A Simultaneous [¹¹C]Raclopride Positron Emission Tomography and Functional Magnetic Resonance Imaging Investigation of Striatal Dopamine Binding in Autism

Abstract

Background: The social motivation hypothesis of autism suggests that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework posits that impaired mesolimbic dopamine (DA) function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Methods: This study evaluated striatal dopaminergic functioning during incentive processing in ASD using simultaneous positron emission tomography (PET) and fMRI using the D2/D3 dopamine receptor antagonist [11C]raclopride. Using a bolus + infusion protocol, voxel-wise binding potential (BPND) was compared between groups (Controls=12, ASD=10) in the striatum. Results: Relative to controls, the ASD group demonstrated relatively decreased phasic DA release to incentives in the right and left putamen and left caudate. Striatal clusters showing significant between-group BPND differences were used as seeds in whole-brain fMRI general functional connectivity analyses. This revealed increased connectivity between the PET-derived right putamen seed and clusters in the precuneus and right insula in the ASD group. Within the ASD group, decreased phasic DA release in the left putamen was related to poorer theory-of-mind skills. Conclusions: ASD was characterized by impaired striatal phasic DA release and abnormally increased functional connectivity, providing support for the social motivation hypothesis of autism. PET measures of dopamine receptor target occupancy may be suitable to evaluate novel ASD therapeutics targeting the striatal dopamine system.

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

“…At the same time, such studies could describe the effects of dopamine modulators on essential circuits, permitting individualized therapy for certain subsets of patients. A recent PET/functional magnetic resonance imaging study reported impaired striatal phasic dopamine release to incentives, providing support for the SMT of ASD [95]. However, Kubota et al [96] reported similar DRD1 binding capacity, while Schalbroeck et al [97] found no significant difference in striatal dopamine synthesis capacity between adults with ASD and neurotypical controls.…”

Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models

“…In turn, PET imaging of radioligand binding to the dopamine active transporter (DAT) showed increased binding in the orbitofrontal cortex of highfunctioning adults with ASD (Nakamura et al, 2010); however, changes in dopaminergic function at rest have not been detected universally (Makkonen et al, 2008). During task performance, a reduction in phasic striatal DA events evoked by social stimuli in children and adolescents with ASD have been reported in several studies (Scott-Van Zeeland et al, 2010;Zürcher et al, 2020). Together, these data support the involvement of functional changes in dopaminergic signaling in ASD.…”