TY - JOUR
T1 - Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter
T2 - A randomised placebo-controlled single-dose crossover trial
AU - Wong, Nichol Ml
AU - Dipasquale, Ottavia
AU - Turkheimer, Federico
AU - Findon, James L
AU - Wichers, Robert H
AU - Dimitrov, Mihail
AU - Murphy, Clodagh M
AU - Stoencheva, Vladimira
AU - Robertson, Dene M
AU - Murphy, Declan G
AU - Daly, Eileen
AU - McAlonan, Grainne M
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Support has also been received from the Sackler Institute for Translational Neurodevelopment at King’s College London, the MRC Centre for Neurodevelopmental Disorders at King’s College London and the Innovative Medicines Initiative 2 Joint Undertaking (grant no. 777394) for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI.
Funding Information:
The authors thank all the volunteers for their participation. The authors acknowledge support from the Maudsley Pharmacy Department and the National Autism Service for Adults at the South London, the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience King’s College London. The views expressed are those of the author(s) and not necessarily those of the IMI, NHS, the NIHR or the Department of Health. A previous version of this article was published as a preprint on bioRxiv ( https://doi.org/10.1101/2021.05.28.446151 ).
Publisher Copyright:
© The Author(s) 2022.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131026281&partnerID=8YFLogxK
U2 - 10.1177/02698811221092509
DO - 10.1177/02698811221092509
M3 - Article
C2 - 35491679
SN - 0269-8811
VL - 36
SP - 723
EP - 731
JO - Journal of Psychopharmacology
JF - Journal of Psychopharmacology
IS - 6
ER -