Académique Documents
Professionnel Documents
Culture Documents
DOI 10.1007/s00213-014-3499-0
ORIGINAL INVESTIGATION
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.
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
Psychopharmacology
Psychopharmacology
Psychopharmacology
Psychopharmacology
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)
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)
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
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)
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)
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
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
either the most extreme data point or median1.5 times the interquartile
range. The circles are outliers meaning data points outside interquartile
range
Psychopharmacology
References
Andersen ML, Kessler E, Murnane KS, McClung JC, Tufik S, Howell LL
(2010) Dopamine transporter-related effects of modafinil in rhesus
monkeys. Psychopharmacology (Berl) 210:439448. doi:10.1007/
s00213-010-1839-2
Beck AT, Steer RA, Brown GK (1996) Manual for the Beck Depression
Inventory (2nd ed.) Pearson, Texas
Psychopharmacology
Knutson B, Bjork JM, Fong GW, Hommer D, Mattay VS, Weinberger
DR (2004) Amphetamine modulates human incentive processing.
Neuron 43:261269. doi:10.1016/j.neuron.2004.06.030
Knutson B, Greer SM (2008) Anticipatory affect: neural correlates and
consequences for choice. Philos Trans R Soc Lond B BiolSci 363:
37713786. doi:10.1098/rstb.2008.0155
Knutson B, Gibbs SE (2007) Linking nucleus accumbens dopamine and
blood oxygenation. Psychopharmacology 191:813822. doi:10.
1007/s00213-006-0686-7
Kojima M, Furukawa TA (2003) Japanese Manual of the Beck
Depression Inventory (2nd ed.). Nihon Bunka Kagakusha, Tokyo
Leung KS, Cottler LB (2009) Treatment of pathological gambling. Curr
Opin Psychiatry 22:6974. doi:10.1097/YCO.0b013e32831575d9
Lynch G, Palmer LC, Gall CM (2011) The likelihood of cognitive
enhancement. Pharmacol Biochem Behav 99:116129. doi:10.
1016/j.pbb.2010.12.024
Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E,
Spencer TJ, Bonab AA, Miller GM, Fischman AJ (2006) Modafinil
occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol
Exp Ther 319:561569. doi:10.1124/jpet.106.106583
McNair DM, Lorr M, Droppleman LF (1992) Profile of Mood States.
Educational and Industrial Testing Service, San Diego
Minzenberg MJ, Carter CS (2008) Modafinil: a review of neurochemical
actions and effects on cognition. Neuropsychopharmacology 33:
14771502. doi:10.1038/sj.npp.1301534
Minzenberg MJ, Yoon JH, Carter CS (2011) Modafinil modulation of the
default mode network. Psychopharmacology (Berl) 215:2331. doi:
10.1007/s00213-010-2111-5
Mller U, Steffenhagen N, Regenthal R, Bublak P (2004) Effects of
modafinil on working memory processes in humans.
Psychopharmacology (Berl) 177:161169. doi:10.1007/s00213004-1926-3
Nakane Y, Williams JBW (2003) A structured interview guide for the
Hamilton Depressive Rating Scale Japanese version. Rinsho Seishin
Yakuri 6:13531368
Nguyen TL, Tian YH, You IJ, Lee SY, Jang CG (2011) Modafinilinduced conditioned place preference via dopaminergic system in
mice. Synapse 65:733741. doi:10.1002/syn.20892
Norris H (1971) The action of sedatives on brain stem oculomotor
systems in man. Neuropharmacology 10:181191. doi:10.1016/
0028-3908(71)90039-6
Oei NY, Rombouts SA, Soeter RP, van Gerven JM, Both S (2012)
Dopamine modulates reward system activity during subconscious
processing of sexual stimuli. Neuropsychopharmacology 37:1729
1737. doi:10.1038/npp.2012.19
Oldfield RC (1971) The assessment and analysis of handedness: the
Edinburgh inventory. Neuropsychologia 9:97113. doi:10.1016/
0028-3932(71)90067-4
Owesson-White CA, Roitman MF, Sombers LA, Belle AM, Keithley RB,
Peele JL, Carelli RM, Wightman RM (2012) Sources contributing to
the average extracellular concentration of dopamine in the nucleus
accumbens. J Neurochem 121:252262. doi:10.1111/j.1471-4159.
2012.07677.x
Peters J, Bchel C (2011) The neural mechanism of inter-temporal
decision-making: understanding variability. Trends Cogn Sci 15:
227239. doi:10.1016/j.tics.2011.03.002
Pirard C, Liscia P, Philippin JN, Mons N, Lafon T, Chauveau F, Van
Beers P, Drouet I, Serra A, Jouanin JC, Bracocha D (2007)
Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice. Pharmacol Biochem Behav
88:5563. doi:10.1016/j.pbb.2007.07.006
Qu WM, Huang ZL, Xu XH, Matsumoto N, Urade Y (2008)
Dopaminergic D1 and D2 receptors are essential for the arousal
effect of modafinil. J Neurosci 28:84628469. doi:10.1523/
JNEUROSCI.1819-08.2008
Psychopharmacology
Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW,
Sahakian BJ (2004) Modafinil improves cognition and attentional
set s hi f t i n g in p a t i e n t s wi t h ch r o ni c s c hi z o ph r e n i a .
Neuropsychopharmacology 29:13631373. doi:10.1038/sj.npp.
1300457
Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang GJ,
Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner D,
King P, Shea C, Xu Y, Muench L, Apelskog-Torres K (2009) Effects
of modafinil on dopamine and dopamine transporters in the male
human brain: clinical implications. JAMA 301:11481154. doi:10.
1001/jama.2009.351
Williams J, Link M, Rosenthal N, Terman M (1988) Structured
Interview Guide for the Hamilton Rating Scale Seasonal
Affective Disorder Version (SIGH-SAD). New York State
Psychiatric Institute, New York