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      Negative Associations of Stress and Anxiety Levels With Cytotoxic and Regulatory Natural Killer Cell Frequency in Chronic Tinnitus

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          Abstract

          Background

          Depression and anxiety are known to be associated with stress-induced changes in the immune system. Bothersome tinnitus can be related to stress and often co-occurs with depression and anxiety. This study investigates associations of psychological and audiological tinnitus-related factors with inflammatory parameters and immune cell subsets in chronic tinnitus patients as well as treatment-related effects.

          Methods

          This longitudinal study of inpatients treated with compact multimodal tinnitus-specific cognitive behavioral therapy included four repeated measurement sessions: baseline ( N = 41), treatment end, 7.8-week ( N = 35), and 13.8-week follow-up ( N = 34). Data collection included audiometric testing, blood sampling, and psychometric questionnaires: Tinnitus Handicap Inventory (THI), Perceived Stress Questionnaire (PSQ-20), and Hospital Anxiety Depression Scale (HADS). Flow cytometry was used to analyze immune cell subsets. Statistical analyses comprised correlation and network analysis (cross-sectional), and linear mixed effect models (longitudinal).

          Results

          Bootstrapped network analysis showed negative averaged cross-sectional associations of cytotoxic natural killer (NKc) cell frequency (CD56 + CD16+) and PSQ-20 (−0.21 [−0.48, 0]) and of regulatory natural killer (NKreg) cell frequency (CD56 + CD16dim/−) and HADS anxiety (−0.14 [−0.38, 0]). No significant treatment effects were found. A negative predictive effect of baseline PSQ-20 scores ( β = −6.22 [−12.18, −0.26], p = 0.041) and a positive predictive effect of baseline ferritin levels ( β = 8.90 [2.76, 15.03], p = 0.004) on NKc cell frequency across the repeated measurement sessions were observed.

          Conclusion

          We observed negative relationships between perceived stress levels and NKc cell frequency and between anxiety levels and NKreg cell frequency in chronic tinnitus patients. These exploratory results suggest stress−/anxiety-related immune alterations in bothersome tinnitus but need to be tested in further confirmatory studies with larger sample sizes. The potential of NK cells as biomarkers of emotional distress in chronic tinnitus should be further investigated.

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          Most cited references68

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          Fitting Linear Mixed-Effects Models Usinglme4

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            Simultaneous inference in general parametric models.

            Simultaneous inference is a common problem in many areas of application. If multiple null hypotheses are tested simultaneously, the probability of rejecting erroneously at least one of them increases beyond the pre-specified significance level. Simultaneous inference procedures have to be used which adjust for multiplicity and thus control the overall type I error rate. In this paper we describe simultaneous inference procedures in general parametric models, where the experimental questions are specified through a linear combination of elemental model parameters. The framework described here is quite general and extends the canonical theory of multiple comparison procedures in ANOVA models to linear regression problems, generalized linear models, linear mixed effects models, the Cox model, robust linear models, etc. Several examples using a variety of different statistical models illustrate the breadth of the results. For the analyses we use the R add-on package multcomp, which provides a convenient interface to the general approach adopted here. Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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              Estimating psychological networks and their accuracy: A tutorial paper

              The usage of psychological networks that conceptualize behavior as a complex interplay of psychological and other components has gained increasing popularity in various research fields. While prior publications have tackled the topics of estimating and interpreting such networks, little work has been conducted to check how accurate (i.e., prone to sampling variation) networks are estimated, and how stable (i.e., interpretation remains similar with less observations) inferences from the network structure (such as centrality indices) are. In this tutorial paper, we aim to introduce the reader to this field and tackle the problem of accuracy under sampling variation. We first introduce the current state-of-the-art of network estimation. Second, we provide a rationale why researchers should investigate the accuracy of psychological networks. Third, we describe how bootstrap routines can be used to (A) assess the accuracy of estimated network connections, (B) investigate the stability of centrality indices, and (C) test whether network connections and centrality estimates for different variables differ from each other. We introduce two novel statistical methods: for (B) the correlation stability coefficient, and for (C) the bootstrapped difference test for edge-weights and centrality indices. We conducted and present simulation studies to assess the performance of both methods. Finally, we developed the free R-package bootnet that allows for estimating psychological networks in a generalized framework in addition to the proposed bootstrap methods. We showcase bootnet in a tutorial, accompanied by R syntax, in which we analyze a dataset of 359 women with posttraumatic stress disorder available online. Electronic supplementary material The online version of this article (doi:10.3758/s13428-017-0862-1) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Journal
                Front Psychol
                Front Psychol
                Front. Psychol.
                Frontiers in Psychology
                Frontiers Media S.A.
                1664-1078
                23 June 2022
                2022
                : 13
                : 871822
                Affiliations
                [1] 1Tinnitus Center, Charité – Universitätsmedizin Berlin , Berlin, Germany
                [2] 2Center for Cognitive Neuroscience and Department of Psychology, University of Salzburg , Salzburg, Austria
                [3] 3Department of Psychiatry and Psychotherapy, University of Regensburg , Regensburg, Germany
                [4] 4Center for Neuroprosthetics, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne , Geneva, Switzerland
                [5] 5Department of Radiology and Medical Informatics, University of Geneva , Geneva, Switzerland
                [6] 6Medical Department, Section of Psychosomatic Medicine, Charité – Universitätsmedizin Berlin , Berlin, Germany
                [7] 7Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin , Berlin, Germany
                [8] 8Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Universitätsklinikum Hamburg-Eppendorf , Hamburg, Germany
                Author notes

                Edited by: Jennifer Lentz, Indiana University Bloomington, United States

                Reviewed by: Alessandra Fioretti, European Hospital, Italy; Yuan He, University of Minnesota Twin Cities, United States

                *Correspondence: Birgit Mazurek, birgit.mazurek@ 123456charite.de

                This article was submitted to Auditory Cognitive Neuroscience, a section of the journal Frontiers in Psychology

                Article
                10.3389/fpsyg.2022.871822
                9262102
                b200e3fe-d729-4fb4-9df3-097782ca1278
                Copyright © 2022 Basso, Boecking, Neff, Brueggemann, El-Ahmad, Brasanac, Rose, Gold and Mazurek.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 February 2022
                : 25 May 2022
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 73, Pages: 16, Words: 9819
                Categories
                Psychology
                Original Research

                Clinical Psychology & Psychiatry
                tinnitus,stress,natural killer cells,depression,anxiety,inflammation,immune phenotyping

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