Search

Introduction: Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis-C virus (HCV) infection. Though clinically effective, IFN-α frequently induces functionally impairing mood and motivation symptoms, particularly fatigue. Unlike mood impairment, which typically emerges after weeks of treatment, fatigue tends to emerge and evolve rapidly, typically within hours of the first IFN-α injection. Despite being a major source of functional impairment during IFN-α and other immune-based therapies, the biological mechanisms underlying fatigue remain poorly understood. Here, we aimed to identify acute immune-response signatures to IFN-α that could predict the later development of fatigue., Methods: In this exploratory study, we analyzed whole blood transcriptomics in a longitudinal sample of 27 HCV patients initiating IFN-α and Ribavirin therapy. Blood samples were obtained at baseline and 4½ hours after the first IFN-α dose and transcriptomic data was obtained using Affymetrix Human Gene 1.1 ST Array Strips. Gene expression data visualization and quality control were assessed using Partek Genomics Suite V6.6 and protein-protein interaction networks using STRING and Ingenuity Pathway Analysis (IPA). A Fatigue Visual Analogue Scale (fVAS) was utilized to record fatigue symptoms at baseline, 4½ hours and 4 weeks after initiation of treatment., Results: IFN-α was associated with an upregulation of 526 transcripts and a downregulation of 228 genes, indicating a rapid transcriptomic response in whole blood within 4½ hours of injection. 93 genes were significantly positively correlated with changes in fatigue, with gene expression changes measured from baseline to 4.5 h and increases in fatigue assessed from baseline to week 4 on the fVAS. We identified a novel network of predominantly cytosolic ribosomal units and ubiquitin proteins implicated in modulating mTOR signaling that was associated with the development of fatigue 4 weeks after initiation of IFN-α treatment (p = 0.0078)., Conclusion: Our findings suggest that acute activation of this anabolic/catabolic network by IFN-α may predispose to the experience of fatigue similar to evidence found in cancer-related fatigue. Further investigation is warranted to confirm the exploratory nature of these observations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1 ng/kg) and placebo. Half (N = 8) received minocycline (100 mg bd) and half (N = 7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 h post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-α, IL-8, IL-10 responses (all condition × time interactions: p < 0.005), none were significantly modulated by minocycline (p > 0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F (1,13)  = 6.10, p = 0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F (1,13)  = 4.28, p = 0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood., Methods: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment., Results: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms., Conclusions: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently, techniques for in-vivo imaging of glia in humans are limited to TSPO (Translocator protein) PET, which is expensive, methodologically challenging, and has poor cellular specificity. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) sensitizes MR spectra to diffusion of intracellular metabolites, potentially providing cell-specific information about cellular morphology. In this preliminary study, we applied DW-MRS to measure changes in the apparent diffusion coefficients (ADC) of glial and neuronal metabolites to healthy participants who underwent an LPS administration protocol. We hypothesized that the ADC of glial metabolites will be selectively modulated by LPS-induced glial activation., Methods: Seven healthy male volunteers, (mean 25.3 ± 5.9 years) were each tested in two separate sessions once after LPS (1 ng/Kg intravenously) and once after placebo (saline). Physiological responses were monitored during each session and serial blood samples and Profile of Mood States (POMS) completed to quantify white blood cell (WBC), cytokine and mood responses. DW-MRS data were acquired 5-5½ hours after injection from two brain regions: grey matter in the left thalamus, and frontal white matter., Results: Body temperature, heart rate, WBC and inflammatory cytokines were significantly higher in the LPS compared to the placebo condition (p < 0.001). The ADC of the glial metabolite choline (tCho) was also significantly increased after LPS administration compared to placebo (p = 0.008) in the thalamus which scaled with LPS-induced changes in POMS total and negative mood (Adj R 2  = 0.83; p = 0.004)., Conclusions: DW-MRS may be a powerful new tool sensitive to glial cytomorphological changes in grey matter induced by systemic inflammation., (Copyright © 2021. Published by Elsevier Inc.)

Objective: There is increasing evidence for a subgroup of major depressive disorder (MDD) associated with heightened peripheral blood inflammatory markers. In this study, we aimed to understand the mechanistic brain-immune axis in inflammation-linked depression by investigating associations between functional connectivity (FC) of brain networks and peripheral blood immune markers in depression., Methods: Resting-state functional magnetic resonance imaging (fMRI) and peripheral blood inflammatory markers (C-reactive protein; CRP, interleukin-6; IL-6 and immune cells) were collected on N = 46 healthy controls (HC; CRP ≤ 3 mg/L) and N = 83 cases of depression, stratified further into low CRP cases (loCRP cases; ≤ 3 mg/L; N = 50) and high CRP cases (hiCRP cases; > 3 mg/L; N = 33). In a two-part analysis, network-based statistics (NBS) was firstly used to ascertain whole-brain FC differences in HC vs hiCRP cases. Secondly, we investigated the association between this network of interconnected brain regions and continuous measures of peripheral CRP (N = 83), IL-6 (N = 72), neutrophils and CD4 + T-cells (N = 36) in depression cases only., Results: Case-control NBS testing revealed a single network of abnormally attenuated FC in the high CRP depression cases compared to healthy controls. Connections within this network were mainly between brain regions located in the left insula/frontal operculum and posterior cingulate cortex, which were assigned to ventral attention and default mode canonical fMRI networks respectively. Within-group analysis across all depression cases, secondarily demonstrated that FC within the identified network significantly negatively scaled with CRP, IL-6 and neutrophils., Conclusions: The findings suggest that inflammation is associated with disruption of functional connectivity within a brain network deemed critical for interoceptive signalling, e.g. accurate communication of peripheral bodily signals such as immune states to the brain, with implications for the pathogenesis of inflammation-linked depression., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The discovery that prolonged administration of interferon-alpha (a pro-inflammatory cytokine) readily precipitates depressive symptoms has played a key role in development of the inflammation theory of major depressive disorder (MDD). However, it remains unclear whether the clinical phenotype of patients with inflammation-associated depression significantly overlaps with, or can be distinguished from that of patients with 'idiopathic' depression. Here we explored the Hamilton depression scale factor structure of 172 patients undergoing interferon-alpha treatment for hepatitis-C at the point of transition to a depressive episode of DSM IV defined major depression severity. The resulting factor structure was first compared with a model derived from 6 previous studies of 'idiopathic' MDD (Cole et al., 2004). This confirmatory factor analysis revealed that the factor structure of HAMD scores in our interferon-alpha treated cohort did not plausibly fit that previously described for 'idiopathic' MDD. Instead, subsequent exploratory factor analysis revealed a distinct four factor model with a novel primary factor grouping cognitive symptoms of depression and anxiety (HAMD items 1, 2, 9, 10, 11, 15). The second sleep disorder factor (items 4, 5, 6) replicated previous findings in 'idiopathic' depression. A third and unique factor grouped somatic symptoms and function (items 7, 12, 13, 14 and item 1). The final factor (also common in idiopathic depression studies), grouped gastrointestinal symptoms and weight loss (items 12 and 16). Severe depression items (3, 8, and 17) were excluded from analysis due to very low variance. At transition, interferon-alpha induced major depressive episodes therefore appears to have more associated anxiety features that covary with depressed mood than classical or 'idiopathic' MDD and a low likelihood of severe features such as suicidal ideation. Identification of this clinical phenotype may help identify patients with an inflammatory depression etiology and support the development of more effective and personalized therapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neuroimaging techniques are increasingly used to characterize the neural circuitry mediating actions of inflammation on mood, motivation, and cognition and its relationship to common mental illnesses, particularly major depressive disorder (MDD). In addition, imaging techniques such as single photon emission tomography (SPECT), positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) can index effects of inflammation on specific neurotransmitters, monoamine transporters, metabolites and even activation of discrete cells such as microglia. The special named series 'Neuroimaging, inflammation and behavior' illustrates the power of neuroimaging techniques to characterize discrete actions of inflammation on the brain at neurochemical, cellular, regional and network levels. Combined with careful cognitive assessment and pre-clinical studies, diverse neuroimaging techniques are helping clarify the mechanisms through which inflammation acts on the brain to reorient behavior and predispose to mental and physical illnesses., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis C infection. Though clinically effective, IFN-α rapidly impairs mood, motivation and cognition, effects that can appear indistinguishable from major depression and provide powerful empirical support for the inflammation theory of depression. Though inflammation has been shown to modulate activity within discrete brain regions, how it affects distributed information processing and the architecture of whole brain functional connectivity networks have not previously been investigated. Here we use a graph theoretic analysis of resting state functional magnetic resonance imaging (rfMRI) to investigate acute effects of systemic interferon-alpha (IFN-α) on whole brain functional connectivity architecture and its relationship to IFN-α-induced mood change. Twenty-two patients with Hepatitis-C infection, initiating IFN-α-based therapy were scanned at baseline and 4h after their first IFN-α dose. The whole brain network was parcellated into 110 cortical and sub-cortical nodes based on the Oxford-Harvard Atlas and effects assessed on higher-level graph metrics, including node degree, betweenness centrality, global and local efficiency. IFN-α was associated with a significant reduction in global network connectivity (node degree) (p=0.033) and efficiency (p=0.013), indicating a global reduction of information transfer among the nodes forming the whole brain network. Effects were similar for highly connected (hub) and non-hub nodes, with no effect on betweenness centrality (p>0.1). At a local level, we identified regions with reduced efficiency of information exchange and a sub-network with decreased functional connectivity after IFN-α. Changes in local and particularly global functional connectivity correlated with associated changes in mood measured on the Profile of Mood States (POMS) questionnaire. IFN-α rapidly induced a profound shift in whole brain network structure, impairing global functional connectivity and the efficiency of parallel information exchange. Correlations with multiple indices of mood change support a role for global changes in brain functional connectivity architecture in coordinated behavioral responses to IFN-α., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Inflammation is a risk factor for both depression and cardiovascular disease. Depressed mood is also a cardiovascular risk factor. To date, research into mechanisms through which inflammation impacts cardiovascular health rarely takes into account central effects on autonomic cardiovascular control, instead emphasizing direct effects of peripheral inflammatory responses on endothelial reactivity and myocardial function. However, brain responses to inflammation engage neural systems for motivational and homeostatic control and are expressed through depressed mood state and changes in autonomic cardiovascular regulation. Here we combined an inflammatory challenge, known to evoke an acute reduction in mood, with neuroimaging to identify the functional brain substrates underlying potentially detrimental changes in autonomic cardiovascular control. We first demonstrated that alterations in the balance of low to high frequency (LF/HF) changes in heart rate variability (a measure of baroreflex sensitivity) could account for some of the inflammation-evoked changes in diastolic blood pressure, indicating a central (rather than solely local endothelial) origin. Accompanying alterations in regional brain metabolism (measured using (18)FDG-PET) were analysed to localise central mechanisms of inflammation-induced changes in cardiovascular state: three discrete regions previously implicated in stressor-evoked blood pressure reactivity, the dorsal anterior and posterior cingulate and pons, strongly mediated the relationship between inflammation and blood pressure. Moreover, activity changes within each region predicted the inflammation-induced shift in LF/HF balance. These data are consistent with a centrally-driven component originating within brain areas supporting stressor evoked blood pressure reactivity. Together our findings highlight mechanisms binding psychological and physiological well-being and their perturbation by peripheral inflammation., (Copyright © 2013 Elsevier Inc. All rights reserved.)