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      Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue

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          Abstract

          Background

          Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α induces marked behavioral changes that, when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear.

          Methods

          Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24.

          Results

          IFN-α injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-α induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms.

          Conclusions

          Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.

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          Most cited references31

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          The Insight ToolKit image registration framework

          Publicly available scientific resources help establish evaluation standards, provide a platform for teaching and improve reproducibility. Version 4 of the Insight ToolKit (ITK4) seeks to establish new standards in publicly available image registration methodology. ITK4 makes several advances in comparison to previous versions of ITK. ITK4 supports both multivariate images and objective functions; it also unifies high-dimensional (deformation field) and low-dimensional (affine) transformations with metrics that are reusable across transform types and with composite transforms that allow arbitrary series of geometric mappings to be chained together seamlessly. Metrics and optimizers take advantage of multi-core resources, when available. Furthermore, ITK4 reduces the parameter optimization burden via principled heuristics that automatically set scaling across disparate parameter types (rotations vs. translations). A related approach also constrains steps sizes for gradient-based optimizers. The result is that tuning for different metrics and/or image pairs is rarely necessary allowing the researcher to more easily focus on design/comparison of registration strategies. In total, the ITK4 contribution is intended as a structure to support reproducible research practices, will provide a more extensive foundation against which to evaluate new work in image registration and also enable application level programmers a broad suite of tools on which to build. Finally, we contextualize this work with a reference registration evaluation study with application to pediatric brain labeling. 1
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            CSF Concentrations of Brain Tryptophan and Kynurenines during Immune Stimulation with IFN-alpha: Relationship to CNS Immune Responses and Depression

            Cytokine-induced activation of indoleamine 2,3 dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during IFN-alpha treatment has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after ~12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 (sTNFR2) and monocyte chemoattractant protein (MCP)-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN, QUIN, KA, and ultimately depressive symptoms.
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              Fatigue and basal ganglia.

              Fatigue is a common symptom in neurology and occurs in the diseases of the central and peripheral nervous system. In order to understand the mechanism of fatigue, it is important to distinguish symptoms of peripheral neuromuscular fatigue from the symptoms of physical and mental fatigue characteristic of disorders like Parkinson's disease or multiple sclerosis. We have introduced and defined the concept of central fatigue for the latter disorders. We have further proposed, with supportive neuropathological data, that central fatigue may occur due to a failure in the integration of the limbic input and the motor functions within the basal ganglia affecting the striatal-thalamic-frontal cortical system.
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                Author and article information

                Contributors
                Journal
                Biol Psychiatry
                Biol. Psychiatry
                Biological Psychiatry
                Elsevier
                0006-3223
                1873-2402
                15 February 2016
                15 February 2016
                : 79
                : 4
                : 320-328
                Affiliations
                [* ]Brighton and Sussex Medical School, University of Sussex
                []Department of Gastroenterology, Brighton & Sussex University Hospitals, Brighton
                []Department of Psychiatry, University of Cambridge
                [§ ]Cambridge and Peterborough National Health Service Foundation Trust, Cambridge
                []Sackler Centre for Consciousness Science, University of Sussex, Falmer
                []Sussex Partnership National Health Service Trust, Brighton, United Kingdom
                [** ]Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy
                Author notes
                [* ]Address correspondence to Neil A. Harrison, M.B.B.S., Ph.D., University of Sussex, Clinical Imaging Sciences Centre, Brighton & Sussex Medical School, Falmer BN1 9RR, United Kingdom n.harrison@ 123456bsms.ac.uk
                Article
                S0006-3223(15)00464-3
                10.1016/j.biopsych.2015.05.015
                4725575
                26169252
                21dad481-dbe2-4826-a3c8-f14c9de9c8b6
                © 2016 Society of Biological Psychiatry. All rights reserved.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 February 2015
                : 21 May 2015
                : 24 May 2015
                Categories
                Archival Report

                Clinical Psychology & Psychiatry
                depression,fatigue,imaging,inflammation,insula,interferon,striatum
                Clinical Psychology & Psychiatry
                depression, fatigue, imaging, inflammation, insula, interferon, striatum

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