; however, it
should be noted that these results did not survive correction for
multiple testing [70]. Using the FreeSurfer software for automated segmentation, a significant decrease of the volume of the pars
orbitalis of the right inferior frontal gyrus and a trend for the
same volume reduction was also found in two independent samples by Winkelman et al. (sample 1, 20 patients with primary
insomnia vs. 15 healthy good sleepers; sample 2, 21 patients
with primary insomnia vs. 20 healthy good sleepers [71]).
The only study which did not report any morphometric abnormalities in the frontal cortex of patients with primary insomnia
also used FreeSurfer-based segmentation in 28 patients with primary insomnia and 38 healthy good sleepers [24]. Of note, the
frontal gray matter loss may be related to the recent finding of
reduced white matter integrity in the anterior internal capsule
[72]. This finding, which was reported for a subsample (24
patients with primary insomnia and 35 healthy good sleepers)
of the abovementioned morphometric study by our group [24],
suggests that abnormal fronto-subcortical connectivity may be a
cause or consequence of the disorder.
Hippocampus
Using manual morphometry, we reported a reduced bilateral
hippocampus volume in eight patients with primary insomnia
in comparison to eight healthy good sleepers [73]. This finding
was recently supported by data from Joo et al. who also reported hippocampal volume loss in 27 patients with primary insomnia compared to 30 healthy good sleepers across several hippocampal subfields [74]. However, several other studies have
not corroborated the finding of reduced hippocampal volumes
in insomnia patients using manual morphometry, VBM, or
FreeSurfer-based segmentation [24, 68, 70, 71, 75, 76].
Anterior Cingulate Cortex
Intriguingly, Winkelman et al. reported increased volume of the
rostral anterior cingulate cortex in two independent samples of
patients diagnosed with primary insomnia, relative to healthy
controls, using FreeSurfer-based segmentation [71]. The authors interpreted these findings as potential evidence of a compensatory brain response triggered by repeated sleep disturbance
as well as a potential indicator of resilience to major depression
Conclusions
In summary, while there has been an explosion in the number of
studies investigating the neural correlates of insomnia with neuroimaging technologies, there appears to be little consistency in
findings across studies. Given the heterogeneity of methods and
study protocols, it is perhaps understandable that we do not yet
have a clear picture of the pathophysiology of insomnia. This
review clearly suggests that replication studies are needed in this
field to confirm previous findings. Moreover, Fig. 1 may remind
us of the importance of investigating adequate sample sizes. At
p<0.05 (one-tailed), the necessary sample sizes per group are
310, 51, and 21 cases for detecting small (d=0.2), medium (d=
0.5), and large (d=0.8) effect sizes, respectively, with a power of
80 %. Thus, a large number of neuroimaging studies are probably underpowered leading to an increased likelihood of false
positive and false negative results. This situation is further complicated by the high degree of flexibility in data collection and
analysis inherent in structural and functional neuroimaging studies. Apart from increasing samples sizes in the individual studies,
data pooling across studies, adopting standardized methodology,
as well as longitudinal research designs permitting within-subject
analyses (e.g., pre- vs. post-treatment comparisons or longitudinal investigations of high-risk groups [78]) may help to increase
statistical power and overcome existing methodological limitations. Moreover, the empirical identification of more homogenous subtypes of insomnia may help to reduce the error variance
of neuroimaging studies in this field. While there is broad agreement that insomnia is a heterogeneous disorder because of the
observed clinical variability, there is little consensus about the
number and description of insomnia subtypes [7982]. This is,
of course, a serious limitation of current neuroimaging research
since it is likely that different mechanisms underlie different types
of insomnia.
A promising approach for investigating insomnia patients
brain activity during sleep may be the combination of EEG
and fMRI [83, 84], which has provided important insights into
healthy human sleep [e.g., 85]. However, a major methodological limitation for sleep-related neuroimaging research is
the fact that sleeping in a scanner is not easily accomplished,
especially for insomnia patients in an MRI scanner. In addition
to this, increasing magnetic field strengths, a more thorough
investigation of resting-state functional connectivity, and realtime fMRI may be promising for investigating insomnia psychopathology in the future.
As an intermediate summary of neuroimaging studies in
the insomnia field, we suggested that four hypotheses emerge
from this work [42]:
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Compliance with Ethics Guidelines
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Conflict of Interest Kai Spiegelhalder, Wolfram Regen, Chiara
Baglioni, and Simon D. Kyle declare that they have no conflict of interest.
Christoph Nissen has received speaker honoraria from Servier.
Dieter Riemann has received honoraria from Abbvie, outside the submitted work.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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