(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.
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’.
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.
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.
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.)
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 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.)
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.
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.)
- See Glutamate – One More Piece in the Chronic Fatigue Syndrome (ME/CFS) Puzzle? The Neuroinflammatory Series Pt. II
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….
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.
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.
- Unusual Type of Nerve Damage Causes Fatigue and Pain in People with Gulf War Illness and Chronic Fatigue Syndrome