The functional and structural associations of aberrant microglial activity in major depressive disorder

Abstract

Background: Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [ 18 F]N-2-(fluoroethoxyl)benzyl-N-(4phenoxypyridin-3-yl)acetamide ([ 18 F]FEPPA) positron emission tomography (PET); the severity of MDD; and functional or structural connectivity among insula or sgACC nodes. Methods: Twelve patients with treatment-resistant MDD (8 female, 4 male; mean age ± standard deviation 54.9 ± 4.5 years and 23 healthy controls (11 female, 12 male; 60.3 ± 8.5 years) completed a hybrid [ 18 F]FEPPA PET and MRI acquisition. From these, we extracted relative standardized uptake values for [ 18 F]FEPPA activity and Pearson r-to-z scores representing functional connectivity from our regions of interest. We extracted diffusion tensor imaging metrics from the cingulum bundle, a key white matter bundle in MDD. We performed regressions to relate microglial activity with functional connectivity, structural connectivity and scores on the 17-item Hamilton Depression Rating Scale. Results: We found significantly increased [ 18 F]FEPPA uptake in the left sgACC in patients with treatment-resistant MDD compared to healthy controls. Patients with MDD also had a reduction in connectivity between the sgACC and the insula. The [ 18 F]FEPPA uptake in the left sgACC was significantly related to functional connectivity with the insula, and to the structural connectivity of the cingulum bundle.[ 18 F]FEPPA uptake also predicted scores on the Hamilton Depression Rating Scale. Limitations: A relatively small sample size, lack of functional task data and concomitant medication use may have affected our findings. Conclusion: We present preliminary evidence linking a network-level dysfunction relevant to the pathophysiology of depression and related to increased microglial activity in MDD.

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine

“…It is suggested that microglial overactivity is related to poor response, longer disease duration, and increased inflammatory response [ 43 ]. A recent preliminary study combined PET and magnetic resonance imaging (MRI) and found a connection between disturbed connectivity and increased microglial activity in MDD [ 44 ].…”

The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

“…A significant decrease in 3-HK levels was observed in the serum of schizophrenic patients [ 82 ]. Thus, these diseases may be associated with microglial activation [ 83 , 84 , 85 ].…”

Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets

“…Importantly, many studies have also demonstrated that changes in the gut microbiota trigger inflammatory cytokines, such as IL-6, IL-1β, IL-2, and IFN-γ. These cytokines can reach the brain through neuroanatomical and neuroendocrine pathways, thus affecting mental health and behavior [ 14 , 15 , 16 , 17 , 45 ].…”

“…Moreover, patients treated with cytokines such as IL-2 and interferon-γ (IFN-γ) for viral infections or cancer may develop depressive symptoms [ 15 ]. Additionally, individuals with autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, fibromyalgia, and inflammatory bowel disease are likely to experience depressive symptoms [ 16 , 17 ]. On the other hand, managing exacerbated inflammation can alleviate depressive symptoms and slow down the progression of both MDD and its comorbidities [ 18 , 19 , 20 ].…”