 |
|
Neural Activity Related to Drug Craving in Cocaine Addiction
Clinton D. Kilts, PhD;
Julie B. Schweitzer, PhD;
Colin K. Quinn, MD;
Robin E. Gross, BA;
Tracy L. Faber, PhD;
Faheemah Muhammad;
Timothy D. Ely, BA;
John M. Hoffman, MD;
Karen P. G. Drexler, MD
Arch Gen Psychiatry. 2001;58:334-341.
ABSTRACT
| |
Background Crack cocaine dependence and addiction is typically associated with
frequent and intense drug wanting or craving triggered by internal or environmental
cues associated with past drug use.
Methods Water O 15 positron emission tomography (PET) studies were used to localize
alterations in synaptic activity related to cue-induced drug craving in 8
crack cocaine–dependent African American men. In a novel approach, script-guided
imagery of autobiographical memories were used as individualized cues to internally
generate a cocaine craving state and 2 control (ie, anger and neutral episodic
memory recall) states during PET image acquisition.
Results The mental imagery of personalized drug use and anger-related scripts
was associated with self-ratings of robust drug craving or anger, and comparable
alterations in heart rate. Compared with the neutral imagery control condition,
imagery-induced drug craving was associated with bilateral (right hemisphere
amygdala activation greater than left) activation of the amygdala, the left
insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus
accumbens area. Compared with the anger control condition, internally generated
drug craving was associated with bilateral activation of the insula and subcallosal
cortex, left hippocampus, and anterior cingulate cortex and brainstem. A brain-wide
pixel-by-pixel search indicated significant positive and negative correlations
between imagery-induced cocaine craving and regional cerebral blood flow (rCBF)
in distributed sites.
Conclusions The collected findings suggest the craving-related activation of a network
of limbic, paralimbic, and striatal brain regions, including structures involved
in stimulus-reward association (amygdala), incentive motivation (subcallosal
gyrus/nucleus accumbens), and anticipation (anterior cingulate cortex).
INTRODUCTION
THE PROGRESSION to cocaine addiction and its chronically relapsing nature
is often attributed to frequent and intense bouts of drug craving that are
triggered by environmental and internal stimuli that have established conditioned
associations with cocaine-induced euphoria or withdrawal.1
Places, people, actions and sensations associated with past drug use, and
their collection as episodic memories thus represent conditioned cues that
trigger drug craving as a conditioned response. An understanding of the regional
brain activity that underlies this drive state could define mechanisms of
relapse following abstinence, and potentially guide the development of new
treatments for addiction. Cocaine craving is also experienced following cocaine
administration,2 and it may motivate the binge
abuse of cocaine through the activation of similar or different neural pathways.
Animal models of drug craving3 have identified
possible neurobiological4, 5, 6
substrates of craving, yet their translation to a definitive picture of the
neural correlates of human drug craving remains unknown. Functional neuroimaging
techniques such as positron emission tomography.
Positron emission tomography (PET) and functional magnetic resonance
imaging (fMRI) are redefining the relationship of the human brain to behavior.
Drug craving in addicted individuals poses significant challenges to study
using PET or fMRI because of its contextual specificity, subjective nature,
and multiple cognitive and physiological corollaries. Using videotape simulations
of cocaine use and drug paraphernalia as generalized inductive cues, previous
PET and fMRI studies have identified frontal and limbic activations associated
with cue-induced craving.7, 8, 9
Such cues, however, induce variable urges for cocaine use10, 11
and do not parse activations related to conditioned drug craving from activations
associated with accompanying features of psychophysiological arousal, anticipation,
memory retrieval, attention, and behavioral planning. To address these limitations,
we developed and implemented alternative craving induction techniques and
multiple control conditions with PET to isolate further the neural correlates
of cue-induced cocaine craving in human cocaine addiction.
Using guided imagery of autobiographical memories of cocaine abuse as
novel personalized cues, we investigated the neural correlates of cue-induced
cocaine craving in crack cocaine–dependent male volunteers. Positron
emission tomography images were acquired during the guided imagery of individualized
scripts describing memories of cocaine use or of an anger-related or emotionally
neutral non–drug-related experience. The anger and neutral scene imagery
tasks served as control conditions for the arousing, attention-grabbing, anticipatory,
and vivid episodic memory properties of the drug use imagery condition and
for the processes of recall of autobiographical memories and their mental
imagery. As a primary analysis, comparisons of task-related regional cerebral
blood flow (rCBF), a correlate of neuronal activity,12
between the drug use and control imagery conditions were used to identify
synaptic activity related to cocaine craving in dependent men. This study
tested the overall hypothesis that cocaine craving associated with addiction
is related to changes in limbic and frontal brain activity that can be dissociated
from activations related to corollaries of drug craving.
SUBJECTS AND METHODS
SUBJECTS
The participating subjects were 8 healthy African American men (7 right-handed
and 1 left-handed; mean ± SD age, 36 ± 6 years) who were admitted
for inpatient treatment of cocaine dependence (a comparative imaging study
in cocaine-dependent women is ongoing). The study design did not include an
exclusion criteria based on race, though African Americans were encouraged
to participate as a disproportionately affected ethnic group. As established
by clinical interview by an addiction psychiatrist, all participants met the
following study diagnostic criteria: (1) DSM-IV defined
active crack cocaine dependence, but not for opiates, ethanol, marijuana,
or benzodiazepines (1 subject fulfilled criteria for nicotine dependence,
and 1 subject fulfilled criteria for marijuana abuse); (2) a lack of other
Axis I or Axis II psychiatric disorders, or current or prior neurologic disease;
and (3) lack of and no history of a major medical illness or current use of
prescription medications. Additional inclusion criteria included (4) positive
urinalysis for cocaine at initial visit and (5) use of cocaine as smoked free-base.
Subjects had a mean ± SD lifetime history of cocaine abuse of 10 ±
6 years, and they had reported the use of cocaine to be an average of 19 of
the 30 days prior to admission (range, 3-30 days). All subjects upheld that
exposure to drug use reminders was associated with an increased desire to
use cocaine. Potential subjects were screened for mental imagery ability using
the 35-item Questionnaire on Mental Imagery (QMI),13
and subjects exhibiting above-average ability (QMI score, <87)14 were invited to participate. Participating subjects
also were selected for the presence of frequent (> 5 per day), intense (mean
± SD rating, 7.7 ± 2.1 of a possible 10) cocaine cravings during
the week preceding study involvement using the Minnesota Cocaine Craving Scale.15 Positron emission tomography images were acquired
at a stage of early withdrawal (range, 7-17 days), associated with relief
from initial mood and cognitive symptoms of a dysphoric syndrome,16 and when the rCBF measures would not be confounded
by the direct effects of cocaine on cerebral hemodynamics.17
Immediately prior to imaging, subjects were established as being drug-free
by urinalysis for drugs of abuse. Subjects gave informed consent to participate
in a study protocol approved by the Human Investigations Committee at the
Emory University School of Medicine, Atlanta, Ga.
IMAGERY SCRIPT CONSTRUCTION
Individual scripts describing personal experiences of cocaine use and
of an anger-related event were constructed using modified versions (available
on request) of the Vietnam Stressful Scene Construction Questionnaire.18 For each experience, the questionnaire collected the
individual's bodily sensations from a 33-item checklist and a hand-written
narrative describing their environmental contexts. Imagery scripts for both
the drug use and anger scenes were assembled from the questionnaire information
in the first person, present tense. Scripts were confined to the memories
of the acts and perceptions associated with anticipation of drug use rather
than the acts and the sensations experienced after use. This was done in an
attempt to focus on the neural correlates of the conditioned incentive rather
than reinforcing properties of cocaine abuse. The anger-related experience
and an additional control experience selected from either a beach or forest
scene19 were chosen from personal experiences
not involving past associations with drug use. Scripts were audiotaped and
edited to a standard length of 60 seconds. An example of a cocaine use script
is provided below:
I'm driving to the apartment complex, knowing that I'm going
to see a dealer I know. It's very dark, but through the trees I can see guys
hanging out. I feel butterflies in my stomach. At this point, as I feel the
anticipation build, I park the car and out of the shadows P____ walks up.
I know he's got some good stuff. I'm so excited now I can feel my stomach
churning. P___ puts a 50 cent piece in my hand. I feel jittery now, I can't
wait to get high. We get in the apartment. It's a mess, but I see the stem
and lighter that I need. I take a look at the rock, it's yellowish and hard
and it looks so good my heart is racing now. I know this is gonna be it, pure
bliss. Trembling, I take the stem and the lighter. I watch the flame melt
the rock. I'm going to burst now. I put the stem to my lips and I inhale,
this is the one.
PET IMAGING
Task-related rCBF was determined with the ECAT 951 PET scanner (Siemens,
Knoxville, Tenn) following the bolus intravenous administration of 45 mCi
of water O 15.20 Each participant was scanned
8 times in an imaging session, twice in each of 4 conditions: rest, neutral
script imagery, cocaine use script imagery, and anger script imagery. The
same order of conditions was repeated with 10 minutes between each condition.
Imagery scripts were presented binaurally with instructions to listen to the
script and then mentally reenact the scene described. Tracer administration
was coincident with the end of each script, and 90-second single-frame studies
were initiated by the detection of head radioactivity and acquired in a 2-dimensional
mode. Differences in responses to script imagery between individuals, conditions,
and trials were estimated subjectively by analog scale responses, and objectively
by heart rate measurements. Following offset of the scanner, the inductive
properties of the imagery scripts were evaluated for each condition using
0- to 10-point analog scales with which the subjects self-rated the vividness
of the mental image (for all imagery scenes) and the experience of drug craving
during imagery of the cocaine use scene, anger during the anger-related scene,
or relaxation during the beach or forest scene. Subjects were asked, "how
vivid was the image?" for all scenes; "how strong was the urge to use?" for
the cocaine use scene; and "how angry are you?" for the anger scene, with
the anchor points for each of these 3 scales labeled "not at all, none" for
0, to "a great deal" for 10. For the neutral scene, subjects were asked, "how
relaxed are you?" with the anchor point 0 labeled "very relaxed, no tension
at all" and 10 labeled "very tense." The possibility of cocaine craving provocation
during anger scene imagery or of anger induction during cocaine use imagery
was also assessed by analog scale responses. Attempts to limit carryover of
an induced state into the subsequent image acquisition involved the engagement
of the subject in conversation related to his or her predetermined occupation
or hobbies. Heart rate measurements were recorded at 10-second intervals for
the 30 seconds prior to script exposure (baseline), and during the following
180 seconds encompassing script listening and scene imagery. Script-guided
imagery was not associated with increased reports of anxiety as assessed by
the State-Trait Anxiety Inventory21 administered
prior to and immediately following the imaging session.
IMAGE AND DATA ANALYSIS
Intact sets of 8 scans were acquired for 8 subjects and were the basis
of image analysis; scans for 2 subjects were discarded owing to missing behavioral
or imaging data. Images were reconstructed using a measured attenuation correction.
The 2 PET scans for each condition were averaged, spatially normalized,22 normalized for global blood flow by proportionate
scaling, and coregistered23 with a population-representative
reference PET atlas centered in Talairach coordinates.24
Coregistered PET images were smoothed to a final isotropic resolution of 9
mm full-width at half maximum. A linear contrast analysis25
based on the general linear model26 used a 2-way
repeated-measures analysis of variance (ANOVA), which compared means across
4 linear contrasts. A t-map image for each contrast was calculated on a pixel-by-pixel
basis. Significant sites of activation were defined by pixel intensity (P<.005) and a spatial extent of at least 50 contiguous
pixels exceeding this probability level.
A possible relationship between significant alterations in rCBF and
self-rated cocaine craving was estimated by the Pearson product-moment correlation
coefficients for sites identified in the comparison of the drug use and anger-related
or neutral imagery conditions.27 Radioactivity,
relative to the global mean, was computed for a sphere having a 9-mm radius
and using the coordinates of the pixel maxima as the centroid for each of
the significant sites of activation, which were derived from the group-averaged
contrast (Table 1) and correlated
with the individual differences in "urge to use" between the drug use and
control imagery conditions. A secondary brain-wide pixel-by-pixel correlation
analysis examined the relationship between self-rated intensity of cocaine
craving in response to drug use imagery and rCBF, estimated from radioactivity
relative to the global mean, and computed for every 1.5 x 1.5 x
1.5-mm pixel in the entire brain that was within the field of view of the
951 PET scanner.28
|
|
|
|
Cocaine Craving–Related Brain Activation Sites Induced by Guided
Imagery of Drug Use in 8 Cocaine-Dependent Men
|
|
|
RESULTS
IMAGERY-INDUCED CRAVING AND ANGER
During script construction, the cocaine-dependent subjects readily described
vivid episodic memories of ritualistic acts of cocaine use and anticipatory
arousal. The decomposition of these memories into scripts and their subsequent
use with guided imagery as personalized drug use cues was associated with
significant self-rated drug craving and alterations in heart rate. During
the PET imaging session, craving analog scale scores reflected a moderate
to intense urge to use cocaine for both replications of the cocaine use scene
imagery (Figure 1), and they did
not differ between replications (paired t8
= 1.31, P = .23). Anger analog scale scores reflected
the experience of moderate to intense internally generated anger for both
replications of the anger scene imagery (Figure
1), and they did not differ between replications (paired t8 = .704, P = .50). Anger-related
script imagery was associated with only mild to no self-rated cocaine craving
(mean ± SD score for "urge to use?" in trial 1 = 2.3 ± 1.4;
trial 2 = 0.3 ± 0.2) and was significantly less than the cocaine craving
response to imagery of the cocaine use script (trial 1, t14 = 5.81, P<.001; trial 2, t14 = 10.03, P<.001).
Furthermore, cocaine use script imagery was associated with little or no self-rated
anger (mean ± SD score for "angry?" in trial 1 = 1.1 ± 1.1;
trial 2 = 0.4 ± 0.3). All of the subjects rated the mental image of
their drug use, anger, and neutral scenes as being highly vivid (mean score
range, 8.5-9.4).
|
|
|
|
Figure 1. Analog scale scores for self-rated
cocaine craving (A) and anger (B) in response to mental imagery of personalized
scripts describing autobiographical memories of cocaine use and anger-provoking
situations, respectively. Data are from 9 cocaine-dependent men. Means ±
1 SD of analog scale scores for each trial are provided in the left and right
margins of each figure.
|
|
|
The provocation of cocaine craving or anger using guided imagery of
personal cocaine use or anger experiences was associated with significant
and similar alterations in heart rate (Figure
2). Compared with the neutral control imagery condition, the absolute
area-under-the-curve values defining the heart rate x time relationship
were significantly greater for both the drug use script imagery (paired t8 = 4.37, P = .002)
and anger script imagery conditions (paired t8 = 6.14, P<.001). Area-under-the-curve
values for the control script imagery and rest conditions did not differ significantly
(paired t8 = 0.68, P = .52).
|
|
|
|
Figure 2. A, Example (subject 8) of heart
rate (beats per minute) response to script-guided imagery of the cocaine use,
anger-related, and control scenes, and a rest condition. The time of injection
of water O 15 and coincident end of script presentation are indicated on the
abscissa. B, Area-under-the-curve (AUC) differences for individual heart rate
x time relationships for cocaine use and anger script imagery compared
with the common control scene imagery condition. Data are from 9 cocaine-dependent
men.
|
|
|
PET IMAGING RESULTS
Pairwise Contrast of Drug Use and Control Imagery Conditions
Compared with neutral scene imagery, drug use imagery was associated
with the activation of the amygdala (right hemisphere amygdala activation
greater than left), the left insula and anterior cingulate gyrus, and the
right subcallosal gyrus and nucleus accumbens areas (Table 1 and Figure 3).
When compared with the neutral imagery condition, drug use imagery was also
associated with decreased activity in the right frontal and left temporal
cortices and the posterior insula. Compared with anger scene imagery, drug
use imagery was associated with sites of activation in limbic and paralimbic
brain structures, including the bilateral insula and subcallosal cortices,
the left posterior caudate nucleus area, and the anterior cingulate cortex
and brainstem (Table 1 and Figure 3). Normalized difference images from
this contrast also revealed decreased activity in the right middle frontal
and fusiform gyri and in the left middle temporal cortex.
|
|
|
|
Figure 3. Location of significant (P<.005) sites of increased blood flow in difference images contrasting
the drug use and neutral scene imagery (A) and the drug use and anger-related
scene imagery (B) conditions. Data are from 8 cocaine-dependent men. Significant
pixels are illustrated on parasagittal (numbers refer to distance in millimeters
from midline) magnetic resonance reference images of the left and right hemisphere
averaged from a separate group of subjects.
|
|
|
Region of Interest Correlation Analysis
For those significant (P<.005) activation
sites identified in difference images, Pearson product moment correlation
coefficients were used to examine the relationship between individual changes
in rCBF and self-rated cocaine craving. For the contrast of the drug use and
neutral scene imagery conditions, significant negative correlations between
changes in rCBF and cocaine craving scale scores for the right subcallosal
cortex (r = -0.89) and the left anterior insula
(r = -0.74) were noted. For the difference
image for the drug use and anger scene imagery conditions, significant (P<.05) negative correlations of rCBF with self-rated
cocaine craving were observed for the brainstem (r
= -0.71) and left posterior caudate nucleus (r
= -0.77). Significant positive correlations to self-rated craving were
not observed in this region of interest correlation analysis.
Pixel-by-Pixel Correlation Analysis
For the brain-wide search, significant (P<.01)
positive correlations were found between individual subjects' self-rated cocaine
craving in response to drug use script imagery and rCBF in the right fusiform
gyrus (+34 mm [x], -24 mm [y], -24 mm [z]), and in the left middle
frontal (-52 mm [x], +4 mm [y], +43 mm [z]) and temporal (-56 mm
[x], -16 mm [y], -8
mm [z]) gyri. Additional positive rCBF correlations
for the left middle frontal gyrus and insula, and the right thalamus and cerebellum
were common to both craving induced by drug use imagery and anger induced
by anger experience imagery (Figure 4).
Similarly, most significant (P<.01) negative correlations
of rCBF to drug use script–induced craving as identified in the pixel-by-pixel
correlation analysis were also shared with the anger response to the anger
script imagery condition; nonshared correlations were noted in the right anterior
cingulate gyrus, and in the left putamen and inferior parietal cortex.
|
|
|
|
Figure 4. Location of brain activity correlated
with both induced cocaine craving and anger for 8 cocaine-dependent men. Maps
of pixels in which individual subject regional cerebral blood flow was significantly
positively correlated (P<.05, 2-tailed) with individual-subject
cocaine craving (yellow) on axial magnetic resonance reference images averaged
from a separate group of subjects. Those pixels that were correlated with
both cocaine craving and anger (blue) are illustrated. Correlation maps at
different axial planes represent the superior or inferior distance from the
commissural line.
|
|
|
COMMENT
When corrected for the processes of mental imagery and memory retrieval,
this study's findings in cocaine-dependent men indicate a cocaine craving–related
activation of a network of paralimbic (insula, anterior cingulate, temporal
cortex), limbic (amygdala), and ventral striatal structures. These task-related
brain activations provide insight into the identity of the neural pathways
through which conditioned drug cues provoke intense drug craving and thereby
redirect behavior toward drug seeking and drug use activities. The observed
activation of the amygdala during internally generated cocaine craving has
been previously observed in response to distinct external drug use cues (videotape
depiction, handling of paraphernalia).7, 9
Activation of the amygdala during conditioned craving is consistent with its
general role in conditioned stimulus-reward associations,29
and more specifically, with the observation that amygdala lesions in animals
impair the cue-mediated acquisition4 and reinstatement5 of cocaine-seeking behavior. When attempting to correct
for arousal, vividness of memory, and attention-grabbing processes by use
of the anger control condition, amygdaloid activation was not associated with
drug use imagery. The differential craving-related amygdaloid activation for
contrasts to the different control conditions (Figure 3) suggests that the amygdala plays an additional significant
role in the arousal related to drug cue exposure. An alternative explanation
for the differential amygdaloid activation between contrasts being related
to anger responses to drug use imagery is supported neither by self-reports
of anger related to drug use imagery nor by anger-related amygdaloid activation
from this study (data not shown) and that of a recent separate PET study.30 Interestingly, amygdaloid activity did not correlate
significantly with self-ratings of induced cocaine craving in either the region
of interest or pixel-by-pixel correlation analyses, raising the possibility
that amygdaloid involvement in conditioned cocaine craving varies between
individuals. The craving-related activation of the amygdala and the closely
interrelated subcallosal gyrus, insula, and ventral striatum may reflect a
neural system underlying the conditioned incentive, autonomic, and visceral
corollaries of cue-induced cocaine craving. The drug cue–induced activation
of the anterior cingulate gyrus and nucleus accumbens area may reflect an
anticipatory state31 or reward expectancy32 associated with drug craving.
A craving-related activation of the prefrontal association cortex was
conspicuously absent from our PET study of internally generated cocaine craving.
A prior PET study of cocaine craving induced by generalized external drug
cues (ie, videotape, drug paraphernalia) indicated an increased metabolic
activity of the bilateral dorsolateral prefrontal cortex that was positively
correlated with self-ratings of cue-induced cocaine craving.7
A recent fMRI,8 but not PET,9
study of cocaine craving provoked by generalized external cues also reported
a craving-related activation of the dorsolateral prefrontal cortex. We did
observe similar activations of the left (Brodmann area [BA] 46) and right
(BA 6 and BA 44) dorsolateral, prefrontal, and temporal cortices (BA 21),
and of the left cerebellum in the normalized difference images comparing the
neutral imagery control condition and the rest condition; neutral scene imagery
in our study was not associated with cocaine craving. This contrast highlights
those brain regions involved in the recall and imagery of autobiographical
memories33 and suggests that the dorsolateral
prefrontal activation sometimes attributed to external cue-induced drug craving7, 8 corresponds to the attempt of addicts
to link their associative memories of drug use to the generalized external
cues, rather than to the provoked state of cocaine craving.
The brain activation sites associated with cue-induced cocaine craving
(Table 1) exhibit many similarities
with brain foci of fMRI signal change identified in a recent study of post–cocaine
administration euphoria and drug craving in cocaine abusers.34
Similarities include increases in insula, subcallosal gyrus or nucleus accumbens,
hippocampus, anterior cingulate, and brainstem, and decreases in the medial
frontal and temporal cortex. The cocaine-induced cocaine craving that provokes
binge drug abuse and the conditioned cue-induced cocaine craving that provokes
relapse following abstinence may thus share at least some neural substrates.
In the fMRI study of cocaine effects,34 only
the signal changes in the nucleus accumbens/subcallosal cortex (positive)
and amygdala (negative) were however differentially correlated with the time
course of self-rated craving following cocaine administration. The activation
of the amygdala during cue-induced cocaine craving in this and prior7, 8 studies relative to the amygdala deactivation
associated with postcocaine craving34 may reflect
differences in the conditioned vs unconditioned nature of provoked drug craving.
Alternatively, the amygdala may be activated in response to the incentive
rather than reinforcing properties of cocaine, and perhaps further, that cocaine
use suppresses the anticipatory increases in amygdala activity. These possibilities,
however, are highly speculative and in need of empirical testing.
For both the region of interest and pixel-by-pixel analyses of craving-correlated
rCBF, negative rather than positive correlations with conditioned craving
predominated; subjects reporting greater cue-induced cocaine craving exhibited
the lesser rCBF. Whether these regions of activation inversely related to
cocaine craving are thus indicative of adaptive rather than maladaptive brain
responses to cocaine addiction will need to be determined by future studies.
For instance, the localization of negatively correlated sites in the autonomic-related35, 36 cortex suggests an adaptive response
to physiological arousal states associated with drug craving. While the brain-wide
pixel-by-pixel correlation analysis revealed frontal, temporal, occipitotemporal,
thalamic, and cerebellar sites significantly correlated (P<.01) with individual subjects' imagery-induced cocaine craving,
many of these sites were similarly correlated with imagery-induced anger.
Because subjects experienced little or no reported cocaine craving in response
to anger scene imagery, those frontal and temporal cortical sites that seem
to be unique to imagery-induced cocaine craving (Figure 4) are worthy of emphasis in future studies of craving-related
brain activity.
As personalized internal cues, autobiographical memories of drug use
represent motivationally powerful conditioned drug cues.37
The conditioned craving response elicited by guided imagery of these cues
was associated with a network of limbic and paralimbic activations. By defining
where in the human brain the neural correlates of cocaine craving are localized,
these results further the understanding of how the cocaine-dependent human
brain craves cocaine and how drug craving can be arrested.
Several limitations of this study need to be considered. As a complex
state, conditioned cocaine craving represents a challenge to attempts to define
those neural activations related to its motivational state. A limitation of
this, or any extant imaging study, is the nonnaturalistic nature of the exposure
to drug use reminders in a scanning environment. In the present study, a guided
mental reenactment of personal behaviors and sensations associated with cocaine
abuse was used to elicit a conditioned drug craving response. This individualized
approach, however, represents only an approximation of the actual contexts
of cocaine abuse that varies with the individual ability to reexperience by
mental imagery the actual experience. The use of a mental imagery questionnaire
as a screening tool was used to attempt to minimize this variable ability.
An additional limitation of the study was the use of a fixed rather than random
order of presentation of the scene imagery conditions in a repeated-measures
design, and the resulting potential confound posed by an order effect to the
use of condition contrasts to define craving-related changes in brain activity.
This design was used to better assess and control for the anticipated larger
confound of a carryover effect between conditions.
Like the majority of PET studies of similarly small sample size, activation
sites identified in the contrast analyses did not survive a correction for
multiple comparisons.38 We therefore attempted
to establish further the relationship between task-related chances in rCBF
and cocaine craving using a secondary pixel-by-pixel analysis.28
This analysis minimized potential confounds posed by the limitations of the
control conditions in the primary contrast analysis. To identify shared activations
indirectly related to cocaine craving and nonshared sites proposed to be related
to cocaine craving, correlation pixel maps for the drug use and anger imagery
conditions were compared.
A criticism of the use of guided imagery of personal drug use to provoke
cocaine craving, compared with more conventional approaches using videotapes
simulating drug use and drug paraphernalia, is that the stimulus is not standardized.
The present approach, however, was alternatively designed in attempting to
standardize the craving response by using individualized cues. Used in the
specific context of a PET scanner, script-guided imagery, compared with videotape
or paraphernalia cues, permits the acquisition of images in the absence of
cue-related sensory stimulation, the use of conditioned stimuli better matched
to the integration time of image acquisition for the short-lasting conditioned
craving response, and the generation and comparison of control conditions.
A head-to-head comparison of these 2 techniques would be of interest to the
larger field of empirical analysis of drug craving associated with addiction.
AUTHOR INFORMATION
Accepted for publication September 5, 2000.
This work was supported by grant DA 11771 from the National Institute
on Drug Abuse, Bethesda, Md.
We also thank Scott Grafton, MD, for image analysis software and advice,
and Delicia Votaw, BS, CNMT, Margie Jones, BS, CNMT, and Michael White, BS,
CNMT, of the Emory Center for PET.
From the Departments of Psychiatry and Behavioral Sciences (Drs Kilts,
Schweitzer, and Quinn, Ms Gross, and Mr Ely) and Radiology (Drs Faber and
Hoffman), the Emory Center for Positron Emission Tomography, School of Medicine,
Emory University, Atlanta, Ga, and the Atlanta Veterans Administration Medical
Center (Drs Quinn and Drexler and Ms Muhammad).
Corresponding author and reprints: Clinton D. Kilts, PhD, Department
of Psychiatry and Behavioral Sciences, School of Medicine, Emory University,
1639 Pierce Dr, Suite 4000, PO Drawer AF, Atlanta, GA 30322 (e-mail: sdpcdk{at}emory.edu).
REFERENCES
| |
1. Pickens RW, Johanson C-E. Craving: consensus of status and agenda for future research. Drug Alcohol Depend. 1992;30:127-131.
FULL TEXT
|
ISI
| PUBMED
2. Jaffe JH, Cascella NG, Kumor KM, Sherer MA. Cocaine-induced cocaine craving. Psychopharmacology. 1989;97:59-64.
FULL TEXT
| PUBMED
3. Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF. Animal models of drug craving. Psychopharmacology. 1993;112:163-182.
FULL TEXT
| PUBMED
4. Whitelaw RB, Markou A, Robbins TW, Everitt BJ. Excitotoxic lesions of the basolateral amygdala impair the acquisition
of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology. 1996;127:213-224.
PUBMED
5. Meil WM, See RE. Lesions of the basolateral amygdala abolish the ability of drug associated
cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res. 1997;87:139-148.
FULL TEXT
|
ISI
| PUBMED
6. Kalivas PW, Cornish J, Ghasemzadeh MB. Cocaine craving and paranoia: a combination of pharmacology and learning. Psychiatr Ann. 1998;28:569-574.
7. Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A. Activation of memory circuits during cue-induced cocaine craving. Proc Natl Acad Sci U S A. 1996;93:12040-12045.
FREE FULL TEXT
8. 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
9. Childress AR, Mozely PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP. Limbic activation during cue-induced cocaine craving. Am J Psychiatry. 1999;156:11-18.
FREE FULL TEXT
10. Ehrman RN, Robbins SJ, Childress AR, O'Brien CP. Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology. 1992;107:523-529.
FULL TEXT
| PUBMED
11. Avants SK, Margolin A, Kosten TR. Differences between responders and nonresponders to cocaine cues in
the laboratory. Addict Behav. 1995;20:215-224.
FULL TEXT
|
ISI
| PUBMED
12. Malonek D, Grinvald A. Interactions between electrical activity and cortical microcirculation
revealed by imaging spectroscopy: implications for functional brain imaging. Science. 1996;272:551-555.
ABSTRACT
13. Sheehan PW. A shortened form of Bett's questionnaire on mental imagery. J Clin Psychol. 1967;23:386-389.
ISI
| PUBMED
14. Sinha R, Lovallo WR, Parsons OA. Cardiovascular differentiation of emotions. Psychosom Med. 1992;54:422-435.
FREE FULL TEXT
15. Halikas JA, Kuhn KL, Crosby R, Carlson G, Crea F. The measurement of craving in cocaine patients using the Minnesota
Cocaine Craving Scale. Compr Psychiatry. 1991;32:22-27.
FULL TEXT
|
ISI
| PUBMED
16. Gawin FH. Cocaine addiction: psychology and neurophysiology. Science. 1991;251:1580-1586.
FREE FULL TEXT
17. Wallace EA, Wisniewski G, Zubal G, vanDyck CH, Pfau SE, Smith EO, Rosen MI, Sullivan MC, Woods SW, Kosten TR. Acute cocaine effects on absolute cerebral blood flow. Psychopharmacology. 1996;128:17-20.
FULL TEXT
| PUBMED
18. Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM. Psychophysiologic assessment of posttraumatic stress disorder imagery
in Vietnam combat veterans. Arch Gen Psychiatry. 1987;44:970-975.
ABSTRACT
19. Bourne EJ. The Anxiety and Phobia Workbook. 2nd ed. Oakland, Calif: New Harbinger Publications Inc; 1995.
20. Mazziotta JC, Huang SC, Phelps ME. A noninvasive positron computed tomography technique using oxygen-15-labeled
water for the evaluation of neurobehavioral task batteries. J Cereb Blood Flow Metab. 1985;5:70-78.
ISI
| PUBMED
21. Speilberger CD, Gorusch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory. Palo Alto, Calif: Consulting Psychologist's Press; 1970.
22. Woods RP, Grafton ST, Holmes CJ, Cherry SR, Mazziotta JC. Automated image registration, I: general methods and intrasubject,
intramodality validation. J Comput Assist Tomogr. 1998;22:139-152.
FULL TEXT
|
ISI
| PUBMED
23. Woods RP, Grafton ST, Watson JDG, Sicotte NL, Mazziotta JC. Automated image registration, II: intersubject validation of linear
and nonlinear models. J Comput Assist Tomogr. 1998;22:153-165.
FULL TEXT
|
ISI
| PUBMED
24. Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. New York, NY: Thieme Medical; 1988.
25. Woods RP, Iacoboni M, Grafton ST, Mazziotta JC. Improved analysis of functional activation studies involving within-subject
replications using a three-way ANOVA model. In: Myers R, Cunningham V, Bailey D, Jones T, eds. Quantification of Brain Function Using PET. San Diego, Calif: Academic
Press; 1996:353-358.
26. Neter J, Kutner MH, Nachtsheim CJ, Wasserman W. Applied Linear Statistical Models. Chicago, Ill: Richard D Irwin Inc; 1996.
27. Kosslyn SM, Thompson WL, Kim IJ, Rauch SL, Alpert NM. Individual differences in cerebral blood flow in area 17 predict the
time to evaluate visualized letters. J Cogn Neurosci. 1996;8:78-82.
28. Hamann SB, Ely TD, Grafton ST, Kilts CD. Amygdala activity related to enhanced memory for pleasant and aversive
stimuli. Nat Neurosci. 1999;2:289-293.
FULL TEXT
|
ISI
| PUBMED
29. Kentridge RW, Shaw C, Aggleton JP. Amygdaloid lesions and stimulus-reward associations in the rat. Behav Brain Res. 1991;42:57-66.
FULL TEXT
|
ISI
| PUBMED
30. Doughtery DD, Shin LM, Alpert NM, Pitman RK, Orr SP, Lasko M, Macklin ML, Fischman AJ, Rauch SL. Anger in healthy men: a PET study using script-driven imagery. Biol Psychiatry. 1999;46:466-472.
FULL TEXT
|
ISI
| PUBMED
31. Murtha S, Chertkow H, Beauregard M, Dixon R, Evans A. Anticipation causes increased blood flow to the anterior cingulate
cortex. Hum Brain Mapp. 1996;4:103-112.
32. Richardson NR, Gratton A. Behavior-relevant ch |
