ORCID
- Hannah Windmill: 0009-0001-0322-5024
Abstract
Hepatic encephalopathy (HE) is a common complication of chronic liver disease, with minimal hepatic encephalopathy (MHE) characterised by subclinical cognitive dysfunction, mood disturbance, and sleep disruption. MHE remains underdiagnosed due to poor correlation of prevalence with disease severity and absence of a standardised clinical diagnostic tool. This thesis employs a multimodal neuroimaging framework, integrating MR spectroscopy (MRS), diffusion MRI, fMRI, and EEG, to identify sensitive early markers of MHE and examine the confounding influence of sleep on brain-based outcomes.Chapter 4 investigated neuroimaging biomarkers of MHE in a cross-sectional cohort of liver disease patients and healthy controls. Primary outcomes were EEG and MRS measures, selected based on existing evidence for their sensitivity to hyperammonaemia-related brain dysfunction. Significant group differences were observed in occipital and frontal myoinositol and glutamine, occipital GABA, and dominant alpha frequency, consistent with metabolic disruption previously associated with hyperammonaemia in liver disease.Chapter 5 presents a single-case longitudinal neuroimaging study pre- and post-liver transplantation, with EEG and MRS chosen as primary outcome measures. Statistically reliable improvements were observed in occipital peak alpha power and alpha blocking, alongside MRS normalisation of GABA, glutamate, and myoinositol, and improved Go-trial reaction time. Persistent post-transplant increases in frontal lactate, mean diffusivity, and reductions in FA and ICVF indicated residual microstructural and metabolic disruption, demonstrating that liver transplantation does not fully reverse MHE-related brain changes within a six-month timeframe.Chapters 6–8 recruited healthy controls to establish normative neuroimaging data and characterise sleep-brain relationships. Chapter 6 demonstrated a dissociation between subjective and objective sleep measures, with global subjective sleep quality associated with trait anxiety and negative affect but not actigraphy-derived metrics, suggesting mood and affective state as correlates of perceived rather than objectively measured sleep. Chapter 7 found that greater variability in sleep duration - implicating inconsistent onset and wake times characteristic of MHE sleep-wake dysregulation - was associated with reduced occipital GABA, increased right insula activation during inhibitory control, reduced left uncinate fasciculus FA, and poorer response accuracy. Chapter 8 demonstrated that poorer subjective sleep quality, prevalent in both the present cohort and in MHE populations, predicted greater alpha blocking magnitude and shorter P3b latencies, consistent with hypervigilant neural processing mediated by anxiety, and suggesting that EEG markers of cognitive processing in MHE may be partly driven by sleep-related arousal states rather than disease pathology alone.Collectively, these findings support a continuum model of MHE in which metabolic and neural vulnerability precedes overt cognitive decline and is not fully captured by psychometric screening. The sleep studies demonstrate that disrupted sleep-wake regulation characteristic of MHE produces overlapping neuroimaging signatures in healthy adults, suggesting sleep disturbance may contribute to MHE symptom burden and that anxiety may represent an added mechanistic pathway through which MHE exerts neuropsychiatric effects. These findings advocate for multimodal, sleep-aware assessment frameworks integrating neurochemical, electrophysiological, and structural measures alongside objective sleep evaluation to improve diagnostic specificity and clinical management of MHE.
Awarding Institution(s)
University of Plymouth
Supervisor
Stephen Hall, Alastair Smith, Ashwin Dhanda, Matt Roser
Keywords
Minimal hepatic encephalopathy, hepatic encephalopathy, covert hepatic encephalopathy, MHE, HE, chronic liver disease, liver cirrhosis, neuroimaging, brain imaging, multimodal neuroimaging, brain dysfunction, magnetic resonance imaging, MRI, magnetic resonance spectroscopy, MRS, diffusion MRI, functional MRI, electroencephalography, EEG, sleep-wake regulation, metabolic dysfunction, hyperammonaemia, psychometric hepatic encephalopathy score, PHES, anxiety, ERP, event related potential
Document Type
Thesis
Publication Date
2026
Embargo Period
2026-08-02
Deposit Date
August 2026
Additional Links
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Recommended Citation
Windmill, H. (2026) Multimodal Imaging Markers of Brain Dysfunction in Minimal Hepatic Encephalopathy: Sleep-Wake Regulation and Metabolic Dysfunction. Thesis. University of Plymouth. Available at: https://doi.org/10.24382/avc5-eg58
