From a systems view to spotting a hidden island: A narrative review implicating insula function in alcoholism. (15th May 2022)

• Record Type: Journal Article
• Authors: Sommer, Wolfgang H.; Canals, Santiago; Bifone, Angelo; Heilig, Markus; Hyytiä, Petri
• Is Part Of: Neuropharmacology. Volume 209(2022)
• Publication Date: 2022-05-15
• Subjects: Alcohol use disorder -- Rat model -- MRI -- MEMRI -- Resting state connectivity -- Graph theory -- Network centrality -- Anterior insula -- cFos -- DREADD -- TMS; AA alcohol accepting rat line -- AAV adeno associated virus -- ACC anterior cingulate cortex -- AUD alcohol use disorder -- BOLD blood oxygen level dependent -- CIE chronic intermittent exposure -- DREADD designer receptors exclusively activated by designer drugs -- fMRI functional MRI -- ICA independent copmponent analysis -- MEMRI manganese enhanced MRI -- Mn2+ manganese ion -- MnCl2 manganese chloride -- MRI magnetic resonance imaging -- msP marchigian sardinian preferring rat line -- PD post-dependent -- PEth phosphatidylethanol -- phMRI pharmacological MRI -- rs-fMRI resting state fMRI -- rTMS repetitive TMS -- TMS transcranial magnetic stimulation; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.108989
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol-induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'. Graphical abstract: Applying principles of systems biology we used functional MRI data from alcoholic patients and animal models to develop mathematical models of the 'relapse-prone' state of brain networks. In these network models the insula emerged as a key node that could be experimentally validated and refined in animals. Distinct network properties may provide biomarkers and therapeutic access points for alcohol addiction in humans. Image 1 Highlights: MRI provides objective measures of brain dysfunction in AUD. These measures allow systematic cross-species translation between humans and animal models. Unbiased analyses of MRI data implicate the insula as an integral part of a 'relapse-prone' network. Insula neurons may coordinate meta-ensembles that bind multimodal external contingencies. Activity of these meta-ensembles modulates alcohol-related behaviors.