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=== Inflammation and brain imaging === {{Main article| page_name=Neuroinflammation}} Whole-brain MRS markers of neuroinflammation have been found in ME/CFS.<ref name="Mueller2019" /> fMRI images document neuroinflammation.<ref name="Zeineh20143">{{Cite journal | last1 = Zeineh | first1 = Michael M | author-link1 = Michael Zeineh | last2 = Kang | first2 = James | author-link2 = James Kang | last3 = Atlas | first3 = Scott W | author-link3 = Scott Atlas | last4 = Raman | first4 = Mira M | author-link4 = Mira Raman | last5 = Reiss | first5 = Allan L | author-link5 = Allan Reiss | last6 = Norris | first6 = Jane L | author-link6 = Jane Norris | last7 = Valencia | first7 = Ian | author-link8 = Ian Valencia | last8 = Montoya | first8 = Jose G | author-link8 = Jose Montoya | title = Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome | journal = Radiology | volume = 274 | issue = 2| pages = 517–526 | date = 2014-10-29 | doi = 10.1148/radiol.14141079 | url = http://pubs.rsna.org/doi/abs/10.1148/radiol.14141079 }}</ref> In 2014, A Japanese [[positron emission tomography]] (PET) study looked at [[neuroinflammation]] in nine patients with ME/CFS and ten 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 | author-link1 = | last2 = Mizuno | first2 = Kei | author-link2 = | last3 = Ishii | first3 = Akira | author-link3 = | last4 = Wada | first4 = Yasuhiro | author-link4 = | last5 = Tanaka | first5 = Masaaki | author-link5 = | last6 = Tazawa | first6 = Shusaku | author-link6 = | last7 = Onoe | first7 = Kayo| author-link7 = | last8 = Fukuda | first8 = Sanae | author-link8 = | last9 = Kawabe | first9 = Joji | author-link9 = | last10 = Takahashi | first10 = Kazuhiro | author-link10 = | last11 = Kataoka | first11 = Yosky | author-link11 = | last12 = Shiomi | first12 = Susumu | author-link12 = | last13 = Yamaguti | first13 = Kouzi | author-link13 = | last14 = Inaba | first14 = Masaaki | author-link14 = | last15 = Kuratsune | first15 = Hirohiko | author-link15 = | last16 = Watanabe | first16 = Yasuyoshi | author-link16 = Yasuyoshi Watanabe | 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> In 2019, Mueller et al. investigated neuroinflammation, and found abnormalities affecting the whole brain rather than only part of the brain in [[ME/CFS]] patients.<ref name="Mueller2019"/> <blockquote>This study is the first to investigate whole-brain MRS markers of neuroinflammation in ME/CFS. We report metabolite and [[Body temperature|temperature abnormalities]] in ME/CFS patients in widely distributed brain areas, suggesting ME/CFS is driven by diffuse pathophysiological processes affecting the whole brain, rather than regionally limited, which is consistent with the heterogeneity of its clinical symptoms. Our findings add support to the hypothesis that ME/CFS is the result of chronic, low-level [[neuroinflammation]]. While the whole-brain results are preliminary, we note that they largely agree with past publications that use MRS in ME/CFS. These results should be replicated in future studies with larger samples to further establish the profile of pathophysiological abnormalities in the brains of ME/CFS patients. Ultimately, the development of sensitive MRI markers of ME/CFS could supplement clinical tests to help guide treatment decisions.<ref name="Mueller2019" /></blockquote> Several neurochemicals have been studied in relation to ME patients. Myoinositol 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="Brooks2000">{{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="Albrecht2016">{{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>and has been shown to be lower in ME patients,<ref name="Chaudhuri2003">{{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><ref name="Brooks2000" />but this was not found in all studies.<ref name="Puri2002">{{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="Tomoda2000">{{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="Albrecht2016" />and has been shown to change compared to controls.<ref name="Chaudhuri2003" /><ref name="Brooks2000" /><ref name="Tomoda2000" /><ref name="Puri2009">{{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="Mathew2009">{{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. | author-link8 = 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="Natelson2017elev">{{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="Murrough2010">{{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="Mathew2009" /><ref name="Murrough2010" />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="Natelson2017elev" /> Though contrasts were found between patients with ME and healthy controls in many of these [[Diagnostic biomarker|biomarker]] studies, researchers are not sure what the changes mean.
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