Curr Neurol Neurosci Rep (2015) 15: 9

DOI 10.1007/s11910-015-0527-3

SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)

Neuroimaging Insights into Insomnia

Kai Spiegelhalder & Wolfram Regen & Chiara Baglioni &
Christoph Nissen & Dieter Riemann & Simon D. Kyle

Published online: 17 February 2015

# Springer Science+Business Media New York 2015

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.

Keywords Insomnia . Neuroimaging . Neurology .

Neuroscience . Neurobiology . Psychiatry

Introduction
Prevalence and Associated Morbidity

W. Regen
e-mail: Wolfram.Regen@uniklinik-freiburg.de

Insomnia is one of the most prevalent health complaints [1,

2]. At a clinical level, approximately 10 % of the population in
Western industrialized countries suffers from insomnia, with
an increasing prevalence with older age [3]. Chronic insomnia
has a significant impact on an individuals health and wellbeing, being associated with a severely reduced quality of life
[4]; cognitive and affective impairments [5, 6]; physical complaints [7]; and an increased rate of home, work, and car accidents [8]. Furthermore, chronic insomnia confers a substantially increased risk for other psychiatric disorders, especially
depression [9, 10], as well as for cardiovascular morbidity and
mortality [11, 12], and, more generally, for ill-health [13].
Accordingly, insomnia is associated with a marked increase
in health care consumption, work disability, and absenteeism
and, consequently, incurs very high costs for society [14].

C. Baglioni
e-mail: Chiara.Baglioni@uniklinik-freiburg.de

Contemporary Understanding of Insomnia

This article is part of the Topical Collection on Sleep

K. Spiegelhalder (*) : W. Regen : C. Baglioni : C. Nissen :
D. Riemann
Department of Psychophysiology/Sleep Medicine, University
Medical Center Freiburg, Hauptstrae 5, 79104 Freiburg, Germany
e-mail: Kai.Spiegelhalder@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

Despite the socioeconomic impact of chronic insomnia, its

pathophysiology is poorly understood. The most enduring
and widely accepted models of insomnia adopt, explicitly or
implicitly, a bio-psycho-social framework, whereby entry and
maintaining pathways are likely to be multifactorial and interactive in nature [1519]. 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

9 Page 2 of 7

Curr Neurol Neurosci Rep (2015) 15: 9

discrepancies between objective and subjective measurements

of sleep and daytime functioning, often with the aim of
uncovering physiological processes that may readily explain
patient reports. Figure 1 gives an overview of these
Bdiscrepancies^ by presenting effect size estimates (Cohens
d) for objective and subjective differences between patients
with primary insomnia and healthy good sleepers obtained
from cross-sectional studies.
The figure clearly illustrates that primary insomnia
manifests primarily as a subjective disorder. This should
not be a complete surprise, however, as diagnostic
criteria for insomnia are based on subjective experience
of patients. Similarly, it has also been known for some
time that insomnia symptoms are more pronounced
when patients self-report after the sleep period relative
to objective indices and that objective markers of daytime performance are less impaired than what one might
expect from listening to patient reports about sleeprelated daytime dysfunction [41]. From our point of
view, however, the most interesting aspect of the figure
is that, like in other fields in medicine, the most

extensively studied biological indices rarely explain

most or all of the variance in subjective reports of illness experience.

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

the two most frequently investigated putative physiological indicators of

hyperarousal in insomnia. Effect sizes for daytime cognitive performance
were taken from the meta-analysis of Fortier-Brochu et al. [5]. For calculating standardized mean effect sizes, studies were pooled with the random effects model and the meta-analytic calculations were performed
using the software BComprehensive Meta-Analysis,^ version 2. PSQI
Pittsburgh Sleep Quality Index, SE sleep efficiency, SOL sleep-onset
latency, EEG electroencephalography, n.s. non-significant

The Promise of Neuroimaging

Presumably, it is the hope of most researchers, who utilize
neuroimaging methods to investigate the neurobiology of
insomnia, that these methods will provide clinically relevant
information that is not obtainable through Bolder^ methods
like EEG, hormone sampling, or methods targeting autonomic nervous system function. While this may be debatable at present, the rapidly increasing number of neuroimaging studies in insomnia suggests that many worldwide
believe in the potential of this technological approach. The
current review covers empirical studies on (1) functional
neuroimaging, (2) chemical neuroimaging, and (3) structural
neuroimaging in insomnia aiming at summarizing the current knowledge and discussing methodological limitations
of the research. By doing so, the current review is an extension of a previous article by our group [42].

Curr Neurol Neurosci Rep (2015) 15: 9

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

Page 3 of 7 9

increased functional connectivity between the insula and salience

networks in 17 patients with insomnia compared to an equal
number of healthy controls [59]. This abnormal pattern of insula
coactivation may indicate that interoceptive awareness of bodily
states, one of the established roles of the insula [60, 61], is impaired in patients with insomnia. However, the lack of simultaneous EEG recordings to ensure defined states of sleep or wakefulness [5658, 62], coupled with application of liberal statistical
thresholds, may partially explain variability in findings across
resting-state fMRI studies in insomnia.

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

9 Page 4 of 7

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

Curr Neurol Neurosci Rep (2015) 15: 9

(which is associated with reduced rACC volume). However, it

must be noted that these findings have not been corroborated by a
study using the same methodology and voxel-based morphometry [24] or by two other studies using voxel-based morphometry
[68, 70].
Pineal Gland
One study that included 23 patients with primary insomnia and
27 healthy good sleepers suggested a reduced volume of the
pineal gland in insomnia [77]. However, similar to the other
described morphometric findings in insomnia, there are a number of studies using VBM or FreeSurfer-based segmentation,
which did not support this finding [24, 68, 70, 71].

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

Curr Neurol Neurosci Rep (2015) 15: 9

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]:
&
&
&
&

Insomnia may be the result of a relative overactivity in

corticolimbic areas interfering with sleep initiation/ sleep
maintenance.
In insomnia patients, daytime performance is characterized by a hypoactivation of task-related areas, especially
in fronto-striatal networks.
Reduced cortical GABA levels are probably a neurochemical characteristic of patients with insomnia.
Insomnia may be associated with altered brain morphometry in the frontal cortex, hippocampus, anterior cingulate
cortex, or pineal gland.

Page 5 of 7 9
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Compliance with Ethics Guidelines
15.
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.

16.

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