Decision-making in people with narcolepsy and healthy age-matched controls

Narcolepsy is a neurological disorder characterized by excessive daytime
sleepiness associated with cataplexy and other REM sleep phenomena, such as
sleep paralysis and hypnagogic hallucinations. Narcolepsy is caused by a loss
of the orexin (hypocretin)-producing neurons in the hypothalamus. Loss of this
peptide is sufficient to produce narcolepsy as mice, rats, and dogs with
disrupted orexin signaling have all the major features of narcolepsy.
The orexins are two peptides, orexin-A (hypocretin 1) and orexin-B
(hypocretin 2) generated from a single precursor and synthesized by a small
number of neurons restricted to the lateral hypothalamus and perifornical area.
Orexin-producing neurons project throughout the CNS, directly exciting
monoaminergic and cholinergic neurons in the locus coeruleus, raphe nuclei, and
basal forebrain regions. These targets play critical roles in attention,
cognition, and the regulation of sleep-wake behavior, and reductions in their
activity may cause the sleepiness, cataplexy, and other symptoms of narcolepsy.
Recent studies suggest the orexin/hypocretin system also plays an important
role in reward processing and addiction. Drugs of abuse and other stimuli are
rewarding because they increase release of dopamine into the nucleus accumbens
(NAc). The main source of this dopamine is neurons of the ventral tegmental
area (VTA). The orexin neurons heavily innervate and excite neurons in both the
VTA and NAc, and orexin is implicated in the development of drug addiction
(Harris). Specifically, orexin increases the excitability of VTA neurons by
increasing their expression of glutamate receptors. In addition, orexin has
been shown to reinstate drug-seeking behavior in rodents in which this behavior
has been previously extinguished. The importance of orexin in the amplification
of reward signals is especially clear in mice lacking orexin, which show little
or no addiction to morphine.
The above studies suggest that orexin may be critical in the
development, maintenance and re-acquisition of addiction and reward-seeking
behaviors in animals. The effects of orexin on addictive and reward-seeking
behaviors in humans have not been studied. Narcoleptic patients, because of
their low orexin levels, may have reduced activity in these VTA and NAc
pathways. Specifically, they may be much less prone to risk and reward-seeking
in their decision-making behavior. Support for this hypothesis comes from the
clinical observation that while narcoleptic patients are often treated with
highly addictive drugs including amphetamines, they rarely become addicted.
When considering orexin signaling in narcoleptic patients, it is
important to distinguish narcolepsy with cataplexy from narcolepsy without
cataplexy. Cataplexy is sudden muscle weakness brought on by strong emotions
such as joking, laughter, or anger. It affects about 60% of patients with
narcolepsy, either at the onset of sleepiness or within 3-5 years. Recent
studies suggest that most narcolepsy patients with cataplexy have impaired
orexin signaling. Approximately 90% of narcoleptic subjects with cataplexy
(N+C) have no detectable orexin-A in their cerebrospinal fluid (CSF) even
within a few months of symptom onset. In contrast, nearly all narcoleptic
subjects without cataplexy (N-C) have normal CSF concentrations of orexin.
Considering orexin*s implication in reward-seeking behaviors and addiction, it
is reasonable to suggest that risk-related decision making behaviors in
narcoleptic patients with cataplexy (low or absent CSF orexin) may be markedly
different from those narcoleptic patients without cataplexy (normal orexin
levels).
Our objective is to investigate decision-making in narcoleptic
patients with and without cataplexy and compare it to that of age-and
gender-matched healthy controls. The primary outcome will be measured by
performance on the Balloon Analogue Risk Task (BART). Behavioral and
personality studies have concluded that the BART is a useful tool in the
assessment of risk-taking. Riskiness on the BART is highly correlated with
measures of sensation seeking, impulsivity and deficiencies in behavioral
constraint, as well as with self-reported occurrence of addictive, health, and
safety risk behaviors. In evaluating the decision-making behaviors of
narcolepsy patients, it is important to distinguish biological causes of lower
reward-seeking and addictive behaviors (such as lower CSF orexin levels) from
behavioral causes such as fear of self-harm due to reduced vigilance and
increased daytime sleepiness with narcolepsy, forcing patients to select
physically safer behaviors. For this reason, the BART, administered on a
computer, without any potential for physical harm, is an appropriate test for
demonstrating risk and reward-seeking in the narcoleptics, as opposed to a more
physical task.

Hypothesis:
We hypothesize that narcoleptic subjects with cataplexy will have lower scores
on an array of psychometric questionnaires associated with reward-seeking and
risk-taking behaviors, as well as on the BART, compared to narcoleptic subjects
without cataplexy, which are expected to be similar to age-and sex-matched
healthy controls.

Psychiatric disorders such as drug and alcohol abuse and dependence,
compulsive overeating and pathologic gambling have been associated with
abnormally high scores on the Zuckerman Sensation Seeking Scale and the Eysenck
Impulsiveness Scale. In turn, high scores on the Zuckerman and Eysenck Scales
were shown by Lejuez et all to be correlated with abnormally high BART scores.
Enrolling subjects with the psychiatric diagnoses of drug and alcohol abuse and
dependence, compulsive overeating and pathologic gambling is likely to yield
BART score outliers and may falsely skew the averages in either the narcoleptic
or control groups towards high risk-taking and mask real differences,
attributable to CSF orexin levels alone.
Smoking has also been associated with producing significantly higher BART
scores, however due to cross-cultural differences between the Netherlands and
the US and high rates of smoking in both narcolepsy patients and healthy people
in the Netherlands, we elected to match the groups for smoking behavior, rather
than screen out potential subjects due to daily smoking. Every attempt will be
made to match the amount of cigarettes smoked per day, in addition to matching
for age and sex.
Performance on the BART and other tests could be altered by reduced vigilance,
so we will measure subjective and objective levels of sleepiness using the
Epworth Sleepiness Scale (ESS) and the Psychomotor Vigilance Task (PVT),
respectively. We will correlate ESS and PVT scores with BART scores to examine
whether reward-seeking is reduced by sleepiness and diminished vigilance.

Our objective is to investigate decision-making in people with narcolepsy with
and without cataplexy and compare it to that of age-and sex-matched healthy
controls using psychometric testing, subjective and objective sleepiness tests
and the Balloon Analogue Risk Task (BART).

Methods:
Following telephone screening for inclusion and exclusion criteria, subjects
will be educated about the purpose of this study, and informed consent will be
obtained if they agree to participate.

Part I - Behavioral Screen Questionnaires:
(All Questionnaires are provided in the Appendix Section)
Following informed consent, subjects will be asked to complete the following
tests to study their risk-taking propensity:
The Zuckerman*s Sensation Seeking Scale(17) - Subjects are asked to choose
between a total of 72 pairs of contrasting statements. The Zuckerman Sensation
Seeking Scale is widely used in psychological studies for evaluation of
Sensation Seeking, Thrill and Adventure Seeking, Experience Seeking,
Disinhibition and Boredom Susceptibility.(13-16). The Sensation Seeking Scale
stratifies screened subjects into high, moderate, and low categories for the
behaviors mentioned above.
The Eysenck Impulsiveness Scale (18) - a 19-question Yes/No test that is a good
measure of impulsive behavior across cognitive and behavioral domains and is
widely used in psychological studies and correlated with substance and alcohol
abuse (14, 16, 19). Eysenck breaks down results by age and sex. It is
reasonable to consider individuals who score at or greater than 2 standard
deviations above the mean Impulsiveness score for their age and sex as
extremely impulsive.
Gormally*s Binge Eating Scale (BES), (20) - a 16-question test used in studies
on eating behaviors to diagnose binge eating disorder. Typically patients
scoring 17 or lower on the BES have been classified as non-binge eaters, those
with a score of 18 to 26 as moderate binge eaters, and those scoring 27 or
higher as severe binge eaters. (21, 22)
The World Health Organization-developed AUDIT (Alcohol Use Disorders
Identification Test) screen - a 10-question screening tool, developed by the
WHO, which has been designed as a as a simple and brief method of screening for
excessive drinking. (23, 24)
The CAGE questionnaire for substance abuse - a 4-question tool widely used in
primary care clinics as an initial screen for alcohol and substance abuse. (25,
26) CAGE is a mnemonic for a questionnaire that asks about attempts to Cut down
on drinking, Annoyance with criticisms about drinking, Guilt about drinking,
and using alcohol/substances as an Eye opener. Even though it was initially
developed as an alcohol screening test, the CAGE questionnaire has been shown
effective for screening of substance abuse. It is thought to be 60 to 90
percent sensitive when two or more questions are positive and 40 to 60 percent
specific for excluding substance abuse (27).
Gamblers Anonymous*s 20 Questions (GA20) - a screening tool shown to be 98%
sensitive and 99% specific for detection of problematic gamblers at the cut
off-level of 7 or more positive questions. (28)
The Epworth Sleepiness Scale (ESS) - an eight-item questionnaire, used as a
simple method for measuring daytime sleepiness in adults.(41)
Modified Edinburgh Handedness Inventory (EHI) - a 20-question handedness test,
will be used to keep a record of handedness. (50, 52)

The above screens will be administered in random order. It is expected that
subjects will complete all of the above screens in approximately 2 hours. A
15-min break will be given midway into Part I, after the first hour. Should
they need it, subjects will be given extra time to complete these screens, as
well as additional brief breaks. All questions should be answered in one visit,
unless unforeseen circumstances arise.

*Specifically, scores of >=27 on the BES, >=8 on the AUDIT, >=2 on the CAGE and >=7
on the GA20 will be considered positive.

Part II - Balloon Analogue Risk Task (BART) and Psychomotor Vigilance Task
(PVT), same visit as Part I:
Subjects will start with the Balloon Analogue Risk Task (BART)

1) Balloon Analogue Risk Task (BART)
Instructions about the Balloon Analogue Risk Test (BART) and about
use of the computer and mouse (if needed) will be provided. Subjects will then
be asked to sit down at a computer in a comfortable environment and take the
BART
The Balloon Analogue Risk Task (BART) is a behavioral measure of
risk taking that has convergent validity with real-world risk related
situations (13). Performance on BART has been correlated with occurrence of
real-world risk behaviors such as substance abuse, risky sexual behaviors,
delinquent behaviors, as well as self-report measures of risk-related
constructs such as sensation seeking, impulsivity and deficiencies in
behavioral constraints (14-16).
The BART is a computerized task that simulates a balloon being inflated
by the participant with the click of a mouse. The whole test can be performed
in less than 15 minutes. During the task, the following items are displayed on
the computer screen: a balloon and a bar that the participant clicks on using a
computer mouse to inflate the balloon (labeled *Press this button to pump up
the balloon*), a button with the label *Press to Collect $$$* that begins the
next trial, a box that displays the total amount of money earned (labeled
*Total Earned*), a box with the amount of money earned per pump, and a box that
displays the amount of money earned on the previous balloon (labeled *Last
Balloon*).
The task begins with a deflated balloon and includes 30 total trials
(balloons). At any point, the participant can use the mouse to press the *Press
to Collect $$$* button and take the amount of money accumulated from the
current balloon and add it to their total earnings. Pressing this button begins
the next trial with a new, deflated balloon. If the balloon explodes before the
participant pressed the *Press to Collect $$$* button, the money earned from
that balloon is not added to the total earned. Instead, that money is lost.
Each balloon has a different explosion point. Therefore, the probability of
losing the money, as well as the potential loss, increases with each pump (13).
Subjects will perform the BART twice. Each time they will be
presented with 30 balloons. In the first trial they will earn 5 cents per pump,
without any compensation. In the second BART trial, subjects will unexpectedly
be told that they will be compensated a monetary amount equal to their
on-screen total BART earning.

NOTE: Reasonable effort will be made to test all subjects in the morning, when
narcoleptic patients are typically most alert.
Subjects will be given a 5-min break following the BART and will be encouraged
to stretch and move around to prevent sleepiness.

This part should take less than 30 minutes.

2) Psychomotor Vigilance Task (PVT)
The Psychomotor Vigilance Task (PVT) is a reliable test of behavioral
alertness, which consists of a series of reaction time (RT) measurements,
usually performed over at least 10 minutes and designed to evaluate the ability
to sustain attention and respond in a timely manner to salient signals (42).
The PVT will be performed using the LUMC computer version of the PVT task. The
subjects are asked to press the space bar as soon as they see a counter running
on the screen. The RTs are measured and recorded for a pre-specified period.
The test will last for 10 minutes as RT*s in narcolepsy patients tend to
decline with time.

This part should take less than 15 minutes.

At the end of Part II, subjects will be compensated $50 for their
participation, as well as the equivalent of their earnings on BART #2, in an
effort to encourage greater risk-taking on the BART.

No risk, 4 hours in hospital (2 hrs questionnaires, 1 hr computer tasks)