Brain functional connectivity and alcohol use disorder: a graph theoretical approach

Resting-state functional MRI(rs-fMRI) represents a powerful means to assess brain functional connectivity in healthy subjects and in neuropsychiatric patients. Aberrant functional connectivity has been observed in subjects affected by Alcohol Use Disorders (AUD) and other forms of substance dependence, a major health issue worldwide with limited treatment options. Despite intense investigation, the specific neuronal substrates involved and the functional implications of aberrant connectivity in these patients remain unknown. Moreover, it is unclear whether treatment can reverse these alterations, and normalize functional connectivity. Several methodological and conceptual questions in the analysis of functional connectivity are still open, and contribute to this uncertainty. Functional connectivity is defined in terms of correlated MR-signal fluctuations, and in-scanner patient motion and other nuisance signals can introduce spurious correlations, thus representing substantial confounding factors. At a more general level, understanding the effects of complex conditions, like AUD, on brain connectivity and their functional implications requires a deep comprehension of the brain organizational principles at multiple scales, a tremendous challenge that is at the heart of modern neuroscience. In this PhD dissertation I address some of the outstanding questions in the analysis and interpretation of aberrant functional connectivity in AUD. To this end, I have embraced the formalism of graph-theory, a powerful framework to assess the effects of alcohol abuse on the local and global topological organization of resting state connectivity. On the methodological side, I have investigated the effects of subject’s motion on the structure of resting state networks, and compared efficacy of different approaches to remove motion-related confounds. Moreover, I demonstrate the importance of network sparsification to remove spurious connections from the graph while maximizing the structural information that can be extracted from the system. Leveraging these methodological developments, I have evaluated functional alterations in different samples of AUD patients. In two independent studies, I demonstrated specific alterations in the topological organization of the insular cortex and subcortical basal structures in recently detoxified alcoholics. Interestingly, protracted abstinence appears to partially normalize functional connectivity, thus suggesting that alcohol-induced alterations in connectivity may be amenable to treatment. Based on these findings, I have studied the effects on brain functional networks of a putative novel treatment based on deep Transcranial Magnetic Stimulation (TMS). Specifically, I analyzed resting state connectivity in AUD patients subjected to repetitive TMS of the bilateral insula and of the anterior cingulate cortex (ACC), and demonstrated treatment-induced changes that may underlie the efficacy of this potential treatment in surrogate clinical read-outs.