Brain atrophy in long-term abstinent alcoholics who demonstrate impairment on a simulated gambling task
Introduction
Alcoholism and drug abuse are disorders in which people continue their use of harmful substances despite major long-term negative consequences (e.g. in the areas of employment, family, education, and health). A number of studies (Bechara, 2001, Bechara et al., 2001, Grant et al., 2000) have examined the mechanisms underlying this aspect of substance dependence using the simulated gambling task (SGT) developed by Bechara et al. (1994). The SGT simulates real-life decision-making that requires an individual to weigh long and short-term rewards and punishments in an atmosphere of uncertain outcomes. A hallmark of drug and alcohol abuse is that users persist in behaviors that have short-term benefits (e.g., intoxication) despite long-term major negative consequences.
The gambling task was initially developed to study patients with acquired sociopathy due to damage to the ventromedial prefrontal cortex (VMPFC) (Bechara et al., 1994, Bechara et al., 1997). Such patients often take part in risky behaviors that are immediately gratifying while ignoring negative future outcomes. It is thought that they cannot see beyond short-term rewards to potential long-term consequences (Bechara et al., 1994). Compared with controls, when engaged in the SGT, patients with VMPFC lesions consistently choose to draw more cards from decks with larger immediate rewards and long-term net losses, than from decks with a smaller immediate reward, smaller delayed punishments and long-term net gains (Bechara et al., 1994, Bechara et al., 1997). Dysfunction of the VMPFC may predispose an individual to make disadvantageous personal choices possibly leading to socially inappropriate, or socially deviant behavior (Bechara et al., 1994, Bechara et al., 1997), or to drink excessively even when it leads to significant problems.
There is also a growing body of literature implicating the amygdala in decision-making and learning (Baxter and Murray, 2002, Baxter et al., 2000, Kahn et al., 2002, Rogers et al., 2004, Tabert et al., 2001, Winstanley et al., 2004). Furthermore, Bechara and others have shown that patients suffering from damage to the amygdala also show impairments on the SGT (Bar-On et al., 2003, Bechara et al., 1999, Bechara et al., 2003, Ernst et al., 2002). Research indicates that the amygdala and VMPFC are part of a ‘circuit’ that is activated in decision-making (Baxter et al., 2000, Bechara et al., 1999, Bechara et al., 2003, Ernst et al., 2002, Winstanley et al., 2004). Findings by Bechara and colleagues indicate that the roles played by the amygdala and VMPFC in decision-making are different (Bechara et al., 1999, Bechara et al., 2003). In an SGT study measuring skin conductance responses, Bechara and colleagues found that patients with either amygdalar or VMPFC damage were impaired on the SGT, but only those with amygdalar damage did not generate skin conductance responses when they received either the positive (winning money) or negative (losing money) feedback. This finding suggests that the amygdala is involved in the attachment of emotional valence to events (i.e., rewards and punishments). In contrast, the VMPFC is involved in integrating associations between events and their outcomes (including the emotional aspects of their outcomes) (Bechara et al., 1999).
Studies show that currently active or recently detoxified alcoholics (Bechara and Damasio, 2002, Bechara et al., 2001, Mazas et al., 2000) and drug abusers (Grant et al., 2000, Petry et al., 1998) exhibit impaired performance on the SGT. Their performance is characterized by favoring larger immediate rewards while disregarding long-term negative consequences. This pattern of impaired decision-making resembles the typical decisions made by an alcoholic to drink excessively to experience the immediate pleasure of intoxication in spite of the many longer-term consequences of intoxication (Clark and Robbins, 2002). Recent research suggests that substance abusers perform poorly on the SGT because they tend to be hyper-responsive to reward and under-responsive to punishment, (Stout et al., 2004), which might reflect differences in amygdalar function. Using mathematical models of SGT performance, Stout et al. (2005) found that cocaine abusers differed significantly from controls on the valence model parameter, reflecting an increased attention/response to gains and decreased attention to losses.
In a recent paper we demonstrated that long-term abstinent alcoholics (AbsAlc) (abstinence duration ranging from 6 months to 13 years, with a mean abstinence duration of 6.7 years) were impaired on the SGT compared to age and gender comparable controls (Fein et al., 2004b). In the current manuscript we used Statical Parametric Mapping (SPM2) voxel based morphometry (VBM) to examine whether the long-term abstinent alcoholics in whom we found SGT impairments also have reduced volumes of their VMPFC or amygdala. SPM2, in its standard form implements voxel-based morphometry using T1-weighted brain images that include the scalp, skull and meninges as inputs, and incorporates a morphological clean-up step to remove ‘non-brain’ tissue. In a recent manuscript (Fein et al., 2006), we found that: (1) SPM2 does a poor job removing the non-brain tissue, (2) poor alignment of individual brains with the brain in the MNI template, resulting in an incorrect delineation of cortical gray matter, and (3) that this incorrect delineation of cortical gray matter dramatically increases the error term in the SPM2 analyses, reducing the sensitivity of standard SPM2 to detect experimental effects. We modified the SPM2 processing pipeline to accept skull-stripped inputs and demonstrated that the modification reduced the error term by about one third, with concomitant increases in the sensitivity to detect experimental effects. In the current manuscript, we use skull-stripped inputs to take advantage of the increased sensitivity that doing so affords. We also corrected for multiple comparisons only in a region of interest (ROI) encompassing the VMPFC and amygdala. Restricting the analysis to a ROI enables testing of a priori hypotheses with increased power (since the analysis needs to be corrected for fewer multiple comparisons). While ROI analyses have been used extensively with fMRI data, we believe the work presented below is the first application of ROI analysis to VBM.
Section snippets
Participants
A total of 101 participants were recruited from the community at large by postings at AA meeting places, café postings, newspaper advertisements and a posting on a local Internet site. Two groups were recruited, controls (n = 58, 21 men and 37 women), and abstinent alcoholics (n = 43, 25 men and 18 women). The inclusion criteria for the control group was a lifetime drinking average of less than 30 drinks per month with no periods of more than 60 drinks per month. Abstinent alcoholic's needed to
Gambling game results
The SGT results are taken from an earlier paper (Fein et al., 2004b). Compared with controls, long-term abstinent alcohol-dependent individuals made more disadvantageous decisions on the SGT (F1,98 = 4.03, p < 0.05), and women made less disadvantageous decisions than men (F1,98 = 4.08, p < 0.05) (see Fig. 1). No group by gender interaction was observed.
VBM results and behavioral correlations
Fig. 2 depicts the results of the ROI SPM2 analysis on a glass brain. Abstinent alcoholics had significant areas of reduced gray matter bilaterally in
Discussion
The results from our VBM ROI analysis revealed that long-term abstinent alcoholics who show impairment on the SGT also show bilateral reduction of gray matter in the area of the amygdala when compared to controls. There was no evidence of differential gray matter reduction between abstinent alcoholics and controls within the VMPFC. These findings suggest that the decision-making deficits in these long-term abstinent alcoholics may reflect an abnormality in brain structure. This structurally
Acknowledgments
This work was supported by Grants AA11311 (GF) and AA13659 (GF), both from the National Institute of Alcoholism and Alcohol Abuse. We also express our appreciation to the NRI recruitment and assessment staff, and to each of our volunteer research participants.
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