Withdrawal-associated increases and decreases in functional neural connectivity associated with altered emotional regulation in alcoholism

Abstract

Alcoholic patients who have undergone multiple detoxifications/relapses show altered processing of emotional signals. We performed functional magnetic resonance imaging during performance of implicit and explicit versions of a task in which subjects were presented with morphs of fearful facial emotional expressions. Participants were abstaining, multiply detoxified (MDTx; n=12) or singly detoxified patients (SDTx; n=17), and social drinker controls (n=31). Alcoholic patients were less able than controls to recognize fearful expressions, and showed lower activation in prefrontal areas, including orbitofrontal cortex and insula, which mediate emotional processing. The decrease in activation was greater in MDTx patients who also showed decreased connectivity between insula and prefrontal areas, and between amygdala and globus pallidus. In the explicit condition, the strength of connectivity between insula and areas involved in regulation of emotion (inferior frontal cortex and frontal pole) was negatively correlated with both the number of detoxifications and dependency (measured by the severity of alcohol dependency (SADQ) and control over drinking score (Impaired Control questionnaire, ICQ)). In contrast, increased connectivity was found between insula and the colliculus neuronal cluster, and between amygdala and stria terminalis bed nucleus. In the implicit condition, number of detoxifications and ICQ score correlated positively with connectivity between amygdala and prefrontal cortical areas involved in attentional and executive processes. Repeated episodes of detoxification from alcohol are associated with altered function both in fear perception pathways and in cortical modulation of emotions. Such changes may confer increased sensitivity to emotional stress and impaired social competence, contributing to relapse.

Figure 1

Brain regions identified with a main effect of group ((a) yellow) or a significant three-way interaction ((b) yellow). Clusters are shown at an uncorrected voxel p-value of 0.001, with a minimum cluster size of 50 voxels. Primary motor cortex and orbitofrontal cortex (OFC) survived FWE corrections; insula was thresholded following correction for multiple comparisons on the basis of spatial extent. Sublenticular extended amygdala (SLEA) was identified based on region of interest analysis. Bar graphs depict changes of BOLD signal (mean±SEM) for the main effect of group (c) and the interaction involving group (d, e). MDTx, multiply detoxified; SDTx, singly detoxified.

Figure 2

Brain regions showing a group effect in connectivity of amygdala (a, b) and insula (c–f) as seed chosen regions. For display purposes, maps are shown at an uncorrected threshold of p<0.001. Bar graphs depict changes of BOLD signal in the different groups for implicit and explicit condition for connectivity between right amygdala and right globus pallidus (a), left amygdala and right BNST/hypothalamus (b), left insula and right VMPFC (c), left insula and left anterior cingulate cortex (d), left insula and left orbitofrontal cortex (OFC) (e), and left insula and right colliculus (f). MDTx, multiply detoxified; SDTx, singly detoxified; VMPFC, ventromedial PFC

Figure 3

Brain regions where connectivity of left (yellow) and right (blue) amygdala, and left (yellow) insula are presented. For display purposes, maps are shown at an uncorrected threshold of p<0.001. Scatterplots show the relationship between left amygdala–left dorsolateral prefrontal cortex and number of multiple detoxifications (a), left amygdala–right dorsolateral prefrontal cortex (DLLPFC) and Impaired Control Questionnaire (ICQ) scores (b) in the implicit condition, and between left insula–right inferior frontal cortex connectivity and number of multiple detoxifications (c), as well as between left insula–right frontal pole and ICQ scores (d) in the explicit condition.

Figure 4

(a) Relative differences (broken line: less, non-broken line greater) between controls and multiply detoxified (MDTx) patients in functional neuronal connections between insula and amygdala as seed regions, and other brain areas. The sign and magnitude of the difference (patient beta coefficient minus control beta coefficient) is given for each neuronal connection. (b) Relationships (r values) between intensity of connectivity and measures of dependency (number of detoxifications (#DTx), Severity of Alcohol Dependency Questionnaire (SADQ) score, and DCQ score). For lateralization of brain areas see Supplementary Table S5, S6, S7 and S8 in the Supplementary Material). DLPFC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; VLPFC, ventrolateral PFC.