on human brain circuits involved in reward and emotion has been explored only sparingly. We administered alcohol intravenously to
social drinkers while brain response to visual threatening and nonthreatening facial stimuli was measured using functional magnetic
limbic regions. Self-ratings of intoxication correlated with striatal activation, suggesting that activation in this area may contribute to
subjective experience of pleasure and reward during intoxication. These results show that the acute pharmacological rewarding and
common lifestyle-related cause of death in the United States
(Mokdad et al., 2004). People like to drink alcohol because of its
ability to alter emotional states. Alcohol induces euphoria, relax-
ation, and disinhibition while reducing stress and anxiety. Con-
sistent with human self-report, animal studies also suggest that
et al., 1990; Blanchard et al., 1993; Spanagel et al., 1995; Da Silva
et al., 2005). Although its euphoric and stress-reducing effects
have been known for centuries and are intuitively understood,
how alcohol changes the function of human brain circuits has
been explored only sparingly.
Where might alcohol recruit circuitry that regulates positive
affect leading to euphoria? A critical area of interest is the ventral
striatum (VS), which is recruited by reward-predictive stimuli
(Knutson et al., 2001; Bjork et al., 2004). A variety of primary
rewards activate this circuit, including fruit juice and water
(Berns et al., 2001; O’Doherty et al., 2002; Pagnoni et al., 2002;
McClure et al., 2003), as well as secondary rewards such as praise
and money (for review, see Knutson and Cooper, 2005). Simi-
larly, functional magnetic resonance imaging (fMRI) studies
have shown striatal activation in response to drugs of abuse such
as cocaine (Breiter et al., 1997) and nicotine (Stein et al., 1998).
Although there have not yet been fMRI studies of the action of
studies demonstrate increased striatal glucose metabolism or
blood flow in response to alcohol (Wang et al., 2000; Boileau et
al., 2003; Schreckenberger et al., 2004). Accordingly, the meso-
maintenance of addiction (Koob et al., 1998).
disruption of threat detection circuitry. The amygdala in partic-
stimuli that signal the requirement for an immediate behavioral
response, such as fight or flight (LeDoux, 2003; Fitzgerald et al.,
2006). Alcohol intoxication increases the incidence of aggression
and social risk taking (Giancola and Zeichner, 1997; Corbin and
Fromme, 2002; Giancola et al., 2002), perhaps by disrupting the
amygdala-mediated differentiation between threatening and
nonthreatening stimuli. Decreased differential response may in-
crease approach while decreasing avoidance, thus facilitating
The current study was designed to characterize the re-
sponse of the brain to alcohol intoxication and emotional
stimuli, and is the first fMRI study to examine acute pharma-
cological effects of alcohol on the neural circuitry underlying
emotion. This study extends previous research by (1) using
intravenous alcohol to minimize individual variability in al-
cohol pharmacokinetics and to maintain a steady-state of
brain alcohol exposure, (2) using fMRI to measure the blood
oxygenation level-dependent (BOLD) signal during alcohol
administration, (3) presenting emotional facial stimuli, which
allows the use of a general linear model (GLM) to examine
main effects for alcohol and emotional cues as well as their
interaction, and (4) collecting subjective measures of intoxi-
cation to correlate with BOLD signal.
This work was supported by the National Institutes of Health, Division of Intramural Clinical and Biological
TheJournalofNeuroscience,April30,2008 • 28(18):4583–4591 • 4583
healthy social drinkers (seven women) partici-
complete medical and psychiatric evaluation,
including clinical laboratory, radiological, and
electrocardiogram examinations. Participants
were excluded from the study if they had an
abnormal physical exam or had laboratory val-
ues outside of normal ranges. Participants were
given the Structured Clinical Interview for the
orders, 4th edition (DSM-IV) and were ex-
cluded if they met criteria for alcohol or other
substance dependency (excluding nicotine) at
a current axis-I psychiatric disorder. Partici-
pants were also excluded if they had never con-
sumed at least two standard drinks of alcohol
within 1 h, or if they reported to have a “facial
flushing” response to the consumption of alco-
hol. They drank an average of 1.9 d per week
ing day (SD, 1.2).
Participants were all right handed (average
age, 26.5 years; SD, 5.6) and none had ever had
a head injury requiring hospitalization. They
prescribed, or over-the-counter medications in
the 14 d period before the study visits. Addi-
tionally, participants were asked to abstain
from alcohol for at least 3 d before each study visit. A urine sample was
obtained from each participant during each study visit for a urine drug
screen and for a pregnancy test in females.
Alcohol infusion procedure. Alcohol was infused as a 6% (v/v) solution
in saline. The infusion rates were based on a physiologically based phar-
macokinetic model for alcohol (Ramchandani et al., 1999), consisting of
an exponentially increasing infusion rate from the start of the infusion
until the target breath alcohol concentration (BrAC) of 0.08 g% was
reached at 15 min, followed by an exponentially decreasing infusion rate
to maintain (or “clamp”) the BrAC at the target level. This infusion-rate
profile was computed using individualized estimates of the model pa-
rameters, which are based on the participant’s height, weight, age, and
sex. This method has been used successfully in several studies of the
pharmacokinetics and pharmacological effects of alcohol in humans
(Kwo et al., 1998; Ramchandani et al., 1999, 2001, 2002; Blekher et al.,
2002; Morzorati et al., 2002).
Experimental design. This study consisted of three infusion sessions
given on separate days, separated by at least 3 d. On each study session,
Day Hospital where BrAC levels were measured and a urine drug screen
and, in women, a urine pregnancy test were performed. An intravenous
catheter was inserted in each forearm; one was used for the infusion of
alcohol or saline and the other for the collection of blood samples.
ical Center Day Hospital. Participants received an alcohol infusion over
45 min, to ensure that they tolerated the alcohol infusion without expe-
riencing nausea or marked sedation, before undergoing the infusions in
the fMRI scanner during the second and third sessions. Serial breatha-
lyzer measurements were obtained every 3–5 min from the start of the
infusion using the Alcotest 7410 handheld breathalyzer (Drager Safety
the target and to enable minor adjustments to the infusion rates to over-
chandani et al., 1999; O’Connor et al., 2000). Subjective response to
alcohol was measured using the Biphasic Alcohol Effects Scale (BAES)
(Martin et al., 1993) and the modified Drug Effects Questionnaire
(DEQ), (de Wit and McCracken, 1990), which were given before the
beginning of the infusion and every 10–15 min during the infusion.
using the Positive and Negative Affect Scale (PANAS) (Watson et al.,
1988). Blood samples (6 ml) were collected at three time points: before
the start of the infusion, and at 15 and 45 min after the start of the
infusion. After the infusion was completed, BrAC measurements were
taken every 30 min. Participants were sent home in a taxi cab when their
BrAC dropped to ?0.02 g%.
On the second and third study sessions, participants received the in-
fusions in the scanner. One of these infusions was saline (placebo) and
one was alcohol, given in a double-blind, randomized order during ses-
ipants were placed in the scanner. A nurse was present in the scanning
room throughout the infusion.
Structural scans were acquired as the infusion began. Target blood
emotional images were presented at 25 min as functional scans were
images, but no response was required. Blood samples (6 ml) were col-
the start of the infusion, and at 45 min, when the infusion ended. The
DEQ was given at baseline, and before and after the set of images. Par-
ticipants also completed the PANAS before and after the scan. The total
duration of the infusion was 45 min, after which participants were es-
corted from the scanner and immediately given a breathalyzer test. They
were then transported to the clinical unit, where BrAC measurements
were taken every 30 min. Participants were sent home in a taxi cab when
their BrAC dropped to ?0.02 g%.
Stimuli. Visual images from a series of standardized emotional facial
expression (EFE) images (Matsumoto, 1988) were used in this study.
Forty-five neutral and 45 fearful faces, as well as a nonemotional control
crosshair condition that served as the interstimulus interval, were pre-
All stimuli were presented using a Linux laptop computer with in-house
stimulus delivery software. They were projected using an Epson (Long
4584 • J.Neurosci.,April30,2008 • 28(18):4583–4591Gilmanetal.•AlcoholandEmotion
MRI scanner bed and were viewed using a mirror mounted on the
fMRI acquisition. Imaging was performed using a 3T General Electric
(Milwaukee, WI) MRI scanner with a 16-channel head coil. Thirty con-
tiguous 5.0-mm-thick axial slices were acquired (in-plane resolution,
3.75 ? 3.75 mm), providing whole-brain coverage including subcortical
regions of interest such as the nucleus accumbens (NAcc), as well as the
OFC (orbitofrontal cortex), together with limbic areas (amygdala), an-
terior cingulate and the paralimbic areas and thalamus. Whole-brain
high-resolution coronal structural scans were collected using a T1-
weighted magnetization-prepared rapid gradient echo pulse sequence,
size, 0.859 ? 0.859 ? 1.2 mm; matrix 256 ? 256 ? 124; repetition time
(TR), 100 ms; echo time (TE), 12 ms; field of view (FOV), 24 cm].
Functional scans were acquired using a T2*-sensitive echoplanar se-
quence that measure changes in BOLD contrast (210 volumes; TR, 2 s;
cm; slice thickness, 5 mm. BOLD images were collected during the pre-
sentation of the stimuli. Because of the short duration of the run, we did
not do any bandpass filtering or detrending of the data.
fMRI analysis. Analyses focused on changes in BOLD signal contrast
(hereafter, activation) that occurred as the participants viewed the im-
ages after alcohol or placebo administration.
Analyses were conducted using Analysis of
Functional Neuroimages software (Cox, 1996).
Echo-planar image volumes were preprocessed
as follows: (1) voxel time series were interpo-
tion and the most inferior slice as a reference).
dimensional space. Motion-correction esti-
mates indicated that no participant’s head
moved ?1.0 mm in any dimension from one
volume acquisition to the next. We imposed a 6
mm full-width half-maximum smoothing ker-
so that all of the background values outside of
the brain were set to zero. This allowed the cal-
culation of the percentage signal change in each
voxel. Statistical maps were generated for each
individual separately by linear contrasts be-
tween the regressors of interest. The regressors
were then analyzed by multiple regression,
the orthogonal regressors of interest and six re-
after volume registration. Regressors of interest
were convolved with a gamma-variate function
that modeled a prototypical hemodynamic re-
sponse before inclusion in the regression model
(Cohen, 1997). Idealized signal time courses
were time-locked to image onset.
Anatomical maps of t statistics were spatially
normalized by warping to Talairach space (Ta-
a group map. Next, a statistical map of the main
effects of alcohol and facial emotion was com-
event-related ? coefficients calculated from the
sion model). In this three-factor mixed-model
ANOVA, drug (alcohol or placebo) and emo-
tion (fearful or neutral) were fixed factors, and
subject was a random factor. Linear contrasts
placebo conditions (alcohol: fearful vs neutral; and placebo: fearful vs
neutral), as well as separately for each emotion type (neutral: alcohol vs
placebo; and fearful: alcohol vs placebo) by performing voxelwise t tests
ing ANOVA results, a familywise error-rate correction (using a Monte
Carlo simulation) was applied to rule out false positives. When comput-
ing familywise error-rate correction, statistical maps were resampled
back into original voxel size. Clusters larger than five voxels at an indi-
vidual voxel threshold level of p ? 0.001 were considered significant. t
ment of actual BOLD signal changes in volumes of interest.
Regions that have been implicated previously in either brain reward
circuits (NAcc, putamen, and caudate) or emotional–visual circuits
(amygdala, fusiform gyrus, and lingual gyrus) were characterized with
volume-of-interest (VOI) analyses, in which time series signal data were
analyzed. The VOIs were drawn as spheres with a radius of 5 mm, which
was a small enough size to average signal data within the boundaries of
small structures such as the NAcc and caudate, which were of a priori
focus, and also allowed us to investigate the source of effects that were
driving significant activations caused by alcohol, emotional valence, or
interactions in other cortical regions post hoc. Signal data were extracted
this three-factor mixed-model ANOVA, alcohol (alcohol or placebo) and emotion (fearful or neutral) were fixed factors, and
Gilmanetal.•AlcoholandEmotionJ.Neurosci.,April30,2008 • 28(18):4583–4591 • 4585
time series, (2) the signal was averaged by stimulus type and spatially
translated into Talairach space, and (3) a mask was created consisting of
the volume of interest through which each individual participant’s data
were extracted. These data were subject to ANOVA using the percentage
signal change in each region as the dependent variable and alcohol (al-
cohol or placebo), emotion (fearful or neutral), and the interaction be-
tween them as the independent variables (package JMP-SAS; SAS Insti-
tute, Cary, NC). The p value for significance (two tailed) was set at 0.05.
In cases of significant interactions, post hoc t tests were performed to
evaluate differences between the conditions.
Correlational analysis. Coefficients of association were computed for
of intoxication, as measured by the DEQ. For these analyses, the VOI
measure was a BOLD “change score,” calculated as the average percent-
average percentage signal change to the same stimulus class during the
placebo session. A positive change score indicates that the participant
exhibited a larger response during the alcohol condition, and a negative
conducted using BOLD signal change under the neutral condition be-
cause this was the emotion type that demonstrated striatal activation.
All participants tolerated the infusion without complications.
0.070 g% (SD, 0.008). All participants reported both stimulation
and sedation effects on the BAES during this session. We saw the
expected subjective effects of alcohol on the DEQ, with signifi-
drug, and “wanting more” of the drug, compared with baseline.
Participants reported peak ratings of intoxication and feeling
high at 25 min after the start of the infusion.
During the scanning sessions, the average blood alcohol con-
centration was 0.0 g% on the placebo day, and 0.072 g% (SD,
0.009) at the end of the infusion on the alcohol day. Participants
were asked to report subjective feelings of intoxication and high
using the DEQ every 10 min during the scans. None of the par-
ticipants reported feeling any alcohol effects on the placebo day,
25 to 45 min after the start of the infusion.
Participants did not differ significantly in self-report of posi-
tive or negative affect, measured by the PANAS, between the
alcohol day, there was no change in negative or positive affect
from prescan to postscan, but on the placebo day, participants
reported a decrease in positive affect from prescan to postscan
( p ? 0.003).
To test for the main effects of the alcohol and the facial emotion
type, as well as the interaction between them, we used a GLM
neutral) were fixed factors, and subject was a random factor. We
found a significant main effect of alcohol intoxication on activa-
tion of VS across facial emotion types (Table 1, Fig. 1A). Activa-
tion was also significant in the right parahippocampal gyrus, left
precuneus, left anterior cingulate, and left superior temporal gy-
rus. Conversely, we found a significant main effect of facial emo-
tion regardless of alcohol administration in the right amygdala,
bilateral lingual gyrus, left superior temporal gyrus, right supe-
rior temporal gyrus, and right anterior cingulate (Fig. 1B). Sig-
nificant interactions between alcohol and facial emotion were
seen in the several regions, including the left insula, right lingual
gyrus, left nucleus accumbens, and bilateral middle frontal gyri
(Fig. 1C). These interactions were characterized in post hoc vol-
ume of interest analyses (see Fig. 3).
During the placebo infusion, fearful faces (in contrast with
ing greater activations to the neutral compared with fearful faces
(Table 2, Fig. 2A). In contrast, when participants were intoxi-
cated, the fearful faces did not elicit a larger response than the
neutral faces in any region.
Although we detected a main effect of alcohol intoxication in
the striatum, this effect was primarily driven by the participants’
reaction to neutral, but not fearful, stimuli. Neutral faces elicited
ventral striatum activation when subjects were intoxicated, but
not when they were sober (Fig. 2B). Fearful faces elicited in-
more ventral region than in the neutral face condition.
We characterized BOLD signal changes in VOIs that have previ-
ously been implicated in either brain reward circuits (e.g., NAcc,
putamen, and caudate) or emotional–visual circuits (e.g., amyg-
dala, fusiform gyrus, and lingual gyrus). Fearful faces elicited
dala, fusiform gyrus, and lingual gyrus (Fig. 3). Alcohol main
effects were not statistically significant in these regions (for val-
ues, see Table 3). The alcohol ? facial emotion interaction effect
RegionVolume(mm3) t-score pvalue
?19 ?15104544 5.22
4586 • J.Neurosci.,April30,2008 • 28(18):4583–4591Gilmanetal.•AlcoholandEmotion
on amygdalar BOLD signal change reached trend level signifi-
demonstrating that whereas fearful faces activated amygdala sig-
nificantly more than did neutral faces ( p ? 0.05) during placebo
in the extracted VOI data), this effect was no longer significant
( p ? 0.10) during alcohol intoxication.
there were significant main effects of alcohol in the right NAcc,
right caudate, right putamen, and left putamen, and significant
the left caudate (Fig. 3; for values, see Table 3). In these two
regions, post hoc one-way comparisons indicated significant
differences between the alcohol and the
placebo condition when participants
viewed the neutral faces, but no differ-
ences during the fearful face condition
There was a significant positive association
between subjective ratings of intoxication
and BOLD change scores in the neutral fa-
cial expression condition in the left NAcc
(r2? 0.467, p ? 0.020) and in the left cau-
that participants who reported feeling
more intoxicated showed a larger BOLD
response to alcohol in these regions (Fig.
4B). Stepwise multiple regression indi-
itive affect on BOLD activation. There was
tion ratings and BAC levels, probably as a
result of the minimal intersubject variabil-
ity in BAC using our ethanol infusion
method. We also did not find the session
order to have a significant effect in any of
This study is the first to use fMRI to mea-
sure BOLD activation during intravenous
alcohol infusion. The rapid intravenous
administration of alcohol allowed us to
achieve pharmacologically effective con-
centrations quickly, thus reducing acute
adaptation and providing a clearer picture
of the direct effects of alcohol. The results
confirmed our expectation that alcohol
would robustly activate striatal reward ar-
eas in the brain, especially the ventral stri-
atum. Activation in the left NAcc and left
in conjunction with subjective ratings of
intoxication. These findings confirm PET
data indicating increased glucose utiliza-
tion during alcohol administration in stri-
atum (Wang et al., 2000; Boileau et al.,
2003; Schreckenberger et al., 2004), and
support Koob’s (1992) hypothesis that all
drugs of abuse activate the striatum.
Despite the use of alcohol in social settings, there have been no
alcohol and emotional cues. A variety of nonimaging human
studies have attempted to experimentally alter emotional states
while administering alcohol or measuring alcohol intake (Gabel
et al., 1980; Stritzke et al., 1996; Curtin et al., 1998; Schroder and
and alcohol: fearful ? neutral), as well as linear contrasts between the fearful and neutral conditions separately under the
performing voxelwise t tests between event-related ? coefficients of each stimulus type. Radiological convention is used to
display left and right. A, Linear contrast between fearful vs neutral faces in the placebo and the alcohol condition. Increased
isshowninyellow/orange( p?0.01),whereasincreasedactivationtoplaceboisshowninblue( p?0.01).Forvalues,see
Gilmanetal.•AlcoholandEmotionJ.Neurosci.,April30,2008 • 28(18):4583–4591 • 4587
hol can have vastly different effects on
emotion depending on factors such as the
point on the blood alcohol concentration
vs time curve, the individual’s drinking
history, and the dose of alcohol consumed
(Levenson et al., 1980; Lukas et al., 1986;
Turkkan et al., 1988; Giancola and Zeich-
ner, 1997; Conrod et al., 2001; King et al.,
controlled these factors.
Our analysis found that visual and lim-
bic brain regions were sensitive to the ef-
fects of alcohol. Emotional facial expres-
sions activated higher-order visual areas
related to emotion, including lingual and
superior temporal gyri as well as the affec-
tive division of the anterior cingulate, as
has been previously reported in studies ex-
ploring the effects of emotional stimuli on
brain activation (Devinsky et al., 1995;
Phillips et al., 2003; Vuilleumier, 2005).
hanced by emotionally valenced visual
stimuli (Vuilleumier, 2005). Importantly,
the increased response to the fearful faces
that we observed in the placebo condition
was abolished in the alcohol condition.
This suggests that alcohol may have atten-
uated the increased sensitivity of the visual
system and limbic areas to emotionally
threatening stimuli, and this may in part
An alternative explanation involves the
ability of alcohol to increase activation in
dopamine terminal regions, including
amygdala, during the viewing of neutral
nal during neutral face presentation de-
creases the difference in amygdala activity
between fearful and neutral faces, making
the amygdala less able to act as a detector
of threatening stimuli. This may not only
lead to anxiolysis, but may also trigger an
increase in both approach and aggression
in some individuals.
More than a third of the volume of the
striatum was activated by alcohol across
emotional conditions. The VS, particu-
tem of the brain (Robinson and Berridge,
1993; Koob and Nestler, 1997; Everitt and
Wolf, 2002), and lesions in this brain re-
gion decrease the rewarding effects of
many drugs of abuse (Di Chiara, 2000).
The reinforcing effects of alcohol most
likely involve multiple neurotransmitter
systems, including the dopaminergic, opi-
oidergic, glutamatergic, GABAergic, and
serotonergic systems. The increase in
Region Alcohol Emotion Interaction
4588 • J.Neurosci.,April30,2008 • 28(18):4583–4591Gilmanetal.•AlcoholandEmotion
BOLD signal in the striatum may result from the increased firing
rate of dopaminergic neurons secondary to the disinhibitory ef-
glutamate-related potassium currents in the ventral tegmental
area (Pierce and Kumaresan, 2006). A recent review of animal
pharmacological MRI suggests that NAcc dopamine release in-
(Knutson and Gibbs, 2007).
Consistent with previous studies that have shown signifi-
cant intersubject variability in subjective responses to alcohol
at constant breath alcohol concentrations (Holdstock and de
Wit, 1998, 2001), we did not find a correlation between sub-
jective ratings of intoxication and actual BACs. We also did
not find a correlation between BOLD response and actual
BAC, which was not entirely unexpected given that the infu-
sion method was designed to minimize the intersubject vari-
ability in BAC exposure. We did find a significant association
between BOLD response in the NAcc and subjective percep-
tions of intoxication, suggesting that under conditions where
the BAC is held constant, the intensity of the subjective feeling
of intoxication is associated with VS activation.
In addition, our results suggest that alcohol-mediated striatal
activation can be modulated by negative
emotional stimuli. The participants’ de-
creased striatal activation when viewing
fearful faces suggests that the threatening
effects of the alcohol in the striatum, sug-
gesting that context and environment in-
fluence the intensity of activation during
This study demonstrates robust activa-
tion in response to intravenous alcohol
infusion in the VS, an area that is critical
in the acquisition and maintenance of
addictive behavior. We were able to cor-
relate striatal activation with subjective
ratings of intoxication, indicating that
the BOLD change in this area is directly
related to an individual’s subjective ex-
also modulates emotional processing in
limbic and visual regions by decreasing
the difference in activation between
threatening and nonthreatening stimuli,
which may contribute to both the anxio-
lytic properties of alcohol and to risky
decision making during intoxication.
The data also indicate an interaction be-
tween alcohol and fearful emotional
assess gender differences, future studies
should examine whether alcohol has dif-
ferent effects on emotion in men and
women, as previous research has shown
that gender does influence emotional pro-
cessing. For example, Klein et al. (2003)
found no significant differences in activa-
tion could be found between pleasant and
unpleasant stimuli in men, but significantly more activation to
unpleasant than pleasant cues in women. Furthermore, studies
can assess gender differences in mood, striatal alcohol response,
and any possible interactions between the subject’s gender and
the gender of the facial stimuli.
Future studies should also further explore the interaction be-
individuals at risk for alcoholism. Previous studies have demon-
strated differences between controls and alcohol-dependent pa-
tients (Heinz et al., 2007; Salloum et al., 2007), and between
nonabusing adults with and without a family history of alcohol-
ing of emotional stimuli. None of these studies, however, has
examined differences among these groups in the effects of acute
alcohol administration. These studies could enhance our under-
standing of how the neural correlates of intoxication and emo-
In addition, it is possible that attenuation of the alcohol-
mediated striatal BOLD response could be used as a surrogate
marker for the clinical effectiveness of medications being devel-
oped for the treatment of alcoholism.
viewed the neutral faces, but no difference during the fearful face condition. B, A coefficient of association was computed
signal change (to the neutral faces) during the placebo session, and intoxication ratings measured by the DEQ. There was a
Gilmanetal.•AlcoholandEmotion J.Neurosci.,April30,2008 • 28(18):4583–4591 • 4589
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