Modulatory effects of modafinil on neural circuits regulating emotion and cognition.
ABSTRACT Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks-a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.
- SourceAvailable from: Nahal Mavaddat[show abstract] [hide abstract]
ABSTRACT: The indirect catecholamine agonist methylphenidate (Ritalin) is the drug treatment of choice in attention deficit/hyperactivity disorder (AD/HD), one of the most common behavioral disorders of childhood (DSM-IV), although symptoms may persist into adulthood. Methylphenidate can enhance cognitive performance in adults and children diagnosed with AD/HD (Kempton et al., 1999; Riordan et al., 1999) and also in normal human volunteers on tasks sensitive to frontal lobe damage, including aspects of spatial working memory (SWM) performance (Elliott et al., 1997). The present study investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug. The results show that the methylphenidate-induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial effects of methylphenidate on working memory were greatest in the subjects with lower baseline working memory capacity. This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for understanding the treatment of AD/HD.Journal of Neuroscience 04/2000; 20(6):RC65. · 6.91 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Neuropsychological and imaging studies indicate that attention deficit hyperactivity disorder (ADHD) is associated with alterations in prefrontal cortex (PFC) and its connections to striatum and cerebellum. Research in animals, in combination with observations of patients with cortical lesions, has shown that the PFC is critical for the regulation of behavior, attention, and affect using representational knowledge. The PFC is important for sustaining attention over a delay, inhibiting distraction, and dividing attention, while more posterior cortical areas are essential for perception and the allocation of attentional resources. The PFC in the right hemisphere is especially important for behavioral inhibition. Lesions to the PFC produce a profile of distractibility, forgetfulness, impulsivity, poor planning, and locomotor hyperactivity. The PFC is very sensitive to its neurochemical environment, and either too little (drowsiness) or too much (stress) catecholamine release in PFC weakens cognitive control of behavior and attention. Recent electrophysiological studies in animals suggest that norepinephrine enhances "signals" through postsynaptic alpha2A adrenoceptors in PFC, while dopamine decreases "noise" through modest levels of D1 receptor stimulation. alpha2A-Adrenoceptor stimulation strengthens the functional connectivity of PFC networks, while blockade of alpha2 receptors in the monkey PFC recreates the symptoms of ADHD, resulting in impaired working memory, increased impulsivity, and locomotor hyperactivity. Genetic alterations in catecholamine pathways may contribute to dysregulation of PFC circuits in this disorder. Medications may have many of their therapeutic effects by optimizing stimulation of alpha2A adrenoceptors and D1 receptors in the PFC, thus strengthening PFC regulation of behavior and attention.Annals of the New York Academy of Sciences 02/2008; 1129:236-45. · 4.38 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Carriers of the short allele of a functional 5' promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.Nature Neuroscience 07/2005; 8(6):828-34. · 15.25 Impact Factor
Modulatory Effects of Modafinil on Neural Circuits Regulating
Emotion and Cognition
Roberta Rasetti1,2, Venkata S Mattay1,2, Beth Stankevich1, Kelsey Skjei1, Giuseppe Blasi1,3,
Fabio Sambataro1,4, Isabel C Arrillaga-Romany1, Terry E Goldberg1,5, Joseph H Callicott1, Jose ´ A Apud1
and Daniel R Weinberger*,1
1Clinical Brain Disorders Branch: Genes, Cognition, and Psychosis Program, NIMH, NIH, Bethesda, MD, USA
Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional
neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but
cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of
modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-
blinded placebo-controlled trial (100mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-
processing task that activates the amygdala and two prefrontally dependent cognitive tasksFa working memory (WM) task and a
variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton
anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed
significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive
cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not
statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as
decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances
the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala,
a brain region implicated in anxiety.
Neuropsychopharmacology (2010) 35, 2101–2109; doi:10.1038/npp.2010.83; published online 16 June 2010
Keywords: modafinil; fMRI; emotion; amygdala; cognitive processing; healthy volunteers
Psychostimulants and other putative arousal-enhancing
drugs have a wide range of potential treatment targets in
neuropsychiatry including cognitive dysfunction, which is a
core feature of a broad range of neuropsychiatric disorders.
Of the different arousal-enhancing agents currently avail-
able, modafinil is gaining increasing popularity because of
its relatively lower liability to abuse (Deroche-Gamonet
et al, 2002) and a lower risk of adverse effects on the
cardiovascular system (Makris et al, 2004; Jr et al, 2009).
Converging evidence from studies in animal models and in
humans suggests that the different behavioral effects
induced by modafinil compared with traditional psychos-
timulants are due to differences in structure and neuro-
chemical profile. Evidence indicates that modafinil directly
binds and inhibits both the dopamine transporter (DAT)
and norepinephrine transporter (NET) with modest potency
leading to significant but relatively small elevations in
extracellular dopamine (DA) and norepinephrine (NE)
levels (Madras et al, 2006). Modafinil administration has
also been shown to decrease g-aminobutyric acid (GABA)
levels and elevate levels of serotonin (5HT), glutamate,
orexin, and histamine, possibly secondary to catecholamine
effects (Minzenberg and Carter, 2008; Qu et al, 2008).
Although there has been considerable effort to define the
effects of modafinil as a cognitive enhancer (Minzenberg
and Carter, 2008; Wesensten, 2006), its effect at the level of
limbic system function and on the information processing
underlying emotion regulation has been relatively unex-
amined. This is an important issue of clinical relevance as
other cognitive enhancers such as amphetamine have been
shown to have a pronounced effect on emotional behavior,
Received 25 February 2010; revised 15 April 2010; accepted 1 May
*Correspondence: Dr DR Weinberger, Genes, Cognition and Psychosis
Program, IRP, NIMH, NIH, Rm. 4S-235, 10 Center DriveFBethesda,
MD 20892, USA, Tel: +301 402 7564, Fax: 301 480 7795,
2These authors contributed equally to this work.
3Current address: Department of Neurological and Psychiatric
Sciences, Psychiatric Neuroscience Group, University of Bari, Bari, Italy
4Current address: Brain Center of Motor and Social Cognition, Italian
Institute of Technology, Parma, Italy
5Current address: Long Island Jewish Medical Center, The Zucker
Hillside Hospital, Glen Oaks, New York, USA
Neuropsychopharmacology (2010) 35, 2101–2109
& 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00
including the generation of fear and anxiety (Angrist and
Gershon, 1970; Ellinwood et al, 1973; Hall et al, 1988) along
with exaggerated amygdala reactivity during the perceptual
processing of angry and fearful facial expressions (Hariri
et al, 2002). Data from animal studies have shown either no
effects of modafinil on anxiety scales (Hermant et al, 1991;
Simon et al, 1994) or an anxiolytic effect (van Vliet et al,
2006). Results from studies conducted on humans are less
consistent; some studies show either an anxiolytic effect
(Becker et al, 2004), or no effect on anxiety ratings (Saletu
et al, 2007; Samuels et al, 2006), while others report an
anxiogenic effect (Broughton et al, 1997; MacDonald et al,
2002; Schwartz et al, 2003; Taneja et al, 2007; Zifko et al,
2002). However, all these studies vary in doses used
(100mg, 200mg, or 400mg) and in the dosing schedule
(one time vs chronic dosing over a week or more), which
may account for the discrepancy in results. This possibility
is consistent with evidence that shows that repeated
administration of modafinil in monkeys results in a
decrease in motor hyperactivity observed after single-dose
administration (Hermant et al, 1991).
In this study, we examined the effect of chronic low-dose
modafinil (100mg/day for 1 week) on both emotion
information-processing as well as cognitive information-
processing circuits in a sample of healthy non-sleep-
deprived volunteers. Subjects were assessed with fMRI
while they performed an emotion information-processing
task that has previously been shown to reliably activate the
limbic circuit including the amygdala (Hariri et al, 2002),
and two prefrontally dependent cognitive tasks well known
to engage the prefrontal cortex (PFC) (Callicott et al, 2003)
and anterior cingulate (Blasi et al, 2005). On the basis of
previous evidence for decreased anxiety (Provigil website
with improved cognition on modafinil, we hypothesized
that this would be reflected at the level of neurobiology
either as no change in amygdala reactivity or as decreased
amygdala reactivity on modafinil during the emotion-
processing task while coincidentally, modafinil would
improve cortical efficiency during cognitive information
processing. Improved cortical efficiency can be defined as
engaging less cortical activity or more focused cortical
activity on modafinil for a similar level of task performance
as during the placebo session. Controlling for task
performance across diagnosis, genotype groups, drug
conditions, and so on, is an approach that has been reliably
used in a number of studies to circumvent the confound
associated with performance related differences in neural
activity (Tan et al, 2007). Improved efficiency during
executive cognitive processing has been reported to be a
characteristic effect of other psychostimulant drugs (eg,
Mattay et al, 2003).
MATERIALS AND METHODS
A randomized, double-blind, placebo-controlled, crossover
design was used to study 38 healthy control subjects who
were recruited from local and national resources as
volunteers for the ‘CBDB/NIMH Sibling Study’ (Table 1a).
Written informed consent was obtained from the subjects
after complete description of the study, to be part of the
drug protocol (# 03-M-0143) approved by the National
Institute of Mental Health Institutional Review Board for
administration of oral modafinil. All participants underwent
a structured clinical interview to rule out an active axis I
or axis II diagnosis (DSM-IV) (APA, 1994) that could
potentially bias the results. Exclusion criteria are reported
in Supplementary Materials and Methods. Four subjects did
not complete the second arm of the study. Several other
subjectsFvarying according to the taskFwere excluded
because of excessive movement or technical problems
during either the drug or placebo sessions. The fMRI
analysis, therefore, was limited to data from subjects with
fMRI data from both days that passed a rigorous quality
control check (all fMRI data were individually examined for
motion artifacts and we excluded from further analysis data
from subjects with excessive inter-scan motion: 42mm
translation, 41.51 rotation on either the placebo or drug
session). This resulted in 19 subjects with usable BOLD
fMRI data for the face-matching task (FMT), 23 subjects
with usable data during the 2-back task, and 11 subjects
with usable data for the variable attentional control (VAC)
task on both days (the VAC task was added to the protocol
half-way through the study) (Table 1b). Paired t-tests
between placebo and modafinil sessions showed no
significant difference in the inter-scan movement para-
meters (mean and max values all p40.1) and the signal-to-
noise ratio values for the fMRI time series images (all
p40.5) for each of the three tasks. There were no
differences in behavioral measures as evaluated by Hamilton
Table 1a Study Population
Years of educationa, years±SD
20 Females, 18 males
aIQ and years of education available for 37 subjects.
Table 1b Subjects with Usable Data for fMRI Analyses
Task FMT2-BACK VACa
N 19 2311
First arm placebo 11145
First arm modafinil896
Abbreviations: F/M, females/males; FMT, face-matching task; VAC, variable
attentional control task.
aThe VAC task was added to the protocol half-way through the study, as a result
of which the number of subjects with usable imaging data on this task is lower
when compared with the 2-back and the FMT.
bData available for 18 subjects.
cData available for 22 subjects.
dData available for 10 subjects.
Modafinil modulates emotion and cognition circuits
R Rasetti et al
anxiety scale (HAM-A) (Hamilton, 1959) and the profile of
mood state (POMS) questionnaire (McNair et al, 1992)
between the subjects included in the three fMRI analyses
and the subjects excluded (all p40.07).
A table of random numbers was used to prepare the
randomization. Both modafinil and placebo were coded.
Coded modafinil (100mg once daily) was administered
orally every morning for 7 days. After a 1-week wash out
period following the first arm, subjects who had received
coded modafinil during the first arm received coded
placebo, while those who started on coded placebo during
the first arm received 100mg of coded modafinil. The order
of drug for each task is reported in Table 1b. The capsules of
modafinil and placebo were identical in appearance (pink
color) and taste. Side effects were minimal or absent at the
dose used and no subject discontinued the protocol because
of side effects.
Functional assessment was performed on days 7 and 21.
fMRI was started E180min after drug administration
(placebo or modafinil), and completed within 4h after
administration. Timing of testing was based on pharmaco-
kinetic data indicating that plasma levels of modafinil peak
2–4h after oral administration (Robertson and Hellriegel,
2003). Three hours after drug administration, just before the
scan, a blood sample was obtained for serum modafinil
levels (measured at Cephalon Inc., Frazer, PA, using high-
performance liquid chromatographyFGorman, 2002). A
clinical assessment including blood pressure and heart rate
was performed before the scan. Each subject also completed
the HAM-A scale and the POMS questionnaire to determine
mood, anxiety, and energy on each test day.
Tasks and Data Acquisition
The FMT, the 2-back task, and the VAC task have been
described previously (Blasi et al, 2005; Callicott et al, 2003;
Hariri et al, 2002).
Face-matching task. The blocked fMRI paradigm consists
of two experimental conditions, an emotional face-matching
condition and a sensorimotor control task. The task
consisted of five blocks of 30-s duration each. Blocks 1, 3,
and 5 were sensorimotor blocks and blocks 2 and 4 were
emotion blocks. Each block of either type consisted of six
trials, each of 5-s duration. Each trial consisted of the
presentation of three images, two in the lower panel and one
in the upper panel. In the six trials of each sensorimotor
block, the two lower images were of shapes, and the upper
panel image was identical to one of the shapes in the lower
panel. Subjects responded with button presses (left or right)
to indicate which of the two lower panel images matched the
upper panel image. In the six trials of each emotion block,
the lower panel consisted of two faces, one angry and one
fearful, derived from a standard set of pictures of facial
affect (Ekman and Friesen, 1976). The upper panel
consisted of one of the two faces shown in the lower panel.
Subject responded with button presses (left or right) to
indicate which lower panel face matched the face in the
2-Back task. The 2-back task consisted of presentation of
visual stimuli in which a series of numbers (1–4) were
presented randomly every 2000ms for 500ms at set
locations at the points of a diamond-shaped box. Subjects
were asked to encode the currently observed number and
simultaneously recall the number observed two times
previously, and respond through a MRI compatible button
box, which had four buttons arranged in the same
configuration as the stimuli presented on the screen. The
task was presented as four blocks of control condition
(0-back) alternating with four blocks of the 2-back condition.
VAC task. Each stimulus was composed of arrows of three
different sizes pointing either to the right or to the left.
Subjects were instructed by a cue word (BIG, MEDIUM, or
SMALL) showed above each stimulus to press the right or
left button corresponding to the direction of the large,
medium, or small arrows. There were three different levels
of attentional control: (1) low level of attentional control
(LOW): all three sizes of arrows were congruent in direction
with each other, and the stimuli were cued with the word
BIG. (2) Intermediate level (INT): the big arrow was
incongruent in direction to the small and the medium
arrows; the cue was either BIG or SMALL. (3) High level
(HIGH): the medium-sized arrows were incongruent in
direction to the big and the small arrows; the cue was either
SMALL or MEDIUM. In addition, a simple bold arrow
pointing to either the left or right was used as a
sensorimotor control condition of no conflict.
Each stimulus was presented for 800ms, and the order of
the stimuli was randomly distributed across the session
(Friston et al, 1999). The total number of stimuli was 241: 50
HIGH, 68 INT, 57 LOW, and 66 simple bold arrows. A
fixation cross-hair was presented during the interstimulus
interval, which ranged from 2000 to 6000ms.
Analysis of Imaging Data
Images were processed as described (Blasi et al, 2005;
Callicott et al, 2003; Hariri et al, 2002) in SPM2
(www.fil.ion.ucl.ac.uk/spm). A complete description of the
image analysis is reported in Supplementary Materials and
All results are reported in MNI coordinates and at a
threshold of po0.05 corrected for multiple comparisons
based on family-wise error (FWE) within region of interests
(ROIs) appropriately chosen according to the task (bilateral
amygdala ROI for FMT; bilateral PFC ROIFencompassing
BAs 46 and 47- for 2-back task, and anterior cingulate
FACCFfor VAC task, defined using the Wake Forest
University PICKATLAS toolbox, version 2.0 http://www.fmri.
wfubmc.edu) (Supplementary Figure).
We analyzed amygdala/supragenual-subgenual cingulate
coupling that is hypothesized to modulate amygdala
reactivity through top–down control (Pezawas et al, 2005).
Modafinil modulates emotion and cognition circuits
R Rasetti et al
A complete description of the method used to assess
functional connectivity is reported in Supplementary
Materials and Methods.
Statistical Analysis on Clinical, Behavioral, and
Paired t-test (heart rate, FMT performances, 2-back task
performance, HAM-A, and POMS) and analysis of variance
for repeated measures (blood pressure, VAC task perfor-
mance) were performed using STATISTICA software
(Statsoft Corp., Tulska, OK). Owing to a computer glitch,
reaction time (RT) could not be collected for one subject
during one of the two sessions for the 2-back task. Similarly,
HAM-A scale and POMS questionnaire could not be
completed on one of the 2 days in five subjects, therefore
analyses were limited on data from subjects that had data
available on both days. Modafinil levels were not available
for three subjects included in 2-back and VAC task analyses
and for five subjects included in FMT analysis. Bonferroni
correction was performed for multiple testing.
Correlation Between Serum Modafinil Levels and
Behavioral and Neuroimaging Data
To examine the relationship between serum modafinil levels
and changes in behavioral measures (HAM-A scale and
POMS questionnaire) and brain activity, we performed
linear correlation analysis; Pearson’s r was used for
neuroimaging data, and a Spearman’s rho correlation
method was used for behavioral data as they did not follow
a normal distribution. For behavioral data, correlation was
carried out between serum modafinil levels and the
difference scores between placebo and modafinil conditions
on the HAM-A scale and POMS subscales.
For neuroimaging data, correlation analysis was carried
out between serum modafinil levels and the mean signal
extracted from a 10-mm radius spherical ROI around the
peak voxel obtained from the contrast looking for a main
effect of drug for each of the task conditions (amygdala for
FMT, PFC, and ACC for 2-back and VAC task; ROI created
Face-matching task. Consistent with previous evidence
(Hariri et al, 2002), perceptual processing of fearful and
angry facial expressions was associated with bilateral
amygdala activity during both placebo and modafinil
sessions (data not shown). A paired t-test analysis showed
a significant effect of drug in the right amygdala with lower
activation on modafinil when compared with placebo (peak
voxel coordinates (x,y,z)¼(26,4,?20), Z¼2.91, p¼0.04
FWE-corrected within bilateral amygdala ROI, Figure 1).
Functional connectivity analysis performed using the
right amygdala as the seed ROI revealed that there was
significantly increased negative coupling between amygdala
p¼0.05 FWE-corrected within the ROI) and significantly
decreased positive coupling between amygdala and subgenual
ACC ((x,y,z)¼(0,41,?10), Z¼2.66, p¼0.05 FWE-corrected
within the ROI) on modafinil relative to placebo.
The coupling between subgenual ACC and supragenual
ACC, positive during both the placebo and modafinil
sessions, did not show any significant difference across
drug sessions. Accuracy and RT during the FMT were
similar between placebo and modafinil sessions (all p40.2),
which suggests that the subjects were attending to the task
similarly during both placebo and modafinil sessions.
2-Back task. The spatial distribution of the activation
responses during the 2-back task included the PFC,
pericingulate cortex, anterior cingulate, and parietal cortex
bilaterally on both drug sessions, as previously described
(Callicott et al, 2003) (data not shown). A paired t-test
revealed a significant main effect of drug with greater
activation in the right PFC during placebo session
compared with the modafinil session (peak voxel coordi-
nates (x,y,z)¼(38,34,?6), Z¼3.61, P¼0.05 FWE-cor-
rected within bilateral PFC ROI) (Figure 2). No significant
PFC activation differences were observed on the reverse
changes in BOLD fMRI signal were observed in the absence
of any difference in accuracy and RT during the 2-back
working memory (WM) task (all p40.2), and therefore
reflect an improvement in prefrontal cortical efficiency on
VAC task. A significant main effect of task, that is, an effect
of increase in demand for attentional control, was found in
several regions, including the dorsolateral PFC, the anterior
cingulate, the parietal cortex, the supplementary motor
area, and the ventrolateral PFC bilaterally (data not shown),
as previously described (Blasi et al, 2005). When looking at
the effect of drug on the ‘level of attentional control’, we
observed a significant drug-effect in anterior cingulate
RIGHT AMYGDALAxyz= 26 4 -20 (a.u.)
of modafinil on amygdala reactivity during an implicit threatening stimuli-
processing task mean parameter estimates extracted from a 10-mm
radius spherical ROI created around the peak voxel in amygdala obtained
from thecontrast placebo4modafinil
(x,y,z)¼(26,4,?20), Z¼2.91, p¼0.04 FWE-corrected). Bars show the
FMT. Main effect of drug: placebo4modafinil (N¼19). Effect
(peak voxel coordinates
Modafinil modulates emotion and cognition circuits
R Rasetti et al
activation (Figure 3a). Specifically, when task load increases
from low to intermediate to the high level of attention,
subjects have higher activation in the anterior cingulate on
placebo when compared with modafinil (peak voxel
FWE-corrected within anterior cingulate ROI), in spite of
Drug?gender interaction. No significant gender?drug
interaction was found either in the behavioral data or
neuroimaging data for all three tasks.
Correlations between serum modafinil level and neuro-
imaging data. There were no significant correlations
between serum modafinil levels and brain activity changes
observed in the amygdala during the FMT, in the PFC
during the 2-back task or in the ACC during the VAC task
Clinical Variables and Drug Levels
There was no significant effect of modafinil at 100mg per
day either on heart rate or on systolic/diastolic blood
pressure (modafinil vs placebo all p40.2). Serum modafinil
level 3h after administration measured just before the
MRI session ranged from 0.2 to 3.38mg/ml (mean±
SD¼1.9±1.1mg/ml). There was a trend for significance
for reduced anxiety level (HAM-A) on modafinil (t¼1.72,
df¼32, p¼0.095). Subjects also reported decreased fatigue-
inertia (t¼2.2, df¼32, p¼0.04) and increased vigor-
activity (t¼?2.32, df¼32, p¼0.03), as well as decreased
anger-hostility (t¼2.01, df¼32, p¼0.05) on the POMS
subscales. These measures, however, did not survive
correction for multiple testing.
There was a significant positive correlation between
modafinil-induced changes in the anger-hostility subscale
and serum modafinil levels (r¼0.42, df¼23, p¼0.02) (ie,
higher modafinil levels were associated with greater
decrement in anger-hostility scores). No other significant
correlations were found between serum modafinil levels and
changes in other POMS subscales or anxiety levels
measured with HAM-A scale (all p40.05).
Our findings show that modafinil in low doses has a
seemingly unique profile of effects on cognitive and
emotion-processing circuitry in the brain, in contrast to
other psychostimulants such as amphetamine. Although
amphetamine at low doses tends to increase amygdala
reactivity (Hariri et al, 2002), consistent with its anxiogenic
effects (Angrist and Gershon, 1970; Ellinwood et al, 1973;
Hall et al, 1988), modafinil, in contrast, reduces amygdala
response to emotionally salient stimuli. Although not
RIGHTPFCxyz= 38 34 -6 (a.u.)
Effect of modafinil on PFC activation during a WM task mean parameter
estimates extracted from a 10-mm radius spherical ROI created around
the peak voxel in PFC obtained from the contrast placebo4modafinil
(peak voxel coordinates (x,y,z)¼(38,34,?6), Z¼3.61, p¼0.05 FWE-
corrected). Bars show the mean.
2-Back task. Main effect of drug: placebo4modafinil (N¼23).
% Correct Responses
Reaction Time (msec)
(a) group statistical parametric maps illustrating a significant effect of modafinil in decreasing anterior cingulate activation when task load increases from low
to intermediate to high level of attention when compared with placebo session. For illustrative purpose, map thresholded at p¼0.01 uncorrected k43;
(b) behavioral data (mean ±95% confidence intervals). Accuracy: there was a significant main effect of increasing demand for attentional control
(F(2,20)¼11, po0.001), with subjects performing worse on the high demand condition relative to the intermediate and low demand conditions, both
during placebo and modafinil session (b left). There was no significant main effect of drug or drug ? condition interaction (all p40.4). RT: there was
a significant main effect of increasing demand for attentional control on RT during both placebo and modafinil sessions (F(2,20)¼96.9, po0.001), with
a statistically significant difference across all three levels of demand for attentional control (post hoc analyses using Fisher’s least significant difference: all
po0.01). Although a decrease in RT was observed during modafinil at all three levels of demand (b right), the main effect of drug on RT as well as the drug
? attentional load interaction were not statistically significant (all p40.1).
VAC task: effect of modafinil on anterior cingulate activation during an attentional control task and behavioral data. Drug effect in the VAC task:
Modafinil modulates emotion and cognition circuits
R Rasetti et al
statistically significant, it should be noted that modafinil
showed a trend toward significance for reduced anxiety
level and hostility, along with an improvement in the
subjective energy state. With respect to the effect of
modafinil on the PFC during cognitive processing, its
effects are similar to amphetamine, with a decrease in PFC
activation occurring without a change in performance
(Mattay et al, 2003). We will discuss these neuroimaging
findings as they relate to the modulatory effects of modafinil
on the neurophysiological response during emotional
information processing and executive cognition.
Modulatory Effect of Modafinil on the Emotional
Our results show that modafinil decreases amygdala
reactivity to fearful stimuli. These findings are in contrast
to other cognition-enhancing psychostimulants. Ampheta-
mine, for example, has a pronounced effect on emotional
behavior, including the generation of fear and anxiety
(Angrist and Gershon, 1970; Ellinwood et al, 1973; Hall et al,
1988). Moreover, using the FMT, Hariri et al (2002) had
previously shown exaggerated amygdala reactivity during
the perceptual processing of angry and fearful facial
expressions with low-dose amphetamine. In addition to
our observation that modafinil induces a diminished
amygdala response during the same circumstances, we also
found increased negative coupling between the supragenual
cingulate and amygdala on modafinil on a functional
Although the molecular mechanisms underlying the effect
of modafinil on amygdala reactivity is not clear, the increase
in negative functional coupling between the supragenual
cingulate and the amygdala suggests that top–down control
mechanisms may be responsible at the neural systems level
for the effects of modafinil in dampening amygdala
reactivity and the reduced amygdala reactivity could
consequently induce the reduction in its positive coupling
with the subgenual ACC. However, because functional
connectivity does not give any information regarding
directionality, further studies are necessary to confirm this
hypothesis. Alternately, as the amygdala is rich in
catecholaminergic and serotoninergic projections, it is
likely that the decreased amygdalar reactivity on modafinil
may be due to alterations in intra-amygdalar signaling
resulting from alterations in levels of NE, DA, serotonin, or
GABA or from a combination of these effects. As reduction
of amygdala reactivityFas observed in our studyFhas
previously been reported after the administration of drugs
that act on noradrenergic system as well as with drugs that
act on 5HT system (see, eg, reboxetine on noradrenergic
system, Norbury et al, 2007; citalopram on serotonergic
system, Harmer et al, 2006), and because modafinil acts on
both these systems as well as on many other neurotrans-
mitter pathways, it is difficult to define the specific
mechanism through which modafinil modulates amygdala
activity. It is likely that the more complex action of
modafinil on different neurotransmitter pathways com-
pared with amphetamine may be responsible for the
differing effect on amygdala reactivity reported with these
two different psychostimulant drugs. Further studies are
warranted to identify which neurotransmitter systems
and interactions that modafinil acts on to modulate
Modulatory Effects of Modafinil on the
Neurophysiological Response During Executive
Our results show that during the WM and VAC tasks,
modafinil decreased BOLD signal in the PFC and ACC,
respectively, when compared with placebo, for the same
level of task performance. This phenomenon may reflect an
improvement in the efficiency of information processing in
these regions that are richly innervated by catecholaminer-
gic neurons and is similar to the results of numerous
neuroimaging studies in the literature involving catechola-
minergic effects (eg, Apud et al, 2007; Cools et al, 2002;
Cools and Robbins, 2004; Gibbs and D’Esposito, 2005, 2006;
Mattay et al, 2002, 2003; Mehta et al, 2000).
The results on WM are consistent with those reported by
Thomas and Kwong (2006) in healthy volunteers without
sleep deprivation, albeit after a single 200mg dose of
modafinil. Furthermore, most functional neuroimaging
studies have shown an improvement in information
processing, within the PFC after modafinil administration.
This has been shown in narcolepsy (Saletu et al, 2007), in
schizophrenia (Hunter et al, 2006; Spence et al, 2005), and
in normal volunteers without sleep deprivation (Minzen-
berg et al, 2008). Although the nature of the block-design of
the 2-back task does not allow the identification of the exact
cognitive subprocesses modulated by modafinil (encoding,
maintenance, retrieval, or updating), the use of the same
paradigm as in previous drug studies permits a comparison
of the effect of modafinil with other cognitive-enhancing
agents, such as amphetamine and tolcapone, albeit in
different participants (Mattay et al, 2003; Apud et al, 2007).
Nevertheless, further studies using event-related WM
paradigms are necessary to clarify which subprocesses are
modulated by the drug. Our results are also in accordance
with animal and human behavioral data that showed an
improvement with modafinil in performance in several
domains of cognition including WM, recognition memory,
sustained attention, and cognitive control (Minzenberg and
Carter, 2008; Turner et al, 2003; Winder-Rhodes et al, 2010,
The improvement in efficiency of information processing
in the ACC during the VAC task are analogous to the results
of Blasi et al (2005) who showed an effect of the val158met
functional polymorphism in the catechol-o-methyl transfer-
ase (COMT) gene, a gene known to modulate cortical DA
levels. They showed that individuals homozygous for the
met allele and putatively higher cortical DA levels had a
more efficient response with decreased activity in the ACC
during the VAC task when compared with the other two
groups, val/val and val/met.
Although the molecular effects of modafinil are generally
regarded to be nonspecific, recent studies showed that
modafinil potentiates both NE and DA transmission
through the inhibition of DAT (Volkow et al, 2009) and
NET (Minzenberg and Carter, 2008). Therefore, it is likely
that the neurophysiologic effects of modafinil on the PFC
and ACC, both of which are rich in catecholaminergic
projections, during executive cognition are most likely
Modafinil modulates emotion and cognition circuits
R Rasetti et al
driven by DA, NE, or both. Converging evidence shows that
monoamines including DA and NE improve the neurophy-
siological signal to noise ratio. Recent animal studies
suggest that NE enhances ‘signals’ through postsynaptic
2A adrenoceptors on PFC dendritic spines, whereas DA
decreases ‘noise’ through modest levels of D1 receptor
stimulation (Brennan and Arnsten, 2008).
The effects of these molecular processes at the neural
system level have also consistently been shown through
functional neuroimaging studies. Medications that mod-
ulate DA and NE system and enhance catecholamine
transmission have been shown to increase efficiency of
information processing in PFC circuits (Apud et al, 2007;
Cools and Robbins, 2004). Taken together with this
previous converging evidence from molecular, behavioral,
and neuroimaging studies, the improvement in PFC and
ACC information processing induced by modafinil that we
observed during executive cognition, is most likely
mediated by the potentiating effects of either or both DA
and NE transmission through the inhibition of DAT
Some limitations of the study need to be acknowledged.
Although the exclusion of data sets based on our rigorous
assessment of image quality resulted in a smaller sample
than what we started with, we believe this step is critical to
ensure comparable image signal and noise characteristics
across drug conditions. Moreover, in our study, we found
a significant effect that survived correction for multiple
comparisons of modafinil during different task paradigms
in spite of reducing the sample size. It should also be noted
that the final sample size in our study is comparable to the
sample sizes of other modafinil neuroimaging studies in the
literature (Hunter et al, 2006; Minzenberg et al, 2008; Saletu
et al, 2007; Spence et al, 2005; Thomas and Kwong, 2006).
Another potential limitation is that this study did not
examine dose-response effects. The absence of any effect of
modafinil on performance during the 2-back WM task and
VAC task as well its weak effects on behavioral mood scales
can most likely be explained by the relatively low dose
(100mg per day) that we used in a small sample of carefully
screened healthy volunteers. These results, therefore, cannot
be extended to the generally prescribed therapeutic dose
(200mg per day) of modafinil. A within-subject dose-
response curve study in a larger sample is warranted to
further examine this. However, it should be noted that a low
dose of 100mg in our study that did not effect cognitive
performance seemed ideal for our imaging purposes,
because matching for performance across drug conditions
in fMRI studies is conditio sine qua non to ensure that the
observed drug-induced regional BOLD signal difference
during the cognitive paradigms was not confounded by a
difference in task performance. In addition, while it is not
clear if modafinil has a direct effect on vascular reactivity, it
is unlikely that our results can be due to such an effect
particularly because it would be more global and not
explain the task and region-specific effects that we
observed. These limitations, together with the potential
abuse liability of modafinil at higher therapeutic doses
(Volkow et al, 2009), suggest that our results should not be
interpreted as a positive endorsement of modafinil as a
cognition or mood enhancer. Moreover, the exact mechan-
ism of modafinil effect on amygdala activity cannot be
explained with our fMRI data. Further studies to investigate
the direct comparison of modafinil with other drugs acting
on the circuit underlying anxiety (such as amphetamine,
nicotine, benzodiazepines) may be useful to elucidate the
neurotransmitter systems implicated in modafinil effects on
Notwithstanding some limitations, to our knowledge, this
is the first in vivo demonstration in humans of multiple
effects of modafinil. Most importantly, modafinil in low
doses in the absence of any changes in blood pressure or
heart rate, while improving the efficiency of cognitive
information processing also seems to dampen reactivity
of the amygdala, a brain region implicated in anxiety, to
threatening stimuli. The latter may confer an advantage to
modafinil over other cognition-enhancing psychostimu-
lants, such as amphetamine, which tend to be anxiogenic
with increased liability to abuse and risk of adverse effects
on the cardiovascular system.
This research was supported by the Intramural Research
Program of the National Institute of Mental Health,
National Institutes of Health. We thank Saumitra Das,
MA, Guilna Alce, BS, Ajay Premkumar, Alan Lazerow, BA,
and Natkai Akbar, BS, for their invaluable research
assistance. We thank Steven H Gorman, BS, and Alexander
Kogan, BS, Cephalon, Inc., for information related to
measurement of plasma modafinil levels, and Cephalon,
Inc., for the measurement of plasma modafinil levels.
Dr TE Goldberg is consultant for MERK and GSK. All other
authors declare no conflict of interest.
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Modafinil modulates emotion and cognition circuits
R Rasetti et al