Disrupted functional connectivity of default mode and salience networks in chronic pancreatitis patients

Highlights

• Chronic pancreatitis (CP) patients had altered functional connectivity in the brain.

• Default mode and salience network coupling was abnormal in CP patients.

• Default mode network connectivity was associated with cingulate glutamate levels.

Abstract

Objective

The functional connectivity of the brain in chronic pancreatitis (CP) remains unknown. This study aimed to investigate functional connectivity in CP patients using resting state functional magnetic resonance imaging (fMRI) and explore the associations to clinical parameters and altered cerebral metabolites.

Methods

Seed-based and ROI-to-ROI analyses were performed to assess connectivity within and between the default mode network (DMN) and salience network (SN). Additionally, functional connectivity in these networks were investigated in relation to clinical parameters (CP etiology, pain, medication, etc.) and cerebral glutamate/creatine level in the anterior cingulate cortex.

Results

Thirty CP patients and 23 healthy controls were analyzed. CP patients showed hyper-connectivity in DMN and SN as compared to healthy controls. Furthermore, CP patients had reduced anti-correlated functional connectivity between DMN and SN (all P ≤ 0.009). The altered DMN connectivity correlated to glutamate/creatine level (r = 0.503, P = 0.020) in patients with pain, but not to the clinical parameters.

Conclusions

CP patients had altered functional connectivity within and between brain networks. Altered DMN functional connectivity had an association to cerebral metabolic changes.

Significance

Altered functional connectivity in CP share similarities with other chronic pain conditions, and support our understanding of altered brain circuitry associated with the CP disease.

Introduction

Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease of the pancreatic gland and is accompanied by a complex clinical presentation (Pham and Forsmark 2018). Chronic visceral pain is the hallmark symptom of CP and is associated with impaired psychosocial functioning, physical disability and reduced quality of life (Juel et al. 2015). A number of clinical studies have demonstrated that pain processing in the central nervous system (CNS) is abnormal in CP patients, with evidence of peripheral and central sensitization and impaired descending pain modulation (Bouwense et al. 2015). In particular, central sensitization is an important characteristic of sensory processing in patients with painful CP and, as such, resembles observations from several other chronic pain conditions (Drewes et al., 2008, Arendt-Nielsen et al., 2018), including other visceral pain syndromes (Bouwense et al. 2015).

Despite extensive research in chronic pain, no single area of the brain has been determined as responsible for abnormal pain processing (Seminowicz and Čeko 2015). A complex network of brain regions comprising sensory, emotional, cognitive and motivational components is involved in pain processing, and the dynamic connectivity between areas involved in pain is likely of more importance than single centers (Morton et al. 2016). Previous studies based on electroencephalography (EEG) suggest functional reorganization of brain networks in CP patients (Dimcevski et al., 2007, Lelic et al., 2014a, Lelic et al., 2014b). Neuroimaging studies have contributed in identifying key neural structures involved in CP pain, mainly using structural magnetic resonance imaging (MRI) techniques. Morphometry studies have reported gray matter changes in pain related regions (Frøkjær et al., 2012, Muthulingam et al., 2018) in addition to extensive white matter alterations (Frøkjær et al. 2011). Utilizing MR spectroscopy, we recently demonstrated that CP patients with high glutamate levels in the anterior cingulate cortex (ACC) had higher pain intensity (Hansen et al. 2019). To our best knowledge, no studies have investigated resting state functional connectivity in CP patients using functional MRI (fMRI), nor assessed whether a commonality exists between altered brain neurotransmitter levels and connectivity between brain centers.

The brain at rest is characterized by an organized baseline called default mode network (DMN) (Čeko et al. 2015). Among others, DMN is one of the key networks which is normally active at rest and deactivated during task or stimulus exposure. On the contrary, the salience network (SN) is activated by attention-demanding stimuli, including pain (Menon 2015). Changes in DMN and SN are the most consistently reported alterations in chronic painful disorders (Inman et al. 2015). Normally, DMN and SN are anti-correlated however, recent studies have shown that DMN and SN are less anti-correlated in chronic pain patients as well as in patients with brain disorders, such as Alzheimer’s disease and attention deficit hyperactivity disorder (ADHD) (Hemington et al. 2016).

The underlying hypothesis of the present study was that the brain networks DMN and SN were altered in CP patients. Specifically, we hypothesized that there was DMN hypo-connectivity and SN hyper-connectivity in CP patients as compared with healthy controls, and that CP patients would demonstrate reduced anti-correlation between DMN and SN compared to healthy controls. Several studies have shown that chronic pain patients consistently exhibit connectivity changes in the ACC (van Ettinger-Veenstra et al. 2019) and in a previous study in the same cohort, CP patients with high ACC glutamate levels had higher pain symptoms (Hansen et al. 2019). Therefore, we also hypothesized that altered brain connectivity could associate to pain related clinical parameters and levels of glutamate/creatine in the ACC.

The main purposes of this study were threefold. First, we aimed to identify alterations within the two brain networks DMN and SN using resting state fMRI in a cohort of well-characterized outpatients with CP patients with and without chronic pain as compared with healthy controls. Second, we sought to detect if the interaction between DMN and SN connectivity is less anti-correlated in CP patients compared with healthy controls. Third, we explored if the altered brain network connectivity in CP patients was associated to clinical parameters, i.e., quality of life and pain scores, and to the cerebral metabolite level of glutamate/creatine in the ACC.