Cited by 112Fibromyalgia and Chronic Fatigue Syndrome ResearchSleep and Wakefulness ResearchSleep and Work-Related Fatigue

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Neurobiological studies of fatigue

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Harrington, Mary E.·2012·Progress in Neurobiology

DOI 10.1016/j.pneurobio.2012.07.004PMC PMC3479364

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Abstract

Fatigue is a symptom associated with many disorders, is especially common in women and in older adults, and can have a huge negative influence on quality of life. Although most past research on fatigue uses human subjects instead of animal models, the use of appropriate animal models has recently begun to advance our understanding of the neurobiology of fatigue. In this review, results from animal models using immunological, developmental, or physical approaches to study fatigue are described and compared. Common across these animal models is that fatigue arises when a stimulus induces activation of microglia and/or increased cytokines and chemokines in the brain. Neurobiological studies implicate structures in the ascending arousal system, sleep executive control areas, and areas important in reward. In addition, the suprachiasmatic nucleus clearly plays an important role in homeostatic regulation of the neural network mediating fatigue. This nucleus responds to cytokines, shows decreased amplitude firing rate output in models of fatigue, and responds to exercise, one of our few treatments for fatigue. This is a young field but very important as the symptom of fatigue is common across many disorders and we do not have effective treatments.

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Sulis, W. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.614982 · Cited by 12
“DSM symptoms linked to these NCRS include: psychomotor retardation [shown to be regulated mostly by dopaminergic systems (25), modulated by mu-opioid and deltaopioid receptor systems], fatigue [linked to serotonin systems (26) which are linked to depression (29–31) and to endurance (26, 31)], impulsivity [linked to in…”
Background
The relationship between fatigue, sleep quality, and sleep deprivation
Ayas, F. Y., & Özcebe, L. H. (2025) · Sleep And Breathing · doi:10.1007/s11325-024-03231-w · Cited by 13
“In light of these interconnections, it is essential to distinguish between fatigue and DTS, as their treatment options are specific to each condition [11, 12].”
Shenling Baizhu San alleviates central fatigue through SIRT1-PGC-1α-Mediated mitochondrial biogenesis
Wang, R., Liu, Y., Jiang, Y., Zhang, Y., Zhang, Y., Wang, B., Lu, H., Su, H., Li, F., Liu, L., et al. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.119110 · Cited by 13
Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder
Freeman, M. P., D, M. F. M., Gommoll, C., Chen, C., Greenberg, W. M., & Ruth, A. (2015) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000104 · Cited by 12
“Neuroimaging studies in patients with disease-related fatigue have shown atrophy or other damage in the striatum and cortex (Harrington, 2012).”
Background
An Explorative Investigation of the Effect of Naturalistic Light on Agitation-Associated Behavior in Nursing Home Residents With Dementia: A Pilot Study
Saidane, H. A., Rasmussen, T., Andersen, K. D., Iversen, H. K., & West, A. S. (2022) · HERD Health Environments Research & Design Journal · doi:10.1177/19375867221146154 · Cited by 9
“…function of SCN is therefore to increase wakefulness and cognitive function during the active period and increase sleep during the inactive period (Harrington, 2012), which may explain the effect that light has in this study and other studies mentioned above, especially in people where cognitive…”
BackgroundResult
Pain in the Elderly
Fillingim, R. B., Turk, D. C., & Yezierski, R. P. (2015) · Springer eBooks · doi:10.1007/978-3-319-23246-1_18 · Cited by 9
Exploring cariprazine as a treatment option for varied depression symptom clusters
Pejušković, B., Munjiza, A., & Pešić, D. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1442699 · Cited by 9
“Neurobiological studies have identi ﬁ ed several key structures involved in the neural network regulation of fatigue, including the ascending arousal system, sleep executive control areas, reward-related regions, and the suprachiasmatic nucleus (73).”
Background
Fatigue in neurological disorders: a review of self-regulation and mindfulness-based interventions
Immink, M. A. (2014) · Fatigue Biomedicine Health & Behavior · doi:10.1080/21641846.2014.957042 · Cited by 9
“”[19]Most clinical assessments of fatigue are based on self-report scales of which there are over 250 for fatigue.[20] These scales vary considerably in terms of the construct of fatigue (e.”
Background
Behavioral alterations, brain oxidative stress, and elevated levels of corticosterone associated with a pressure injury model in male mice
de Aquino, G. Â., de Sousa, C. N. S., Medeiros, I. D. S., de Almeida, J. C., Filho, F. M. S. C., Júnior, M. A. S., & Vasconcelos, S. M. M. (2021) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2021-0056 · Cited by 7
Elevated preoptic brain activity in zebrafish glial glycine transporter mutants is linked to lethargy-like behaviors and delayed emergence from anesthesia
Venincasa, M. J., Randlett, O., Sumathipala, S. H., Bindernagel, R. G., Stark, M. J., Yan, Q., Sloan, S. A., Buglo, E., Meng, Q. C., Engert, F., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-82342-w · Cited by 6
Network Control Mechanisms
Faingold, C. L. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-415804-7.00007-1 · Cited by 7
Sleep fragmentation intensifies sleep architecture disruption and fatigue after traumatic brain injury
Cotter, C., Tapp, Z. M., Ren, C., Houle, S., Mitsch, J., Sheridan, J. F., Godbout, J. P., Peng, J., Ingiosi, A. M., & Kokiko‐Cochran, O. N. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115544 · Cited by 6
“An unmotivated decrease in cage activity with no change in wakefulness further reflects key aspects of fatigue (Harrington, 2012).”
EFFECTS OF GC-MACROPHAGE ACTIVATING FACTOR IN HUMAN NEURONS; IMPLICATIONS FOR TREATMENT OF CHRONIC FATIGUE SYNDROME
Smith (2013) · American Journal of Immunology · doi:10.3844/ajisp.2013.120.129 · Cited by 6
“3 were obtained in serum-free medium, thus ruling out the effects of possible confounding factors present in serum (Inui et al., 2013).”
Background
Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson’s disease
Dekundy, A., Mela, F., Hofmann, M. C. J., & Danysz, W. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1326-8 · Cited by 6
“Currently there are no accepted animal models of PDrelated fatigue available (Harrington 2012).”
BackgroundInfluential
Induction Murine Models of Chronic Fatigue Syndrome byBrucella abortusAntigen Injections: Is Anemia Induced or Not?
Moriya, J., He, Q., Uenishi, H., Akazawa, S., Yamakawa, J.-I., Kobayashi, J., & Ishigaki, Y. (2015) · BioMed Research International · doi:10.1155/2015/191489 · Cited by 5
“Most studies used the immunologically induced fatigue [8].”
Background
Transforming fatigue assessment: Smartphone-based system with digitized motor skill tests
Valla, E., Toose, A.-J., Nõmm, S., & Toomela, A. (2023) · International Journal of Medical Informatics · doi:10.1016/j.ijmedinf.2023.105152 · Cited by 6
Chronic Fatigue Syndrome (CFS) or “Systemic Immune Disorder” (SID)?
Comhaire, F. H., & Devriendt, G. (2016) · Internal Medicine Open Access · doi:10.4172/2165-8048.1000225 · Cited by 5
“Neuro-inflammation [65] and oxidative overload severely disturb cerebral function [66].”
Background
Exercise and retinal health
Li, H., Rong, S.-S., Hong, X., Guo, R., Yang, F., Liang, Y., Li, A., & So, K. (2019) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-190945 · Cited by 5
“The activation of microglia is associated with mis-cellaneous CNS disorders, including CNS-derived fatigue (Harrington, 2012), AD (Lu et al., 2017a), PD (Joers, Tansey, Mulas, & Carta, 2017) and multiple sclerosis (Xu, He, & Bai, 2016).”
Fatigue and perceived energy in a sample of older adults over 10 years: A resting state functional connectivity study of neural correlates
Hengenius, J. B., Ehrenkranz, R. C., Zhu, X., Glynn, N. W., Huppert, T. J., & Rosano, C. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112388 · Cited by 4
“However, this evidence is mostly in animal models (Harrington, 2012), young adults (Marcora, 2016), or neurological patients (Chaudhuri and Behan, 2000; Kluger et al., 2016; Barbi et al., 2022).”
Differential Co-Occurring Patterns Between Depressive Symptomatology and Sleep-Wake-Related Disturbances in Mood Disorders
Chen, S.-Y., Chen, C., Lo, C., Lu, M., Hsu, C.-D., Chiu, Y.-H., Chen, C.-H., Lin, S., Huang, M., Chen, H., et al. (2021) · Nature and Science of Sleep · doi:10.2147/nss.s301357 · Cited by 4
Opiate Action on Sleep and Breathing
Lydic, R., Keifer, J. C., Baghdoyan, H. A., Craft, R. M., & Angel, C. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-24288-2.00024-6 · Cited by 4
Paclitaxel Chemotherapy Disrupts Circadian Gene Transcription and Function of the Suprachiasmatic Nuclei in Female Mice
Tapp, Z. M., Seng, M. M., Ghosh, A. K., Obrietan, K. H., & Pyter, L. M. (2025) · eNeuro · doi:10.1523/eneuro.0061-25.2025 · Cited by 3
“Alternatively, chemotherapy and circadian challenges may be contradictory drivers of fatigue, differentially affecting elements of fatigue behavior such as motivation, muscle exhaustion, or sleep disturbances (Harrington, 2012).”
Neural and computational mechanisms of effort under the pressure of a deadline
Pisauro, M. A., Pollicino, D., Fisher, L., & Apps, M. A. J. (2026) · Nature Communications · doi:10.1038/s41467-026-75987-6 · Cited by 3
“However,whilethereis evidence thatanimals can change theirpreferences for how willing they are to exert effort over time 2,23 – 25 , and people self-report liking more the result of effortful behaviours 22,26 , there is little empirical study of how people make decisions to exert effort when it…”
A novel mutation in Slc2a4 as a mouse model of fatigue
de Groot, M. H. M., Castorena, C. M., Cox, K. H., Kumar, V., Mohawk, J. A., Ahmed, N. I., & Takahashi, J. S. (2019) · Genes Brain & Behavior · doi:10.1111/gbb.12578 · Cited by 2
“The mouse is an ideal model organism to investigate physiological and neurological pathways involved in fatigue.(10,11) Currently, there Received: 18 March 2019 Revised: 1 May 2019 Accepted: 2 May 2019”
BackgroundInfluential
Mental fatigue and cognitive functioning in patients presenting with non-enhancing gliomas
Neimantaite, A., Vecchio, T. G., Rydén, I., Harba, D., Jakola, A. S., & Smits, A. (2025) · Acta Neurochirurgica · doi:10.1007/s00701-025-06434-6 · Cited by 2
“Fatigue is a broadly used term including physical, mental and other aspects [14, 18].”
“One Model Fits All Nodes”: Neuron Activation Pattern Analysis-Based Attack Traffic Detection Framework for P2P Networks
Xu, S., Fu, C., Li, Q. L., & Xu, K. (2025) · IEEE Transactions on Networking · doi:10.1109/ton.2025.3546735 · Cited by 2
“Particularly, existing studies demonstrate that the fatigue status of human brain, which leads to poor decisions, reflects on chemical status of brain neuron cells [32], [56].”
Suprachiasmatic hypothalamic nuclei (SCN) in regulation of homeostasis: a role beyond circadian control?
Stoynev, A. G., Ikonomov, O. C., & Stoynev, N. (2021) · Biological Rhythm Research · doi:10.1080/09291016.2021.1920125 · Cited by 3
Therapeutic Viewpoint on Rat Models of Locomotion Abnormalities and Neurobiological Indicators in Parkinson's Disease
Chaudhary, R., & Singh, R. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230518111323 · Cited by 2
Shared Microglial Mechanisms Underpinning Depression and Fatigue and Their ComorbiditiesPreprint
Filho, A. J. M. C., Macêdo, D. S., de Lucena, D. F., & Maes, M. H. J. (2019) · Preprints.org · doi:10.20944/preprints201902.0029.v1 · Cited by 1
“Recent results obtained from animal models of fatigue revealed that this condition is associated with activated microglia and brain release of cytokines and chemokines [23].”
Epileptic seizure clustering and accumulation at transition from activity to rest in GAERS rats
Tran, H., Mahzoum, R. E., Bonnot, A., & Cohen, I. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2023.1296421 · Cited by 1
“Such pathways of central fatigue include complex multifactorial mechanisms based on monoamines and cytokines (37), which play a key role in wake/sleep switching and global metabolic homeostasis.”
Background
Fatigue in major depression is linked to depression severity, not sleep duration or anterior cingulate cortex neurochemistry
Batheja, S., Yang, J., Liao, Y., Wengler, K., He, X., Ali, F., Rozensky, R., & DeLorenzo, C. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.121076 · Cited by 1
“…fatigue, a feeling of low energy, diminished focus, and tiredness, requiring rest but not necessarily sleep (Shen et al., 2006), is also one of the most common symptoms of depression experienced by 73–97 % of depressed patients (Ferentinos et al., 2009; Harrington, 2012; Tylee et al., 1999).”
Investigation of the Adaptability of Pt/HfO2/n+Si Memristors with Self‐Limiting Oxygen‐Deficient Hafnium Oxide Films under Repetitive Pulse Stimuli
Wang, K., Lü, J., Xiang, Z., Shi, M., Wu, L., Yan, F., & Jiang, R. (2024) · Advanced Physics Research · doi:10.1002/apxr.202400047 · Cited by 1
Changes in striatal dopamine transporter and tyrosine hydroxylase expression associated with fatigue and their reversal by blueberry juice
Jiang, B., Zheng, S., An, L., Guo, J., & Asakawa, T. (2019) · Journal of Berry Research · doi:10.3233/jbr-180350 · Cited by 1
“Reportedly, fatigue is a self-protective inhibition that aims to prevent defatigation [1], and it is associated with the limbic input in the basal ganglia related to dopaminergic neurons [2].”
Basal kroppskännedom och psykomotorisk funktion hos personer med allvarlig psykisk sjukdom
Hedlund, L. (2014) · Lund University Publications (Lund University) · Cited by 1
Broken Connections: The Evidence for Neuroglial Failure in ME/CFSPreprint
Renz‐Polster, H. (2021) · OSF Preprints (OSF Preprints) · doi:10.31219/osf.io/ef3n4 · Cited by 1
Pain, fatigue, function and transcutaneous electrical nerve stimulation in individuals with fibromyalgia
Dailey, D. L. (2013) · doi:10.17077/etd.qkvfhaca
“fatigue, and in parallel increase expression of pro-inflammatory cytokines [53,93].”
Background
Circadian Regulation of Arousal and its Role in Fatigue
Bonsall, D. R., & Harrington, M. E. (2015) · Wiley eBooks · doi:10.1002/9781118467831.ch5
Self-citation
DETERMINAÇÃO DAS ALTERAÇÕES BIOMECÂNICAS DE IDOSOS CAIDORES E NÃO CAIDORES SUBMETIDOS A PROTOCOLO INCREMENTAL DE FADIGA
Karuka, A. H. (2014) · Americanae (AECID Library)
THE ANALYSIS OF RELATIONSHIP BETWEEN LESION OF FUNCTIONAL SYSTEMS OF NERVOUS SYSTEM AND SEVERITY OF FATIGUE IN PATIENTS WITH MULTIPLE SCLEROSIS
Mialovytska, O. A., & Khyzhniak, Y. (2017) · EUREKA Health Sciences · doi:10.21303/2504-5679.2017.00273
“Fatigue is characterized by a lack of energy, feelings of exhaustion that are unaided by sleep, and the perception that one is unable to perform mental and physical activities [9].”
Background
Asleep at the Wheel: Forward Genetic ENU Mutagenesis Screen for Mouse Models of Chronic Fatigue Identifies a Mutation in Slc2a4 (GLUT4)Preprint
de Groot, M. H. M., Castorena, C. M., Kumar, V., Mohawk, J. A., Ahmed, N. I., & Takahashi, J. S. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/163378
“51 The mouse is an ideal model organism to investigate physiological and 52 neurological pathways involved in fatigue (9, 17).”
BackgroundMethodInfluential

Authors: Harrington, M. E.
Affiliations: Smith College (US)
Corresponding author: Harrington, Mary E.
ORCID: Harrington, Mary E.
Venue: Progress in Neurobiology
Publisher: Elsevier BV
Published: 2012-11
Volume: 99
Issue: 2
Pages: 93-105
ISSN: 0301-0082 (ISSN-L)
DOI: 10.1016/j.pneurobio.2012.07.004
PMC: PMC3479364
OpenAlex: W2038548714
Cited by: 112
References: 168
Citations by year: 2026: 3 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 5 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 11 · 2017: 8 · 2016: 10 · 2015: 12 · 2014: 11 · 2013: 4
FWCI: 1.16
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neurobiology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Smith ScholarWorks (Smith College) (submittedVersion)
Funders: National Institutes of Health
National Cancer Institute (R21CA125215)
National Institute of Nursing Research (R21NR012845)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
Keywords: fatigue, microglial activation, cytokines, chemokines, ascending arousal system, reward, suprachiasmatic nucleus, homeostatic regulation, physical activity, quality of life
MeSH terms: Animals, Brain, Disease Models, Animal, Fatigue, Humans, Neurobiology, Fatigue Syndrome, Chronic, Autoimmune Diseases of the Nervous System

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