Whole-brain modeling explains the context-dependent effects of cholinergic neuromodulation

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2023-01, Vol.265, p.119782-119782, Article 119782
• Main Authors: Coronel-Oliveros, Carlos, Gießing, Carsten, Medel, Vicente, Cofré, Rodrigo, Orio, Patricio
• Format: Article
• Language: English
• Subjects: Acetylcholine; Acetylcholine - pharmacology; Behavior; Brain; Brain - physiology; Brain architecture; Brain mapping; Cholinergic Agents - pharmacology; Cholinergic transmission; Computational neuroscience; Connectome; Feedback inhibition; Fmri; Functional magnetic resonance imaging; Humans; Hypotheses; Magnetic Resonance Imaging - methods; Nerve Net - physiology; Neural networks; Neuromodulation; Neurons; Nicotine; Nicotine - pharmacology; Segregation; Time series; Whole-brain models
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2022.119782

•Nicotine promotes functional segregation in task, but not in resting-state.•In-task segregation correlates with visual-attentional performance.•A decrease in global coupling and local inhibition reproduces the effects of nicotine.•Modeling suggests mechanisms for the cholinergic influence on connectivity. Integration and segregation are two fundamental principles of brain organization. The brain manages the transitions and balance between different functional segregated or integrated states through neuromodulatory systems. Recently, computational and experimental studies suggest a pro-segregation effect of cholinergic neuromodulation. Here, we studied the effects of the cholinergic system on brain functional connectivity using both empirical fMRI data and computational modeling. First, we analyzed the effects of nicotine on functional connectivity and network topology in healthy subjects during resting-state conditions and during an attentional task. Then, we employed a whole-brain neural mass model interconnected using a human connectome to simulate the effects of nicotine and investigate causal mechanisms for these changes. The drug effect was modeled decreasing both the global coupling and local feedback inhibition parameters, consistent with the known cellular effects of acetylcholine. We found that nicotine incremented functional segregation in both empirical and simulated data, and the effects are context-dependent: observed during the task, but not in the resting state. In-task performance correlates with functional segregation, establishing a link between functional network topology and behavior. Furthermore, we found in the empirical data that the regional density of the nicotinic acetylcholine α4β2 correlates with the decrease in functional nodal strength by nicotine during the task. Our results confirm that cholinergic neuromodulation promotes functional segregation in a context-dependent fashion, and suggest that this segregation is suited for simple visual-attentional tasks.