Consistent with our a priori hypothesis, results point to a change in the neural habituation responses to practice on an incentive sustained attention task as a function of cocaine addiction. As predicted, this change encompassed the PFC. Specifically, cocaine abusers demonstrated significant BOLD signal attenuations
from novelty to practice in the ACC/vmrPFC and MedFG (deactivations returned towards baseline), and in the dorsolateral PFC (MFG/SFG) and also the cerebellum (activations returned towards baseline) (.2 and ). This pattern in the cocaine subjects was associated with more severe cocaine use (encompassing craving, frequency of use and length of abstinence). In contrast, control subjects demonstrated significant BOLD signal amplifications
(i.e., an increase in deactivations further away from baseline) in posterior areas (CUN and preCUN) (.1 and ). Moreover, practice-related BOLD signal decreases in the thalamus correlated with practice-related reaction time decreases, in the cocaine abusers but not control subjects (). Thus, although we report secondary analyses of separately published data, which renders the task not optimized for the assessment of neural responses to habituation, our task design (exact repetition of the same block of events) allowed us to add new information about the effect of psychopathology on neural habituation to repeated stimuli (see one prior fMRI study with auditory stimulation in 11 patients with major depressive disorder, (Michael et al., 2004
In healthy human volunteers, habituation after prolonged or repeated exposure to a certain stimulus or task is frequently associated with fMRI BOLD signal changes in a distributed network spanning the PFC (ACC/vmrPFC and dorsolateral PFC), insula, parietal and occipito-temporal regions (including the CUN and preCUN) (Chein and Schneider, 2005
) as well as subcortical regions (putamen) and the cerebellum (Puttemans et al., 2005
). Specifically, two major patterns have been identified: (1) BOLD signal attenuations (i.e., decreases towards baseline): these may reflect the more precise task-related functional map (where processes specific to novelty are removed) (Garavan et al., 2000
) that accompanies greater stimulus familiarity and task exposure (Asaad et al., 1998
); and (2) BOLD signal amplifications (i.e., increases away from baseline): these may instead reflect an expanded cortical representation of the task-relevant information (Karni et al., 1995
) or indicate a regional role in long-term memory formation that accompanies the automatization or overlearning of a response (Puttemans et al., 2005
The former pattern of fMRI BOLD signal attenuation with practice has frequently been observed in the PFC. The PFC is the main area considered to perform a ‘scaffolding’ role; that is, it copes with novel demands during unskilled and effortful performance. After practice, processes or associations are more efficiently stored and accessed and the scaffolding network falls away, evidenced by decreased signal (Petersen et al., 1998
). The latter pattern of fMRI BOLD signal amplification with practice has frequently been observed in the deactivations that characterize the more posterior regions (including the CUN and preCUN); it has been interpreted to reflect increased neural efficiency in the brain networks underlying task performance (Kelly and Garavan, 2005
), stronger representation of task demands and guidance of task output (Kirschen et al., 2005
), or an amplification of neural activity within task-relevant processing systems (Milham et al., 2003
). Note also that deactivations in the preCUN and adjacent posteromedial cortical regions have been implicated in altered states of consciousness such as sleep (reviewed in (Cavanna and Trimble, 2006
)); therefore these regions may be associated with maintaining alertness which one would expect to decrease with practice and habituation to novelty. Together, both patterns are interpreted as a learning-related transition from attention/control-demanding and declarative mechanisms to more automatic/procedural processes (reviewed in (Kelly and Garavan, 2005
The first pattern (fMRI signal attenuation with practice) was not significant in any of the inspected regions in the control subjects. In contrast, in the cocaine abusers, attenuations to practice were significant in the ACC/vmrPFC and MedFG BA 6 (deactivations returned/decreased towards baseline) and the MFG/SFG (dorsolateral PFC) and cerebellum (activations returned/decreased towards baseline). Recent fMRI studies documented decreases in the rostral ACC (BA 24/32) and MedFG (BA 6) to repeated presentations of emotionally salient stimuli in healthy subjects (Feinstein et al., 2002
; Phan et al., 2003
). Similarly, roles for the dorsolateral PFC (Chein and Schneider, 2005
) and cerebellum (Puttemans et al., 2005
) in intact practice-related processing were previously described (note that although we had no a priori hypotheses regarding the cerebellum, the cerebellum forms an integral part of the cortical-subcortical network that subserves higher cognitive function (Ramnani, 2006
)). Therefore, lack of similar results in the healthy control subjects in the current study may indicate that the control group continued responding to our incentive manipulation longer than did the cocaine group; this lingering responsivity to monetary reward may indeed be related to the control subjects’ increased ability to maintain the alert state as suggested below. Thus, although all study subjects provided higher interest and excitement ratings to the higher than lower monetary conditions, we cannot rule out the possibility that there may have been differences between the groups in their conscious awareness of the emotional saliency of the stimulus; indeed a failure to see differences in these self-reports between the groups could reflect disrupted interoception in the cocaine abusers as we suggested separately (Goldstein et al., 2007
). The use of on-line (and not post-task) self-reports may be more sensitive to these group differences.
The second pattern (fMRI signal amplification with practice) was observed only in the control and not cocaine subjects and encompassed the CUN and preCUN, consistent with an increasing reliance as practice progresses on performance-related areas located posteriorly in the brain (reviewed in (Kelly and Garavan, 2005
)). Recall that our task was simple and average performance was very high in all subjects (>96% accuracy). Therefore, this second pattern in the control subjects may also be indicative of a relative decrease in goal-directed processes (recruited during N) and a return to resting states (at P); these resting states are devoted to general information gathering and evaluation (Gusnard and Raichle, 2001
) possibly in the service of maintaining an alert consciousness (Cavanna and Trimble, 2006
) especially when the novelty elements from the task decrease with repetition. The absence of similar results (BOLD signal amplifications/increases) in the cocaine abusers cannot be entirely attributed to the group differences in task difficulty level, because performance accuracy did not differ between N and P and it was also treated as a nuisance variable in all SPM analyses. Our results therefore suggest that in cocaine addiction, a practice-dependent development of efficient, automatic, and procedural neural processes or the regulation of return to a relatively task-disengaged but alert resting state may be impaired.
Finally, in the current study where we used secondary analyses of previously published data, the fMRI BOLD signal change in the thalamus was correlated with a behavioral change to practice, such that the more the activation decreased, the faster was the behavioral response in the current sample of cocaine addicted subjects. These results are consistent with a recent implication of the thalamus in goal-directed behavior (e.g., abolishing bias for large-reward option of action and pursuing a requested
small-reward action instead (Minamimoto et al., 2005
)). Overall, both the correlation between the thalamus and speed of response () and the PFC practice effects () observed in the cocaine abusers but not control subjects in the current study may be indicative of dopaminergic influences on habituation in the former group (for dopaminergic thalamic contributions see (Sanchez-Gonzalez et al., 2005
); for similar PFC associations see (Volkow et al., 2005
)). Nevertheless, our results do not negate the potential contribution from other neurotransmitter systems (such as glutamate, GABA, norepinephrine and serotonin) that are also altered in cocaine addiction (e.g., (Cornish and Kalivas, 2000
Limitations mostly pertain to the secondary analysis nature of this study, consequently not allowing us to optimize the task or the sample size for the current purposes. The following limitations are of particular mention. First, similarly to other studies (e.g., (Landau et al., 2004
)), in our study changes in activation occurred in the absence of performance changes, i.e., the neural effects of practice were independent of evidence of changes in the behavioral data; we attribute this to the pre-task training which achieved an asymptotic behavior in all subjects and to the decreased performance variability induced by the restricted level of difficulty on the current simple task. We were therefore not able to directly attribute behavior on the task to its neural changes; use of a more difficult task could allow documentation of behavioral changes in performance during the novel block, with asymptotic levels of performance reached by the second block, and may also render the fMRI analyses more sensitive to neural habituation. Nevertheless direct brain-behavior correlations suggested that such neural habituation-related changes were behaviorally meaningful, at least for the cocaine abusers, even in the absence of overt behavioral differences between novelty and practice. We were also not able to examine error-related signal changes, and this finer analysis remains to be conducted in future studies; for example, commission errors may be indicative of increased impulsivity while non-commission errors may instead be indicative of diminished ability to maintain interest or salience attribution to the monetary reward in the cocaine addicted individuals (see for example (Garavan et al., 2003
Second, because this was one of the first fMRI studies to target habituation effects in psychopathology, power considerations led us to model responses over as many trials as possible; consequently, we may have missed habituation effects that occur rapidly, i.e., within few trials. Moreover, since this study used a block design, practice may have influenced not only sustained attention but also any one or all of the other processes involved in the task including other attention, sensory and memory processes, motor preparation, motor response and incentive motivation. Future studies using event-related designs on a trial-by-trial basis would be needed to allow a finer-grained characterization of such psychopathology-driven habituation dynamics.
Third, although activations/deactivations in the selected ROIs were not associated with age, urine status for cocaine (i.e., acute withdrawal), or cigarette smoking, the effect of these variables on practice-related neural habituation remains to be more systematically explored in larger and more homogeneous samples with drug addiction or other psychopathology. The potential effects of task-related differences () and other factors (e.g., measures of premorbid functioning) that commonly differ between subjects with an identifiable psychopathology and healthy control subjects should also be considered. In such future efforts, results need to be replicated in subgroups equated for size. In the current study group sizes were unequal; although we adjusted for this sample size difference in our analyses, we consequently also restricted the possibility of a residual Type I error or unreliable results by using stringent Bonferroni corrections. Thus, important results may have been missed.
We report habituation-related neural adaptation to a sustained attention task in frontal brain regions, encompassing the ACC/vmrPFC, dorsolateral PFC, and MedFG, and also in the cerebellum in cocaine abusers. In contrast, in control subjects, neural habituation encompassed posterior brain regions (including the CUN and preCUN). Increased response speed with practice was correlated with a respective decreased activation in the thalamus only in the cocaine abusers. The practice-related habituation of the PFC and the thalamic correlation with behavioral change in the cocaine abusers and not control subjects possibly reflect the disruption of thalamo-frontal circuits in drug addiction; structural (e.g., decreased gray or increased white matter) and functional (e.g., decreased responsiveness to neuropsychological tasks) abnormalities in this circuit have been frequently demonstrated in drug addicted individuals as previously reviewed. It is further intriguing to note that the practice-related changes in this circuit in the current study were correlated with severity of drug use (encompassing cocaine craving, frequency of cocaine use, and abstinence length). Overall, we conclude that cocaine abusers habituate faster to the environmental conditions linked with the task; this may reflect disruption of the physiological mechanisms (including dopamine and norepinephrine) involved with maintenance of interest and alertness not mitigated by a compromised PFC ability to attribute salience to a reward.
Of final note is the fact that the current study focused on the practice main effect while our separately reported analyses (Goldstein et al., 2007
) focused on the monetary main effect on this task in subjects with cocaine use disorders. Future studies using event-related designs need to employ different levels of both reward and habituation/practice, studied orthogonally, to allow for the inspection of these variables’ main and potential interaction effects on neural and behavioral responses to a sustained attention and other cognitive tasks in drug addiction.