Original Article
The effect of modafinil on cortical excitability in patients with narcolepsy:
A randomized, placebo-controlled, crossover study
Eun Yeon Joo
a
, Seung Bong Hong
a,
⇑
, He-Jung Kim
a
, Yang-Hee Lim
a
, Dae-Lim Koo
a
,
Ki-Hwan Ji
a
, Woo Suk Tae
b
a
Sleep Center, Department of Neurology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea
b
Neuroscience Research Institute, Kangwon National University College of Medicine, Chunchon, Korea
article info
Article history:
Received 11 February 2010
Received in revised form 7 July 2010
Accepted 10 July 2010
Keywords:
Transcranial magnetic stimulation
Narcolepsy
Modafinil
Cortical excitability
Motor evoked potential
Cortical silent period
abstract
Objective: To investigate the effect of modafinil on cortical excitability in patients with narcolepsy using
transcranial magnetic stimulation (TMS).
Methods: Nineteen drug-naïve narcolepsy patients with cataplexy (10 males, 9 females, and mean age
28.5 years) and 25 age- and sex-matched healthy controls were recruited. In this double-blind, random-
ized, crossover study, patients and controls received a single dose of 400 mg modafinil or placebo. Mod-
afinil and placebo administrations were separated by a 2-week washout period. TMS parameters, such as
resting motor thresholds (RMT), motor-evoked potential (MEP) amplitudes, cortical silent periods (CSP),
short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF), were measured before and
3 h after administering modafinil or placebo. The differences of TMS parameters were statistically tested
between patients and controls and between before and after modafinil or placebo administration.
Results: Narcolepsy patients had significantly increased CSP durations compared to controls (indepen-
dent t-test, P < 0.05), indicating decreased excitability of cortical networks in human narcolepsy. In
patients after modafinil administration, MEP amplitudes, SICI, and ICF increased, and CSP duration short-
ened significantly, meaning enhanced motor excitability, whereas in controls modafinil did not change
TMS parameters significantly. Placebo administration did not affect TMS parameters both in patients
or controls.
Conclusions: Narcolepsy patients with cataplexy showed decreased cortical excitability than normal
healthy controls. Single dose modafinil significantly increased motor excitability in narcolepsy patients
but had no effect in healthy controls.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
Narcolepsy is a neurological disorder with a main symptom of
excessive daytime sleepiness and cataplexy. Modafinil is a first-line
pharmacological treatment for daytime sleepiness in narcolepsy
patients and irresistible episodes of sleep [1]. The involvement of
adrenergic alpha-1 stimulation [2], indirect and direct interactions
of dopamine systems [3–6], and the involvements of serotonergic/
GABAergic mechanisms [4] have been suggested to possibly under-
lie the effects of modafinil, which is also effective at treating fati-
gue in patients with multiple sclerosis [7]. Furthermore, fatigue
phenomena in multiple sclerosis patients are known to be associ-
ated with abnormal excitability and metabolism in the motor sys-
tem [8,9].
Transcranial magnetic stimulation (TMS) provides a noninvasive
means of studying excitability in the human motor cortex. A previ-
ous TMS study reported increased motor thresholds and intracorti-
cal inhibition in 13 drug-naïve narcolepsy patients, which
suggested that excitatory and inhibitory intracortical circuit balance
was impaired in narcolepsy [10]. In this previous study, the authors
suggested that a hypocretin deficiency may be related to changes in
the excitabilities of intrinsic circuits and that this is responsible for
excessive daytime sleepiness in narcolepsy. Another study in 10 nor-
mal subjects showed a single oral dose of 200 mg modafinil demon-
strated no changes in motor cortex excitatory or inhibitory
properties or in alpha motoneuronal excitability [11].
Our aim was to investigate the effects of modafinil on cortical
excitability in the narcoleptic brain. In the present study, we mea-
sured parameters of cortical excitability and assessed subjective
daytime sleepiness before and after a single dose of modafinil or
placebo in narcolepsy patients and age- and gender-matched
healthy controls.
1389-9457/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.sleep.2010.07.003
⇑
Corresponding author. Address: Department of Neurology, Sleep Center,
Samsung Medical Center, Sungkyunkwan University, 50 Irwon-dong, Gangnam-
gu, Seoul 135-710, Republic of Korea. Tel.: +82 23410 3592; fax: +82 2 3410 0052.
E-mail addresses: sbhong@skku.edu, sbhongsmc@gmail.com (S.B. Hong).
Sleep Medicine 11 (2010) 862–869
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