Altered Extended Locus Coeruleus and Ventral Tegmental Area Networks in Boys with Autism Spectrum Disorders: A Resting-State Functional Connectivity Study

Abstract

Introduction: Previous studies have suggested that cerebral projections of the norepinephrine (NE) and dopamine (DA) systems have important etiology and treatment implications for autism spectrum disorder (ASD).

Methods: We used functional magnetic resonance imaging to evaluate spontaneous resting state functional connectivity in boys aged 7-15 years with ASD (n=86) and age-, intelligence quotient-matched typically developing boys (TD, n=118). Specifically, we investigated functional connectivity of the locus coeruleus (LC) and ventral tegmental area (VTA), the main source projection of neurotransmitters NE and DA, respectively.

Results: 1) Both the LC and VTA showed reduced connectivity with the postcentral gyrus (PoCG) in boys with ASD, reflecting the potential roles of NE and DA in modulating the function of the somatosensory cortex in boys with ASD. 2) The VTA had increased connectivity with bilateral thalamus in ASD; this alteration was correlated with repetitive and restrictive features. 3) Altered functional connectivity of both the LC and VTA with brain regions such as the angular gyrus (AG), middle temporal gyrus visual area (MT/V5), and occipital face area (OFA) in ASD group.

Discussion: Our findings implicate the role of LC-NE and VTA-DA systems from the perspective of functional neuroimaging and may shed light on pharmacological studies targeting NE and DA for the treatment of autism in the future.

Keywords: autism spectrum disorder; dopamine; functional connectivity; locus coeruleus; norepinephrine; ventral tegmental area.

Figure 1

Between-group resting-state functional connectivity results of the LC and VTA as seed. (A) LC seed region; (B) middle and right panel: brain regions that showed decreased and increased functional connectivity to the LC in ASD boys compared to typically developing (TD); the color bar indicates the range of t value; (C) VTA seed region; (D) middle and right panel: brain regions that showed decreased and increased functional connectivity to the VTA in ASD boys compared to typically developing (TD); the color bar indicates the range of t value.

Figure 2

Left panel: demonstrating increased connectivity between VTA and bilateral thalamus in boys with ASD; middle panel: boxplot of SRS restrictive and repetitive behaviors subscore between ASD and TD group; right panel: scatterplot of VTA-thalamus connectivity with significant correlation to SRS restricted and repetitive behavior subscore (ASD: r=0.3, p=0.004, N=86; TD: r=0.1, p=0.439, N=118, adjusted for covariates).