Association of chronic inflammation and perceived stress with abnormal functional connectivity in brain areas involved with interoception in hepatitis C patients
Introduction
Sickness behavior is a highly organized adaptive strategy to support the organism’s defense against pathogens, and is characterized by changes in behavior, mood and cognition (Dantzer, 2001a, Garcia et al., 1955, Miller and Raison, 2016, Stieglitz, 2015).
The experience of “feeling sick” is common during acute infections or inflammatory responses to trauma (Hart, 1988, Miller and Raison, 2016). It clinically presents as a set of neurovegetative symptoms such as fatigue, anorexia, psychomotor retardation and increased sensitivity to pain, and is also associated with increased irritability, anhedonia, social responsiveness and increased stress sensitivity (Capuron and Miller, 2004, Dantzer et al., 2008, Maes et al., 2012). Animal and human studies suggest that soluble mediators, such as the pro-inflammatory cytokines interleukin- (IL-) 1, IL-6 and tumor necrosis factor-α (TNF-α), play a direct role in the development of sickness-related behaviors (Aubert et al., 1997, Avitsur et al., 1997, Dantzer, 2001b, Hart, 1988, Kent et al., 1996, Kent et al., 1992). Moreover, it has been observed that peripheral immunological activation may drive inflammation in the central nervous system, involving neurons, astrocytes and the microglia (Dantzer, 2009, Haroon et al., 2012, Miller et al., 2013).
Furthermore, neuroimaging studies have indicated that cortical and sub-cortical brain structures might play a relevant role in sickness behavior, identifying the insula, subgenual anterior cingulate cortex (sgACC) and basal ganglia, particularly the ventral striatum and substantia nigra (Harrison, 2017), as sensitive to peripheral inflammation. These studies involved inducing acute inflammation through the direct inoculation of endotoxins, such as the Salmonella typhi vaccine or lipopolysaccharide (LPS), or patients receiving treatment with the pro-inflammatory cytokine interferon- (IFN-) α (Capuron et al., 2012, Eisenberger et al., 2011, Harrison et al., 2009a, Udina et al., 2012). Situations in which the initial noxious stimulus cannot be removed could lead to prolonged and dysfunctional sickness behavior. Examples of this include chronic infections (i.e., human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infections), auto-immune disorders (i.e., rheumatoid arthritis or inflammatory bowel disease) or chronic inflammatory conditions (i.e., cancer, diabetes or obesity), which have been often linked to an increased prevalence of depression (Liu et al., 2017). In this regard, increased perceived stress, fatigue, and irritability, which are also common in depressed patients (Chung et al., 2015, Farabaugh et al., 2004, Fava et al., 2010), have often been observed in chronic inflammatory conditions such as rheumatic diseases (Louati and Berenbaum, 2015), obesity (Capuron et al., 2016), cancer (Bower and Lamkin, 2013), and inflammatory bowel disease (Targownik et al., 2015).
Major depressive disorder (MDD) displays a phenomenological overlap with sickness behavior, and has been consistently associated with increased levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) and acute-phase proteins (such as the C-reactive protein) (Haapakoski et al., 2015, Kohler et al., 2016). Moreover, brain structural and functional alterations have been identified in several neuroimaging studies on depression, mainly in the prefrontal-limbic-subcortical areas that are involved in emotional processing and awareness, similar to those involved during acute inflammatory challenges (Drevets et al., 2008, Feng et al., 2016, Harrison, 2017, Mulders et al., 2015, Savitz and Harrison, 2018, Savitz and Drevets, 2009). However, the type of symptoms and illness course differ between MDD and sickness behavior. Typically, MDD is considered a lifetime progressive disease, which differs from the acute and adaptive nature of sickness behavior (Freeman et al., 2017, Oriolo et al., 2018a).
Moreover, depression can involve biological pathways that are different from those associated with acute pro-inflammatory cytokine stimulation, such as cell-mediated immune activation, dysregulated anti-inflammatory mechanisms, neural sensitization to immune responses or auto-immunity processes (Dantzer et al., 2008). Importantly, the activation of oxidative and nitrosative stress (O&NS) pathways, resulting in increased levels of reactive oxygen and nitrogen species (ROS and RNS, respectively) that damage lipids, proteins and DNA, may be crucial in the chronic and progressive course of depression (Liu et al., 2015, Moylan et al., 2013).
Thus, as sickness behavior and depression share clinical phenomenology, inflammatory pathways and brain functional changes, it has been hypothesized that prolonged and dysregulated sickness behavior may contribute to the development of MDD in vulnerable patients (Capuron and Castanon, 2012, Rosenblat et al., 2014). Some studies in chronic hepatitis C (CHC) patients have tried to elucidate the neurobiological and neuroanatomical links between chronic inflammatory conditions and prolonged sickness behavior, excluding subjects with current severe mental illness and considering several ranges of neuropsychiatric symptoms such as depression, anxiety, fatigue or cognition (Aregay et al., 2018, Huckans et al., 2014, Loftis and Hauser, 2008). Depression is the leading cause of disability worldwide (World Health Organization, 2017), affecting >300 million people, a substantial proportion of whom do not respond adequately to current pharmacological therapies (Rush et al., 2006, Stotland, 2012); therefore, understanding the pathophysiological mechanisms linking inflammation to sickness and MDD seems to be crucial in developing new therapeutic targets (Udina et al., 2015, Udina et al., 2014). Moreover, CHC is a well-known systemic disease with a plethora of extrahepatic manifestations such as chronic kidney disease, mixed cryoglobulinemia, increased rates of insulin resistance, diabetes, and atherosclerosis, increased cardiovascular morbidity and neuropsychiatric symptoms, among others (Grignoli et al., 2015). Accordingly, the purpose of this study was to elucidate the clinical and neurobiological correlates of a prolonged sickness condition associated with chronic inflammation in a case-control study of patients with CHC not treated with IFN-α or others antiviral therapies, and without MDD. We hypothesized that chronic low-grade inflammation secondary to CHC can induce alterations in brain connectivity in areas associated with interoceptive integration and awareness, emotional processing and orientation of motivational state, with such alterations correlating with some aspects of sickness behavior.
Section snippets
Participants
Fifty-one Caucasian outpatients aged between 18 and 55 years with CHC who were candidates for antiviral treatment, either with the pegylated IFN-α and ribavirin (RBV) combination or with the new direct-acting antivirals (DAA), were recruited between 2014 and 2016 at the Liver Units of two general university hospitals (Hospital Clínic and Hospital del Mar) in Barcelona. None of the patients had previously received anti-viral treatment (pegylated IFN-α or DAA). The exclusion criteria for the
Characteristics of the study participants
The study sample comprised 35 patients with CHC and 30 control subjects without HCV infection matched for sex, age and laterality. About two-thirds of the participants were male (66.1%) and the mean age of the study sample was 40.2 years (SD = 9.4; range 18–52) (Table 1). Genotype 1 was the most common HCV genotype (80%), whereas the route of HCV infection could not be ascertained in most of the cases (74.3%). The median of HCV RNA (viral load) was 1.5x106 IE/mL (range = 3.0 × 105–6.3 × 106).
Discussion
Results from this study indicate that increased inflammation, as reflected by increased IL-6 and PGE2 serum levels, and greater perceived stress and subclinical depressive symptoms in patients with CHC are associated with abnormal functional connectivity in brain regions associated with interoceptive awareness (see Figure S6).
We observed that patients with CHC perceived more stress and reported greater levels of irritability and fatigue than control subjects, as expected for patients with
Conclusions
Patients with CHC infection exhibited increased perceived stress and subthreshold depressive symptoms, as well as higher levels of inflammatory markers, compared to control subjects. These subtle clinical and inflammatory differences were reflected by functional connectivity changes in brain areas involved in interoceptive awareness, psychomotor functions and emotional processing. Our findings provide evidence that chronic inflammation may induce prolonged activation of interoceptive pathways,
Acknowledgments
RMS is grateful to the Instituto de Salud Carlos III, the Spanish Ministry of Economy and Competiveness, the Centro para la Investigación Biomédica en Red de Salud Mental (CIBERSAM), the Institut d’Investigacions Biomèdica August Pi i Sunyer (IDIBAPS), and the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement, Grups consolidats de recerca (2014_SGR_1431 and 2017_SGR_1798).
Funding
This study was supported by the Instituto de Salud Carlos III, FIS: PI10/02206 (RMS) and FIS: PI10/02291 (RS). It was co-funded by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo General (FEDER, “A Way to Build Europe”).
Conflicts of interest to declare
RMS, GO, LBH, RN, DMH, MC,DG, JC, LC, and JP: none.
XF received unrestricted grant support from Abbvie and Gilead, and acted as Advisor for Abbvie and Gilead.
ZM acted as advisor for Gilead and received speaker fees from Abbvie, Gilead, Jansen, and MSD.
RS reports receiving consulting fees from Roche Pharma, Bristol Myers Squibb, Gilead Sciences, Novartis, Roche/Genentech, Tibotec and Jansen, lecture fees from Bristol Myers Squibb, Gilead Sciences, Novartis, Roche/Genentech and Jansen, and grant
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