Functional connectivity alterations in patients with chronic hepatitis C virus infection: A multimodal MRI study

Abstract

Chronic hepatitis C virus (HCV) infection is associated with fatigue and depression. Cognitive impairments are also reported in a smaller number of HCV-positive patients. Recent studies linked HCV to low-grade inflammation in brain. Here, we test the hypothesis that chronic HCV is associated with 3T-neuroimaging-derived grey matter volume (GMV) and functional connectivity alterations in a sample of chronic HCV (1b), without severe liver disease. Regional GMV and resting-state fMRI-derived eigenvector centrality (EC) were compared between 19 HCV-positive patients and 23 healthy controls (all females, 50-69 and 52-64 years, respectively), controlling for white matter hyperintensities and age. Standard tests were used to assess fatigue, depression and cognitive performance. Also, liver fibrosis stage and viral load were quantified among patients. In comparison with controls, HCV-positive patients had higher scores in fatigue and depression, and worse alertness scores. The groups performed similarly in other cognitive domains. We report higher EC in a cluster in the right anterior superior parietal lobule in patients, while no differences are found in GMV. Post hoc functional connectivity analysis showed increased connectivity of this cluster with primary and secondary somatosensory cortex, and temporal and occipital lobes in patients. Higher mean EC in the superior parietal cluster, adjusted for mean framewise displacement, was associated with better memory and attention performance, but not with fatigue, depression, viral load or level of liver fibrosis, among patients. These results suggest a compensatory mechanism in chronic hepatitis C and explain equivocal results in the literature about cognitive deficits in infected persons. Further studies should define the relation of these connectivity changes to the brain's inflammatory activity.

Functional MRI and delay discounting in patients infected with hepatitis C

“…The present study is also generally consistent with previous neuroimaging studies demonstrating a range of HCV associated CNS effects (Forton, Allsop et al 2001, Taylor, Letendre et al 2004, Weissenborn, Krause et al 2004, McAndrews, Farcnik et al 2005, Grover, Pavese et al 2012, Bladowska, Zimny et al 2013, Bladowska, Knysz et al 2014, Thames, Castellon et al 2015, Pflugrad, Meyer et al 2016, Kharabian Masouleh, Herzig et al 2017, Kumar, Deep et al 2017), and with the literature on neuroimmune pathways leading to HCV associated neuropsychiatric symptoms and CNS changes. Viruses can cross tight junctions due to high levels of viremia and inflammation, and HCV RNA has been detected in cerebrospinal fluid and brain parenchyma (Laskus, Radkowski et al 2002, Laskus, Radkowski et al 2005, Letendre, Paulino et al 2007, Adinolfi, Nevola et al 2015).…”

“…Specifically, our primary objective was to determine whether, relative to non-infected controls, individuals with HCV exhibit differences in brain activation during a DDT. Previous neuroimaging studies comparing untreated adults with HCV to non-infected controls have found a variety of HCV associated changes using various methods (electroencephalogram (EEG) (Weissenborn, Krause et al 2004); magnetic resonance spectroscopy (MRS) (Forton, Allsop et al 2001, Taylor, Letendre et al 2004, Weissenborn, Krause et al 2004, McAndrews, Farcnik et al 2005, Bladowska, Zimny et al 2013, Thames, Castellon et al 2015); multimodal MRI or diffusion tensor imaging (DTI) (Bladowska, Zimny et al 2013, Thames, Castellon et al 2015, Kharabian Masouleh, Herzig et al 2017, Kumar, Deep et al 2017); perfusion-weighted MRI (Bladowska, Zimny et al 2013, Bladowska, Knysz et al 2014); positron emission tomography (PET) (Grover, Pavese et al 2012, Pflugrad, Meyer et al 2016)). Collectively, findings could be interpreted to suggest that HCV causes or is associated with central nervous system (CNS) inflammation, damage, and/or neurodegeneration.…”

“…Alternatively, findings could suggest that markers may in part represent compensatory (protective) mechanisms of the CNS to HCV infection. For example, HCV associated increases in microglial activation were associated with improved cognitive function in HCV infected patients in one study (Pflugrad, Meyer et al 2016), and HCV associated increases in functional connectivity were associated with better memory and attention performance in HCV infected patients in another study (Kharabian Masouleh, Herzig et al 2017). …”

Systematic review with meta‐analysis: neuroimaging in hepatitis C chronic infection

“…Of these, 14 articles were excluded for various reasons (see Figure and supporting information). Finally, 18 unique references met the inclusion criteria and were included in this systematic review . Figure provides a PRISMA flowchart of study selection for this systematic review.…”

“…Moreover, the samples selected are heterogeneous, especially with regard to the clinical severity of the CHC, the presence of neuropsychiatric comorbidities and the diagnosis of active substance use disorder. Finally, the attempts to find correlation between neuroimaging findings and cognitive or psychiatric symptoms have yielded inconclusive results …”