Although psychedelic drugs show great promise for the treatment of neuropsychiatric diseases such as depression and addiction, still little is known about the substances’ underlying mechanisms in the brain. It is known that effects of psychedelic drugs, in part, are based on the action of a serotoninergic neurotransmitter called 5HT2A. Blocking this specific receptor in the human brain has been seen to greatly decrease the psychedelic response. But the effects depend on non-linear brain dynamics that are difficult to study in the human brain. In general, there are currently significant gaps in the understanding of non-linear interactions, between neural activity and neurotransmitters in the whole brain.

Now, an international team of researchers has achieved significant breakthroughs in the understanding of the neural activity that depends on the neurotransmitters, and in particular they have discovered the causal mechanisms underlying the effects of LSD (lysergic acid diethylamide) in the global dynamics of the brain. The results of this research are to be published on 27 September in the journal Current Biology. The study is co-directed by Gustavo Deco, ICREA research professor with the Department of Information and Communication Technologies (DTIC) and director of the Center for Brain and Cognition (CBC) at Pompeu Fabra University (UPF), together with the lecturer Morten Kringelbach, researcher neuroscientist at Queen’s College, Oxford (United Kingdom) and the University of Aarhus (Denmark).

The researchers and their respective teams have used human brain data obtained via neuroimaging, to create an advanced computational model that is able to simulate precisely the dynamics of the entire brain using real brain connectivity between different brain regions.

For the first time, this neural activity model of the whole brain has been taken into account and has integrated concentrations of the neurotransmitter 5HT2A. For this work, the brain distribution of serotonin neurotransmitters (including 5HT2A) was obtained by the team led by professor Gitte M Knudsen, co-author of the study, at The Center for Integrated Molecular Brain Imaging (CIMBI) in Copenhagen (Denmark).

Integrating this information to the computational model enabled finding out the non-linear causal interactions between neural activity and the concentration of neurotransmitters. Thus, they observed that as the concentration of neurotransmitters changes in one or more regions, the dynamics of the brain also change, but crucially, that is to say, non-linearly, hence they had to design a computational model capable of predicting this behaviour.

The scientists, using neuroimaging techniques, obtained data from healthy participants who received LSD and a placebo, which was the responsibility of the team of Robin Carhart-Harris, a researcher at Imperial College London (United Kingdom), also co-author of the study. The results showed that the activity caused by LSD in the human brain was significantly related to the precise distribution of the concentration of the 5HT2A receptor. The availability of a computational model obtained through whole brain neuroimaging techniques enabled the team of researchers to establish a causal link between the serotoninergic receptor and brain activity.

Professor Gustavo Deco, first author of the study says: “These findings are exciting because they provide a new, very powerful tool to model the data obtained by neuroimaging techniques in a causal way, in which, for example, the changing concentrations of a neurotransmitter in different parts of the model can be used to predict the potential outcome of a treatment. As such, the method could be useful to better understand how and why psychedelic drugs can help rebalance the brain dynamics in neuropsychiatric disease”.

“Ultimately, this promising new method may be useful in discovering new drugs in which the effects of a change of receptor could be used in the design, evaluation and prediction of the effectiveness of new therapeutic substances”, said professor Morten Kringelbach, principal investigator of the study.

Related work:

Deco G., Cruzat J., Cabral J., Knudsen GM, Carhart-Harris RL, Whybrow PC, Logothetis NK & Kringelbach ML (2018), "Whole-brain multimodal Neuroimaging model using serotonin receptor maps explains non lineal functional effects of LSD", 27 de setembre, Current Biology.

Figure 1: Overview of Integrating Multimodal Data Including Neuromodulation into a Whole-Brain Neuronal Model

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