THE PHARMACOLOGICALLY DIVERSE HUMAN BRAIN: HOW NEUROSIGNALLING SYSTEMS REGULATE NEUROTYPICAL AND NEURODIVERGENT RESTING-STATE NETWORKS

Abstract Background Functionally inter-connected large-scale brain networks underpin complex human behaviour and a wide range of alterations in this landscape have been consistently reported in psychiatric and neurodevelopmental conditions, including autism. Evidence from preclinical and correlational human studies suggest that these differences arise from underlying differences in neurotransmitter systems. However, to directly assess how a given neurotransmitter system modulates functional connectivity, we need to change it and observe a shift in network connectivity. Aims & Objectives To report on how resting-state connectivity is differentially modulated by different drug classes and how responses differ between autistic and non-autistic individuals. Methods Here we establish a common framework to capture the modulation of functional connectivity within and between brain functional networks by neurosignalling systems targeted by a range of pharmacological probes. Alterations in functional connectivity are reported for seven cortical networks following activation of the serotonin, dopamine, opioid, cannabinoid and glutamate-GABA systems in neurodiverse (autistic and non-autistic) individuals. Reproducible differences in resting-state network functional connectivity, including both hyper- and hypoconnectivity of within- and between-network interactions, are reported in autism. Thus, we also assessed whether there are group-level network responsivity differences between autistic and non-autistic participants to drug challenge, or whether the response profile was primarily individual/ heterogeneous in either group. Results One common finding across pharmacological probes was that networks with reproducible baseline differences in autism (e.g. sensory and attentional networks) were also those that respond differently to drug challenge. Broadly, the cannabinoid compounds (cannabidiol and cannabidivarin) decreased functional connectivity in autistic individuals compared to non-autistic controls. By contrast, the other compounds such as the GABAergic drugs AZD7325 & arbaclofen (which activate GABAA and GABAB receptors, respectively), increased functional connectivity in autistic individuals relative to non-autistic controls. Discussion & Conclusion This is important to not only to advance our understanding of how neurotransmitter systems regulate fundamental functional networks in both the neurotypical and neurodivergent brain, but to provide a common framework for evaluating pre-existing and novel neuro-active compounds in the living human brain. We hope this work can be extended to form the basis of a human neuropharmacological reference library of neuro-active compounds across individuals and diagnoses.