Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

Cearns, Micah; Clark, Scott; Toben, Catherine; Grotegerd, Dominik; Heindel, Walter; Kugel, Harald; Teuber, Anja; Minnerup, Heike; Berger, Klaus; Dannlowski, Udo; Baune, Bernhard T.

doi:10.1503/jpn.180208

Cited by 38 publications

(24 citation statements)

References 50 publications

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“…There is also evidence that increased interleukin-6 is inversely correlated with the cortical thickness of OFC in MDD [13], and that it controls the expression of the serotonin transporter and consequently serotonin reuptake, with potential relevance for behavioral features of MDD [62]. In addition, high-sensitivity C-reactive protein has been related to reduced gray-matter volume in the prefrontal cortex, indicating the potential role of inflammatory activation in the anatomic alterations associated with MDD [63]. Further, there is postmortem evidence for a reduced density of pyramidal neurons in OFC that could contribute to the decreased cortical thickness of OFC observed in our meta-analysis of MDD [64].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder

Zhao

Chen

et al. 2019

Neuropsychopharmacol.

126

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Alterations in cortical thickness have been identified in major depressive disorder (MDD), but findings have been variable and inconsistent. To date, no reliable tools have been available for the meta-analysis of surface-based morphometric (SBM) studies to effectively characterize what has been learned in previous studies, and drug treatments may have differentially impacted findings. We conducted a comprehensive meta-analysis of magnetic resonance imaging (MRI) studies that explored cortical thickness in medication-free patients with MDD, using a newly developed meta-analytic mask compatible with seed-based d mapping (SDM) meta-analytic software. We performed the meta-regression to explore the effects of demographics and clinical characteristics on variation in cortical thickness in MDD. Fifteen studies describing 529 patients and 586 healthy controls (HCs) were included. Medication-free patients with MDD, relative to HCs, showed a complex pattern of increased cortical thickness in some areas (posterior cingulate cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) and decreased cortical thickness in others (gyrus rectus, orbital segment of the superior frontal gyrus, and middle temporal gyrus). Most findings in the whole sample analysis were confirmed in a meta-analysis of studies recruiting medication-naive patients. Using the new mask specifically developed for SBM studies, this SDM meta-analysis provides evidence for regional cortical thickness alterations in MDD, mainly involving increased cortical thickness in the default mode network and decreased cortical thickness in the orbitofrontal and temporal cortex.

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Section: Discussionmentioning

confidence: 99%

Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder

Zhao

Chen

et al. 2019

Neuropsychopharmacol.

126

View full text Add to dashboard Cite

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“…In particular, the upregulation of several pro-inflammatory cytokines in the brain, including interleukin-1β (IL-1β; Almeida-Suhett et al, 2017) and interleukin-6 (IL-6; Wakabayashi and Kunugi, 2019), has been implicated in murine behavioral responses to HFD. Dysregulation of GSK3β (Jope, 2011;Karege et al, 2012;Ren et al, 2013;Ronai et al, 2014;Chen et al, 2015) and inflammation (Syed et al, 2018;Giridharan et al, 2019;Opel et al, 2019;Osimo et al, 2019) have both been identified in clinical studies examining psychiatric patients as well, thus supporting their likely importance in behavioral dysfunction. Given that both brain inflammation (Lu et al, 2017;Khodanovich et al, 2018) and GSK3β activity (Li et al, 2004;Beaulieu et al, 2008) are known to be influenced by brain 5-HT levels, the current work examined whether low 5-HT impacts the effects of HFD on GSK3β phosphorylation or the mRNA expression of several genes involved in inflammation.…”

Section: Introductionmentioning

confidence: 97%

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3β Phosphorylation in the Hippocampus

Karth

Baugher

Daly

et al. 2019

Front. Mol. Neurosci.

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Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods. The brain serotonin (5-HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5-HT exacerbates depression-and anxiety-like behaviors induced by stress and blocks reductions in depression-like behavior induced by antidepressants, but the effects of brain 5-HT deficiency on responses to high-fat diet (HFD) have not been explored. The current work used genetically modified mice to evaluate the effects of low 5-HT on behavioral and molecular alterations induced by chronic exposure to HFD. Our results reveal that HFD decreases depression-like behavior and increases some anxiety-like behaviors in wild-type (WT) mice. However, genetic brain 5-HT deficiency blocks HFD-induced reductions in forced swim immobility and prevents HFD-induced increases in hippocampal GSK3β phosphorylation despite having no significant effects on HFD-induced changes in body weight or anxiety-like behavior. Together, our results suggest that brain 5-HT deficiency significantly impacts a subset of behavioral and molecular responses to HFD, a finding that could help explain the complex relationships between obesity and mental illness.

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“…However, at present there is little evidence of associations between elevated serum CRP in MDD and alterations in brain structure or morphology. One exception is the large imaging study by Opel and colleagues that reported significantly increased CRP levels in association with reduced grey matter volume in 514 patients with MDD compared to 359 healthy controls, however associations with white matter integrity were not investigated ( Opel et al, 2019 ). Further, although serum CRP is viewed as a proxy measure of inflammatory activity, it can be influenced by a number of current state factors such as recent infections, injuries, body mass index (BMI), or chronic inflammatory conditions ( Kathiresan et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Green

Shen

Stevenson

et al. 2021

Brain, Behavior, and Immunity

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Highlights First study of both serum and DNAm CRP associations with depression/neuroimaging. Serum CRP is associated with somatic symptoms and reduced entorhinal cortex thickness. DNAm CRP is associated with widespread reductions in white matter integrity. Evidence for central effects of peripheral inflammation from serum and DNAm markers.

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Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

Cited by 38 publications

References 50 publications

Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder

Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3β Phosphorylation in the Hippocampus

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

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