The findings of this study support the hypothesis that cocaine craving is associated with differential activation of limbic structures that are thought to be important in motivation and affect. Limbic regions demonstrated a significant increase in regional CBF in response to the cocaine video within the cocaine patient group, and the regional CBF increases in the amygdala and anterior cingulate were reliably different from the pattern in the comparison subjects. The relative specificity of these regional CBF increases in cocaine patients is suggested by the absence of increases in nonlimbic comparison regions and by the absence of similar limbic activation in the comparison subjects in response to the cocaine video. The regional specificity of activation, and its restriction to the cocaine patients, also makes it unlikely that increases in regional CBF in response to the cocaine video were simply a function of the ordering of the videos or time in the scanner. The nondifferential activation of the thalamus and visual cortices by both videos points to their general comparability on sensory dimensions and indicates that the increases in limbic regional CBF in response to the cocaine video were not attributable to gross differences in sensory load or visual attention.
Coactivation of the amygdala and anterior cingulate during cue-induced craving is consistent with the importance of these two regions in affective behavior and in emotional learning (36
). The amygdala is critical for learning the relationships between biologically significant stimuli (food, sexual partners, pain) and the signals for them (37
), and in animal studies it has been shown to play a similar role in processing signals for cocaine (20
). The anterior cingulate shares reciprocal connections with the amygdala (40
) and has, among diverse functions, a known role in mood and emotional responsivity (42
). Both structures are anatomically linked with the nucleus accumbens (40
), a brain region important for the reinforcing properties of cocaine (16
) and natural rewards (22
) in animals. These interconnected regions allow the organism not only to experience the pleasure of rewards but also to learn the signals for them (critical for survival). Cocaine's supranormal stimulation of this reward circuitry results in robust, entrenched incentive learning. As shown in this study, the subjective (incentive motivational) and associated limbic effects of cocaine signals are preserved despite hypoactivity in parts of the same circuit (35
) and despite other potential effects of chronic cocaine in the brain (47
The drop in basal ganglia regional CBF during craving may also reflect the influence of these interconnected limbic structures (51
), perhaps representing active inhibition of reward-irrelevant responses. The lack of hippocampal activation during craving suggests the subordination of explicit (factual) memory (52
) to an amygdala-driven emotional state (53
). The developing brain signature of cue-induced craving is thus consistent with its clinical phenomenology: the drug user is gripped by a visceral emotional state, experiences a highly focused incentive to act, and is remarkably unencumbered by the memory of negative consequences of drug taking.
Our findings in the amygdala are supported by the recent report of positive correlations between changes in cue-induced craving and changes in glucose metabolism (another index of synaptic activity) in the medial temporal lobe (10
). On the other hand, the current paradigm induced craving without differential stimulation of the dorsolateral prefrontal cortex, a “working memory” region (54
) activated by drug-related videos both in the cited glucose metabolism study and in a recent cue study using functional MRI to index regional blood flow (11
). The videos in these studies were either repeated (10
) or intermittent (11
), making potentially greater demands on working memory than the narrative videos used in the current study. Neither our own nor the functional MRI cue findings (11
) support a role for the cerebellum in cue-induced craving, as proposed by the glucose metabolism correlative study (10
Our interpretations of the data should be taken in the context of our study's possible limitations. Although we propose that the limbic activation observed in the cocaine patients during the cocaine video reflects, at least in part, an increase in druglike cocaine desire, we cannot, of course, completely rule out the possibility that the cocaine video produced other, unmeasured or less specific subjective responses. For example, imaging studies have shown amygdalar activation in response to a variety of emotional stimuli (56
), and the anterior cingulate has a known role in selective attention (40
). However, alternative explanations such as anxiety or distress are unsupported by the pattern of findings in the current study, as there was no difference in relaxation/tension, global well-being, or the wish to get rid of bad feelings between the two video conditions. It is also theoretically possible that some difference between the patients and the comparison subjects other than cocaine history could account for the differential limbic activation in response to the cocaine video, but the pattern of demographic and clinical status variables argues against this interpretation. Finally, the possibility that seeing a second video of any type affects cocaine patients differently than comparison subjects—and in the very specific way predicted by the hypotheses—cannot be ruled out with the current design, but this explanation is less straightforward than attributing differences to the intended explicit difference between the two groups, i.e., their experience with cocaine.
Since cocaine itself can also prime a focused state of desire (5
), imaging studies with the drug might be expected to confirm limbic activation. Limbic activation has indeed been demonstrated in four animal studies (58
) and in a recent human study using functional MRI (62
). Cocaine's rapid temporal dynamics (63
) and/or local vasoconstrictive actions may have prevented a demonstration of limbic effects in several other studies (64
). Cocaine's multiple, and sometimes opposed, actions in the brain remain a significant technical challenge for in vivo imaging.
The finding of some overlap in hypoactive limbic structures with those activated during cue-induced craving suggests that the cocaine patients’ resting state could modulate the response to cues. Although this study did not find a significant correlation between resting limbic flow and the limbic response to cues, group size may have limited the ability to detect a correlation. The overlap between hypoactive and cue-activated limbic structures may also help explain the frustrated search for medications to prevent cocaine relapse. “Antiwithdrawal” agents intended to restore or enhance the dopaminergic tone of hypoactive limbic regions may actually generate an internal state experienced as craving and/or may enhance the response to external cocaine cues (70
). Conversely, “anticraving” agents that block limbic dopamine receptors may reduce cue-related craving (71
), but their blunting of mood and motivation makes compliance problematic (72
). Medications that target either specific receptor subgroups (73
) or dopamine-modulating transmitter systems (75
) may offer more promise.
In sum, the current findings in cocaine patients offer both a foundation and a strategy for studying the brain substrates of drug desire, a hallmark of drug dependence disorders. Both the results and the strategy may be generalizable not only to craving for other drugs of abuse but also to the appetitive states associated with natural rewards such as food and sexual activity.