Narcolepsy - a functional MRI study

Narcolepsy is a primary sleep disorder, with an estimated prevalence of 5-6 per
10,000 in the Western population. The main symptoms are excessive daytime
sleepiness and attacks of muscle weakness called cataplexy, but other features
like fragmented nocturnal sleep, decreased vigilance and memory deficits are
very often present. It is a disabling disease: somnolence and decreased
vigilance interfere with work and education. Patients have an increased risk of
accidents and tend to avoid social gatherings because of the embarrassment
caused by cataplexy and sleep attacks. Not even optimal therapy can abolish
such problems, so narcolepsy presents a large burden for patients as well as
their relatives.

Cataplexy is defined as a sudden and transient loss of muscle tone, triggered
by emotion. The spectrum of muscle weakness ranges from mild buckling of the
knees to generalized paralysis of all striated skeletal muscles, sometimes
lasting minutes. Consciousness is completely preserved, showing that only motor
systems are affected. One of the most puzzling features of cataplexy is its
induction by emotions or situations associated with emotions. Laughter is
undoubtedly the most frequent trigger.

Less thoroughly explored symptoms of narcolepsy include decreased vigilance and
impaired nocturnal sleep. Patients often fall asleep quickly, but awake
frequently during the night. The total sleep time over a 24-hour period is not
increased in comparison to healthy subjects despite their daytime naps.
Although impaired night sleep may contribute to a decreased vigilance during
the day, nocturnal sleep disturbances do not explain vigilance problems during
the day sufficiently, as their treatment does not solve the problem 6.

The vast majority of patients with narcolepsy-cataplexy lack the
neurotransmitter hypocretin (also called orexin). This peptide is found only in
the lateral hypothalamus, a structure that is not directly involved in either
motor control or the regulation of emotions. However, the hypocretin neurons
project widely throughout the brain. How a loss of hypocretinergic cells leads
to the different symptoms of narcolepsy, is still unknown.

This study aims to further clarify the pathophysiological mechanisms underlying
the decreased vigilance, sleep/wake lapses, and the emotional processing
leading to cataplexy.

In this comparative study, will use simultaneous electro-encephalography (EEG)
and functional Magnetic Resonance Imaging (fMRI) recordings to analyse brain
activity in narcoleptics and healthy controls under three different
circumstances:

1. During a presentation of emotional stimuli (funny and non-funny pictures)

2. During an attention task (the Sustained Attention to Response Task)

3. During quiet resting state (ultimately leading to sleep).

Subjects are not allowed to take medication with influence on the central
nervous system two weeks prior to and during the study. We will try to recruit
narcoleptic patients without medication preferentially, but may have to take
recourse to ask patients to stop their drugs temporarily for the purpose of the
study. Withdrawal from anti-narcoleptic medication may lead to an increase in
daytime sleepiness and cataplexy during this period. However, the symptoms are
reversible when medication is restarted. We will guide patients during this
period and they are free to withdraw their consent any time, without any
negative consequences for present or future treatment.

Considering the possibility of asymptomatic intracranial abnormalities in this
study, two different issues should be addressed. In the first place, fMRI scans
use other settings than regular diagnostic scans. As a consequence, there is a
possibility that an actual abnormality may not come to light. In other words,
the absence of abnormalities on our scan doesn*t exclude their presence.
Subjects will be informed accordingly.
Furthermore, there is a possibility of detecting relevant abnormalities not
(yet) causing complaints, even with the settings of scientific scans. These
findings must be anticipated. Part of the informed consent is that such
clinical relevant findings will be reported to the subject. When subjects
refuse to be informed about possible incidental findings on their scan, they
will not be included in this study.