Mood, immunity and brain connectivity in patients with chronic hepatitis C

Abstract

INTRODUCTION. Sickness behavior is a highly organized adaptive strategy elicited by inflammation to support the organism’s defense against pathogens. It is characterized by changes in behavior, mood and cognition similar to those observed in patients with major depressive disorder. Despite its adaptive function, sickness behavioral changes may become prolonged and dysfunctional when the pathogen stimulus cannot be removed and may contribute to the development of depression in vulnerable patients. The study of the mechanisms linking inflammation to sickness behavior and depression would be crucial for a better understanding of the pathophysiology of depression and to develop new therapeutic approaches. HYPOTHESIS AND OBJECTIVES. Patients with a low-degree chronic inflammatory disease such as chronic hepatitis C (CHC), compared to healthy controls, would present changes in brain morphology, activity, connectivity and metabolism in areas linked to sickness behavior and depression, and that such alterations would be related to mood symptoms and inflammatory markers. The main objective of this thesis was to elucidate the clinical and neurobiological correlates of a prolonged sickness condition associated with chronic inflammation, such as CHC. STUDY 1: METHODS AND RESULTS. A systematic review with meta-analysis of neuroimaging research was conducted in CHC treatment naïve patients. A computerized literature search was performed in main databases from inception up until 1 May 2017 for peer-reviewed studies on structural or functional neuroimaging assessment of no treated patients without cirrhosis or encephalopathy, neuropsychiatric disease or substance use disorder with control group. The primary measures of interest varied according to the neuroimaging technique used and the secondary outcome were the correlation of these measures with neuropsychiatric symptoms. Meta-analysis was conducted when possible. Of 1403 records, 32 full-text articles were assessed for eligibility. The final sample was of 25 studies. The whole sample was of 509 patients of mild liver disease, and 491 healthy controls. A meta‐analysis of magnetic resonance spectroscopy studies showed increased levels of choline/creatine ratio, creatine and glutamate plus glutamine in basal ganglia and increased levels of choline/creatine ratio in centrum semiovale white matter in CHC patients. Other structural and functional brain abnormalities were also reported by individual studies as marker of neuroinflammation, oxidative stress and neuron-glia or axon-myelin integrity disruption. Central nervous system metabolic changes were mainly correlated with neurocognitive impairment and fatigue symptoms, thought controversial results were observed. STUDY 2: METHODS AND RESULTS. A cross-sectional, case-control study of 35 CHC no treated patients, and 30 healthy controls, age and sex matched. Exclusion criteria were decompensated cirrhosis or hepatocarcinoma, any chronic disease or inflammatory condition, any neuropsychiatric and substance use disorder. All patients were evaluated for perceived stress (PSS), depression (PHQ-9), fatigue and irritability through a visual analog scale (VAS), as well as serum levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and oxidative stress markers. Functional magnetic resonance imaging was performed, measuring resting-state functional connectivity using a region-of-interest (seed)-based approach focusing on the bilateral insula, subgenual anterior cingulate cortex (sgACC) and bilateral putamen. Between-group differences in functional connectivity patterns were assessed with two-sample t-tests, while the associations between symptoms, inflammatory markers and connectivity patterns were analyzed with multiple regression analyses. We observed that CHC patients had higher PSS, PHQ-9 and VAS scores for fatigue and irritability, as well as increased IL-6 levels, PGE2 concentrations and antioxidant system activation compared to controls. Increased perceived stress and depressive symptoms were associated with changes in inflammatory marker levels and in functional connectivity between the insula and putamen, areas involved in interoceptive integration, emotional awareness, and orientation of motivational state. Of note, PGE2 and PSS scores accounted for 46% of the variance in functional connectivity between the anterior insula and putamen. CONCLUSIONS. The results supported the hypothesis of a direct or indirect involvement of hepatitis C virus in central nervous system disturbances and provide valuable information on the brain areas involved in perceived stress, fatigue and subclinical depressive symptoms during chronic inflammation, highlighting the crucial role of interoception in coordinating prolonged sickness behavior. Using the CHC disease as a model of low-grade inflammation, new neurobiological and neuroanatomical links between sickness behavior and chronic inflammatory conditions have been elucidated. These findings may be crucial in understanding pathophysiological mechanisms related with psychiatric diseases such as depression and open new research perspectives centered on the development of new therapeutic targets.

INTRODUCCIÓN. La conducta de enfermedad es una estrategia adaptativa y coordinada que tiene la finalidad de defender el organismo en contra de agente patógenos. Los cambios conductuales pueden persistir de forma prolongada y volverse disfuncionales. El estudio de los mecanismos subyacentes que relacionan la inflamación, conducta de enfermedad y depresión mejoraría el conocimiento de la fisiopatología de la depresión. HIPÓTESIS Y OBJETIVOS. Los pacientes con hepatitis C crónica (HCC) podrían presentar cambios cerebrales a nivel estructural, funcional, conectividad y metabolismo en áreas asociadas con la conducta de enfermedad y la depresión, y dichas alteraciones podrían estar relacionadas con síntomas anímicos y marcadores inflamatorios. El objetivo de esta tesis es elucidar los correlatos clínicos y neurobiológicos de la conducta de enfermedad prolongada asociada a HCC. ESTUDIO 1: MÉTODOS Y RESULTADOS. Realizamos revisión sistemática con meta-análisis de estudios sobre neuroimagen en pacientes con HCC no tratados. Se llevó a cabo una búsqueda computerizada de los estudios de neuroimagen publicados en las principales bases de datos. La variable primaria dependió de la técnica de neuroimagen utilizada. De 1403 estudios encontrados, 25 fueron seleccionados. La muestra final comprendió 509 pacientes con HCC y 491 controles sanos. En los meta-análisis de los estudios de espectroscopia se observaron niveles incrementados de la ratio entre colina y creatina, de la creatina y de glutamato plus glutamina en los ganglios basales de pacientes. Las alteraciones metabólicas en el sistema nervioso central estaban relacionadas a alteraciones neurocognitivas de forma controvertida. ESTUDIO 2: MÉTODOS Y RESULTADOS. Estudio transversal, caso-control, que compara 35 pacientes de ambos sexos, entre 18 y 55 años, con HCC sin tratar y 30 controles sanos. Se evaluaron el estrés percibido (PSS), depresión (PHQ-9), fatiga e irritabilidad mediante escala visual analógica (VAS), así como las concentraciones séricas de interleuquina-6 (IL-6), prostaglandina E2 (PGE2) y marcadores de estrés oxidativo. Se realizó una resonancia magnética cerebral funcional estudiando la conectividad cerebral en estado de reposo, mediante la selección a priori de regiones de interés: ínsula bilateral, cortex cingulado anterior subgenual (sgACC), y el putamen bilateral. Las asociaciones entre síntomas clínicos, marcadores inflamatorios y patrones de conectividad funcional fueron analizadas mediante regresión múltiple. Los pacientes con HCC presentaban puntuaciones mayores en las escalas de PSS, PHQ-9, VAS-F y VAS-I, un incremento de las concentraciones séricas de IL-6 y PGE2 y una mayor activación del sistema anti-oxidativo comparado con los controles sanos. El incremento del estrés percibido y los síntomas depresivos estaban asociados a alteraciones de los marcadores inflamatorios y de la conectividad entre ínsula y putamen. Los niveles de PGE2 y los valores de PSS eran responsables del 46% de la variación de la conectividad funcional entre ínsula anterior y putamen. CONCLUSIONES. Los resultados observados proporcionan información importante sobre las áreas cerebrales involucradas en el estrés percibido y los síntomas depresivos subclínicos durante un estado de inflamación crónica. Se han podido ilustrar nuevos enlaces neurobiológicos y neuroanatómicos entre la conducta de enfermedad e la inflamación crónica que podrían ayudar en la comprensión de mecanismos fisiopatológicos relacionados con la depresión, y abrir nuevas perspectivas de investigación centradas en el desarrollo de nuevas dianas terapéuticas.