ORIGINAL RESEARCH article
Front. Neurol.
Sec. Applied Neuroimaging
Gray Matter Microstructural Alterations and their Correlation with Systemic Biomarkers in Hepatic Encephalopathy: A NODDI Study Using Gray-matter Based Spatial Statistics
Fengli Xie
Xiaohui Wang
Huina Zhang
Juan Wang
Shaofeng Wang
Peng Cheng
Jiangong Zhou
Haohui Zhan
Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
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Abstract
Background: Hepatic encephalopathy (HE) involves complex neurobiological changes that are often difficult to quantify using conventional MRI. This study aims to utilize Neurite Orientation Dispersion and Density Imaging (NODDI) combined with Gray-matter Based Spatial Statistics (GBSS) to characterize microstructural alterations in patients with HE and explore their relationship with clinical biochemical markers, specifically within the globus pallidus (GP). Methods: Thirty-three patients with HE and 31 healthy controls underwent 3T MRI including a multi-shell diffusion protocol for NODDI. GBSS was performed to assess differences in the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI). Pearson correlation analyzed relationships between GP NODDI parameters and blood biochemical indices. Results: HE patients exhibited significantly decreased NDI across widespread cortical and subcortical regions (frontal, parietal, temporal, cingulate, insula, thalamus) and increased ODI in the posterior cerebellum/vermis. Exploratory ROI analysis of the globus pallidus (GP) - a region known for manganese deposition but showing no significant group-level differences in this study-revealed that, the NDI of the right GP showed positive correlations with indirect bilirubin and prothrombin international normalized ratio (all uncorrected p<0.05), while the ODI of the left GP positively correlated with hemoglobin concentration (uncorrected p=0.046). Conclusions: NODDI reveals extensive microstructural alterations consistent with reduced neurite density index and cerebellar disorganization in HE. The dissociated correlation patterns of GP NDI and ODI with distinct blood markers may be compatible with a hypothetical "double-hit" pathophysiological model: toxic metabolite accumulation may drive cellular swelling (increased NDI), while systemic factors like anemia may reduce structural complexity (decreased ODI). however, these exploratory associations do not allow causal inference. These findings highlight NODDI could be a useful tool for monitoring the progression and metabolic impact of HE.
Summary
Keywords
biomarkers5, Globus Pallidus4, Gray-matter Based Spatial Statistics (GBSS)3, Hepatic Encephalopathy1, Neurite Orientation Dispersion and Density Imaging(NODDI)2
Received
08 January 2026
Accepted
19 February 2026
Copyright
© 2026 Xie, Wang, Zhang, Wang, Wang, Cheng, Zhou and Zhan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Haohui Zhan
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