Accepted Manuscript

Waking EEG signs of non-restoring sleep in primary insomnia patients

María Corsi-Cabrera, Olga A. Rojas-Ramos, Yolanda del Río-Portilla

PII: S1388-2457(15)01074-3
DOI: http://dx.doi.org/10.1016/j.clinph.2015.08.023
Reference: CLINPH 2007659

To appear in: Clinical Neurophysiology

Accepted Date: 10 August 2015

Please cite this article as: Corsi-Cabrera, M., Rojas-Ramos, O.A., del Río-Portilla, Y., Waking EEG signs of non-
restoring sleep in primary insomnia patients, Clinical Neurophysiology (2015), doi: http://dx.doi.org/10.1016/
j.clinph.2015.08.023

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 Waking EEG signs of non-restoring sleep in primary insomnia
patients

Corsi-Cabrera, María1; Rojas-Ramos, Olga A.1,2; del Río-Portilla, Yolanda1

1
Sleep Laboratory, Facultad de Psicología, Universidad Nacional Autónoma de México, Av.
Universidad 3004, D.F. México 04510
2
Departament of Psychophysiology, Facultad de Psicología, Universidad Nacional Autónoma de
México, Av. Universidad 3004, D.F. México 04510

Corresponding author:
María Corsi-Cabrera, PhD
Sleep Laboratory, Facultad de Psicología, Posgrado, Universidad Nacional Autónoma
de México, Av. Universidad 3004, México, D.F. 04510, México
Tel.: +52-55 56222251
Fax: +52-55 56222310
E-mail: corsi@unam.mx

0
ABSTRACT
Objective: Subjective feelings of insufficient and non-restorative sleep are core
symptoms of primary insomnia. Sleep has a restorative effect on next-day waking EEG
activity, whereas sleep loss has non-restorative effects in good sleepers. We proposed to
explore waking EEG activity in primary insomniacs the evening before, and the
morning after, a night of sleep, in order to detect signs of morning hyper-arousal and
non-restoring sleep that might explain the subjective feelings despite the absence of
objective signs in polysomnography.
Method: pre-sleep (10 pm) and post-sleep (10 am) waking EEG activity was analyzed in
10 non-medicated primary insomniacs and matched control subjects. Beta and Gamma
absolute power and EEG temporal coupling were obtained. Participants also evaluated
subjective sleep quantity and quality.
Results: Insomnia patients evaluated their sleep as non-restorative and insufficient.
Compared to pre-sleep, during post-sleep control subjects exhibited significantly
decreased Beta and Gamma power and reduced synchronization among anterior and
posterior regions, consistent with restoring effects of sleep. Insomnia patients showed
no beneficial effects of sleep on these EEG parameters.
Conclusion: insomniacs are hyper-aroused during morning wakefulness and they do not
benefit from preceding sleep.
Significance: our study adds new knowledge to our understanding of the
physiopathology of insomnia.

Keywords: Primary insomnia, spectral analysis, EEG signs of non-restoring sleep, Beta-
Gamma activity, temporal coupling, Beta-Gamma synchronization.

Highlights
• Insomnia patients showed no beneficial effects of sleep on EEG parameters.
• Insomniacs are hyper-aroused during morning wakefulness.
• Non-restorative sleep is correlated with post-sleep Gamma.

1
 1. Introduction
Primary insomnia (PI) is characterized by subjective feelings of insufficient and non-
restorative sleep, complaints of daytime tiredness, unwellness, and impairments in
cognitive functioning in emotional, social or professional fields (Riemann et al., 2010;
Shekleton et al., 2010). According to the “hyper-arousal” model of PI, insomniac
patients suffer higher 24-hour physiological and cognitive arousal during both sleep and
wakefulness (Bonnet and Arand, 2010).
With few exceptions (see, for example, Wu et al., 2013) the results of quantitative EEG
studies generally support the idea that PI patients are hyper-aroused during pre-sleep
waking at bedtime. These studies have shown that PI patients are more cortically-
activated than good-sleepers or normal subjects during both sleep and the wake-sleep
transition period. Awake, state-related, Gamma, Beta and Alpha EEG frequencies are
higher in PI patients than good-sleepers or normal subjects during the wake-sleep
transition period when they are trying to fall asleep (Cervena et al., 2014; Figueredo-
Rodríguez et al., 2009; Maes et al., 2014; Merica and Galliard, 1992; Lamarche and
Ogilvie, 1997; Perlis et al., 1997, 2001a, 2001b; Staner et al., 2003).
The prefrontal cortex and posterior association areas are particularly aroused in PI
patients when they are trying to sleep. In a previous study, we found higher Beta
absolute power and current density in the frontal cortex and left posterior association
areas in PI patients than normal controls. Also, functional relationships or the temporal
coupling of fast frequencies – which are involved in binding functions and information
processing (Llinás et al., 1998; Tononi, 2010; Uhlhaas et al., 2009) – that link frontal,
parietal and posterior midline regions of the left hemisphere are enhanced during the
wake-sleep transition in these patients, suggesting that frontal deactivation and
disengagement of the brain regions involved in executive control (Fuster, 2003), inner
attention (Corbetta, 1998), and self-awareness (Kjaer et al., 2002; Mazoyer et al., 2001)
are impaired in PI patients during the wake-sleep transition (Corsi-Cabrera et al., 2012).
According to the 24-hour hyper-arousal model, such cortical activation should also be
expected during the day. One study that analyzed waking EEG activity during the day in
consecutive sleep sessions of a routine diagnostic multiple sleep latency test (MSLT) it
was found that insomnia patients show higher relative power of fast Beta activity (18-30
Hz) at central regions than controls (Wolynczyk-Gmaj and Szelenberger, 2011)
however, temporal coupling of waking EEG activity in PI patients during the day has
not yet been investigated.

2
On the other hand, while some studies have found that PI patients show some
polysomnographic (PSG) signs of disturbed sleep, such as longer sleep latency, more
stage 1 sleep and less stage 3 and 4 sleep than good sleepers (Reite et al., 1995), these
differences do not fully explain the subjective feelings of tiredness and unwellness
reported by PI patients that are often worse than the objective PSG signs (Orff et al.,
2007; Rosa and Bonnet, 2000).
A large body of evidence from quantitative EEG analyses has demonstrated that sleep
loss has profound effects on brain functioning during subsequent wakefulness,
suggesting that poor sleep has a deteriorating effect on next-day brain activity; whereas
sleep is involved in the restoration of brain function (Huber et al., 2013). Sleep
deprivation has been associated with a compensatory increase in Beta frequencies of the
EEG spectrum in next-day waking (Cajochen et al., 1995; Corsi-Cabrera et al., 1992;
Dumont et al., 1999; Forest and Godbout, 2000; Koenis et al., 2013; Lorenzo et al.,
1995). Functional relationships, or temporal coupling among brain regions of fast
frequencies, are also disorganized after sleep deprivation: EEG temporal coupling of
Beta and Gamma activity within the same hemisphere is enhanced after sleep
deprivation in humans compared to after a regular diurnal or nocturnal period of sleep
(Corsi-Cabrera et al., 1992). In addition, brain network topology is disrupted (Koenis et
al., 2013). After recovery sleep, waking spectral power and temporal coupling return to
pre-deprivation values, suggesting a reorganizing effect of sleep on cortical activation
and functional relationships among cortical networks (Cajochen et al., 1995; Corsi-
Cabrera et al., 1992; Dumont et al., 1999; Ferri et al., 2008; Forest and Godbout, 2000;
Lorenzo et al., 1995). Thus, as PI patients often complain of insufficient and poor sleep
even in the absence of objective signs on the PSG, waking activity in the morning after
a night of subjectively-rated unsatisfactory sleep should show EEG signs of non-
restoring sleep.
Given (1) that Beta and Gamma activity during waking is associated with brain
activation, attention and information processing; (2) that the temporal coupling of
Gamma electrical activity between brain regions is involved in the processing and
integration of disperse information in the brain; (3) that PI patients show enhanced Beta
and Gamma activity and temporal coupling; and, (4) that sleep deprivation is followed
by a rebound in Beta activity and enhanced Beta and Gamma temporal coupling in the
same hemisphere in normal subjects; it might be expected that PI patients would show
higher Beta and Gamma activity and temporal coupling than control participants after a

3
night of poor sleep. Thus, the present study examined Beta and Gamma absolute power
and temporal coupling during resting waking at bedtime before going to sleep, and in
the morning after a night of sleep, in order to elucidate whether PI patients show signs
of morning hyper-arousal and non-restorative sleep associated with subjective ratings of
sleep quality compared to normal subjects. According to the 24-hour hyper-arousal
model of primary insomnia (Bonnet and Arand, 2010), we hypothesized that PI patients
would show signs of hyper-arousal; i.e., higher Beta and Gamma power and temporal
coupling between frontal and posterior regions in the evening as well as in the morning,
in comparison to healthy controls, and that PI patients would present EEG signs of non-
restoring sleep during next-day EEG waking activity, in the form of smaller changes in
power and temporal coupling after a night of subjectively-poor sleep quality compared
to healthy controls.

2. Method
Participants were the same subjects as in our own previous study (Corsi-Cabrera et al.,
2012) except for two additional control subjects; that is, 10 young (19-32-year-old)
patients (4 women) who met the International Classification of Sleep Disorders
(American Academy of Sleep Medicine, 2005) criteria for primary insomnia and 10
controls (5 women), matched by age and education, who reported their sleep as
restorative and satisfactory, and had regular sleep habits. All participants were right-
handed and none had any medical, psychiatric or neurological conditions, nor had they
been medicated for insomnia or suffered other sleep disorders. All participants were free
of medication, including over-the-counter drugs. The drug-free condition was
corroborated before performing polysomnography using the Multi-Drug 6 Panel Urine
Test (MEDIMPEX United Inc, Bensalem, PA). Women were recorded between days 3
and 5 of their menstrual cycle (Solís-Ortiz et al., 1994). All participants underwent a
general medical and psychiatric structured interview and completed a 15-day log to
assess subjective sleep quality and sleep habits. Insomnia symptoms, or the absence of
sleep complaints, were verified using the Pittsburgh Sleep Quality Index (Buysse et al.,
1989), the Athens Insomnia Scale (Soldatos et al., 2000), and the Insomnia Severity
Index (Bastien et al., 2001). The absence of clinical depression was ascertained with the
Beck Depression Inventory (Beck et al., 1961) and Hamilton Depression Scale
(Hamilton, 1967).

4
There were no significant differences between the two groups in terms of age, sex
distribution or education (Table 1), or with respect to any PSG variable for the entire
night, as reported elsewhere (Corsi-Cabrera et al., 2012).

Insert Table 1 about here

All participants gave their informed, written consent and were offered treatment if they
so desired. The protocol was approved by the Ethics Committee of the Faculty of
Medicine at the Universidad Nacional Autónoma de México.

2.1. Self-reported measures

Two evaluations of subjective feelings of poor sleep quality were considered, one for
chronic subjective complaints with the Pittsburgh Sleep Quality Index (Buysse et al.,
1989), and another for sleep quality the preceding night using a subjective estimation of
sleep quality questionnaire that is applied regularly at the Laboratory the morning after
spontaneous awakening. This instrument covers the following questions: 1) my sleep
was very bad-very good; 2) refreshing-non-refreshing; 3) light-deep; 4) mood after
waking up was terrible-excellent, answered on a Lickert-type scale with “zero”
indicating very bad, and 100% very good; and, 5) hours of additional sleep desired.

2.2. Polysomnography
Standard polysomnography (PSG) were performed at the laboratory. PSG was recorded
and scored in 30-sec epochs by two experts who were blind to the subject group, as per
standard procedures (Rechtschaffen and Kales, 1968).

2.3. EEG recording

Two minutes of EEG activity with eyes closed in bed after a regular period of
wakefulness before saying good night to the participant (PM), and at 10 a.m., after a
regular period of sleep (AM), were analyzed. EEG activity was recorded at 19 locations
of the 10-20 International System, referred to the ipsilateral earlobe with filter settings
at 0.03-70 Hz. EEG data were digitalized and stored at 1024 Hz with a 12-bits A/D
converter using the acquisition program GRASS-GAMMA version 4.4.

2.4. EEG analysis

5
The EEGs from PM and AM of the insomnia (IN) and control groups (CL) were
segmented into non-overlapping 2-sec epochs and carefully inspected for artifacts. Each
artifact-free, 2-sec epoch was then Fast Fourier Transformed (using a square window)
with the POTENCOR program (Guevara et al., 2002). Temporal coupling between pairs
of electrodes was assessed by cross-correlation functions with zero time delay,
calculated in the time domain by POTENCOR. The absolute power values for each 0.5
Hz bin and cross-correlation values were averaged to obtain two broad bands: Beta (13-
30 Hz) and Gamma (31-50 Hz), for each subject over the same electrode and condition.
In order to approximate these to a normal distribution, logarithmic transformations were
applied to the absolute power values (Gasser et al., 1982) and cross-correlation values
were transformed into Fisher’s Z-scores before conducting statistical comparisons (John
et al., 1980).
We focused on Beta and Gamma frequencies at frontal and posterior derivations of the
left hemisphere because they are associated with cortical activation in PI patients
(Cervena et al., 2014; Corsi-Cabrera et al., 2012; Lamarche and Ogilvie, 1997; Maes et
al., 2014; Merica and Gaillard, 1992; Perlis et al., 1997, 2001a, 2001b; Staner et al.,
2003), and with sleep loss in healthy subjects (Cajochen et al., 1995; Corsi-Cabrera et
al., 1992; Dumont et al., 1999; Forest and Godbout, 2000; Koenis et al., 2013; Lorenzo
et al., 1995). Power and temporal coupling in posterior regions were also analyzed
because it has been reported that insomniacs maintain attention to, and awareness of,
their surroundings and continue sensory information processing (Bastien et al., 2008;
2013; Hairston et al., 2010; Perlis et al., 1997, 2001a, 2001b; Tang et al., 2007; Turcotte
et al., 2011; Yang et al., 2007). Frontal and posterior regions are important cortical
nodes for both endogenous attention control (Corbetta, 1998; Fuster, 2003) and
conscious awareness (Kjaer et al., 2002; Mazoyer et al., 2001), and insomnia patients
have enhanced temporal coupling in the frontal and posterior attentional network during
the wake-sleep transition period (Corsi-Cabrera et al., 2012).

2.5. Statistical analysis

The sleep quality evaluations were compared by independent Student t- tests. Separate
mixed three-way ANOVAs were performed for Beta and Gamma absolute power, one
for left frontal regions (Fp1, F7 and F3), and another for posterior regions (P3, T5, O1
and Pz), with groups as the independent variable, and time (PM, AM) and derivations as
the within-subjects variables. Similar mixed ANOVAs were performed for temporal

6
coupling on the pairs of electrodes of interest, one for anterior temporal coupling (Fp1-
F3, Fp1-F7 and F3-F7), another for posterior temporal coupling (P3-O1, P3-T5, T5-O1,
P3-Pz, T5-Pz and O1-Pz), and one more for fronto-posterior temporal coupling (Fp1-P3,
F3-P3 and F7-P3). These electrodes were chosen for analysis because our previous
study on sleep onset with the same PI patients showed significantly higher absolute
power at F3 and F7, and higher temporal coupling between F3-P3, F3-Pz, Fp1-P3 and
Fp1-Pz, whereas there were no significant differences for AP, nor any significant group-
by-stage-by-derivation interaction, for temporal coupling in the right hemisphere. The
significance level was set at 0.05. Only significant results of group and time (AM-PM)
main effects, group-by-time and group-by-time-by-derivation interactions were
considered and are described. Post-hoc planned comparisons for significant interactions
were made with protected Tukey’s Student t-tests to control for multiple comparisons.
Partial correlations between those EEG parameters that showed significant results in the
ANOVAs and the Pittsburgh Sleep Quality Index, and the results of the subjective
sleep quality questionnaire, were used to corroborate that the differences in power
and/or temporal coupling before and after sleep were related to subjective feelings of
poor sleep quality.

3. Results
3.1. Self-reported measures
The PI group had significantly higher scores than CL on the Pittsburgh Sleep Quality
Index (t(18)= 7.45; p < 0.0001), thus confirming the insomnia diagnoses in those subjects,
and the absence of sleep complaints in the CL group, while indicating that PI patients
evaluate their sleep as being chronically poor (Table 1 and Figure 1A).
Significant differences in self-reported measures on the subjective estimation of the
sleep quality questionnaire for the preceding night after morning awakening showed
that PI patients rated their sleep as lighter compared to the CL group (t(18) = -2.98; p <
0.008), worse (t(18) = 2.96; p < 0.02), and non-refreshing (t(18) = 2.36; p < 0.03),
compared to the CL group, and that they expressed the desire for more than 2 hours (t(18)
= 2.98; p < 0.01) of additional sleep (Figure 1B). Mood after awakening did not show
significant differences between the two groups.

Insert Figure 1 about here

7
3.2. Anterior absolute power
There were no significant main effects for group in Beta or Gamma absolute power.
However, time main effects and group-by-time interactions were significant for both
Beta and Gamma absolute power (Table 2). Time main effects showed a decrease in
Beta and Gamma activity from PM to AM in the two groups; however, the significant
group-by-time interaction for Beta activity revealed that the decrease in Beta power
from PM to AM was significant only in CL, with no change in the IN group. AM Beta
absolute power was higher for the IN group compared to AM of the CL group (Figure
2). The significant group-by-time interaction for Gamma indicates that Gamma absolute
power decreased significantly from PM to AM only in the CL group (Figure 2).
Insert Table 2 and Figure 2 about here

3.3. Posterior absolute power

Beta and Gamma absolute power at posterior derivations also showed significant time
main effects, which showed a decrease in Beta and Gamma activity from PM to AM in
the two groups, and group-by-time interactions. As it can be seen in Figure 3, post-hoc
comparisons showed that, both Beta and Gamma power decreased significantly from
PM to AM only in the CL group, whereas there was no change from PM to AM in the
IN group. The IN group had higher Beta and Gamma absolute power at AM than the CL
group at AM. There were no significant main effects for group in Beta or Gamma
absolute power.

Insert Figure 3 about here

The difference from PM to AM in anterior and posterior Beta and Gamma power was
negatively correlated with the Pittsburgh Sleep Quality Index (Table 3) for all
derivations except Fp1 and F3 in Beta and F3 in Gamma, where the correlation did not
reach statistical significance although it showed the same trend (shown for F3 and T5 as
representative data in Figure 4), suggesting that smaller decreases from PM to AM in
anterior and posterior Beta and Gamma power are associated with chronic poorer sleep
quality.
Insert Table 3 about here

8
Subjective evaluation of sleep depth the preceding night correlated with the decrease
from PM to AM in Beta power in anterior regions (F3: r = 0.53, p<0.03; F7: r = 0.50; p
< 0.04), and in T5 (r = 0.54; p<0.02).

Insert Figure 4 about here

3.4. Temporal coupling

There were no significant group main effects in temporal coupling between frontal
derivations, nor between fronto-posterior regions, but there were significant time main
effects for Beta temporal coupling between frontal regions and for Gamma temporal
coupling between posterior regions, and group-by-time-by-derivation interactions
among posterior derivations for both Beta and Gamma temporal coupling (Table 4).
The significant group-by-time-by-derivation interaction for Beta temporal coupling
showed that the IN group had higher temporal coupling than the CL group between P3-
T5, and T5-O1 at PM and AM (Figure 5A), and among all pairs of derivations at AM
(not shown).
Post-hoc comparisons for group-by-time-by-derivation interaction for Gamma temporal
coupling showed that the IN group had higher temporal coupling between T5-O1 than
the CL group at PM and AM (Figure 5B) and among all pairs of derivations at AM.
Temporal coupling among all pairs of derivations, except for T5-O1 decreased from PM
to AM in the CL group, but did not change in the IN group in any pair of derivations
(data not shown).

Insert Table 4 and Figure 5 about here

4. Discussion
The aim of the present study was to explore waking EEG activity in primary insomnia
patients and healthy controls the evening before, and the morning after, a night of sleep,
in order to detect signs of morning hyper-arousal and non-restoring sleep that might
explain the subjective feelings of insufficient and poor sleep in the absence of objective
signs in the polysomnography.

4.1. Morning signs of cortical hyper-arousal

9
The expected higher Beta and Gamma activity in insomnia patients at AM was
confirmed; however the hypothesized higher Beta and Gamma at PM was not. Primary
insomnia patients showed higher Beta power at frontal, and higher Beta and Gamma
power at posterior derivations in the morning than healthy controls. These results are in
line with the data reported by Wolynczyk-Gmaj and Szelenberger (2011), who
demonstrated signs of hyper-arousal in central regions during the day, and extend them
to frontal and posterior regions, thus supporting the notion that insomnia patients are
also hyper-aroused during the morning, as proposed by the 24-hour hyper-arousal
model of primary insomnia.
However, contrary to our expectations, and in contrast to previous findings which
showed that insomnia patients are hyper-aroused during the wake-sleep transition and
show enhanced temporal coupling linking regions involved in behavioral and attentional
control (frontal and parietal) (Corbetta, 1998; Fuster, 2003), Beta and Gamma absolute
power and temporal coupling were not significantly different between the two groups at
PM. These results apparently contradict both some earlier findings and the hyper-
arousal theory of insomnia; however, the lack of differences between insomnia and
control participants at PM may also be explained by the recording conditions. the
increase in Beta and Gamma activity and temporal coupling in insomnia patients has
been found during the wake-sleep transition period when patients are actively trying to
sleep; whereas, in the present study, we recorded EEG activity during a resting
condition before saying good night to the subjects ― i.e., when they were not yet trying
to sleep and were not engaged in any known cognitive activity.
Primary insomnia patients also showed higher Beta and Gamma temporal coupling
between temporal and occipital regions than the control group the evening before sleep,
and among posterior sensory (P3-O1, P3-T5, T5-O1) and posterior midline regions (P3-
Pz, T5-Pz, O1-Pz) in the morning. Enhanced Beta and Gamma temporal coupling
among brain regions has been shown to be important for information processing (Llinás
et al., 1998; Tononi, 2010; Uhlhaas et al., 2009) and self-awareness (Kjaer et al., 2002;
Mazoyer et al., 2001).
The enhanced temporal coupling found among posterior sensory areas in our study is
consistent with the higher environmental information-processing (Perlis et al., 1997,
2001a, 2001b) and difficulty in inhibiting environmental stimuli (Bastien et al., 2008;
2013; Hairston et al., 2010; Tang et al., 2007; Turcotte et al., 2011; Yang et al., 2007)
experienced by primary insomniacs, and are in line with the neurocognitive hypothesis

10
of primary insomnia (Perlis et al., 2001a, 2001b). These findings are also consistent
with results showing higher metabolic functional relationships among posterior sensory
regions found in poor-sleepers (Killgore et al., 2013). The posterior cingulate cortex and
temporo-parietal regions are important nodes for conscious awareness (Kjaer et al.,
2002; Mazoyer et al., 2001). Therefore, the enhanced temporal coupling between
posterior sensory regions and posterior midline suggests that primary insomnia patients
have enhanced functional relationships between the external environment and the self
awareness processing systems that may underlie the difficulty they experience in
disengaging themselves from environmental stimuli that can interfere with sleep and
persist in the morning (Corsi-Cabrera et al., 2012).

4.2. Signs of non-restoring sleep

Although there were no significant polysomnographic differences between the two
groups – as reported previously for this group of subjects (Corsi-Cabrera et al., 2012) –
the insomnia patients rated the sleep of the preceding night as unsatisfactory, while
expressing the desire for more hours of additional sleep than controls.
Signs of non-restoring sleep were evaluated by the degree of pre-sleep (PM) to
post-sleep (AM) changes in Beta and Gamma activity in each group. The healthy
controls showed EEG changes from evening waking activity to morning waking activity
in absolute power and temporal coupling measurements consistent with the restoring
effects of sleep. Beta and Gamma absolute power in the anterior and posterior regions
were lower in the morning after what control participants rated as a good-quality night
of sleep than in the evening before sleep in the CL group, but remained as high in the
morning after what participants in the insomnia group rated as poor sleep quality the
preceding night. Moreover, the greater the decrease in anterior and posterior Beta and
Gamma power, the better the subjective ratings of chronic sleep quality; whereas the
feeling of non-restoring sleep the preceding night was associated with a smaller
decrease in Beta power from PM to AM in anterior and temporal regions.
These EEG patterns suggest a beneficial effect of sleep on next-day waking-EEG
activity in healthy subjects, but its absence in insomnia patients, and agree with
previous results for healthy subjects which show that Beta and Gamma activity
increases after total sleep deprivation but decreases in the morning after sleep (Cajochen
et al., 1995; Corsi-Cabrera et al., 1992; Dumont et al., 1999; Forest and Godbout, 2000;
Koenis et al., 2013; Lorenzo et al., 1995).

11
Gamma temporal coupling among posterior and midline regions also decreased from
pre-sleep to post-sleep in the CL group, but did not change in insomnia patients who, in
addition showed higher temporal coupling in Beta and gamma activity in the morning.
This concurs with results reporting decreased intra-hemispheric temporal coupling after
sleep, and enhanced after sleep loss in healthy controls (Corsi-Cabrera et al., 1992). The
lack of improvement in temporal coupling in posterior associative regions and midline
in the PI group after sleep might be related to the frequent subjective complaints of
difficulties in attention and concentration during the day reported by those patients, and
with impairment on tasks that demand executive control of attention (Edinger et al.,
2008; Shekleton et al., 2010).
The results of this study suggest that a good night of sleep has restoring effects on the
level of EEG activation and temporal coupling in frontal and posterior associative
regions in healthy controls, and support the idea that sleep plays an important role in
preparing the brain for the next day’s demands by modulating brain excitability (Huber
et al., 2013), and fine-tuning the networks involved in high cognitive functions. The
smaller EEG changes from pre-sleep to post-sleep in PI patients associated with the
feeling of chronic poor sleep quality suggest that some micro-structural sleep-related
processes were not efficient in restoring next-day EEG activity in those patients. Hence,
it is important to investigate whether micro-structural sleep processes that have been
found altered in insomnia patients (Feige et al., 2013), such as high Beta-Gamma and
low Delta activity during sleep (Buysse et al., 2008; Lamarche and Ogilvie, 1997;
Marzano et al., 2008; Merica et al.1998; Perlis et al., 2001a, 2001b; Spiegelhalder et al.,
2012; Staner et al., 2003; St-Jean et al., 2013), sigma power (Krystal et al., 2002), K-
complexes (Colrain, 2005; Forget et al., 2011), and the presence of alpha-delta sleep
(Martinez et al., 2010), and CAPs (Parrino et al., 2009) are directly related to our
findings of non-restoring sleep in post-sleep waking EEG activity in primary insomnia
patients.
These results should be taken as exploratory, as the small number of participants
and lack of correction for multiple correlations between subjective feelings and EEG
changes limit the possibility of generalizing them to larger populations. However, we
preferred to concentrate on a homogeneous group of young adults that met the clinical
diagnosis of primary insomnia so as to avoid confounding factors such as age,
depression and previous treatment history (medications). Future studies with larger
samples and high electrode density recordings may well provide additional evidence of

12
neurophysiological disturbances in the waking EEG activity of primary insomnia
patients. The present study analyzed only Beta and Gamma activities in the left frontal
and posterior associative regions. Future studies should include the analysis of other
EEG bands, as well as finer analyses that take into account relative proportions of fast
frequencies over other common EEG rhythms.
It is important to keep in mind that alterations in temporal coupling are not specific to
insomnia patients, as they have also been found in other conditions, such as
schizophrenia, depression and Alzheimer’s (Uhlhaas et al., 2009), so future research is
needed to investigate whether similar changes in Beta and Gamma activity and temporal
coupling also occur after poor sleep in such psychiatric conditions, as well as in other
sleep disorders, such as OSA and RLS. Nonetheless, these results do suggest new
insights related to non-restoring signs of sleep in morning waking EEG activity in
insomniacs.

5. Conclusion
Although preliminary, our findings add new knowledge to the understanding of the
physiopathology of insomnia by showing that these patients are hyper-aroused during
morning wakefulness, and do not benefit from preceding sleep as do healthy controls.
The study also underlines the importance of studying waking EEG activity during the
day and focusing on pre-sleep to post-sleep changes that may provide information on
sleep quality and be useful for the understanding of primary insomnia pathology.

13
Conflict of Interest
None. This was not an industry supported study. The authors have indicated no financial
conflicts of interest.

Acknowledgments
This work was funded by CONACyT Project #50709. We thank Gerardo Sánchez
Dinorín for his technical assistance, and Paul Kersey for correcting the English version
of the manuscript.

14
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Figure Legends

Figure 1: Significant effects obtained in the analysis of subjective ratings of chronic

sleep quality from the Pittsburgh Sleep Quality Index and sleep quality of the preceding
night from the Sleep Quality Questionnaire. Pittsburgh Sleep Quality Index (A) and
sleep quality of the preceding night from the Sleep Quality Questionnaire (B). Mean
and standard error for the control (CL) and the insomnia group (IN) in the evening
before sleep (PM) and in the morning after sleep (AM). Asterisks indicate significant
differences.

Figure 2: Significant group-by-time interactions in Beta and Gamma absolute power.

Mean and standard error of Beta and Gamma absolute power, log-transformed in
anterior regions for the control (CL) and insomnia groups (IN) in the evening before
sleep (PM), and in the morning after sleep (AM). Brackets indicate significant post-hoc
differences between two bars.

Figure 3: Significant group-by-time interactions in Beta and Gamma absolute power.

Mean and standard error of Beta and Gamma absolute power, log-transformed in
posterior regions for the control (CL) and insomnia groups (IN) in the evening before
sleep (PM), and in the morning after sleep (AM). Brackets indicate significant post-hoc
differences between two bars.

Figure 4: Significant correlations between pre-sleep to post-sleep changes in Beta

absolute power for representative derivations (F3 and T5) and the Pittsburgh Sleep
Quality Index. Circles represent control and triangles insomnia participants.

Figure 5. Significant group-by-time interactions in Beta and Gamma temporal coupling

among posterior regions. Mean and standard error of Beta (A) and Gamma (B) cross-
correlations transformed to Fisher´s Z scores for the control (CL) and insomnia groups
(IN) in the evening before sleep (PM), and the morning after sleep (AM). Brackets
indicate significant post-hoc differences between two bars.

20
 Sleep Deepness
(scores)

Figure 1
CL
Pittsburgh Sleep Quality Index
(scores)

0
2
4
6
8
10
12
14
16

IN
CL

B
Additional Sleep Desired
A

(hours)
IN
*

CL
*

IN
 Beta Gamma
5.2 4

4.9 3
mV2 (ln)

mV2 (ln)
4.6 2

4.3 1

4 0
PM AM PM AM PM AM PM AM
CL IN CL IN

Figure 2
 Beta Gamma
4

5.2

3
mV2 (ln)

mV2 (ln)
4.8
2

4.4
1

4 0
PM AM PM AM PM AM PM AM
CL IN CL IN

Figure 3
 F3 T5

Change in Gamma PM-AM

Change in Beta PM-AM

Pittsburgh Sleep Quality Index Pittsburgh Sleep Quality Index

Figure 4
 A
P3-T5 T5-O1
1.2 1.4
Fisher’s Z Scores

Fisher’s Z Scores
0.8

0.7

0.4

0 0
PM AM PM AM PM AM PM AM
CL IN CL IN

B
T5-O1
1.6

1.2
Fisher’s Z Scores

0.8

0.4

0
PM AM PM AM
CL IN

Figure 5
 Table 1. Demographic and subject characteristics by group.
IN CL t p
Age 25.8 (1.7) 26.6 (1.6) 0.3 0.75
Education (yr) 14.6 (0.3) 16.8 (0.3) 2.1 0.08
Illness duration (mo) 64 (1.4) ------- ------- ------
PSQ 13.4 (0.7) 2.5(0.7) 7.5 0.0001
AIS 13.3(1.19) 2.3(0.7) 7.9 0.00001
Sleep log
Sleep: quality 5.4 (0.6) 7.8 (0.5) 2.9 0.02
Sleep: bad-good 5.5 (0.6) 7.8 (0.5) 3.2 0.007
Sleep: refreshing 5.2 (0.8) 7.6 (0.7) 2.4 0.03
Sleep:depht 5.0 (0.6) 7.4 (0.5) 2.9 0.008
Mood 6.9 (0.4) 8.1 (0.1) 0.98 0.35
Additional sleep desired
3.32 (0.6) 0.94 (0.2) 3.6 0.009
(hr)
IN, insomnia group; CL, control group; PSQ, Pittsburgh Sleep Quality Index; AIS, Athens
Insomnia Scale. Numbers in bold indicate significant differences, p < 0.05

21
 Table 2. Significant differences in Beta and Gamma absolute power.
Group Time Derivation Group by Group by
Time Time by
Derivation
Df=1, 18 Df=1, 18 Df=2, 36 Df=1, 18 Df=*
F p F p F p F p F p
Beta
Frontal regions 0.23 0.64 12.25 0.002 26.11 0.00001 9.23 0.007 0.27 0.77
Posterior regions 0.11 0.7 13.35 0.002 9.84 0.0001 6.42 0.01 0.74 0.53
Gamma
Frontal regions 0.01 0.93 12.65 0.002 24.17 0.00001 5.90 0.02 0.07 0.92
Posterior regions 0.07 0.79 17.85 0.0008 2.06 0.11 8.91 0.008 1.50 0.22
Mixed Group x Time x Derivation ANOVAs, Group, insomnia and control group; Time, PM and AM;
Derivation, electrodes; Frontal regions, Fp1, F7 and F3; Posterior regions, P3, T5, O1 and Pz; Df, degrees
of freedom. Df=*, degrees of freedom for regions, Frontal regions, 2, 119, Posterior regions, 3, 159.
Numbers in bold indicate significant differences, p < 0.05

22
Table 3. Pearson correlation coefficients for the
Pittsburgh Sleep Quality Index and PM-AM
differences in Absolute Power.
Beta Gamma
r p r p
F1 -0.26 0.32 -0.26 0.32
F3 -0.50 0.04 -0.35 0.17
F7 -0.54 0.03 -0.555 0.03
P3 -0.67 0.01 -0.581 0.02
PZ -0.63 0.01 -0.515 0.04
T5 -0.59 0.02 -0.681 0.01
O1 -0.65 0.01 -0.671 0.01
Note: significant Pearson correlation
coefficients are shown in bold

23
 Table 4. Significant differences in Beta and Gamma temporal coupling.
Group Time Derivation Group by Group by
Time Time by
Derivation
Df=1, 18 Df=1, 18 Df= 5, 90 Df=1, 18 Df= *
F p F p F p F p F p
Beta
Anterior 0.95 0.65 4.37 0.04 4.98 0.01 0.60 0.54 0.29 0.75
Posterior 1.82 0.19 0.38 0.55 86.54 0.00001 0.38 0.55 4.48 0.001
Fronto-posterior 3.04 0.09 0.03 0.85 18.65 0.00001 1.46 0.23 2.04 0.08
Gamma
Anterior 1.52 0.23 0.80 0.61 1.04 0.36 0.85 0.62 0.48 0.63
Posterior 0.94 0.65 5.66 0.02 64.26 0.00001 3.07 0.09 2.88 0.01
Fronto-posterior 2.96 0.09 0.07 0.79 20.24 0.00001 1.25 0.27 1.71 0.14
Mixed Group x Time x Derivation ANOVAs, Group, insomnia and control group; Time, PM and AM;
Derivation, electrodes; Anterior, Fp1-F3, Fp1-F7 and F3-F7: Posterior, P3-O1, P3-T5, T5-O1, P3-O1, P3-
T5, T5-O1, P3-Pz, T5-Pz and O1-Pz; Fronto-posterior, Fp1-P3, F3-P3 and F7-P3; Df, degrees of freedom.
Df = *, degrees of freedom for regions, Anterior, 2, 119, Posterior and Fronto-posterior, 5, 239. Numbers in
bold indicate significant differences, p < 0.05

24