Psychopharmacology

DOI 10.1007/s00213-014-3499-0

ORIGINAL INVESTIGATION

Modafinil augments brain activation associated with reward

anticipation in the nucleus accumbens
Takuya Funayama & Yumiko Ikeda & Amane Tateno &
Hidehiko Takahashi & Yoshiro Okubo &
Haruhisa Fukayama & Hidenori Suzuki

Received: 14 September 2013 / Accepted: 8 February 2014

# Springer-Verlag Berlin Heidelberg 2014

Abstract
Rationale The nucleus accumbens (NAc) works as a key
brain structure of the reward system, in which reward-related
neural activity is well correlated with dopamine release from
mesolimbic dopaminergic neurons.
Objectives Since modafinil can modulate dopaminergic transmission through re-uptake inhibition of dopamine, we investigated whether modafinil affects the reward-related brain
activity in the NAc in healthy subjects.
Methods Twenty healthy participants underwent two series of
functional magnetic resonance imaging while performing
monetary incentive delay task in which they were cued to
anticipate and respond to a rapidly presented target to gain or
avoid losing varying amounts of money, under modafinil or
placebo condition. Blood oxygenation-level dependent
(BOLD) activation signals during gain and loss anticipations
were analyzed in the NAc as an a priori region of interest as
well as the whole brain.

Results Modafinil significantly changed subjective feelings

toward positive ones. The activation of BOLD signals was
observed during gain anticipation under the placebo and
modafinil conditions in the left and bilateral NAc, respectively. The modafinil condition showed significantly higher
BOLD signal change at the highest gain (+500) cue compared to the placebo condition.
Conclusions The present study showed that modafinil affects
reward processing in the NAc in healthy subjects through
enhancing more positive anticipation, and it may provide a
basis for the use of this drug for treating anhedonia observed
in psychiatric disorders.
Keywords Mesolimbic dopaminergic neuron . fMRI .
Modafinil . Monetary incentive delay task . Nucleus
accumbens . Reward

Introduction
T. Funayama : H. Fukayama
Anesthesiology and Clinical Physiology, Graduate School, Tokyo
Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku,
Tokyo 113-8549, Japan
Y. Ikeda : H. Suzuki (*)
Department of Pharmacology, Graduate School of Medicine, Nippon
Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
e-mail: hsuzuki@nms.ac.jp
A. Tateno : Y. Okubo
Department of Neuropsychiatry, Graduate School of Medicine,
Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku,
Tokyo 113-8602, Japan
H. Takahashi
Department of Psychiatry, Graduate School of Medicine, Kyoto
University, 54 Shogoin-kawaharamachi, Sakyo-ku, Kyoto 606-8507,
Japan

Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide) is a

psychostimulant approved for the treatment of excessive somnolence in narcolepsy worldwide, and may also be used offlabel as a cognitive enhancer to treat cognitive dysfunction in
patients with psychiatric disorders such as schizophrenia and
major depression (Minzenberg and Carter 2008).
Pharmacological effects of modafinil on cognitive functions
have been examined in humans (Minzenberg and Carter
2008), although there is conflicting literature on these effects
(Lynch et al. 2011). In healthy humans, working memory and
sustained attention are reportedly enhanced by modafinil
(Minzenberg and Carter 2008; Mller et al. 2004; Randall
et al. 2005). In patients with schizophrenia, who show cognitive impairment as a core symptom, modafinil improves cognitive functions such as working memory, problem solving,
control, and flexibility, as well as emotion, suggesting that

Psychopharmacology

modafinil acts on the prefrontal and limbic brain areas

(Scoriels et al. 2011, 2013; Turner et al. 2004). Therefore,
modafinil seems to affect specific cognitions dependent on
psychological states of subjects rather than having widespread
effects evenly across the brain through its arousal effect
(Lynch et al. 2011; Minzenberg and Carter 2008). Modafinil
exerts its effects on a number of neurotransmitter systems.
Administration of modafinil causes significantly elevated
levels of extracellular dopamine, noradrenaline, serotonin,
glutamate, and histamine as well as decreased extracellular
GABA in various brain regions, although the effects on dopamine and noradrenaline appear to be primary, and serotonin,
glutamate, histamine, GABA, and orexin may be secondary to
catecholamine (Minzenberg and Carter 2008). In animal studies, blockade of dopamine receptors (Qu et al. 2008) or
dopamine transporter knockout (Wisor et al. 2001) abolishes
or blunts the arousal effects of modafinil. In addition,
modafinil has been shown to have reinforcing effects in addictive drug-experienced rhesus monkeys (Andersen et al.
2010) and rats (Gold and Balster 1996), increase locomotor
activity (Zolkowska et al. 2009), and improve working memory (Pirard et al. 2007) through the interaction with dopamine
transporters (see Scoriels et al. 2013 for review). Modafinil
reportedly has rewarding properties through binding dopamine receptors and dopamine transporters in the prefrontal
cortex, the caudate putamen, and the nucleus accumbens
(NAc; Nguyen et al. 2011). In a positron emission tomography (PET) study in nonhuman primates, it was reported that
modafinil occupies substantial DAT sites in the striatum
(Madras et al. 2006). A human PET study also showed that
modafinil at a therapeutic dose decreases [11C]cocaine binding potential in the NAc, indicating that modafinil occupies
dopamine transporters (Volkow et al. 2009). Collectively,
modafinil enhances dopamine neurotransmission by at least
partly inhibiting dopamine transporters (Madras et al. 2006;
Minzenberg and Carter 2008).
Midbrain dopaminergic neurons are well known for their
crucial roles in reward processing (Bromberg-Martin et al.
2010; Haber and Knutson 2010; Schultz 1997). Reward delivery or reward-predicting cue activates dopaminergic neurons in the substantia nigra pars compacta (SNc) and the
ventral tegmental area (VTA; Bromberg-Martin et al. 2010;
Haber and Knutson 2010; Schultz 1997), which then send
their information to the dorsal and ventral striatum and prefrontal cortex. The NAc, a part of the ventral striatum, works
as a key brain structure of reward processing (BrombergMartin et al. 2010; Chau et al. 2004; Haber and Knutson
2010; Knutson and Greer 2008; Peters and Bchel 2011;
Schultz 1997). The NAc receives input from the medial and
orbital prefrontal cortex, amygdale, and hippocampus, as well
as the VTA, and projects to the ventral pallidum, VTA, SN, the
bed nucleus of stria terminalis, and the lateral hypothalamus
(Bromberg-Martin et al. 2010; Haber and Knutson 2010;

Peters and Bchel 2011). In human studies using PET or

functional MRI (fMRI), exposure to both primary (pleasant
tastes and sound) and secondary (monetary gain) rewards
increases ventral striatum activation (Haber and Knutson
2010). Further, reward-related neural activity in the ventral
striatum/NAc is well correlated with dopamine release in the
ventral striatum (Buckholtz et al. 2010; Schott et al. 2008).
Abnormality of the reward circuitry is observed in patients
with psychiatric disorders, including substance use disorders,
schizophrenia, depression, and pathological gambling (Chau
et al. 2004; Reuter et al. 2005; Russo and Nestler 2013), who
also show dysfunction of mesolimbic dopaminergic systems
(Chau et al. 2004).
Modafinil at therapeutic doses binds to the dopamine transporters (Madras et al. 2006; Zolkowska et al. 2009) and
inhibits dopamine reuptake, resulting in significant dopamine
release in the NAc (Volkow et al. 2009). Given that rewardrelated neural activity in the ventral striatum/NAc is well
correlated with dopamine release in the ventral striatum
(Buckholtz et al. 2010; Schott et al. 2008), modafinil could
also modulate the reward system by at least enhancing dopaminergic transmission in humans. Actually, armodafinil is
reported to improve negative symptoms such as anhedonia
caused by dysfunction of the reward system in patients with
schizophrenia (Bobo et al. 2011). The monetary incentive
delay (MID) task is designed to elicit neural responses to
monetary incentive anticipation (Knutson et al. 2001). The
MID task with fMRI allows us to separately visualize brain
activity in response to incentive anticipation. Previous imaging studies showed that NAc activation clearly increased in
proportion to the magnitude of the anticipated monetary reward (Knutson et al. 2001; Yacubian et al. 2006). In the
present study, we therefore adopted the MID task to examine
the effect of modafinil on reward processing in the NAc in
healthy subjects.

Materials and methods

Participants
Twenty physically and psychiatrically healthy volunteers over
20 years of age (12 males and 8 non-pregnant females; mean
age, 29.90 years) participated in the study. Participants did not
suffer from diseases such as hypertension, hepatic disorder,
and renal dysfunction and had taken no medication such as
contraceptives, vasopressor, monoamine oxidase inhibitor,
warfarin, or phenobarbital for at least 2 weeks prior to the
experiment, and they had no history of psychiatric disorders,
cardiac disorders, epilepsy, or allergy to modafinil. The baseline mood and subjective states of the participants were
assessed and the participants were excluded according to
criteria as described below in the Subjective ratings section.

Psychopharmacology

They did not have any contraindications to fMRI including

cardiac pacemaker, mechanical heart valve, metal implants,
potential pregnancy, tattoo, or claustrophobia. For assessment
of baseline mood and subjective state, the participants
underwent various psychological tests: Beck Depression
Inventory (BDI; Beck et al. 1996; Kojima and Furukawa
2003), Epworth Sleepiness Scale (ESS; Johns 1991;
Takegami et al. 2009), and StateTrait Anxiety Inventory
(STAI; Hidano et al. 2000). These tests consisted of 21, 8,
and 40 question items rated by 4-point scales, respectively. We
selected subjects whose scores were below set criteria (BDI<
10, ESS<9, STAI-state<41, and STAI-trait<44). Data of
participants whose head movements were excessive (more
than 2 mm of translation or 2 degrees of rotation) during
fMRI acquisition were excluded. All subjects were righthanded according to the Edinburgh Handedness Inventory
(Oldfield 1971). All subjects provided written informed consent before the experiments, and the present study was approved by the ethics committee of Nippon Medical School
(approval number 223019).
Experimental design
A randomized single-blind placebo-controlled within-subjects
cross-over design was applied. Each participant came to the
imaging center for two series separated by a 2-week wash-out
period. Modafinil (200 mg as a Modiodal 100-mg tablet
formula, Alfresa Pharma, Japan; Minzenberg et al. 2011) or
placebo was administered orally with water in the first series,
and the second compound (modafinil or placebo) was administered in the second series of the study. The order of drug
administration was randomly allocated with equal probability.
Medication was administered 2.5 h prior to the start of the
fMRI scan. Timing of the scan was based on pharmacokinetic
data indicating that the 200-mg dose of modafinil reaches the
peak plasma level at 2.5 h after oral administration (Robertson
and Hellriegel 2003). The participants took part in the fMRI
scan during the MID task as described below.
The task was presented on a personal computer using Eprime (version 2.0; Psychology Software Tools, USA) and
viewed by the participants on a monitor at the foot of the
scanner bed via mirrors mounted on the head coil. We recorded their behavioral responses using an MRI-compatible keypad and calculated their accuracy and reaction times with Eprime.
Subjective ratings
Before, 2 h (just before MRI scanning) after the drug administration in each series, transient subjective emotional states
were also evaluated with Profile of Mood States (POMS;
McNair et al. 1992; Yokoyama et al. 1990), Hamilton
Depression Scale (HAM-D; Nakane and Williams 2003;

Williams et al. 1988) and Hamilton Anxiety Scale (HAM-A;

Inada 2010; Shear et al. 2001), and visual analogue scales
(VAS for feeling; Norris 1971). A questionnaire of POMS
consists of 65 adjectives rated by the participants on a 5-point
scale. HAM-D and HAM-A included 21 and 14 question
items, respectively. A researcher asked participants these
questions and scored answers on a 3- or 5-point scale. VAS
for feeling involved 10-cm lines with opposing feeling and
mood adjectives at each end, and included 16 dimensions
(Norris 1971). The measures used in this study were as follows: 1alertdrowsy, 2calmexcited, 3strongfeeble,
4muzzyclear-headed, 5well-coordinatedclumsy, 6
lethargicenergetic, 7contenteddiscontented, 8troubledtranquil, 9mentally slowquick-witted, 10tenserelaxed, 11attentivedreamy, 12incompetentproficient,
13happysad, 14antagonisticamicable, 15interestedbored, and 16withdrawngregarious. The items were
divided into the following four domains of effects: (a) mental
awareness (items 1, 4, 9, and 11); (b) physical energy (items 3,
5, 6, and 12); (c) tranquility (items 2, 7, 8, and 10); and (d)
sociability (items 13, 14, 15, and 16). The position of each
mark was measured by ruler to the nearest mm. Items 1, 3, 5,
8, 10, 11, 13, and 15 were measured right-to-left and the others
left-to-right (Norris 1971). Following the scanning, the participants rated on 10-cm VAS scales how much effort they put in
when they saw each of the cues during the task (VAS for
effort, Stoy et al. 2011) for assessing their subjective eagerness
to achieve monetary incentives.
Statistical analyses of behavioral data and psychological
measures
Values were expressed as median (interquartile range). The
Wilcoxon signed-rank test was used to compare values in
POMS, HAM-D, HAM-A, VAS for feeling, VAS for effort,
hit rate, and reaction time during a series of the fMRI study
between the placebo and modafinil treatments. Values of
p<0.05 were considered to indicate statistical significance.
Monetary incentive delay task
Participants performed a slightly modified MID task (Knutson
et al. 2008; Saji et al. 2013) to examine neural responses to
monetary anticipation. Before entering the scanner, participants received a verbal description of the task and completed
a 6-min practice version. This practice task minimized later
learning effects and provided an estimate of mean reaction
time for individually standardizing the task difficulty among
all participants. Participants were informed that they would
receive a gift voucher according to the amount of money they
could earn by the end of the second series. Participants
monetary gain depended on their performance in a simple
reaction time task at the end of each trial, which required

Psychopharmacology

pressing a button upon the brief presentation of a visual target.

Prior to executing the task, a photograph of cash was shown to
the participants via the monitor in the scanner.
The MID task was run twice, making a total of 180 trials
(Fig. 1). During each trial, participants saw one of nine geometric figures (cue) for 2,000 ms, which indicated that they
could either gain or avoid losing different amounts of money
(0, 20, 100, or 500) if they pressed the response button
during the target presentation. Participants were instructed to
respond as fast as possible. A cue signaled the potential
reward (number of total signals presented in two sessions,
n=72; denoted by circles), potential punishment (n=72; denoted by squares), or no response requirement (n=36; denoted
by triangles). Reward cues (circles) consisted of four signals
with the possibility of gaining 0 (n=18; no lines), 20
(n=18; one horizontal line), 100 (n=18; two horizontal
lines), or 500 (n=18; three horizontal lines). Similarly, punishment cues (squares) were further divided into four signals
with the possibility of losing 0 (n=18; no lines), 20 (n=18;
one horizontal line), 100 (n=18; two horizontal lines), or
500 (n=18; three horizontal lines). No response trials (n=36;
triangles) indicated that the subject should not respond during
that trial and instead should wait until the appearance of the
cue signaling the next trial. Trial types were pseudo-randomly
ordered within each session. Between cues and target, an xshaped fixation cross was inserted for a variable anticipation
delay period (2,0002,500 ms). Then a solid white target
square appeared for a variable length of time (160470 ms;
target) urging the participants to press a button. Feedback
(1,900 ms) following the disappearance of the second delay
(1,1301,940 ms) notified the participant how much money
they had gained or lost during the preceding trial and the
Fig. 1 Task structure for
representative trial in the
monetary incentive delay task.
The procedure is described in the
text. All cues in the task are
shown as follows: no line square
0 loss, square with one horizontal
line 20 loss, square with two
horizontal lines 100 loss, square
with three horizontal lines 500
loss, no line circle 0 gain, circle
with one horizontal line 20 gain,
circle with two horizontal lines
100 gain, circle with three
horizontal lines 500 gain,
triangle no response

cumulative amount of money they had earned by that time

point during the session. Due to the application of an adaptive
algorithm for target duration, task difficulty was standardized
to a hit rate of approximately 66 % for all participants.
MRI data acquisition
Imaging was performed with Intera Achieva 1.5 T Nova
(Phillips Electronics, The Netherlands). For the acquisition
of high-resolution T1-weighted anatomical images, the following parameters were used: repetition time (TR)=9.3 ms,
echo time (TE)=4.6 ms, flip angle=8, field of view (FOV)=
250 mm, matrix=256256, slice thickness=1.2 mm, number
of slices=160. Functional images were acquired with the
following parameters: TR = 2,000 ms, TE = 40 ms, flip
angle=90, FOV=256 mm, matrix=6464. A total of 740
functional images were acquired from each participant with a
T2*-weighted gradient-echo echo-planer imaging sequence
sensitive to blood oxygenation level-dependent (BOLD) contrast. Whole brain coverage was obtained with 5-mm slice
thickness and 28 axial slices.
fMRI data analysis
The analyses focused on changes in BOLD activation occurring during the anticipatory period and were conducted with
SPM8 (Wellcome Department of Imaging Neuroscience, UK)
running with MATLAB (Mathworks, USA). The anatomical
T1 image and the functional images were manually reoriented
to the anterior commissureposterior commissure line. Slicetime correction was performed to adjust for time differences
due to multi-slice imaging acquisition. To correct for between-

Psychopharmacology

scan movements, the functional images were realigned to the

first image of the session and again realigned to the mean
image created after the first realignment. The individual anatomical T1 image was then co-registered to the mean functional image. The transformed anatomical image was then
segmented to create spatial normalization parameters that
were applied to functional images in the next normalization
step. The functional images were spatially normalized into the
standard space defined by the Montreal Neurological Institute
(MNI) template. After normalization, all scans were
resampled at a resolution of 222 mm. The functional
images were spatially smoothed with an isotropic Gaussian
kernel (full width at half maximum of 8 mm) to increase the
signal-to-noise ratio. For subject-level statistical analyses, the
functional images were analyzed using the general linear
model. Hemodynamic responses to each stimulus were
modeled with a function convolved with a synthetic hemodynamic response function time-locked to the onset time of
delay following the cue and feedback. Low frequency noise
was removed by applying a high-pass filter (cutoff period,
128 s) to the fMRI time-series data of each voxel. The statistical parametric map for each contrast, (a) gain anticipation
(+20, +100, and +500>+0) and (b) loss anticipation
(20, 100, and 500>0) of the t statistic, was calculated on a voxelvoxel basis.
For group-level analyses, the one-sample t test was
performed to determine group-level activation for each
effect. Then, for group comparisons, paired t test was
performed to assess the difference between the placebo
and modafinil administrations. The contrast images obtained from subject-level statistical analyses were entered
into paired t test analyses. All results on activation in the
whole brain were reported at p<0.001 uncorrected with a
minimum cluster size of 63 voxels. The cluster size
threshold was determined using a cluster-extent correction
procedure as implemented in SPM8. Only results surviving the cluster-correction (p < 0.05) were reported. For
anatomical location, peak voxels were converted from
MNI to Talairach coordinates (Talairach and Tournoux
1988). Based on previous fMRI studies using the MID
task by other researchers and us (Saji et al. 2013), we set
the NAc as an a priori region of interest (ROI) for
incentive anticipation. The bilateral NAc ROIs were anatomically defined by the left and right NAc templates
using the Wake Forest University (WFU) PickAtlas and
were analyzed at familywise error (FWE)-corrected
p<0.05. The percent signal change within the ROI was
calculated for the anticipatory period using MarsBar.
Because the values of percent signal change were not
subject to normal distribution, they were analyzed using
the Wilcoxon signed-rank test with incentive valence
(gain, loss) and magnitude (0, 20, 100, and 500)
between placebo and modafinil treatments.

Results
Effects of drugs on subjective emotional states
Table 1 shows the mean scores of each test before the drug
treatments (HAM-D, HAM-A, and POMS), indicating that
the subjects enrolled in this study showed no tendency to have
psychotic features, and their mood states were almost comparable between the two series of fMRI studies. Table 2 shows
the values calculated by subtracting the scores before the drug
administration from those 2 h after the drug administration. As
for VAS for feeling, the subjects were significantly more alert
(p=0.026), clearer-headed (p=0.012), more energetic (p=
0.020), more attentive (p=0.029), and more gregarious (p=
0.036) with the modafinil treatment compared to the placebo
treatment. Among the 4 domains for feeling, modafinil significantly increased the mental awareness of subjects
(p<0.001).
Effects of modafinil on task performance and VAS for effort
We then examined the effects of modafinil on reaction times in
response to cues and VAS effort scores. Median reaction times
for each cue did not differ significantly between placebo and
modafinil (Table 3). On the other hand, VAS effort scores for
+500 and 500 cues were significantly higher under
modafinil than placebo conditions (+500, p=0.025; 500,
p=0.023; Table 3). The hit rates were standardized to 66 % for
all participants, as described, so that the actual median values
of the hit rate were 64.60 % with placebo and 64.25 % with
modafinil, showing no difference. We analyzed behavioral
differences in the commission error to the no-response trials
between under modafinil and placebo conditions. Modafinil
significantly decreased the commission error compared to
placebo (mean error rates, placebo, 1.11 %, modafinil,
0.14 %; p=0.038).
Table 1 Baseline rating of subjective mood

HAM-D
HAM-A
POMS
TensionAnxiety
DepressionDejection
AngerHostility
Vigor
Fatigue
Confusion

Placebo
mean (SEM)

Modafinil
mean (SEM)

0.90 (0.26)
0.55 (0.25)

0.60 (0.21)
0.50 (0.20)

3.35 (0.70)
2.05 (1.03)
2.30 (0.76)
17.90 (1.45)
3.15 (1.05)
3.75 (0.79)

3.45 (0.77)
2.75 (1.16)
2.90 (1.01)
17.80 (1.77)
3.15 (0.95)
2.90 (0.62)

HAM-D Hamilton Depression Scale, HAM-A Hamilton Anxiety Scale,

POMS Profile of Mood States, SEM standard error of the mean

Psychopharmacology
Table 2 Subjective ratings of
emotional states

Placebo median
(IQR)

Modafinil median
(IQR)

0 (1.000)
0 (00)

0 (01.00)
0 (00)

0 (2.250)
0 (00)
0 (1.250)
1.00 (2.500)
0 (1.000)
0 (1.000)

0 (1.001.00)
0 (1.000)
0 (1.000)
0 (2.002.25)
0 (1.250)
0 (00)

1. Alertdrowsy*
2. Calmexcited
3. Strongfeeble
4. Muzzyclear-headed*
5. Well-coordinatedclumsy
6. Lethargicenergetic*
7. Contenteddiscontented
8. Troubledtranquil
9. Mentally slowquick-witted
10. Tenserelaxed
11. Attentivedreamy*
12. Incompetentproficient
13. Happysad
14. Antagonisticamicable
15. Interestedbored
16. Withdrawngregarious*
Mental awareness*** (1, 4, 9, 11)
Physical energy (3, 5, 6, 12)

1.00 (16.5014.25)
3.00 (0.5015.25)
1.00 (1.002.75)
0.50 (10.255.75)
0 (1.255.25)
4.00 (11.003.25)
0 (5.754.00)
2.00 (7.503.25)
0.50 (6.502.25)
1.50 (7.257.25)
1.50 (10.752.50)
0 (6.252.00)
0 (3.004.00)
1.00 (3.00-6.25)
0.50 (4.753.50)
2.00 (7.753.00)
0 (10.255.25)
0 (4.254.00)

1.00 (1.2518.50)
0 (2.2517.75)
0.50 (1.008.00)
11.00 (2.0026.25)
2.00 (0.256.75)
2.50 (1.2511.75)
2.00 (8.508.25)
1.00 (7.508.25)
3.50 (2.5010.75)
0.50 (8.2514.00)
7.00 (1.0010.50)
0.50 (7.253.25)
0.50 (3.253.25)
0 (4.504.00)
4.00 (1.009.25)
6.00 (0.5010.50)
6.00 (2.0017.25)
1.00 (2.007.25)

Tranquility (2, 7, 8, 10)

Sociability (13, 14, 15, 16)

0 (5.506.25)
0 (5.003.25)

0 (8.0012.00)
2.00 (2.259.00)

HAM-D
HAM-A
POMS
TensionAnxiety
DepressionDejection
AngerHostility
Vigor
Fatigue
Confusion
VAS for feeling

HAM-D Hamilton Depression

Scale, HAM-A Hamilton Anxiety
Scale, IQR interquartile range,
POMS Profile of Mood States,
VAS visual analogue scale
*p < 0.05 between placebo and
modafinil treatments;
***p < 0.001 between placebo
and modafinil treatments

Whole brain analysis during gain and loss anticipations

in the MID task under the placebo and modafinil conditions
Activations under the placebo condition
Consistent with previous studies (Saji et al. 2013), the contrast
of gain anticipation showed a significant increase in BOLD
signal in the left NAc (p<0.05 FWE-corrected for NAc ROI).
Other activated areas during gain anticipation were observed
in the bilateral insula and medial frontal gyri, right inferior
frontal gyrus, bilateral thalamus and precentral gyri, right
postcentral gyrus, right paracentral lobule and precuneus,
bilateral middle occipital gyri and right cerebellum (p<0.001
uncorrected). The contrast of loss anticipation showed a significant increase in BOLD signal in the left putamen, left
insula, left cingulated and precentral gyri, and right precuneus
(p<0.001 uncorrected; Table 4).

Activations under the modafinil condition

The contrast of gain anticipation showed increased BOLD
signal in the bilateral NAc, left middle frontal and precentral
gyri, and left cuneus. The contrast of loss anticipation showed
BOLD signal activation in the bilateral putamen, right thalamus, bilateral insula, right superior and middle frontal gyri,
left medial and right inferior frontal gyri, right precentral
gyrus, bilateral superior temporal gyri, left inferior occipital
gyrus, right inferior parietal lobule, bilateral cuneus, and right
cerebellum (p<0.001 uncorrected; Table 4).

Direct dose-wise differences

Group-level analyses the whole brain revealed no differences
in BOLD response between the placebo and modafinil

Psychopharmacology
Table 3 Behavioral and affective reactions
Placebo median (IQR)
Reaction time (ms)
+0
235.59 (219.67252.48)
+20
226.55 (215.10232.59)
+100
223.57 (216.11231.13)
+500
224.22 (211.35229.35)
0
232.57 (222.29247.49)
20
226.60 (212.60240.38)
100
231.88 (209.90239.70)
500
219.00 (215.74228.98)
VAS for effort
+0
7.15 (5.388.48)
+20
7.55 (6.459.40)
+100
9.00 (7.5810.00)
+500*
9.75 (9.1010.00)
0
6.45 (4.989.03)
20
8.55 (6.739.50)
100
9.35 (7.9510.00)
500*

9.80 (9.5510.00)

Direct dose-wise differences

Modafinil median (IQR)

225.75 (215.05252.18)
218.31 (211.07238.77)
222.50 (214.82235.24)
217.05 (199.51238.18)
227.28 (214.05241.51)
230.98 (218.29242.11)
225.46 (216.45243.59)
228.25 (211.79240.42)
7.20 (4.789.30)
7.80 (6.559.75)
9.25 (7.989.90)
10.00 (9.5810.00)
7.30 (4.889.45)
8.30 (6.289.93)
9.25 (7.939.93)
10.00 (9.8010.00)

IQR interquartile range, VAS visual analogue scale

*p<0.05 between placebo and modafinil treatments

conditions in all brain areas including the NAc (p<0.001

uncorrected).

NAc ROI analysis of gain and loss anticipations in the MID

task under the placebo and modafinil conditions
We further focused on the NAc activity as an a priori ROI for
gain and loss anticipations under the modafinil condition
during the MID task. We constructed bilateral NAc ROIs with
default settings of the right and left NAc in the WFU
PickAtlas.

Activations under the placebo condition

The contrast of gain anticipation revealed that the BOLD
signal was increased in the left NAc, while the contrast of loss
anticipation showed no activation in NAc (p<0.05 FWEcorrected; Fig. 2).

Activations under the modafinil condition

The contrast of gain and loss anticipations revealed that the
BOLD signals were increased in the bilateral and left NAc,
respectively (p<0.05 FWE-corrected; Fig. 2).

Group-level analyses revealed that modafinil did not show a

significant increase in BOLD signal in the NAc during gain
and loss anticipations as compared with the placebo (p<0.05
FWE-corrected for NAc ROI). We next examined the percent
changes in BOLD signal of individual cues. In the gain
anticipation, the modafinil condition showed higher BOLD
signal change at the +500 gain cue than the placebo condition (p=0.048; Fig. 3). In loss anticipation, however, there
were no significant differences for any of the incentive cues
between the placebo and modafinil conditions (Fig. 3). There
were no significant correlations between percent signal
change and VAS for effort in the placebo (p=0.862 for +
500, p=0.836 for 500) or in the modafinil condition (p=
0.734 for +500, p=0.258 for 500).

Discussion
In this study, BOLD signals were increased in several brain
regions including the NAc during gain and loss anticipations.
These results clearly show that the present fMRI study with
the MID task could efficiently depict the functional role of the
NAc in the reward system, consistent with previous results
(Carter et al. 2009; Saji et al. 2013). Although the overall
effects of modafinil on BOLD signals in the NAc during the
anticipations were not significant as compared with those of
the placebo, modafinil caused larger BOLD signal change
than the placebo during the gain anticipation for the +500
cue. Previous pharmacological fMRI studies have shown that
dopamine-releasing agents increase the BOLD signal in the
NAc in humans (Knutson and Gibbs 2007; Oei et al. 2012). Ldopa, a dopamine precursor, is effective in increasing BOLD
activity during the reward task in elderly subjects (Chowdhury
et al. 2013). In addition, an fMRI study combined with PET
measures also demonstrated that the BOLD response to reward anticipation in the NAc correlates positively with dopamine release in the NAc during a reward task in humans
(Buckholtz et al. 2010; Schott et al. 2008). Modafinil at
therapeutic doses binds to the dopamine transporters
(Madras et al. 2006; Zolkowska et al. 2009) and inhibits
dopamine reuptake, resulting in significant dopamine release
in the NAc (Volkow et al. 2009). Collectively, the present
study provides the first evidence that modafinil modulates
positive reward processing (gain anticipation), possibly by
increasing extracellular dopamine in the NAc through dopamine transporter inhibition.
Interestingly, modafinil showed larger BOLD signal
change compared with the placebo during the highest gain
anticipation. On the other hand, Knutson et al. (Knutson et al.
2004) reported that amphetamine elicits reduced peak activation at the highest gain level and increased peak activation at

Psychopharmacology
Table 4 Activation by gain and loss anticipation under placebo and modafinil conditions
Contrast

Gain anticipation
Placebo

Region

Nucleus accumbens
Insula
Medial frontal gyrus

Loss anticipation
Placebo

Modafinil

13
13
6

Inferior frontal gyrus

Thalamus

44

Precentral gyrus

6
6
23
2
5
7
18

Posterior cingulate
Postcentral gyrus
Paracentral lobule
Precuneus
Middle occipital gyrus

Modafinil

BA

Cerebellum
Nucleus accumbens
Middle frontal gyrus
Precentral gyrus
Cuneus

6
6
18

Putamen
Insula
Cingulate gyrus
Precentral gyrus
Precuneus
Putamen

13
24
6
7

Thalamus
Insula
Superior frontal gyrus
Middle frontal gyrus
Medial frontal gyrus
Inferior frontal gyrus
Precentral gyrus
Superior temporal gyrus
Inferior occipital gyrus
Inferior parietal lobule
Cuneus
Cerebellum
All other results p<0.001 uncorrected
BA Brodmann area, L left, R right
*p<0.05 FWE-corrected for nucleus accumbens

13
13
10
46
6
46
4
22
22
18
40
17

Talairach coordinates
X

t value

L
L
R
L
R
R
L
R
L
R
R
R
R
R
L
R
R
L
R
L
L
L

16
46
40
8
2
63
12
16
24
26
6
44
6
20
28
34
22
16
14
16
46
26

9
6
2
0
4
7
15
15
23
15
28
23
35
55
89
85
41
9
11
11
2
93

11
2
7
48
50
16
10
12
49
56
24
44
48
34
1
3
33
11
7
58
41
2

3.57*
5.26
4.67
6.98
6.80
5.52
6.93
6.90
6.86
4.51
7.00
4.19
3.75
5.22
12.25
9.44
4.19
5.34
4.10
9.14
8.70
8.68

L
L
L
L
R
L
R
R
L
R
R
R
L
R
R
L
R
L
R
L
R
R

18
28
14
36
12
22
28
4
40
36
36
42
10
48
46
53
57
34
55
6
2
4

4
26
9
6
56
7
16
13
12
6
55
49
1
41
9
8
8
88
42
71
73
49

0
18
29
33
43
6
4
3
2
0
16
9
57
7
50
0
1
6
24
11
13
16

4.72
8.37
4.89
7.88
4.66
4.18
6.28
5.64
4.48
6.59
3.92
5.09
7.58
5.49
7.33
4.95
7.26
6.41
7.27
4.53
4.35
7.28

Psychopharmacology
Fig. 2 Neural responses to gain
anticipation in the bilateral
nucleus accumbens. a Brain
activation in the bilateral nucleus
accumbens during gain
anticipation under placebo and b
modafinil conditions. Familywise
error-corrected p<0.05. Color bar
indicates t statistics

the middle loss level, resulting in equalization of the NAc

activity levels. They speculated that this result was due to
enhancement of tonic dopaminergic activation over phasic
activation by amphetamine (Knutson et al. 2004).
Mesolimbic dopamine neurons transmit dopamine signals in
tonic and phasic mode, and phasic dopamine responses are
triggered by many types of rewards and reward-related sensory cues (Bromberg-Martin et al. 2010). Previous animal
studies have shown that the extracellular level of dopamine
is largely established by phasic dopamine release (OwessonWhite et al. 2012) and that dopamine transporter inhibition
increases extracellular dopamine levels, changing both frequency and size of dopamine transients in the NAc (Heien
et al. 2005; Owesson-White et al. 2012; Robinson and
Wightman 2004). Thus, modafinil appears to bind to and
inhibit dopamine transporters (Minzenberg and Carter 2008),
resulting in changes in both frequency and size of dopamine
transients (Heien et al. 2005; Owesson-White et al. 2012;
Robinson and Wightman 2004), whereas amphetamine raises
extracellular dopamine levels by inducing stimulationindependent dopamine efflux via reverse transport through
the DA transporter and decreases stimulation-dependent

vesicular dopamine release (Schmitz et al. 2001; Sulzer et al.

2005).
The reason why modafinil showed significantly larger
BOLD signal change compared with the placebo at the highest
gain cue, but minimal change at other cues, remains unknown.
It is intriguing that tyrosine/phenylalanine depletion, which is
expected to result in reduction of dopamine synthesis, causes
reduction in percent signal change in the BOLD signal in the
NAc compared with a control condition during only the higher
gain anticipation with a similar reward task (Bjork et al. 2013).
In a previous study with reward task using low incentive, there
were no significant effects of modafinil on low incentive
reward in patients with a first episode of psychosis (Scoriels
et al. 2011).
The brain reward circuitry has been reported to be dysregulated in patients with several psychiatric disorders, including
substance use disorders, schizophrenia, depression, and pathological gambling (Chau et al. 2004; Reuter et al. 2005; Russo
and Nestler 2013). Several drugs have been proposed as
candidates to treat such dysfunction in the reward circuitry
(Forray and Sofuoglu 2012; Green et al. 2008; Leung and
Cottler 2009). For instance, bupropion, which inhibits

Fig. 3 Percent signal changes in the left nucleus accumbens during a

gain and b loss anticipation. Lower and upper hinges of boxes denote 25th
and 75th percentiles, respectively. Median (50th percentile) of each
distribution is indicated by solid line. Whiskers on either side extend to

either the most extreme data point or median1.5 times the interquartile
range. The circles are outliers meaning data points outside interquartile
range

Psychopharmacology

dopamine and norepinephrine reuptake, reduces use among

light methamphetamine users (Forray and Sofuoglu 2012). In
patients with schizophrenia and major depression, anhedonia
driven by loss of reward function is a serious symptom requiring treatment (Choi et al. 2013; Der-Avakian and Markou
2012). Modafinil at a therapeutic dose enhanced larger gain
anticipation in our study, and it might augment pleasurable
effects of reward. Therefore, the present results could help to
discover appropriate treatments of anhedonia and facilitate our
understanding of the brain reward circuitry.
Limitations of the study
In this study we examined the effects of single-dose modafinil
on the reward system. However, to treat patients with schizophrenia and major depression, modafinil needs to be chronically administered. Further, anhedonia scales were not
assessed. Therefore, we need to further clarify the effectiveness of chronic modafinil administration in these patients
using appropriate clinical measures.
In addition, we focused on the dopaminergic system to
discuss modafinil effects in the present study. However, the
involvement of other neurotransmitter systems in modafinil
effects will remain to be further analyzed in the NAc because
modafinil exerts its effects on a number of neurotransmitter
systems other than catecholamines, including glutamate, serotonin, orexin, and histamine.
Acknowledgements We thank Dr. Knutson for his helpful advice on
the MID task, Mr. Nagaya, Mr. Kanaya, Mr. Suda, Ms. Takei and Mr.
Sakurai (Clinical Imaging Center for Healthcare, Nippon Medical
School) for their assistance in performing the MRI examinations. We
also thank Ms. Kishi and Ms. Fukano for help as clinical research
coordinators and Dr. Gerz for his English editing of our manuscript. This
study was supported by a Grant-in-Aid for Encouragement of Young
Scientists (B) (24791237 to Y.I.) and a Grant-in-Aid for Challenging
Exploratory Research (22659212 to Y.O.) from the Japan Society for
the Promotion of Science, and a grant (S0801035 to H.S.) from the
Ministry of Education, Culture, Sports, Science and Technology, Japan.
Conflict of interest statement Dr. Suzuki has received speaker's honoraria from Pfizer and Eisai within the past 3 years. Dr. Okubo has
received grants or speaker's honoraria from Dainippon Sumitomo
Pharma, GlaxoSmithKline, Janssen Pharmaceutical, Otsuka, Pfizer, Eli
Lilly, Astellas, Yoshitomi, and Meiji within the past 3 years. For the
remaining authors, none were declared.

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