{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T05:28:54Z","timestamp":1773811734008,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T00:00:00Z","timestamp":1628467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-16-1-0632"],"award-info":[{"award-number":["W81XWH-16-1-0632"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-16-1-0552"],"award-info":[{"award-number":["W81XWH-16-1-0552"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-13-2-0085"],"award-info":[{"award-number":["W81XWH-13-2-0085"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000125","name":"National Institute for Occupational Safety and Health","doi-asserted-by":"publisher","award":["Intramural funds"],"award-info":[{"award-number":["Intramural funds"]}],"id":[{"id":"10.13039\/100000125","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood\u2013brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic\u2013pituitary\u2013gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA\u2013HPG\u2013Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal\u2013glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.<\/jats:p>","DOI":"10.3390\/ijms22168546","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T05:17:06Z","timestamp":1628486226000},"page":"8546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness"],"prefix":"10.3390","volume":"22","author":[{"given":"Francisco J.","family":"Carrera Arias","sequence":"first","affiliation":[{"name":"Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-3652","authenticated-orcid":false,"given":"Kristina","family":"Aenlle","sequence":"additional","affiliation":[{"name":"Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Abreu","sequence":"additional","affiliation":[{"name":"Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary A.","family":"Holschbach","sequence":"additional","affiliation":[{"name":"Department of Psychology & Neuroscience, College of Psychology, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay T.","family":"Michalovicz","sequence":"additional","affiliation":[{"name":"Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1146-3137","authenticated-orcid":false,"given":"Kimberly A.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1459-3268","authenticated-orcid":false,"given":"Nancy","family":"Klimas","sequence":"additional","affiliation":[{"name":"Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James P.","family":"O\u2019Callaghan","sequence":"additional","affiliation":[{"name":"Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7244-6317","authenticated-orcid":false,"given":"Travis J. A.","family":"Craddock","sequence":"additional","affiliation":[{"name":"Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Psychology & Neuroscience, College of Psychology, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Computer Science, College of Engineering and Computing, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"ref_1","unstructured":"Binns, J., Bloom, F., Bunker, J., Crawford, F., Golomb, B., Graves, J., Hardie, A., Knox, M.L., Meggs, W.J., and Nettleman, M.D. (2014). Research Advisory Committee on Gulf War Veterans\u2019 Illnesses. Gulf War Illness and the Health of Gulf War Veterans: Research Update and Recommendations, 2009\u20132013."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.biopsych.2007.04.027","article-title":"Twenty-four Hour Plasma Cortisol and Adrenocorticotropic Hormone in Gulf War Veterans: Relationships to Posttraumatic Stress Disorder and Health Symptoms","volume":"62","author":"Golier","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.psyneuen.2015.11.001","article-title":"A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness","volume":"64","author":"Golier","year":"2016","journal-title":"Psychoneuroendocrinology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.psyneuen.2009.04.004","article-title":"Pituitary response to metyrapone in Gulf War veterans: Relationship to deployment, PTSD and unexplained health symptoms","volume":"34","author":"Golier","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.psyneuen.2006.08.005","article-title":"Enhanced cortisol suppression to dexamethasone associated with Gulf War deployment","volume":"31","author":"Golier","year":"2006","journal-title":"Psychoneuroendocrinology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bbi.2012.11.007","article-title":"Altered immune pathway activity under exercise challenge in Gulf War Illness: An exploratory analysis","volume":"28","author":"Broderick","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Janulewicz, P., Krengel, M., Quinn, E., Heeren, T., Toomey, R., Killiany, R., Zundel, C., Ajama, J., O\u2019Callaghan, J., and Steele, L. (2018). The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical\/Biological Weapons Exposure and Mild Traumatic Brain Injury. Brain Sci., 8.","DOI":"10.3390\/brainsci8110198"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.bbr.2009.05.002","article-title":"Gulf War illness: Effects of repeated stress and pyridostigmine treatment on blood\u2013brain barrier permeability and cholinesterase activity in rat brain","volume":"203","author":"Amourette","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.bbr.2008.08.031","article-title":"Repeated stress in combination with pyridostigmine: Part I: Long-term behavioural consequences","volume":"197","author":"Lamproglou","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.bbr.2008.08.032","article-title":"Repeated stress in combination with pyridostigmine: Part II: Changes in cerebral gene expression","volume":"197","author":"Barbier","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ebiom.2015.11.037","article-title":"Reduced Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)","volume":"3","author":"Georgopoulos","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Radhakrishnan, K., Hauser, E., Polimanti, R., Helmer, D., Provenzale, D., McNeil, R., Maffucci, A., Quaden, R., Zhao, H., and Whitbourne, S. (2021). Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990\u20131991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study. Brain Sci., 11.","DOI":"10.3390\/brainsci11070845"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.bbi.2020.01.020","article-title":"In-vivo imaging of neuroinflammation in veterans with Gulf War illness","volume":"87","author":"Alshelh","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ebiom.2016.08.030","article-title":"A Magnetoencephalographic (MEG) Study of Gulf War Illness (GWI)","volume":"12","author":"Engdahl","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rayhan, R.U., Stevens, B.W., Raksit, M.P., Ripple, J.A., Timbol, C.R., Adewuyi, O., VanMeter, J., and Baraniuk, J.N. (2013). Exercise Challenge in Gulf War Illness Reveals Two Subgroups with Altered Brain Structure and Function. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063903"},{"key":"ref_16","first-page":"41","article-title":"Gulf War Illnesses: Causes and Treatments","volume":"2","author":"Nicolson","year":"2001","journal-title":"Armed Forces Med Dev."},{"key":"ref_17","first-page":"92","article-title":"Diagnosis and Integrative Treatment of Intracellular Bacterial Infections in Chronic Fatigue and Fibromyalgia Syndromes, Gulf War Illness, Rheumatoid Arthritis, and Other Chronic Illnesses","volume":"1","author":"Nicolson","year":"2000","journal-title":"Clin. Pract. Altern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"896","DOI":"10.7205\/MILMED-D-10-00332","article-title":"The relationship between Gulf War illness, brain N-acetylaspartate, and post-traumatic stress disorder","volume":"176","author":"Weiner","year":"2011","journal-title":"Mil. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40359-021-00561-2","article-title":"Post-traumatic stress impact on health outcomes in Gulf War Illness","volume":"9","author":"Jeffrey","year":"2021","journal-title":"BMC Psychol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.3389\/fpsyg.2019.02088","article-title":"Neuropsychological Findings in Gulf War Illness: A Review","volume":"10","author":"Jeffrey","year":"2019","journal-title":"Front. Psychol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.bbi.2013.01.081","article-title":"Association between posttraumatic stress disorder and inflammation: A twin study","volume":"30","author":"Plantinga","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1002\/da.20564","article-title":"Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder","volume":"26","author":"Hoge","year":"2009","journal-title":"Depression Anxiety"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1995-7645(12)60048-0","article-title":"Study on serum cytokine levels in posttraumatic stress disorder patients","volume":"5","author":"Guo","year":"2012","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.neuropharm.2011.02.027","article-title":"Biomarkers of PTSD: Neuropeptides and immune signaling","volume":"62","author":"Baker","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cyto.2014.11.019","article-title":"Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis","volume":"72","author":"Khaiboullina","year":"2015","journal-title":"Cytokine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.bbi.2010.10.011","article-title":"A pilot study of immune network remodeling under challenge in Gulf War Illness","volume":"25","author":"Broderick","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/nm1296-1382","article-title":"Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response","volume":"2","author":"Friedman","year":"1996","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1124\/jpet.102.038497","article-title":"Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrier Permeability Induced by Acute Stress","volume":"303","author":"Esposito","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1530\/JOE-10-0472","article-title":"Rapid non-genomic effects of corticosteroids through the membrane-associated MR and GR and their role in the central stress","volume":"2","author":"Groeneweg","year":"2011","journal-title":"J. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nrn2639","article-title":"Effects of stress throughout the lifespan on the brain, behaviour and cognition","volume":"10","author":"Lupien","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/S0306-4530(03)00090-8","article-title":"Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats","volume":"29","author":"Mikics","year":"2004","journal-title":"Psychoneuroendocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rankin, J., Walker, J.J., Windle, R., Lightman, S.L., and Terry, J.R. (2012). Characterizing Dynamic Interactions between Ultradian Glucocorticoid Rhythmicity and Acute Stress Using the Phase Response Curve. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030978"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Walker, J.J., Spiga, F., Waite, E., Zhao, Z., Kershaw, Y., Terry, J.R., and Lightman, S.L. (2012). The origin of glucocorticoid hormone oscillations. PLoS Biol., 10.","DOI":"10.1371\/journal.pbio.1001341"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1098\/rspb.2009.2148","article-title":"Origin of ultradian pulsatility in the hypothalamic\u2013pituitary\u2013adrenal axis","volume":"277","author":"Walker","year":"2010","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00285-010-0384-2","article-title":"The minimal model of the hypothalamic\u2013pituitary\u2013adrenal axis","volume":"63","author":"Vinther","year":"2011","journal-title":"J. Math. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ben-Zvi, A., Vernon, S.D., and Broderick, G. (2009). Model-Based Therapeutic Correction of Hypothalamic-Pituitary-Adrenal Axis Dysfunction. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000273"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1742-4682-4-8","article-title":"Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability","volume":"4","author":"Gupta","year":"2007","journal-title":"Theor. Biol. Med. Model."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Craddock, T.J., Fritsch, P., Rice, M.A., Del Rosario, R.M., Miller, D.B., Fletcher, M.A., Klimas, N.G., and Broderick, G. (2014). A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0084839"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.4161\/sysb.28948","article-title":"Succumbing to the laws of attraction: Exploring the sometimes pathogenic versatility of discrete immune logic","volume":"1","author":"Fritsch","year":"2014","journal-title":"Syst. Biomed."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1742-4682-3-13","article-title":"A method for the generation of standardized qualitative dynamical systems of regulatory networks","volume":"3","author":"Mendoza","year":"2006","journal-title":"Theor. Biol. Med. Model."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/BF02460618","article-title":"Dynamical behaviour of biological regulatory networks\u2014I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state","volume":"57","author":"Thomas","year":"1995","journal-title":"Bull. Math. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1063\/1.1349893","article-title":"Multistationarity, the basis of cell differentiation and memory. II. Logical analysis of regulatory networks in terms of feedback circuits","volume":"11","author":"Thomas","year":"2001","journal-title":"Chaos Interdiscip. J. Nonlinear Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-5193(05)80350-9","article-title":"Regulatory networks seen as asynchronous automata: A logical description","volume":"153","author":"Thomas","year":"1991","journal-title":"J. Theor. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cantu-Paz, E., Foster, J.A., Deb, K., Davis, L.D., Roy, R., O\u2019Reilly, U.-M., Beyer, H.-G., Standish, R., Kendall, G., and Wilson, S. (2003, January 12\u201316). Quad search and hybrid genetic algorithms. Proceedings of the Genetic and Evolutionary Computation Conference, Chicago, IL, USA.","DOI":"10.1007\/3-540-45110-2"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jtbi.2006.02.015","article-title":"A reduced mathematical model of the acute inflammatory response II. Capturing scenarios of repeated endotoxin administration","volume":"242","author":"Day","year":"2006","journal-title":"J. Theor. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jtbi.2006.02.016","article-title":"A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation","volume":"242","author":"Reynolds","year":"2006","journal-title":"J. Theor. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.janxdis.2013.09.004","article-title":"Diagnostic accuracy of three scoring methods for the Davidson Trauma Scale among U.S. military Veterans","volume":"28","author":"McDonald","year":"2014","journal-title":"J. Anxiety Disord."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/1467-9868.00346","article-title":"A direct approach to false discovery rates","volume":"64","author":"Storey","year":"2002","journal-title":"J. R. Stat. Soc. Ser. B (Stat. Methodol.)"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.cortex.2015.08.022","article-title":"Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment","volume":"74","author":"White","year":"2016","journal-title":"Cortex"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1111\/jnc.14071","article-title":"Corticosterone primes the neuroinflammatory response to Gulf War Illness-relevant organophosphates independently of acetylcholinesterase inhibition","volume":"142","author":"Locker","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/jnc.13088","article-title":"Corticosterone primes the neuroinflammatory response to DFP in mice: Potential animal model of Gulf War Illness","volume":"133","author":"Kelly","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.bbi.2017.08.003","article-title":"Corticosterone potentiates DFP-induced neuroinflammation and affects high-order diffusion imaging in a rat model of Gulf War Illness","volume":"67","author":"Koo","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"336","DOI":"10.3389\/fncel.2018.00336","article-title":"A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation","volume":"12","author":"Craddock","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1093\/toxsci\/kfy130","article-title":"The Neuroinflammatory Phenotype in a Mouse Model of Gulf War Illness is Unrelated to Brain Regional Levels of Acetylcholine as Measured by Quantitative HILIC-UPLC-MS\/MS","volume":"165","author":"Miller","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Jones, B.C., Miller, D.B., Lu, L., Zhao, W., Ashbrook, D.G., Xu, F., Mulligan, M.K., Williams, R.W., Zhuang, D., and Torres-Rojas, C. (2020). Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness. Brain Sci., 10.","DOI":"10.20944\/preprints202002.0288.v1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bbi.2020.06.018","article-title":"Genome-wide transcriptome architecture in a mouse model of Gulf War Illness","volume":"89","author":"Xu","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s12974-018-1113-9","article-title":"Epigenetic impacts of stress priming of the neuroinflammatory response to sarin surrogate in mice: A model of Gulf War illness","volume":"15","author":"Ashbrook","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"818","DOI":"10.3389\/fnins.2020.00818","article-title":"Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness","volume":"14","author":"Gao","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1002\/glia.23668","article-title":"Oligodendrocyte involvement in Gulf War Illness","volume":"67","author":"Belgrad","year":"2019","journal-title":"Glia"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.bbi.2020.10.022","article-title":"A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain","volume":"91","author":"Lacagnina","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neuro.2018.10.006","article-title":"Corticosterone and pyridostigmine\/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness","volume":"70","author":"Michalovicz","year":"2019","journal-title":"NeuroToxicology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.bbi.2020.07.006","article-title":"Alterations in high-order diffusion imaging in veterans with Gulf War Illness is associated with chemical weapons exposure and mild traumatic brain injury","volume":"89","author":"Cheng","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_63","unstructured":"Kansagara, D., Emily, G.G., Ayers, C.K., Winchell, K.A., Freeman, M., Press, A.M., Paynte, R., Kansagara, D., and Nugent, S.M. (2020). Biological Measures and Diagnostic Tools for Gulf War Illness: A Systematic Review. Evid. Synth. Program."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"119360","DOI":"10.1016\/j.lfs.2021.119360","article-title":"Biological measures and diagnostic tools for Gulf War Illness\u2014A systematic review","volume":"275","author":"Gean","year":"2021","journal-title":"Life Sci."},{"key":"ref_65","unstructured":"National Library of Medicine US (2020, February 05). TNF and Glucocorticoid Antagonist for GWI Associated Multi-symptom Disease Homeostasis Reset (E\/M) Identifier: NCT04254627, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04254627."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Craddock, T.J.A., Del Rosario, R.R., Rice, M., Zysman, J.P., Fletcher, M.A., Klimas, N.G., and Broderick, G. (2015). Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132774"},{"key":"ref_67","first-page":"29","article-title":"Major reproductive health characteristics in male Gulf War Veterans. The Danish Gulf War Study","volume":"48","author":"Andersson","year":"2001","journal-title":"Dan. Med Bull."},{"key":"ref_68","first-page":"43","article-title":"Prevalence of male sexual problems in the Danish Gulf War Study","volume":"4","author":"Ishoy","year":"2001","journal-title":"Scand. J. Sexol."},{"key":"ref_69","first-page":"416","article-title":"State of health after deployment in the Persian Gulf. The Danish Gulf War Study","volume":"46","author":"Suadicani","year":"1999","journal-title":"Dan. Med Bull."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1097\/00043764-200112000-00001","article-title":"Surveillance of Depleted Uranium Exposed Gulf War Veterans: Health Effects Observed in an Enlarged \"Friendly Fire\" Cohort","volume":"43","author":"McDiarmid","year":"2001","journal-title":"J. Occup. Environ. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1080\/15287394.2011.539138","article-title":"Longitudinal Health Surveillance in a Cohort of Gulf War Veterans 18 Years After First Exposure to Depleted Uranium","volume":"74","author":"McDiarmid","year":"2011","journal-title":"J. Toxicol. Environ. Heal. Part A"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1097\/01.HP.0000259850.66969.8c","article-title":"Health Surveillance Of Gulf War I Veterans Exposed to Depleted Uranium: Updating The Cohort","volume":"93","author":"McDiarmid","year":"2007","journal-title":"Heal. Phys."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1080\/15287390490273541","article-title":"Health Effects of Depleted Uranium on Exposed Gulf War Veterans: A 10-Year Follow-Up","volume":"67","author":"McDiarmid","year":"2004","journal-title":"J. Toxicol. Environ. Heal. Part A"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1006\/enrs.1999.4012","article-title":"Health Effects of Depleted Uranium on Exposed Gulf War Veterans","volume":"82","author":"McDiarmid","year":"2000","journal-title":"Environ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1097\/HP.0b013e31827b1740","article-title":"The Gulf War depleted uranium cohort at 20 years: Bioassay results and novel approaches to fragment surveillance","volume":"104","author":"McDiarmid","year":"2013","journal-title":"Health Phys."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00420-005-0006-2","article-title":"Biological monitoring and surveillance results of Gulf War I veterans exposed to depleted uranium","volume":"79","author":"McDiarmid","year":"2005","journal-title":"Int. Arch. Occup. Environ. Heal."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1177\/0748233707080908","article-title":"Testicular toxicity of chlorpyrifos (an organophosphate pesticide) in albino rat","volume":"23","author":"Joshi","year":"2007","journal-title":"Toxicol. Ind. Heal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"20859","DOI":"10.1007\/s11356-017-9617-x","article-title":"Low doses of chlorpyrifos interfere with spermatogenesis of rats through reduction of sex hormones","volume":"24","author":"Peiris","year":"2017","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_79","first-page":"1532","article-title":"Individual and combined effect of chlorpyrifos and cypermethrin on reproductive system of adult male albino rats","volume":"24","author":"Abouhashem","year":"2016","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kudavidanage, E.P., Dissanayake, D.M.I., Keerthirathna, W.L.R., Nishshanke, N.L.W., and Peiris, L.D.C. (2020). Commercial Formulation of Chlorpyrifos Alters Neurological Behaviors and Fertility. Biology, 9.","DOI":"10.3390\/biology9030049"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10553","DOI":"10.1021\/acs.jafc.9b03602","article-title":"Chlorpyrifos Induces Metabolic Disruption by Altering Levels of Reproductive Hormones","volume":"67","author":"Li","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.intimp.2015.05.020","article-title":"A novel use for testosterone to treat central sensitization of chronic pain in fibromyalgia patients","volume":"27","author":"White","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.intimp.2015.05.016","article-title":"Treatment of pain in fibromyalgia patients with testosterone gel: Pharmacokinetics and clinical response","volume":"27","author":"White","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1080\/21628130.2015.1127498","article-title":"Gulf War Illness: Is there lasting damage to the endocrine-immune circuitry?","volume":"2","author":"Rice","year":"2014","journal-title":"Syst. Biomed."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/S0006-3223(98)00131-0","article-title":"Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events","volume":"45","author":"Maes","year":"1999","journal-title":"Biol. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bbi.2018.08.015","article-title":"Posttraumatic stress disorder is associated with enhanced interleukin-6 response to mental stress in subjects with a recent myocardial infarction","volume":"75","author":"Lima","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/S2215-0366(15)00309-0","article-title":"Inflammatory markers in post-traumatic stress disorder: A systematic review, meta-analysis, and meta-regression","volume":"2","author":"Passos","year":"2015","journal-title":"Lancet Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12868-015-0169-z","article-title":"A pre-conditioning stress accelerates increases in mouse plasma inflammatory cytokines induced by stress","volume":"16","author":"Cheng","year":"2015","journal-title":"BMC Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.bbr.2016.04.039","article-title":"Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K\/Akt\/mTOR mediated BDNF\/TrkB pathway","volume":"308","author":"Tao","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s11064-010-0367-0","article-title":"Chronic Variable Stress Alters Inflammatory and Cholinergic Parameters in Hippocampus of Rats","volume":"36","author":"Tagliari","year":"2010","journal-title":"Neurochem. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.neuroscience.2015.01.001","article-title":"Peripheral and central effects of repeated social defeat stress: Monocyte trafficking, microglial activation, and anxiety","volume":"289","author":"Reader","year":"2015","journal-title":"Neuroscience"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e14137","DOI":"10.7554\/eLife.14137","article-title":"Author response: Cyclooxygenase-2 inhibition reduces stress-induced affective pathology","volume":"5","author":"Baldi","year":"2016","journal-title":"Elife"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jpsychires.2016.02.003","article-title":"Fluoxetine treatment prevents the inflammatory response in a mouse model of posttraumatic stress disorder","volume":"76","author":"Kao","year":"2016","journal-title":"J. Psychiatr. Res."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Ebenezer, P.J., Wilson, C.B., Wilson, L.D., Nair, A.R., and J, F. (2016). The Anti-Inflammatory Effects of Blueberries in an Animal Model of Post-Traumatic Stress Disorder (PTSD). PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160923"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.psyneuen.2018.05.012","article-title":"A peripheral immune response to remembering trauma contributes to the maintenance of fear memory in mice","volume":"94","author":"Young","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1001\/jama.280.11.981","article-title":"Chronic multisymptom illness affecting Air Force veterans of the Gulf War","volume":"280","author":"Fukuda","year":"1998","journal-title":"JAMA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1472-6963-3-25","article-title":"Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution","volume":"3","author":"Reeves","year":"2003","journal-title":"BMC Health Serv. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0197-2456(02)00192-7","article-title":"The antibiotic treatment trial of Gulf War Veterans\u2019 Illnesses: Issues, design, screening, and baseline characteristics","volume":"23","author":"Collins","year":"2002","journal-title":"Control. Clin. Trials"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Kelly, K.A., Michalovicz, L.T., Miller, J.V., Castranova, V., Miller, D.B., and O\u2019Callaghan, J.P. (2018). Prior exposure to corticosterone markedly enhances and prolongs the neuroinflammatory response to systemic challenge with LPS. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0190546"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"987","DOI":"10.2307\/2529826","article-title":"400: A method for combining non-independent, one-sided tests of significance","volume":"31","author":"Brown","year":"1975","journal-title":"Biometrics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8546\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:42:44Z","timestamp":1760164964000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,9]]},"references-count":100,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168546"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168546","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,9]]}}}