Dysfunction and recovery of the cortical connectome gradient and its association with gene expression profiles in...

The hierarchy and segregation of community-based brain networks can be characterized by functional connectome gradient (FCG). Whether the cortical FCG was disrupted and could even be reversed after prolonged abstinence in substance use disorders (SUDs) remained unclear. Less is known about the underlying genetic basis.

We utilized three independent datasets (n = 247) to investigate cortical FCG dysfunction and recovery after prolonged abstinence in methamphetamine use disorder (MUD) (n = 131), and validated in heroin use disorder (HUD) (n = 36). Furthermore, magnetic resonance spectroscopy (MRS) was employed to test the relationship between the glutamate in the ventral tegmental area (VTA) and cortical FCG. Postmortem gene expression was utilized to assess the transcriptional profiles related to cortical FCG alterations. Support vector regression (SVR) model based on the baseline cortical FCG was built to predict craving changes after long-term abstinence.

MUD and HUD individuals exhibited similar cortical FCG dysfunction and recovery at global and network levels, mainly in dorsal and ventral attentions network (DAN and VAN), frontoparietal network (FPN) and default mode network (DMN). The glutamate levels in VTA were correlated with the gradient distance between FPN and limbic network (LIM). The transcriptional profiles explained variance of the altered gradient pattern, with the most related genes enriched in synaptic signaling. Baseline cortical FCG significantly predicted craving changes after long-term abstinence.

We provided novel insights into the understanding of SUD as treatable health conditions from cortical FCG changes, which could be considered as the potential biomarkers of craving changes after prolonged abstinence for SUDs.