Stress response in narcolepsy type 1

Narcolepsy type 1 (NT1) is a very disabling sleep-wake disorder caused by a
cerebral deficiency of hypocretin (Hcrt, also known as orexin). A recent
post-mortem brain study of the hypothalamus in NT1 not only showed a major
reduction of Hcrt cells, but also a 88% reduction of corticotrophin-releasing
hormone (CRH)-positive neurons (Shan et al., 2022) in the paraventricular
nucleus (PVN). CRH in this nucleus is known for its role as
hypothalamic-pituitary-adrenal (HPA) axis activator. This matches with the
earlier finding of reduced basal pituitary adrenocorticotropic hormone (ACTH)
secretion in patients with NT1 (Kok et al., 2002). Therefore it is expected
that patients with NT1 have a lowered cortisol (stress) response compared to
matched controls. Better understanding of the HPA activity in patients with NT1
may give better insights in the effects of lost CRH-positive cells in this
population. This knowledge may contribute to greater understanding of the
etiology of the disease and the development of potential novel treatments in
the future.

To investigate in people with NT1 and matched controls, after an experimentally
induced social stress test:

Primary:
- Direct HPA activation (plasma cortisol).

Secondary:
- Direct autonomic stress response (ACTH and HR).
- HPA activity and autonomic stress after a recovery time (plasma cortisol,
ACTH and HR).
- Subjectively experienced stress directly after the stress test and after
recovery time.
- The association between subjective and objective stress markers, and their
relationship with any background variables.

A quasi-experimental case-control intervention in n=12 patients with NT1 and
n=12 controls matched for age and sex. All participants will be exposed to the
Trier Social Stress Test for Groups (TSST-G) in six groups of four participants
each. Before the TSST-G (T0), directly after (T1), after a 15-minute recovery
period (T2) and after a second 15-minute recovery period (T3), we will assess:
plasma ACTH and cortisol and subjective stress. Heart rate (HR) will be
measured continuously.

The TSST-G is an effective stress intervention, where participants are
instructed to give a public speech, followed by a mental arithmetic task,
before a non-supportive jury while thinking they are being videotaped. This
test has shown in previous studies to effectively induce psychophysiological
stress and activate the HPA axis (Von Dawans, Kirschbaum & Heinrichs, 2011).

Participants visit the research center once for about 4 hours in total.
Participants are told that they participate in a study about social competence
and resilience. During their visit they will be exposed to a stress test
(TSST-G). In total, four blood samples will be taken via a cannula to avoid the
stress of multiple punctures, which may be unpleasant and induces a regular
(small) risk of local hemorrhage. The subjective questionnaires will take about
15 minutes each time, inducing minimal burden. Potential negative feelings
regarding the TSST-G will be taken away as much as possible during an extensive
debriefing. The TSST-G is a validated test which does not lead to extreme
perceived anxiety levels or burden. Participants will not personally benefit
from this study. They will be compensated with ¤50 for participation. Patients
with NT1 will have the opportunity to take a nap at the research center after
the experiment.