Reduced corpus callosum white matter microstructural integrity revealed by diffusion tensor eigenvalues in abstinent methamphetamine addicts
Introduction
Methamphetamine (MA), also known as “ice” or “crystal,” is a cationic lipophilic molecule with potent action on the central nervous system. It stimulates the mesolimbic reward pathway, causing euphoria and excitement, and is thus a highly addictive substance associated with a range of serious health problems that include cognitive impairment (Steketee, 2003, Nordahl et al., 2003). The neurotoxic effects of MA have been extensively reviewed (Axt et al., 1994, Kleven and Seiden, 1992, O’Callaghan and Miller, 2000, Davidson et al., 2001), and the various types of brain abnormalities present in long-term MA abusers have been reported in neuroimaging studies (Paulus et al., 2002, Sekine et al., 2003, Jernigan et al., 2005). Although most neuroimaging studies of MA abusers have focused on damage to the frontal gray matter, a magnetic resonance spectroscopy (MRS) study also reported neurochemical deficits of the frontal white matter in MA-abusing subjects (Ernst et al., 2000). Several positron emission tomography (PET) studies demonstrated that MA abusers exhibit lower levels of dopamine transporters in the striatum (McCann et al., 1998, Sekine et al., 2001, Volkow et al., 2001) and prefrontal cortex (Sekine et al., 2003), and differences in regional cerebral glucose metabolism (Volkow et al., 2001, London et al., 2004) compared with corresponding measures in control subjects. A recent diffusion tensor imaging (DTI) study reported that abstinent MA abusers had disrupted integrities in the frontal white matter (WM) (Chung et al., 2007). The results of these neuroimaging studies suggest that damage to frontal brain regions after MA abuse may contribute to the wide range of cognitive deficits observed in MA abusers.
The corpus callosum (CC) is the largest white matter structure in the brain, consisting mainly of interhemispheric fibers. Although structural MRI studies have confirmed alterations in brain structures, including the CC, in patients with drug addiction (Hommer et al., 1996, Thompson et al., 2004), diffusion tensor imaging has increasingly been employed in investigating the neuropathology of addiction. In patients with alcohol dependence, DTI showed white matter microstructural abnormalities in the CC consistent with reduced fractional anisotropy (FA) and intervoxel coherence of fibers (Pfefferbaum and Sullivan, 2005). In cocaine dependence, results showed significantly reduced FA in the genu and rostral body of the anterior CC compared with controls (Moeller et al., 2005). Most recently, Moeller et al. (2007) reported significantly smaller longitudinal (λ1) eigenvalues along the principal diffusion axis in the rostral body of the corpus callosum in 3,4-methylenedioxymethamphetamine (MDMA, known as “ecstasy”) users.
DTI is a unique method for characterizing white matter micro-integrity because it relies on the principle that water diffusion is highly anisotropic in brain white matter structures (Beaulieu, 2002). Many DTI studies reported that fractional anisotropy was decreased in lesions attributable to different neuropsychiatric conditions that may reflect edema, demyelination, and axonal loss (Kubicki et al., 2002, Ardekani et al., 2003); however, in many neuropsychiatric DTI studies, the possible physiological sources of FA alteration are not fully discussed. Recent evidence (Moeller et al., 2007) suggests that longitudinal (λ1) and transverse (λ2 and λ3) eigenvalues provide more specific information about myelination and the axonal morphology of white matter than do FA and mean diffusivity (Dav). In addition, while previous studies have explored abnormalities of the frontal lobe of the brain related to cognitive impairment in MA use, none have investigated the white matter abnormalities of CC in MA abusers, despite its functional significance. Because frontal white matter tracts cross between hemispheres in the CC, it is possible that white matter integrity in the CC could also be altered in drug-dependent subjects. For example, Moeller et al. (2005) observed compromised white matter integrity in the genu and rostral body of the CC in cocaine users.
In the present study, we used DTI to observe whether abstinent MA abusers demonstrate differences in the white matter integrity of the CC, compared with control subjects. Specifically, it was of interest whether FA is a good functional marker for MA-related change in the CC; if so, the individual eigenvalues might provide more specific information regarding damage to the white matter integrity of the CC. No previous DTI studies have clearly defined abnormalities of CC integrity in abstinent MA abusers. We hypothesized that MA abusers would show abnormalities of the corpus callosum not observed in those of non-drug users, reflecting alteration of white matter integrity caused by long-term MA use. Furthermore, we sought to interpret the microstructural source of abnormal changes in abstinent MA abusers in cases of a difference in white matter integrity in the CC of healthy controls and abstinent MA abusers by analyzing the eigenvalues of the diffusion ellipsoid. Finally, we assessed the relationship between white matter integrity and impaired cognitive function in abstinent MA abusers, using the Wisconsin Card Sorting Test (WCST).
Section snippets
Subjects
Thirteen healthy, right-handed male subjects and 11 abstinent male MA abusers participated in this study. All abstinent MA subjects recruited for this study were diagnosed solely with MA dependence and were without lifetime exposure to any other addictive substance except nicotine and caffeine. In addition, all MA subjects who had administered MA intravenously met the following inclusion criteria: (1) no previous history of comorbid psychiatric disorders, (2) no alcohol dependence, and (3)
Demographics
The mean age of the MA abusers was 34.4 ± 2.9 years, ranging from 28 to 39 years. The mean age of the healthy controls was 35.5 ± 2.1 years, ranging from 33 to 38 years. There was no statistically significant difference in age between the groups (t = 1.079, df = 22, p = 0.292); thus, DTI measures (FA and eigenvalues) were unaffected by age-related changes. The mean duration of MA abuse was 10.6 ± 2.7 years, ranging from 6 to 15 years. The dose per year ranged from 6.7 to 85.0 g. The mean abstinence period
Discussion
In the present study, DTI-derived scalar measures (FA and eigenvalues of the diffusion ellipsoid) revealed change in white matter integrity in abstinent MA abusers compared with healthy comparison subjects. MA abusers had reduced FA values in the genu of the CC. Our finding is consistent with the results of previous studies that showed reduced FA in the anterior CC in cocaine-dependent subjects (Moeller et al., 2005). Because all MA subjects were without lifetime exposure to other drugs, drug
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This research was supported by Advanced Research Center for Recovery of Human sensibility funded by Ministry of Health and Welfare (Grant #02-PJ3-PG6-EV10-0001). This work was also supported by the Brain Korea 21 Project in 2008.
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