Download Orbitofrontal Cortex and Human Drug Abuse: Functional Imaging

Orbitofrontal Cortex and Human Drug
Abuse: Functional Imaging
Edythe D. London, Monique Ernst, Steven Grant,
Katherine Bonson and Aviv Weinstein
Brain Imaging Center, National Institute on Drug Abuse,
Baltimore, MD 21224, USA
The orbitofrontal cortex (OFC), a paralimbic region, participates
in association functions, integrating emotion with behavior and
various sensory processes (Hof et al., 1995). Its dysfunction has
been implicated in psychiatric disorders that involve inappropriate emotional and behavioral responses to stimuli. The best
example is that of obsessive compulsive disorder (Rauch et
al., 1994; Breiter and Rauch, 1996; Zald and Kim, 1996), but
post-traumatic stress disorder (Semple et al., 1993), disorders
of mood (Pardo et al., 1993; Baker et al., 1997), antisocial
personality disorder (Meyers et al., 1992) and aggression
(Fornazzari et al., 1992; Siever et al., 1999) are also included.
A lthough symptoms may overlap among these and other disorders (e.g. compulsive drug-seeking by addicts, reminiscent
of behavior that characterizes obsessive compulsive disorder),
the range of pathologies linked to the OFC supports its central
role in human behavior. More specifically, the OFC contributes
to a variety of behavioral states and functions, including the
processing of reward, emotion and decision making (Bechara et
al., 2000; Rolls, 2000; Schultz et al., 2000), which are essential
components of motivational-directed behavior. The motivational
values can be innate (such as the drive for food); or they may be
learned with repeated reinforcement. Substance abuse, which
can be conceptualized as a dysregulation of motivationaldirected behavior, is an example of the latter case.
The OFC is placed in a position to code the motivational
attributes of responses to stimuli. It is a heterogeneous region
that has connections with other prefrontal, limbic, sensory and
premotor areas (Cavada et al., 2000; Öngür and Price, 2000).
Linked to the mesolimbic dopamine system that is critical for
drug reward (Di Chiara and Imperato, 1988; Koob and Bloom,
1988; London et al., 1996; Wise, 1996), it receives inputs from
association areas of each sensory modality (olfactory, gustatory,
visual, auditory and somatosensory) (Pandya and Yeterian,
1990; Morecraft et al., 1992; Cavada et al., 2000; Öngür and
Price, 2000). Therefore, the OFC has the information needed
to integrate the sensory characteristics of a stimulus-object
(Carmichael and Price, 1996). The OFC can attach an emotional
valence to the stimulus-object through its relationship with
the amygdala (Barbas and De Olmos, 1990; Morecraft et al.,
1992). Furthermore, it can evaluate these characteristics against
previous experience through its connections with regions known
to subserve memory [dorsolateral prefrontal cortex and mediodorsal nucleus of the thalamus, pars magnocellularis (Morecraft
et al., 1992; Ray and Price, 1993), hippocampus and hippocampal gyrus (Cavada et al., 2000; Öngür and Price, 2000)].
Finally, the OFC–striatum–globus pallidus–thalamus–OFC loop
(Alexander and Crutcher, 1990) can mediate reinforcement of
the motivational attribute of a stimulus-object.
A modular approach to the role of the OFC, although heuristic,
may help tease out the various mechanisms that mediate
substance abuse. Using such a strategy, individual components
of aberrant behavior in substance abusers can be studied
separately. One of these components is expectancy that is based
on predictions of reward and attribution of probabilistic
rewarding properties to the stimulus-object. Another is compulsive drive (motivational state) to use drugs, which is linked
to craving. Lastly, decision making, based on the motivational
attributes of the stimulus and the balance between expectation
of immediate reward and long-term losses, is an important aspect
of substance abuse behavior.
While considering how the OFC is involved in these three
behaviors, it is important to appreciate the heterogeneous nature
of this region, histologically and anatomically (Morecraft et
al., 1992; Carmichael et al., 1994). Anatomically, the OFC can
be divided into anterior regions, which connect with higher
association cortices (such as the dorsolateral prefrontal cortex),
and posterior regions, which have selective connections with
the amygdala, and entorhinal and perirhinal cortices. Therefore,
anterior regions schematically would be important in decisionmaking processes, and posterior regions in the emotional and
autonomic aspects of craving. Both regions could contribute to
expectancy, which depends on the evaluation of the emotional
valence of the stimulus. Along a transaxial plane, the medial OFC
is connected with the ventral striatum and the lateral OFC is
connected with the caudate nucleus, which suggests that the
medial OFC would be more important to reinforcement than the
lateral OFC.
This review covers findings from brain imaging studies that
support important contributions of the OFC to the persistent
behavioral states characteristic of addiction. To date, most
functional imaging studies have been unable to distinguish
accurately between the different regions of the OFC that might
take part in the respective behaviors. The enhanced spatial
resolution of new generation positron emission tomography
(PET) scanners and improved technology of functional mag-
© Oxford University Press 2000
Cerebral Cortex Mar 2000;10:334–342; 1047–3211/00/$4.00
The orbitofrontal cortex (OFC) plays a central role in human behavior.
Anatomically connected with association areas of all sensory
modalities, limbic structures, prefrontal cortical regions that mediate
executive function and subcortical nuclei, this brain region can serve
to integrate the physical and emotional attributes of a stimulusobject and establish a motivational value based on estimation of
potential reward. To the extent that addictive disorders reflect a
dysregulation of the ability to evaluate potential reward against harm
from drug self-administration, it would be anticipated that substance
abuse disorder might reflect dysfunction of the OFC. With the
application of brain imaging techniques to the study of human
substance abuse, evidence has been obtained that activity in the OFC
and its connections plays a role in several components of the
maladaptive behavior of substance abuse, including expectancy,
craving and impaired decision making.
Figure 1. Images of rCMRglc in a selected subject from a group of polydrug abusers (right, n = 10) and a group of control subjects who were not substance abusers but were drawn
form the same population (left, n = 10) (Stapleton et al., 1995). The arrow points to the orbitofrontal gyrus, which exhibited significantly higher rates of rCMRglc in the substance
abuse group when metabolic rates were adjusted for global metabolism. Drug abuse subjects also showed higher adjusted rCMRglc in the superior and middle temporal gyri.
netic resonance imaging (fMRI), however, offer the promise of
isolating functional activity in subregions of the OFC.
OFC Metabolism in Polysubstance Abusers: Personality Traits,
Expectancy and Motivation
PET studies, performed to elucidate abnormalities in brain
function that might contribute to the perpetuation of addiction,
have provided evidence for dysfunction of the OFC in drug
abusers. In one of these studies, regional cerebral metabolic
rate for glucose (rCMRglc), an index of local brain function
(Sokoloff et al., 1977; Phelps et al., 1979; Reivich et al., 1979),
was measured in polydrug abusers and in control subjects who
were drawn from the same community (Stapleton et al., 1995).
Twenty polydrug abusers took part in a study of the acute
effects of cocaine on rCMRglc, measured using PET with the
[18F]f luorodeoxyglucose (FDG) method (London et al., 1990).
Polydrug abusers completed two test sessions, one in which
cocaine was administered and another in which saline (placebo)
was given. Ten control subjects, recruited for comparison, also
participated in two PET sessions, but never received cocaine.
Measures of rCMRglc during only the placebo administration
were used for comparison with data from control subjects. To
avoid order effects on rCMRglc (Stapleton et al., 1997), data from
only those drug abusers (n = 10) who received placebo in their
first PET session and data from the first PET session of the control
subjects (n = 10) were used. Although the substance abusers did
not know whether they would receive placebo or cocaine for
their first session, control participants knew that they would
receive placebo for all sessions. Prior to the PET scan, each
substance abuser participated in four preliminary test sessions,
two with placebo and two with cocaine (20 and 40 mg i.v.), in
order to acquaint them with the subsequent test procedures.
Mean global metabolic rate for glucose (mg/100 g tissue/min)
in the substance abusers (6.91 ± 0.17) did not differ significantly
from the rate in the control group (7.27 ± 0.21), but the pattern
of rCMRglc differed between the two groups. Visual inspection
of the brain images revealed that control participants showed
relatively uniform cortical glucose metabolism compared with
the substance abusers, whose rCMRglc was reduced in posterior
regions (Fig. 1). When metabolic rate data for each region were
submitted to analysis of covariance with the global metabolic
rate as a covariate, the substance abusers showed higher glucose
utilization than the control group in the OFC, superior frontal
gyrus, middle temporal gyrus and insula (Table 1, Fig. 1).
Notably, the greatest group difference was in the OFC
(Stapleton et al., 1995). Of the ten substance abusers, six met
criteria for antisocial personality disorder and one met criteria
for pathological gambling. Therefore, differences in rCMRglc
of the OFC between the groups could ref lect psychological
characteristics associated with substance abuse. This view is
consistent with previous findings of abnormal rCMRglc of OFC
in individuals diagnosed with disorders of behavioral control,
Cerebral Cortex Mar 2000, V 10 N 3 335
Table 1
Regional cerebral metabolic rates for glucose, adjusted for global metabolisma
Control
Left
Frontal lobe
Superior frontal gyrusA,B
Middle frontal gyrusB,AB
Inferior frontal gyrus
Precentral gyrusB,AB
Gyrus rectus
Orbitofrontal cortexA
Anterior cingulate gyrus
Temporal lobe
Temporal pole
Superior temporal gyrusA,B
Middle temporal gyrusA
Inferior temporal gyrus
InsulaA,AB
Substance abuse
Midline
8.05
9.47
10.10
10.68
Right
Left
8.26
10.40
10.07
10.98
8.43
9.94
10.33
10.46
8.08
8.97
8.47
7.92
Right
8.86
9.95
10.04
11.37
9.00
10.06
6.07
6.59
7.84
8.61
10.09
Midline
9.12
10.63
6.00
6.19
8.09
8.23
9.81
6.17
7.26
8.54
8.66
10.53
6.18
7.01
8.71
8.70
11.09
a
Each value is the mean regional cerebral metabolic rate for glucose (rCMRglc, mg/100 g/min),
adjusted for global glucose metabolism as indicated in Materials and Methods.
A
Group factor: Substance Abuse different from Control, P < 0.05.
B
Laterality factor: Left different from Right, P < 0.05.
AB
Interaction of Group by Laterality factors, P < 0.05.
such as obsessive compulsive disorder (Baxter 1990; Benkelfat
et al. 1990). In addition, impulsive–aggressive patients showed
a blunted metabolic response in OFC after fenf luramine challenge, consistent with a deficit in serotonergic modulation of this
brain region in patients with personality disorders characterized
by a high level of impulsivity and aggressiveness (Siever et al.,
1999).
Emotional state, related to expectancy of drug reward,
may have also been ref lected in the higher rCMRglc in the OFC
of the substance abusers. As they took part in a double-blind
procedure in which the injection could have been placebo or
cocaine, they likely experienced a negative emotional reaction
(e.g. disappointment) when they realized that they had received
placebo. In contrast, control participants would not have been as
likely to have this emotional response. This interpretation is
supported by our findings from a recent study (Grant et al.,
1996) in which normalized rCMRglc was negatively correlated
with self-reported mood in a number of OFC regions when
neutral (not drug-related) visual cues were presented.
The elevated rCMRglc in other cortical areas (insula, temporal
lobe and superior frontal gyrus) in addition to OFC in the
substance abusers suggests that the response to the placebo
injection included activation of a circuit related to a component
of motivation. Classic work of Mesulam and Mufson in the old
world monkey has demonstrated connections between the
OFC and insula, which also receives projections from the
temporal pole and other paralimbic areas (Mesulam and Mufson,
1982a–c). On the basis of this and other work, these authors
suggest that the paralimbic brain, particularly its insulo-orbitotemporopolar component, provides integration between extrapersonal stimuli and the internal milieu (Mesulam and Mufson,
1982a,c). In this light, elevated rCMRglc in the OFC and insula
(and also in temporal and superior frontal areas) is consistent
with an interpretive response to placebo administration in the
context of expectancy of drug reward. Such integration can be
critical to the ‘motivational state’ or drive to use drugs.
Although the PET study situation was markedly different from
the typical conditions of drug self-administration, the substance
abusers may have shown conditioned drug effects, as they had
336 Orbitofrontal Cortex and Drug Abuse • London et al.
previously received cocaine under test conditions that were
in some ways similar to the PET session. Thus, the higher
rCMRglc as compared with control values may ref lect activation
in response to conditioned, drug-related cues (i.e. an injection
given by an investigator who administered cocaine previously in
a test situation). Nonetheless, substance abusers also exhibit
higher normalized rCMRglc under conditions where there are
no drug-related cues or expectancy of drug administration. A
supplementary analysis of the data collected in our study of
cue-elicited cocaine craving (Grant et al., 1996) compared
rCMRglc in seven OFC brain regions of substance abusers and
controls only in the session where a non-drug (arts and crafts)
stimulus complex was presented. Drug abusers exhibited a
significantly higher normalized rCMRglc than controls in the
medial prefrontal cortex.
Role of the OFC and its Connections in Drug Craving
In addition to the aforementioned evidence that the OFC shows
an abnormality in rCMRglc, which may be related to some
degree to conditioned responses and motivation, findings obtained with PET and fMRI have suggested that activation of the
OFC and its connections accompanies cocaine craving (Table 2).
Although it is not definitively proven that the activation reported
ref lects the mechanism by which craving is induced, the findings are consistent with an integrative function of the OFC,
as supported by its anatomical connections. It is tempting to
speculate that activation of cortical regions with sensory and
limbic functions, along with activation of the OFC, ref lects an
interplay of related networks. Thus, sensory information about
environmental (or internal) stimuli might be interpreted at
the level of the OFC, which connects with the amygdala in
evaluating the motivational value of the stimuli, and labeling the
emotional response as craving.
One approach to the study of the neurobiological substrates of
craving has involved the induction of craving by presentation
of stimuli that have previously been associated with drug use.
There is substantial evidence that exposure to cues, such as
the paraphernalia used during drug self-administration, which
are strongly associated with previous drug taking, can trigger
craving for drugs of abuse (Childress et al., 1992).
Our research group studied cue-elicited cocaine craving in
cocaine abusers (n = 13) and control participants (n = 5), who
were presented with a stimulus complex, including a cocainerelated videotape and paraphernalia in one session and a videotape and objects related to arts and crafts in another session
(Grant et al., 1996). We also measured rCMRglc by the FDG
method and PET. Exposure to cocaine-related cues produced
self-reports of craving and activation in the medial OFC and
five other composite cortical brain regions in cocaine abusers:
dorsolateral prefrontal, peristriate, temporal/parietal, retrosplenial and temporal (see Fig. 2). Furthermore, self-reports
of craving were positively correlated with metabolic increases
in the dorsolateral prefrontal cortex, medial temporal lobe
(amygdala) and cerebellum. These effects were not seen in
non-drug-abusing control participants. The activation pattern
seen in our study, involving the OFC and several areas to which
it is linked anatomically, is consistent with an integrative
function of OFC, involving brain areas that participate in sensory
processing (peristriate cortex) and episodic memory
(dorsolateral prefrontal cortex and temporal areas), as well as
emotional coding (amygdala).
Childress et al., by assay of regional cerebral blood f low
(rCBF) with 15O-labeled water, also investigated the response to
Table 2
Brain regions showing altered function during craving for drugs of abuse
Type of study
Study
Treatment effects
Correlations with craving
Drug administration
Cocaine-induced craving
fMRI (Breiter et al., 1997)
nucleus accumbens, subcallosal cortex, striatum, basal
forebrain, thalamus, cingulate, parahippocampal gyrus,
lateral prefrontal cortex, striate/extrastriate (increases)
temporal pole, medial prefrontal cortex, amygdala
(decreases)
anterior cingulate, right thalamus, cerebellum
nucleus accumbens, subcallosal cortex, parahippocampal
gyrus, lateral prefrontal cortex (positive correlation)
right amygdala (negative correlation)
Methylphenidate-induced craving
in cocaine abusers
Cue-induced craving
Cocaine cues
PET rCMRglc (Volkow et al., 1999)
Cocaine cues
fMRI (Maas et al., 1998)
Cocaine cues
PET rCBF O15 (Childress et al., 1999)
Cocaine cues
PET rCMRglc (Wang et al., 1999)
dorsolateral prefrontal cortex, medial OFC, temporal/parietal, dorsolateral prefrontal cortex, medial temporal lobe,
peristriate, temporal, retrosplenial
cerebellum (positive correlation)
anterior cingulate, left dorsolateral prefrontal
anterior cingulate, left dorsolateral prefrontal cortex (positive
correlation)
amygdala and anterior cingulate (increased)
not reported
basal ganglia (decreased)
medial OFC, left insula, cerebellum
right insula (positive correlation)
PET rCMRglc (Volkow et al., 1991)
PET rCMRglc (Grant et al., 1996)
medial OFC
medial prefrontal cortex (relative to control subjects)
Spontaneous craving
For cocaine
For cocaine
PET rCMRglc (Grant et al., 1996)
right OFC, right striatum (positive correlation)
striatum (relative to control subjects)
anterior OFC (negative correlation)
Figure 2. Images of rCMRglc, determined in a selected cocaine abuser (from a group with n = 13), during two test sessions in which either neutral (left) or cocaine-related (right)
stimuli were presented (see Grant et al., 1996). The subjects abstained from cocaine use for at least 36 h before each assay of rCMRglc. The figure shows pseudo-colored metabolic
(PET) images superimposed on the respective structural (MRI) images. The arrow points to the medial orbitofrontal cortex (MO), which exhibited a significant increase in rCMRglc
during the active cues session. Subjects also showed increases of rCMRglc in other cortical regions (temporal lobe, TL; parahippocampal gyrus, PH; peristriate cortex, PS) and reported
cocaine craving. In contrast to the metabolic increases in the cocaine abuser group, control subjects tended to show decreases in rCMRglc.
exposure to cocaine-related cues (Childress et al., 1999). While
watching a cocaine-related videotape, cocaine users experienced craving and showed a pattern of increase in limbic
(amygdala and anterior cingulate) normalized rCBF and
decreases in basal ganglia normalized rCBF relative to their
responses to a neutral videotape (nature film). These findings
generally supported our previous observations (1996) in demonstrating that limbic activation accompanies cue-induced cocaine
craving, but did not show activation of the OFC or the dorsolateral prefrontal cortex. Differences in experimental conditions
Cerebral Cortex Mar 2000, V 10 N 3 337
may account for the discrepancies. For example, the two studies
differed in the time courses of the measurements (greater
temporal resolution with rCBF than with rCMRglc), in the spatial
resolution afforded by the respective measurements (greater
spatial resolution with FDG than with 15O-labeled water), in the
stimuli (shorter duration of the videotape, repeated more often
in the rCMRglc than in the rCBF study) and in the characteristics
of the research participants (cocaine abusers had previously
demonstrated reactivity to the cues in the rCBF study but not the
rCMRglc study).
The issue of the anatomical substrates of cue-induced craving
was also addressed with fMRI (Maas et al., 1998). Audiovisual
stimuli containing alternating intervals of drug-related and
neutral scenes were presented to six men with histories of crack
cocaine use and six control participants. Activation was detected
in the anterior cingulate and left dorsolateral prefrontal cortex
in the cocaine users. In addition, self-reported levels of craving
were correlated with activation in these regions. No data were
presented for the OFC or the amygdala, which are difficult to
evaluate with fMRI because of the susceptibility to artifacts in
regions near the sinuses induced by the air-tissue interface.
A pattern of activation that was generally consistent with
the studies reviewed above was observed when drug craving
was elicited by script-driven imagery. In an FDG–PET study,
Wang et al. conducted interactive interviews in 13 active cocaine
abusers about either neutral themes or cocaine-themes during
the FDG uptake period (Wang et al., 1999). Cocaine-related
paraphernalia were also presented to the subject during the
cocaine-theme session. Increases in both absolute and normalized rCMRglc were seen in the medial OFC and left insular
cortex, and increased normalized glucose metabolism was seen
in the cerebellum. Since no control subjects were studied, it
is possible that differences in the physical properties of the
stimuli in the neutral versus cocaine-cues session could have
contributed to some portion of the observed changes in cerebral
metabolism. Self-reported cocaine craving was correlated with
absolute and normalized rCMRglc in the right insular region.
Finally, preliminary results have shown rCBF activation with
PET in the basal ganglia, insula, cerebellum and left parahippocampal gyrus in heroin-dependent individuals who listened
to personalized audiotapes (Weinstein et al., 1998). Subjects
listened to six of their own audiotaped neutral scripts and
six audiotaped craving scripts at random, each script lasting for
1.5 min, with a rest of 8 min between scripts (120 min total).
The main regions of activation were the medial prefrontal gyrus
and the anterior cingulate. Activation in the anterior cingulate
was positively correlated with self-reports of craving.
Craving induced by drug administration has been studied
with both PET and fMRI (Breiter et al., 1997; Volkow et al.,
1999). When cocaine was administered to cocaine-dependent
subjects in an fMRI study, craving was correlated with early
and sustained activation of regions that included the nucleus
accumbens, left amygdala and right parahippocampal gyrus, and
some regions of the lateral prefrontal cortex (Breiter et al.,
1997). Sustained negative signal change in the amygdala was
correlated with ratings of craving. Cocaine-induced perceptions
of ‘rush’ were associated with short-term activation of the
ventral tegmentum, pons, basal forebrain, caudate, cingulate and
most regions of the lateral prefrontal cortex. In a FDG–PET study,
craving for cocaine in cocaine abusers was elicited by injection
of methylphenidate, which has a pharmacological mechanism
of action similar to that of cocaine (Volkow, 1999). Cocaine
craving was correlated with increased normalized rCMRglc in
338 Orbitofrontal Cortex and Drug Abuse • London et al.
the posterior portion of the OFC and the striatum of the right
hemisphere. Although the report on the fMRI study indicated no
signal changes in the OFC, it is unclear whether this absence
ref lected susceptibility artifacts that precluded imaging of this
region, as in the study by Maas et al. (Maas et al., 1998). Even
though these findings suggest that activation of the OFC is
common to both cue- and drug-elicited craving, it is important to
note that there are differences in the circuitry affected when
craving is induced by cocaine itself or by cocaine-related cues.
Drug-related cues activated the amygdala and medial temporal
lobe, simulating the direct effects of cocaine. However, other
regions, such as the nucleus accumbens, which presented no
significant change in cue activation studies, showed direct
pharmacological effects of cocaine.
In addition to these findings, related to experimentally
induced craving, findings from brain imaging studies where
spontaneous craving was noted also showed involvement of
the OFC. For example, in recently abstinent cocaine abusers,
rCMRglc in the OFC and dorsoprefrontal area were correlated
with retrospective self-reports of cocaine craving during the
week that preceded the PET scan (Volkow et al., 1991). In
contrast we observed a negative correlation of cocaine-craving
with rCMRglc in the OFC in additional analysis of data from the
study by Grant et al. (Grant et al., 1996). Here, increased levels
of self-reported cocaine craving during presentation of neutral
stimuli was related to lower levels rCMRglc in the right anterior
OFC. One possible reason for the differences in direction of
the correlations is that in the study by Grant et al., subjects had
been abstinent from cocaine for only 48 h, whereas the subjects
studied by Volkow were abstinent for up to 1 week. Another
possibility may be related to the greater level of cocaine use in
the subjects studied by Volkow.
These data suggest that the OFC is involved in the induction of
craving, at least for cocaine; however, methodological factors
complicate the issue. Craving induced by cocaine itself, though
perceived by users as the drive to acquire and use more drug,
may be anatomically distinct from craving that is triggered
by stimuli conditioned through repetitive drug use. Whereas
humans may not be able to discriminate between these states,
the observations that different neurobiological substrates are
associated with these states may have profound implications for
therapeutic interventions.
The OFC and Decision Making in Drug Abusers
In light of the aforementioned evidence for a functional contribution of the OFC to expectancy states and drug craving, it is
of interest to determine how dysfunction of this brain region
might also inf luence cognitive processes, particularly decision
making in substance abusers. Despite the behavioral alterations
associated with OFC lesions, patients with such brain damage
failed to show impairments on classic neuropsychological tests
of frontal lobe function (Stuss et al., 1998; Bechara et al., 2000).
However, novel tasks that can serve as specific probes for the
functional role of the OFC have been developed (Freedman et
al., 1998; Bechara et al., 2000).
As a first step toward determining whether drug abusers
have a functional deficit involving the OFC, we have utilized a
task that was specifically designed to evaluate human patients
with lesions of the ventromedial portion of the OFC (VmOFC)
Bechara et al., 2000). Patients with these lesions demonstrate
generally irresponsible behaviors, including poor judgement
in business and personal decisions. The Gambling Task was
developed to capture these traits in a laboratory setting by
requiring subjects to make choices based on the long-term
consequences of complex reward/punishment contingencies.
The task is performed as a card game in which the participant selects cards from four decks that differ with respect to the
payoff for each card selection and the frequency and severity
of penalties, indicated by certain cards. It has face validity for
drug abuse since poor performance results from making choices
that yield large short-term rewards even when such choices
eventually lead to net losses. Indeed, one of the DSM IV criteria
for substance abuse disorder states (on p. 181) that ‘substance
abuse is continued despite knowledge of having a recurrent
physical or psychological problem that is likely to have been
caused or exacerbated by the substance’ (American Psychiatric
Association, 1994). Similarly, the World Health Organization
(1992) uses the criterion for disorders due to psychoactive substance use of ‘persisting . . . despite harmful consequences’
(p. 321). Although the Gambling Task models some aspects of
drug abuse behavior, the balance between reward and negative
consequences differs somewhat from the real life situation of
the drug abuser. One difference is the fact that the certainty of
reward is greater when considering self-administration of a drug
than drawing a card in the model task.
In our study, polydrug abusers were compared with a group
of subjects who did not use illicit drugs of abuse (Grant et al.,
2000). The scores on the GT were nearly 50% lower in drug
abusers (n = 30) than in controls (n = 24), but not as low as
those of patients with VmOFC lesions (Bechara et al., 1994).
In contrast to GT results, there was no difference in performance between drug abusers and controls on the Wisconsin Card
Sorting Task, which is sensitive to lesions of the dorsolateral
prefrontal cortex but not the OFC (Stuss et al., 1998). These
results suggest the working hypothesis that there is a functional abnormality, as opposed to a frank lesion, specifically
in the ventromedial prefrontal cortex of drug abusers, but not
necessarily in the frontal lobe as a whole. Further, they are
consistent with the notion that the OFC is linked to the ability to
balance short-term gains against longer-term consequences in
the process of decision making.
Other studies have also shown that drug abusers are likely to
make maladaptive decisions when faced with short-term versus
long-term outcomes, especially under conditions that involve
risk and uncertainty. In one of these, opioid-dependent participants placed less value on delayed monetary rewards than control
subjects (Madden et al., 1997), underscoring the concept that
drug abusers are overly biased towards the immediate value
of rewards and less able to evaluate the consequences of their
actions in the future. In another study, amphetamine abusers,
opiate abusers, non-drug-using comparison subjects and patients
with VmOFC lesions were tested on a decision-making task
similar to the Gambling Task (Rogers et al., 1999). Amphetamine
users and lesion patients performed more poorly than subjects
in the other groups, although the amphetamine users did not do
as badly as the lesioned patients. Furthermore, there was a
negative correlation between task performance and years of
stimulant use. Interestingly, experimentally induced depletion
of tryptophan, the precursor of the neurotransmitter serotonin,
in non-drug-using comparison subjects led to impaired task
performance. These results suggest that specific classes of drugs
of abuse may have a differential impact on the processes
underlying decision-making abilities, and the impact may be
inf luenced by the drug’s effect on serotonergic, and perhaps
other aminergic, neurotransmission.
Our research group has begun a series of experiments to
investigate whether impaired performance on the Gambling
Task in drug abusers is directly due to dysfunction of the
VmOFC. The aim of the first set of studies was to demonstrate
that the VmOFC is involved in Gambling Task performance in
neurologically intact subjects. We therefore conducted PET
assays of rCMRglc during performance of the Gambling Task.
Preliminary results from seven subjects indicate that the level of
performance on the Gambling Task is positively correlated with
activation of the VmOFC (Grant et al., 1999) (see Fig. 3). These
results suggest that successful Gambling Task performance
requires anatomical integrity as well as adequate metabolic
activity of the VmOFC. Our results are convergent with those
of previous neuroimaging studies showing activation of the
ventromedial prefrontal cortex in subjects who had to guess
about task-related reward contingencies (Elliott et al., 1997) or in
subjects who experienced violations in expectancies (Nobre et
al., 1999; Elliot et al., 2000).
It is important to emphasize that these imaging studies do not
preclude the participation of other brain regions in complex
decision making, especially regions with anatomical connections with the VmOFC. For example, in our study, there was also
a strong positive correlation (r = 0.93) between rCMRglc in the
amygdala and Gambling Task performance. This is consistent
with the recent demonstration of impaired performance on the
Gambling Task in patients with amygdala lesions (Bechara et al.,
1999). As reviewed in the previous section, work in our
laboratory (Grant et al., 1996) and others (Table 2) has
implicated the amygdala in behavioral processes related to
addiction, such as craving. Having obtained a preliminary
description of the brain circuitry associated with Gambling Task
performance, we have initiated PET studies to test the
hypotheses that during performance of the Gambling Task, drug
abusers will exhibit little or no activation in the VmOFC or other
relevant brain regions, such as the amygdala.
Conclusion
This review presents findings of neuroimaging studies that
implicate the OFC in several behavioral aspects of substance
abuse, including anticipation of drug reward, craving for the
drug, and possible impairments in judgement that could inf luence the decision to abstain or take the drug. For example,
cocaine-abusing research participants have manifested elevated
normalized rCMRglc in the OFC when they were in a test
situation where they anticipated possible cocaine administration but were drug-free. Furthermore, the OFC and some of its
afferents (e.g. amygdala, insula) showed activation when drug
abusers are presented with drug-related cues, such as videotapes
or their own audiotapes relating their drug experiences, which
induced drug craving. Craving induced by psychostimulant
drug administration was also correlated with changes in signal
measured from the amygdala in a fMRI study and with normalized rCMRglc in the OFC. Lastly, individuals with recent histories
of drug abuse show impairment on cognitive tasks that require
decision making, particularly the Gambling Task, their performance appearing to be related to activation of the OFC. The extent
to which differences between substance abusers and naive
control subjects, particularly related to the function of the OFC,
ref lect a pre-existing condition, which confers vulnerability
to addiction and promotes its perpetuation, is not known.
Although unproven, it is reasonable to hypothesize that the
negative consequences of drug abuse may include a negative
impact on the function of the OFC. If this were the case, drug
Cerebral Cortex Mar 2000, V 10 N 3 339
Figure 3. Saggital, transaxial and coronal sections through the VmOFC, and corresponding scores of two subjects who performed the Gambling Task. The subject, whose data are
shown in the top panel, exhibited a marked increase in metabolic activity in the VmOFC and amygdala, and performed well as indicated by positive scores in the top right graph. The
subject in the bottom panel exhibited a marked decrease in metabolic activity in the VmOFC and amygdala, and performed as poorly as subjects with VmOFC lesions, as indicated by
negative scores in the bottom right graph. Images show color-coded differences in normalized glucose metabolism measured at two times: when the subject performed a control task
and the Gambling Task. Metabolic data are superimposed on the subject’s MRI. The more red the color, the greater the decrease. Cross hairs show the plane of section. Overall
performance on the Gambling Task during the PET session is broken down into 10 min blocks (100 cards/block). Negative numbers indicate poorer performance.
abuse would damage the very substrates of brain function that
are required for recovery.
The initial impression from the work reviewed supports the
view that the OFC, through its anatomical connections with
sensory and limbic systems, serves as a critical ‘node’ in the
processing of environmental and internal cues to generate
feeling states that inf luence the motivation to seek and selfadminister a drug. Even if this inference ultimately were proven
to be true, however, several important tasks would still lay
before us. We would need to identify the neural networks that
code for the different behavioral components of substance
abuse, such as drug expectancy, craving, and impaired decision
making. It then would be important to characterize the role
of the OFC in these networks as primary or secondary; and to
evaluate the contribution of possible dysfunction of the OFC
to the deviant behaviors of substance abuse (e.g. necessary but
insufficient, sufficient but not necessary, or insufficient and
not necessar y). A final step would be identification of the
340 Orbitofrontal Cortex and Drug Abuse • London et al.
neurochemical messengers that operate in the networks. Even
before these tasks are tackled, however, it is important to consider the findings reviewed above in the design of therapeutic
approaches for substance abuse. This instruction is particularly
relevant to the implementation of a cognitive therapy that would
require executive functioning that requires integrity of the OFC
and its connections.
Notes
Address correspondence to Edythe D. London, PhD, Brain Imaging
Center, NIDA, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Email: [email protected].
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