Abstract

--- - Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although whole-brain computational models have reproduced this neuromodulatory effect, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, we introduce a local inhibitory feedback as a plausible biophysical mechanism that enables the integration of whole-brain activity, and that interacts with the other neuromodulatory influences to facilitate the transition between different functional segregation/integration regimes in the brain. - Author summary - Segregation of brain activity refers to the fact that some brain regions are specialized to handle particular features of external and internal stimuli. However, to produce a coherent behavioral outcome, the brain must coordinate the activity of these specialized brain areas, and this is called integration of brain activity. Based on a fixed connectome (the brain anatomical structure), the neuromodulatory systems are one of the plausible candidates to manage the transitions of brain states in short timescales. Understanding the role of neuromodulators in brain dynamics and the segregation/integration balance is relevant, in particular, as it is known that in several neuropsychiatric disorders the segregation/integration balance its impaired. Here, we used a computational model of the whole brain to study the dual effect of the cholinergic and noradrenergic neuromodulatory systems in the switching from segregated to integrated brain states. The novelty of our work is the inclusion of a homeostatic local inhibitory loop. This specific inhibition, modulated by the cholinergic system, maintains the excitation/inhibition balance while promoting integration. Our work links the local effects of cholinergic neuromodulation, with the more global influences of the structural connectivity and neuromodulatory systems. This constitutes a step forward in the understanding of the neural mechanisms behind the segregation/integration balance of brain activity.