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Activation of Prefrontal Cortex and Anterior Thalamus in Alcoholic Subjects on Exposure to Alcohol-Specific Cues
Mark S. George, MD;
Raymond F. Anton, MD;
Courtnay Bloomer, BA;
Charlotte Teneback, BS;
David J. Drobes, PhD;
Jeffrey P. Lorberbaum, MD;
Ziad Nahas, MD;
Diana J. Vincent, PhD
Arch Gen Psychiatry. 2001;58:345-352.
ABSTRACT
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Background Functional imaging studies have recently demonstrated that specific
brain regions become active in cocaine addicts when they are exposed to cocaine
stimuli. To test whether there are regional brain activity differences during
alcohol cue exposure between alcoholic subjects and social drinkers, we designed
a functional magnetic resonance imaging (fMRI) protocol involving alcohol-specific
cues.
Methods Ten non–treatment-seeking adult alcoholic subjects (2 women) (mean
[SD] age, 29.9 [9.9] years) as well as 10 healthy social drinking controls
of similar age (2 women) (mean [SD] age, 29.4 [8.9] years) were recruited,
screened, and scanned. In the 1.5-T magnetic resonance imaging scanner, subjects
were serially rated for alcohol craving before and after a sip of alcohol,
and after a 9-minute randomized presentation of pictures of alcoholic beverages,
control nonalcoholic beverages, and 2 different visual control tasks. During
picture presentation, changes in regional brain activity were measured with
the blood oxygen level–dependent technique.
Results Alcoholic subjects, compared with the social drinking subjects, reported
higher overall craving ratings for alcohol. After a sip of alcohol, while
viewing alcohol cues compared with viewing other beverage cues, only the alcoholic
subjects had increased activity in the left dorsolateral prefrontal cortex
and the anterior thalamus. The social drinkers exhibited specific activation
only while viewing the control beverage pictures.
Conclusions When exposed to alcohol cues, alcoholic subjects have increased brain
activity in the prefrontal cortex and anterior thalamus—brain regions
associated with emotion regulation, attention, and appetitive behavior.
INTRODUCTION
SUBSTANCE-induced stimulation and craving are key features of developing
and maintaining an addictive disorder. In those seeking treatment for an addiction,
substance-related environmental stimuli and craving are clinically important
because of their ability to trigger relapse.1
Animal models of addiction consistently implicate key brain structures, such
as the septum, amygdala, nucleus accumbens, and other regions that are part
of the anterior paralimbic system.2, 3, 4, 5
Several recent functional imaging studies in cocaine addicts have shown that
these structures as well as the prefrontal cortex are activated by cocaine
stimuli.6, 7 There has been little
brain imaging work done to date using alcohol, a more commonly abused substance,
but one with an even greater burden on public health.8
Alcohol, compared with other substances of abuse, has benefits and liabilities
with respect to functional brain imaging research.8
Although with alcohol one can study easily both alcoholic and nonalcoholic
control subjects (social drinkers), the degree of self-report of craving for
alcohol is generally less than for other substances.9
We sought to test whether individuals could experience alcohol craving inside
the magnetic resonance imaging (MRI) scanner, and if so, whether the amount
of craving differed between alcoholic subjects and matched social drinkers.
Furthermore, independent of potential differences in self-reported alcohol
craving, we wondered whether specific brain regions would be differentially
activated in alcoholic subjects while viewing alcohol cues compared with neutral
beverage cues, and whether this activation differed in magnitude or location
from that in social drinkers. Based on results from animal studies and those
reported in cue-induced brain-imaging studies done in cocaine subjects, we
hypothesized that alcoholic subjects would have increased activation in prefrontal
cortex and anterior paralimbic structures during alcohol-specific cue presentations.
To test this hypothesis, we used functional MRI (fMRI) to image neural activity
during alcohol cue presentation in non–treatment-seeking alcoholic subjects
and a control sample of social drinkers. Immediately before subjects viewed
the images, they were given a sip of alcohol to maximize the interest in alcohol
cues, following on the study cited by Modell and Mountz,10
who used this same method.
SUBJECTS AND METHODS
SUBJECTS
Eleven non–treatment-seeking alcoholic subjects (3 women) (mean
[SD] age, 31.7 [11.2] years) and 13 social drinking controls (5 women) (mean
[SD] age, 30.7 [9.4] years) were initially recruited at least 12 days after
participation in another alcohol-related study11
and offered $100 to participate in the fMRI study. The intent was to generate
a usable data set of 10 matched pairs. Thus, social drinkers were recruited
based on age and gender to match each previously scanned alcoholic subject.
One alcoholic subject and 1 social drinker had large movement artifact (>3
mm), and their scans were not used for further analysis. Therefore, from these
initial 11 scans, 10 non–treatment-seeking alcoholic subjects had usable
data (2 women) (mean [SD] age, 29.9 [9.9] years). These subjects met DSM-IV12 criteria for current
alcohol dependence, including criterion 4 (persistent desire or unsuccessful
efforts to cut down or control drinking), and drank an average of 7 standard
drinks per drinking day. Exclusion criteria included meeting DSM-IV criteria for any other substance abuse dependency disorder or
any other Axis 1 disorder, and the inability to remain alcohol-free for at
least 1 day. Subjects were given a urine drug screen to detect other substances
of abuse and were not included if the drug screen was positive. They were
recruited through advertisements in the local community (including newspaper,
restaurant, and radio advertisements), signed written informed consent approved
by the Medical University of South Carolina Institutional Review Board, and
were screened using
the Structured Clinical Interview for
the DSM-IV.13
Additionally, 13 age- and sex-matched
healthy adults who did not have a substance or alcohol abuse problem were
recruited from the same study.11 Of the fMRI
scans from these 13, 10 were deemed both usable (no excessive movement) and
matched the alcohol cohort on a pairwise basis (2 women) (mean [SD] age, 29.4
[8.9] years). All subjects were medication-free for a minimum of 12 days before
scanning. All subjects underwent a Breathalyzer test on the morning of the
study and immediately before the MRI procedure and were not scanned if there
was any detection of alcohol or any evidence of alcohol withdrawal.
PROCEDURES
On the day of the MRI scan, subjects were rated using the following
instruments: Beck Depression Inventory,14 Beck
Anxiety Inventory,15 Revised Clinical Institute
Withdrawal Assessment Scale for Alcohol,16 Obsessive-Compulsive
Drinking Scale,17, 18 a timeline
followback for drinking in the past 90 days,19
and a 5-item visual analog alcohol craving scale. All scans were performed
between 6 and 10 PM.
Alcohol and nonalcohol beverage picture cues were drawn primarily from
the Normative Appetitive Picture System (Figure
1).20 To avoid repeating the same
stimuli during the scanning sequence, additional similar pictures (27 of the
58 total) were selected from advertisements in several contemporary magazines
(eg, Glamour, Cigar Afficionado) and scanned on a flatbed scanner. Visual control pictures were then
created from the alcohol pictures in Adobe Photoshop (Adobe Systems Inc, San
Jose, Calif) by various distortion effects (eg, blurring, smoothing), resulting
in pictures that matched the alcohol cues in color and hue but lacked any
object recognition. A 9-minute script for stimulus presentation was created
in Superlab 1.68 (Cedrus Corp, San Pedro, Calif) on a Power Macintosh computer
consisting of six 90-second epochs. Each epoch contained three 24-second blocks:
1 block each of alcohol (ALC), nonalcohol beverage (BEV), and visual control
pictures (VIS) and one 18-second rest (REST) (cross-hair). Each 24-second
block consisted of 5 individual pictures, each displayed for approximately
4.8 seconds. The 6 ALC blocks were each specific to a beverage type (beer,
wine, or liquor), with 2 blocks per type. To control for time and order effects,
the order of the individual pictures, the blocks within the epoch, and the
epochs were all randomized. In addition, a 10-minute relaxation script was
created, consisting of 20 scenic pictures drawn from the International Affective
Picture System,21 each displayed for 30 seconds.
These pictures were displayed during MRI scanning setup, tuning sequences
and structural scan before the actual functional imaging study. The computer
was connected to an MRI-compatible nonferromagnetic projector, which displayed
the pictures on an MRI-compatible translucent screen placed at their feet
on the scanner gantry. Subjects wore prism glasses, which enabled them to
view the screen while supine and in the MRI scanner.
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Figure 1. Representative stimuli and a diagram
of the functional magnetic resonance imaging alcohol-induction paradigm.
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On the evening of the scan, subjects completed self-assessment questionnaires
(Beck Depression Inventory and Beck Anxiety Inventory) and were escorted into
the MRI suite. They were fitted with prism glasses and a small plastic tube
was placed in the corner of their mouth (for giving a sip of the subject's
alcoholic beverage of choice as a taste cue but producing negligible blood
alcohol levels) in a procedure similar to that used by Modell and Mountz.10 After subjects were positioned in the scanner, they
were checked to ensure that they could view the cues. During initial scanner
tuning and structural scanning, subjects were shown the relaxation pictures.
For the fMRI sequence, subjects were initially rated while in the magnet for
alcohol craving and anxiety level using visual analog scales, and were then
given a sip of their preferred beverage and rated again. They were then shown
9 minutes of alternating visual cues concurrent with blood oxygen level–dependent
image acquisition (Figure 1). Subjects
were retrospectively rated for their beverage craving during the different
stimuli (alcohol and nonalcohol beverage), and were taken out of the scanner.
A Breathalyzer test was performed and they were given instructional material
about the hazards of drinking, which they read during a 1-hour waiting period
after the completion of the scan. They were then allowed to leave.
MRI IMAGE ACQUISITION
Subjects wore earplugs and head movement was restricted using inflatable
cushions. Magnetic resonance imaging scans were performed in a Picker Edge
1.5-T MRI scanner (Marconi, Cleveland, Ohio) with actively shielded magnet
and high-performance whole-body gradients. An initial high-resolution, 142-slice,
1-mm-thick, sagittal T1-weighted scan was acquired for later volumetric and
coregistration analysis and to ensure that there were no large infarctions
or tumors. A structural scan was then taken consisting of 15 coplanar coronal
slices (5-mm-thick/2-mm gap) centered around the septum as determined on a
sagittal scout image. After more tuning, the cue-induction paradigm was performed
while also acquiring blood oxygen level–dependent-weighted coronal scans
in the exact plane as before using a gradient echo, echo-planar fMRI sequence
(flip angle, 90°; echo time, 40 milliseconds; repetition time, 3000 milliseconds;
field of view, 27.0 cm; fifteen 5-mm-thick slices; and gap, 2.0 mm, with frequency
selective fat suppression).
DATA ANALYSIS
Subject demographics (Table 1)
and clinical rating scales were compared between groups using analysis of
variance with post hoc t tests. Craving ratings during
the fMRI procedure were analyzed using mixed-design analysis of variance,
with group as the between-subjects factor and time as the repeated measure.
Magnetic resonance imaging scans were transferred into ANALYZE format and
then further processed on Sun workstations (Sun Microsystems, Palo Alto, Calif).
Scans were checked using MEDx 3.0 (Sensor Systems Inc, Sterling, Va) for movement
across runs, and then were coregistered to a mean image using automatic image
registration.22 For all subjects, movement across
the 9-minute study was less than 3 mm in all 3 axes.
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Table 1. Subject Demographics*
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Functional images were analyzed using 2 separate techniques—a
within-subject technique that involved no spatial distortion, and a group
analysis involving transformation into a common brain atlas. Both methods
produced similar results, with alcoholic subjects activating more brain regions
during presentation of the alcohol cues. Only the spatially transformed group
analysis results are described.
Scans were checked using MEDx for movement across runs, and were then
motion corrected for movement if greater than 2 mm but less than 3 mm. Scans
with less than 2-mm movement were not corrected for motion. There were 2 subjects
(1 alcoholic subject and 1 social drinker) with greater than 4-mm movement
in the initial 24 studies who were not included for final data analysis. Two
alcoholic subjects required motion correction for movement of approximately
2.5 mm, which was corrected to a maximum movement of approximately 1.5 mm.22 We then only used a subject's coregistered data for
data analysis if it showed less than 2-mm movement in all planes after coregistration.
After corrections for motion, we spatially transformed each subject's scans
into the Talairach Atlas and performed within-individual analyses as well
as averaging brain activity at each time point by group and performing within-group
and between-group comparisons of brain activity across conditions.
Using the Statistical Parametric Mapping 99 module23
in MEDx 3.0, we transformed and spatially normalized,23
and transformed (input voxel dimensions, 2.1 x 2.1 x 7 mm, to
output voxel dimensions, 3 x 3 x 3 mm) and smoothed (6 x
3 mm) the data. We next intensity-masked (40%) and intensity-normalized each
person's data. At this stage, we performed a within-subject analysis of each
person's brain activity while viewing the different cues. To test for group
differences (alcoholic subjects and social drinkers) across the tasks, we
generated a mean group image of brain activity at each time point. Thus, using
the Tool Command Language scripting capabilities within MEDx 3.0, we averaged
(for alcoholic subjects and social drinkers separately) all subjects' functional
data to generate group data at each of the 180 time points.
Using Statistical Parametric Mapping statistics in MEDx 3.0 on the group
data, we then performed a cluster analysis (2-tailed z
map threshold of P<.01, and spatial extent threshold
of P<.05) to find brain regions where the group
showed statistically more blood oxygen level–dependent-fMRI signal during
the alcohol cue condition than during the control beverage cues.24
We assumed an uncorrected F threshold UFp>.99 to preserve as many voxels as
possible for the cluster analysis. Only clusters showing a statistical weight
(spatial extent threshold) of P<.05 were considered
to be significantly activated. We used a delayed boxcar model, employed a
high-pass filter to remove signal drift, cardiac and respiratory effects,
and other low-frequency artifacts, and temporally smoothed the data.
RESULTS
CRAVING INDEXES
The average self-reported urge to drink alcoholic beverages on a 0 to
100 visual analog scale is shown for each group before and after the sip of
alcohol, during the picture viewing (rated retrospectively), and then at the
completion of the 9-minute study (Figure 2). At all time points, alcoholic subjects had a higher self-report
of urge to drink alcohol (craving) (F1,18 = 10.20, P = .005) than social drinkers. In addition, craving ratings for the
entire sample tended to show a modest, yet significant, increase over the
course of the cue-induction procedures (F3,54 = 3.18, P = .03)
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Figure 2. Mean craving ratings and SEM before,
during, and after scanning.
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BRAIN ACTIVITY ANALYSIS
Brain regions that significantly differed across conditions within each
group are listed in Table 2 and
are depicted in Figure 3. We discuss
them here in ascending order of specificity for addressing the issue of differential
specific brain activation between alcoholic subjects and social drinkers.
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Table 2. Brain Regions Activated by Group and by Condition*
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Figure 3. Within-group Standard Parametric
Mapping data by contrast. Brain regions that are significantly increased in
one task compared with another are depicted in color for each group (alcoholic
subjects [left] and social drinkers [right]) on representative transverse
structural magnetic resonance imaging scans. Posterior brain regions that
were not imaged and for which there are no dates are shaded in black. The
threshold for determining significance is an extent cluster threshold of P<.05. The top row shows brain regions significantly increased while
viewing alcohol cues compared with the beverage cues at the level of the anterior
commisure (AC) (left image, 17; and 30 mm above the AC line, 28). The next
2 rows depict brain activity while viewing the alcohol or beverage cues compared
with the visual control at 30 and 36 mm above the AC–posterior commisure
(AC-PC) line. Note that only the social drinkers have significant increases
in activity in the nonalcohol beverage contrast. The bottom row shows significant
brain activity by group in the contrast of looking at the nonobject visual
control compared with a "rest" task of viewing a cross. Note that both groups
have increased activity across this comparison both 12 mm below and 28 mm
above the AC-PC line. These results in the bottom row suggest that the group
differences seen in the other contrasts are not a function of the failure
of either group in general to activate the brain.
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GENERAL NONSPECIFIC ACTIVATION
As would be expected, both groups showed areas of significant increases
while viewing the visual control images (complex color shapes) compared with
the rest (crosshair) images—largely in the anterior temporal and prefrontal
cortex. The amount of voxels (655 for alcoholic subjects and 685 for social
drinkers) that met the significance threshold was similar across the 2 groups.
(Note that we did not acquire blood-flow data from the primary or secondary
visual cortex.)
COMPARISONS OF BEVERAGE CUES WITH THE CROSSHAIR "RESTING" CONTROL
The alcohol group had no significant increases when viewing the nonalcohol
beverage cues compared with the resting crosshair control. In contrast, the
social drinkers had significant increases in 3 clusters—the cerebellum,
the medial temporal cortex, and the prefrontal cortex.
Both groups displayed increases in brain activity when viewing the alcohol
cues compared with the resting control images. Alcoholic subjects had increased
activity in the anterior thalamus and bilateral prefrontal cortex. The control
subjects showed increased activity in the medial temporal lobes and the right
prefrontal cortex.
COMPARISONS OF BEVERAGE CUES WITH THE NONOBJECT VISUAL CONTROLS
These comparisons control for differences in color, pitch, and hue,
and theoretically, the only thing that differs across this comparison are
the identifiable objects (eg, beer mugs, coffee cups). Neither group had significant
activations in the alcohol cues minus visual control comparison. There were
no areas of significantly increased activity in the alcoholic subjects when
comparing brain activity while viewing beverage cues compared with while viewing
the visual controls. In contrast, the social drinkers had increased activity
in the left prefrontal cortex with this comparison.
DIRECT COMPARISON OF ACTIVITY DURING ALCOHOL BEVERAGE CUES MINUS NONALCOHOL
BEVERAGE CUES
This comparison is the most important and directly tests the study hypothesis.
It directly compares the summation of all potential brain activity generated
by the neutral (control) beverage cues and subtracts this from all the potential
brain activity generated by the alcohol beverage cues. Theoretically, the
brain regional activity remaining should be specifically related to the alcohol-specific
content of the pictures.
There was no increased activity in this comparison in the social drinkers.
In contrast, the alcohol group had increased activity in the thalamus and
the prefrontal cortex.
COMMENT
To our knowledge, this is the first report to use fMRI to investigate
the brain regions associated with visual cues for alcohol. The results demonstrate
that it is possible to combine fMRI and short time domains (24 seconds) to
evaluate alcohol cue-induced brain activity in both alcoholic subjects and
social drinkers. The brain regions that are activated by alcoholic subjects
while viewing alcohol cues are in the anterior paralimbic system (thalamus)
or cortical regions that are known to connect with this system. This anterior
paralimbic cortex has long been associated with regulating appetitive behavior
and emotion. These findings are likely important in understanding the neural
aspects of craving and alcohol addiction. However, this initial study suffers
from several limitations that bear on the interpretation of results.
In this study, we had a relatively small sample size of mildly dependent
non–treatment-seeking alcoholic subjects. Although we employed conservative
approaches in the data analysis, and performed 2 distinct sets of data analysis,
which generated convergent results (only the second analysis results are presented
here), this study needs replication with larger samples.
The regions activated in this study should not be interpreted as correlates
of craving per se, but rather as brain areas that activate in alcoholic subjects
during alcohol cue presentation. Thus, these results should not necessarily
be construed as implying that these regions are causing, or mediating (enhancing
or diminishing) craving. Directly proving that these regions (prefrontal cortex
and anterior thalamus) actually mediate craving could be approached in several
ways. One could more closely temporally link variations in subjective craving
with specific regional activity changes. For example, in ongoing work, we
are measuring subjective craving in real time during fMRI scanning and cue
presentation, and plan to perform analyses directly investigating changes
in regional brain activity that temporally correlate with subjective craving
for alcohol. Alternatively, one could modify regional brain activity, either
pharmacologically (eg, naltrexone) or with a physical intervention (eg, transcranial
magnetic stimulation), and see if this directly changes both regional brain
activity and craving.
Because our blood oxygen level–dependent fMRI method repeatedly
switched from control to task, we employed 1 standard set of visual cues and
did not tailor the specific cues to each individual as has been done in some
other craving and imaging studies. Individualized cues may increase the degree
of craving, while sacrificing the generalizability of the task and control.
While the majority of the visual alcohol cues used in this study have been
standardized and tested in the Normative Appetitive Picture System,20 to our knowledge they have not been used previously
in alcoholic subjects during functional brain imaging. Interestingly, while
using taste stimulation alone, Modell and Mountz10
reported increased blood flow (by single-photon emission computed tomography
imaging) in the basal ganglia, which correlated with the level of craving.10 Whether taste cues and visual cues of alcohol differentially
stimulate different brain regions is open to further study. Our goal in this
initial study was to maximally stimulate with several alcohol cues (taste
and visual) to enhance our chances of detecting a brain activation effect.
Our choice of control tasks (neutral beverages) was designed to mimic all
visual aspects of the alcohol-specific cues. While alcohol beverage cues induced
an urge to drink (craving) in some subjects, all alcoholic subjects started
from a higher baseline of craving, which may have provided a "ceiling effect"
on craving stimulation. Interestingly, some social drinking subjects reported
craving for the nonalcoholic beverage pictures.
One might argue that the differences seen in this study might represent,
simply, directed attention. Although the cingulate and dorsolateral prefrontal
cortex are involved in selective attention, no studies of selective attention
have found anterior paralimbic activation.9, 25, 26
Nevertheless, future studies employing this paradigm along with a control
study of selective attention would help differentiate the regions activated
in this study from those commonly seen in mere selective attention. It would
nevertheless continue to be significant that specific brain regions are involved
in the enhanced "selected attention" for alcohol found in alcohol-dependent
individuals. Cue-based research in addiction focuses on the evaluation of
stimulus-generated physiological and psychological effects that may initiate
a drinking bout or cause relapse. The "selected attention" paid to alcohol
cues by alcoholic subjects may be the basis for the maintenance of alcohol
dependence or the triggering of a relapse drinking episode.1
Finally, we only imaged the anterior third of the brain and do not have
data about changes in the visual cortex, which might be useful in interpreting
some of the control tasks. While confining the brain regions under investigation
helps to reduce the chance of a type II error, we cannot make statements about
changes in brain regions where we did not scan.
Some subjects had recently (within the last month) participated in a
clinical laboratory study testing opiate antagonist effects on alcohol intake
(8 days of ingestion). Regardless of whether they had received active or placebo
medication in that short trial, many alcohol subjects were drinking and craving
less at the time of the fMRI procedure than in their natural prestudy state.11 While no medication had been ingested for at least
12 days before the scan, the participation in this prior trial might have
masked even more stark differences in cue-induced regional brain activity
between the alcoholic subjects and social drinkers.
This study has several important findings. It seems that the confining
nature of the MRI scanner and the loud noises did not prevent us from performing
alcohol cue stimulation. With both forms of image data analysis, alcoholic
subjects had much more brain activation than social drinkers when exposed
to alcohol-specific cues. Furthermore, the specific regions activated during
alcohol-specific cues in alcoholic subjects are the prefrontal cortex and
the anterior thalamus. Although the exact definition of craving is hotly disputed, it likely involves appetite drives and emotional
changes like arousal. In this light, the brain regions activated by alcoholic
subjects during alcohol cue stimulation may participate in these behaviors.
Differences in the regions activated in the current study and those
reported in cocaine abusers may be caused by several important variables.
These variables may be related to the abused substance, the stimulation paradigm,
or the scanning methods. Despite these differences, the current study results
overlap with previous imaging studies in cocaine users, which used scripted
cue-induced craving in cocaine subjects. For instance, Grant and colleagues,6 using visual presentations that are similar in design
to the current study, found increased activation of the dorsolateral prefrontal
cortex in cocaine subjects while viewing cocaine stimuli. Childress and colleagues7 examined brain activity in 14 detoxified cocaine users
and 6 healthy controls during presentation of cocaine-related videos. There
was increased activation in the anterior cingulate and amygdala during the
cocaine cues in the cocaine users but no differential activation of the dorsolateral
prefrontal cortex, thalamus, cerebellum and visual cortex between cocaine
users and controls. Maas and colleagues27 used
fMRI to measure brain activity in 6 subjects with a history of crack cocaine
use and 6 matched controls. The cocaine-using group had significantly increased
activity in the anterior cingulate and left dorsolateral prefrontal cortex
while viewing drug-related scenes.
Only more alcohol cue-induced brain imaging studies in alcoholic subjects
will provide data to address the sensitivity and specificity of brain regional
activation.
This study suggests that changes in brain activity caused by tasting
alcohol and viewing alcohol cues can be measured by an fMRI procedure. Alcoholic
subjects, compared with social drinking controls, report higher rates of craving
at baseline, after a taste of alcohol and while viewing alcohol-related cues.
During alcohol cue presentations, alcoholic subjects have specific activation
in the anterior thalamus and the prefrontal cortex. Future work is warranted
to determine if this paradigm might be useful to better understand the pathophysiology
of craving and addiction, to evaluate potential anticraving medications, or
to predict relapse.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
Funded in part by center grant AA10761-03, from the National Institute
on Alcohol Abuse and Alcoholism, Bethesda, Md, and grants from the National
Alliance for Research in Schizophrenia and Depression, Great Neck, NY, and
the Stanley Foundation, Bethesda (Dr George).
Presented in abstract form at the annual meeting of the American College
of Neuropsychopharmacology, Los Croabas, Puerto Rico, December 12, 1998.
We thank Carrie Randall, PhD, James C. Ballenger, MD, and Layton McCurdy,
MD, for their helpful comments, and Mary Radin for her assistance in the preparation
of this article.
From the Departments of Radiology
(Drs George and Vincent), Psychiatry (Drs George, Anton, Drobes,
Lorberbaum, and Nahas and Mss Bloomer and Teneback), and Neurology (Dr
George), Medical University of South Carolina, Charleston; and the
Ralph H. Johnson Veterans Hospital, Charleston, SC
(Dr George).
Corresponding author and reprints: Mark S. George, MD, Radiology
Department, Medical University of South Carolina, 171 Ashley Ave, Charleston,
SC 29425 (e-mail: georgem{at}musc.edu).
REFERENCES
| |
1. Koob GF, Markou A, Weiss F. Opponent process and drug dependence: neurobiological mechanisms. Semin Neurosci. 1993;5:351-358.
2. Hubner CB, Koob GF. The ventral pallidum plays a role in mediating cocaine and heroin self-administration
in the rat. Brain Res. 1990;508:20-29.
FULL TEXT
|
ISI
| PUBMED
3. Koob GF, Roberts AJ. Brain reward circuits in alcoholism. CNS Spectrums. 1999;4:23-37.
4. Kalivas PW, Duffy P. Sensitization of repeated morphine injection in the rat: possible involvement
of A10 dopamine neurons. J Pharmacol Exp Ther. 1987;241:204-212.
FREE FULL TEXT
5. Kalivas PC, Barnes CD. Limbic Motor Circuits and Neuropsychiatry. Boca Raton, Fla: CRC Press; 1994.
6. Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci U S A. 1996;93:12040-12045.
FREE FULL TEXT
7. Childress AR, Mozley PD, McElgin W, Fitzgerald J. Limbic activation during cue-induced cocaine craving. Am J Psychiatry. 1999;156:11-18.
FREE FULL TEXT
8. George MS, Teneback CC, Bloomer CW, Horner MD, Anton RF. Using neuroimaging to understand alcohol's brain effects. CNS Spectrums. 1999;4:88-92.
9. Carter BL, Tiffany ST. Meta-analysis of cue-reactivity in addiction research. Addiction. 1999;94:327-340.
FULL TEXT
|
ISI
| PUBMED
10. Modell JG, Mountz JM. Focal cerebral blood flow change during craving for alcohol measured
by SPECT. J Neuropsychiatry Clin Neurosci. 1995;7:15-22.
FREE FULL TEXT
11. Drobes DJ, Anton RF. Drinking in alcoholics following an alcohol challenge research protocol. J Stud Alcohol. 2000;61:220-224.
ISI
| PUBMED
12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition. Washington, DC: American Psychiatric Association; 1994.
13. First MB, Spitzer RL, Williams JBW, Gibbon M. Structured Clinical Interview for DSM-IV (SCID). Washington, DC: American Psychiatric Association; 1997.
14. Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571.
15. Beck AT, Brown G, Epstein N, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56:893-897.
FULL TEXT
|
ISI
| PUBMED
16. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal
Assessment for Alcohol Scale (CIWA-Ar). Br J Addict. 1989;84:1353-1357.
FULL TEXT
|
ISI
| PUBMED
17. Anton RF, Moak DH, Latham P. The Obsessive-Compulsive Drinking Scale: a self-rated instrument for
the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res. 1995;19:92-99.
FULL TEXT
|
ISI
| PUBMED
18. Anton RF, Moak DH, Latham PK. The Obesssive-Compulsive Drinking Scale: a new method of assessing
outcome in alcoholism treatment studies. Arch Gen Psychiatry. 1996;53:225-231.
FREE FULL TEXT
19. Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliability of a timeline method: assessing normal drinkers' reports
of recent drinking and a comparative evaluation across several populations. Br J Addict. 1988;83:393-402.
FULL TEXT
|
ISI
| PUBMED
20. Breiner MJ, Stritzke WGK, Lang AR, Patrick CJ. The Normative Appetitive Picture System [photographic
slides]. Tallahassee: Florida State University; 1995.
21. CSEA-NIMH. The International Affective Picture System
[photographic slides]. Gainesville: University of Florida; 1995.
22. Woods RP, Cherry SR, Mazziotta JC. Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr. 1992;16:620-633.
ISI
| PUBMED
23. Talairach J, Tournoux P. Co-planar Sterotaxic Atlas of the Human Brain: 3-Dimensional
Proportional System: An Approach to Cerebral Imaging. New York, NY: Thieme-Stratton Inc; 1988.
24. Friston KJ, Worsley KJ, Frackowiak RS. Assessing the significance of focal activations using their spatial
extent. Hum Brain Mapp. 1994;1:210-220.
FULL TEXT
25. George MS, Ketter TA, Parekh PI. Regional brain activity when selecting a response despite interference:
an H2150O PET study of the Stroop and an emotional Stroop. Hum Brain Mapp. 1994;1:194-209.
FULL TEXT
26. Pardo JV, Pardo PJ, Janer KW, Raichle ME. The anterior cingulate cortex mediates processing selection in the
Stroop attentional conflict pardigm. Proc Natl Acad Sci U S A. 1990;87:256-259.
FREE FULL TEXT
27. Maas LC, Lukas SE, Kaufman MJ, Weiss RD, Daniels SL, Rogers VW, Kukes TJ, Renshaw PF. Functional magnetic resonance imaging of human brain activation during
cue-induced cocaine craving. Am J Psychiatry. 1998;155:124-126.
FREE FULL TEXT
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