Sleep State Misperception Mispercieved?

Primary insomnia, or psychophysiological insomnia is a poorly understood
condition that affects a considerable percentage of the population up till
about 40% of the elderly population. Chronic insomnia increases the risk of
physical and mental health problems, and is a major factor affecting quality of
life (Van Someren, 2000). Polysomnography, i.e. the continuous overnight
recording of electroencephalography (EEG), electromyography (EMG) and
electrooculography (EOG) may reveal a reduced total sleep duration, decreased
slow wave sleep, and increased fragmentation and interruptions by wakefulness.
However, a considerable number of subjects that seek treatment for their
subjective poor sleep do not show any objective sleep disturbance according to
standardized polysomnographic scoring rules (Rechtschaffen and Kales, 1968).
Subjects with such discrepancy between objective and subjective sleep
disturbances are diagnosed with *Sleep State Misperception*, a term that
strongly suggests that they do indeed sleep sound and have no reason to
complain. None of subjects suffering from this condition agree, even after
showing them polysomnographic data in the morning or waking them up during the
night (Mercer et al., 2002). They*re convinced that these records may show
anything but their sleep. And, importantly, their misperception is not without
consequences for daytime functioning. Most striking is the finding that
subjective rather than objective sleep complaints are negatively correlated
with daytime performance on memory acquisition during the Selective Reminding
Test (Buschke and Fuld, 1974; Szelenberger and Niemcewicz, 2000; 2001). Of
note, this very test has in longitudinal aging studies shown to be one of the
most sensitive tasks for quantifying age-related memory decline (Small et al.,
1999) and risk of dementia (Grober et al., 2000). This suggests the possibility
that the brain in fact suffers from its *misperception* of sleep. A recent
unpublished observation (C. Bastien, personal communication) moreover indicates
alterations in the amplitude (larger) and phase (advances) of event related
potentials N2, P2 and N350 during an auditory oddball task; another sign of
altered brain function.
We recently found insomniacs to respond differently on transcranial magnetic
stimulation (Biol Psychiatry 2010). Because this reaction, the cortical
excitability is highly heritable (Pellicciari et al, J Neurosci 2009) we may
have discovered the first *endophenotype* of insomnia. We would like to
immediately follow up on the finding by including the measurement in our
ongoing protocol.
We aim to gain insight in the brain processes associated with sleep state
misperception.

We aim to establish whether our judgment of *misperception* is really doing
justice to the condition paradoxical insomniacs suffer from. We should keep in
mind that our present definition of sleep, based on the standardized
polysomnographic scoring rules, by no means mirrors all the details of the
cortical activities that occur during the night. If we would allow the
possibility that the polysomnographic scoring rules may miss the very neuronal
activity patterns that we all subjectively experience as sleep, the sleep
clinician might turn out to be the one misperceiving the condition of sleep
state misperception.
We are not aware of any previous study that has specifically focused on EEG
markers of sleep state misperception, other than a reported trend towards an
increase in average EEG power in the 14-35 Hz range (Perlis et al., 2001),
which has on the other hand been reported to be a generic finding in insomnia
(Merica et al., 1998), i.e. not specific to the sleep state misperception
variant. In the present study we specifically address the hypotheses that
nocturnal synchronization of oscillations is essential to the experience of
sleep. We focus on synchronization of oscillations during slow wave sleep, when
cortically generated slow oscillations increase the spatiotemporal coherence
over widespread cortical areas (Steriade, 1999; Steriade and Timofeev, 2003). A
recent unpublished observation (C. Bastien, personal communication) indicates
alterations in the amplitude (larger) and phase (advances) of event related
potentials N2, P2 and N350 during an auditory oddball task assessed during
wakfulness in subjects suffering from sleep state misperception. We would
therefore like to include both ERP and an fMRI study in order to evaluate brain
activation related to auditory stimulation. The MRI session will also include a
structural scan in order to allow for voxel-based morphometry - we recently
found a reduction in orbitofrontal grey matter volume in elderly insomniacs
without significant misperception - as well as a resting state fMRI recording -
in the same insomniacs, we recently found a reduction in perfusion assessed
using arterial spin labeling in areas that are part of the *default network*.

In brief, we will apply a cross-sectional case-control design using
actigraphy, high-density EEG and ERP, resting-state fMRI and task-related fMRI.
The first phase covers baseline actigraphy and sleep log measurements, meant
to verify previous diagnoses of primary insomnia with and without sleep state
misperception, and to verify normal sleep in control subjects.
Sub-classification of SSM:
SSM insomnia sufferers have to show on four out of seven actigraphic recording
nights:
a) a Total Sleep Time (TST) > 380 minutes or a Sleep Efficiency (SE) >= 80%, as
well as
b) using sleep logs and actigraphy, an overestimation >= 60 minutes of Sleep
Onset Latency (SOL), an underestimation >= 60 minutes of TST or >= 15%
underestimation of their SE.
For definite confirmation and inclusion in analyses SSM insomnia sufferers have
to show on two consecutive PSG recording nights (one available from history,
two assessed in the present study):
a) a TST > 380 minutes or a SE >= 80%, as well as
b) an overestimation >= 60 minutes of SOL, an underestimation >= 60 minutes of
TST or >= 15% underestimation of their SE.

The second phase covers one fMRI scan and two nights of high-density EEG
recording, with an interval ranging between at least one day and at most one
week. The fMRI study will evaluate (1) brain activation related to auditory
stimulation (same oddball task as the subsequent oddball task with ERP
recording) (2) a structural scan in order to allow for voxel-based morphometry
and (3) resting state BOLD fluctiations. EEG will be recorded using a Micromed
LDM-64 ambulatory recorder and a dedicated Easycap 61-channel equidistant
electrode cap with 61 flat equidistant EEG electrodes and additional electrodes
to record EMG and EOG. Participants have the choice of either being recorded in
an apartment at the Boelelaan, or - distance allowing - at home. The cap will
be affixed during the early evening. A wake resting state and alpha attenuation
task (eyes open and closed) will be recorded at application of the montage in
the late afternoon, as well as an auditory oddball task. The motor evoked
potential (MEP) response on single and double-pulse transcranial magnetic
stimulation is being measured, which lasts at most half an hour including
preparation.

Participants keep a sleep diary and wear a wrist-watch-sized activity logger or
one week, without behavioral restrictions. For nocturnal EEG recording,
participants wear a 64-channel EEG-cap and a recorder all night, and have the
choice of either being recorded in an apartment at the Boelelaan, or - distance
allowing - at home. Two nights will be recorded, of which the first acts as
adaptation night. EEG montage takes place in the late afternoon or early
evening. EEG removal takes place the next morning. On each of the days, eyes
closed and eyes open rest-EEG will be recorded, as well as an auditory oddball
ERP task, concertedly lasting no more than 15 minutes. On one of the two days,
an MRI scan lasting 60 minutes at most will be recorded. The motor evoked
potential (MEP) response on single and double-pulse transcranial magnetic
stimulation is being measured, which lasts at most half an hour including
preparation.No risk is associated with any of the procedures.