Sommer Wolfgang H, Canals Santiago, Bifone Angelo, Heilig Markus, Hyytiä Petri
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Bethania Hospital for Psychiatry, Psychosomatics, and Psychotherapy, Greifswald, Germany.
Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550, Sant Joan d'Alacant, Spain.
Neuropharmacology. 2022 May 15;209:108989. doi: 10.1016/j.neuropharm.2022.108989. Epub 2022 Feb 22.
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.
过度饮酒会促进酒精成瘾的发展，但对于酒精如何导致大脑改变进而引发成瘾的理解仍然有限。为了深化这一理解，我们采用了基于系统医学原理的无偏发现策略。我们使用了来自酒精成瘾样行为患者和动物模型的功能磁共振成像数据，并开发了“易复发”网络状态的数学模型，以确定可通过治疗干预进行选择性靶向的脑区和功能网络。我们在系统层面、非局部且基本无偏的分析聚焦于少数几个明确的脑区，其中岛叶是各项研究中最一致的发现之一。在概念验证实验中，我们能够证明在动物身上引导网络动力学以增强恢复力是可行的，但最初针对岛叶的临床试验却失败了。在此，在一篇叙述性综述中，我们总结了从识别人类和动物的“易复发”网络状态到靶点验证及干预试验这一完整发现周期的关键实验、方法学进展以及所获得的知识。未来需要共同努力，从状态依赖、回路特异性和细胞群体的角度更深入地理解岛叶功能，并开发针对岛叶的干预手段，才有可能对该结构进行治疗靶向。
