Mechanisms of the non-linear interactions between the neuronal and neurotransmitter systems explained by causal whole-brain modeling

Although a variety of studies have shown the role of neurotransmitters at the neuronal level, their impact on the dynamics of the system at a macroscopic scale is poorly understood. Here, we provide a causal explanation using the ​first whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical and functional data with a detailed map of the serotonin 2A receptor (5-HT​2AR​) densities obtained with positron emission tomography (PET). This allowed us to model the resting state and mechanistically explain the functional effects of 5-HT​2AR​ stimulation with lysergic acid diethylamide (LSD). The whole-brain model used a dynamical mean-field quantitative description of populations of excitatory and inhibitory neurons as well as the associated synaptic dynamics, where the neuronal gain function of the model is modulated by the 5-HT​2AR​ density. The results show that the precise distribution of 5-HT​2AR​ is crucial to predict the neuromodulatory effects of LSD. The model identified the causative mechanisms for the non-linear interactions between the neuronal and neurotransmitter system, which are uniquely linked to the underlying neuroanatomical network, the modulation by the specific brain-wide distribution of neurotransmitter receptors, and the non-linear interactions between the two