Neuroinflammation is a term used to describe activation of the resident immune cells in the central nervous system (CNS). 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.
The immune cells activated in neuroinflammation are the tissue-resident macrophages of the CNS, which, for historical reasons, are called microglia. Like other macrophages, microglia fight infections and repair tissue damage. 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 cytokines to attract help from blood-borne immune cells.
- 1 Diseases associated with neuroinflammation
- 2 Causes
- 3 Possible neurological biomarkers of ME
- 4 Notable studies
- 5 Talks and interviews
- 6 See also
- 7 Learn more
- 8 References
Diseases associated with neuroinflammation[edit | edit source]
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, and changes in the neurochemicals produced by the brain. These effects also occur in ME which is why researchers are searching to more strongly show neuroinflammation in these patients.
Causes[edit | edit source]
Microglia activation[edit | edit source]
The blood brain barrier (BBB), a membrane that separates the brain from the rest of the body, may become compromised in ME patients. If there are cytokines circulating in the bloodstream, they may get into the brain through opened sections of the BBB. 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 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.
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.
Oxidative and nitrosative stress[edit | edit source]
The oxidative and nitrosative stress pathway or O&NS pathway results in tissue damage which could lead to neuroimflammation in ME/CFS.
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/ and the breakdown of the oxidative and nitrosative stress pathway.
Activation of cyclical neuroinflammation: A self-perpetuating cycle[edit | edit source]
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. 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. In this attempt, a chemical called damage-associated molecular patterns (DAMPs) triggers the release of more inflammatory molecules, some of which activate the TLRs (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.
Possible neurological biomarkers of ME[edit | edit source]
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.
N-acetylacetate (NAA) shows neuron density, which has been found in other neurological disorders and has been shown to be lower in ME patients, but this was not found in all studies.
Lactate increases when more energy is being expended and has been shown to be higher than controls, and significantly differs from lactate levels in people with psychological disorders. 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.
Though contrasts were found between ME people and controls in many of these 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[edit | edit source]
- 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 - (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 - (Abstract)
- 2010, Autopsies of four deceased ME patients showed various pathological phenomena in the CNS and peripheral nervous systems.
- 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.
- 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.
- 2019, Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy
Talks and interviews[edit | edit source]
- 2016, What is neuroinflammation?
- 2016, Do you have a hot brain?
- 2017, Brain on Fire with Dr. Mary Ackerley, MD
- 2017, Brain on Fire Webinar - Brain Changes in Mold Illness with Dr. Mary Ackerley
- 2018, ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study
See also[edit | edit source]
Learn more[edit | edit source]
- Mary Ackerley, MD
- 2014, Brain on Fire - The Role of Toxic Mold in Triggering Psychiatric Symptoms
- 2016, Schizophrenia risk from complex variation of complement component 4
- 2016, Reversal of cognitive decline in Alzheimer’s disease
- 2017, Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study
- 2018, Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS)
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 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 muscles during exercise.
References[edit | edit source]
- Aguzzi, Adriano; Barres, Ben A.; Bennett, Mariko L. (Jan 11, 2013). "Microglia: Scapegoat, Saboteur, or Something Else?". Science (New York, N.Y.). 339 (6116): 156–161. doi:10.1126/science.1227901. ISSN 0036-8075. PMC . PMID 23307732.
- Mrak, Robert E.; Griffin, W. Sue T. (Apr 20, 2004). "Welcome to the Journal of Neuroinflammation!". Journal of Neuroinflammation. 1 (1): 1. doi:10.1186/1742-2094-1-1. ISSN 1742-2094. PMC . PMID 15285806.
- Graeber, Manuel B.; Li, Wei; Rodriguez, Michael L. (Dec 1, 2011). "Role of microglia in CNS inflammation". FEBS letters. 585 (23): 3798–3805. doi:10.1016/j.febslet.2011.08.033. ISSN 1873-3468. PMID 21889505.
- Ginhoux, Florent; Greter, Melanie; Leboeuf, Marylene; Nandi, Sayan; See, Peter; Gokhan, Solen; Mehler, Mark F.; Conway, Simon J.; Ng, Lai Guan (Nov 5, 2010). "Fate mapping analysis reveals that adult microglia derive from primitive macrophages". Science (New York, N.Y.). 330 (6005): 841–845. doi:10.1126/science.1194637. ISSN 1095-9203. PMC . PMID 20966214.
- DiSabato, Damon J.; Quan, Ning; Godbout, Jonathan P. (Oct 2016). "Neuroinflammation: the devil is in the details". Journal of Neurochemistry. 139 Suppl 2: 136–153. doi:10.1111/jnc.13607. ISSN 1471-4159. PMC . PMID 26990767.
- Chen, Wei-Wei; Zhang, Xia; Huang, Wen-Juan (Apr 2016). "Role of neuroinflammation in neurodegenerative diseases (Review)". Molecular Medicine Reports. 13 (4): 3391–3396. doi:10.3892/mmr.2016.4948. ISSN 1791-2997. PMC . PMID 26935478.
- Albrecht, Daniel S.; Granziera, Cristina; Hooker, Jacob M.; Loggia, Marco L. (Apr 20, 2016). "In Vivo Imaging of Human Neuroinflammation". ACS chemical neuroscience. 7 (4): 470–483. doi:10.1021/acschemneuro.6b00056. ISSN 1948-7193. PMC . PMID 26985861.
- Morris, Gerwyn; Maes, Michael (Dec 2013). "A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome". Metabolic Brain Disease. 28 (4): 523–540. doi:10.1007/s11011-012-9324-8. ISSN 1573-7365. PMID 22718491.
- Nakatomi, Yasuhito; Mizuno, Kei; Ishii, Akira; Wada, Yasuhiro; Tanaka, Masaaki; Tazawa, Shusaku; Onoe, Kayo; Fukuda, Sanae; Kawabe, Joji (Jun 2014). "Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study". Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 55 (6): 945–950. doi:10.2967/jnumed.113.131045. ISSN 1535-5667. PMID 24665088.
- Pietrangelo, Tiziana; Fulle, Stefania; Coscia, Francesco; Gigliotti, Paola Virginia; Fanò-Illic, Giorgio (Sep 7, 2018). "Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome". European Journal of Translational Myology. 28 (3). doi:10.4081/ejtm.2018.7688. ISSN 2037-7460.
- Gárate, Iciar; Garcia-Bueno, Borja; Madrigal, Jose Luis Muñoz; Caso, Javier Rubén; Alou, Luis; Gomez-Lus, Marisa L.; Micó, Juan Antonio; Leza, Juan Carlos (Jan 1, 2013). "Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway". Biological Psychiatry. 73 (1): 32–43. doi:10.1016/j.biopsych.2012.07.005. ISSN 1873-2402. PMID 22906518.
- Liu, JiaJun; Buisman-Pijlman, Femke; Hutchinson, Mark R. (2014). "Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder". Frontiers in Neuroscience. 8: 309. doi:10.3389/fnins.2014.00309. ISSN 1662-4548. PMC . PMID 25324715.
- Morris, Gerwyn; Berk, Michael; Walder, Ken; Maes, Michael (Feb 6, 2015). "Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses". BMC Medicine. 13 (1). doi:10.1186/s12916-014-0259-2. ISSN 1741-7015. PMC . PMID 25856766.
- Chaudhuri, A.; Condon, B. R.; Gow, J. W.; Brennan, D.; Hadley, D. M. (Feb 10, 2003). "Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome". Neuroreport. 14 (2): 225–228. doi:10.1097/01.wnr.0000054960.21656.64. ISSN 0959-4965. PMID 12598734.
- Brooks, J. C.; Roberts, N.; Whitehouse, G.; Majeed, T. (Nov 2000). "Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome". The British Journal of Radiology. 73 (875): 1206–1208. doi:10.1259/bjr.73.875.11144799. ISSN 0007-1285. PMID 11144799.
- Puri, B. K.; Counsell, S. J.; Zaman, R.; Main, J.; Collins, A. G.; Hajnal, J. V.; Davey, N. J. (Nov 2002). "Relative increase in choline in the occipital cortex in chronic fatigue syndrome". Acta Psychiatrica Scandinavica. 106 (3): 224–226. ISSN 0001-690X. PMID 12197861.
- Tomoda, A.; Miike, T.; Yamada, E.; Honda, H.; Moroi, T.; Ogawa, M.; Ohtani, Y.; Morishita, S. (Jan 2000). "Chronic fatigue syndrome in childhood". Brain & Development. 22 (1): 60–64. ISSN 0387-7604. PMID 10761837.
- Puri, B. K.; Agour, M.; Gunatilake, K. D. R.; Fernando, K. a. C.; Gurusinghe, A. I.; Treasaden, I. H. (Nov 2009). "An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome)". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 81 (5-6): 303–305. doi:10.1016/j.plefa.2009.10.002. ISSN 1532-2823. PMID 19906518.
- Mathew, Sanjay J.; Mao, Xiangling; Keegan, Kathryn A.; Levine, Susan M.; Smith, Eric L. P.; Heier, Linda A.; Otcheretko, Viktor; Coplan, Jeremy D.; Shungu, Dikoma C. (Apr 2009). "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". NMR in biomedicine. 22 (3): 251–258. doi:10.1002/nbm.1315. ISSN 0952-3480. PMID 18942064.
- Shungu, Dikoma C.; Weiduschat, Nora; Murrough, James W.; Mao, Xiangling; Pillemer, Sarah; Dyke, Jonathan P.; Medow, Marvin S.; Natelson, Benjamin H.; Stewart, Julian M. (Sep 2012). "Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology". NMR in biomedicine. 25 (9): 1073–1087. doi:10.1002/nbm.2772. ISSN 1099-1492. PMC . PMID 22281935.
- Natelson, Benjamin H.; Vu, Diana; Coplan, Jeremy D.; Mao, Xiangling; Blate, Michelle; Kang, Guoxin; Soto, Eli; Kapusuz, Tolga; Shungu, Dikoma C. (2017). "Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia". Fatigue: Biomedicine, Health & Behavior. 5 (1): 15–20. doi:10.1080/21641846.2017.1280114. ISSN 2164-1846. PMC . PMID 29308330.
- Murrough, James W.; Mao, Xiangling; Collins, Katherine A.; Kelly, Chris; Andrade, Gizely; Nestadt, Paul; Levine, Susan M.; Mathew, Sanjay J.; Shungu, Dikoma C. (Jul 2010). "Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder". NMR in biomedicine. 23 (6): 643–650. doi:10.1002/nbm.1512. ISSN 1099-1492. PMID 20661876.
- Twisk, Frank; Maes, Michael (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" (PDF). BMC Medicine. 8 (35).
- Maes, Michael; Twisk, Frank N.M.; Kubera, Marta; Ringel, Karl; Leunis, Jean-Claude; Geffard, Michel (Feb 2012). "Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome". Journal of Affective Disorders. 136 (3): 909–917. doi:10.1016/j.jad.2011.09.010.
- "Pathology of ME/CFS: pilot study of four autopsy reports". www.meassociation.org.uk. Jan 2011. Retrieved Aug 10, 2018.
- Tuller, David (Nov 24, 2014). "Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder". Well. Retrieved Aug 10, 2018.
- Zeineh, Michael M.; Kang, James; Atlas, Scott W.; Raman, Mira M.; Reiss, Allan L.; Norris, Jane L.; Valencia, Ian; Montoya, Jose G. (2015). "Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome". Radiology. 274 (2): 517–526. doi:10.1148/radiol.14141079. ISSN 0033-8419.
- "Study finds brain abnormalities in chronic fatigue patients". News Center. Oct 28, 2014. Retrieved Sep 22, 2018.
- Nakatomi, Yasuhito; Mizuno, Kei; Ishii, Akira; et al. (Mar 24, 2014), "Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study", Journal of Nuclear Medicine, 2014 Jun;55(6): 945-50, doi:10.2967/jnumed.113.131045, PMID 24665088
- Tuller, David (Nov 24, 2014), "Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder", NY Times
- Younger, Jarred (Apr 4, 2016). "What is neuroinflammation?". YouTube – via Younger Lab.
- Younger, Jarred (Apr 25, 2016). "Do you have a hot brain?". YouTube – via Younger Lab.
- "ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study". YouTube. SolveCFS. Dec 14, 2018.
- Sekar, Aswin; Bialas, Allison R.; de Rivera, Heather; Davis, Avery; Hammond, Timothy R.; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matthew (Feb 11, 2016). "Schizophrenia risk from complex variation of complement component 4". Nature. 530 (7589): 177–183. doi:10.1038/nature16549. ISSN 1476-4687. PMC . PMID 26814963.
- Bredesen, Dale E.; Amos, Edwin C.; Canick, Jonathan; Ackerley, Mary; Raji, Cyrus; Fiala, Milan; Ahdidan, Jamila (Jun 2016). "Reversal of cognitive decline in Alzheimer's disease". Aging. 8 (6): 1250–1258. doi:10.18632/aging.100981. ISSN 1945-4589. PMC . PMID 27294343.
- Holmes, Sophie E.; Hinz, Rainer; Conen, Silke; Gregory, Catherine J.; Matthews, Julian C.; Anton-Rodriguez, Jose M.; Gerhard, Alexander; Talbot, Peter S. (Jan 1, 2018). "Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study". Biological Psychiatry. 83 (1): 61–69. doi:10.1016/j.biopsych.2017.08.005. ISSN 1873-2402. PMID 28939116.
- Johnson, Cort (Sep 24, 2018). "Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS) - Health Rising". Health Rising. Retrieved Sep 26, 2018.
central nervous system (CNS) - One of the two parts of the human nervous system, the other part being the peripheral nervous system. The central nervous system consists of the brain and spinal cord, while the peripheral nervous system consists of nerves that travel from the central nervous system into the various organs and tissues of the body.
myalgic encephalomyelitis (ME) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.
systemic exertion intolerance disease (SEID) - A term for ME/CFS that aims to avoid the stigma associated with the term "chronic fatigue syndrome", while emphasizing the defining characteristic of post-exertional malaise (PEM). SEID was defined as part of the diagnostic criteria put together by the Institute of Medicine (IOM) report of 10 February 2015.
metabolite - A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.
chronic fatigue syndrome (CFS) - A controversial term, invented by the U.S. Centers for Disease Control, that generally refers to a collection of symptoms as “fatigue”. There have been multiple attempts to come up with a set of diagnostic criteria to define this term, but few of those diagnostic criteria are currently in use. Previous attempts to define this term include the Fukuda criteria and the Oxford criteria. Some view the term as a useful diagnostic category for people with long-term fatigue of unexplained origin. Others view the term as a derogatory term borne out of animus towards patients. Some view the term as a synonym of myalgic encephalomyelitis, while others view myalgic encephalomyelitis as a distinct disease.