As expected from prior reports on cognitive performance in MA-dependent subjects, learning performance of the MA group was worse than that of the control group in the placebo condition. However, modafinil improved the performance of the MA group to levels equivalent to those of the control group. This improvement in performance of the MA group was commensurate with greater activation in the bilateral insula, inferior frontal gyrus, and ACC during task performance. These activations were not simply related to performance differences across sessions, as we controlled for correct/incorrect responses in our fMRI analyses.
The greater impact of modafinil on learning performance in the MA group than in healthy control subjects is consistent with previous observations that individuals who perform poorly on cognitive tasks, relative to those who perform well, show greater improvement after receiving modafinil (Finke et al, 2010
; Kalechstein et al, 2010
; Spence et al, 2005
). Indeed, in the present study, a post hoc
analysis of low- and high-performing control participants (determined by a median split of performance accuracy during placebo conditions) showed a bigger effect of modafinil on performance for low- than for high-performing participants (difference in accuracy between modafinil and placebo conditions: low performers, 8% vs
high performers, 0.7% t
=0.02). Therefore, the lack of modafinil effect we observed in the control group as a whole was likely driven by the high performance of subjects who were already performing at near-ceiling levels with minimal room for improvement.
Our observation of greater activation of the ACC under modafinil than placebo conditions in the MA group has particular therapeutic relevance, as the ACC has been shown to be hypoactive in MA subjects (as compared with activity in control subjects) during tests of cognitive control (Salo et al, 2009
) and vigilance (London et al, 2005
). The boost in ACC activation observed with modafinil likely reflects greater engagement of cognitive processes important for learning, especially as ACC activation has been previously shown to correlate positively with learning performance on this task in control subjects (Ghahremani et al, 2010
). Similar correlations have been observed in schizophrenic patients on modafinil between working-memory performance and ACC activation (Spence et al, 2005
). The fact that we did not observe a modafinil effect on ACC activation in control subjects, coinciding with a null behavioral effect of the treatment in this group, suggests that modafinil influenced an improvement in MA behavioral performance by facilitating activation in this region.
In addition to the ACC, the anterior insula/ventrolateral prefrontal cortex also showed greater bilateral activation during modafinil than placebo conditions in the MA group, a difference that was not found in the control group. As activation of the anterior insula and ventrolateral prefrontal cortex is commonly observed in studies of cognitive control (eg, Cools et al, 2002
; Ghahremani et al, 2010
), and as MA subjects show neurocognitive deficits associated with this region (London et al, 2005
; Tabibnia et al, in press
), it is possible that the anterior insula/ventrolateral prefrontal activation is related to enhanced cognitive control associated with improved task performance.
The insula has been implicated in a range of psychological processes that have been characterized as involving interoceptive awareness (Craig, 2009
), with meta-analyses suggesting that it integrates multiple functions to provide a coherent world experience (Kurth et al, 2010
). Given its involvement in awareness of subjective states, along with reports of damage to this region reducing craving in cigarette smokers (Naqvi et al, 2007
) and its activation associated with drug craving (Bonson et al, 2002
; Brody et al, 2002
; Filbey et al, 2009
), the insula has been highlighted as having an important role in substance abuse (Garavan, 2010
; Naqvi and Bechara, 2009
). Although the specific mechanism by which the insula influences substance-abuse behavior is not yet clear, further empirical investigations are warranted to determine the therapeutic relevance of pharmacological manipulations of insula activation for improving treatment outcomes in MA dependence.
Despite evidence for modafinil operating on multiple neurochemical systems in the brain, including those involving serotonin, glutamate, gamma
aminobutyric acid, hypocretin/orexin, and histamine, its effects on catecholamines have been proposed to primarily underlie cognitive enhancement (Minzenberg and Carter, 2008
). Modafinil has been shown to elevate extracellular levels of dopamine in humans by blocking the dopamine transporter (DAT) (Volkow et al, 2009
), and dopamine regulation in both the anterior cingulate and insular cortices by DAT has been demonstrated in humans (Ciliax et al, 1999
). Both the ACC and the dopamine-rich striatal areas to which it projects comprise major neural circuitry, which supports the associative learning ability examined in our study (Haber and Knutson, 2010
). Given that MA subjects show reduced striatal DAT availability related to poor learning and memory (McCann et al, 2008
; Volkow et al, 2001b
), modafinil likely operates on the DAT in these regions, enhancing dopamine transmission to facilitate learning.
The reason for the mismatch between modafinil-induced increases in brain activation in control participants without improvement in performance is not clear. One explanation is that the activation was driven by participants with low performance who showed a behavioral enhancement with modafinil. Unfortunately, separately analyzing fMRI data from low- and high-performing participants was not feasible because of the small sample sizes. However, discrepancies between behavioral performance and brain activation when examining modafinil are not unique to this study. A prior fMRI study in which modafinil (100
mg) was given daily for 7 days showed no effect of the medication on performance in a test of attentional control, but reduced ACC activation during task performance (Rasetti et al, 2010
), also showing a mismatch between behavioral and fMRI effects of modafinil. Moreover, it is important to note that the mixed results found for the cognition-enhancing effects of modafinil on behavior in healthy participants often depend on the particular behavioral task, measures employed, and dosing regimens (Repantis et al, 2010
). It is possible that the specific learning paradigm or the particular dosing procedure (single-dose of 200
mg) used in this study was not sensitive enough to capture measurable cognition-enhancing effects on performance (at least, in the participants with high performance), which may have been reflected in brain activation differences.
Although we found improved learning performance with modafinil in the MA group in functional circuits important for learning, we cannot rule out the possibility that modafinil may have had a more general effect of increasing motivation and vigilance among participants, as has been shown previously in rodents (Young and Geyer, 2010
) and humans (Baranski et al, 2004
Our study used a learning task to assess prefrontal function because of the importance of learning for engagement in behavioral therapies, and evidence that modafinil can enhance learning and memory (eg, Turner et al, 2003
). Further neuromaging studies of modafinil are required to examine its effects on the neural substrates underlying other important cognitive functions, such as response inhibition and decision making, that are often compromised in substance abuse.
With continued interest in modafinil as a potential pharmacotherapy for stimulant abuse (Karila et al, 2010
), our results indicate that improvements in cognitive function elicited by the medication may augment traditional behavioral therapies and increase their efficacy. Modafinil or other cognition-enhancing medications may therefore be useful adjuncts to behavioral treatments for stimulant dependence.