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Curr Biol. 2018 Oct 8;28(19):3065-3074.e6. doi: 10.1016/j.cub.2018.07.083. Epub 2018 Sep 27.

Whole-Brain Multimodal Neuroimaging Model Using Serotonin Receptor Maps Explains Non-linear Functional Effects of LSD.

Author information

1
Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Roc Boronat 138, 08018 Barcelona, Spain; Institució Catalana de la Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain; Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany; School of Psychological Sciences, Monash University, Melbourne, Clayton VIC 3800, Australia. Electronic address: gustavo.deco@upf.edu.
2
Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Roc Boronat 138, 08018 Barcelona, Spain.
3
Department of Psychiatry, University of Oxford, Oxford, UK; Center for Music in the Brain, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.
4
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Copenhagen University, DK-2100 Copenhagen, Denmark.
5
Psychedelic Research Group, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, London, UK.
6
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
7
Max Planck Institute for Biological Cybernetics, 72076 Tübingen, Germany; Imaging Science and Biomedical Engineering, University of Manchester, Manchester M13 9PT, UK.
8
Department of Psychiatry, University of Oxford, Oxford, UK; Center for Music in the Brain, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; Institut d'études avancées de Paris, Paris, France. Electronic address: morten.kringelbach@psych.ox.ac.uk.

Abstract

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.

KEYWORDS:

5-HT; LSD; PET; drug discovery; fMRI; music; neuromodulation; psychedelics; serotonin; whole-brain modeling

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PMID:
30270185
DOI:
10.1016/j.cub.2018.07.083
[Indexed for MEDLINE]
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