(Exercise stress tests suggest a process that provides energy to the brain during exercise and intense mental activity may be broken and causing severe cognitive dysfunction in one group of GWS/ME/CFS patients (decreasers). A second GWS/ME/CFS group (increasers) with an intact brain lactate processing in the brain actually improves their cognitive functioning during exercise.
Baraniuk’s team is finding multiple irregularities in brain function in some people GWS and ME/CFS
The high brain lactate levels found at rest in all GWS patients suggest metabolic or mitochondrial problems may be present (and validate the high lactate readings found in prior ME/CFS studies). A trend towards differing glutamine/glutamate ratio’s in the two groups suggests high extracellular glutamate levels may cause cognitive problems by interfering with nervous system transmission. The authors push for similar studies in chronic fatigue syndrome.)
Veterans with Gulf War Illness (GWI) present with symptoms of cognitive dysfunction, chronic fatigue, and widespread pain that overlap with a larger group of idiopathic illnesses that include Chronic Fatigue Syndrome (CFS), Myalgic Encephalomyelitis (ME) and Fibromyalgia. Raynal, Baraniuk et. al.
Gulf War Illness with a Chronic Fatigue Syndrome Emphasis – You’ve got to love how Baraniuk starts his papers. This study is on Gulf War Syndrome or, as he calls it, Chronic Multisymptom Illness (CMI). But in the very first paragraph of this one he highlights both fibromyalgia and chronic fatigue syndrome. Then he gets the ‘fatigue’ in ME/CFS just right by calling it ‘exertional exhaustion’.
Turning Trash into Gold: the Bad and Good of Lactate
Baraniuk is angling for something entirely new here. Right off he springs the news that exercise-induced pain in laboratory animals is (get this) not due to lactate buildup in the muscles, but to the up-regulation of certain genes that control brainstem function; i.e., the poor energy found in ME/CFS/FM/GWS is due to poor ‘brain energetics’.
The brain turns a toxic by-product into gold when it uses lactate produced by the muscles to solve complex problems
Then he shows that lactate–that toxic by-product of exercise–is actually an important energy source for the brain. The brain mostly runs on glucose, but the huge amount of glucose snatched up by the muscles during exercise typically leaves the brain at a huge deficit (glucose is typically down a third). The brain makes up for this deficit by using the lactate produced by the muscles to provide energy.
When the brain is working hard, it also reduces its glucose stores rather quickly and it then turns to lactate to produce energy. Thus, levels of lactate increase during ‘brain activation’ and then return to baseline when the brain activity is reduced.
But increased brain lactate levels when the brain is at rest are not good. In fact, they have been associated with impaired metabolism, nerve dysfunction and mitochondrial failure.
To sum up:
- Increased brain lactate levels at rest – BAD
- Increased brain lactate levels during exercise or during difficult cognitive tasks – GOOD
The Glutamate Connection
The neurons use up 80% of the brain’s available energy, and glutamate causes them to fire. The chief excitatory neurotransmitter in the brain, glutamate, is recycled (turned into glutamine and then transported back into the neurons) by astrocytes wrapped around the neurons. If too much glutamate is produced for the astrocytes to handle, or if the astrocytes are damaged, the glutamate will be turned into lactate. If too much glutamate is hanging around outside the neurons, it’ll flood the nerve synapses (remember they’re supposed to turn it into glutamine), tweaking the nerves and causing ‘neuronal dysfunction’.
Baraniuk’s own internal studies have shown a wide range of brain lactate levels can be present in ME/CFS, but no one’s measured brain lactate levels after exercise in GWS or ME/CFS. Given the importance lactate plays in cognitive functioning and the cognitive problems GWS/ME/CFS patients have after exercise, exercise studies sound like a very good thing to do, and that’s what Baraniuk did. In fact, he did them twice.
The two-day exercise test program was created to validate ‘exertional exhaustion’ in ME/CFS, and it does. But two-day exercise studies have been few and far between. And here Baraniuk was doing one… but in GWI studies.
The Study
That fact, plus the lactate connection and the cognitive tests Baraniuk did before and after exercise, made this a very interesting study, indeed. fMRIs and MRS scans of the brain were done and the participants engaged in a difficult cognitive test that focused on ‘working memory’. Functional Magnetic Resonance Imaging (fMRI) studies determine which parts of the parts of the brain are engaged in which tasks, and Magnetic Resonance Spectroscopy (MRS) scans determine which chemicals are present in which parts of the brain.
Working memory refers to the amount of information you can hold in your brain at one time. Working memory is what we use to plan things, to figure our problems, to understand sentences, etc.
The study included exercise testing, fMRI and MRS scans. and a working memory test
Baseline – Having the participants do the working memory test while in the fMRI allowed Baraniuk to see which parts of the brain they were using before exercise. (Test results done at ‘baseline’, i.e., before exercise, tend to be less revealing than those done after exercise).
After Exercise – Doing the fMRI (and cognitive tests) and MRS scans after the second exercise test allowed them to determine if a) exercise had affected their working memory and brain activity, and b) if the chemical composition of the brain itself was different.
Maximal oxygen consumption (VO2 max) and similar tests were done to determine how much energy the participants were able to generate; those results will be published in another paper.
All the veterans met the criteria for ME/CFS, and as expected, their quality of life scores were hugely different from the healthy controls (p < .001, meaning a one in a 1,000 chance that the results were wrong.)
Results
No stressor was needed to highlight working memory problems in the CMI patients, as they flunked the pre-exercise working memory test badly (p < .001).
Exercise
“Exercise proved to be a critical stressor” Rayhan et. al.
The exercise test changed everything.
Before exercise we had one big cognitively perturbed CMI group. After exercise, one group of CMI patients flourished cognitively, and the other tanked. They were called, appropriately enough, the ‘increasers’ and the decreasers.’
The Increasers (Improvers): The working memory of this group of CMI patients (labeled ‘increasers’) improved significantly after exercise (p < .000018) bringing them up to the normal range, suggesting, of course, that exercise helped. (This might be the graduated exercise group (GET) improvement group.)
The Decreasers: The working memory of the other group, however, continued to tank, declining another twenty-five percent. After the second bout of exercise the scores of the ‘decreaser group’ were so low relative to the norm (about a third that of the healthy controls and the increasers) that one wonders how to define them. Mentally disabled might be the kindest term. (This would probably not be the GET improvement group.)
Lactate should replenish energy stores in the brain when glucose runs out during mental and physical exertion but in one group of GWS/ME/CFS it didn’t – with dire cognitive consequences
The brain lactate test suggested the ability of the increaser group to get access to more brain lactate was the key. The brain lactate levels of the ‘increasers’ went up significantly after exercise, and their working memory improved. This group got their lactate, and they were able to do better on the working memory tests.
The brain lactate levels of the patients who had more working memory problems after exercise (the ‘decreasers’), on the other hand, didn’t budge. Their brains did not get the ‘lactate boost’, and with their brains taking the standard 30% glucose hit during exercise, their working memory actually was significantly worse. With their brains essentially running on empty, their working memory scores were a decidedly scary 60% less than the increasers and healthy controls.
Brain Energetics 101
We suggest that alterations in brain energetics may be in part responsible for a subgroup of GWI and underlie some of the symptoms present in the patient population.
It made sense: increased lactate after exercise => improved brain energy => improved cognitive functioning; reduced lactate after exercise => reduced brain energy => reduced brain functioning. (What a nice validation it was to have ‘reduced energy’ show up physiologically in the brain!)
But get this twist: the low brain lactate, working memory impaired ‘decreasers’ actually had significantly higher lactate levels in their brains before exercise. (Feel your brain glucose levels starting to drop??) A number of studies have found high brain lactate levels at rest in ME/CFS–higher than found in anxiety or major depression. As we noted earlier, high brain lactate levels at rest are associated with impaired metabolism, nerve dysfunction and mitochondrial failure.
Lactate is turning out to be a very interesting substance, indeed. At rest the brain runs on glucose, but give it something challenging to gnaw on and it immediately turns to lactate to power itself up; but unless your brain’s getting its glucose stores depleted by exertion (physical or mental) you don’t want much lactate there. There’s a time and place for high lactate levels in the brain, but the resting state is not one of them.
The ‘decreasers’ got it exactly wrong: they had high lactate levels when they should have had low lactate levels and vice versa.
Figuring out the Post Exertional Brain Drain in GWS/ME/CFS
The big question is: what is going on?
Several possibilities exist. The ability to either import lactate into the brain or utilize it once it’s there may be impaired, or the mitochondria themselves may be whacked. Mitochondrial dysfunction can induce a shift to glycolysis, thus interfering with the shift to lactate use that should be occurring.
Key players in glutamate regulation and lactate transfer, the astrocytes could be ground zero in GWS/ME/CFS
In the end, however, it may all come down to the astrocytes, those wire-like cells that cover the neuronal synapses like a glove. The most abundant cell in the brain, the astrocytes store glycogen (glucose), provide lactate to the neurons, transport glutamate, regulate nerve signal transmission and blood flows, and repair nerve cells.
The Glutamate Connection Part II
A trend towards elevated glutamine/glutamate levels in the increasers suggested that glutamate levels might be peaking and impairing nervous system functioning in the decreasers. Since exercise increases brain glutamate levels (as well as lactate levels) if the astrocytes are too beaten up to turn that extra glutamate into glutamine (and get it away from the nerve synapses), high glutamate levels could be inhibiting brain functioning as well. (Too much of the main excitatory neurotransmitter, glutatmate, causes nervous system transmission to crawl to a halt.)
Provisos: This was a very small study and needs to be validated with larger groups, which Baraniuk hopes to do. He’s always got his eye on chronic fatigue syndrome, and he ended the paper the way he started it, focusing on ME/CFS.
These CMI subjects also met CFS criteria, so future studies will be needed to confirm and expand our conclusions for the entire population of Persian Gulf War veterans, and to identify pathophysiological similarities with CFS.
Baraniuk and Raynal are concentrating on proving dysfunction and no treatment recommendations were made but if the glutamate/glutamine imbalance is off in GWS/ME/CFS some treatments options are available. (More about that in a future blog.)
Meanwhile potential ME/CFS subsets are showing up at a high rate; Baraniuk and Raynal have the low lactate level during exertion group, Natelson has his high lactate, low cerebral blood flow, neurologically impaired group without mood disorders, Jason found a high pain group that doesn’t respond to pacing, Dr. Peterson has his Vistide responsive HHV6/CMV group, there’s the Rituximab responder group, and as we’ll soon see we may have a small fiber neuropathy group and many more are surely out there (NK cell dysfunction group, the failing VO2 max group); it’s all getting very interesting (and complicated). Hopefully, someone somewhere is putting the pieces together….
Conclusions
Exercise stress tests suggest a broken lactate loop that provides energy to the brain during exercise and intense mental activity causes severe cognitive dysfunction in one group of GWS/ME/CFS patients (decreasers). A second GWS/ME/CFS group (increasers) with an intact brain lactate processing in the brain actually improved their cognitive functioning during exercise.
Baraniuk’s Georgetown research team’s focus on the brain is bearing fruit
The high brain lactate levels found at rest in all GWS patients suggest metabolic or mitochondrial problems may be present (and mayvalidate the high lactate readings found in prior ME/CFS studies). A trend towards differing glutamine/glutamate ratios in the two groups suggests high extracellular glutamate levels could cause the cognitive problems present by interfering with nervous system transmission. The authors pushed for similar studies in chronic fatigue syndrome.
Baraniuk’s Georgetown research team is on a roll. Just last month they proposed that damage found in a key nerve circuit in the brains of GWS patients with ME/CFS could explain the high levels of fatigue, pain and ‘distracted arousal’ present. Now they’ve provided evidence that impaired brain energy production could explain the cognitive problems in these disorders. Still on the teams docket are the VO2 max findings from the two-day exercise test, and multiple studies from Baraniuk’s brain proteome study. At the Ottawa IACFS/ME conference Baraniuk said the studies were going to begin to flow out and there would be alot of them. This may just be the beginning.
Good job Cort.
That’s a pretty complex paper to summarise and I’m still trying to fully understand the implications (accepting the small sample size).
OMGosh! I’ve just experienced such an embarrassing moment with a loan officer from the bank. He was in the neighbor’s yard looking over the banks loss due to non-payment of mortgage. We spoke about the neighbor’s home and yard that was entirely trashed. We exchanged names and phone #’s regarding the property. Not only did I forget the paper in the house with my info on it, but again after getting it I handed him his paper back instead of mine. And that was after losing track of my conversation twice, arousing his curiosity as to whether or not I was possibly drunk or on drugs, perhaps. I just laughed telling him I have chronic illnesses that affect my cognitive abilities for the worse. Sheeeese….bottom line here, I had just been busy for a good hour pushing myself and sweating relentlessly the entire time. My brain couldn’t make sense of a thing. Embarrassing, but then again, laughable.
Sounds familiar Brenda.
It reminds me of a quote from some Swedish researchers from and earlier blog :
“Intense mental activity with high glutamate signalling can lead to astrocytes swelling, especially if their glutamate uptake capacity is impaired. This state, which is locked, may resemble the feeling of cramp in a muscle and the signalling takes a long time to be restored. This may explain the total exhaustion experienced by a person suffering from mental fatigue, when being too active and doing too many things.”
That sums me up pretty well. Put on the spot I can find my brain just doesn’t seem to operate at all. A complete blank – even when the ‘problem’ is trivial such as would you prefer rice or pasta or is the door locked or unlocked. Simple black or white decisions seem to be more difficult than a discussion around the ‘grey areas’ of a problem.
Ask me to write an essay on the pros and cons – no problem. Ask me for a quick decision yes or no – forget it!
Enjoyed that! Keep the info coming. I love the new “Cort and Company”!
Issie
Wow, Wow, and Wow!!
I love that Baranuik’s studies are begining to come out with such valuable results. Having gone to Georgetown U. and being part of one of his studies, seeing what he is coming out with makes the effort of having done that so worthwhile!!
Thank you, Cort. I just wish my brain comprehended all that you report on better than it does. You do an amazing job of culling everything done to be easily (??!!) understood, but, still.. we are working with CFS brains.
I do get alot of it especially when I read it two or three times.
Jeanie
I’m taking pregabalin for years now. Something tells me it diminishes brain deterioration.
I still notice cognitif dysfunction but lowering glutmate by increasing gaba makes life just a bit more bareable.
That’s interesting. I take Gabapentin – the earlier version of pregabin. It was advised by Dr Hyams who had undertaken work comparing drug treatments alongside Dr Cheyney almost two decades ago and of those trialled, patients tended to do better with Gabapentin. I can’t recall the other drugs they looked at. My cognitive function and pain are definitely worse if I am late with my dose.
Thanks Fran for the insight.
Nice job giving a clear explanation of a complex topic, Cort. Thanks.
It would be interesting to know whether the difference between the two groups correlates with anything else in their history, such as duration of illness, severity of symptoms, sudden vs. gradual onset, etc.
Yes indeed.
Is the compensatory switch brain metabolism at rest in decreasers compared to increasers due to longer duration or increased severity?
Which then ‘tanks’ under stress?
Dr. Baraniuk ROCKS! that is all- love him and his dedication…
Right on!
Cort, thanks for sharing your understanding of the work of these two researchers from Georgetown Univ.A month ago, I was looking up and trying to separate out their work on CFS from GWI, which is not easy with these certain findings. There may be some similarities but I feel they are distinctly different illnesses in every way. (I studied GWI at onset of ME/CFS, as I was wanting understanding of it, and luckily my military co-workers did not suffer from this.) I am still awaiting CD’s from the London conference, and could not believe the timing of their brain imaging studies for GWI—proof, finally, well publicized. Will their studies of similar findings for CFS be publicized? I wish enthusiasm could be equally shared for the patients of CFS/ME, and be utilized by the NIH. (As well as previous studies that found evidence on brain imaging.) I understand your illustration concerning neurotransmitters, and glutamate, but this is almost impossible to prove as a causative factor of ‘brain drain’. It is difficult to understand proper functioning of the brain, much less dysfunction. I use the illustration of an electrical impulse along the course of a nerve that fizzles out….yet personally know for myself it is a circulatory decrease at fault. I am happy for these two physicians and researchers, and saw their findings on GWI everywhere. Better late than never! Hope to hear of more concentrated efforts on issues affecting us, as patients. MC
I hope they are connected – that would make things so much easier. Baraniuk feels they are – he felt so 6 years ago and he feels so now but the proof awaits as do those ME/CFS studies…Hopefully the hold up doesn’t mean somethings gone wrong.
antibiotic to clear excessive glutamate from CFS brains?????
http://bergleslab.com/pdf/Rothstein_et_al_2005.pdf
Yep
Hopefully coming up in my next blog (and more).
Excessive Glutamate? According to Shungu et. al. 2012 there are low levels of glutathione in the brain. Contradiction?
Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.
Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. NMR Biomed. 2012 Sep;25(9):1073-87. doi: 10.1002/nbm.2772. Epub 2012 Jan 27. PMID: 22281935 [PubMed – indexed for MEDLINE]
I don’t think so.
Although when broken down one of the constituents of glutathione is glutamate, as far as I’m aware ‘whole’ glutathione and glutamate are pretty much antagonistic.
Plus a low antioxidant/low energy state exacerbates glutamate excitotoxicity.
e.g. (not a great example but you get the gist) :
http://www.ncbi.nlm.nih.gov/pubmed/11990449
I certainly hope so as I regularly take a glutathione precursor 🙂
Personally, I do believe my fatigue is related to something happening in my brain. I’ve been diagnosed with CFS/ME. The only thing that has ever helped me immediately was Adderall (generic) while in grad school. Since it works on the brain, my feeling is that the source of the problem is there. I didn’t have the brain energy to read this in depth tonight, but I think research is on the right track by looking there.
Adderall is so interesting…As a stimulant it probably should wipe people with ME/CFS out but it works well for some people. I wonder if helps with that distracting DAN activity talked about in the blog…
No doubts its on the way Cort, WHAT crashes – where, why – more physiological understanding needed.
Yes…good to see you again Enid…We’re getting closer and we just got a good study on exercise intolerance….more on that later. Things are looking up…
My head is swimming after reading this and I certainly don’t understand most of it, but it grabbed my attention. My son, 19, has dx of CFS and POTS (personally I think it’s all one condition whatever name you want to give it). Symptoms became obvious around age 10 – 11 years but in retrospect were certainly there back to very early years. While symptoms are many, the overwhelming fatigue and sleep issues are the most disabling. There is some depression as well which seems to be situational which is to be expected under the circumstances. Exercise (physical and mental) exacerbate the fatigue greatly. Extensive labs have been normal. Only test that was abnormal was the tilt test which was significantly positive. About five years ago we were seeing a naturopath who suggested neurotransmitter testing which was done through NeuroScience. Glutamate and glycine were extremely high, dopamine and taurine were high, and serotonin was remarkably low. We tried a few supplements on recommendation of the naturopath based on those results but we didn’t really see any results though I can’t say we were very diligent in giving them a fair trial. However, I have always wondered if there were not some clues there about the cause of the condition.Doctors that we have seen since that time have never given these results even a passing glance or acknowledged them at all. This article makes me wonder again if they may well likely have some meaning afterall. I’ve always thought they likely do. My son is not able to work and was not able to come close to completing high school and we are very concerned about his future ability to support himself and just have some quality of life. I would be interested to hear any thoughts here on how such neurotransmitter results might fit in the picture of the results found in this research. I would also be interested to know if others have had neurotransmitter testing and what type of results you had. Since physicians we have seen will not even acknowledge it, I wonder if they consider this type of testing to not be valid. Would be interested to her your thoughts on the validity of such testing. It might be very interesting to run these again but I would like to do a bit more research before doing so and thus would be very interested in feedback here on this issue.
Cort, I have tried to open the link to the glutamate article that is referenced in the above article, but when I click on “read more” I just get another copy of the same page with the “read more” link again. I don’t know if it is a broken link or if the issue is with my computer. I have tried it on two different computers with the same result. Would definitely like to read that one as well.
Thank you!
The problem with neurotransmitter testing is it is a snapshot of that moment. But, I think – as with other testing, that gives you an at the moment result – it could be beneficial. It would make sense that the dopamine levels would be high if the glutamate levels are high. That is a precursor to glutamate. I’ve wondered if others would find that to be the case and it’s nice to have at least one person confirming my suspicions. Interesting that his serotonin levels were low. I also have POTS and think that these imbalances could be one of the contributing factors with our symptoms. I’ve been researching glutamate vs. GABA balance thinking there was a connection. I had in the past used things to increase dopamine and that for sure made my POTS worse. (Because I have a tremor (probably POTS related) – my first wrong DX was Parkinsons. So, they trialed me on things to increase dopamine. WRONG–thing to do!!!! I don’t do well on any of the meds that mess with those type of transmitters. I also can’t use GABA – even though I feel that I need to have my parasympathetic system increased and my sympathetic system decreased. It actually will make me worse. And I’ve had reports of others that have felt the same way with this supplement. Some sort of paradox reaction happens.) I think the findings that some have problems with NET function may be the key for some of us. I have the HyperPOTS form of the illness which means that my NE (noriepi) levels go way high when I stand up. That gives you that surge and spike in heart rate and causes the blood pressure to increase. The body is trying to signal the heart to get the blood to moving to the upper body – as we seem to have problems with it not going to our hearts and brains like it should. That boost of NE causes the body to start this reaction to increase blood flow. It is probably a compensatory thing and even though very uncomfortable – is probably our bodies way of trying to correct a problem. We for sure need the blood to our heart and brains. It’s a very complex problem and things are slowly —very slowly —getting sorted out and understood. What is causing the problems with blood flow? That is what needs to be figured out. Why doesn’t the blood flow to our upper body correctly? Is the blood too thick or sludgy? Is there something hindering that blood flow – faulty veins or valves in the veins or something in the veins that may cause issues with contraction (plaque, protozoa)? Is it, in fact, malfunction with the catecholamines – some sort of imbalance between them – causing the problem? POTS is considered an autonomic nervous system disorder – the part of the nervous system that controls every function of our body and every organ – the part we have absolutely no control over. It’s not something that our thoughts control – it’s the automatic part of the function of our bodies. What causes this system to break down and start to malfunction – OR is it a compensatory thing and our body IS trying to compensate for something external or foreign that maybe we could correct? There’s still so many un-answered questions.
Issie
Cort
Great explanation of a complex topic.
Having just read your other report on Thiamine deficiency, I was interested to see that there is some relationship between Thiamine deficiency and problems with glutamate uptake/astrocytes…
http://www.ncbi.nlm.nih.gov/pubmed/21256174
http://www.ncbi.nlm.nih.gov/pubmed/21130821
http://www.ncbi.nlm.nih.gov/pubmed/19428817
http://www.ncbi.nlm.nih.gov/pubmed/19801831
I wonder if the relationship between thiamine deficiency and glutamate uptake in ME/CFS is something Dr Baraniuk would consider looking into?
I always spent my half an hour to read this
webpage’s content daily along with a cup of coffee.