Two million dollars for chronic fatigue syndrome (ME/CFS) research…You don’t hear those words very often. The NIH just gave Dr. Shungu and associates a big two million dollar grant to peer into chronic fatigue syndrome patients brains.

This is the kind of study that makes you love the NIH; it’s expensive, it’s big and if it works it could really change things.

Oxidative Stress and Glutathione Get Their Day…

RIch Von Konynenburg  glutathione depletion theory got a boost when Shungu found significantly reduced glutathione levles in the brain.

RIch Von Konynenburg glutathione depletion theory got a boost when Shungu found significantly reduced glutathione levles in ME/CFS patients brain.

Perhaps no finding has been more consistent in ME/CFS than increased levels of oxidative stress but it’s always been hard to know what to do with these findings. High free radical levels, after all, occur in many chronic disorders. You certainly don’t want a bunch of free radicals smacking your cells and then releasing more free radicals that simply feed a free radical firestorm but the finding was too general to base a biomarker on.

Rich Van Konynenburg’s  glutathione depletion theory and his corresponding methylation protocol has been used successfully by patients and even been picked up by doctors but study evidence for the theory was weak.  Both oxidative stress and glutathione, at least, at the research level appeared to be at something of a dead end…. until Shungu came along and fixed both problems. 

The Brain – On Fire

Shungu’s 2012 study found an an alarming (36%) decrease in the body’s chief antioxidant, glutathione (GSH), in the cortical regions of the brain. (Rich Von Konynenburg, a longtime proponent of the glutathione reduction theory in ME/CFS, must have been smiling broadly.)

Shungu'sstudies suggest damaged mitochondria in the brain's of ME/CFS patients are producing lactate

Shungu’sstudies suggest damaged mitochondria in the brain’s of ME/CFS patients are producing lactate

The NIH was no doubt highly impressed with the fact that the low GSH levels were associated with increased levels of free radicals and Shungu’s other findings of increased levels of cerebrospinal fluid lactate and reduced blood flows. Shungu believed free radicals whipped up by pro-inflammatory cytokines in the brain whacked the mitochondria  hard enough to shut largely shut them down, causing lactate levels in the brain to rise.  Dr. Teitelbaum pointed out that high lactate levels could contribute to anxiety/hyperventilation (think sympathetic nervous system activation/’arousal’).

Shungu hit a snag, though, when he did not find ‘significant’ differences between ME/CFS patients and patients with major depressive disorder but he did find a trend; ie a finding that almost reached the major number (p<.05) at which findings suddenly become ‘significant’.

Shungu’s small sample size (n=15; CFS, MDD and controls) suggested he didn’t have much differentiating power anyway, suggesting that simply increasing the sample size could very well turn the differences between ME/CFS and MDD patients into something ‘significant’ . Shungu would clearly love to differentiate MDD from ME/CFS patients but he’s actually up to much more than that, and it’s at that point this study really takes off.

Shungu thinks he can produce subsets based on brain biochemical findings.

Shungu thinks he can produce subsets based on brain biochemical findings.

Shungu knows he has a big problem with subsets in ME/CFS; that all you probably need to do is scratch the surface of this disorder to get a Pandora’s box full of subsets laughing at researchers attempts to get ahold of this disorder. This subset problem is almost certainly the problem holding this field back; it’s holding it back from getting recognition, it’s holding it back from getting funding and it’s probably holding back the biomarker hunt big-time.

Shungu is taking the bull by the horns; he’s going to try to break up both chronic fatigue syndrome and depressed patients into subgroups first and then scan the heck out of them. The NIH brief doesn’t say what tests he’s using to stratify patients but if he can do this successfully we could end up with a range of subsets; ‘pure’ CFS patients who don’t have a hint of depression, CFS patients with a bit of depression, MDD patients with some CFS characteristics ( post-exertional malaise?), and ‘pure’ MDD patients you’d never mistake for ME/CFS patients – all with different brain signatures..

Why Depression?

Why depression? Because many of the symptoms in the two disorders are similar and that makes depression, particularly if you’re doing brain studies, a good proving ground for a biomarker. If researchers can distinguish ME/CFS patients brains from depressed patients brains they’ve probably got a pretty darn good biomarker.

Plus many people outside the community still view ME/CFS as a kind of ‘depression’ and the only way to prove it’s not, is to do studies that prove it isn’t. This isn’t to say that the two don’t share some relationships; Hornig and Maes and others believe that inflammatory processes underlie both ‘depression’ and ME/CFS. Some otherwise healthy people, after all, wake up one morning with ‘depression'; no trauma needed, just some sort of mysterious system reset – just as occurs with ME/CFS. Some forms of depression do respond to counseling ..others don’t.

Dig Deeper – Marco’s Neuroinflammatory blogs propose that a neuroinflammatory condition characertized by, yes, high rates of oxidative stress, underlies ME/CFS and many other conditions

The important part of this study is NOT proving that chronic fatigue syndrome is not depression; we know that…it’s identifying brain abnormalities (biomarkers) unique to this disorder. Every possible biomarker is going to have to get tested against other ‘similar’ disorders to ensure that its real. To Shungu’s credit he’s way ahead of the game here; he ticked off anxiety with a 2009 study showing lactate levels in were higher in ME/CFS than in generalized anxiety. If Shungu can now snag depression as well as anxiety he’s got a solid basis for a biomarker.

The lactate levels weren’t just ‘higher’ in ME/CFS patients, they were 300% higher. Anxiety/arousal has been a touchy topic in ME/CFS but Shungu’s work lays out a clean biological basis for those problems. Teitelbaum’s assertion that hyperventilation is a natural outcome of increased brain lactate levels is doubly intriguing given the propensity some patients have for ‘shortened breath’ patterns.

The Natelson Connection

The Natelson tie-in is fascinating. One of the studies co-investigators is trying to do much the same thing, with different brain tests, inside the chronic fatigue syndrome community. Expanding on his earlier work Natelson is exploring whether ME/CFS patients with depression have less brain dysfunction than ME/CFS patients without depression.


Shungu-ME-CFS-researcher-Any study that could uncover unique brain abnormalities in ME/CFS is a big win. The fact that it’s tied with Dr. Natelson and his suite of studies on subgroups adds some extra juice. The fact that the increased lactate levels could help explain the ‘anxiety’ or arousal issues in ME/CFS (but not in generalized anxiety disorder) is another plus.  If Shungu’s study works out it’s even possible that the research world will wing its way back to Rich Van Konynenburg’s theory.

The  CFIDS Association, which provided funding for Shungu’s pilot studies,  must be happy to see its pilot study program working out so well as well.

All in all, a good day for this disorder.




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