Fatigue

==Mechanisms==

The mechanisms that cause fatigue are not well understood.<ref name="pmid31447842"/> Several mechanisms may be in operation within a patient,<ref name="pmid31682277">{{Cite journal|title=Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms|first1=S Mechiel|last1=Korte|first2=Rainer H|last2=Straub|date=November 15, 2019|journal=Rheumatology|volume=58|issue=Suppl 5|pages=v35–v50|doi=10.1093/rheumatology/kez413|pmid=31682277|pmc=6827268}}</ref> with the relative contribution of each mechanism differing over time.<ref name="pmid34599320" />

Some mechanisms proposed as active in fatigue are inflammation, heat shock proteins and reduced brain connectivity.

=== Inflammation ===
Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks,<ref>{{cite journal |last1=Korte |first1=S Mechiel |last2=Straub |first2=Rainer H |title=Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms |journal=Rheumatology |date=November 2019 |volume=58 |issue=Suppl 5 |pages=v35–v50 |doi=10.1093/rheumatology/kez413 |pmid=31682277 |pmc=6827268 }}</ref> and has been linked to many types of fatigue.<ref name="pmid31447842"/><ref>{{cite journal |last1=Omdal |first1=Roald |title=The biological basis of chronic fatigue: neuroinflammation and innate immunity |journal=Current Opinion in Neurology |date=June 2020 |volume=33 |issue=3 |pages=391–396 |doi=10.1097/WCO.0000000000000817 |pmid=32304437 |s2cid=215819309 }}</ref> Findings implicate [[neuroinflammation]] in the [[etiology]] of fatigue in [[Autoimmunity|autoimmune]] and related disorders.<ref name="pmid34599320"/><ref name="pmid31447842"/> Low-grade inflammation may cause an imbalance between energy availability and expenditure.<ref>{{cite journal | pmc=5932180 | year=2018 | last1=Lacourt | first1=T. E. | last2=Vichaya | first2=E. G. | last3=Chiu | first3=G. S. | last4=Dantzer | first4=R. | last5=Heijnen | first5=C. J. | title=The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure | journal=Frontiers in Behavioral Neuroscience | volume=12 | page=78 | doi=10.3389/fnbeh.2018.00078 | pmid=29755330 | doi-access=free }}</ref>

[[Cytokines]] are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue.<ref>{{cite journal | doi=10.3389/fimmu.2017.00021 | doi-access=free | title=Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms | year=2017 | last1=Karshikoff | first1=Bianka | last2=Sundelin | first2=Tina | last3=Lasselin | first3=Julie | journal=Frontiers in Immunology | volume=8 | page=21 | pmid=28163706 | pmc=5247454 }}</ref><ref name="Tarn Evans Traianos et al 2023"/> However a 2019 review was inconclusive as to whether cytokines play any definitive role in [[ME/CFS]].<ref>{{Cite journal|title=A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)|first1=Matthew|last1=Corbitt|first2=Natalie|last2=Eaton-Fitch|first3=Donald|last3=Staines|first4=Hélène|last4=Cabanas|first5=Sonya|last5=Marshall-Gradisnik|date=August 24, 2019|journal=BMC Neurology|volume=19|issue=1|pages=207|doi=10.1186/s12883-019-1433-0|doi-access=free |pmid=31445522|pmc=6708220}}</ref>

The inflammation model may have difficulty in explaining the "unpredictability" and "variability" (i.e. appearing intermittently during the day, and not on all days) of the fatigue associated with inflammatory rheumatic diseases and autoimmune diseases (such as [[multiple sclerosis]]).<ref name="pmid34599320"/>

=== Heat shock proteins ===
A small 2016 study found that primary [[Sjögren's syndrome]] patients with high fatigue, when compared with those with low fatigue, had significantly higher plasma concentrations of [[Hsp90|HSP90α]], and a tendency to higher concentrations of HSP72.<ref>{{cite journal | pmc=4804286 | year=2016 | last1=Bårdsen | first1=K. | last2=Nilsen | first2=M. M. | last3=Kvaløy | first3=J. T. | last4=Norheim | first4=K. B. | last5=Jonsson | first5=G. | last6=Omdal | first6=R. | title=Heat shock proteins and chronic fatigue in primary Sjögren's syndrome | journal=Innate Immunity | volume=22 | issue=3 | pages=162–167 | doi=10.1177/1753425916633236 | pmid=26921255 }}</ref> A small 2020 study of Crohn's disease patients found that higher fatigue visual analogue scale (fVAS) scores correlated with hgher HSP90α levels.<ref name="pmid31601148">{{cite journal |last1=Grimstad |first1=Tore |last2=Kvivik |first2=Ingeborg |last3=Kvaløy |first3=Jan Terje |last4=Aabakken |first4=Lars |last5=Omdal |first5=Roald |title=Heat-shock protein 90 α in plasma reflects severity of fatigue in patients with Crohn's disease |journal=Innate Immunity |date=February 2020 |volume=26 |issue=2 |pages=146–151 |doi=10.1177/1753425919879988 |pmid=31601148 |pmc=7016405 }}</ref> A related small 2012 trial investigating if application of an IL-1 receptor antagonist ([[anakinra]]) would reduce fatigue in primary Sjögren's syndrome patients was inconclusive.<ref>{{cite journal |last1=Norheim |first1=Katrine Brække |last2=Harboe |first2=Erna |last3=Gøransson |first3=Lasse G. |last4=Omdal |first4=Roald |title=Interleukin-1 Inhibition and Fatigue in Primary Sjögren's Syndrome – A Double Blind, Randomised Clinical Trial |journal=PLOS ONE |date=10 January 2012 |volume=7 |issue=1 |pages=e30123 |doi=10.1371/journal.pone.0030123 |doi-access=free |pmid=22253903 |pmc=3254637 |bibcode=2012PLoSO...730123N }}</ref><ref>{{cite journal |last1=Omdal |first1=Roald |last2=Gunnarsson |first2=Ragnar |title=The effect of interleukin-1 blockade on fatigue in rheumatoid arthritis—a pilot study |journal=Rheumatology International |date=September 2005 |volume=25 |issue=6 |pages=481–484 |doi=10.1007/s00296-004-0463-z |pmid=15071755 }}</ref><ref>{{cite journal |last1=Skoie |first1=Inger Marie |last2=Bårdsen |first2=Kjetil |last3=Nilsen |first3=Mari M. |last4=Eidem |first4=Live E. |last5=Grimstad |first5=Tore |last6=Dalen |first6=Ingvild |last7=Omdal |first7=Roald |title=Fatigue and expression of heat-shock protein genes in plaque psoriasis |journal=Clinical and Experimental Dermatology |date=June 2022 |volume=47 |issue=6 |pages=1068–1077 |doi=10.1111/ced.15068 |pmid=34921435 }}</ref>

=== Reduced brain connectivity ===
Fatigue has been correlated with reductions in structural and functional connectivity in the brain.<ref name="Qi-2019">{{Cite journal|title=Neural Mechanisms of Mental Fatigue Revisited: New Insights from the Brain Connectome|first1=Peng|last1=Qi|first2=Hua|last2=Ru|first3=Lingyun|last3=Gao|first4=Xiaobing|last4=Zhang|first5=Tianshu|last5=Zhou|first6=Yu|last6=Tian|first7=Nitish|last7=Thakor|first8=Anastasios|last8=Bezerianos|first9=Jinsong|last9=Li|first10=Yu|last10=Sun|date=April 1, 2019|journal=Engineering|volume=5|issue=2|pages=276–286|doi=10.1016/j.eng.2018.11.025|doi-access=free|bibcode=2019Engin...5..276Q }}</ref> This has included in post-stroke,<ref>{{Cite journal|title=Disruptions in Structural and Functional Connectivity Relate to Poststroke Fatigue|first1=Judith D.|last1=Schaechter|first2=Minhae|last2=Kim|first3=Baileigh G.|last3=Hightower|first4=Trevor|last4=Ragas|first5=Marco L.|last5=Loggia|date=February 28, 2023|journal=Brain Connectivity|volume=13|issue=1|pages=15–27|doi=10.1089/brain.2022.0021|pmid=35570655|pmc=9942175}}</ref> MS,<ref>{{Cite journal|title=Regional Brain Atrophy and Functional Connectivity Changes Related to Fatigue in Multiple Sclerosis|first1=Álvaro Javier|last1=Cruz Gómez|first2=Noelia|last2=Ventura Campos|first3=Antonio|last3=Belenguer|first4=César|last4=Ávila|first5=Cristina|last5=Forn|date=October 22, 2013|journal=PLOS ONE|volume=8|issue=10|pages=e77914|doi=10.1371/journal.pone.0077914|doi-access=free |pmid=24167590|pmc=3805520|bibcode=2013PLoSO...877914C }}</ref> NMOSD and MOG,<ref name="pmid37180990"/> and ME/CFS.<ref>{{Cite journal|title=Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses|first1=Charles W.|last1=Gay|first2=Michael E.|last2=Robinson|first3=Song|last3=Lai|first4=Andrew|last4=O'Shea|first5=Jason G.|last5=Craggs|first6=Donald D.|last6=Price|first7=Roland|last7=Staud|date=February 1, 2016|journal=Brain Connectivity|volume=6|issue=1|pages=48–56|doi=10.1089/brain.2015.0366|pmid=26449441|pmc=4744887}}</ref> This was also found for fatigue after brain injury,<ref name="pmid35221951">{{Cite journal|title=Cingulo-Opercular and Frontoparietal Network Control of Effort and Fatigue in Mild Traumatic Brain Injury|first1=Amy E.|last1=Ramage|first2=Kimberly L.|last2=Ray|first3=Hannah M.|last3=Franz|first4=David F.|last4=Tate|first5=Jeffrey D.|last5=Lewis|first6=Donald A.|last6=Robin|date=January 30, 2021|journal=Frontiers in Human Neuroscience|volume=15|doi=10.3389/fnhum.2021.788091|doi-access=free |pmid=35221951|pmc=8866657 }}</ref> including a significant linear correlation between self-reported fatigue and brain functional connectivity.<ref name="pmid26878885">{{Cite journal|title=Post mTBI fatigue is associated with abnormal brain functional connectivity|first1=Love Engström|last1=Nordin|first2=Marika Christina|last2=Möller|first3=Per|last3=Julin|first4=Aniko|last4=Bartfai|first5=Farouk|last5=Hashim|first6=Tie-Qiang|last6=Li|date=February 16, 2016|journal=Scientific Reports|volume=6|issue=1|page=21183|doi=10.1038/srep21183|pmid=26878885 |pmc=4754765 |bibcode=2016NatSR...621183N }}</ref>

Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex,<ref name="pmid26878885" /> fronto-parietal and cingulo-opercular,<ref name="pmid35221951" />  and default mode network, salience network, and thalamocortical loop areas.<ref name="Qi-2019" /><ref>{{cite journal |last1=Borghetti |first1=Lorraine |last2=Rhodes |first2=L. Jack |last3=Morris |first3=Megan B. |title=Fatigue Leads to Dynamic Shift in Fronto-parietal Sustained Attention Network |journal=Proceedings of the Human Factors and Ergonomics Society Annual Meeting |date=September 2022 |volume=66 |issue=1 |pages=606–610 |doi=10.1177/1071181322661056 |s2cid=253205546 }}</ref>