In this sample of predominately Caucasian male, treatment seeking, alcohol dependent individuals, the primary findings were as follows: 1) The ALC cohort (i.e., Relapsers + Abstainers) demonstrated significantly lower neocortical thickness in 12 of 16 individual BRS regions than Controls as well as lower total BRS and global thickness. The same pattern of lower thickness was evident in both Abstainers and Relapsers relative to Controls. There were no statistically significant differences between Relapsers and Abstainers on neocortical thickness in any ROI. 2) There were no significant differences in surface area measures between the ALC cohort and Controls; however, Relapsers exhibited significantly lower total BRS surface area than Controls and Abstainers. Relapsers and Abstainers were not significantly different on global surface area. Abstainers and Controls were not significantly different on any surface area in any ROI or global measure. 3) ALC showed significantly lower volumes than Controls in most BRS regions as well as total BRS and global volumes. Relapsers demonstrated smaller volumes than Controls in neocortical 17 of 20 ROIs as well as total BRS and global volume, while Abstainers showed smaller volumes than Controls in the bilateral superior frontal cortex, insula, amygdalae and hippocampi and total BRS and global volume. Relapsers had significantly smaller total BRS volume and smaller volumes than Abstainers in the bilateral OFC and the right rostral and right caudal middle frontal gyri, but Relapsers and Abstainers were not significantly different on global volume. 4) After controlling for age, there were no significant relationships in the alcohol dependent cohort between regional measures of brain morphology and pre-treatment measures of alcohol and cigarette consumption. 5) In Relapsers, several measures of regional baseline surface area and volume showed moderate-to-strong relationships with post-treatment alcohol consumption variables.
The alcohol dependent participants in this study demonstrated distinct patterns for regional and total volume, surface area, and thickness in the BRS. The volume differences between Controls, the alcohol dependent group, as a whole, and in terms of relapse status, were primarily driven by markedly lower global cortical thickness across ROIs in the alcohol dependent participants. The alcohol dependent group, as a whole, was not significantly different than Controls on regional, total and global BRS surface area; this finding was driven by the Abstainers who were not significantly different than Controls on any surface area measure, while Relapsers had lower total BRS surface area than Abstainers and lower total BRS and global surface area than both Controls and Abstainers.
Neocortical thickness is decreased in neurodegenerative diseases (Tosun et al., 2010
) and cocaine dependence (Makris et al., 2008a
), but there are no previous reports on neocortical thickness and surface area in alcohol use disorders. In a MRI-based study, Makris and colleagues (Makris et al., 2008b
) observed smaller global BRS volume in long-term abstinent alcoholics (5.9 ± 10.4 years of sobriety) relative to controls, with the most pronounced volume reductions in alcoholics apparent in the left amygdala, right DLPFC, insula and nucleus accumbens. Wrase and colleagues (Wrase et al., 2008
) observed lower volumes in alcohol dependent individuals abstinent for 16 ± 23 days in the amygdala, ventral striatum and hippocampus than controls. The authors reported relapsers showed lower baseline volumes than controls in all three regions, but abstainers demonstrated lower volumes than controls only in the ventral striatum. Relapsers also showed lower amygdala volumes than abstainers. Alcohol and cigarette consumption variables were not related to amygdala, hippocampal or ventral striatum volume in the alcohol dependent group. In the present study, the ALC group and both Abstainers and Relapsers showed significantly lower amygdala and hippocampal volumes than Controls and there were no significant differences between Abstainers and Relapsers in these regions. Similar to Wrase et al., 2008
, pre-enrollment alcohol and cigarette consumption were not related to volumes, thickness and surface area of the regions assessed. However, baseline amygdala and hippocampal volumes in Relapsers were robustly related to post-treatment alcohol consumption. In our previous spectroscopic imaging (Durazzo et al., 2010b
) and perfusion (Durazzo et al., 2010a
) studies, we observed that Relapsers demonstrated lower baseline NAA in the DLPFC and lower frontal GM perfusion than both Controls and Abstainers. Abstainers did not differ from Controls on baseline metabolite or perfusion levels in any ROI, which is generally congruent with the pattern of findings for regional surface area and volumes in this report.
AUD-associated changes in neocortical neuronal and/or glial morphology may result in alterations of GM surface area and/or thickness. Correspondingly, GM volume would be influenced if surface area and/or thickness were altered. Several post mortem neuropathological studies in AUD report neuronal loss in superior frontal neocortical regions [see (Harper, 2009
) for review], reduced glial cell density and size in the DLPFC (Miguel-Hidalgo et al., 2002
), and lower neuronal and glial cell density in the OFC (Miguel-Hidalgo et al., 2006
). Other neuropathological studies of AUD, however, found no abnormalities in neocortical neuronal cell volumes, neuronal and glial cell numbers or lobar and global neocortical surface area, thickness and volume (Fabricius et al., 2007
; Jensen and Pakkenberg, 1993
). In this alcohol dependent cohort, pre-treatment medical and psychiatric comorbidities, alcohol and cigarette consumption were not associated with any of the MR-based morphologic measures in BRS components or global measures. Therefore, the potential mechanisms contributing to the variability in regional surface areas, thickness and corresponding volumes observed in the alcohol dependent participants are unclear and likely involve genetic, comorbid and/or environmental factors not evaluated in this research.
Although Relapsers demonstrated significantly lower total BRS volumes and surface area than Abstainers, these groups were not significantly different on global neocortical volume or surface area. This suggests measures of volume and surface area in the BRS may better distinguish Abstainers and Relapsers compared to global neocortical measures. Within the BRS, the greatest morphological differences between Abstainers and Relapsers were apparent in left and right lateral OFC, where Relapsers demonstrated significantly smaller surface area and volume. Intact OFC functions are critical for adaptive and flexible inhibitory decision-making processes. Neurobiological abnormalities in the OFC have been linked to emotional and behavior disturbances that may confer risk for the relapse/remit cycle commonly observed in all substance use disorders (Baler and Volkow, 2006
; Kalivas and O’Brien, 2008
; Kalivas and Volkow, 2005
). Specifically, the OFC is involved in emotion-related learning and regulation of internal affective and drive states (Dom et al., 2005
14230; Rolls, 2004
). The OFC is proposed to be principally involved in the representation of the reinforcing, affective and goal values of a stimulus (Rolls and Grabenhorst, 2008
), which is critical for self-modification of behavior in accordance with changes in reinforcement contingencies (Dom et al., 2005
; Rolls and Grabenhorst, 2008
; Spinella, 2002
). Behavioral manifestations of OFC injury/dysfunction include impulsivity/disinhibition, inaccurate interpretation of social and emotional cues from others and inappropriate expression of emotional and internal drive states in complex social contexts. Some distinctions have been made between the functions subserved by the medial and lateral regions of the OFC (Rolls and Grabenhorst, 2008
), but it is unclear if there is any regional functional specificity within the OFC in alcohol use disorders.
While the mechanisms contributing to the regional and global morphology exhibited by Abstainers and Relapsers are unclear, there are distinct functional implications for baseline surface area, thickness and volume measured in the BRS for these alcohol dependent cohorts. Overall, the morphological findings in Abstainers and Relapsers suggest that the clinical syndrome of alcohol dependence in this cohort is primarily associated with significantly thinner neocortex in components of the BRS as well as for the global neocortex; this may represent a premorbid condition and serve as a proxy measure for increased risk for the development of AUD. These assertions are supported by the significantly lower neocortical thickness across the majority of BRS ROIs, the lower total BRS and global thickness in both Abstainers and Relapsers relative to Controls and the lack of associations of regional and global morphologic measures with comorbid psychiatric, substance use, medical conditions and pre-treatment alcohol and cigarette consumption in the alcohol dependent cohort. Additionally, Abstainers reported an average of 3 years (1028 ± 679 days) of continuous sobriety following outpatient treatment at long-term follow-up despite demonstrating significantly lower baseline neocortical thickness in 11 of 16 ROIs and lower total BRS and global thickness than Controls. With respect to surface area measures, results suggest that the surface areas of components of the BRS in this cohort may not be exclusively mediated by the clinical syndrome of alcohol dependence. Specifically, Relapsers exhibited lower total BRS surfaces area than Abstainers and Controls, whereas Abstainers and Controls were not significantly different on any surface area measure. With respect to volumes, the differences between Abstainers and Controls were driven by lower cortical thickness in Abstainers. Additionally, BRS volume and surface area measures in Relapsers demonstrated moderate to strong relationships with the magnitude of their post-treatment alcohol consumption, while no associations between baseline cortical thickness measures and severity of relapse were observed. Taken together, this suggests that both neocortical surface area and volume in the BRS ROIs investigated may serve as proxy markers for risk of relapse and/or predict the level of severity of an episode of relapse in this cohort. However, it must be noted that approximately 60% of the alcohol dependent participants had at least one previous treatment and it is unknown if the Abstainers and Relapsers evidenced the same regional morphological pattern observed in this report at the times of their previous treatments.
Limitations of this study include the reliance on self-report and/or medical records for the determination of drinking status at follow-up for some participants, the inability to examine for sex effects due to the small number of female participants, and the modest number of participants in the Abstainer group. We did not examine the influence of coping skills, stress response, self-esteem/self-efficacy, social support, neurocognition and personality disorders, neurocognitive variables, or gene polymorphisms reported to predict relapse after treatment for AUD [e.g., (Bradizza et al., 2006
; Krampe et al., 2006
; Miller et al., 1996
; Sinha and Li, 2007
; Teichner et al., 2001
; Walter et al., 2006
; Wojnar et al., 2009
)]. It is highly likely that the magnitude and chronicity of alcohol consumption before and after treatment in our alcohol dependent cohort was influenced not only by the integrity of their brain morphology, but also by genetic or other premorbid and environmental factors not assessed in this phase of our research.
The results from this morphological study, combined with our previous neuroimaging findings in this cohort, suggest Relapsers demonstrate significant adverse neurobiological changes in multiple nodes of the BRS. Taken together, our MR studies with this cohort suggest Relapsers experience dysfunction in regions involved in the “top down” regulation/modulation of internal drive states, emotions, reward processing and reward-related behavior (Baler and Volkow, 2006
; Kalivas and Volkow, 2005
; Paulus, 2007
; Redish et al., 2008
; Rolls and Grabenhorst, 2008
; Sinha and Li, 2007
), which may impart increased risk for the relapse/remit cycle that afflicts many with AUD. The clinical relevance of the morphological abnormalities is suggested by the associations of baseline surface areas and volumes in multiple components of the BRS with measures of post
-treatment alcohol consumption in Relapsers. Results also highlight the importance of examining both cortical thickness and surface area to better understand the nature of regional volume loss frequently observed in AUD. It is well documented that sustained abstinence from alcohol is associated with neocortical volume increases in those with AUD. Longitudinal studies examining both surface area and cortical thickness may clarify the nature of abstinence related volume changes. Additionally, longitudinal assessment over periods of sustained abstinence, combined with potential genetic markers of vulnerability [e.g., (Wojnar et al., 2009
)] will further assist in identifying premorbid factors that may influence the risk of relapse in AUD.