Neurobiological studies of fatigue

“Fatigue is an important symptom of frailty in aged populations (Fried et al., 2001) and predicts functional limitation (Avlund et al., 2003a), disability (Avlund et al., 2003b) and mortality (Hardy and Studenski, 2008, Moreh et al., 2010).”

“3) (Dantzer et al., 2008).”

“In one study mice given a single injection of LPS showed increased TNF-a in the brain for 10 months, even when serum levels had returned to normal by 9 h post-injection (Qin et al., 2007).”

“dominating this and other fields (Beery and Zucker, 2011), could help us to determine if the research we are conducting might be broadly relevant across multiple species, ages and genders.”

“Interestingly, studies of the genes driving circadian oscillators via transcription-translation feedback loops (Ko and Takahashi, 2006) show only relatively minor alterations due to age (Asai et al., 2001; Kolker et al., 2003; Nakamura et al., 2011), neurodegenerative disease (Kudo et al., 2011a,b)…”

“Infusions of BDNF into the hippocampus did not alter level of locomotor activity in an open field (Shirayama et al., 2002).”

“In support of this, people with hepatitis C treated with the cytokine IFN-a show high incidence of fatigue and depression, with the depressive symptoms responding to serotonergic antidepressants but the fatigue symptoms being resistant to this treatment (Capuron and Miller, 2011).”

“rate for 3 h/week), and possibly also benefits from anaerobic exercise and relaxation training (McNeely et al., 2006).”

“Sleep deprivation leads to increased theta power in the EEG (Vyazovskiy and Tobler, 2005) and periods of reduced neural activity in cortical areas during waking (Vyazovskiy et al., 2011).”

“Healthy older adults show disruptions of the pattern of sleep and wake which include difficulty initiating sleep, frequent night time awakenings, early morning waking and high sleep propensity during the latter half of the day (Bliwise, 1993).”

“Permeability of the blood-brain barrier may depend on age and gender (Bake and Sohrabji, 2004, Bake et al., 2009) possibly leading to changes in neural response to peripheral inflammation (Dantzer, 2009).”

“Both IL-1b and TNF-a regulate sleep in the normal animal (Imeri and Opp, 2009) with levels in the brain increasing around the time of day when the animal is likely to sleep.”

“A study in squirrel monkeys indicates that SCN lesions reduce total wakefulness (Edgar et al., 1993), suggesting the SCN may function to increase wakefulness during the active period.”

“Following lesions to VLPO neurons animals show less time asleep and more fragmented sleep bouts (Lu et al., 2000).”

“Both mental fatigue (increased cognitive effort, difficulty sustaining attention) and physical fatigue (failing to initiate physical acts) can arise from central nervous system derived fatigue (Chaudhuri and Behan, 2000).”

“Lesions of the DMH, a major target of SCN efferents, reduces total time awake (Chou et al., 2003).”

“EGFR is widely expressed in the brain and is present in the cells of the subparaventricular zone, a major target for SCN efferents, just dorsal to the SCN (Kramer et al., 2001) as well as in the SCN (Jobst et al.”

“A recent review suggested that, instead of molecular rhythms, ‘‘neural activity rhythms in the SCN may be the ‘weak link’ of the circadian system’’ (Colwell, 2011).”

“Wheel running is self-reinforcing, and many species have demonstrated they are motivated to use a running wheel (Sherwin, 1998).”

“A different cytokine, TNF-a, suppresses expression of clock genes driven by E-box promoters in fibroblasts (Cavadini et al., 2007); this may explain effects of CD40 antibody as well as some aspects of LPS-driven immune activation (Okada et al., 2008; Taraborrelli et al., 2011).”

“Treatments are limited, although exercise and cognitive behavior therapy have some benefits (Price et al., 2008), as can psychostimulants (Horneber et al.”

“For example, IFN-a has dramatic effects on clock genes in neurons of the SCN, suppressing expression of key clock genes Clock, Bmal1, and Period (Koyanagi and Ohdo, 2002; Ohdo et al., 2001).”

“For example, LPS-induced acute suppression of motor activity (circa 1.5 h following LPS administration) was linked to reduced activation in the dopaminergic VTA and histaminergic TMN and orexin neurons in the LH (Gaykema and Goehler, 2011).”

“Interestingly, studies of the genes driving circadian oscillators via transcription-translation feedback loops (Ko and Takahashi, 2006) show only relatively minor alterations due to age (Asai et al., 2001; Kolker et al., 2003; Nakamura et al., 2011), neurodegenerative disease (Kudo et al.”

“reduced serotonin transporter binding in caudate, putamen, ventral striatum, and thalamus when compared to similar patients without the symptom of fatigue (Pavese et al., 2010).”

“The SCN may also function to increase sleep during the inactive period (Mistlberger, 2005).”

“A cytokine response to a treatment such as an injection of poly I:C can be measured both peripherally and centrally and is complex in terms of the number of cytokines increased and the time course (Cunningham et al., 2007). flammation can take 4 main routes to influence the nervous system.”

“Prior work with clinical samples has shown associations between fatigue symptoms and more stable downstream indicators of IL-1b activity (e.g. IL-1 receptor antagonist; Bower et al., 2009; Schubert et al., 2007).”

“A short-term inflammatory response has greater effects on activity levels and brain IL-1b in aged (20–24 mo) mice (Abraham and Johnson, 2009; Godbout et al., 2008).”

“They also share some level of centrally increased cytokines and chemokines as well as activated microglia (Corona et al., 2012; Perry, 2010).”

“followed by lasting fatigue and sleep disorders (Cantor et al., 2008).”

“3–5 weeks, also showing a persistent increase in IL-6 (Sasu et al., 2010).”

“Treatments are limited, although exercise and cognitive behavior therapy have some benefits (Price et al., 2008), as can psychostimulants (Horneber et al., 2012).”

“Increased levels of IL-1 receptor antagonist are associated with increased fatigue in women with breast cancer independent of associations with sleep quality (Liu et al., 2012b).”

“Signs of atrophy in the striatum, thalamus, frontal and parietal cortex were observed in a sample of multiple sclerosis patients with fatigue (Calabrese et al., 2010).”

“Sleep deprivation leads to increased theta power in the EEG (Vyazovskiy and Tobler, 2005) and periods of reduced neural activity in cortical areas during waking (Vyazovskiy et al., 2011).”

“Cognitive behavioral therapy delivered via the internet was recently shown to be more effective than usual care for adolescents with chronic fatigue syndrome (Nijhof et al., 2012).”

“Other brain areas implicated in the neurobiology of wheel-running by studies using Fos staining were the dentate gyrus of the hippocampus, the caudate-putamen, the prefrontal, medial frontal and sensory cortex, and the lateral hypothalamus (Rhodes et al., 2003, 2005).”

“Injections of IFN-a or IFN-g show a time-of-day-dependent effect on circadian activity rhythm amplitude and clock gene expression in the SCN (Ohdo et al., 2001).”

“Fatigue is an important symptom of frailty in aged populations (Fried et al., 2001) and predicts functional limitation (Avlund et al., 2003a), disability (Avlund et al., 2003b) and mortality (Hardy and Studenski, 2008, Moreh et al., 2010).”

“Self-reported fatigue is twice as prevalent in older women than in men (Vestergaard et al., 2009).”

“Interestingly, a new study indicates that lesions to the basal ganglia (striatum, caudate/putamen, globus pallidus) change level of wakefulness and fragmented sleep in rats (Qiu et al., 2010), supporting the suggestion from human brain imaging studies that this brain region might play an important role in fatigue.”

“Modafinil was shown to be effective in treating patients with severe cancer-related fatigue (Jean-Pierre et al., 2010), and HIV-related fatigue (Rabkin et al., 2011) but was not effective for fatigue associated with multiple sclerosis (Kos et al., 2008).”

“A clinical report of a case study with damage to the circadian pacemaker in the SCN suggests that such damage does leave a person feeling fatigued (Cohen and Albers, 1991).”

“Increased IL-1b is predicted to increase other pro-inflammatory cytokines, TNF-a and IL-6 and IL-18, as well as levels of IL-1 receptor antagonist (Bandeen-Roche et al., 2009; Morley and Baumgartner, 2004).”

“For example, animal models for Parkinson’s disease (mice with over-expression of alphasynuclein) show reduced amplitude wheel-running rhythms and reduced firing rate recorded from the SCN but surprisingly little change in the clock gene Per2 (Kudo et al., 2011a).”

“Current recommendations from systematic reviews suggest that the specific measurement scale to use for assessment of fatigue should be selected for the specific clinical population being studied (Elbers et al., 2011).”

“family that utilizes the gp130 receptor (Kraves and Weitz, 2006).”

“A clinical trial testing a recombinant IL-1receptor antagonist as a potential treatment for fatigue reported encouraging results in a post hoc analysis, but the primary endpoint was not statistically significant and the sample size was small (total n = 26) (Norheim et al., 2012).”

“hippocampus, an area where Fos induction was highly correlated with wheel-running (Rhodes et al., 2005).”

“Interestingly, deletion of either the PK2 gene or its receptor suppresses the amplitude of circadian locomotor activity rhythms (Li et al., 2006; Prosser et al., 2007).”

“For example, animal models for Parkinson’s disease (mice with over-expression of alphasynuclein) show reduced amplitude wheel-running rhythms and reduced firing rate recorded from the SCN but surprisingly little change in the clock gene Per2 (Kudo et al., 2011a).”

“Interestingly, studies of the genes driving circadian oscillators via transcription-translation feedback loops (Ko and Takahashi, 2006) show only relatively minor alterations due to age (Asai et al., 2001; Kolker et al., 2003; Nakamura et al., 2011), neurodegenerative disease (Kudo et al.”

“Interestingly, deletion of either the PK2 gene or its receptor suppresses the amplitude of circadian locomotor activity rhythms (Li et al., 2006; Prosser et al., 2007).”

“Aged animals show decreased amplitude rhythms of SCN electrical activity (Nakamura et al., 2011; Satinoff et al., 1993; Watanabe et al., 1995) which some researchers have proposed might be due to action of cytokines on the SCN (Coogan and Wyse, 2008; see Fig.”

“Older humans show alterations in the circadian timing system, including reduced amplitude of rhythms (Monk et al., 1995; Munch et al., 2005).”

“Fatigue is an important symptom of frailty in aged populations (Fried et al., 2001) and predicts functional limitation (Avlund et al., 2003a), disability (Avlund et al., 2003b) and mortality (Hardy and Studenski, 2008, Moreh et al., 2010).”

“The SCN projects to the VTA, likely via a relay in the MnPO, and a sub-population of VTA neurons shows diurnal modulation of firing rate (Luo and Aston-Jones, 2009); this circuit might mediate circadian regulation of reward-seeking.”

“Permeability of the blood-brain barrier may depend on age and gender (Bake and Sohrabji, 2004, Bake et al., 2009) possibly leading to changes in neural response to peripheral inflammation (Dantzer, 2009).”

“Interestingly, studies of the genes driving circadian oscillators via transcription-translation feedback loops (Ko and Takahashi, 2006) show only relatively minor alterations due to age (Asai et al., 2001; Kolker et al., 2003; Nakamura et al., 2011), neurodegenerative disease (Kudo et al.”

“Older humans show alterations in the circadian timing system, including reduced amplitude of rhythms (Monk et al., 1995; Munch et al., 2005).”

“…brucei, associated in humans with human African trypanosomiasis or ‘‘sleeping sickness’’, show reduced amplitude circadian activity rhythms, mirroring effects in humans infected with this parasite who show diurnal somnolence and nocturnal insomnia (Kristensson et al., 2010; Lundkvist et al., 2010).”

“Researchers have demonstrated a genetic basis for running wheel activity, in part by experiments involving selective breeding of rats based on wheel revolutions, apparently selecting for speed of running rather than duration (Knab and Lightfoot, 2010).”

“cage filled with water to about 2 cm (Tanaka et al., 2003).”

“Polymorphisms in the IL-1b gene predict fatigue in a small sample of breast cancer survivors (Collado-Hidalgo et al., 2008).”

“The negative emotions associated with fatigue include helplessness, vulnerability, impatience, anxiety, and emotional numbness (Barsevick et al., 2010).”

“Similarly, reduced wheel-running in rats treated with LPS was reversed by a capsase-1 inhibitor icv, preventing cleavage of pro-IL-1b to the active form, again implicating central IL-1b in behavioral manifestation of fatigue (Harden et al., 2011).”

“Aged animals show decreased amplitude rhythms of SCN electrical activity (Nakamura et al., 2011; Satinoff et al., 1993; Watanabe et al., 1995) which some researchers have proposed might be due to action of cytokines on the SCN (Coogan and Wyse, 2008; see Fig.”

“Increased levels of IL-1 receptor antagonist are associated with increased fatigue in women with breast cancer independent of associations with sleep quality (Liu et al., 2012b).”

“Particularly useful are measures of spontaneous effortful activity, such as voluntary wheel-running or burrowing (Deacon, 2009).”

“Orexin neurons project to neurons in the VTA where they modulate the effects of prefrontal cortex inputs to the dopamine-containing VTA neurons (Moorman and Aston-Jones, 2010).”

“The neurons of the SCN also project to orexin-containing neurons in the DMH and then to the LC, a structure that modulates arousal by noradrenergic innervation of many regions including the frontal cortex (Benca et al., 2009).”

“Another study showed activation of cortical microglia and altered spine density up to one month postLPS injection (Kondo et al., 2011).”

“perceiving it as something that is time-limited and has less severe consequences (Knoop et al., 2012).”

“, 2001) and mice bred for high levels of openfield activity do not show changes in voluntary wheel-running (DeFries et al., 1970).”

“Cells in the ventrolateral preoptic area (VLPO) appear to serve an ‘‘executive’’ function in inducing sleep (Rosenwasser, 2009).”

“Fatigue is an important symptom of frailty in aged populations (Fried et al., 2001) and predicts functional limitation (Avlund et al., 2003a), disability (Avlund et al., 2003b) and mortality (Hardy and Studenski, 2008, Moreh et al., 2010).”

“With age comes increased risk for persistent fatigue (Clark et al., 1995).”

“Fatigue in cancer patients is correlated with disrupted diurnal rhythms, reduced light exposure during the day, and delayed phase, with some preliminary results indicating benefits from light therapy (Ancoli-Israel et al., 2012).”

“Effects of aging on the immune system are gender-specific (Goetzl et al., 2010).”

“LPS can induce a phase shift in mouse locomotor activity and the expression of c-Fos in the SCN (Marpegán et al., 2005).”

“Damage to the basal ganglia and internal capsule was predictive of post-stroke fatigue (Tang et al., 2010).”

“, 2007); this may explain effects of CD40 antibody as well as some aspects of LPS-driven immune activation (Okada et al., 2008; Taraborrelli et al., 2011).”

“1), and then gradually recovering over the next week (Katafuchi et al., 2003).”

“Several studies indicate the endocannabinoid system mediates voluntary physical activity in part (De Chiara et al., 2010; Dubreucq et al., 2010).”

“For example, TGF-a is expressed at high levels in the SCN of Syrian hamster, rats, mice, and rhesus macaques (Kramer et al., 2001; Li et al., 2002; Ma et al., 1994; Van der Zee et al., 2005).”

“For example, mice bred for high levels of wheel-running do not show changes in locomotor activity in an open field (Bronikowski et al., 2001) and mice bred for high levels of openfield activity do not show changes in voluntary wheel-running (DeFries et al.”

“lites in mice bred for high rates of wheel-running even when mice were not allowed wheel access (Mathes et al., 2010).”

“Aged animals show decreased amplitude rhythms of SCN electrical activity (Nakamura et al., 2011; Satinoff et al., 1993; Watanabe et al., 1995) which some researchers have proposed might be due to action of cytokines on the SCN (Coogan and Wyse, 2008; see Fig.”

“Brain imaging of fatigued human subjects has provided little agreement to date of brain regions mediating the experience of fatigue, but striatum and cortical areas often are highlighted (DeLuca et al., 2009).”

“This is synthesized by SCN neurons and is found in many regions targeted by SCN efferents (Zhang et al., 2009).”

“They also share some level of centrally increased cytokines and chemokines as well as activated microglia (Corona et al., 2012; Perry, 2010).”

“It has been demonstrated that mice administered IL-1b over 5 days show reduced general locomotor activity and decreased circadian variation in activity (Anisman et al., 2008) (see Fig.”

“Inflammation can lead to fatigue that is experienced as more severe in older patients (Bautmans et al., 2010).”

“no reason’’, a common report in people suffering from fatigue (Kirsh et al., 2001), leads to reduced ability to work, to enjoy life,”

“A short-term inflammatory response has greater effects on activity levels and brain IL-1b in aged (20–24 mo) mice (Abraham and Johnson, 2009; Godbout et al., 2008).”

“In addition, orexin A can induce spontaneous locomotor activity (Teske et al., 2008, 2010).”

“Several studies indicate the endocannabinoid system mediates voluntary physical activity in part (De Chiara et al., 2010; Dubreucq et al., 2010).”

“Mice treated with repeated injections of killed B. abortus antigen show hippocampal atrophy associated with reduced expression of brain-derived neurotrophic factor (BDNF) and increased expression of acetylated p53 protein in the hippocampus (Moriya et al., 2011).”

“Permeability of the blood-brain barrier may depend on age and gender (Bake and Sohrabji, 2004, Bake et al., 2009) possibly leading to changes in neural response to peripheral inflammation (Dantzer, 2009).”

“Fatigue eight days following administration of poly I:C is accompanied by increased IFN-a, p38 mitogen-activated protein kinase (MAPK), and serotonin transporter expression in lateral POA and median preoptic area (MnPO) and as well as cortex (Katafuchi et al., 2005).”

“B. abortus can cause astrocyte proliferation and apoptosis, secretion of pro-inflammatory cytokines and chemokines in the brain (Garcia Samartino et al., 2010).”

“The dopamine D1 receptor in the nucleus accumbens (NAc), a major target for VTA neurons, plays a role in rats showing high levels of voluntary wheel use (Roberts et al., 2011).”

“cognitive dysfunction, sleep disturbance, myalgia, arthralgia, headache, gastrointestinal upset, sore throat and painful lymph nodes (Christley et al., 2012).”

“A recent study showed effects of 8 weeks of voluntary wheel-running on gene expression in the hippocampus (Kohman et al., 2011).”

“Fatigue is an important symptom of frailty in aged populations (Fried et al., 2001) and predicts functional limitation (Avlund et al., 2003a), disability (Avlund et al., 2003b) and mortality (Hardy and Studenski, 2008, Moreh et al., 2010).”

“, 1998a), and in vitro studies show effects of LPS combined with TNF-a and IFNg on excitatory postsynaptic activity and the amplitude of the circadian rhythm in firing rate in rat SCN (Lundkvist et al., 2002).”

“For example, IFN-a has dramatic effects on clock genes in neurons of the SCN, suppressing expression of key clock genes Clock, Bmal1, and Period (Koyanagi and Ohdo, 2002; Ohdo et al., 2001).”

“In addition, orexin A can induce spontaneous locomotor activity (Teske et al., 2008, 2010).”

“associated with a polymorphism and increased expression of the circadian clock gene NPAS2 (Smith et al., 2011).”

“Rats infected with the parasite T. brucei show reduced amplitude circadian activity rhythms and the SCN spontaneous firing rate rhythm is dampened as well (Lundkvist et al., 1998b, 2010).”

“Similarly, reduced wheel-running in rats treated with LPS was reversed by a capsase-1 inhibitor icv, preventing cleavage of pro-IL-1b to the active form, again implicating central IL-1b in behavioral manifestation of fatigue (Harden et al., 2011).”

“Humans with narcolepsy, thought to be due to loss of brain orexin, show high rates of fatigue, separable from the excessive daytime sleepiness that is also seen with this disorder (Droogleever Fortuyn et al., 2012), suggesting orexin might play a role in the neurobiology of fatigue.”

“Similar effects are reported for neuregulin-1 that acts via the ErbB4 receptor (Snodgrass-Belt et al., 2005) and the cardiotrophin-like cytokine, a cytokine in the IL-6”

“…appears to lead to a short-term illness that is followed by a long-lasting state of fatigue, accompanied by changes in immunological markers (Ottenweller et al., 1998), mirroring some of the most puzzling cases in humans where the inducing disease seems to be in abeyance yet fatigue remains…”

“Mice deficient in this peptide show decreased locomotor activity, but daily voluntary exercise can help organize the circadian rhythm in these mice (Hannibal et al., 2011; Power et al., 2010).”

“Although it has been suggested that we could develop 4 types of animal models of fatigue (Katafuchi et al., 2006), targeting physical”

“Researchers have differentiated ‘‘peripheral fatigue’’ and ‘‘central fatigue’’ (Cantor, 2010), although some question if this is a useful distinction (Gerber, 2010).”

“Activation of astrocytes and microglia as well as increased levels of pro-inflammatory cytokines and the chemokine CXCL10 are observed in the brains of rats infected with T. brucei (Bentivoglio et al., 2011).”

“Cells in the SCN express and respond to several proinflammatory cytokines in an age-dependent manner (Beynon and Coogan, 2010; Cavadini et al., 2007; Kwak et al., 2008; Sadki et al., 2007).”

“In vivo recordings from the VTA while mice ran in wheels demonstrated that nondopaminergic VTA neurons fire in a rhythmic pattern closely correlated with the running speed as well as the cyclicity of limb movements during running (Wang and Tsien, 2011).”

“For example, LPS-induced acute suppression of motor activity (circa 1.5 h following LPS administration) was linked to reduced activation in the dopaminergic VTA and histaminergic TMN and orexin neurons in the LH (Gaykema and Goehler, 2011).”

“Mice deficient in this peptide show decreased locomotor activity, but daily voluntary exercise can help organize the circadian rhythm in these mice (Hannibal et al., 2011; Power et al., 2010).”

“The suppressors of cytokine signaling (SOCS) 1 and 3 are also expressed in the mouse SCN (Sadki et al., 2007).”

“Aged mice treated with LPS showed disrupted memory consolidation and increased IL-1b expression in hippocampus and cortex (Tarr et al., 2011).”

“Both Cryptosporidium parvum and Toxoplasma gondii infections cause a drop in wheel running in mice lasting several weeks (Chao et al., 1992).”

“Reduced amplitude circadian rhythms following infection with simian immunodeficiency virus is associated with activated microglia in the subparaventricular zone, a target for many SCN efferents (Huitron-Resendiz et al., 2007).”

“It is hard on the animals; approximately one-third of the mice die during the period of repeated injections (Chen et al., 2008; Moriya et al., 2011).”

“Rats infected with the parasite T. brucei show reduced amplitude circadian activity rhythms and the SCN spontaneous firing rate rhythm is dampened as well (Lundkvist et al., 1998b, 2010).”

“Administration of LPS to the SCN brain slice induces a dose-dependent increase in vasopressin release (Nava et al., 2000).”

“The cytokine TNF-a is able to excite a subset of SCN neurons modulating the spontaneous firing and synaptic transmission in the SCN (Nygard et al., 2009).”

“Mice treated with poly I:C show upregulation of multiple chemokines and their receptors across many brain areas, with the cerebellum particularly sensitive (Fil et al., 2011).”

“A different cytokine, TNF-a, suppresses expression of clock genes driven by E-box promoters in fibroblasts (Cavadini et al., 2007); this may explain effects of CD40 antibody as well as some aspects of LPS-driven immune activation (Okada et al., 2008; Taraborrelli et al., 2011).”

“Injections of the cytokines IFN-g and TNF-a icv in mice elicits activation of SCN microglia (Bentivoglio et al., 2006).”

“Rats infected with the parasite T. brucei show reduced amplitude circadian activity rhythms and the SCN spontaneous firing rate rhythm is dampened as well (Lundkvist et al., 1998b, 2010).”

“…murine gammaherpesvirus 68 showed prolonged signs of fatigue following LPS injection, with reduced wheel running for 5 days following LPS treatment in the previously infected group, a much more prolonged response than was seen in the group given LPS without a pre-treatment (Olivadoti et al., 2011).”

“Suppression of SCN firing rate via tetrodotoxin reduces levels of PK2 in the SCN (Baba et al., 2008).”

“For example, TGF-a is expressed at high levels in the SCN of Syrian hamster, rats, mice, and rhesus macaques (Kramer et al., 2001; Li et al., 2002; Ma et al., 1994; Van der Zee et al., 2005).”

“, 2007); this may explain effects of CD40 antibody as well as some aspects of LPS-driven immune activation (Okada et al., 2008; Taraborrelli et al., 2011).”

“On the other hand, one study of male rats with IL-1b delivered directly into the brain icv reports that aged rats show diminished NREM sleep response even when the induced fever was equivalent to that seen in younger rats (Imeri et al., 2004).”

“Modafinil was shown to be effective in treating patients with severe cancer-related fatigue (Jean-Pierre et al., 2010), and HIV-related fatigue (Rabkin et al., 2011) but was not effective for fatigue associated with multiple sclerosis (Kos et al., 2008).”

“For example, one group has studied rats subjected to electric shock and either restraint stress or cold water swim on a daily basis for 23 days as a model for chronic fatigue syndrome (Zou et al., 2010).”

“Women are more likely to report having fatigue, often report more severe fatigue (Torres-Harding and Jason, 2005), and are more likely to seek medical help for their fatigue (Cope, 1992).”

“Researchers have differentiated ‘‘peripheral fatigue’’ and ‘‘central fatigue’’ (Cantor, 2010), although some question if this is a useful distinction (Gerber, 2010).”

“Several brain areas are associated with modulating fatigue (Table 2) (243), although this area of research remains poorly investigated.”

“A large body of evidence in support of the cytokine hypothesis comes from animal literature (8, 89).”

“Yet, the available treatment options rarely cause significant improvements in fatigue in neuropsychiatric and neurological disorders (Harrington, 2012; Kluger et al., 2013).”

“8,9 Fatigue is mainly categorized as physical and mental fatigue.”

“…good agreement with the literature in terms of the structures typically affected during this state: Dysfunction of monoaminergic signaling related to arousal, sleep/wake or reward systems is commonly discussed as one neurobiological basis of fatigue 45 .”

“…and physical symptoms – and o  en compounded by external stressors, is another area in which the needs of neurodivergent individuals di ff er signi fi cantly, as they might experience periods (hours, days, or weeks) in which they grapple with physical, emotional, or mental fatigue [16],[36],[66].”

“This area is related to reward, cognition and movement, being primarily responsible for the symptoms of lack of motivation, fatigue and psychomotor alterations observed in depressed patients (Harrington, 2012; Walther et al., 2012).”

“Finally, animal models have shown that the overexpression of alpha-synuclein in mice could diminish their performance over wheel-running compared with wildtype control, probably related to reduction of the daytime electrical activity of the suprachiasmatic nucleus neurons (SCN) and motor centers who are targets of the…”

“Previous knowledge about longer-lasting effects of immune stimulation in the form of cognitive and mental dysfunction may provide indirect support to these findings, although most of the literature describes far longer time spans between cause and effect [22,42].”

“…correlates of fatigue in disease states such as Parkinson's disease, traumatic brain injury, stroke and multiple sclerosis (Deluca et al., 2009; Harrington, 2012; Kluger et al., 2013; Rocca et al., 2014); however, neural correlates of fatigability have not been identified in older adults free…”

“The use of appropriate animal models for fatigue, mainly in rodents, has recently begun to advance our understanding of the underlying neurobiology (reviewed in [68]), and automated monitoring systems to measure animal behavior have greatly advanced this field of research.”

“Introduction Fatigue is a common symptom among individuals living with chronic illness, and there is growing evidence from animal models (Harrington, 2012) and adults with chronic illness (Bower et al., 2013; Miaskowski et al., 2010) that fatigue is associated with inflammation and cytokine…”

“Normal fatigue is described as an experience of tiredness after an exertion where energy is restored after rest, while pathological fatigue is seldom reduced after rest (Harrington 2012).”

“Another subcortical structure widely implicated in fatigue in animal studies is the hippocampus such that the hippocampal involvement in fatigue correlates with disrupted memory consolidation (Harrington, 2012).”

“N ieto-Q uero et al. Neurobiology of Stress 15 (2021) 100356 6 energy (Harrington, 2012).”

“Increasing EEG spectral power from high to low theta frequency indicates a higher propensity towards sleep (Harrington, 2012; Vyazovskiy and Tobler, 2005).”

“Initial global disruption of LMA, followed by a resumption of circadian activity patterns, is commonly reported (Harrington, 2012).”

“Fatigue is essentially a subjective experience with individual physical, emotional and mental symptoms (Harrington, 2012; Ponsford et al., 2012), which may affect each person’s daily life differently.”

“Numerous theories of fatigue have been proposed in cancer survivors (4), however, given the co-occurrence of other symptoms (pain, sleep disturbance, mood, and cognitive impairment) the possibility that central neurobiological factors may play a key pathologic role has recently gained traction (5).”

“The neurobiology of fatigue is complex, involving dopamine, orexin, and partly mediated via disruption of circadian systems, which also involve serotonergic, and noradrenergic systems (Krishnan and Nestler, 2010; Harrington, 2012).”

“CF is induced by strenuous physical or mental tasks, leading to cognitive and memory impairment, reduced physical endurance, negative emotions (e.g., anxiety, depression, hostility), and various metabolic disturbances in the central and peripheral systems (Harrington, 2012).”

“Physical activity, sedentary behavior, and sleep are under control from distinct, but interacting, neurobiological systems (Dishman et al., 2006; Harrington, 2012).”

“Subjective fatigue has also been linked to lesions in the ascending arousal system (Harrington, 2012; Saper, Fuller, Pedersen, Lu, & Scammell, 2010).”

“Neurobiological studies have indicated that the suprachiasmatic nucleus plays an important role in the homeostatic regulation of the neural network that mediates fatigue.(54) Fatigue is caused by poor sleep and depression; the reasons may be related to disrupted sleep and desynchronized sleep-wake rhythms.”

“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…”

“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].”

“Neuroimaging studies in patients with disease-related fatigue have shown atrophy or other damage in the striatum and cortex (Harrington, 2012).”

“…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…”

“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).”

“”[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.”

“An unmotivated decrease in cage activity with no change in wakefulness further reflects key aspects of fatigue (Harrington, 2012).”

“3 were obtained in serum-free medium, thus ruling out the effects of possible confounding factors present in serum (Inui et al., 2013).”

“Currently there are no accepted animal models of PDrelated fatigue available (Harrington 2012).”

“Most studies used the immunologically induced fatigue [8].”

“Neuro-inflammation [65] and oxidative overload severely disturb cerebral function [66].”

“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).”

“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).”

“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).”

“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…”

“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”

“Fatigue is a broadly used term including physical, mental and other aspects [14, 18].”

“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].”

“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].”

“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.”

“…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).”

“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].”

“fatigue, and in parallel increase expression of pro-inflammatory cytokines [53,93].”

“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].”

“51 The mouse is an ideal model organism to investigate physiological and 52 neurological pathways involved in fatigue (9, 17).”