Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter: A randomised placebo-controlled single-dose crossover trial

Abstract

Background: 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 functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. Methods: We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion 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, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps. Results: Using REACT with the SERT map, we found a baseline group difference in the SERT-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. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps. Conclusions: Our findings suggest that the SERT-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.

From Neurotransmitters to Networks: Transcending Organisational Hierarchies with Molecular-informed Functional Imaging

“…In humans, testing this working model has been mostly restricted to pharmacological interventions targeting specific neurotransmitter systems. Here, plausible links between drug targets and target-enriched FC have been demonstrated (Dipasquale et al, 2020(Dipasquale et al, , 2019Lawn et al, 2022aLawn et al, , 2022bDaniel Martins et al, 2022;Wong et al, 2022), strengthening the confidence that molecular-enriched networks are sensitive to variations in concomitant neurotransmission. However, the complex patterns of affinity of most drugs and the risk of non-specific vascular effects that might affect neuroimaging signals necessitate further confirmatory studies.…”

“…REACT offers two additional options to assess task-based changes in molecularenriched connectivity. Firstly, a modification of the generalised psycho-physiological interaction analysis (gPPI) can be conducted in which the subject-specific dominant BOLD fluctuation related to a certain molecular system, derived from the first GLM of a REACT analysis, is combined with the task regressor by means of scalar multiplication, to produce an interaction regressor to be used in the second GLM to estimate a molecular-enriched task-dependent network (Wong et al, 2022). When expanding this approach to different molecular systems and tasks, the resulting networks can be used to examine the differential engagement of those systems FC under different task conditions.…”

“…Providing a biological grounding to FC holds significant promise for novel biomarkers and the concomitant development of targeted treatments informed by biological mechanisms. In a recent study, mapping molecular-enriched networks with REACT has provided novel insights into aberrant brain function and pharmacotherapy in the context of social processing in autism (Wong et al, 2022). First, the authors demonstrated that serotonin transporter (SERT)-enriched FC was greater during the presentation of emotional faces than shapes (faces>shapes) within a range of regions implicated in facial emotion processing.…”

“…Despite offering initial insights through ease of use, the spatial correlation analyses described above are limited in their ability to exploit the rich spatiotemporal dynamics of brain-wide BOLD fluctuations. In order to overcome this, novel analytical approaches have been developed to enrich fMRI data with the molecular information provided by PET and SPECT imaging (Cercignani et al, 2021;Dipasquale et al, 2020Dipasquale et al, , 2019Lawn et al, 2022aLawn et al, , 2022bDaniel Martins et al, 2022;Wong et al, 2022), and gene expression data from the AHBA (Salvan et al, 2022). Compared to the spatial correlation analyses, the derivation and analyses of molecular-enriched networks offers two key benefits.…”

The Effects of Propofol Anaesthesia on Molecular-enriched Networks During Resting-state and Naturalistic Stimulation

“…One solution to this has been to incorporate molecular information from positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) into fMRI analyses, as in Receptor-Enriched Analysis of functional connectivity by targets (REACT), to help bridge the gap between these micro-and macroscale systems (Dipasquale et al, 2019). The resultant receptor-enriched networks have demonstrated alterations under pharmacological challenge (Dipasquale et al, 2019(Dipasquale et al, , 2020Lawn et al, 2022) and within disease states (Cercignani et al, 2021;Martins et al, 2022;Wong et al, 2022), but also offer a promising tool to probe the molecular substrates of cognition and consciousness. Each modulatory system engages with a set of target receptors which exhibit diversity in their patters of expression as well as downstream effects which interact in a complex pleiotropic manner.…”