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Neurobiological studies of fatigue

JaimeS

Senior Member
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Silicon Valley, CA
I'm finding this interesting, even though it's not directly related to ME/CFS:

Neurobiological studies of fatigue

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479364/

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.

Keywords: fatigue, cytokine, suprachiasmatic, circadian, animal model
 
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JaimeS

Senior Member
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3,408
Location
Silicon Valley, CA
Treatments are limited, although exercise and cognitive behavior therapy have some benefits (Price et al., 2008)

:oops::oops::oops::oops::oops:

It appears that the critical component of this therapy is the success in changing negative cognitions about fatigue, but instead perceiving it as something that is time-limited and has less severe consequences (Knoop et al., 2012). 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). Combining cognitive therapy with exercise is more beneficial than cognitive therapy alone for post-stroke fatigue (Zedlitz et al., 2012).

You cannot escape the CBT...!
 

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
In one study mice given a single injection of LPS showed increased TNFα in the brain for 10 months, even when serum levels had returned to normal by 9 h post-injection (Qin et al., 2007). This response was not observed in mice without the TNF receptor, offering a control condition that should be useful in studies focused on the role of central cytokines in fatigue. Another study showed activation of cortical microglia and altered spine density up to one month post-LPS injection (Kondo et al., 2011).

Then they discuss an IL1-B model of fatigue...

Researchers are just starting to develop models that will help us to better understand why some people show vulnerability to developing fatigue and others are more resilient. For example, mice previously exposed to 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).

Yes, I've heard that viral infection can prime LPS responses. It's of note that people seem more likely to contract ME/CFS post herpesvirus infection as per IOM Report analyses.
 

JaimeS

Senior Member
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3,408
Location
Silicon Valley, CA
What is common across many of these models is that fatigue appears to arise when some stimulus induces increased proinflammatory cytokines in the brain and/or activated microglia and increased expression of chemokines. A peripheral immune challenge is thought to impact the central nervous system through several possible routes: by direct cytokine transport across the blood-brain barrier, by stimulation of circumventricular organs and choroid plexus cells to produce cytokines, by vagal nerve stimulation, or by direct activation of brain vasculature...

Well, so any way at all. ;)

Then they discuss endocannabanoids and dopamine.

And then discuss how cytokines interact with the HPA axis:

Cytokines can directly influence these circuits. Both IL-1β and TNF-α 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. IL-1β directly inhibits wake-promoting neurons and stimulates sleep-promoting neurons in the POA and basal forebrain (BF) (Imeri and Opp, 2009). IL-1β inhibits serotonergic neurons of the dorsal raphe nuclei by enhancing the effects of the inhibitory neurotransmitter GABA (Imeri and Opp, 2009). IL-1β also stimulates 5-HT release from axon terminals in the POA which stimulates sleep and serotonin stimulates IL-1β mRNA transcription in the hypothalamus, providing positive feedback.
 

JaimeS

Senior Member
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3,408
Location
Silicon Valley, CA
Fatigue appears to be linked to CNS response to immune activation. To better treat fatigue we might consider that it might be helpful to block the signal from peripheral immune challenge that causes increased cytokines in the brain. In laboratory animals treatment with a COX inhibitor, a capsase-1 inhibitor, or an IL-1β antagonist were able to reverse behavioral signs of fatigue following LPS challenge (Harden et al., 2011, Konsman et al., 2008, Teeling et al., 2007), suggesting that this might be an encouraging direction for future research.
 

ljimbo423

Senior Member
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4,705
Location
United States, New Hampshire
In one study mice given a single injection of LPS showed increased TNFα in the brain for 10 months, even when serum levels had returned to normal by 9 h post-injection.

That's really interesting, that the TNFa in the brain, stayed increased for 10 months after one injection.

LPS can also cause an increase in B cell activation and either a TH-1 or TH-2 polarization, depending on weather the dose of LPS is high or low. LINK

Low doses (< 10 ng/ml) of LPS-activated B cells drove T helper type 2 polarization whereas high doses (> 0·1 μg/ml) of LPS-activated B cells resulted in T regulatory type 1 cell polarization. In conclusion, LPS-activated B cells acquire differential modulatory effects on T-cell polarization. Such modulatory effects of B cells are dependent on the stimulation with LPS in a dose-dependent manner.