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Abstract:
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 [1]. Specifically, we combined anatomical and functional data with a detailed map of the serotonin 2A receptor (5−HT2AR) densities obtained with positron emission tomography (PET) [2]. This allowed us to model the resting state and mechanistically explain the functional effects of (5−HT2AR) stimulation with lysergic acid diethylamide (LSD).
The whole-brain model was composed of 90 anatomically delineated brain regions linked by the structural connectivity (SC) matrix of fiber densities obtained by tractography [3,4]. The activity of each region was represented by a dynamic neuronal mean-field model derived from the collective behavior of empirically validated integrate-and-fire neurons [5,6]. The population responses for pools of excitatory neurons were given by independent sigmoid functions, regulated by a gain parameter sE common in all brain regions and initially set to zero. Notably, the model only uses two parameters: a neuronal parameter scaling the global coupling of neuronal populations, G, and a neuromodulator parameter scaling the effects of neurotransmitters on the neuronal gain function weighted by the empirical regional receptor density. To take into account the spatiotemporal fluctuations in functional brain dynamics over time, the model was fitted to the spatiotemporal dynamics of the data (i.e., to the functional connectivity dynamics [FCD] [7,8]).
The present results show that the precise distribution of (5−HT2AR) 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 (1) the underlying neuroanatomical network, (2) the modulation by the specific brain-wide distribution of neurotransmitter receptor density, and (3) the non-linear interactions between the two. Taking neuromodulatory activity into account when modeling global brain dynamics will lead to novel insights into human brain function in health and disease and opens exciting possibilities for drug discovery and design in neuropsychiatric disorders.
