Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)

Pyrrhus

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Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)
https://doi.org/10.1007/s00213-021-05986-6

This is a study that confirms Shungu's 2012 finding of lower levels of the key anti-oxidant glutathione in the brains of patients. A lower level of glutathione in the brain is a strong indicator of oxidative stress in the brain.

The study also found a lower level of creatine, which is a less specific indicator of oxidative stress, and a lower level of myo-inositol, which is non-specifically consistent with neuroinflammation.

Oxidative stress in the brain could mean neuroinflammation, impaired energy metabolism, and/or impaired blood flow to the brain. It could also be a possible predictor of localized vitamin B12 or tetrahydrobiopterin (BH4) degradation in the brain.

Unfortunately, both this study and Shungu's 2012 study used the Fukuda diagnostic criteria.

This study chose the anterior cingulate cortex as the location in the brain to study. This is an interesting choice as this part of the cortical brain is very closely connected to the sub-cortical brain. The cingulate cortex was the only part of the cortical brain that showed neuroinflammation in the classic (Nakatomi et al. 2014) study of ME-ICC patients. (All other neuroinflammation was found in the sub-cortical brain.)

Excerpt:
Godlewska et al 2021 said:
Rationale
Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction.

Methods
We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference.

Results
Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants.

Conclusions
The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.
 

Pyrrhus

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This is a study that confirms Shungu's 2012 finding of lower levels of the key anti-oxidant glutathione in the brains of patients.

Shungu's 2012 study is discussed here:
https://forums.phoenixrising.me/threads/increased-ventricular-lactate-in-cfs.14392/

And here:
The following is the abstract from the paper. Note that "GSH" is a nickname for glutathione, and "MRS" is an abbreviation for Magnetic Resonance Spectroscopy.


Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology
Shungu et al 2012 said:
Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using 1H MRS, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD).

In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) 1H MRSI to measure CSF lactate; (ii) single-voxel 1H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) 31P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction.

We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.
(emphasis and spacing added)

So, in a nutshell, the researchers used a technique called Magnetic Resonance Spectroscopy to measure the levels of lactic acid (lactate) and glutathione (GSH) in the brains of ME/cfs patients.

They found elevated lactic acid and low glutathione in the brains of ME/cfs patients, which together indicated higher levels of oxidative stress in the brains of ME/cfs patients compared to healthy people.
 

Pyrrhus

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This study chose the anterior cingulate cortex as the location in the brain to study. This is an interesting choice as this part of the cortical brain is very closely connected to the sub-cortical brain. The cingulate cortex was the only part of the cortical brain that showed neuroinflammation in the classic (Nakatomi et al. 2014) study of ME-ICC patients. (All other neuroinflammation was found in the sub-cortical brain.)

Nakatomi's 2014 study is discussed in the following two threads:
https://forums.phoenixrising.me/threads/neuroinflammation-in-patients-with-cfs-me-pet-study.29219/
https://forums.phoenixrising.me/thr...roinflammation-in-me-subcortical-brain.80923/


And the anterior cingulate cortex is discussed here:
Interestingly, the Anterior Cingulate Cortex (ACC) in the cortical brain also figures prominently in research studies on Attention Deficit Disorder (ADD).[1] One reason why the ACC may be critical for maintaining attention is its connections with the thalamus in the sub-cortical brain.[2] The thalamus is the part of the subcortical (autonomic) brain that is most closely connected to the cortical (conscious) brain.

Although the thalamus is best known as a relay station that provides all the body's sensory information to the cortical brain, the cortical brain also provides "feedback" to the thalamus, allowing the thalamus to suppress certain sensory information. It is thought that this cortical "feedback" is how the conscious brain decides which sensory information to pay attention to, and which sensory information to ignore, a phenomenon called "sensory gating". If there is a problem with this "feedback", then the conscious brain may be inundated with too much sensory information.

References
[1] https://pubmed.ncbi.nlm.nih.gov/23713508/
[2] https://pubmed.ncbi.nlm.nih.gov/23371564/

And here:
As described above, the thalamus is the part of the subcortical brain that is most closely connected to the cortical brain. Although the subcortical brain is where most autonomic (unconscious) activity is controlled, a few parts of the cortical brain are often mentioned because they have strong connections with the thalamus:
  • The Anterior Cingulate Cortex (ACC) is a part of the cortical brain that has strong connections with the thalamus and is therefore often mentioned in relation to subcortical activity, even though it is anatomically part of the cortical brain.
  • The Insular Cortex (insula) is a part of the cortical brain that also has strong connections with the thalamus and is therefore often mentioned in relation to subcortical activity, even though it is anatomically part of the cortical brain.
  • The Prefrontal Cortex (PFC) is a part of the cortical brain that also has strong connections with the thalamus. It is well-known for its role in "executive function" and decision-making. Its connections to the thalamus are so strong that one definition of the Prefrontal Cortex is "those areas of the cortical brain that are connected to the medial dorsal nucleus of the thalamus." The Prefrontal Cortex is therefore often mentioned in relation to subcortical activity, even though it is anatomically part of the cortical brain.
 

Pyrrhus

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Does this have any implication for treatment?
A somewhat timely question. Many people, including Dikoma Shungu, have raised the possibility of using relatively simple nutritional interventions to calm the oxidative stress and related metabolic dysfunction in the brain.

Anthony Komaroff and others raise the idea in their recent publication "Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome".

A 2019 review paper also raised the idea: Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities (Morris et al., 2019)

Jesus Castro-Marrero has already run clinical trials, with results published in 2016 and in 2021.

The goal of such a nutritional intervention would NOT be to cure ME, it would ONLY be to alleviate the symptoms related to oxidative stress and related metabolic dysfunction in the brain. To put it another way, the intervention would not stop the physiological process that is causing the oxidative stress, but it might prevent the oxidative stress from worsening existing symptoms.

The likely elements of such a nutritional intervention would probably be familiar to any long-time reader of Phoenix Rising:
  • N-acetyl-cysteine (NAC) to increase production of glutathione.
  • Vitamin B12 to replace the B12 locally degraded by the localized oxidative stress. (the cobalt ion in B12 is extremely susceptible to oxidation)
  • Other B vitamins or co-factors (CoQ10, NADH, etc.) to ensure mitochondrial energy metabolism despite the damaging effects of oxidative stress on mitochondria. (and perhaps to prevent faulty mitochondria from adding to any oxidative stress)
  • If there has been prolonged B12 depletion in specific parts of the brain, even without body-wide B12 deficiency, there might be a localized methyl-folate trap - as specifically described in (Scott and Weir, 1981) and confirmed in (Smulders et al., 2006) - in those specific parts of the brain, leading to a downstream deficiency of other important nutrients such as creatine or choline. In this case, supplementation with creatine or choline might alleviate symptoms, although the temporary start-up effects of such supplementation are often not tolerated by some patients.
  • And any other nutrients that are known to be depleted in oxidative stress, or that are suspected to be depleted due to their known depletion in inflammation.

As you know @Hubris, I have been using a simple such nutritional protocol for a number of years and I have seen somewhat significant improvement, roughly moving from somewhat severe ME to moderate ME. However, it was absolute hell to deal with the temporary start-up effects that came with such a nutritional protocol, so I can not recommend it to another patient, at least not without a long list of disclaimers.

(Before starting said protocol I had such severe cognitive dysfunction that I could not compose a simple email and I spent 6 years lurking here on Phoenix Rising, cognitively unable to even compose an introductory post.)

Of more current note, Dikoma Shungu is currently conducting a clinical trial of the simplest such protocol:
The following is some information on Dikoma Shungu's current clinical trial of NAC. (Remember that "GSH" is a nickname for glutathione.)


Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (NAC ME/CFS)
https://clinicaltrials.gov/ct2/show/NCT04542161
Excerpt:
Shungu said:
This phase two, single-site study will utilize a double-blind, placebo-controlled, randomized, pre-/post-treatment design to investigate the effect of NAC dosing on brain GSH levels and measure temporally concordant plasma levels of several established circulating markers of oxidative stress. Three study groups, of 20 subjects each (for a total of 60 who completed all components of the study), will each be administered a different dose (0 mg/day, 900mg/day, 3600mg/day) of the study intervention over a four week period; N-acetylcysteine (NAC) treatment. Subjects receiving 0 mg/day dose will be administered a placebo. Baseline visit assessments will include blood collection, survey questionnaires, MRI and MRS imaging. Subjects whose initial screening confirms low GSH level at baseline will be provided with a 4-week supplement of anonymized NAC or placebo caplets. After 4 weeks, subjects will then undergo a follow-up visit to repeat the baseline assessments.
(I have already attempted, without success, to contact Shungu to warn him about the hellish start-up effects that might come with NAC for some people, expressing concerns that the study doses might be too large and that a 4-week treatment period may be too short to evaluate the long-term response to treatment...)
 
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A timely question. Both Dikoma Shungu and Anthony Komaroff have raised the possibility of using relatively simple nutritional interventions to calm the oxidative stress and related metabolic dysfunction in the brain.

The goal of such a nutritional intervention is NOT to cure ME, it is ONLY to alleviate the symptoms related to oxidative stress and related metabolic dysfunction in the brain. To put it another way, the intervention would not stop the physiological process that is causing the oxidative stress, but it would prevent the oxidative stress from worsening existing symptoms.

The elements of such a nutritional intervention should be familiar to any long-time reader of Phoenix Rising:
  • N-acetyl-cysteine (NAC) to increase production of glutathione
  • Vitamin B12 to replace the B12 locally degraded by the localized oxidative stress (the cobalt ion in B12 is extremely susceptible to oxidation)
  • Other B vitamins to protect the mitochondria from the damaging effects of oxidative stress
  • If there has been prolonged B12 depletion in specific parts of the brain, even without body-wide B12 deficiency, there may be a localized methyl-folate trap - as specifically defined in (Scott and Weir, 1981) and verified in (Smulders et al., 2006) - in those specific parts of the brain, leading to a deficiency of other important nutrients such as creatine and choline. In this case, supplementation with creatine and choline may alleviate symptoms, although the temporary start-up effects of such supplementation are simply not tolerated by many patients.
  • Other nutrients that are known to be depleted in oxidative stress, or that are suspected to be depleted due to their known depletion in inflammation.

As you already know @Hubris, I have been using such a nutritional protocol for many years and I have seen significant improvement, roughly moving from severe ME to moderate ME. However, it was absolute hell to deal with the temporary start-up effects that come with such a nutritional protocol, so I could not recommend it to other patients, at least not without a long list of disclaimers.

And as you already know @Hubris, before starting the protocol I had such severe cognitive dysfunction that I could not compose a simple email and I spent 6 years lurking here on Phoenix Rising, cognitively unable to even compose an introductory post.

Dikoma Shungu may be attempting the first clinical trial of such a protocol in ME:

(I have attempted, without success, to contact Shungu to warn him about the hellish start-up effects that can come with NAC.)
Thanks, as far as i remember you never sent me that protocol though (i might remember wrong). What dosages do you recommend for those supplements?
 

Pyrrhus

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Why not add glutamine and glycine?
Cysteine is traditionally seen to be the rate-limiting precursor to glutathione.
In other words, it is the lack of cysteine that usually prevents production of new glutathione molecules.

But there may possibly be situations where glutamate or glycine becomes the rate-limiting precursor...
 
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Alvin2

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N-acetyl-cysteine (NAC) to increase production of glutathione
No effect except making falling asleep easier. This has persisted despite discontinuation of it. No idea how that could happen.

Vitamin B12 to replace the B12 locally degraded by the localized oxidative stress (the cobalt ion in B12 is extremely susceptible to oxidation)
My B12 levels were low but after supplementation for a long time was very high, so i am off it, dropping about 1 point a day, in another 2-3 years i will be below 500 (whatever units). No ME effect.

Other B vitamins to ensure mitochondrial metabolism despite the damaging effects of oxidative stress
A B complex will give me a slight boost for a bit but it wears off. Another poster, perhaps JaimeS mentioned something similar.
I also tried inositol at 4g/day dose, no effect.
If there has been prolonged B12 depletion in specific parts of the brain, even without body-wide B12 deficiency, there might be a localized methyl-folate trap - as specifically described in (Scott and Weir, 1981) and confirmed in (Smulders et al., 2006) - in those specific parts of the brain, leading to a deficiency of other important nutrients such as creatine or choline.
Methylfolate (or folic acid) reduces headache severity but nothing else.
Choline and Creatine supplementation did nothing.

Why not add glutamine and glycine?
Both had no effect when supplemented.
 

Alvin2

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Maybe your body is capable of making glutathione sufficiently or there is no need for it so that cystine etc are used for other polypeptides
In my case the worst part has been that nothing has any appreciable effect.
Except acetyl carnitine helps cognition slightly. And its costs way too much.
 

Pyrrhus

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No effect except making falling asleep easier. This has persisted despite discontinuation of it. No idea how that could happen.
My B12 levels were low but after supplementation for a long time was very high, so i am off it, dropping about 1 point a day, in another 2-3 years i will be below 500 (whatever units). No ME effect.
A B complex will give me a slight boost for a bit but it wears off. Another poster, perhaps JaimeS mentioned something similar.
Methylfolate (or folic acid) reduces headache severity but nothing else.
Choline and Creatine supplementation did nothing.
As any longtime Phoenix Rising reader knows, people can have vastly different responses to simple nutritional supplements such as NAC and B vitamins.

The fact that patients can have such very different responses to nutrients that should calm oxidative stress is going to make any clinical trial very tricky.

Of course if someone manages to perform a clinical trial designed to calm oxidative stress with nutritional supplements, and if the trial enrolls enough people, it might just shed some light on subgroups of patients...
 

lenora

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Yes, @Pyrrhus, it's amazingly true that so many of us have so many different responses to the same item. I'm including meds in that, too. Very seldom does one thing work in all ways for everyone.

That in itself should tell us that this there is not going to be an easy fix for this illness....too many patients with the same, yet different symptoms. I love a good puzzle and this is certainly one of them. I hope I'm still around when this is finally solved.

Thanks for offering us the information and trying to make it easier to understand. It is appreciated. Yours, Lenora
 

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Of more current note, Dikoma Shungu is currently conducting a clinical trial of the simplest such protocol:
The following is some information on Dikoma Shungu's current clinical trial of NAC. (Remember that "GSH" is a nickname for glutathione.)


Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (NAC ME/CFS)
https://clinicaltrials.gov/ct2/show/NCT04542161
Excerpt:
Shungu said:
This phase two, single-site study will utilize a double-blind, placebo-controlled, randomized, pre-/post-treatment design to investigate the effect of NAC dosing on brain GSH levels and measure temporally concordant plasma levels of several established circulating markers of oxidative stress. Three study groups, of 20 subjects each (for a total of 60 who completed all components of the study), will each be administered a different dose (0 mg/day, 900mg/day, 3600mg/day) of the study intervention over a four week period; N-acetylcysteine (NAC) treatment. Subjects receiving 0 mg/day dose will be administered a placebo. Baseline visit assessments will include blood collection, survey questionnaires, MRI and MRS imaging. Subjects whose initial screening confirms low GSH level at baseline will be provided with a 4-week supplement of anonymized NAC or placebo caplets. After 4 weeks, subjects will then undergo a follow-up visit to repeat the baseline assessments.
(I have already attempted, without success, to contact Shungu to warn him about the hellish start-up effects that might come with NAC for some people, expressing concerns that the study doses might be too large and that a 4-week treatment period may be too short to evaluate the long-term response to treatment...)

Last month @Cort wrote a piece for Health Rising that provided some fascinating insight into Shungu's clinical trial:
Health Rising said:
The NIH has been fiercely resistant to funding clinical trials for ME/CFS. In fact, the NIH states in the title of its two 2020 Program Announcements for ME/CFS that it will not fund clinical trials.
[...]
So how did Shungu manage to get the NIH to fund a 5-year $2 million-plus clinical trial in ME/CFS? Shungu did that by bypassing the ME/CFS Program Announcement (PA) and used one (PA-18-345) specifically designed to support clinical trials. It’s been thought that anti-ME/CFS bias would preclude any clinical trial from being funded through such a generic PA – yet Shungu managed to get his through.
[...]
The study started in 2020 and is taking place at Cornell University in Ithaca, New York. It’s slated to last through 2025 and is still is listed as still recruiting patients.

Personally, I am still a bit worried that the study might fail due to the subset of patients who have dramatically negative start-up effects on NAC, and who need 8-12 weeks to start seeing the positive effects of NAC. Maybe this is a very small subset of patients, or maybe not. For this reason, I would feel more hopeful if the study used lower doses (0 mg/day, 100mg/day, 1000mg/day) and used 16 weeks of treatment.

There may be another complication related to supraphysiological NAC doses - supraphysiological doses of cysteine (NAC) can have a sedative effect. This is why high-dose NAC is currently of interest in psychiatry for treating anxiety. A 2005 paper [1] provided evidence for a possible mechanism of action for the observed sedative effect:
  1. At high concentrations in the nervous system, cysteine self-reacts to form cystine.
  2. Cystine in the synaptic cleft binds to the pre-synaptic cystine-glutamate antiporter and is taken into the pre-synaptic neuron, simultaneously releasing glutamate by the pre-synaptic neuron.
  3. The glutamate binds to the inhibitory pre-synaptic mGluR2 receptor.
  4. Synaptic transmission is reduced.
Since the average dietary intake of cysteine is somewhere between 600mg-1200mg, and 1000mg NAC = 740mg cysteine, I would probably consider any NAC dose above 1600mg/day to be supraphysiological...

Reference:
[1] https://www.jneurosci.org/content/25/27/6389.long
 
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lenora

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12 wks. is a long time to perhaps feel rather rotten. Maybe earlier results will be available...that would be nice. Yours, Lenora.