From a systems view to spotting a hidden island: A narrative review implicating insula function in alcoholism
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.
Section snippets
MRI as a tool to obtain a global view of brain connectivity
An overall view of brain activity can be obtained from resting-state functional Magnetic Resonance Imaging (rs-fMRI). By measuring the temporal correlation of low-frequency fluctuations in blood-oxygen-level-dependent (BOLD) signals, it is possible to outline resting-state networks, sets of brain regions with temporally coherent activity. Recent studies have suggested rs-fMRI to be a powerful tool in the study of the dynamic course of alcoholism and the long-term effects of alcohol (Fede et
Manganese-enhanced MRI enables integration of network-activity and behavioral studies in rodents
An attractive alternative is provided by manganese-enhanced MRI (MEMRI), which permits recording of brain-wide network activation produced during awake, behaving conditions. The paramagnetic ion manganese (Mn2+) enters cells through voltage-gated calcium channels and accumulates in depolarized neurons. Since Mn2+ clearance is slow, the pattern of activity-dependent Mn2+ accumulation produced while awake can then be measured as an increased signal intensity in T1-weighted images (Silva et al.,
Advanced network analysis
Investigating the functional role of brain networks in health and disease depends on an understanding of their organizational principles under these conditions. To this end, a powerful framework is provided by graph theoretical methods, an approach that is widely used to examine e.g. social networks, and that has more recently been applied to neuroscience (Bullmore and Sporns, 2009). Graph analysis is based on an explicit network representation describing the statistical interdependencies
Advanced network statistics reveal the distinct role of insula in alcohol cue reactivity in rodents
The principles and power of advanced statistical network analysis as described above are first illustrated by an experiment in rats that aimed to investigate mechanisms of reward representation in the brain. In this study, rats learned to concurrently seek either alcohol or a sweet saccharin solution as drug or natural rewards, respectively. Importantly, all rats had the same training history with both alcohol and saccharine. Recall of alcohol or saccharine memories elicited remarkably similar
Network analysis of resting state fMRI implicate the insula a hub in AUD patients
Indeed, a stronger participation of the insula in brain network states of AUD patients is suggested by advanced network analysis of rs-fMRI connectivity data. We used an unbiased approach based on a large-scale network defined by more than 600 a priori defined nodes (Crossley et al., 2013) and assessed the modular organization, i.e. the presence of tightly connected substructures within a network. We then identified brain regions responsible for network integration. Data were obtained from a
Rodent models of alcohol addiction
To establish causality is challenging in clinical studies, both with respect to revealing alcohol as a causal factor and the feasibility of manipulating specific brain regions or circuits. Thus the altered brain network states observed in the trial described above could be due to many factors. We therefore turned to animal studies to investigate the effect of alcohol on brain network states more directly. Two conditions are required to develop alcohol addiction in humans – brain exposure to
MEMRI experiments in rat models of alcohol addiction
Human brain imaging studies can identify signatures of neurocircuit activity associated with subjective alcohol effects that promote the motivation to consume alcohol. For instance, in a seminal paper, Gilman et al. approached this question in an elegant fMRI experiment, in which alcohol robustly activated striatal reward circuits while attenuating responses to fearful stimuli in visual and limbic regions (Gilman et al., 2008). To reiterate, however, establishing causality is challenging in
rs-fMRI in rat models of alcohol addiction
The detailed mechanisms underlying manganese uptake may be too complex for detailed circuit dissection, especially in conjunction with neurochemical interference. However, because MEMRI avoids the need of anesthesia and scanner confinement during network labeling and is not subject to the uncertainties of neurovascular coupling (Moreno et al., 2013), MEMRI complements fMRI experiments, and can be used to corroborate findings from these. We recently employed a combined fMRI/MEMRI approach in a
Targeting insula function to reduce alcohol drinking in rats and humans
The mounting evidence implicating the insula in alcohol and other addictions prompts the question whether targeting this region could have therapeutic potential. We approached this question both in animal experiments and a clinical trial.
First, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption in rats (Haaranen et al., 2020b). Excitatory or inhibitory “designer receptors exclusively activated by designer drugs”
Discussion
Following the seminal work of Naqvi et al. (2007), showing that damage to the insula was able to disrupt drug-seeking behaviors in smokers, the insula has gained growing attention in the study of addiction, including AUD. In fact, the insula is implicated in many functions ranging from sensory processing to representing feelings and emotions, autonomic and motor control, risk prediction and decision-making, bodily- and self-awareness, and complex social functions like empathy, many of which are
Conclusions and perspective
To conclude, the network analyses using cFos expression and rsfMRI data support an involvement of the insula in three different behavioral paradigms representing different stages in the development of alcohol addiction, from responding to alcohol associated cues to excessive, aversion-resistant alcohol consumption and alcohol-induced post-dependent state. Remarkably, in all analyses the insula emerges as an integral brain area in networks featuring striatal and medial prefrontal areas, as well
Acknowledgements
The authors acknowledge funding from the European Union Horizon 2020 research and innovation program under Grant Agreement No. 668863 (SyBil-AA), the ERA-Net NEURON framework with grants given to the project “Translational Neuroimaging in Alcoholism” (TRANSALC) by the Bundesministerium für Bildung und Forschung (FKZ01EW1112), the Spanish Ministerio de Ciencia e Innovación (PIM2010ERN-00679) and the Academy of Finland (TRANSALC 01EW1112). WHS was further supported by Deutsche
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