Extrastriatal dopamine D2/3 receptor binding, functional connectivity, and autism socio-communicational deficits: a PET and fMRI study

• Published in: Molecular psychiatry 2022-04, Vol.27 (4), p.2106-2113
• Main Authors: Murayama, Chihiro, Iwabuchi, Toshiki, Kato, Yasuhiko, Yokokura, Masamichi, Harada, Taeko, Goto, Takafumi, Tamayama, Taishi, Kameno, Yosuke, Wakuda, Tomoyasu, Kuwabara, Hitoshi, Senju, Atsushi, Nishizawa, Sadahiko, Ouchi, Yasuomi, Yamasue, Hidenori
• Format: Article
• Language: English
• Subjects: 59/36; 59/78; 631/1647; 692/699/476/1373; Autism; Behavioral Sciences; Biological Psychology; Brain mapping; Cerebellum; Dopamine; Dopamine D2 receptors; Functional magnetic resonance imaging; Intelligence; Medicine; Medicine & Public Health; Motivation; Neural networks; Neuroimaging; Neurosciences; Occipital lobe; Pharmacotherapy; Positron emission tomography; Psychiatry; Pulvinar; Reinforcement; Social organization; Superior temporal sulcus; Temporal cortex; Thalamus; Therapeutic targets
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01464-3

The social motivation hypothesis of autism proposes that social communication symptoms in autism-spectrum disorder (ASD) stem from atypical social attention and reward networks, where dopamine acts as a crucial mediator. However, despite evidence indicating that individuals with ASD show atypical activation in extrastriatal regions while processing reward and social stimuli, no previous studies have measured extrastriatal dopamine D2/3 receptor (D2/3R) availability in ASD. Here, we investigated extrastriatal D2/3R availability in individuals with ASD and its association with ASD social communication symptoms using positron emission tomography (PET). Moreover, we employed a whole-brain multivariate pattern analysis of resting-state functional magnetic resonance imaging (fMRI) to identify regions where functional connectivity atypically correlates with D2/3R availability depending on ASD diagnosis. Twenty-two psychotropic-free males with ASD and 24 age- and intelligence quotient-matched typically developing males underwent [ 11 C]FLB457 PET, fMRI, and clinical symptom assessment. Participants with ASD showed lower D2/3R availability throughout the D2/3R-rich extrastriatal regions of the dopaminergic pathways. Among these, the posterior region of the thalamus, which primarily comprises the pulvinar, displayed the largest effect size for the lower D2/3R availability, which correlated with a higher score on the Social Affect domain of the Autism Diagnostic Observation Schedule-2 in participants with ASD. Moreover, lower D2/3R availability was correlated with lower functional connectivity of the thalamus-superior temporal sulcus and cerebellum–medial occipital cortex, specifically in individuals with ASD. The current findings provide novel molecular evidence for the social motivation theory of autism and offer a novel therapeutic target.