Performance on standard (i.e., non drug-related) neuropsychological tasks is frequently compromised in drug addicted individuals as compared to healthy control subjects (Woicik et al., 2008
). In contrast, compared to neutral stimuli (including words), drug stimuli/words can enhance behavioral
responses in drug addicted individuals; although relatively better, these unique drug-related behavioral responses predict disadvantageous treatment outcome in this population (Cox et al., 2006
). Our results show, for the first time, that drug words (uniquely human learned verbal descriptors of stimuli) increased fMRI BOLD responses in the mesencephalon, a major source of dopaminergic release to motivationally salient or conditioned stimuli (Robinson and Berridge, 1993
; McClure et al., 2003
), in cocaine addicted individuals. These results may reflect the strong conditioned incentive properties of the drug words in the addicted group. It is therefore possible that this increased mesencephalic response to drug words reflects activation from prefrontal glutamaterigc projections that regulate dopamine cell firing and drive enhanced dopamine responses to conditioned stimuli (Kalivas, 2004
; Wise, 2009
). Further, possibly through mesencephalon’s extensive connections with the limbic prefrontal cortex (Devinsky et al., 1995
), these cue-reactive neural responses may culminate in drug-biased behaviors (e.g., uncontrollable drug seeking or craving) (Goldstein and Volkow, 2002
) in drug addicted/susceptible individuals. This latter interpretation is consistent with the significant correlations in our study between the drug-related responses in the mesencephalon with similar responses in the prefrontal cortex (); however, this interpretation remains to be validated with additional direct measures of drug-biased responses in drug addicted individuals.
A confound in our study is the use of monetary gain in this task. Here, evidence suggests that rewarding stimuli are directly related to enhanced dopaminergic tone and increased mesencephalic activation (Koch et al., 2008
). Indeed, altered fMRI responses to reward in drug users have been previously reported by our group (Goldstein et al., 2007c
) and others (Bjork et al., 2008
) as indicative of dopaminergic alterations in addiction (Volkow et al., 2004
). Nevertheless, in the current study, the word by group interaction in the mesencephalon was observed after averaging the fMRI BOLD signal across all monetary reward conditions, suggesting that the contribution of drug-word cue-reactivity in this region in addiction is significant and unique. Another limitation is that results could be attributed to several neuropsychological mechanisms, including enhanced drug word familiarity, salience, attention bias and memory processes in the CUD as compared to controls. The fMRI task controlled for some of these processes (e.g., the drug and neutral words were matched for frequency in the English language). However, similar processes remain to be tested in the self-generated drug fluency task (e.g., with simultaneous fMRI or recordings of autonomic responses). Finally, the current results need to be replicated in other subgroups of drug addicted individuals (e.g., treatment-seekers recruited from treatment centers and larger samples where the potential impact on results of individual variables such as sex and race can be studied).
In summary, our results are consistent with the effect of drug words on other (less localized/scalp) psychophysiological responses (Herrmann et al., 2000
) and with neuroimaging studies showing similar cue-induced increases in dopaminergic responses when addicted individuals view drug images
(pictures or movies) as associated with craving, withdrawal symptoms and addiction severity (Heinz et al., 2004
; Volkow et al., 2006
). Our results for the first time demonstrate that, in addicted individuals, drug words
alone can elicit an fMRI BOLD mesencephalic response, as possibly associated with dopaminergic
(and glutamatergic) mechanisms (Schott et al., 2008
) that are crucial to conditioning (D’Ardenne et al., 2008
). Moreover, the correlation between a very brief verbal fluency test, which can be easily administered (crucial for clinical studies), and fMRI cue-reactivity could be used as a biomarker of neurobiological changes in drug addiction.