Search

Pharmacological treatment in alcohol use disorder suffers from modest effect sizes. Efforts have been undertaken to identify patient characteristics that help to select individuals that benefit from pharmacological treatment. Previous studies indicated that neural alcohol cue-reactivity (CR) might provide a marker that identifies patients, which benefit from naltrexone treatment.We investigated the reproducibility of the association between ventral striatum (VS) activation and naltrexone (NTX) treatment response by analyzing data from a recent longitudinal clinical trial in N = 44 abstinent treatment-seeking alcohol-dependent patients. A follow-up was conducted over 3 months. We computed the percentage of significant voxels in VS and tested main effects and interactions with NTX treatment on relapse risk using Cox Regression models.We found a significant interaction effect between pre-treatment cue reactivity in the VS and NTX treatment on time to first heavy relapse (Hazard Ratio = 7.406, 95% CI 1.17–46.56, p = 0.033), such that the patient group with high VS activation (defined by a mean split) showed a significant medication effect (Hazard Ratio = 0.140, 95% CI 0.02–0.75, p = 0.022) with a number needed to treat of 3.4 [95% CI 2.413.5], while there was no significant effect in the group with low VS activation (Hazard Ratio = 0.726, p = 0.454).Thus, using an independent sample we replicated the previously described positive association between VS activation and NTX efficacy. Although our results should be considered cautiously in light of the small sample size, our results support the potential of neural alcohol CR as a tool for precision medicine approaches in alcohol dependence.

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., This work was supported by the European Union's Horizon 2020 research and innovation programme (668863-SyBil-AA), the ERA-Net NEURON programme (FKZ 01EW1112-TRANSALC) and Deutsche Forschungsgemeinschaft (center grants SFB636 and TRR 265 subproject B0867). SC acknowledges the Spanish State Research Agency through the Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2017-0723) and the Ministerio de Economía y Competitividad (MINECO) and FEDER funds under grants BFU2015-64380-C2-1-R and BFU2015-64380-C2-2-R., Open Access Funding provided by Istituto Italiano di Tecnologia within the CRUI-CARE Agreement.

Background Recent data suggest that ghrelin is involved in the pathophysiology of alcohol use disorders, affecting alcohol self-administration and craving. Gastric ghrelin secretion is reduced by stomach distension. We now tested the hypothesis whether the clinically well-known effects of high-volume water intake on craving reduction in alcoholism is mediated by acute changes in ghrelin secretion. Methods In this randomized human laboratory study, we included 23 alcohol-dependent male inpatient subjects who underwent alcohol cue exposure. Participants of the intervention group drank 1000 ml of mineral water within 10 min directly thereafter, compared to the participants of the control group who did not. Craving and plasma concentrations of acetylated ghrelin were measured ten times during the 120 min following the alcohol cue exposure session. Results In the intervention group, a significant decrease in acetylated ghrelin in plasma compared to the control group was observed. This decrease was correlated to a reduction in patients’ subjective level of craving. In the control group, no decrease of acetylated ghrelin in plasma and no association between alcohol craving and changes in plasma concentrations of acetylated ghrelin were observed. Conclusions Our results present new evidence that the modulation in the ghrelin system by oral water intake mediates the effects of volume intake with craving reduction in alcohol use disorders. Hence, in addition to pharmacological interventions with ghrelin antagonists, the reduction of physiological ghrelin secretion might be a target for future interventions in the treatment of alcohol craving.

[Importance] Although the detrimental effects of alcohol on the brain are widely acknowledged, observed structural changes are highly heterogeneous, and diagnostic markers for characterizing alcohol-induced brain damage, especially in early abstinence, are lacking. This heterogeneity, likely contributed to by comorbidity factors in patients with alcohol use disorder (AUD), challenges a direct link of brain alterations to the pathophysiology of alcohol misuse. Translational studies in animal models may help bridge this causal gap., [Objective] To compare microstructural properties extracted using advanced diffusion tensor imaging (DTI) in the brains of patients with AUD and a well-controlled rat model of excessive alcohol consumption and monitor the progression of these properties during early abstinence., [Design, Setting, and Participants] This prospective observational study included 2 cohorts of hospitalized patients with AUD (n = 91) and Marchigian Sardinian alcohol-preferring (msP) rats (n = 27). In humans cross-sectional comparison were performed with control participants (healthy men [n = 36]) and longitudinal comparisons between different points after alcohol withdrawal. In rats, longitudinal comparisons were performed in alcohol-exposed (n = 27) and alcohol-naive msP rats (n = 9). Human data were collected from March 7, 2013, to August 3, 2016, and analyzed from June 14, 2017, to May 31, 2018; rat data were collected from January 15, 2017, to May 12, 2017, and analyzed from October 11, 2017, to May 28, 2018., [Main Outcomes and Measures] Fractional anisotropy and other DTI measures of white matter properties after long-term alcohol exposure and during early abstinence in both species and clinical and demographic variables and time of abstinence after discharge from hospital in patients., [Results] The analysis included 91 men with AUD (mean [SD] age, 46.1 [9.6] years) and 27 male rats in the AUD groups and 36 male controls (mean [SD] age, 41.7 [9.3] years) and 9 male control rats. Comparable DTI alterations were found between alcohol and control groups in both species, with a preferential involvement of the corpus callosum (fractional anisotropy Cohen d = −0.84 [P, [Conclusions and Relevance] Using a translational DTI approach, comparable white matter alterations were found in patients with AUD and rats with long-term alcohol consumption. In humans and rats, a progression of DTI alterations into early abstinence (2-6 weeks) suggests an underlying process that evolves soon after cessation of alcohol use., This study was supported by grant 668863-SyBil-AA from the European Union’s Horizon 2020 research and innovation programme, grants FKZ 01EW1112-TRANSALC and PIM2010ERN-00679 from the ERA-Net NEURON program, grant SEV- 2017-0723 from the Spanish State Research Agency through the Severo Ochoa Program for Centres of Excellence in R&D, and Center grant SFB636 from the Deutsche Forschungsgemeinschaft. Further financial support was obtained from grant BFU2015-64380-C2-1-R from the Ministerio de Economía y Competitividad (MINECO) and FEDER funds (Dr Canals), Ministerio de Sanidad, Servicios Sociales e Igualdad grant 2017I065 (Dr Canals), Young Investigator Grant 25104 from the National Alliance for Research on Schizophrenia and Depression (Dr De Santis), and Marie Skłodowska-Curie Individual Fellowship 749506 from the European Research Council.

Bringing novel medications from preclinical to clinical development is challenging, especially when efficacy predictors are based on subjective assessments. Neuroimaging methods such as magnet resonance imaging (MRI) may allow for objective human-animal comparisons and thus to identify imaging signatures that are comparable …