In neuropathology where white matter is affected, white matter volume loss likely contributes to impairments in cognition, emotion, and behavior. Neuroimaging has documented alcoholism-related abnormalities in gray matter (Fein et al., 2002; Makris et al., 2008), as well as in white matter microstructure (Harris et al., 2008; Pfefferbaum et al., 2009; Rosenbloom et al., 2003; Yeh et al., 2009) and macrostructure (Demirakca et al., 2011; Pfefferbaum et al., 1992, 1997). This white matter damage could contribute to diminishment of communication among gray matter regions that normally function together as a network, leading to impairments that resemble disconnection syndromes (Geschwind, 1965). Indeed, numerous associations between white matter pathology and impairments in alcoholics have been reported for visuospatial abilities (Muller-Oehring et al., 2009), cognitive flexibility (Chanraud et al., 2009), executive functions (Chanraud et al., 2007), and balance and psychomotor speed (Pfefferbaum et al., 2010). Identification of regional variability in white matter loss can inform the etiology of these and other behavioral impairments in alcoholism.
Although diffusion tensor imaging has allowed for precise localization of white matter pathology in alcoholism, white matter volume loss most often is assessed at a fairly gross level. In this study, we employed a parcellation algorithm that allows for investigation of cortical white matter volumetrics on a finer scale (Salat et al., 2009) to confirm and more precisely localize previous reports of the relationship between prolonged alcohol abuse and white matter tissue volume in the corpus callosum, the cerebrum, and the cerebellum, as well as in the ventricles (Demirakca et al., 2011; Filley, 2001; Hommer et al., 2001; Kril et al., 1997; Oscar-Berman and Marinkovic, 2007; Pfefferbaum et al., 1997; Sullivan, 2003). We expected that control participants would have larger white matter volumes than alcoholics, particularly in the corpus callosum and frontal lobes, as well as smaller ventricles. We further anticipated that among alcoholics, longer durations of alcoholism and higher quantities of alcohol consumed would be associated with smaller white matter volumes and larger ventricles. In addition, because it has been demonstrated that there is potential for white matter regrowth following injury in adult brain tissue (Davies et al., 1997), and because recovery of white matter after periods of even brief abstinence among alcoholics has been reported (Agartz et al., 2003; Bartsch et al., 2007; Gazdzinski et al., 2010; Shear et al., 1994), we expected that longer durations of sobriety would be associated with larger white matter and smaller ventricular volumes. Because rates of recovery of white matter following abstinence from alcohol may change over time (Mon et al., 2011), we expected that the effect of sobriety duration would vary between early (<1 year) and later (1 year or more) abstinence.
Finally, the issue of gender differences related to the impact of chronic alcoholism on white matter has yielded conflicting results, with studies suggesting greater impact on women (Hommer et al., 2001), greater impact on men (Pfefferbaum et al., 2001), regionally specific gender differences (Pfefferbaum and Sullivan, 2002), or no gender differences (Demirakca et al., 2011). Differential findings likely are related to methodological differences among studies, especially participant characteristics such as drinking severity and length of abstinence. As such, we investigated white matter and ventricular volumes and their relationships with drinking variables separately in alcoholic men and women, as well as tested for gender interaction effects.
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- Materials and Methods
In this study, the relationships among drinking history variables and white matter and ventricular volumes were assessed in alcoholic men and women. Our multilevel data analysis approach allowed us to confirm effects in total/lobe-level white matter and ventricular regions, and then to explore these effects on a more focal ROI level than has been previously reported. Further, the interactions of alcoholism and drinking history with gender were studied. These analyses yielded stronger alcoholism group effects among men than women in corpus callosum volume (Fig. 2). Years of drinking impacted alcoholic women primarily in frontal and temporal white matter (Fig. 3A), whereas alcoholic men showed effects of prolonged alcoholism in the corpus callosum (Fig. 3B). Quantity of alcohol consumed was associated with larger ventricles and smaller corpus callosum volumes among alcoholic women only (Fig. 4), whereas LOS was associated with larger corpus callosum volumes among alcoholic men only (Fig. 5). Examining early and later abstinence separately, white matter increases with longer durations of sobriety were observed among alcoholic women in the first year of sobriety, but after more prolonged abstinence among alcoholic men (Fig. 6).
Alcoholism Effects on White Matter and Ventricular Volumes
These analyses demonstrated a difference in corpus callosum volume between alcoholics and controls. In spite of evidence for larger corpus callosum volumes among alcoholic men with longer durations of sobriety, we found a stronger alcoholism group difference for men than for women, consistent with previous reports of alcoholism effects in the corpus callosum (Pfefferbaum et al., 1996; Pfefferbaum et al., 2002). Alcoholic men also showed a stronger impact of years of heavy drinking in the corpus callosum, where negative associations between years of drinking and volume were larger than they were among alcoholic women. Taken together, these results suggest that alcoholic men may be more vulnerable to white matter damage in the corpus callosum than alcoholic women. The corpus callosum was the only region in our analyses where significant group differences were identified, perhaps as a result of positive associations between longer durations of sobriety and larger white matter volumes in men and women alike (mean LOS among alcoholics was over 8 years). Thus, white matter volume group differences that may have been detectable after shorter durations of abstinence were possibly ameliorated. In addition, our results suggest that even when group-level differences cannot be detected in white matter volume, the impact of chronic alcoholism still can be detected by variability in volume on the basis of drinking history, in agreement with previous findings (Pfefferbaum et al., 2002).
Drinking History Variable Associations with White Matter and Ventricular Volumes
More years of heavy drinking were associated with smaller white matter volumes in different regions for alcoholic men and women. This association was present for alcoholic women in cortically-associated white matter regions in the frontal and temporal lobes. In contrast, among alcoholic men, DHD was not associated with smaller volumes in any cortical white matter regions, but was in the corpus callosum. Many of the frontal white matter regions we identified as being sensitive to years of heavy drinking in alcoholic women are those that play a role in emotional regulation and reward functioning, consistent with other reports of white matter disruption contributing to impairments in these functions (Schulte et al., 2010). Although DHD was positively associated with age, multiple regression analyses showed that DHD was a stronger predictor of yearly white matter volume loss in many regions.
This study demonstrated a negative correlation between quantity of drinking and corpus callosum volume in alcoholic women, but not alcoholic men. Larger ventricular volumes also were observed among only alcoholic women in relationship with the quantity of alcohol they consumed. Research demonstrating associations between white matter damage and binge drinking behavior (McQueeny et al., 2009) suggests that high concentrations of blood alcohol could be related to severe white matter deficits. Because women generally have higher blood alcohol levels with the same amount of alcohol consumed (Graham et al., 1998), the impact of alcohol consumption quantity may be more easily detectable among women. This may explain in part why higher quantities of alcohol consumed were associated with smaller white matter volumes and larger ventricles among women, but not among men.
When considering alcoholic participants in early and later abstinence together, LOS was positively associated with corpus callosum volume among alcoholic men, but not among alcoholic women. That this effect was identified only among alcoholic men may be related to the finding that alcoholic men also showed stronger alcoholism group effects in the corpus callosum (suggesting that they had greater capacity for potential gains in corpus callosum volume relative to alcoholic women). The positive association between corpus callosum volume and sobriety duration among men only was consistent with the pattern found for participants later in abstinence (i.e., sober for more than 1 year), as described below.
Relationship of Length of Sobriety with White Matter and Ventricular Volume in Early and Later Abstinence
Throughout the brain, including corpus callosum, frontal, cingulate, temporal, and occipital regions, increases in white matter volume with longer abstinence were observed among alcoholic women with <1 year of abstinence. However, this relationship was not observed in any white matter region in alcoholic women with more than a year of sobriety. Conversely, no regional white matter volumes correlated with LOS among alcoholic men with less than a year of abstinence, but LOS was significantly correlated with corpus callosum and frontal white matter volumes among alcoholic men sober for a year or more. This preliminary double dissociation, although based on a small sample size, suggests that white matter recovery may occur following shorter durations of abstinence for alcoholic women than for alcoholic men. In agreement with our results, a positive correlation between cortical white matter and LOS has been reported among alcoholic women with <1 year of sobriety (Pfefferbaum et al., 2002).
When alcoholic participants were grouped by early and later abstinence, we found positive associations between LOS and white matter volumes, particularly among several frontal areas, consistent with frontal white matter restoration reported from a longitudinal study of alcoholics after 5 weeks of recovery (Gazdzinski et al., 2010). While many longitudinal studies have reported increases in white matter following abstinence (Agartz et al., 2003; Cardenas et al., 2007; Demirakca et al., 2011; Gazdzinski et al., 2010), these effects were consistently observed following brief (<1 year) periods of abstinence. A study comparing recovering alcoholics to those still drinking included some participants with longer periods of abstinence and found larger frontal white matter volumes among recovering alcoholics; however, this study included both men and women and did not specifically address gender differences in white matter recovery (O'Neill et al., 2001).
Of note, in the sample used in this study, alcoholic men sober for less than a year had larger ventricles with longer LOS. As positive white matter associations with sobriety length were never observed in alcoholic men in association with these shorter durations of abstinence, we would not expect a corresponding decrease in ventricular volume. However, an increase in ventricular volumes with LOS is nonetheless unexpected, and may suggest that brain tissue shrinkage continues through the first year of abstinence in alcoholic men.
In this study, our primary objective was to further localize effects within regions that are known to suffer white matter damage in chronic alcoholism, rather than to do an exploratory analysis of all regions in the brain. However, by only exploring subregions when a total/lobe-level region was significant, we may have failed to identify effects in isolated subregions (i.e., where similar effects did not exist elsewhere nearby).
In this sample of alcoholics, men tended to have indicators of more severe alcoholism than women, consistent with typical drinking history patterns reported in the literature (Dawson and Archer, 1992). Although this contributes to differential effects by gender, it lends ecological validity to the findings. We recognize that several factors known to contribute to the integrity of white matter were not included in these analyses, such as cigarette smoking, body mass index, hormone therapy, and comorbid mood disorders. How these factors interact with drinking variables to influence white matter and ventricular volumes are important avenues of further study.
Whereas we included age as a covariate in our analyses, some studies have shown that aging effects on white matter volumes may be nonlinear (Westlye et al., 2010), and that the interaction of aging and alcoholism on brain volumes is dynamic (Pfefferbaum et al., 1992, 1997). Furthermore, the effects of gender and alcoholism on volume may interact differently throughout the lifespan (Medina et al., 2008); thus, continued study of the interactions of aging effects with gender and drinking history is warranted. In addition, it has been suggested that microstructural changes in white matter precede macrostructural volumetric changes in alcoholism (Pfefferbaum and Sullivan, 2002). Future studies should closely address the relationship between microstructural white matter changes and white matter volume loss in alcoholism.