Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression

Aruldass, Athina R; Kitzbichler, Manfred G.; Morgan, Sarah E.; Lim, Sol; Lynall, Mary-Ellen; Turner, Lorinda; Vértes, Petra E.; Disease, Alzheimer’s; Cavanagh, Jonathan; Cowen, P J; Pariante, Carmine; Harrison, Neil A.; Bullmore, Edward T.

doi:10.1016/j.bbi.2021.08.226

Cited by 45 publications

(27 citation statements)

References 74 publications

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“…This observation is consistent with emerging evidence that systemic inflammation can be correlated with, or could cause, changes in functional connectivity between the areas of limbic, prefrontal and temporal cortices, and anatomically related subcortical nuclei 104 , 105 that form the ‘medial prefrontal network’, which mediates and regulates emotional behaviour and comprises the neurocircuitry of mood disorders 106 . These data thus provide evidence that interactions of immune activation with brain interoceptive mechanisms can mediate discrete changes in brain and behaviour within the context of infection and inflammation 107 , 108 .…”

Section: Assessment Of Mechanismmentioning

confidence: 69%

Immune targets for therapeutic development in depression: towards precision medicine

Drevets

Wittenberg

Bullmore

et al. 2022

Nat Rev Drug Discov

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112

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Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups: a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.

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Section: Assessment Of Mechanismmentioning

confidence: 69%

Immune targets for therapeutic development in depression: towards precision medicine

Drevets

Wittenberg

Bullmore

et al. 2022

Nat Rev Drug Discov

Self Cite

112

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“…We constructed a MDD case-control map by conducting multiple t tests for the difference in nodal weighted degree of FC between two groups of resting state fMRI data from an independent sample ( 39 , 40 ) of 46 healthy controls and 50 MDD cases (see the “Colocation with depression” section in Supplementary Text and table S8). We then correlated the ΔMI map with the MDD case-control t map and tested for significant colocation using the spin-test procedure to control for spatial autocorrelation in both maps ( Fig.…”

Section: Methodsmentioning

confidence: 99%

“…In relation to our first hypothesis, we found that there was a sex-related difference in adolescent brain network development: Females had significantly more disruptive development of FC in a default mode cortical, limbic, and subcortical network. In relation to our second hypothesis, we found that this developmentally divergent brain system was colocated with loci of brain activation by reward-related tasks, with expression of a weighted function of the whole genome enriched for X chromosome genes, genes expressed during various phases of brain development, and genes identified by genome-wide association with major depressive disorder (MDD), and colocated with an anatomical map of depression-related differences in FC from an independent case-control fMRI study of MDD ( 39 , 40 ). The robustness of all these results to potentially confounding effects of sex differences in head movement, intracranial volume, or global FC was evaluated (and supported) by five sensitivity analyses; see the “Sensitivity analyses” section in Supplementary Text.…”

Section: Introductionmentioning

confidence: 99%

Sexually divergent development of depression-related brain networks during healthy human adolescence

et al. 2022

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Sexual differences in human brain development could be relevant to sex differences in the incidence of depression during adolescence. We tested for sex differences in parameters of normative brain network development using fMRI data on N = 298 healthy adolescents, aged 14 to 26 years, each scanned one to three times. Sexually divergent development of functional connectivity was located in the default mode network, limbic cortex, and subcortical nuclei. Females had a more “disruptive” pattern of development, where weak functional connectivity at age 14 became stronger during adolescence. This fMRI-derived map of sexually divergent brain network development was robustly colocated with i prior loci of reward-related brain activation ii a map of functional dysconnectivity in major depressive disorder (MDD), and iii an adult brain gene transcriptional pattern enriched for genes on the X chromosome, neurodevelopmental genes, and risk genes for MDD. We found normative sexual divergence in adolescent development of a cortico-subcortical brain functional network that is relevant to depression.

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“…Previous studies have suggested that structural and functional abnormalities in these regions may underlie some of the phenotypic traits of depression, including anhedonia, emotion dysregulation, cognitive impairment, and anxiety [3,[7][8][9]. Interestingly, recent network-based analyses have also shown that reduced resting-state functional connectivity within and between these corticolimbic regions is associated with elevated markers of inflammation [4,[10][11][12]. Given the fact that white matter pathways support the function and functional connectivity of the aforementioned brain regions [13,14], systemic inflammation may alter structural connections between these regions, leading to functional alterations.…”

Section: Introductionmentioning

confidence: 99%

Elevated Systemic Inflammation Is Associated with Reduced Corticolimbic White Matter Integrity in Depression

Thomas

Savitz

Zhang

et al. 2021

Life

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(1) Background: Growing evidence indicates that inflammation can induce neural circuit dysfunction and plays a vital role in the pathogenesis of major depressive disorder (MDD). Nevertheless, whether inflammation affects the integrity of white matter pathways is only beginning to be explored. (2) Methods: We computed quantitative anisotropy (QA) from diffusion magnetic resonance imaging as an index of white matter integrity and regressed QA on C-reactive protein (CRP), controlling for age, sex, and BMI, in 176 participants with MDD. (3) Results: The QA values of several white matter tracts were negatively correlated with CRP concentration (standardized beta coefficient = −0.22, 95%CI = −0.38–−0.06, FDR < 0.05). These tracts included the bilateral cortico-striatal tracts, thalamic radiations, inferior longitudinal fasciculi, corpus callosum (the forceps minor portion and the tapetum portion), cingulum bundles, and the left superior longitudinal fasciculus III. Importantly, the association remained robust after regressing up to twelve potential confounders. The bilateral fornix and a small portion of the thalamic radiation showed a positive association with CRP levels, but these associations did not remain significant after adjusting for confounders. (4) Conclusions: Peripheral inflammation may contribute to the etiology of MDD by impacting the microstructural integrity of brain corticolimbic white matter pathways.

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Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression

Cited by 45 publications

References 74 publications

Immune targets for therapeutic development in depression: towards precision medicine

Immune targets for therapeutic development in depression: towards precision medicine

Sexually divergent development of depression-related brain networks during healthy human adolescence

Elevated Systemic Inflammation Is Associated with Reduced Corticolimbic White Matter Integrity in Depression

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