Insular dysfunction within the salience network is associated with severity of symptoms and aberrant inter-network connectivity in major depressive disorder

Abstract

Major depressive disorder (MDD) is characterized by altered intrinsic functional connectivity within (intra-iFC) intrinsic connectivity networks (ICNs), such as the Default Mode- (DMN), Salience- (SN) and Central Executive Network (CEN). It has been proposed that aberrant switching between DMN-mediated self-referential and CEN-mediated goal-directed cognitive processes might contribute to MDD, possibly explaining patients' difficulties to disengage the processing of self-focused, often negatively biased thoughts. Recently, it has been shown that the right anterior insula (rAI) within the SN is modulating DMN/CEN interactions. Since structural and functional alterations within the AI have been frequently reported in MDD, we hypothesized that aberrant intra-iFC in the SN's rAI is associated with both aberrant iFC between DMN and CEN (inter-iFC) and severity of symptoms in MDD. Twenty-five patients with MDD and 25 healthy controls were assessed using resting-state fMRI (rs-fMRI) and psychometric examination. High-model-order independent component analysis (ICA) of rs-fMRI data was performed to identify ICNs including DMN, SN, and CEN. Intra-iFC within and inter-iFC between distinct subsystems of the DMN, SN, and CEN were calculated, compared between groups and correlated with the severity of symptoms. Patients with MDD showed (1) decreased intra-iFC within the SN's rAI, (2) decreased inter-iFC between the DMN and CEN, and (3) increased inter-iFC between the SN and DMN. Moreover, decreased intra-iFC in the SN's rAI was associated with severity of symptoms and aberrant DMN/CEN interactions, with the latter losing significance after correction for multiple comparisons. Our results provide evidence for a relationship between aberrant intra-iFC in the salience network's rAI, aberrant DMN/CEN interactions and severity of symptoms, suggesting a link between aberrant salience mapping, abnormal coordination of DMN/CEN based cognitive processes and psychopathology in MDD.

Desynchronization and Plasticity of Striato-frontal Connectivity in Major Depressive Disorder

“…The default-mode network (DMN) has been of particular interest to depression research, given the role this network is thought to play in self-referential processing (Raichle et al 2001;Morcom and Fletcher 2007;Spreng and Grady 2010) and its overlap with structures previously implicated in MDD like the hippocampus (Sheline et al 1999) and medial cortical regions (Drevets et al 1997;Mayberg et al 1999). Studies of MDD have identified hyperconnectivity between the DMN and specific brain regions including ventral anterior cingulate and adjacent ventromedial prefrontal cortex (Greicius et al 2007;Manoliu et al 2013), mediodorsal thalamus (Greicius et al 2007), and dorsolateral prefrontal cortex (Sheline et al 2009). More recently, connectivity between the DMN and other RSNs has been considered, particularly with RSNs involving lateral prefrontal regions (e.g., "task-positive" networks Manoliu et al 2013]).…”

“…Studies of MDD have identified hyperconnectivity between the DMN and specific brain regions including ventral anterior cingulate and adjacent ventromedial prefrontal cortex (Greicius et al 2007;Manoliu et al 2013), mediodorsal thalamus (Greicius et al 2007), and dorsolateral prefrontal cortex (Sheline et al 2009). More recently, connectivity between the DMN and other RSNs has been considered, particularly with RSNs involving lateral prefrontal regions (e.g., "task-positive" networks Manoliu et al 2013]). …”

Molecular, Functional, and Structural Imaging of Major Depressive Disorder

“…Advanced methods for analyzing functional connectivity using MRI (for review, see [54]), such as seed-based correlation analysis, independent component analysis, regional homogeneity, and amplitude of low-frequency fluctuations, have been increasingly used. Through these techniques, aberrant functional connectivity has been identified in MDD, such as in the salience network (SN) [55,56], default mode network (DMN) [57][58][59][60], cognitive control network (CCN) [59,61], and affective network (AN) [60,62]. The SN, predominantly consisting of the anterior insular cortex and dorsal ACC, serves to assess the correlation of internal and external stimuli to produce appropriate responses and direct behaviors [63].…”

Relation between patterns of intrinsic network connectivity, cognitive functioning, and symptom presentation in trauma‐exposed patients with major depressive disorder

“…Resting‐state fMRI studies in patients with depression have consistently identified abnormalities across ICNs, suggesting a reorganization of intrinsic functional connectivity that could contribute to symptoms of MDD (Manoliu et al., 2013). The majority of these studies have focused on the DMN, reporting that patients with MDD tend to show abnormal activation during goal‐directed tasks, and increased functional connectivity during rest (for a review, see Broyd et al.…”