The objective is to identify non-invasive neuroimaging biomarkers and mechanisms characterizing different phenotypes of central disorders of hypersomnolence (narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia) as compared to groups of…
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
We will aim at assessing non-invasive MRI-related neural biomarkers in
narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia by comparing
them with acutely sleep-deprived controls and healthy controls. To create a
reliable and elaborate combination of possible markers, the following
neuroimaging will be used:
- Brain responses across the sleep-wake cycle using simultaneous EEG-fMRI
- Brain responses during wakefulness using fMRI, especially in correlation with
behavioral results in attentional and rewarded-associative memory tasks
- Regional brain volumes and cortical thickness using MRI morphometry
- White matter connectivity using DTI
- Brain connectivity using structural covariance and resting-state fMRI
functional connectivity
- Regional GABA levels in the medial prefrontal cortex and posterior cingulate
using MRS
Secondary outcome
The secondary analyses will include:
- Correlation between neuroimaging activation maps and behavioral performance
on the cognitive tasks.
- Relationship between neuroimaging activation maps and clinical patient
profiles (e.g. disease duration, subjective sleepiness and depression and
anxiety scores)
- Effect of sleep inertia on performance on the rewarded-associative memory task
- The difference in molecular composition of exhaled breath between NT1, NT2
and IH and secondary in comparison to acutely sleep-deprived controls and HC
- Effect of acute sleep deprivation on molecular exhaled breath composition in
healthy controls
As an exploratory objective, patients with idiopathic hypersomnia will be
subcategorized in short (< 11 hours) and long (> 11 hours) sleepers and their
neuroimaging profiles as defined in the primary objectives will be compared.
Background summary
Central disorders of hypersomnolence are mainly characterized by excessive
daytime sleepiness despite normal timing of nocturnal sleep. All disorders
greatly impair daily functioning. Three subtypes of central disorders of
hypersomnolence are being distinguished: narcolepsy type 1, narcolepsy type 2,
and idiopathic hypersomnia. While narcolepsy type 1 originates from a selective
loss of hypothalamic hypocretin-producing neurons, the pathophysiology
underlying narcolepsy type 2 and idiopathic hypersomnia remains to be fully
elucidated. It is probable that different causes may lead to these phenotypes.
The underlying brain circuit abnormalities of only narcolepsy type 1 have so
far been identified using small sample groups, but their correspondence with
other hypersomnolence disorders has yet to be investigated. As distinctive
features between narcolepsy type 2 and idiopathic hypersomnia have not clearly
been defined and given the clinical similarities between these two disorders,
the question arises whether the current third edition of the International
Classification of Sleep Disorders (ICSD-3) classification addresses two
separate entities or arbitrarily splits a heterogeneous group of patients. This
is further emphasized by > 50% diagnosis crossover of narcolepsy type 2 and
idiopathic hypersomnia after repetition of diagnostic testing. In the future,
the neural signatures of different central disorders of hypersomnolence could
reveal transdiagnostic disease dimensions and help to improve classification of
central disorders of hypersomnolence and potentially treatment options. The
molecular exhaled breath composition will also be compared between the patient
groups. If the differences in this pattern are robust and sensitive, this could
substantially improve diagnostic possibilities of central disorders of
hypersomnolence in the future.
Study objective
The objective is to identify non-invasive neuroimaging biomarkers and
mechanisms characterizing different phenotypes of central disorders of
hypersomnolence (narcolepsy type 1, narcolepsy type 2 and idiopathic
hypersomnia) as compared to groups of partially sleep-deprived and healthy
control subjects.
Study design
Cross-sectional multi-center study with harmonized data collection across two
sites (Netherlands & Canada), including three patient groups (narcolepsy type
1, narcolepsy type 2 and idiopathic hypersomnia) and one group of healthy
controls. Healthy controls will undergo the study protocol twice, once with a
regular sleep-wake pattern and once with a night of partial sleep deprivation
(<4 hours of sleep) before MRI acquisition. The study paradigm consist of one
week of actigraphy, after which all subjects will administer multiple clinical
and cognitive questionnaires and undergo two MRI sessions. They will also
undergo a short breathing measurement.
Study burden and risks
The participation burden will consist of:
- Signing informed consent (at home for patients and during a visit to the VUmc
for control subjects, minimal burden)
- Wear an actigraphy watch and keep a sleep diary (at home for 1 week, minimal
burden)
- Visiting the Spinoza Centre (total duration: ±4 hours, preparation before the
MRI ±1 hour, MRI protocol including a break ±2 hours and 40 minutes). The MRI
protocol will consist of 2 sessions (respectively 78 and 38 minutes), separated
by a short break of an hour. During the first session simultaneous EEG-MRI will
be used.
In total the study procedures will take 2-3 weeks for patients (exact duration
depends on the exact date of signing the informed consent and the availability
of the MRI scanner)
Control subjects will undergo the aforementioned protocol twice (signing the
informed consent form will be done once), separated by roughly 2 weeks without
study procedures. Before 1 of the visits to the Spinoza Centre, the control
subject will be partially sleep deprived for 1 night at home (<4 hours of
sleep). In total the burden for control subjects will be: signing informed
consent, 2x1 week of wearing an actigraphy watch and keeping a sleep diary, 2x4
hours visit to the Spinoza Centre and 1 night partial sleep deprivation.
In total the study procedures will take 5-6 weeks for control subjects (exact
duration depends on the exact date of signing the informed consent and the
availability of the MRI scanner). Study participation therefore does require a
time investment from the subjects.
Possible benefits related to participation:
Besides financial compensation, subjects will not have any direct benefit from
participating in the study. However, participation is expected to result in
increased insight in the neurobiological background of sleep in general and
central disorders of hypersomnolence.
Potential risks when participating and how we tried to minimize them:
- Temporal halt of psychoactive medication intake in patients:
Patients may experience distress, withdrawal symptoms and increase of symptom
severity (depending on the type of medication mainly sleepiness, sleep duration
and cataplexy rate). Clear instructions will be given to the patients on the
possible effects of temporarily stopping their medication before inclusion.
Patients are also allowed to continue medication directly after MRI
acquisition. In previous research by our research group, patients were asked to
refrain from medication intake for 14-31 days, not leading to problems. In this
study we tried to minimize the period by just asking patients to stop for up to
7 days.
- Risks associated with MRI (and simultaneous EEG acquisition):
Simultaneous EEG-fMRI may potentially be a risk for patient safety, due to
excess heating as a result of eddy currents. Some people may experience
distress due to the claustrophobic environment of an MR scanner. Some may also
experience the sound of the scanner as loud. There also is a chance that
incidental brain abnormalities will be found.To avoid the potential issue of
heating up subjects during EEG-fMRI we will omit the EEG electrodes during MRI
sequences that produce a high SAR (specific absorption rate). Standard
procedures and equipment will be used, so patient risk is negligible. For
subjects who are sensitive to claustrophobia, the positioning in an MRI scanner
might provoke feelings of distress or in extreme situations panic attacks. In
case a subject feels uncomfortable in the scanner, it is possible to terminate
the scanning session at any moment without any consequences for the
participant. In case of incidental findings of abnormalities in the MRI scans,
participants will be immediately notified.
- Risks associated with partial sleep deprivation (only in the acutely
sleep-deprived control group):
Acute sleep deprivation (< 4 hours sleep for 1 night) may cause distress and
lead to increased sleepiness and reduced attention. Acutely sleep-deprived
controls will be advised to not drive after the night with limited sleep and
will be reimbursed for their (public transport) travelling costs.
Given that the this will not be an intervention study and that the risks are
negligible, we believe that the potential knowledge gain on central
hypersomnolence disorders in general outweighs the possible risks.
De Boelelaan 1108
Amsterdam 1081HZ
NL
De Boelelaan 1108
Amsterdam 1081HZ
NL
Listed location countries
Age
Inclusion criteria
Patients:
- Definite narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia,
diagnosed according to the International Classification for Sleep Disorders -
Third Edition (ICSD-3) criteria
- Age between 18 and 65 years old
- Normal or corrected-to-normal vision
- Capacity to provide informed consent
Healthy controls:
- Age between 18 and 65 years old
- Normal or corrected-to-normal vision
- Capacity to provide informed consent
Exclusion criteria
The following exclusion criteria will apply:
- Systemic or neurological diseases (e.g., infections, inflammatory disorders,
dementia, epilepsy);
- Presence of another sleep-related disorder:
For patients:
Previous REM sleep behaviour disorder, insomnia, obstructive sleep apnoea, REM
sleep behaviour disorder or Restless legs syndrome diagnosis according to the
medical records
For healthy controls:
REM sleep behaviour disorder as screened by the Single-Question Screening for
REM Sleep Behaviour Disorder
Restless legs syndrome as screened by the Restless Legs Syndrome Screening
Questionnaire (score > 6)
High-risk for obstructive sleep apnoea according to the Stop-Bang questionnaire
(score > 4)
Insomnia disorder by the Insomnia Severity Index (score > 14)
Circadian rhythm disorder
- Short sleepers (< 6 hours on average) or irregular sleep schedules
- Having worked on night shifts during the last month
- < 18 or > 65 years of age
- Major psychiatric disorder (e.g., major depression, psychotic or bipolar
disorder)
- History of trauma capitis, encephalopathy, former intracranial surgery,
alcoholism or substance abuse
- Contraindications for MRI exam (e.g., claustrophobia, metallic implants)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL68388.029.18 |