Autistic Neural Shiftability: The Distinct Pharmacological Landscape of the Autistic Brain

Functionally inter-connected large-scale brain networks regulated by multiple neurotransmitter systems underpin complex human behaviour. A wide range of alterations in this neurofunctional landscape have been associated with autism. However, this evidence is mostly derived from cross-sectional analyses and thus assumes that any differences are static. Indeed, large sample sizes are required to identify reproducible baseline differences in functional connectivity between autistic and non-autistic individuals. Instead, we propose that what is different in autism is not necessarily the baseline functional connectivity of resting-state networks, but rather their responsivity or regulation by neurotransmitter systems. We tested this hypothesis using a uniform analytical framework to capture the modulation of functional connectivity by single doses of pharmacological probes targeting three major neurotransmitter systems implicated in autism, namely gamma-amino-butyric-acid (GABA), serotonin (5HT) and -opioid systems. Every drug challenge altered resting-state network connectivity differentially in the autistic compared to the non-autistic group. However, regardless of the neurotransmitter system probed, drug challenge elicited increases in between-network connectivity in autistic participants but minimal or decreased between-network connectivity in their non-autistic peers. There was no group difference in the responsivity of within-network connectivity. Thus, there is altered responsivity of neurotransmitter systems in the autistic brain. This has important implications for pharmacotherapy in autism because these neurotransmitter systems are the targets of several medications commonly prescribed to manage mental health conditions that frequently co-occur in autism. Investigating if these drug-induced shifts in functional connectivity can help provide better targeted clinical interventions, will be important next translational steps. One Sentence SummaryThe autistic brain is differentially responsive to pharmacological modulation of the GABA, serotonin and -opioid neurotransmitter systems.