Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD

Understanding the underlying mechanisms of the human brain in health and disease will require models with necessary and sufficient details to explain how function emerges from the underlying anatomy and is shaped by neuromodulation. Here, we provide such a detailed causal explanation using a whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical data from diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) with neurotransmitter data obtained with positron emission tomography (PET) of the detailed serotonin 2A receptor (5-HT2AR) density map. This allowed us to model the resting state (with and without concurrent music listening) and mechanistically explain the functional effects of 5-HT2AR stimulation with lysergic acid diethylamide (LSD) on healthy participants. 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-HT2AR density. 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 anatomical connectivity, (2) the modulation by the specific brainwide 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.G.D. is supported by the ERC Advanced Grant DYSTRUCTURE (295129), the Spanish Research Project PSI2016-75688-P, and the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2). M.L.K. is supported by the ERC Consolidator Grant: CAREGIVING (615539) and Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). R.L.C.-H. is supported by the Alex Mosley Charitable Trust, and the study that yielded the empirical LSD data was carried out as part of a Beckley-Imperial research collaboration. J. Cabral is supported under the project NORTE-01-0145-FEDER-000023 from the Northern Portugal Regional Operational Program (NORTE 2020) under the Portugal 2020 Partnership Agreement through the European Regional Development Fund (FEDER). G.M.K. and the Cimbi database were supported by a centre grant from the Lundbeck Foundation (2010-5364)