Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter

Abstract

Alterations in the serotonergic control of brain pathways responsible for facial-emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched fMRI brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. Here, we used REACT to estimate the dominant fMRI signal related to the serotonin transporter (5-HTT) distribution during processing of aversive facial expressions of emotion processing in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, i.e. a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of 5-HTT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptor maps. We found a baseline group difference in the 5-HTT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram 'shifted' the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Our findings suggest that the 5HTT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.

Molecular-enriched functional connectivity in the human brain using multiband multi-echo simultaneous ASL/BOLD fMRI

“…The application of REACT to clinical and pharmacological blood oxygen leveldependent (BOLD) fMRI studies has demonstrated its ability to uncover new patterns of functional alterations in neurotransmission-related circuits in patients with brain disorders and suggests potential drug-target mechanisms at the system level that could underlie the functional effects of pharmacological treatment (Cercignani et al, 2021; Dipasquale et al, 2020; Dipasquale et al, 2019; Martins et al, 2021; Wong et al, 2021). However, the BOLD signal is an indirect measure of neuronal activity, resulting from the combination of changes in both oxygen consumption and regional cerebral blood flow (CBF), as well as changes in regional blood volume (CBV) (Buxton et al, 2004).…”