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==ME/CFS == {{Main article|Neurology of ME/CFS}} === Anatomical changes === Significant changes in white and gray matter volumes have frequently been found in patients with ME/CFS but no consistent pattern has been found.<ref name="Shan2016" /><ref name="Goldman20141028">{{Cite journal | last1 = Goldman | first1 = Bruce | author-link1 = | title = Study finds brain abnormalities in chronic fatigue patients | journal = Stanford Medicine News Center | date = 2014-10-28 | url = http://med.stanford.edu/news/all-news/2014/10/study-finds-brain-abnormalities-in-chronic-fatigue-patients.html }}</ref><ref name="Zeineh2014">{{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><ref name="Puri, 2012">{{Cite journal | last1 = Puri | first1 = BK | author-link1 = Basant Puri | last2 = Jakeman | first2 =PM | author-link2 = | last3 = Agour | first3 = M | author-link3 = | last4 = Gunatilake | first4 = KDR | author-link4 = | last5 = Fernando | first5 = KAC | author-link5 = | last6 = Gurusinghe | first6 = AI | author-link6 = | last7 = Treasaden | first7 = IH | author-link7 = | last8 = Waldman | first8 = AD | author-link8 = | last9 = Gishen | first9 = P | author-link9 = | title = Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study | journal = British Journal of Radiology | volume = 85 | issue = 1015 | page = e270-3 | date = 2012 | pmid = | doi = 10.1259/bjr/93889091 }}</ref> {| class="wikitable" !Year !Authors !N !Criteria !Findings !Ref |- |2004 |Okada, et al |16 | |Reduced gray-matter volume in the bilateral prefrontal cortex. Volume reduction in the right prefrontal cortex correlated with fatigue severity. |<ref name="Okada2004">{{Cite journal | last = Okada | first = Tomohisa | last2 = Tanaka | first2 = Masaaki | last3 = Kuratsune | first3 = Hirohiko | last4 = Watanabe | first4 = Yasuyoshi | last5 = Sadato | first5 = Norihiro | date = 2004-10-04 | title = Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome | url =https://doi.org/10.1186/1471-2377-4-14 | journal = BMC Neurology | volume = 4 | issue = 1 | pages = 14|doi=10.1186/1471-2377-4-14|issn=1471-2377|pmc=524491|pmid=15461817}}</ref> |- |2016 |Shan, et al | |Fukuda & CCC |Decreases in [[white matter]], [[gray matter]] and blood volume deficits |<ref name="Shan2016" /> |- |2012 |Basant Puri, et al | | |Reduced grey matter volume in the occipital lobes, the right angular gyrus and the posterior division of the left parahippocampal gyrus. |<ref name="Puri, 2012" /> |- |2014 |Zeineh, et al | | |Diminished white matter, white matter abnormalities in the right hemisphere. |<ref name="Zeineh2014" /> |} === Blood flow === Several studies have ME/CFS patients have found evidence of reduced cerebral blood flow,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995" /><ref name="Barnden2011" /><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref> including the [[brainstem]]<ref name="Costa1995" /><ref name="Barnden2011" /> and cerebral cortex.<ref name="Yoshiuchi2006" /> A 1995 study found hypoperfusion (reduced blood flow) to the brainstem in patients with ME/CFS.<ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref> In 2011, a study of brain involvement in CFS found "a strong correlation" between brainstem gray matter volume and pulse pressure, "suggesting impaired cerebrovascular autoregulation."<ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref> A study of 429 ME/CFS patients by found that 90% ME/CFS patients had reduced cerebral blood flow with a head-up tilt test, even in the absence of [[Postural orthostatic tachycardia syndrome]] or [[Orthostatic hypotension]].<ref>{{Citation | title = CMRC Conference 2017 day 1- Prof Dr Frans Visser |url =https://www.youtube.com/watch?v=IWRA23D_MUg|language=en | access-date = 2019-09-03}}</ref><ref>{{Cite journal | last = van Campen | first = C. (Linda) M.C. | last2 = Verheugt | first2 = Freek W.A. | last3 = Rowe | first3 = Peter C. | last4 = Visser | first4 = Frans C. | date = 2020-01-01 | title = Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography | url = http://www.sciencedirect.com/science/article/pii/S2467981X20300044 | journal = Clinical Neurophysiology Practice|language=en | volume = 5 | pages = 50–58|doi=10.1016/j.cnp.2020.01.003|issn=2467-981X | issue = |pmc=|pmid=|quote= | author-link = Linda van Campen | author-link2 = |access-date= | author-link3 = Peter Rowe | author-link4 = Frans Visser | author-link5 = |via=}}</ref> === Metabolism === A 2003 study of cerebral [[glucose]] metabolism in 26 patients with [[chronic fatigue syndrome]] via 18-fluorodeoxyglucose positron emission tomography (FDG-PET) found evidence of hypometabolism (reduced glucose consumption) in approximately half of patients.<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref> A 1998 PET study also found evidence of reduced metabolism in 18 patients.<ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref> Patients with ME/CFS have also been found to have lower brain glutathione<ref name="Natelson, 2017" /> and higher brain ventricular lactate.<ref name="Natelson, 2017" /> Abnormal distribution of [[Carnitine|acetyl-L-carnitine]] uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex.{{Citation needed|reason=clarify}}<ref name="Okada2004" /> {{See also|Mitochondria dysfunction|||||}} === 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. === Electrical activity === 2016, A qEEG/LORETA study of nine controls and nine CFS patients (per [[DePaul Symptom Questionnaire]] (DSQ) and [[Canadian Consensus Criteria]] (CCC) definitions), found significantly decreased eLORETA source analysis oscillations in the occipital, parietal, posterior cingulate, and posterior temporal lobes in Alpha and Alpha-2. This research suggests that "disruptions in these regions and networks could be a neurobiological feature of the disorder, representing underlying neural dysfunction."<ref name="Zinn2016P2">{{Citation | last1 = Zinn | first1 = Marcie | author-link1 = Marcie Zinn | last2 = Zinn | first2 = Mark| author-link2 = Mark Zinn | last3 = Jason | first3 = Leonard | author-link3 = Leonard Jason | title = Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with Myalgic Encephalomyelitis: A Pilot Study | journal = Applied Psychophysiology and Biofeedback | volume = 41 | issue = 3 | page = 283-300 | date = 2016 | pmid = 26869373 | doi = 10.1007/s10484-016-9331-3 }}</ref> 2016, A qEEG/LORETA study of one CFS patient (per DSQ and CCC definitions), found deregulation of the functional connectivity networks. This may explain the common symptom of perceived cognitive deficits such as [[slowed thought|slow thinking]], difficulty in reading comprehension, reduced learning and [[memory problems|memory abilities]] and an overall feeling of being in a “[[Brain fog|fog]]".<ref name="sciforschenonline" /> [[File:CLROA-2-110-F1.gif|850px|thumb|center|Figure 1: Results of LORETA current source density in a case with CFS showing widespread decreased current density for delta at 2 Hz and beta (12- 15 Hz) demonstrating a global reduction in brain functioning (blue). The higher frequencies (beta) have been shown to be a function of delta frequencies. In other words, local oscillations are under constant influence of global brain dynamics (Buzsaki, 2006).<ref name="sciforschenonline">{{Cite web | url = https://www.sciforschenonline.org/journals/clinical-research/CLROA-2-110.php | title = qEEG / LORETA in Assessment of Neurocognitive Impairment in a Patient with Chronic Fatigue Syndrome: A Case Report | last = Zinn | first = Marcie L | author-link = Marcie Zinn | date = 2016 | website = sciforschenonline.org|archive-url=|archive-date= | access-date = 2018-08-28 | last2 = Zinn | author-link2 = Mark Zinn | first2 = Mark A. | last3 = Jason | first4 = | first3 = Leonard|issn=2469-6714| publisher = SciForschen|doi=10.16966/2469-6714.110}}</ref>|link=https://www.me-pedia.org/wiki/File:CLROA-2-110-F1.gif]] ===T2 Hyperintensities in MRI=== {{bookmark|T2 hyperintensity}} [[File:T2hyperintensitiesVRS.jpg|400px|thumb|MRI image with small white T2 hyperintensities, which are labelled as "Virchow-Robin spaces". Use allowed for educational purposes, courtesy of radiologyassistant.nl]] Possible white matter abnormalities of unknown etiology are found on MRIs of some [[ME/CFS]] patients.<ref name="Shan2016" /><ref name="Natelson1993">{{Cite journal | last = Natelson | first = B.H. | last2 = Cohen | first2 = J.M. | last3 = Brassloff | first3 = I. | last4 = Lee | first4 = H.J. | date = 1993-12-15 | title = A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8138812 | journal = Journal of the Neurological Sciences | volume = 120 | issue = 2 | pages = 213–217|doi=10.1016/0022-510x(93)90276-5|issn=0022-510X|pmid=8138812|pmc=|quote= | author-link = Benjamin Natelson | author-link2 = |access-date=|via=}}</ref><ref name="Lange1999">{{Cite journal | last = Lange | first = G. | last2 = DeLuca | first2 = J. | last3 = Maldjian | first3 = J.A. | last4 = Lee | first4 = H. | last5 = Tiersky | first5 = L.A. |last6 = Natelson | first6 = B.H. | date = 1999-12-01 | title = Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/10567042 | journal = Journal of the Neurological Sciences | volume = 171 | issue = 1 | pages = 3–7|doi=10.1016/s0022-510x(99)00243-9|issn=0022-510X|pmid=10567042}}</ref> White matter abnormalities identified by T2 hyperintensities might indicate lesions or abnormally dilated perivascular spaces (also known as Virchow-Robin spaces).<ref>{{Cite journal | last = Kwee | first = Robert M. | last2 = Kwee | first2 = Thomas C. | date = 2007-07-01 | title = Virchow-Robin Spaces at MR Imaging | url =https://pubs.rsna.org/doi/full/10.1148/rg.274065722 | journal = RadioGraphics | volume = 27 | issue = 4 | pages = 1071–1086|doi=10.1148/rg.274065722|issn=0271-5333}}</ref> * 1993, A comparison of brain MRI scans from 52 CFS patients and 52 controls found that 27% of CFS patients had findings considered abnormal, while only 2% of controls had findings considered abnormal. Abnormalities included T2 hyperintensities and ventricular enlargement.<ref name="Natelson1993" /> * 1999, A comparison of brain MRI scans from 39 CFS patients and 19 controls found that the 21 CFS patients who did not have a psychiatric diagnosis had significantly more T2 hyperintensities, compared to either controls or the 18 CFS patients with a psychiatric diagnosis.<ref name="Lange1999" /> Since T2 hyperintensities are found in many different [[:Category:Neurological diseases and disorders|neurological conditions]], some neurologists consider them to be diagnostically insignificant. Others point out that perhaps they should not be ignored, as they are correlated with cognitive disability and poor motor function.<ref>{{Cite journal | last = Jeong | first = Eun Hye | last2 = Lee | first2 = Yong Joo | last3 = Kim | first3 = Sang Joon | last4 = Lee | first4 = Jae-Hong | date = 2015 | title = Is the Severity of Dilated Virchow-Robin Spaces Associated with Cognitive Dysfunction? | url = http://dx.doi.org/10.12779/dnd.2015.14.3.114 | journal = Dementia and Neurocognitive Disorders | volume = 14 | issue = 3 | pages = 114|doi=10.12779/dnd.2015.14.3.114|issn=1738-1495}}</ref><ref>{{Cite journal | last = Sachdev | first = P.S. | last2 = Wen | first2 = W. | last3 = Christensen | first3 = H. | last4 = Jorm | first4 = A.F. | date = 2005-03-01 | title = White matter hyperintensities are related to physical disability and poor motor function | url =https://jnnp.bmj.com/content/76/3/362 | journal = Journal of Neurology, Neurosurgery & Psychiatry|language=en | volume = 76 | issue = 3 | pages = 362–367|doi=10.1136/jnnp.2004.042945|issn=0022-3050|pmid=15716527}}</ref><ref>{{Cite journal | last = Paradise | first = Matthew | last2 = Crawford | first2 = John D. | last3 = Lam | first3 = Ben C.P. | last4 = Wen | first4 = Wei | last5 = Kochan | first5 = Nicole A. | last6 = Makkar | first6 = Steve | last7 = Dawes | first7 = Laughlin | last8 = Trollor | first8 = Julian | last9 = Draper | first9 = Brian | date = 2021-01-27 | title = The Association of Dilated Perivascular Spaces with Cognitive Decline and Incident Dementia | url = https://n.neurology.org/content/early/2021/01/27/WNL.0000000000011537 | journal = Neurology|language=en|doi=10.1212/WNL.0000000000011537|issn=0028-3878|pmid=33504642}}</ref>
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