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Increased network centrality of the anterior insula in early abstinence from alcohol.

ABSTRACT: Abnormal resting-state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph-theoretical analyses, enabling improved resolution and fine-grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large-scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region-specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular-supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment.

SUBMITTER: Bordier C

PROVIDER: S-EPMC9286046 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Persons with alcoholism who are abstinent exhibit persistent impairments in the capacity for response inhibition, and this form of impulsivity is significantly associated with heightened relapse risk. Brain-imaging studies implicate aberrant prefrontal cortical function in this behavioral pathology, although the underlying mechanisms are not understood. Here we present evidence that deficient activation of glycine and serine release in the ventral medial prefrontal cortex (vmPFC) contributes to increased motor impulsivity during protracted abstinence from long-term alcohol exposure. Levels of 12 neurotransmitters were monitored in the rat vmPFC during the performance of a challenging variant of the five-choice serial reaction time task (5-CSRTT) in which alcohol-exposed rats exhibit excessive premature responding. Following long-term ethanol exposure, rats showed blunted task-related recruitment of vmPFC glycine and serine release, and the loss of an inverse relationship between levels of these neurotransmitters and premature responding normally evident in alcohol-naive subjects. Intra-vmPFC administration of the glycine transport inhibitor ALX5407 prevented excessive premature responding by alcohol-exposed rats, and this was reliant on NMDA glycine site availability. Alcohol-exposed rats and controls did not differ in their premature responding and glycine and serine levels in vmPFC during the performance of the standard 5-CSRTT. Collectively, these findings provide novel insight into cortical neurochemical mechanisms contributing to increased impulsivity following long-term alcohol exposure and highlight the NMDA receptor coagonist site as a potential therapeutic target for increased impulsivity that may contribute to relapse risk.SIGNIFICANCE STATEMENT Persons with alcoholism demonstrate increased motor impulsivity during abstinence; however, the neuronal mechanisms underlying these behavioral effects remain unknown. Here, we took advantage of an animal model that shows deficiencies in inhibitory control following prolonged alcohol exposure to investigate the neurotransmitters that are potentially responsible for dysregulated motor impulsivity following long-term alcohol exposure. We found that increased motor impulsivity is associated with reduced recruitment of glycine and serine neurotransmitters in the ventromedial prefrontal cortex (vmPFC) cortex in rats following long-term alcohol exposure. Administration of glycine transport inhibitor ALX5407 in the vmPFC alleviated deficits in impulse control.

Project description:ImportanceThis is the first study to date to examine volumetric alterations in the anterior insula (AI) as a potential biomarker for the course of childhood major depressive disorder (MDD).ObjectivesTo examine whether children with a history of preschool-onset (PO) MDD show reduced AI volume, whether a specific symptom of PO MDD (pathological guilt) is related to AI volume reduction (given the known relationship between AI and guilt processing), and whether AI volumes predict subsequent likelihood of having an episode of MDD.Design, setting, and participantsIn a prospective longitudinal study, 306 children (age range, 3.00-5.11 years) and caregivers completed DSM diagnostic assessments at 6 annual time points during 10 years as part of the Preschool Depression Study. Magnetic resonance imaging was completed on a subset of 145 school-age children (age range, 6.11-12.11 years).Main outcomes and measuresWhole-brain-adjusted AI volume measured using magnetic resonance imaging at school age and children's diagnosis of MDD any time after their imaging.ResultsCompared with children without a history of PO MDD, school-age children previously diagnosed as having PO MDD had smaller left and right AI volumes (Wilks Λ = 0.94, F2,124 = 3.37, P = .04, Cohen d = 0.23). However, the effect of PO MDD on reduced AI volumes was better explained by children's experience of pathological guilt during preschool (Λ = 0.91, F2,120 = 6.17, P = .003, d = .30). When covarying for children's lifetime history of MDD episodes, their experience of pathological guilt during preschool, as well as their sex and age at the time of imaging, schoolchildren's right-side AI volume was a significant predictor of being diagnosed as having an MDD episode after imaging (odds ratio, 0.96; 95% CI, 0.01-0.75; P = .03).Conclusions and relevanceThese results provide evidence that structural abnormalities in AI volume are related to the neurobiology of depressive disorders starting in early childhood. The present findings are consistent with mounting research in adult MDD suggesting that insula function and structure may be a target biomarker for major depression.

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Increased network centrality of the anterior insula in early abstinence from alcohol.

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