Dynamic coupling of whole-brain neuronal and neurotransmitter systems, Morten L. Kringelbach et al., 2020

Dynamic coupling of whole-brain neuronal and neurotransmitter systems

Morten L. Kringelbach, Josephine Cruzat, Joana Cabral, Gitte Moos Knudsen, Robin Carhart-Harris, Peter C. Whybrow Nikos K. Logothetis, and Gustavo Deco

PNAS, 2020, 1-11

doi : 10.1073/pnas.1921475117


Remarkable progress has come from whole-brain models linking anatomy and function. Paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. Neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. Here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neuro transmitter systems. We demonstrate that this framework is crucial to advance our understanding of wholebrain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dMRI], functional magnetic resonance imaging [fMRI], and positron electron tomography [PET]) to explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. This advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. Overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neuro-transmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity. serotonin | PET | psilocybin | neurotransmitter | whole-brain modeling Human connectomics has been very successful in revealing how function arises from structure (1, 2), and by showing how anatomy can give rise to a complex dynamical neuronal system as measured with multimodal neuroimaging (3–5). Despite the attractiveness of the idea that function is shaped by anatomy, it is also clear that the single fixed structure of the anatomical connectome should not be able to give rise to the full palette and complexity of brain function. However, evolution has found a solution to this apparent paradox by dynamically modulating the connectome over time through neuromodulatory systems, enabling the richness of behaviors needed for survival. Indeed, the necessary dynamics of human brain function can be obtained by modulating the effective connectivity of the coupling over time, as proposed by Friston and many others (6, 7). Still, a principled and mechanistic description of the dynamic connectome must bring together the anatomical, neuronal, and neurotransmitter systems at the whole-brain level (8).

Here, we show how the mutual coupling between the neuronal and neurotransmitter systems is fundamental to understanding the dynamic connectome. This can be achieved through wholebrain modeling of multimodal neuroimaging data using a mutually coupled neuronal–neurotransmitter whole brain model where the structural anatomical connectivity can be measured using diffusion magnetic resonance imaging (dMRI), the functional connectivity with functional magnetic resonance imaging (fMRI), and neurotransmission (receptor density) with positron electron tomography (PET). In this model, the synaptic/neuronal activity and the neurotransmitter diffusive system are portrayed in a realistic biophysical way by a set of separate dynamical equations, which are mutually coupled through the receptor maps and synaptic dynamics (neurotransmitters to neuronal), and the excitation of the projections from the brain regions producing the neurotransmitters (neuronal to neurotransmitters). The explicit linkage between this dual-coupled dynamical system yields a deeper understanding of the crucial mutual coupling between neuronal and neurotransmitters systems at the whole-brain level. We perceive this as a significant improvement compared to our previous unique wholebrain study, which had only one neuronal dynamical system influenced by static neurotransmitter concentrations modulating the neuronal gain (9). Specifically, we demonstrate the explanatory and predictive power of this mutually coupled whole-brain model by investigating the effects of psychedelics on brain activity.


In a technical tour de force, we have created a framework demonstrating the underlying fundamental principles of bidirectional coupling of neuronal and neurotransmitter dynamical systems. Specifically, in the present study, we combined multimodal neuroimaging data to causally explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. Longer term, this could provide a better understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction.


Psilocybin, the prodrug of psilocin (4-OH-dimethyltryptamine), is a good model system to demonstrate the power of a mutually coupled whole-brain model, since it has been shown to act mainly through the serotonin 2A receptor (5-HT2AR) (10), rather than more complex interactions between many receptors. The serotonin system works through the projections of the raphe nucleus. In addition, conveniently, the 5-HT receptor density maps have recently been mapped with PET (11). Here, we were interested in revealing the effects of mutual coupling of both neuronal and neurotransmitter systems on brain repertoire and specifically the effects of psilocybin on resting-state activity on healthy human participants.

Specifically, the bidirectional coupling of the neuronal and neurotransmitter systems was modeled in the following way: For the placebo condition, we used a standard whole-brain model to simulate the neuronal system, i.e., modeling spontaneous brain activity at the whole-brain level (measured with blood oxygen level-dependent [BOLD] fMRI), where each node represents a brain area and the links between them are represented by white matter connections (measured with dMRI). For the psilocybin condition, we mutually coupled the whole-brain neuronal and neurotransmitter systems by including an explicit description of the neurotransmitter dynamical system and the mutual coupling with the neuronal system. This was done by modeling the dynamics of the neurotransmitter system through simulating the release-and-reuptake dynamics, where the serotonin receptor density of each brain area is measured with PET. The neurotransmitter dynamics are then in turn coupled with the neuronal activity through the firing rate activity of the raphe nucleus, source of the serotonin neurotransmitter.

The relevance of the whole-brain modeling developed here is strongly supported by recent studies that have started to demonstrate the functional neuroanatomy underlying the experience of unconstrained cognition and enhanced mind-wandering reported following psilocybin (12–15). Due to its therapeutic action for the treatment of neuropsychiatric disorders such as depression, anxiety, and addiction (16–18), psilocybin has begun to elicit significant interest from the neuropsychiatric community as a potential treatment (19). Long term, the in silico framework presented here for investigating the dynamical connectome has the potential to bring insights and help design interventions for brain disease including neuropsychiatric disorders, which are otherwise difficult to study with traditional animal models.