L-Cystine is associated with the dysconnectivity of the default-mode network and salience network in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Distributed dysconnectivity within both the default-mode network (DMN) and the salience network (SN) has been observed in ADHD. L-cystine may serve as a neuroprotective molecule and signaling pathway, as well as a biomarker of ADHD. The purpose of this study was to explore whether differential brain network connectivity is associated with peripheral L-cystine levels in ADHD patients. We recruited a total of 31 drug-naive patients with ADHD (mean age: 10.4 years) and 29 healthy controls (mean age: 10.3 years) that underwent resting state functional magnetic resonance imaging scans. Functional connectomes were generated for each subject, and we examined the cross-sectional group difference in functional connectivity (FC) within and between DMN and SN. L-cystine plasma levels were determined using high-performance chemical isotope labeling (CIL)-based liquid chromatography-mass spectrometry (LC-MS). Compared to the control group, the ADHD group showed decreased FC of dorsal DMN (p = 0.031), as well as decreased FC of precuneus-post SN (p = 0.006) and ventral DMN-post SN (p = 0.001). The plasma L-cystine levels of the ADHD group were significantly higher than in the control group (p = 0.002). Furthermore, L-cystine levels were negatively correlated with FC of precuneus-post SN (r = -0.404, p = 0.045) and ventral DMN-post SN (r = -0.540, p = 0.007). The findings suggest that decreased synergies of DMN and SN may serve as neurobiomarkers for ADHD, while L-cystine may be involved in the pathophysiology of network dysconnectivity. Future studies on the molecular mechanism of the cystineglutamate system in brain network connectivity are warranted.