Children with Autism Spectrum Disorder Display Increased Functional Connectivity in the Periaqueductal Gray Network

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interactions, communication, and restricted and repetitive behaviors. Nevertheless, the underlying mechanism of ASD remains unclear due to its complex presentation.

Objectives: We investigated resting-state functional connectivity (rsFC) differences of the periaqueductal gray (PAG) between boys with autism spectrum disorder (ASD) and typically developed (TD) controls, and the association between PAG rsFC and clinical outcomes (Autism Diagnostic Interview-Revised (ADI-R) and executive function scores.

Methods: ASD (n=103) and TD (n=127) were selected from the Autism Brain Imaging Data Exchange II project.

Results: The demographic and clinical characteristics of ASD and TD are shown in Table 1. There were no significant differences in age (t ₍₂₂₈₎ = 0.64, p = 0.53) or intelligence (F-IQ) (t ₍₂₂₈₎=-0.96, p = 0.35) between the ASD and TD groups. Compared with the TD group, boys with ASD showed significantly increased PAG rsFC with left thalamus / hippocampus / parahippocampus, and middle temporal gyrus (Table 2,Figure 1). There were no significant decreased rsFC between PAG with other regions in boys with ASD than TD. The rsFC of PAG- thalamus / hippocampus / parahippocampus showed significant negative correlation with ADI-R verbal scores; the rsFC of PAG-left middle temporal gyrus showed significant positive correlation with subscale scores of executive function including inhibit, shift and behavioral regulation. The rsFC of the control seed located at the fourth ventricle showed no significant difference between ASD and TD groups.

Table 1 Demographic and Clinical Characteristics

Variable	ASD (Mean(SD))	TD (Mean(SD))	Statistic
Number	103	127
Age (years)	10.80(1.99)	10.64(1.63)	0.53
IQ	111.43(13.50)	112.91(10.04)	0.35
ADI-R
Social	18.80(5.42)	-----------------
Verbal	14.85(4.45)	-----------------
RRB	5.66(2.37)	-----------------
BRIEF
Inhibit	61.14(10.96)	44.24(7.21)	< 0.001
Shift	68.47(12.79)	43.72(7.23)	< 0.001
Emotional control	59.91(11.85)	43.70(7.10)	< 0.001
BRI	64.49(10.39)	42.82(6.91)	< 0.001
Initiate	64.30(9.91)	45.19(7.20)	< 0.001
Working memory	64.57(9.91)	44.16(7.82)	< 0.001
Plan/organize	64.18(10.38)	44.16(8.76)	< 0.001
Organization	59.40(10.14)	47.11(9.65)	< 0.001
Monitor	63.84(9.88)	43.19(9.70)	< 0.001
MI	65.74(9.25)	43.67(8.71)	< 0.001
GEC	66.52(9.16)	42.77(7.89)	< 0.001

ADI-R, Autism Diagnostic Interview-Revised; RRB, restricted and repetitive Behaviors.

GEC: general executive composite; BRI: behavioral regulation index; MI, metacognition index.

Table 2 rsFC change in ASD compared with TD and regression of ASD with ADI-R

Conditions			MNI coordinates			Peak z value
	Region	Cluster size	X	Y	Z
ASD > TD	Left thalamus/hippocampus /parahippocampus	168	-10	-32	0	3.78
	Left middle temporal gyrus	191	-52	-52	2	3.48
ASD < TD	None

Conclusions: Our findings demonstrate increased PAG rsFC with brain regions associated with sensations, cognition, emotion and facial expressions in ASD patients, and specific association patterns with different clinical outcomes, which may provide insights into the underlying mechanism of ASD.