Functional connectome gradient alterations in herpes zoster and postherpetic neuralgia: associations with gene expression profiles

Herpes zoster (HZ) and postherpetic neuralgia (PHN) are severe neuropathic pain disorders. However, the alterations in their macroscopic brain-functional architecture and their potential molecular correlations remain poorly understood. This study was aimed at characterizing the altered functional connectivity patterns in the brains of patients with HZ and PHN using a connectome gradient analysis and further explore the potential associations with gene expression patterns through a spatial transcriptomics correlation analysis. In this study, 95 patients with HZ, 89 patients with PHN, and 84 matched healthy controls were characterized through a connectome gradient analysis. Additionally, transcriptomic neuroimaging association analyses were conducted using gene expression data derived from the Allen Human Brain Atlas and case‒control gradient differences to identify the genes that were associated with gradient variations. Finally, an enrichment analysis was performed on the identified significant genes to explore the biological pathways and cell types in which they may be involved. Compared with the healthy controls, HZ exhibited in the whole-brain gradients shrinkage. HZ showed abnormal subgradient values within the sensorimotor and dorsal attention networks, with exploratory associations to anxiety scores. PHN was characterized by reduced main gradient values in the frontoparietal control network, with exploratory associations to depression scores. The transcriptomic neuroimaging association analysis revealed that the gradient abnormalities in HZ were spatially correlated with gene expression patterns involving synaptic functions and ion channels, whereas the abnormalities in PHN were spatially correlated with the genes involved in postsynaptic signaling and the regulation of endogenous opioids. Cellular analysis indicated that HZ-associated genes were predominantly enriched in inhibitory and excitatory neurons and astrocytes, whereas PHN-associated genes were enriched in both neuron types. This study is the first to identify functional connectome and associated gene expression profiles in HZ and PHN through a cross-scale perspective that encompasses both functional connectome gradients and gene expressions. Our findings provide novel insights into the spatial transcriptomic correlates of functional alterations in the brain under these conditions and provide a foundation for conducting hypothesis-driven research on potential biomarkers and therapeutic strategies.