Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape

Abstract

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 18 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 7 different mind-altering drugs including anaesthetics, psychedelics, and cognitive enhancers. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. Intriguingly, the effects of both anaesthetics and psychedelics on brain function, though opposite, are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brain's functional architecture.

Distinct genetic underpinnings of inter-individual differences in the sensorimotor-association axis of cortical organisation

“…It is possible that, although generally resting state networks are topologically organised along the S-A axes, their individual fluctuations reflect physiological variability not captured by its microstructural scaffold (31). Indeed, various works have reported network integration and segregation to align with neural gain, which could be explained by alterations in neuromodulatory systems (32, 33).…”

Molecular and micro-architectural mapping of gray matter alterations in psychosis

“…Furthermore, the spatial distribution of neurotransmitter receptors and transporters 65 , and the connectional hierarchy 66 have been associated with cognitive processes and disease vulnerability. Additionally, a study has suggested that regions that are structurally most vulnerable to disease may also be the most susceptible to rebalance their functional organization through appropriate pharmacological interventions 67 .…”

Topographic variation in neurotransmitter receptor densities explains differences in intracranial EEG spectra

“…For example, neuropharmacological interventions, such as anticonvulsants or antidepressants, rely on interpreting clinical phenotypes to target specific mechanisms or components of neurotransmission and neuromodulation. And whilst medications’ affinity for types of neurotransmitter receptors is often well-characterised at microscale (24), their effects on meso- and macroscopic dynamics is less accessible — as they depend on a multitude of factors, including balancing mechanisms of non-targeted interacting neurotransmitter systems (25). Conversely, measuring and describing patients’ brain dysfunction, allows only phenomenological, but not aetiological, diagnoses (26, 27).…”

“…Despite the complexity, there is evidence that interrelations between synaptic neurotransmitter systems and whole-brain dynamics are identifiable. For example, there are statistical associations between regional cortical oscillatory rhythms measured using magnetoencephalography (MEG) and neurotransmitter receptor expression measured using positron emission tomography (PET) (32), and between multiple microstructural features of the human cortex and MEG signals (33); additionally, regional neuroreceptor profiles in part explain medication-induced changes in fMRI (25). Similarly, spatially distributed neuroreceptor gene expression, assessed through post-mortem microarray profiles, correlate with fMRI activation patterns during cognitive tasks along gradients of microstructural organisation of the human cortex (34).…”