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[[File:Microglia and Astrocyte Dysfunction.png|thumb|Possible mechanism showing the decline of microglia and astrocyte function and structure.]] '''Neuroinflammation''' is a term used to describe activation of the resident immune cells in the [[central nervous system]] (CNS).<ref name=":10">{{Cite journal | last = Aguzzi | first = Adriano | last2 = Barres | first2 = Ben A. | last3 = Bennett | first3 = Mariko L. | date = 2013-01-11 | title = Microglia: Scapegoat, Saboteur, or Something Else?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431634/|journal=Science (New York, N.Y.)|volume=339|issue=6116|pages=156–161|doi=10.1126/science.1227901|issn=0036-8075|pmc=4431634|pmid=23307732}}</ref><ref>{{Cite journal | last = Mrak | first = Robert E. | last2 = Griffin | first2 = W. Sue T. | date = 2004-04-20 | title = Welcome to the Journal of Neuroinflammation!|url=https://doi.org/10.1186/1742-2094-1-1|journal=Journal of Neuroinflammation|volume=1|issue=1|pages=1|doi=10.1186/1742-2094-1-1|issn=1742-2094|pmc=483051|pmid=15285806}}</ref> This contrasts with classical Greco-Roman [[inflammation]], which was originally defined as swelling, redness, heat, and pain, but has come to mean infiltration of tissues by blood-borne immune cells. Unlike classical inflammation, neuroinflammation does not imply infiltration of tissues by blood-borne immune cells. As such, the term “neuroinflammation” must not be confused with the term “[[encephalitis]]”, which implies classical inflammation. Because of this distinction, the relatively recent term “neuroinflammation” has generated considerable confusion in the scientific community.<ref name=":0">{{Cite journal | last = Graeber | first = Manuel B. | last2 = Li | first2 = Wei | last3 = Rodriguez | first3 = Michael L. | date = 2011-12-01 | title = Role of microglia in CNS inflammation | url =https://www.ncbi.nlm.nih.gov/pubmed/21889505|journal=FEBS letters|volume=585|issue=23|pages=3798–3805|doi=10.1016/j.febslet.2011.08.033|issn=1873-3468|pmid=21889505}}</ref> The immune cells activated in neuroinflammation are the tissue-resident [[Macrophage|macrophages]] of the CNS, which, for historical reasons, are called [[microglia]].<ref name=":10" /><ref>{{Cite journal | last = Ginhoux | first = Florent | last2 = Greter | first2 = Melanie | last3 = Leboeuf | first3 = Marylene | last4 = Nandi | first4 = Sayan | last5 = See | first5 = Peter | last6 = Gokhan | first6 = Solen | last7 = Mehler | first7 = Mark F. | last8 = Conway | first8 = Simon J. | last9 = Ng | first9 = Lai Guan | date = 2010-11-05 | title = Fate mapping analysis reveals that adult microglia derive from primitive macrophages|url=https://www.ncbi.nlm.nih.gov/pubmed/20966214|journal=Science (New York, N.Y.)|volume=330|issue=6005 | pages = 841–845|doi=10.1126/science.1194637|issn=1095-9203|pmc=3719181|pmid=20966214}}</ref> Like other macrophages, microglia fight infections and repair tissue damage.<ref name=":1">{{Cite journal | last = DiSabato | first = Damon J. | last2 = Quan | first2 = Ning | last3 = Godbout | first3 = Jonathan P. | date = Oct 2016 | title = Neuroinflammation: the devil is in the details|url=https://www.ncbi.nlm.nih.gov/pubmed/26990767|journal=Journal of Neurochemistry|volume=139 |issue =Suppl 2|pages=136–153|doi=10.1111/jnc.13607|issn=1471-4159|pmc=5025335|pmid=26990767}}</ref> In the case of minor infections or minor tissue damage, microglia can often resolve the situation on their own. In more serious situations, the microglia will secrete [[cytokine]]s to attract help from blood-borne immune cells. ==Diseases associated with neuroinflammation== Neuroinflammation is a symptom of many diseases and thought to be a part of ME. [[Alzheimer's disease]], [[Parkinson's disease]], and [[multiple sclerosis]] are illnesses in which the brain experiences decline in structure and function, and also where it shows clear signs of neuroinflammation. [[Inflammation]] of the [[brain]] is linked to activated [[microglia]], [[cytokine]] presence in the brain,<ref>{{Cite journal | last = Chen | first = Wei-Wei | last2 = Zhang | first2 = Xia | last3 = Huang | first3 = Wen-Juan | date = Apr 2016 | title = Role of neuroinflammation in neurodegenerative diseases (Review)|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805095/|journal=Molecular Medicine Reports|volume=13|issue=4|pages=3391–3396|doi=10.3892/mmr.2016.4948|issn=1791-2997|pmc=4805095|pmid=26935478}}</ref> and changes in the neurochemicals produced by the brain.<ref name=":2">{{Cite journal | last = Albrecht | first = Daniel S. | last2 = Granziera | first2 = Cristina | last3 = Hooker | first3 = Jacob M. | last4 = Loggia | first4 = Marco L. | date = 2016-04-20 | title = In Vivo Imaging of Human Neuroinflammation | url =https://www.ncbi.nlm.nih.gov/pubmed/26985861|journal=ACS chemical neuroscience|volume=7|issue=4 | pages = 470–483|doi=10.1021/acschemneuro.6b00056|issn=1948-7193|pmc=5433433|pmid=26985861}}</ref> These effects also occur in [[Myalgic encephalomyelitis|ME]] which is why researchers are searching to more strongly show neuroinflammation in these patients. ==Causes== === Microglia activation === The [[blood brain barrier]] (BBB), a membrane that separates the brain from the rest of the body, may become compromised in [[Myalgic encephalomyelitis|ME]] patients. If there are [[Cytokine|cytokines]] circulating in the bloodstream, they may get into the brain through opened sections of the BBB<ref name=":3">{{Cite journal | last = Morris | first = Gerwyn | last2 = Maes | first2 = Michael | date = Dec 2013 | title = A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/22718491|journal=Metabolic Brain Disease|volume=28|issue=4 | pages = 523–540|doi=10.1007/s11011-012-9324-8|issn=1573-7365|pmid=22718491}}</ref>. While this initially starts as a normal brain response so that the brain can get the body back to normal, healthy functioning, this process can be predisposed to dysfunction and activation may be sustained longer than usual. [[Microglia]] are cells that can act as the brain’s primary immune response. If cytokines or immune cells from outside the [[Central nervous system|CNS]] enter the brain through the BBB, the microglia will respond to the immune threat and attempt to clear the infiltrators out. However, this process increases neuron activation and the release of more cytokines potentially leading to a cycle of neuroinflammation<ref name=":3" />. One study used a radioligand, a tracer that lights up in the presence of a specific molecule, in a positron emission tomography (PET) scanner in search of activated microglia in ME patients’ brains. Activated microglia cells are believed to be correlated to neuroinflammation. Increased radioligand presence in ME subjects’ brains was observed; however, further analysis of these data and replication of their results are needed<ref>{{Cite journal | last = Nakatomi | first = Yasuhito | last2 = Mizuno | first2 = Kei | last3 = Ishii | first3 = Akira | last4 = Wada | first4 = Yasuhiro | last5 = Tanaka | first5 = Masaaki | last6 = Tazawa | first6 = Shusaku | last7 = Onoe | first7 = Kayo | last8 = Fukuda | first8 = Sanae | last9 = Kawabe | first9 = Joji | date = Jun 2014 | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study|url=https://www.ncbi.nlm.nih.gov/pubmed/24665088|journal=Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine|volume=55|issue=6 | pages = 945–950|doi=10.2967/jnumed.113.131045|issn=1535-5667|pmid=24665088}}</ref>. ===<span id="ONS_pathway">Oxidative and nitrosative stress</span>=== The '''oxidative and nitrosative stress pathway''' or '''O&NS pathway''' results in tissue damage which could lead to neuroimflammation in [[ME/CFS]]. [[File:CauseofCFSME.jpg|thumb|403x403px|Scheme of cascade events in CFS/ME/SEID showing O&N pathway.Source: Eur Jrnl of Translational Myology 28(3).<ref>{{Cite journal | last = Pietrangelo | first = Tiziana | last2 = Fulle | first2 = Stefania | last3 = Coscia | first3 = Francesco | last4 = Gigliotti | first4 = Paola Virginia | last5 = Fanò-Illic | first5 = Giorgio | date = 2018-09-07 | title = Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome|url=http://dx.doi.org/10.4081/ejtm.2018.7688|journal=European Journal of Translational Myology|volume=28|issue=3|doi=10.4081/ejtm.2018.7688|issn=2037-7460}}</ref> License: CC-BY-NC-4.0]] Neuroinflammation may also be related to excess [[oxygen]] and nitrogen molecules in tissues. This can cause oxidative or nitrosative stress (O&NS), leading to tissue damage. The O&NS pathway helps maintain the blood brain barrier, an important membrane keeping the brain protected from harmful substances present in the blood. When the pathway is dysfunctional, the blood-brain barrier becomes less effective at keeping out particles. Breakdown of this barrier could lead to immune cells entering the brain and trigger an immune response, leading to neuroinflammation. Researchers propose a link between the dysfunction of brain tissues in ME/CFS and the breakdown of the oxidative and nitrosative stress pathway.<ref name=":3" /> {{See also|Nitrogen hypothesis}} === Activation of cyclical neuroinflammation: A self-perpetuating cycle === When a patient gets an infection, the body attempts to return homeostasis. The immune system has regulatory structures called toll-like receptors (TLRs). High amounts of stress or a previous injury can predispose an individual’s TLRs to be more sensitive, releasing inflammatory molecules more readily in response to an immune stressor.<ref>{{Cite journal | last = Gárate | first = Iciar | last2 = Garcia-Bueno | first2 = Borja | last3 = Madrigal | first3 = Jose Luis Muñoz | last4 = Caso | first4 = Javier Rubén | last5 = Alou | first5 = Luis | last6 = Gomez-Lus | first6 = Marisa L. | last7 = Micó | first7 = Juan Antonio | last8 = Leza | first8 = Juan Carlos | date = 2013-01-01 | title = Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway|url=https://www.ncbi.nlm.nih.gov/pubmed/22906518|journal=Biological Psychiatry|volume=73|issue=1|pages=32–43|doi=10.1016/j.biopsych.2012.07.005|issn=1873-2402|pmid=22906518}}</ref> One of the downstream pathways of TLRs, the oxidative and nitrosative stress pathway (O&NS) can get activated. If this pathway is overstimulated, the body will produce a larger-scale response in an effort to return to normal.<ref>{{Cite journal | last = Liu | first = JiaJun | last2 = Buisman-Pijlman | first2 = Femke | last3 = Hutchinson | first3 = Mark R.| date = 2014 | title = Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder |url =https://www.ncbi.nlm.nih.gov/pubmed/25324715|journal=Frontiers in Neuroscience|volume=8|pages=309|doi=10.3389/fnins.2014.00309|issn=1662-4548|pmc=4179746|pmid=25324715}}</ref> In this attempt, a chemical called damage-associated molecular patterns (DAMPs) triggers the release of more inflammatory molecules, some of which activate the TLRs<ref>{{Cite journal | last = Morris | first = Gerwyn | last2 = Berk | first2 = Michael | last3 = Walder | first3 = Ken | last4 = Maes | first4 = Michael | date = 2015-02-06 | title = Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses|url=https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0259-2|journal=BMC Medicine|language=en|volume=13|issue=1|doi=10.1186/s12916-014-0259-2|issn=1741-7015|pmc=4320458|pmid=25856766}}</ref> (Morris et al., 2015). The process of activation from TLRs to the O&NS pathway to the production of more inflammatory molecules then becomes a cycle.<ref name=":4">{{Cite journal | last = Chaudhuri | first = A. | last2 = Condon | first2 = B.R. | last3 = Gow | first3 = J.W. | last4 = Brennan | first4 = D. | last5 = Hadley | first5 = D. M. | date = 2003-02-10 | title = Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12598734|journal=Neuroreport|volume=14|issue=2|pages=225–228|doi=10.1097/01.wnr.0000054960.21656.64|issn=0959-4965|pmid=12598734}}</ref> == Possible neurological biomarkers of ME == When the brain is going through challenges such as neuroinflammation or neurodegeneration, several chemicals become dysregulated. These changes are able to be recorded using a special function of magnetic resonance (MR) scanners. Because each chemical has a distinct molecular structure, the magnetic field formed by the scanner will bounce off of each chemical in unique ways. This allows the technician to measure the amounts of these chemicals in the brain. Several neurochemicals have been studied in relation to ME patients. Myo-inositol is thought to be involved in astrocyte function (Albrecht et al. 2016) and trended to be higher in ME patients compared to controls.<ref name=":5">{{Cite journal | last = Brooks | first = J.C. | last2 = Roberts | first2 = N. | last3 = Whitehouse | first3 = G. | last4 = Majeed | first4 = T. | date = Nov 2000 | title = Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11144799|journal=The British Journal of Radiology|volume=73|issue=875|pages=1206–1208|doi=10.1259/bjr.73.875.11144799|issn=0007-1285|pmid=11144799}}</ref> N-acetylacetate (NAA) shows neuron density, which has been found in other neurological disorders<ref name=":2" /> and has been shown to be lower in ME patients,<ref name=":4" /><ref name=":5" /> but this was not found in all studies.<ref>{{Cite journal | last = Puri | first = B. K. | last2 = Counsell | first2 = S.J. | last3 = Zaman | first3 = R. | last4 = Main | first4 = J. | last5 = Collins | first5 = A.G. | last6 = Hajnal | first6 = J.V. | last7 = Davey | first7 = N.J. | date = Nov 2002 | title = Relative increase in choline in the occipital cortex in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12197861|journal=Acta Psychiatrica Scandinavica|volume=106|issue=3|pages=224–226|issn=0001-690X|pmid=12197861}}</ref><ref name=":6">{{Cite journal | last = Tomoda | first = A. | last2 = Miike | first2 = T. | last3 = Yamada | first3 = E. | last4 = Honda | first4 = H. | last5 = Moroi | first5 = T. | last6 = Ogawa | first6 = M. | last7 = Ohtani | first7 = Y. | last8 = Morishita | first8 = S. | date = Jan 2000 | title = Chronic fatigue syndrome in childhood | url =https://www.ncbi.nlm.nih.gov/pubmed/10761837|journal=Brain & Development|volume=22|issue=1 | pages = 60–64|issn=0387-7604|pmid=10761837}}</ref> [[Choline]] is linked to activation of glia, loss of energy and expression of macrophages in the brain<ref name=":2" /> and has been shown to change compared to controls.<ref name=":4" /><ref name=":5" /><ref name=":6" /> <ref>{{Cite journal | last = Puri | first = B.K. | last2 = Agour | first2 = M. | last3 = Gunatilake | first3 = K.D.R. | last4 = Fernando | first4 = K.A.C. | last5 = Gurusinghe | first5 = A.I. | last6 = Treasaden | first6 = I.H. | date = Nov 2009 | title = An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome)|url=https://www.ncbi.nlm.nih.gov/pubmed/19906518|journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids|volume=81|issue=5-6 | pages = 303–305 |doi=10.1016/j.plefa.2009.10.002|issn=1532-2823|pmid=19906518}}</ref> Lactate increases when more energy is being expended and has been shown to be higher than controls,<ref name=":7">{{Cite journal | last = Mathew | first = Sanjay J. | last2 = Mao | first2 = Xiangling | last3 = Keegan | first3 = Kathryn A. | last4 = Levine | first4 = Susan M. | last5 = Smith | first5 = Eric L.P. | last6 = Heier | first6 = Linda A. | last7 = Otcheretko | first7 = Viktor | last8 = Coplan | first8 = Jeremy D. | last9 = Shungu | first9 = Dikoma C. | date = Apr 2009 | title = Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study|url=https://www.ncbi.nlm.nih.gov/pubmed/18942064|journal=NMR in biomedicine|volume=22|issue=3|pages=251–258|doi=10.1002/nbm.1315|issn=0952-3480|pmid=18942064}}</ref><ref>{{Cite journal | last = Shungu | first = Dikoma C. | last2 = Weiduschat | first2 = Nora | last3 = Murrough | first3 = James W. | last4 = Mao | first4 = Xiangling | last5 = Pillemer | first5 = Sarah | last6 = Dyke | first6 = Jonathan P. | last7 = Medow | first7 = Marvin S. | last8 = Natelson | first8 = Benjamin H. | authorlink8 = Benjamin Natelson | last9 = Stewart | first9 = Julian M. | date = Sep 2012 | title = Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology|url=https://www.ncbi.nlm.nih.gov/pubmed/22281935|journal=NMR in biomedicine|volume=25|issue=9|pages=1073–1087|doi=10.1002/nbm.2772|issn=1099-1492|pmc=3896084|pmid=22281935}}</ref><ref name=":8">{{Cite journal | last = Natelson | first = Benjamin H. | last2 = Vu | first2 = Diana | last3 = Coplan | first3 = Jeremy D. | last4 = Mao | first4 = Xiangling | last5 = Blate | first5 = Michelle | last6 = Kang | first6 = Guoxin | last7 = Soto | first7 = Eli | last8 = Kapusuz | first8 = Tolga | last9 = Shungu | first9 = Dikoma C. | date = 2017 | title=Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia|url=https://www.ncbi.nlm.nih.gov/pubmed/29308330|journal = Fatigue: Biomedicine, Health & Behavior |volume=5|issue=1|pages=15–20|doi=10.1080/21641846.2017.1280114|issn=2164-1846|pmc=5754037|pmid=29308330}}</ref><ref name=":9">{{Cite journal | last = Murrough | first = James W. | last2 = Mao | first2 = Xiangling | last3 = Collins | first3 = Katherine A. | last4 = Kelly | first4 = Chris | last5 = Andrade | first5 = Gizely | last6 = Nestadt | first6 = Paul | last7 = Levine | first7 = Susan M. | last8 = Mathew | first8 = Sanjay J. | last9 = Shungu | first9 = Dikoma C. | date = Jul 2010 | title = Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder |url =https://www.ncbi.nlm.nih.gov/pubmed/20661876|journal=NMR in biomedicine|volume=23|issue=6 | pages = 643–650|doi=10.1002/nbm.1512|issn=1099-1492|pmid=20661876}}</ref> and significantly differs from lactate levels in people with psychological disorders.<ref name=":7" /><ref name=":9" /> Both ME patients and [[fibromyalgia]] patients were found to have similar levels of elevated lactate, so more tests would be needed to differentiate the two.<ref name=":8" /> Though contrasts were found between ME people and controls in many of these [[Diagnostic biomarker|biomarker]] studies, researchers are not sure what the changes mean specifically because the metabolites are used in multiple brain processes. Furthermore, the results shown by these papers has not been largely replicated. However, if repeated, these biomarkers could potentially become an objective measure for diagnosing ME. ==Notable studies== *2010, Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways<ref name="Twisk, 2010">{{Cite journal | last1 = Twisk | first1 = Frank | authorlink = Frank Twisk | last2 = Maes | first2 = Michael | authorlink2 = Michael Maes | title = Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways|journal=BMC Medicine|volume=8|issue=35 | page = | date = 2010 | url= https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901228/pdf/1741-7015-8-35.pdf}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901228/pdf/1741-7015-8-35.pdf (Full text)] *2011, Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome<ref>{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | authorlink2=Frank Twisk | last3 = Kubera | first3 = Marta | authorlink3 = | last4 = Ringel | first4 = Karl | authorlink4 = | last5 = Leunis | first5 = Jean-Claude | authorlink5 = | last6 = Geffard | first6 = Michel | authorlink6 = | date = Feb 2012 | title = Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome|url=https://linkinghub.elsevier.com/retrieve/pii/S0165032711005362|journal=Journal of Affective Disorders|language=en|volume=136|issue=3 | pages = 909–917|doi=10.1016/j.jad.2011.09.010|quote=|via=}}</ref> - [[pubmed:21967891|(Abstract)]] *2010, Autopsies of four deceased ME patients showed various pathological phenomena in the CNS and [[peripheral nervous system]]s.<ref>{{Cite web|url=https://www.meassociation.org.uk/2011/01/pathology-of-mecfs-pilot-study-of-four-autopsy-reports/ | title = Pathology of ME/CFS: pilot study of four autopsy reports | last = | first = | date = Jan 2011 | website = [[The ME Association]]|language=en-US|archive-url=|archive-date=|access-date=2018-08-10}}</ref> *2014, [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder]]. NY Times Well article by [[David Tuller]] on the [[brain scans]] of [[ME/CFS]] patient's researched by [[Stanford ME/CFS Initiative]].<ref>{{Cite news | url=http://well.blogs.nytimes.com/2014/11/24/brains-of-people-with-chronic-fatigue-syndrome-offer-clues-about-disorder/?_r=0 | title = Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder | last = Tuller | first = David | date = Nov 24, 2014|work=Well|access-date=2018-08-10|archive-url=|archive-date=|language=en}}</ref><ref>{{Cite journal | last = Zeineh | first = Michael M. | last2 = Kang | first2 = James | last3 = Atlas | first3 = Scott W. | last4 = Raman | first4 = Mira M. | last5 = Reiss | first5 = Allan L. | last6 = Norris | first6 = Jane L. | last7 = Valencia | first7 = Ian | last8 = Montoya | first8 = Jose G. | date = 2015 | title=Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome|url=https://pubs.rsna.org/doi/abs/10.1148/radiol.14141079|journal=Radiology|language=en|volume=274|issue=2 | pages = 517–526|doi=10.1148/radiol.14141079|issn=0033-8419|via=|quote= | author-link = Michael Zeineh | authorlink2 = | authorlink3 = | authorlink4 = | authorlink5 = | authorlink6 = Jane Norris | authorlink7 = Ian Valencia | authorlink8 = Jose Montoya}}</ref><ref>{{Cite web|url=http://med.stanford.edu/news/all-news/2014/10/study-finds-brain-abnormalities-in-chronic-fatigue-patients.html | title = Study finds brain abnormalities in chronic fatigue patients | last = | first = | date = Oct 28, 2014 | website = News Center|language=en|archive-url=|archive-date=|access-date=2018-09-22}}</ref> * 2014, A Japanese PET study looked at neuroinflammation in 9 patients with ME/CFS and 10 controls. They measured a protein expressed by activated [[microglia]], and found that values in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%–199% higher in ME/CFS patients than in healthy controls. The values in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the values in the cingulate cortex and thalamus positively correlated with pain score, and the value in the hippocampus positively correlated with depression score.<ref name="Nakatomi2014">{{citation | last1 = Nakatomi | first1 = Yasuhito | authorlink1 = | last2 = Mizuno | first2 = Kei | authorlink2 = | last3 = Ishii | first3 = Akira | authorlink3 = | last4 = Wada | first4 = Yasuhiro | authorlink4 = | last5 = Tanaka | first5 = Masaaki | authorlink5 = | last6 = Tazawa | first6 = Shusaku | authorlink6 = | last7 =Onoe | first7 = Kayo | authorlink7 = | last8 =Fukuda | first8 = Sanae | authorlink8 = | last9 = Kawabe | first9 = Joji | authorlink9 = | last10 = Takahashi | first10 = Kazuhiro | authorlink10 = | last11 = Kataoka | first11 = Yosky | authorlink11 = | last12 = Shiomi | first12 = Susumu | authorlink12 = | last13 = Yamaguti | first13 = Kouzi | authorlink13 = | last14 = Inaba | first14 = Masaaki | authorlink14 = | last15 = Kuratsune | first15 = Hirohiko | authorlink15 = | last16 = Watanabe | first16 = Yasuyoshi | authorlink16 = Yasuyoshi Watanabe | display-authors = 3 | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study | journal = Journal of Nuclear Medicine | volume = 55|issue =6 | page = 945-50 | date = 2014-03-24 | pmid = 24665088 | doi = 10.2967/jnumed.113.131045 | url = http://jnm.snmjournals.org/content/55/6/945.long }}</ref><ref name="Tuller20141124NYT">{{citation | last1 = Tuller | first1 = David | authorlink1 = David Tuller | title = Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder | journal = NY Times | date = 2014-11-24 | url = http://well.blogs.nytimes.com/2014/11/24/brains-of-people-with-chronic-fatigue-syndrome-offer-clues-about-disorder/?_r=0 }}</ref> *2016, [https://doi.org/10.1038/nature16549 Schizophrenia risk from complex variation of complement component 4]<ref>{{Cite journal | last = Sekar | first = Aswin | last2 = Bialas | first2 = Allison R. | last3 = de Rivera | first3 = Heather | last4 = Davis | first4 = Avery | last5 = Hammond | first5 = Timothy R. | last6 = Kamitaki | first6 = Nolan | last7 = Tooley | first7 = Katherine | last8 = Presumey | first8 = Jessy | last9 = Baum | first9 = Matthew | date = 2016-02-11 | title = Schizophrenia risk from complex variation of complement component 4|url=https://www.ncbi.nlm.nih.gov/pubmed/26814963|journal=Nature|volume=530|issue=7589|pages=177–183|doi=10.1038/nature16549|issn=1476-4687|pmc=4752392|pmid=26814963}}</ref> * 2016, [https://doi.org/10.18632/aging.100981 Reversal of cognitive decline in Alzheimer’s disease]<ref>{{Cite journal | last = Bredesen | first = Dale E. | last2 = Amos | first2 = Edwin C. | last3 = Canick | first3 = Jonathan | last4 = Ackerley | first4 = Mary | last5 = Raji | first5 = Cyrus | last6 = Fiala | first6 = Milan | last7 = Ahdidan | first7 = Jamila | date = Jun 2016 | title = Reversal of cognitive decline in Alzheimer's disease|url=https://www.ncbi.nlm.nih.gov/pubmed/27294343|journal=Aging|volume=8|issue=6|pages=1250–1258|doi=10.18632/aging.100981|issn=1945-4589|pmc=4931830|pmid=27294343}}</ref> * 2017, [https://doi.org/10.1016/j.biopsych.2017.08.005 Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study]<ref>{{Cite journal | last = Holmes | first = Sophie E. | last2 = Hinz | first2 = Rainer | last3 = Conen | first3 = Silke | last4 = Gregory | first4 = Catherine J. | last5 = Matthews | first5 = Julian C. | last6 = Anton-Rodriguez | first6 = Jose M. | last7 = Gerhard | first7 = Alexander | last8 = Talbot | first8 = Peter S. | date = 2018-01-01 | title = Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study|url=https://www.ncbi.nlm.nih.gov/pubmed/28939116|journal=Biological Psychiatry|volume=83|issue=1 | pages = 61–69|doi=10.1016/j.biopsych.2017.08.005|issn=1873-2402|pmid=28939116}}</ref> * 2019, [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy]]<ref name="Mueller2019">{{Cite journal|url=https://link.springer.com/epdf/10.1007/s11682-018-0029-4 | title = Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy | last = Mueller | first = Christina | authorlink=Christina Mueller | last2 = Lin | first2 = Joanne C | authorlink2 = Joanne Lin | date = 2019 | doi=10.1007/s11682-018-0029-4|archive-url=|archive-date=|access-date=2019-01-17 | authorlink3 = Sulaiman Sheriff | authorlink4 = Andrew Maudsley | authorlink5 = Jarred Younger | last3 = Sheriff | last4 = Maudsley | last5 = Younger | first3 = Sulaiman | first4 = Andrew A | first5 = Jarred W|volume=14|issue=2 | pages = 562-572|journal=Brain Imaging and Behavior}}</ref> *2019, Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation<ref>{{Cite journal | last = Albrecht | first = Daniel S. | authorlink = Daniel Albrecht | last2 = Forsberg | first2 = Anton | authorlink2 = | last3 = Sandström | first3 = Angelica | authorlink3 = | last4 = Bergan | first4 = Courtney | author-link4 = | last5 = Kadetoff | first5 = Diana | authorlink5 = | last6 = Protsenko | first6 = Ekaterina | authorlink6 = | last7 = Lampa | first7 = Jon | last8 = Lee | first8 = Yvonne C. | last9 = Höglund | first9 = Caroline Olgart|display-authors=8 | date = 2019-01-01 | title = Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation | url =http://www.sciencedirect.com/science/article/pii/S0889159118302423|journal=Brain, Behavior, and Immunity|language=en|volume=75|issue= | pages = 72–83|doi=10.1016/j.bbi.2018.09.018|issn=0889-1591|pmc=|pmid=|access-date=|quote=|via= | last10 = Catana | first10 = Ciprian | first11 = Simon | last11 = Cervenka | last12 = Akeju | first12 = Oluwaseun | last13 = Lekander | first13 = Mats | last14 = Cohen | first14 = George | last15 = Halldin | first15 = Christer | last16 = Taylor | first16 = Norman | last17 = Minhae | first17 = Kim | last18 = Hooker | first18 = Jacob M. | last19 = Edwards | first19 = Robert R. | last20 = Napadow | first20 = Vitaly | last21 = Kosek | first21 = Eva | last22 = Loggia | first22 = Marco L.}}</ref> - [https://www.sciencedirect.com/science/article/pii/S0889159118302423 (Full text)] *2020, In-vivo imaging of neuroinflammation in veterans with Gulf War illness<ref name="Loggia2020">{{Cite journal | last = Alshelh | first = Zeynab | authorlink = | last2 = Albrecht | first2 = Daniel S. | authorlink2= | last3 = Bergan | first3 = Courtney | authorlink3 = | last4 = Akeju | first4 = Oluwaseun | authorlink4 = | last5 = Clauw | first5 = Daniel J. | authorlink5 = Daniel Clauw | last6 = Conboy | first6 = Lisa | authorlink6 = | last7 = Edwards | first7 = Robert R. | last8 = Kim | first8 = Minhae | last9 = Lee | first9 = Yvonne C.|display-authors=8 | date = 2020-02-04 | title = In-vivo imaging of neuroinflammation in veterans with Gulf War illness|url=http://www.sciencedirect.com/science/article/pii/S0889159119313340|journal=Brain, Behavior, and Immunity|language=en|volume=87|issue= | pages = 498-507|doi=10.1016/j.bbi.2020.01.020|issn=0889-1591|pmc=|pmid=|access-date=|quote=|via= | last10 = Protsenko | first10 = Ekaterina | last11 = Napadow | first11 = Vitaly | last12 = Sullivan | first12 = Kimberly | authorlink12 = Kimberly Sullivan | author-link13 = Marco Loggia | last13 = Loggia | first13 = Marco F.}}</ref> - [https://www.sciencedirect.com/science/article/pii/S0889159119313340 (Full text)] ==Talks and interviews== *2016, [https://www.youtube.com/watch?v=_ijlkRwORfM What is neuroinflammation?]<ref>{{Cite web|url=https://www.youtube.com/watch?v=_ijlkRwORfM | title = What is neuroinflammation? | last = Younger | first = Jarred | date = Apr 4, 2016 | website = YouTube|via=Younger Lab|archive-url=|archive-date=|access-date=}}</ref> - Jarred Younger *2016, [https://www.youtube.com/watch?v=1p6UojKL010 Do you have a hot brain?]<ref>{{Cite web|url=https://www.youtube.com/watch?v=1p6UojKL010 | title = Do you have a hot brain? | last = Younger | first = Jarred | date = Apr 25, 2016 | website = YouTube|via=Younger Lab|archive-url=|archive-date=|access-date=}}</ref> - Jarred Younger *2017, [https://www.betterhealthguy.com/episode49 Brain on Fire with Dr. Mary Ackerley, MD] *2017, [https://www.moldillnessmadesimple.com/brain-on-fire-brain-changes-in-mold-illness-with-dr-ackerley/ Brain on Fire Webinar - Brain Changes in Mold Illness with Dr. Mary Ackerley] * 2018, [https://www.youtube.com/watch?v=rxdzaWD5wfU ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study]<ref>{{Cite web|url=https://www.youtube.com/watch?v=rxdzaWD5wfU | title = ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study | date = Dec 14, 2018|access-date=|website=YouTube | last = | first = | authorlink = Jarred Younger | last2 = | first2 = | authorlink2 = |archive-url=|archive-date=|publisher=SolveCFS}}</ref> - SolveCFS == See also == *[[Brain]] *[[Neurology of ME/CFS]] [[Autopsy]] *[[Microglia]] *[[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis]] *[[Jarred Younger]] *[[Chronic pain]] ==Learn more== *[http://mypassion4health.com/ Mary Ackerley, MD] *[https://www.healthrising.org/blog/2020/05/02/fibromyalgia-chronic-fatigue-syndrome-gulf-war-illness-neuroinflammation/? Fibromyalgia, Chronic Fatigue Syndrome, Gulf War Illness – the Widespread Neuroinflammation Diseases] - Cort Johnson * 2018, [https://www.healthrising.org/blog/2018/09/24/brain-fire-neuroinflammation-found-chronic-fatigue-syndrome-me-cfs/ Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS)]<ref>{{Cite news | url=https://www.healthrising.org/blog/2018/09/24/brain-fire-neuroinflammation-found-chronic-fatigue-syndrome-me-cfs/ | title = Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS) - Health Rising | last = Johnson | first =Cort | date = 2018-09-24|work=Health Rising|access-date=2018-09-26|archive-url=|archive-date=|language=en-US}}</ref> - Cort Johnson :<blockquote>[[Jarred Younger|Younger’s]] new approach looked at the entire [[brain]] and found signs of [[inflammation]] almost everywhere. When asked what could cause that, Younger said that any neurodegenerative/ neuroinflammatory disorder like [[Multiple sclerosis|MS]] or a severe brain injury that tweaks the [[microglia]] (immune cells in the brain) enough to produce a sustained period of inflammation, burns up the oxygen in the system. Once that happens, the cells resort to [[anaerobic metabolism]] and lactate builds up just as it does in the [[Muscle|muscles]] during [[exercise]].</blockquote> *2014, [http://paradigmchange.me/wp/fire/ Brain on Fire - The Role of Toxic Mold in Triggering Psychiatric Symptoms] - Paradigm Change ==References== {{Reflist}} [[Category:Body systems]] [[Category:Neurology]] [[Category:Immunology]]
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