Inflammation - A Key to Fatigue and Depression Found?

Cort

Founder of Health Rising and Phoenix Rising
Staff member
This basal ganglia (striatum) is one of my favorite research areas. I am so glad that the research in this area is continuing...

Biol Psychiatry. 2016 Feb 15;79(4):320-8. doi: 10.1016/j.biopsych.2015.05.015. Epub 2015 Jun 4.Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue. Dowell NG1, Cooper EA2, Tibble J3, Voon V4, Critchley HD5, Cercignani M6, Harrison NA7.

We know that hepatitis C patients receiving IFN-a and ME/CFS patients have very similar problems with fatigue and identical problems in the basal ganglia. That by itself is really interesting. It's not people with hep C infections who are similar to ME/CFS patients it's hep C patients receiving a major immune booster - IFN-a - that do. That suggests that immune activation is whacking both ME/CFS and hep C patients with IFN-a.

[fright]
Basal-ganglia.jpg
[/fright]This review focused somewhat depression but I would discard that term and just call it "sickness behavior". (The understanding that IFN-a administration in hep C patients caused fatigue, depression, etc. helped researchers understand that the immune system - not the infection - was largely responsible for the flu-like symptoms we experience when we have a cold.

Miller has found that reduced activation of the reward system in the basal ganglia in both hep C patients on IFN-a and ME/CFS was highly associated with fatigue. He believes that reduced dopamine levels in the BG result in an increased sensitivity to inflammation.

Now comes this study which directly shows what happens in the brain when an inflammatory mediator like IFN-a is added. It found that microstructural changes in the striatum in the brain (a part of the BG) began to occur within hours of the IFN-a injection. The more changes seen in the striatum early on the more fatigue the patients experienced later on.

This could very be a model for what happens in ME/CFS patients during triggering infections. We know that people who come down with a post-infectious illness produce more cytokines early in an infection. What we don't know is why they remain sick. Changes to the striatum very early on in the infection could help explain why.

The study also found that changes in the striatum could also help explain why some people with ME/CFS get fatigued and depressed while others only become fatigued. Different circuits in the striatum seem to predispose for fatigue while others predispose for depression. If both circuits in your striatum got whacked you got the full monty - fatigue plus depression. If only the fatigue circuit got whacked you got something like ME/CFS and if only the depression circuit got whacked you just became depressed.

Press Release: Elsevier, February 2, 2016. A new study by Neil Harrison and colleagues published in Biological Psychiatry suggests that a brain reward center, the striatum, may be directly affected by inflammation and that striatal change is related to the emergence of illness behaviors.

Inflammation increases the risk for depression. More specifically, inflammation induces behavioral changes similar to depression that are often associated with illness, including fatigue, difficulty concentrating, lack of motivation, and reduced experience of pleasure.

The authors recruited 23 patients with hepatitis C who were beginning treatment with interferon-alpha (INF-α). This treatment provokes an immediate inflammatory response, confirmed by measuring cytokines in the blood.

Four hours after INF-α administration, a specialized type of imaging, called magnetization transfer imaging, was performed that showed evidence of microstructural changes in the striatum when compared to scans conducted prior to INF-α administration. This suggests that the striatum is highly sensitive to IFN-α.

IFN-α also induced fatigue and depression in the patients, particularly over weeks 4 through 12 of treatment. Interestingly, the early striatal structural change predicted the later emergence of fatigue, but not depression, in the study participants.

Changes in the striatum were heterogeneous with some changes associated with the risk for fatigue, while other changes seemed to be protective against developing fatigue.

"Inflammation-related fatigue and depression are big clinical problems," said Dr. John Krystal, Editor of Biological Psychiatry. "This study highlights that the brain regions central to reward and motivation are directly altered by inflammation in ways that that appear to predispose or protect against developing fatigue but not depression. The heterogeneous striatal response may suggest that fatigue and mood are supported by different microcircuits within the striatum."

"These findings are important as they show that a relatively simple MRI technique can be used to measure effects of inflammation on the brain," Harrison commented. "Inflammation is increasingly implicated in the cause of common mental illnesses, particularly depression. This technique could be a powerful way to identify patients who are most sensitive to effects of inflammation on the brain. It could also be used to monitor response to novel anti-inflammatory therapies that are now being tested in depression."
Journal Reference: Nicholas G. Dowell, Ella A. Cooper, Jeremy Tibble, Valerie Voon, Hugo D. Critchley, Mara Cercignani, Neil A. Harrison. Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue. Biological Psychiatry, 2016; 79 (4): 320 DOI:10.1016/j.biopsych.2015.05.015
 

IrisRV

Well-Known Member
The problem I have with this is that what I experience with ME/CFS is not fatigue in the sense of feeling tired. It's not the sickness behavior associated with flu-like illness in which you feel tired, but there's no actual loss of energy.

I have what is described by the ICC:
This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.
The inability to produce sufficient energy is very different from your brain telling you you are tired so you will rest. It's not feeling tired. It is the body's inability to produce sufficient energy -- a very different situation. This inability is documented in CPET tests, which test actual metabolic function, not sickness behavior cytokine-induced fatigue.

I'm tired (sorry, not intentional ;)) of research focusing on a minor symptom (fatigue) that exists in many other conditions and ignoring the metabolic research that shows our lack of energy is an entirely different beast.

I'm fine with using funding for other illnesses (depression, post-chemo syndrome) to study sickness behavior fatigue, which may be the cause of fatigue in their illnesses. If the research can be applied to some/many PWME who have sickness behavior on top of an inabiity to produce sufficient energy, great. I don't want ME/CFS funding to be spent on the wrong type of "fatigue" and ignoring PEM/PENE which is our real problem.

We SO need to ditch the word 'fatigue' with this illness. It is misleading patients, the public, researchers, politicians, and goodness know who else into thinking we just feel tired, when our energy problems are much more complex.
 

Strike me lucky

Well-Known Member
The problem I have with this is that what I experience with ME/CFS is not fatigue in the sense of feeling tired. It's not the sickness behavior associated with flu-like illness in which you feel tired, but there's no actual loss of energy.

I have what is described by the ICC:

The inability to produce sufficient energy is very different from your brain telling you you are tired so you will rest. It's not feeling tired. It is the body's inability to produce sufficient energy -- a very different situation. This inability is documented in CPET tests, which test actual metabolic function, not sickness behavior cytokine-induced fatigue.

I'm tired (sorry, not intentional ;)) of research focusing on a minor symptom (fatigue) that exists in many other conditions and ignoring the metabolic research that shows our lack of energy is an entirely different beast.

I'm fine with using funding for other illnesses (depression, post-chemo syndrome) to study sickness behavior fatigue, which may be the cause of fatigue in their illnesses. If the research can be applied to some/many PWME who have sickness behavior on top of an inabiity to produce sufficient energy, great. I don't want ME/CFS funding to be spent on the wrong type of "fatigue" and ignoring PEM/PENE which is our real problem.

We SO need to ditch the word 'fatigue' with this illness. It is misleading patients, the public, researchers, politicians, and goodness know who else into thinking we just feel tired, when our energy problems are much more complex.

Im happy with cfids for now. Atleast it mentions the immune dysfunction thats commonly found as well as fatigue which is a main symptom although still not fond of it and malaise is probably a better description of feeling ill. As we keep saying, they need to add biomarkers even if not isolated only to cfs/me, to criterias used to diagnose cfs/me.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
The problem I have with this is that what I experience with ME/CFS is not fatigue in the sense of feeling tired. It's not the sickness behavior associated with flu-like illness in which you feel tired, but there's no actual loss of energy.

I have what is described by the ICC:

The inability to produce sufficient energy is very different from your brain telling you you are tired so you will rest. It's not feeling tired. It is the body's inability to produce sufficient energy -- a very different situation. This inability is documented in CPET tests, which test actual metabolic function, not sickness behavior cytokine-induced fatigue.

I'm tired (sorry, not intentional ;)) of research focusing on a minor symptom (fatigue) that exists in many other conditions and ignoring the metabolic research that shows our lack of energy is an entirely different beast.

I'm fine with using funding for other illnesses (depression, post-chemo syndrome) to study sickness behavior fatigue, which may be the cause of fatigue in their illnesses. If the research can be applied to some/many PWME who have sickness behavior on top of an inabiity to produce sufficient energy, great. I don't want ME/CFS funding to be spent on the wrong type of "fatigue" and ignoring PEM/PENE which is our real problem.

We SO need to ditch the word 'fatigue' with this illness. It is misleading patients, the public, researchers, politicians, and goodness know who else into thinking we just feel tired, when our energy problems are much more complex.
I see what you mean - fatigue vs an actual loss of energy - an inability to do things...I hadn't thought of it that way. Fatigue is a kind of messy concept...
 

IrisRV

Well-Known Member
I see what you mean - fatigue vs an actual loss of energy - an inability to do things...I hadn't thought of it that way. Fatigue is a kind of messy concept...
It is indeed. It doesn't help that many of us could have multiple kinds of 'fatigue' -- sickness behavior fatigue from immune rxns, fatigue associated with OI, inability to produce energy. It's complicated. But as far as I'm concerned, the big issue for all of us -- the one that needs addressing first -- is the inability to produce sufficient energy. I'm guessing that's mitochondrial, but I've been wrong before. :D
 

Strike me lucky

Well-Known Member
It is indeed. It doesn't help that many of us could have multiple kinds of 'fatigue' -- sickness behavior fatigue from immune rxns, fatigue associated with OI, inability to produce energy. It's complicated. But as far as I'm concerned, the big issue for all of us -- the one that needs addressing first -- is the inability to produce sufficient energy. I'm guessing that's mitochondrial, but I've been wrong before. :D

I think many of us can produce energy but its the recovery process thats up the creek. But as this recovery process falls behind several days in a row we are left in a fatigue state from doing nothing that day but in reality has built up over the previous several days.

I still think many of us cant produce energy 100% normally but hard to distinguish how much is about producing energy or how much is from poor recovery?
 

Strike me lucky

Well-Known Member
Malaise is a word not used much but to me it incorporates fatigue but also a feeling of being ill just like have a flu.

We dont hear many people with the flu say they feel fatigued but will say they feel sick and lethargic, which a dr would right in his notes as the patient is showing symptoms of malaise. Where a normal person who has had a long busy day at work feels fatigued but wouldn't use the word malaise after a long busy day at work.

Fatigue is something normal people experience regularly but malaise only if they are sick. Probably the big part of why they have fatigue in cfs, to discredit it as everyone has fatigue . Also fatigue and malaise are a symptom not a condition. Is there any wonder why cfs is looked at as insignificant???
 

IrisRV

Well-Known Member
I think many of us can produce energy but its the recovery process thats up the creek. But as this recovery process falls behind several days in a row we are left in a fatigue state from doing nothing that day but in reality has built up over the previous several days.

I still think many of us cant produce energy 100% normally but hard to distinguish how much is about producing energy or how much is from poor recovery?
I think you're right. Energy production is not just about producing energy in the moment, but the whole process of production and recovery.

That said, the common finding of low AT in PWME suggests that there is an initial inability to produce energy at normal levels using normal paths. The data looks like we don't have normal aerobic energy production. We go from low level anaerobic metabolism to high level anaerobic metabolism very quickly, suggesting that the aerobic metabolism which should be taking most of the load between those two is not working up to par.

Just suppose we have too few or poorly performing mitochondria. We would not produce a normal amount of energy in the moment AND we wouldn't have enough mitochondrial function to quickly rebuild the energy stores we used up. If we keep exerting, it becomes impossible for our mitochondria to keep up because we're using energy faster than they can rebuild our stores. Eventually we crash.

If that hypothesis is true (and that's a big if), degrees of disability could be related to the level of mitochondrial dysfunction. Those with only mildly diminished mito dysfunction might be able to do quite a bit -- like work full-time -- but need a lot more rest time than healthy people to rebuild depleted energy stores. Severe patients may have such severe mito dysfunction that they can't even produce enough energy to keep critical functions operating normally.
 

Get Our Free ME/CFS and FM Blog!



New Threads

Forum Tips

Support Our Work

DO IT MONTHLY

HEALTH RISING IS NOT A 501 (c) 3 NON-PROFIT

Shopping on Amazon.com For HR

Latest Resources

Top