Working memory fMRI activation in cocaine-dependent subjects: Association with treatment response
Introduction
Research on cocaine abuse has used brain imaging to examine differences in brain function in cocaine-dependent (CD) subjects. Brain-imaging studies in CD subjects that focused on the long-term effects of cocaine use have studied cocaine users after a period of abstinence ranging from 1 week to several months, and have shown differences in dopamine receptor availability and lower metabolic activity in the frontal cortex that persist for months (Volkow et al., 1992, Volkow et al., 1993). Other studies measuring brain function within minutes after a dose of cocaine have shown that cocaine acutely affects brain function in a wide distribution of brain regions including, but not limited to, regions involved in reward, memory, and decision making (Breiter et al., 1997, Breiter and Rosen, 1999). Studies focusing on the state of brain function in cocaine users during the period of early abstinence (ranging from hours to days after last use of cocaine), in which the subjects were not intoxicated with cocaine but often had urine drug screens that were positive for the cocaine metabolite benzoylecgonine, have also shown differences in brain function between chronic cocaine users and controls (Volkow et al., 1991, Kaufman et al., 2003, Tomasi et al., 2007a, Tomasi et al., 2007b). Brain function measured in this early abstinence period after cocaine use may be most relevant for treatment studies, since a majority of outpatient treatment-seeking cocaine users present for treatment research in early abstinence (Sayre et al., 2004). Using positron emission tomography (PET), Volkow et al. (1991) showed that chronic cocaine users who were within 1 week of cocaine withdrawal had higher rates of regional brain metabolism in the basal ganglia and orbitofrontal cortex than normal control subjects. These differences were not found in subjects who were studied after 2 to 4 weeks of cocaine withdrawal (Volkow et al., 1991). Studies using functional magnetic resonance imaging (fMRI) have also shown differences in brain function in cocaine users who were in early abstinence. fMRI activation in the cingulate, presupplementary motor cortex, and insula was significantly reduced in cocaine users while performing a go–nogo task compared with controls (Kaufman et al., 2003). More recently, using a sustained visual attention task, Tomasi et al. (2007a) showed that cocaine users in early abstinence had hypoactivation in the thalamus and hyperactivation in occipital and frontal cortices compared with controls. One of the few studies to examine brain function during working memory in cocaine users showed that cocaine users in early abstinence had lower activation in the mesencephalon and thalamus compared with controls (Tomasi et al., 2007b). The authors pointed out that these are brain regions where either dopamine neurons are located (mesencephalon) or are the target of dopamine pathways (thalamus) (Tomasi et al., 2007b).
In parallel to brain-imaging studies in cocaine users, a separate line of research has measured baseline behavioral characteristics as potential predictors of treatment response in cocaine dependence. Moeller et al. (2001) showed that impulsivity as measured by the Barratt Impulsiveness Scale (BIS-11) was a significant predictor of treatment retention; CD subjects who had scores above the median on the BIS-11 were significantly more likely to drop out of treatment than CD subjects who had scores below the median. This finding was replicated by Patkar et al. (2004). More recently, other behavioral and cognitive measures have been examined as predictors of treatment response in cocaine dependence. Aharonovich et al. (2006) examined the relationship between baseline performance on a cognitive assessment battery and subsequent treatment response in CD subjects. Results of that study were that subjects who dropped out of treatment had significantly lower scores on a computerized MicroCog than subjects who remained in treatment for 12 or more weeks (Aharonovich et al., 2006). Green et al. (2009) examined the relationship between treatment outcome and baseline performance on a measure of decision making, the Iowa Gambling Task (IGT) in CD subjects. Findings of that study were that CD subjects who had better decision making as measured by the IGT were more likely to show a reduction in cocaine-positive urines when treated with citalopram (Green et al., 2009).
Although there have been several studies showing differences in brain function between cocaine users and non-drug-using controls, and some studies showing that baseline cognitive function predicts treatment response in cocaine users, to date there have been few studies showing a relationship between differences in brain activation and subsequent treatment response in cocaine users. To our knowledge, the only published study linking brain activation on fMRI and subsequent treatment response was published by Brewer et al. (2008), comparing CD subjects in early abstinence with controls while performing a Stroop color word interference task. Results of that study showed that CD subjects had a significant correlation between pretreatment activation in the right putamen and subsequent percent negative cocaine urine drug screens (Brewer et al., 2008).
In order to further examine pretreatment brain function in CD subjects who are in early abstinence, fMRI was conducted on treatment-seeking cocaine users and non-drug-using controls while performing a working memory task. A working memory task was chosen for use in the scanner, since the relationship between working memory and dopamine is well established (Goldman-Rakic, 1996), and chronic cocaine users have been shown to have alteration in dopamine function in previous imaging studies (Volkow et al., 2004), which is predictive of the choice of cocaine over money in the laboratory (Martinez et al., 2007). The hypotheses of the study were: 1) cocaine users would show differences in brain activation in brain regions known to be associated with dopamine function compared with controls while performing a working memory task; 2) these differences would be correlated with subsequent treatment response in cocaine users. CD subjects showing the greatest differences from controls would show the worst treatment outcome.
Section snippets
Subjects
This study was approved by the Institutional Review Board (IRB) for the University of Texas Health Science Center-Houston, and was in accordance with the 1964 Declaration of Helsinki. Subjects were recruited prior to treatment initiation in two IRB-approved treatment studies at the UT-Houston Treatment Research Clinic. Subjects were recruited using IRB-approved advertisements. Subjects were fully informed of the procedures, risks, and benefits of all studies, and written informed consent was
Demographics
The final sample consisted of 19 CD and 14 NORM subjects. Two NORM subjects and 6 CD subjects were included whose FLAIR MRI brain scans showed a few small white matter hyperintensities that were judged to be clinically insignificant by the radiologist (LAK) and the other physician coauthors (FGM and JLS) prior to the experimental analysis. None of the other subjects had any brain abnormalities on FLAIR scans. All the CD subjects met DSM-IV criteria for both current and past cocaine dependence.
Discussion
CD subjects showed reduced activation relative to non-drug using controls in prefrontal cortex, striatum, and thalamus. These brain regions are part of a cortico–thalamic–striatal circuit, which is associated with both motor and cognitive brain functions, including working memory (reviewed in Haber and McFarland, 2001). Results of this study support previous research showing alteration in brain function in recently abstinent cocaine dependent subjects. Consistent with our results, Tomasi et al.
Acknowledgements
This study was supported by grants from the National Institute on Drug Abuse (P50DA009262, and K02DA00403 (FGM)) and CCTS/CRU grant number UL1 RR024148.
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