All posts by Cort Johnson

MAIT Immune Cell Findings Unite U.S. and U.K. ME/CFS Researchers

The US and the UK are said to have a “special relationship”. That special relationship hasn’t generally extended to ME/CFS research, given a decidedly different focus on ME/CFS in the two countries – a strong focus on biological research in the US and more of a focus on CBT/GET in the UK.  That might be changing, though.

Derya Unutmaz at Jackson Labs and Jacqueline Cliff of the London School of Hygiene and Tropical Medicine | LSHTM appear to have both independently landed on the same immune cell in chronic fatigue syndrome (ME/CFS). Given the multitude of immune cells found in the body, that has the potential to be rather special.

UK ME/CFS Biobank

A large NIH funded UK Biobank enabled these researchers to produce one of the largest ME/CFS immune studies done.

The specialness doesn’t stop there. The samples tested by these two teams – all 300 of them – come from the UK ME/CFS Biobank – which since 2014 has received major funding from the National Institutes of Health (NIH) in the US. (The Biobank has also received funding from The ME Association, Action for ME, and ME Research UK.) Plus, the NIH provided most of the funding for the Cliff project.

The UK ME/CFS Biobank is big. It contains serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA samples from over 500 ME/CFS and multiple sclerosis patients and healthy controls. Plus, it includes an extensive dataset of 700 clinical and socio-demographic variables.

The Cliff study focused on the immune system – a natural system to target given the infectious onset many experience and the symptoms common to all patients. An immune “hole” could give a pathogen time to do more damage, set off an autoimmune response, or alter immune functioning in some other way.

Immune studies in ME/CFS are not uncommon, but the Cliff team researchers (sounding very English at least to my ears) described their results as “discrepant” and inconclusive. Interesting research findings have not been reproduced in ME in part, they asserted, because of small study sizes, varied research methods, and sometimes a less than stellar quality of the studies.

This Biobank study is different, they believe. A large study with a well characterized patient group, they clearly believe its results will stand the test of time.

The Study

Front Immunol. 2019 Apr 16;10:796. doi: 10.3389/fimmu.2019.00796. eCollection 2019. Cellular Immune Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Cliff JM1, King EC1, Lee JS1, Sepúlveda N1,2, Wolf AS1, Kingdon C3, Bowman E3, Dockrell HM1, Nacul L3, Lacerda E3, Riley EM1.

The Patients

The Cliff study examined the samples from over 400 patients and controls (251 ME/CFS (54 severely affected and 197 mild/moderate), 46 multiple sclerosis, 107 healthy controls.)

The patients met either the Canadian Consensus Criteria or the 1992 Fukuda Criteria (or both) and were mostly recruited via the UK National Health Service. The patients were determined to meet either criteria after their responses to a Symptoms Assessment form were fed into a computerized algorithm that maps their symptoms onto the different ME/CFS study case definitions.

Since the Fukuda definition does not require post-exertional malaise – the core symptom of ME/CFS –  it was surprising to see the group potentially accept patients who only met that definition. It wasn’t clear from the study what proportion of patients, if any, met only the Fukuda criteria, though. Severely ill patients were mostly home or bed bound. Their blood samples were taken during home visits.

People who had taken antiviral medications or drugs known to alter immune functioning, had a recent history of vaccination, had a history of other chronic diseases such as tuberculosis, cancer, uncontrolled diabetes, etc., had a severe mood disorder, or who had been pregnant or breastfeeding in the past 12 months were excluded.

One part of the study focused on natural killer (NK) cells – key players in the early, innate immune response. Given the NK findings in ME/CFS, the group’s decision to analyze NK cells was not a surprise, but they gave their analysis a twist. Because cytomegalovirus (CMV) infections have such profound effects on our NK cells (and the rest of our immune system), the relationship between CMV infections and NK cells was assessed to determine whether a past CMV infection could be responsible for the NK cell abnormalities seen in ME/CFS.

Results

The Next Big Thing in Immune Research? MAIT cells Pop Out Again

The big news from the Cliff study is the increased frequency of the CD8+ mucosal associated invariant T cells or MAIT cells.  The UK authors noted that an increased frequency of MAIT T-cells has not been published before, which is true, but Derya Unutmaz, leader of the NIH ME/CFS Research Center at the Jackson Labs, has been talking about them in ME/CFS for several years.

MAIT cells

MAIT cells form a bridge between the gut and the immune system. (From Dr. Oh’s NIH Conference presentation)

Unutmaz reported finding high levels of MAIT cells in ME/CFS patients.  Unutmaz’s findings suggest that the MAIT T-cells have been repeatedly activated in ME/CFS and that they evidence the same activated/burned out pattern he’s found in other T-cells.  He and Dr. Oh at Jackson Labs are trying to determine which stomach bacteria has turned them on and then find a way to eliminate or reduce it.

MAIT cells are known for the role they play protecting the lining of the gut against toxic bacteria. Their name – mucosal invariant T-cells – derives from the high levels of these cells gathered around the mucosal surfaces of the gut (e.g. the lining). In effect they are the gut’s innate immune cells – sentinels guarding the gut wall which can, in contrast to other T-cells, react immediately to invaders.

They’re different from other T-cells which get activated after being triggered by an antigen from a pathogen. Instead, they’re activated by fats and vitamin B2 metabolites produced by plants, bacteria (E. coliPseudomonas aeruginosaKlebsiella pneumoniaL. acidophilusS. aureus, and S. epidermidisC. albicansC. glabrata, and S. cerevisiae ) and fungi. Because cytokines produced by viral infections can activate them as well, the high degree of MAIT cell activation is not necessarily due to bacteria in the gut – but it’s the most likely scenario.

MAIT research only started popping up after 2010, when studies revealed these unusual cells were able to detect bacteria and fungi and respond with pro-inflammatory cytokines. Since then many studies have suggested that MAIT cells play an important role in infectious diseases, autoimmune diseases and cancer. MAIT cells are not always pro-inflammatory, but increased levels, particularly of cytotoxic MAIT cells, are believed to be associated with pathogenic states.

In contrast to Unutmaz’s apparent (but unpublished) findings of high levels of MAIT cells in ME/CFS overall, this study found a high proportion of MAIT cells only in the severely ill ME/CFS patients. They noted that a small number of the severely ill patients were reported to have “exceedingly high” frequencies of these cells.

Most of the MAIT cells in the severely affected ME/CFS patients (as well as in the MS patients) were in their cytotoxic (killing) form.  They’d probably been activated by a bacterium in the gut and were apparently on the prowl, ready to pounce. While the increased proportion of MAIT cells only weakly discriminated the severe ME/CFS patients from the healthy controls, the high percentage of killer T-cells (cytotoxic T-cells) found was moderately discriminative.

Interestingly, the Cliff study authors pointed out that peripheral MAIT cell levels in healthy volunteers can increase 2-fold following exercise. Finding similarly high levels of MAIT cells in the severely ill patients suggested they were in a similar post-exercise state without having engaged in any exercise.

Slight Increase in ESR Surprises

Interestingly, symptoms associated with inflammation/infection were more common and more severe in the ME/CFS cohort than in the MS cohort (go figure!). Perhaps that’s not a surprise, since ME/CFS has been shown to impact functioning to a greater degree than MS.

The slight raise in erythrocyte sedimentation rate (ESR) – an inflammatory marker – in mild/moderate cases of ME/CFS compared to the other groups (Including the severe ME/CFS group) was surprising, though, given that very low ESR’s are thought to be typical in this disease.

Laboratory studies. These tests can be used to exclude other diseases associated with fatigue. The most consistent laboratory abnormality in patients with CFS is an extremely low erythrocyte sedimentation rate (ESR), which approaches zero. Typically, patients with CFS have an ESR of 0 to 3 mm/h. A normal ESR or one that is in the upper reference range suggests another diagnosis. https://www.consultant360.com/content/chronic-fatigue-syndrome-update-diagnosis-primary-care

Natural Killer Cells

As the Cliff study introduced a new factor into ME/CFS research (MAIT cells), it took a hatchet to the last big immune finding in ME/CFS – natural killer cells. The study found no significant differences in NK cell proportions, types, KIR receptors or activation markers before or after they stimulated them.

Some NK markers did stand out, but only in patients who had been exposed to CMV. The authors suggested a past CMV infection in some of the ME/CFS patients had likely caused the NK cell abnormalities in ME/CFS – not ME/CFS.

The Cliff study, however, used a different test of NK cell functioning than some groups have used in the past. The British group assessed both T and NK cell functioning by determining how the cells responded to stimulation; i.e., did they produce distinctive markers and/or start producing cytokines. The ME/CFS patients’ cells apparently whizzed through that test – they perked up and started producing cytokines, leaving the authors to report that no functional issues with these cells are present.

NK cell functioning

The Cliff study suggested that the NK cell findings in ME/CFS may be due to patients with past CMV infections. They did, not, however, use a NK cell functional test used by others in the past.

Dr. Klimas, however, uses a more direct functional NK cell assay which measures the number of target cells killed. Plus, instead of the PBMC’s used in the Cliff study, she uses whole blood – possibly a critical factor, given Ron Davis’ and Fluge’s findings that something in the plasma is affecting the cells. In fact the first hint of a blood-borne factor in ME/CFS showed up in NK cell studies.  That idea that something in the blood was impacting functioning first showed up when Dr. Klimas realized that a study which found no evidence of problems with NK cell functioning had not used whole blood in its tests.

The UK study authors noted that small study sizes have hampered immune results in this disease, but size was not an issue for the 2011 Klimas/Fletcher study (176 ME/CFS patients, 230 healthy controls) which found significant declines in NK cell functioning, and those declines were associated with increased fatigue levels. In an Australian study, Brenu also used a target cell killing test to show reductions in T-cell functioning. The UK study authors did not allude to other possible functional tests or the whole blood issue in their manuscript.

Exhausted T-cells?

The UK study authors did find a number of T-cell abnormalities: increased proportions of effector memory CD8+ T cells, decreased proportions of terminally differentiated effector TEMRA cells, and some minor changes elsewhere – whose effects are unclear. The UK authors suggested, though, they could be due to “ongoing antigenic stimulation” due to an unresolved infection or autoimmunity.

Either could presumably produce a state of “immune exhaustion” which some have hypothesized is present in ME/CFS.

Derya Unutmaz focused on key players in autoimmunity and inflammation called TH17 cells in his U.S. study. He wasn’t surprised to find high levels of TH17 cells – which are regulated by the gut –  but he was shocked to find low levels of the IL-17 cytokine they produce. That finding also suggested that the immune cells in ME/CFS might be in a state of exhaustion.

The Cliff study’s IgG antibody tests found no evidence of increased herpes virus reactivation in ME/CFS, and some evidence of it in MS. The group didn’t close the book on the possibility of herpesvirus reactivation in ME/CFS, though, stating that other antibody tests for EBV might produce different results.

Conclusion

The Cliff study was a large UK Biobank study using both Fukuda and/or Canadian Consensus Criteria to identify its patients. The study’s finding of moderately increased ESR levels in the mild/moderate patients was surprising, given past reports of low ESR levels in ME/CFS.

Except in patients who have been exposed to cytomegalovirus (CMV) in the past, the study found no evidence of natural killer cell issues in ME/CFS. The researchers did not, however, use a functional assay used successfully in the past which more directly measures NK or T-cell killing capacity.

The study’s major finding was a significant increase of specialized T-cells called MAIT cells in the severely ill patients. MAIT cells are found across the body but are most known for the role they play protecting the gut lining from toxic bacteria. High levels of MAIT cells have been associated with infectious diseases, autoimmunity and cancer.

This is the second recent and, it should be noted, independent report of high levels of MAIT cells in ME/CFS. In fact, these two reports are the first time MAIT cells have been implicated in this disease.

Dervy Unutmaz and Dr. Oh of the Jackson Labs are currently trying to isolate the bacteria triggering the high levels of MAIT cells they’ve found in ME/CFS.

The Cliff study did find moderate T-cell anomalies which could possibly reflect a state of chronic T-cell activation caused by an infection or autoimmune response. Derya Unutmaz also recently reported he’d found evidence of immune cell exhaustion in his T-cell studies.

East African Disease Informs Nath’s Search for the Cause of ME/CFS

Could a disease found in the remote villages of East Africa end up being a model for chronic fatigue syndrome (ME/CFS)?

Ugandan Village

Ugandan Village (from the NIH)

Dr. Avindra Nath – the leader of the NIH Intramural study on ME/CFS –  thinks perhaps so. He’s not daunted by mysterious diseases and nor should he be. Just a couple of years ago his NIH team was able – by bringing new technology to bear – to unravel a mysterious disease plaguing children in Africa. Using a much larger array of tests he’s hoping to do the same in ME/CFS.

Nath became acquainted with “nodding syndrome” at a meeting in Uganda in 2012. This strange and often devastating disease, found in the remote regions of Uganda, Tanzania and South Sudan, causes children’s heads to periodically nod  and can produce seizures, mild to severe cognitive impairment, muteness, gait problems, paralysis and often death. Brain scans have shown significant brain atrophy.

Studies suggested that the disease was linked to a parasite, Onchocerca volvulus, carried by the black fly, but numerous efforts to find the parasite in the brain or cerebral spinal fluid failed.  Attempts to tie it to immune factors including autoantibodies, as well as genetics, toxins, nutritional factors, and others came to naught as well.

Like ME/CFS the speculation regarding the cause of nodding syndrome has been rife with possible connections to autism spectrum disorder, Alzheimer’s, poor nutrition, PTSD and others being put forth. Ugandan psychiatrists have even proposed that the disease is a form of “Developmental Trauma Disorder” brought on by the war.

Enter Nath, Tory Johnson, a former postdoc fellow of his, and Thomas Nutman, a National Institute of Allergy and Infectious Disease (NIAID) researcher.  Suspecting the problem was autoimmunity, they brought out one of their big guns – a kind of protein chip technology that allowed them to screen for thousands of antibodies at once.

The results were tantalizing. The levels of four antibodies were 100 fold higher in the sick children compared to the healthy children.  Further testing revealed that two of these antibodies were more reactive or active in the sick children. They ended up focusing on one antibody found in both the blood and cerebral spinal fluid.

This antibody – which was linked to the leiomodin-1 protein  – reacted 33,000 times more strongly in the children with nodding syndrome.  Interestingly, both groups – the sick and the healthy children – carried the antibodies, but they were elevated in the sick children.

Leiomodin-1 staining neurons

Staining reveals Leiomodin-1 antibody (green) interacts with human neurons

After finding this link, they deepened their search. The leiomodin-1 protein had been found primarily in smooth muscle tissue and the thyroid, but if it was causing the neurodegenerative symptoms it had to be in the brain as well. Further testing, including immunostaining human neurons, indicated that protein was indeed found in parts of the brain imaging studies had indicated were associated with nodding syndrome.

Having established a putative link between the antibody and the disease (that it was found in and could potentially affect the brain) the next step was to demonstrate that the antibody could indeed be causing the disease. Subjecting cultured human neurons to the antibody showed that the antibodies could indeed be damaging the childrens’ neurons.

Getting at the source of the antibody was next. The authors hypothesized that an immune attack against the parasitic worm had gone awry and was attacking the ill childrens’ neurons. This could only happen, though, if the parasitic worm and human neurons shared genetic sequences that could cause the immune system to mistakenly attack human neurons. Studies confirmed that a very short sequence of the parasite’s tropomyosin gene was quite similar to a sequence expressed in human neurons.

autoimmune responses ME/CFS

Nath believes the infections may have triggered a variety of autoimmune responses targeting the brain in ME/CFS

With that, the circle was closed. They had identified an antibody, shown it was in the brains of the sick children, showed that it could do damage to the neurons that were damaged in the children, and demonstrated similar genetic sequences were present in the parasite and humans.

There was still the nagging issue of antibody prevalence, though.  Only slightly over 50% of the sick children had antibodies to leiomodin-1. If the antibody to leiomodin-1 was causing the disease in these children, what was causing the disease in the others?

Nath et al proposed that the parasite triggers a different immune response in different children.  Some of the children developed autoantibodies that damaged neurons in their CNS  – and produced nodding syndrome (which is now understood to be a form of autoimmune epilepsy).

This syndrome is likely not a disease mediated by a single immune specificity. We speculate that nodding syndrome may not be a single antibody syndrome.  Nath et al.

Citing test results which showed a range of elevated autoantibodies in the sick children, they suggested that some children with nodding syndrome have developed antibodies to  neuronal proteins other than leiomodin-1.

A Model for Chronic Fatigue Syndrome (ME/CFS)?

Nath reported that his approach to ME/CFS has been shaped by his experiences with nodding syndrome. He suspects the infectious onset that so many people with this disease experienced triggered their immune system to accidentally produce autoantibodies that are attacking their central nervous system or other parts of the body.

If suspect antibodies show up, future research efforts will presumably proceed down the same pathway as they did in Nodding Disease: first they will identify the proteins the antibodies are attacking, and then they will determine where those proteins are found, and demonstrate experimentally that the antibodies are likely doing damage.

Nath and his compatriots uncovered the antibody connection to nodding disease seven years ago – a long time in this age of fast moving medical technology. Nath reported he’ll be using a newer approach involving mass spectrometry, or phage display, in ME/CFS which will allow him to “probe almost infinite numbers of proteins/peptides”.

Seven years ago, extensive testing had failed to find a culprit leaving the cause of nodding syndrome a complete mystery. In 2017 Nath et. al. produced a clear pathway that explains about 50% of nodding syndrome victims.

Technology Paves the Way

Note that the breakthrough didn’t come from the slow accumulation of results over decades; –  it occurred very quickly and simply required the right technology being applied to the disease. When that happened, a cause of the disease became clear, and researchers simply proceeded down established pathways to prove  it.

Nath and the NIH are looking at much more than antibodies in their intramural study, and ME/CFS, with its multiplicity of triggers, is likely to be more complex than nodding syndrome. The same principle, though, – a variety of autoimmune processes produced by an infectious trigger – may apply.

Dr. Nath appears to have gotten at a cause of one mysterious disease. May he be as successful with this one.

Check out an interview with Dr. Nath

Dr Nath Talks on the ME/CFS NIH Intramural Study

The NIH’s Accelerating Research on ME/CFS Conference

Because of a death in the family, Brian Wallitt will be presenting in Dr. Nath’s place at the NIH conference. Dr. Nath reported that Wallit will present on the high rate of rare diseases found during the first half of the study and some other data but will not present statistical analyses. With just half of the projected participants having finished the first part of a two-part study, the lack of statistical analyses is not really a surprise.

Brian Wallitt will be presenting at 10:00 AM EST on April 5th (day two) of the Accelerating Research on ME/CFS conference – the first NIH sponsored research conference on the disease since 2011. Check out the agenda here.

Learn more about the NIH Conference below.

NIH Brings in New Faces and Looks to the Future in Accelerating ME/CFS Research Conference

A Former Doctor Goes Through the NIH’s ME/CFS Intramural Study

Robert’s Story

Robert, an MD, is board certified in internal medicine. After the worst flu-like illness he ever had, he ended up in the hospital.  A regular exerciser prior to becoming ill, his legs were so weak that he could hardly walk afterwards.

His path to a chronic fatigue syndrome (ME/CFS) diagnosis was rapid. Three months of testing left him no other conclusion – it was clear to him that he had ME/CFS.  He was able to work on and off for a few years, but his health has deteriorated. He’s been unable to work for the last three years.

ME/CFS diagnosis

Robert, a former MD, was able to rapidly diagnose himself but remains severely ill.

Thankfully, he had a wide array of doctor friends who knew him before he became ill and didn’t encounter the skepticism and invalidation so commonly experienced in our community. He noted that our current medical culture doesn’t offer much for the complex patient. Doctors are busy and often time-constrained and if you don’t fit into one of the medical pigeon-holes, they don’t have much to offer.

Rating his level of health on a scale of 1-10 at 2, he’s one of the sickest, if not the sickest, ME/CFS patient to participate in the grueling two-part intramural study at the NIH. He was the first patient to go through the second phase of the Intramural trial which involved, among other things, the exercise study and an extended stay in a metabolic chamber.

One theme – validation – cropped up several times during Robert’s week long stay at the NIH hospital in Maryland. It was clearly apparent from the gestures of sympathy from the occupational therapist during a test to assess functioning.  Given cards which identified an activity, Robert put them into two piles – activities he used to do and activities he still did. The occupational therapist – who has probably given this test hundreds if not thousands of times – registered dismay at the few cards left in his “still do” pile. Those few cards left made the extra level of devastation that ME/CFS is so good at causing clear. It’s rare for people who are not elderly to be so sick.

Given his abysmal level of functioning, Robert’s willingness to participate in a study that Dr. Nath thought few might be willing to undergo was a real testament to the courage and determination that so impressed Dr. Nath. Despite Robert’s low functional level (1-2 on a 10-point scale), he was disappointed that the NIH was not doing a two-day exercise test (!).

The second part of the study is centered around the exercise stressor. Participants do cognitive testing, blood tests, the Seahorse mitochondrial test, a functional MRI and transcranial magnetic stimulation before and after the maximal exercise test.  (The NIH communicated with the Workwell Foundation on doing the exercise test with ME/CFS patients).

Exercise is finally getting its due in ME/CFS, and over the next couple of years several large studies should tell us much. With its extensive blood draws and millions of data points, Dr. Klimas’s exercise studies have informed her models of ME/CFS and laid the foundations for her clinical trial.  With help from the Solve ME/CFS Initiative, David Systrom has added gene expression to his already complex invasive cardiopulmonary exercise testing.  Maureen Hanson has incorporated exercise into her large NIH Research Center studies at Cornell, as well.  None of these studies, though, can match the sheer breadth of this NIH exercise study with its brain scans, lumbar punctures, Seahorse data, blood draws, etc..

Metabolic Chamber

Robert spent about three days in the metabolic chamber – a sparse box containing a bed and a toilet that’s designed to produce precise measures of metabolic activity – before and after the exercise test.  (I will expand on the metabolic chamber).  He wore an EEG, blood pressure and Holter monitor, while in the chamber.

Only thirty metabolic chambers exist in the world, and three of them are at the NIH. With 400 metabolic chamber studies underway every year, they’re pretty much in use all the time. These airtight 11-by-11.5-foot rooms aren’t much to look at or stay in: they come with a bed, an exercise bike, a toilet, and nothing else. Precisely measured meals are delivered through a small, air-locked opening in the wall.

metabolic chamber NIH

An early metabolic chamber at the NIH in 1957

Metal pipes running along the ceiling that measure oxygen consumption and CO2 production allow researchers to precisely calculate an individual’s metabolic rate.  From the O2 and CO2 readings, researchers can calculate calories burned and what type of fuel (carbs/fats) was used to burn them. Urine is collected to assess protein oxidation.

Metabolic chamber studies have demonstrated how flexible the body is with respect to metabolism. One reporter wrote, for instance, that they’ve debunked the idea that ketogenic diets (high-fat/low-carb) cause the body to burn more fat than high-carb diets.

Energy is burned in our body in three ways. It turns out that simply staying alive is pretty energy intensive. Most of the calories we burn (65-80%) are used simply to keep our body running (basal metabolism). Digestion is no walk in the park either; digesting our food takes up about 10% of the calories we burn in a day, with physical activity accounting for the remainder (10-30%).

If ME/CFS patients’ metabolic production and ability to produce energy is altered by exercise – as Workwell’s and Dr. Keller’s tests suggest it is – that will hopefully be picked up by the metabolic chamber.

Robert noted that if they can pair the findings from the metabolic chamber – which is measuring the metabolic effects of exercise – with the Seahorse tests- which are measuring energy production on the cellular level, they may really be onto something.

Brain Scan

The functional MRI – which Robert said was combined with a cognitive test – will assess the impact of exercise on a) cognitive functioning and b) brain functioning. A similar study by the CDC suggested that exercise negatively impacted both cognitive and brain functioning.

People who do cognitive tests tend to improve the more they do them but not in this case – not in people with ME/CFS after exercise.  Familiarity did not breed more competence. Despite doing the tests multiple times, the people with ME/CFS did worse and worse on them after exercise and the brain scans indicated why. Exercise had knocked out one area of the brain devoted to sustained attention causing the brain – in a mostly futile attempt to compensate – to increase activity in other parts of the brain (devoted to executive functioning).

A Chronic Fatigue Syndrome Brain on Exercise – Not a Pretty Sight

The end result was that people with ME/CFS expended more effort during the cognitive test and yet did worse. By the end of the test they were making about double the errors of the healthy controls.

rTMS Test

motor cortex

The rTMS test appeared to be designed to stimulate Robert’s motor cortex to activate his muscles.

The repetitive transcranial magnetic stimulation (rTMS) test proved enormously interesting but physically draining.  Robert reported that in a process that took hours, data from a previous fMRI was used map the exact location of his motor cortex in order to stimulate the muscles of his right hand/fingers.  The goal was apparently to determine the speed at which the signal traveled from the brain to the muscle of his finger before and after exercise.  A time delay after exercise would presumably indicate that exercise had interfered with the ability of the motor cortex to activate the muscles.

A 2003 study, in fact, suggested that reduced muscle recruitment due to reduced motor cortex output was occurring in ME/CFS. The motor cortex, it turns out, plans our movements in advance. The study, titled “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“ suggested that problems in the “motor preparatory areas of the brain” might be hampering physical movements in ME/CFS. It has never to my knowledge been followed up on.

rTMS has relieved pain in fibromyalgia but it had the opposite effects in Robert. He wasn’t clear whether it was the effects of the rTMS or the rigors of setting up the test itself or both which triggered for him what turned out to be an extraordinary bout of PEM (post exertional malaise). The 2 hours it took – sitting up – to get the electrodes correct was in itself draining. (He suggested that they use a reclining chair for future patients if possible.)

At the end of test Robert felt exhausted and experienced transient vertigo, auditory disturbance, headache and sensitivity to light and noises.  His nurse was shocked at how poorly he looked.  He’d mentioned the documentary Unrest to her the day before. After seeing the movie, she said she could better appreciate what he was going through. (Hopefully she knows that watching the film will get her continuing medical education (CME) credits)

The rTMS test proved immediately much more exhausting than the exercise test, the effects of which took a day to kick in. The rTMS specialist/researcher was surprised at the effect the test had on Robert and its cause is unknown. Was it the long preparatory period or the activity of the rTMS machine on the muscle activation pathways or both?  It’ll be fascinating to see how other patients fare.

Robert was also tested for small fiber neuropathy via skin biopsy, underwent a post exercise lumbar puncture and quadricep muscle biopsy.  The possibility of integrating the brain scan, cerebral spinal fluid, Seahorse and metabolic chamber results after exercise – not to mention the immune tests – is an enticing one for sure.

NIH intramural ME/CFS study data collection

The study, which is going to generate an enormous amount of data, is still several years away from completion.

Plus there are the muscle biopsy results. Robert’s experience of a rather hefty muscle biopsy suggests that the NIH is not stinting on this area – which Dr. Nath believes may tell us much about ME/CFS.

Plenty of rest periods were provided during the study but at times the testing was lengthy, and the study, predictably, ended up being a rather grueling seven days for this courageous but very disabled ME/CFS patient. Participating in it wasn’t easy but the fact that Robert, even with his abysmal level of functionality, made it through it and recovered, was a good sign. Robert said he was touched by a chaplain who stopped by to see how he was doing.

He’s stayed in touch with the investigators from time to time alerting them of developments in the ME/CFS field.

Participating in the Study

The NIH needs more participants. If you’re interested in helping to further ME/CFS research by participating in the study, check out the study criteria below.

All participants must be 18-60 years old and have at least a 7th grade education. People whose ME/CFS started after an episode of infection and who have severe symptoms lasting from 6 months to 5 years are eligible to participate in the study.

Find out how to participate here.

Learn more about the Intramural Study

Dr Nath Talks on the ME/CFS NIH Intramural Study

Dr Nath Talks on the ME/CFS NIH Intramural Study

It looked like we were going to be late … again. It was pouring cats and dogs as we eased the van around tangled web of streets that is the NIH campus scanning glumly at the rain-obscured buildings. Even our guide on the phone seemed to be lost.

It had been a wild 12 hours. The night before, reaching up to turn on the fan on my brother’s porch, I’d let loose a rather large bug which tumbled into my eye. Howling with pain I stumbled off to the bathroom where I managed to wash it out – leaving my eye reddened and swollen. The next morning, my eye still swollen, my partner insisted I see an eye doctor.

 

NIH

Getting to Dr Nath’s office proved to be a challenge

To our surprise we found somebody. The problem was was that his office was right in the heart of downtown Washington DC. – where parking is scarce and traffic cops take their jobs very seriously. Finding no parking we stopped in a loading zone across from the doctor’s office, hoping that the big yellow van with it’s solar panels, Nevada license plate and all would for the next 15 minutes be taken for a loading van –

After being assured the appointment would be short, I dashed inside where I was  bombarded by frantic calls from my partner (who does not drive the van). She had immediately been accosted by first one then another traffic cop.

After seeing the doctor who informed me (for $250 dollars) that insects in the eyes almost never cause problems (but who did give me drops) I dashed back out to the van to find my now none-too happy partner.

We sped off in the rain – still seemingly on time for the appointment with Dr. Nath. Hauling up to the NIH we tried no less than three entrances – only to be turned away at each them (our oversize vehicle thwarting one attempt) – and directed to the next. Finally, as our appointment time came and went, we found the right entrance – for, ironically, delivery vehicles.

After going through an extensive (and time-consuming) security check we headed off into the labyrinth that is the NIH clutching small hard to decipher maps and immediately got lost. The  minutes continued to tick by and rain strengthened into a deluge and eventually we managed to steer onto the right street. Our guide, still on the phone, told us to stop, we jumped out of the car and looked up, rain pouring down, at a steep, muddy climb.

Five minutes later – 45 minutes late for our hour appointment, we strode, soaked and bedraggled into Dr. Nath’s office. He immediately set us at ease, and with his next appointment running late stayed overtime with us. We were there to talk about the NIH Intramural ME/CFS study.

The NIH Intramural ME/CFS Study

Dr. Nath informed us that the applications to be in the NIH Intramural ME/CFS study have been gratifyingly robust.  Dr. Nath noted that it was entirely possible that this is the most rigorously examined patient group ever assembled for a study.

Dr. Nath

Dr. Nath is leading the study. He has been around. He received his MD degree from Christian Medical College in India in 1981, completed a residency in Neurology from The University of Texas Health Science Center in Houston, did a fellowship in Multiple Sclerosis and Neurovirology at the same institution, and then another fellowship in Neuro-AIDS at NINDS.

Then it was up to Canada, where he held a faculty position at the University of Manitoba (1990-97), and then he was at The University of Kentucky (1997-02). In 2002, he became Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections at Johns Hopkins.

in 2011, he became the Clinical Director of NINDS, the Director of the Translational Neuroscience Center, and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of nervous system infections and their outcomes, and the development of new diagnostic and therapeutic approaches for these diseases. He’s heavily involved in HIV research, the role endogenous retroviruses play in neurological diseases, and “undiagnosed neuroimmune and neuroinfectious diseases”.

He recently wrote a paper on Herpes Viruses, Alzheimer’s Disease, and Related Dementias: Unifying or Confusing Hypothesis?, which examined what role herpesviruses might be playing in dementia.

The NIH Intramural Chronic Fatigue Syndrome Study

The study takes place in two parts: a one week part which further assesses the potential participant and another one week section which measures a wide variety of parameters before and after an exercise test.

Requirements for entry are high, however, and not often met. You might say that many have been called – or rather have called – but few have been chosen. That was OK with Dr. Nath. “We need,” he explained, “to make sure that we’re studying the right population. That’s the best way to get to the answer, and then it’ll be broadly applicable.”

The response has been excellent.  Many people are traveling to participate, and they’re coming from all over. The NIH is even getting interest from people in other countries.

As of Dec. last year, 337 people had inquired about the study. One hundred and seventy-three were quickly screened out, and 164 participated in phone interviews. One hundred and twenty-seven made it to the medical record assessment stage.

Multiple reasons thwarted would-be participants from participating in the study.  The study required onset within 5 years which was triggered by infection. One-third had had the disease for too long, 20% had no evidence of infectious process (doctor’s records are required), 9% were too sick to travel, and just 3% were unwilling to have a lumbar puncture.

community ME/CFS

Nath noted that the ME/CFS community was very motivated to be in the study

The researchers were surprised at the last two figures. They expected, based on their experience from past studies, much higher percentages of people who were too sick to travel or unwilling to have a lumbar puncture. Dr. Nath well knows how difficult it can be to get people to participate in a study, but that’s not a problem here. Calling the numbers “very good”, Dr. Nath said the ME/CFS community was clearly “very motivated to participate in the study”.

It is not an easy study! It’s a two-part, two-week plus study on a population, which studies suggest, has the lowest functionality of any disease. The study includes a lumbar puncture, a maximal exercise test, several nights in a metal box (metabolic chamber), tilt table test, muscle biopsy, brain scans, lengthy neuropsychological tests and scads of blood tests. Every part of you is going to be probed.

Plus, you have to provide your entire medical history, get interviewed several times, and then, most likely travel.

Dr. Nath said he looked at the study – which is clearly larger and more intensive than most  – and said, “who is going to enroll in this study?” Laughing, he joked that, “I wouldn’t volunteer on my own study!” He was afraid no one was going to show up!  Instead he said the patients were very willing to undergo all the tests and are grateful for it.

Recruitment has been good, but as with any study, Dr. Nath said, it was high at first, and now it’s tailed off. As of March of this year, 19 ME/CFS patients and 21 healthy controls had completed the first phase of the study, and six people with ME/CFS and 7 controls had completed phase II.

Thus far, then, about half the projected participants (n=40 ME/CFS; 40 healthy controls) have gone through the first week of the study and about 15% have completed the entire study.

Quite a few people with autoimmune disorders have shown up during the filtering out process. Nath suggested that could be an interesting cohort to study on its own.  He’s also found quite a bit of head injury and loss of consciousness – which makes MRI and brain scans difficult to assess – and people with seizures and strokes. Interestingly, bnly one person had had a diagnosis of major depression….

High Percentage of Rare Diseases 

It’s a small sample set but it’s remarkable how many people participating in the first week were diagnosed with a rare disease. In something of a testament to the thoroughness of the study, almost third of week one participants (6/19) were found to have a rare disorder which the researchers believed was probably causing their symptoms and dismissed from the study. One appeared to have Parkinson’s Disease, another a neurological disease and I’m unsure of the others.

The study was designed to catch these people.  In fact because ME/CFS is something of a wastebasket diagnosis it went to extra lengths to ensure it was really studying ME/CFS.  Plus Dr. Nath reported that neurological diseases are inherently hard to diagnose anyway.  It is not unusual for people with multiple sclerosis, Parkinson’s, etc to be misdiagnosed with some other disease initially.  Plus, the opposite can happen (and has happened in ME/CFS) with some patients being misdiagnosed with M.S. for many years only to find later that they have some other immune disorder.

Big Data

They are gathering lots and lots of data – which brings its own problem. The study includes two different brain scans, blood, saliva, urine and stool samples, exercise data, tilt table data, spinal taps, Seahorse data, metabolic room data, cognitive testing, muscle and skin biopsies, and I’m probably missing some. I asked Nath, how will they able to integrate all this disparate data?

rare disorder chronic fatigue

Rare disorders are popping up at a high rate in the study group

Nath agreed that it was a challenge, but noted that that kind of challenge is a pretty common challenge now. Some of the really big Alzheimer’s and Parkinson’s studies contain thousands of individuals, each of whom has done thousands of tests. Computational biology has become a major part of medical research.

Google, not surprisingly, is collaborating with the NIH to create better ways to analyze data. Many of the discoveries in medicine today, Nath said, actually occur as breakthroughs in physics; MRI and CT scans, for example – came from physics.

Their general hypothesis is that an infection triggers brain and immune system issues (ranging from persistent immune activation to immune dysregulation) that stay stuck.  They don’t believe the nature of the infection is particularly important.

Check out a disease Nath believes could prove a model for ME/CFS

East African Disease Informs Nath’s Search for the Cause of ME/CFS

No Preliminary Findings Yet

Nath was unable to give me any preliminary findings. One reason is that they are storing samples so they can run them all at the same time. Another is that, echoing Ron and Mark Davis’s thoughts, they don’t want to even try to come up with hypotheses yet. They simply want to gather more and more data.

Making a conclusion on the basis of small samples is, Nath said, the kiss the death. They will not even try to interpret their findings until about half the study is done.

If, when they get to the end of the study, they see trends but don’t quite have a significant result, they’ll do sample size calculations to determine how many more patients they’ll need to see to get to statistical significance. If the calculation says do another 10 patients, they’ll probably expand the study to do 12 more. If the calculation says do another 100 patients, that’s too much.

They’re preventing another kind of bias by recoding the samples, so the analyst doesn’t know which are from patients and which are from controls.

The Study

Brian Vastag’s visit raised the issue of mitochondrial problems. Nath believes studying the muscle itself may be more important than assessing mitochondrial problems using the blood, and added muscle biopsies to the study. The muscle biopsies will be tested for DNA analysis, structural issues, and staining for various kinds of cells.

The Open Medicine Foundation and Ron Davis apparently believe likewise. They’ve pumped a million dollars into an ME/CFS Collaborative Research Center at Harvard lead by Ron Tompkins which will focus on figuring out what is going on in the muscles.

muscles ME/CFS

Dr. Nath believes the muscles could tell us much about ME/CFS

Because lots of patients have autonomic symptoms, the NIH is doing tilt table tests. Once those turn out positive, Nath said, the next question is why the autonomic nervous system problems are present. They’re doing small fiber neuropathy skin tests and examining the heart, peripheral nerves, adrenal glands, and sympathetic nervous system functioning.

I asked him if there were any surprises, and there were.  As Robert’s story will show, the NIH doesn’t seem to be prepared for the level of devastation ME/CFS can wreak in a relatively young group of patients.

Nath said his personal contact with the patients has led him to develop a real appreciation for the disease. These patients, he said, “are devastated”. Whether or not this study finds a cause, the reality, Nath said, is that the lives of the study patients are “totally messed up.” Then he made an important point.  Seeing the patients in the flesh naturally causes him and other researchers to develop additional empathy for them and “another level of appreciation” for them and their disease.

It was clear that just by being there and exposing the researchers and doctors at the NIH to this disease, the participants in the study are making a difference.  The lengths to which some patients are going to participate in this study are amply illustrated by Robert’s story.

Participating in the Study

The NIH needs more participants. If you’re interested in helping to further ME/CFS research by participating in the study, check out the study criteria below.

All participants must be 18-60 years old and have at least a 7th grade education. People whose ME/CFS started after an episode of infection and who have severe symptoms lasting from 6 months to 5 years are eligible to participate in the study.

Find out more here.

A former doctor on his experience going through the NIH’s intramural study

A Former Doctor Goes Through the NIH’s ME/CFS Intramural Study

The Brainstem, Vagus Nerve, Neuroinflammation and Chronic Fatigue Syndrome: The VanElzakker Way

In 2013, Michael VanElzakker produced one of the most intriguing hypotheses to date in ME/CFS. His Vagus Nerve Hypothesis proposed that an infection/inflammation near the vagus nerve was causing it to send an unending stream of messages to the brain, telling it to essentially shut the body down by producing fatigue, pain and other symptoms. Since then, he’s been particularly interested in the connection between the vagus nerve, the brainstem and the ME/CFS.

He’s not the only one interested in the brainstem. In 2019 once his brainstem compression was alleviated, Jeff completely recovered from his severe ME/CFS, POTS and MCAS. Since he published his story over a dozen people have been diagnosed with craniocervical instability – a condition which compresses the brainstem.

In this critical review paper, VanElzakker et. al. pick apart some of the research done and provide a guide to successfully getting at the brainstem and other regions of the brain. It’s called a “Critical Review” and is critical, indeed. It finds many past ME/CFS studies wanting, but then points a way to a better possible future. If brainstem problems play a role in ME/CFS these researchers demonstrate how to get at them.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.  Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Front. Neurol., 10 January 2019 https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full

First, VanElzakker et. al. examines one of the sacred cows in the chronic fatigue syndrome (ME/CFS) community – the preferred term for so many: myalgic encephalomyelitis (ME), which refers to muscle pain (myalgia) related to central nervous system inflammation (encephalomyelitis).

While muscle pain is common, it’s not universal. Even people with severe ME may not report pain.

Still, the core part of the definition deals with central nervous system inflammation – a description that, with the emergence of the 2015 Yakatomi and the 2019 Younger studies, seems more and more likely to stick. (A 2018 PET scan study also found neuroinflammation in fibromyalgia as well.)

The idea that inflammation plays a key role in this illness makes sense, given the infectious trigger so commonly (but not universally) found. The authors are just a few among many (Avindra Nath, Jarred Younger, Andrew Lloyd and others) who believe that an infectious event has triggered changes in the brain that are producing fatigue, pain and other problems in ME/CFS.

They point to three ways an infectious trigger could produce central nervous system inflammation in ME/CFS:

A) immune factors (e.g. cytokines) triggered by the infection could get transported across the blood-brain barrier (BBB) that protects the brain. The normally taut blood–brain barrier makes blood-borne infections of the brain rare, but it can, like the gut, become leaky in inflammatory states, allowing immune factors and pathogens entry. Once in the central nervous system, they could trigger a large inflammatory response, or

B) High concentrations of immune factors could allow pathogens to passively diffuse across the BBB, or

C) Immune factors in the blood could trigger the vagus nerve to send signals to the brainstem and brain, which then sparks an inflammatory response.

It’s the last option that primarily concerns these authors. VanElzakker is the author of the Vagus Nerve Hypothesis, which proposes that an infection/inflammation near the vagus nerve is causing it to send an unrelenting stream of signals to the brain, telling it to produce the flu-like symptoms that constitute “sickness behavior” (withdrawal to bed), which isolates infected people from the community and keeps them from spreading an infection.

The largest nerve in the body, the vagus nerve transmits sensory, autonomic, immune and other signals to the brainstem – making it potentially a key player in a possible neuroinflammatory disease like ME/CFS.

Studies indicate that inflammation in the periphery tends to produce a mirror inflammatory response from the immune cells (the glia) in the brain. Even small levels of cytokines in the periphery or body have the potential to activate the chemoreceptors in the vagus nerve, which then activate the immune system in the brain.

That brain activation, interestingly, tends to occur in regions (basal ganglia, limbic system organs (amygdala, hippocampus and hypothalamus), anterior cingulate cortex, prefrontal cortex, and thalamus), which studies suggest are also involved in ME/CFS.

The Brainstem

brainstem

The brainstem regulates many vital functions in the body

The authors believe the brainstem (which, as it name implies, is found at the very base of the brain, above the termination of the spinal cord), could play a key role in chronic fatigue syndrome (ME/CFS) for four reasons:

  1. Immune signals from the vagus nerve to the brain travel through the brainstem.
  2. The brainstem is dense with mast cells, and mast cell activation syndrome (MCAS) appears to be common in ME/CFS.
  3. The brainstem regulates autonomic nervous system functioning – a common trouble area for ME/CFS and related disorders.
  4. The brainstem also regulates immune functioning; in particular, it triggers an anti-inflammatory response that should limit the inflammatory response.

Whether caused by a structural problem (as in Jeff’s case), inflammation or an infection, the brainstem is a centrally placed brain component that produces many of the issues in ME/CFS.

Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Brainstem Series

Seeing the Brainstem in Chronic Fatigue Syndrome (ME/CFS)

Consistent inflammation of the brainstem has not, however, been found in ME/CFS. The authors argue, though, that researchers have rarely used the right kind of imaging needed to investigate this.

The most commonly used method for measuring inflammation in the brain involves measuring the 18kD translocator protein (TSPO) with a PET scan. This protein is produced when the immune cells of the brain – the microglia – become activated. Because the microglia are the chief producers of inflammation in the brain, the TSPO provides a reliable way to indirectly measure neuroinflammation and its effects.

The Nakatomi Study

Nakotomi’s small ME/CFS study using TSPO made a big splash in 2014.   Tony Komaroff called the finding of central nervous system inflammation the most important study in decades. Five years later, Van Elzakker et. al. called it “important” and potentially “groundbreaking”. The study used TSPO imaging to find widespread neuroinflammation, particularly in the areas leading from the brainstem to the thalamus.

While the authors regard Nakatomi’s study as potentially groundbreaking, the study is not without significant issues. The authors, in fact, seemed a bit shocked that Nakatomi found as many effects as he did, given the techniques used.

The neuroimaging techniques Nakatomi used (and which most researchers use) were not designed to address brainstem inflammation. Nakatomi used a spatial “registration” technique that aligns the image on the neocortex or upper part of the brain. This kind of alignment is typically done because researchers tend to focus on the upper, “higher” functioning areas of the brain. It can, however, impair the sensitivity of imaging done on the lower, more densely packed, primitive areas of the brain, such as the brainstem, and lead to false negatives.

The PK-1195 tracer

Nakatomi also used an older tracer (PK-11195) which does not penetrate deeply into the brain and can bind to unintended elements in the brain. Differences in blood-brain barrier permeability between the ME/CFS patients and healthy controls – a distinct possibility – could have confounded the results, as well. Nakatomi’s use of the cerebellum as a kind of baseline measure could have introduced further issues if problems with the cerebellum (another possibility) exist in ME/CFS.

Plus, the hypometabolism believed present in ME/CFS could have resulted in lower amounts of the tracer being metabolized than usual – causing higher amounts of the tracer to reach the brain – and producing a false positive. Because exercise may affect how much of the tracer is taken up into the cells, Nakatomi’s use of healthy, non-sedentary controls instead of sedentary controls introduced another issue.

Finally, because the brainstem actually pulses with every heartbeat, that movement needs to be accounted for – and usually isn’t in ME/CFS studies.  The very small but important nuclei in the brainstem are also often not picked up with the standard imaging techniques used in ME/CFS research.

Nakatomi’s study results make sense given what we know, and were given a sort of validation by Jarred Younger’s recent results using thermal mapping – a new technology – but we need more validation.

The takeaway is that the brainstem – because of the role it plays in autonomic nervous system functioning, immune regulation and the transmission of motor signals – could play a major role in ME/CFS, but is essentially, according to these authors, still something of a black box.

Barnden’s Brainstem – the Australian Study

It’s not completely a black box, though. Researchers using other techniques have found evidence of brainstem problems in ME/CFS. Barndem in Australia, in particular, has done a series of MRI studies which have found striking brainstem issues in ME/CFS.

(During his talk at the 2019 Emerge conference, Barnden noted how he had to shift his MRI to avoid the alignment problem (that VanElzakker mentioned) which prevented him from getting a good image of the brainstem. )

One study found that reduced brainstem grey matter volume – suggesting that damage to the neurons in the brainstem had occurred – was correlated with autonomic nervous system problems in ME/CFS.

Barnden brainstem damage ME_CFS

Using the right imaging approach Barnden found extensive evidence of damage to the neurons (myelin) in the brainstem. (From the 2019 Emerge Conference Livestream)

Another study finding of impaired communication from the brainstem nuclei to other nuclei in the brain suggested the same, and found increased signs of myelination in the sensorimotor cortex of the brain.  Barnden proposed that decreased signaling from a damaged brainstem provoked a compensatory increase in myelination in the sensorimotor region as it bulked up to try to understand the limited signaling coming from the brainstem. The impaired brainstem-sensorimotor connection might be, Barnden thought, impacting motor functioning in ME; i.e. the ability to carry out physical activity.

Signals to move muscles pass from the motor cortex to the sensorimotor cortex down to the thalamus and then through the brainstem to the muscles. (Signals from the muscles to the brain pass up through the same pathways.) Barnden proposed that the movement problems in ME/CFS could start with the brainstem’s inability to properly relay signals to the motor cortex to activate the muscles.

Barnden’s most recent brainstem study validated the idea that inadequate communication between the brainstem nuclei and other nuclei in the brain, including the vasomotor region, hypothalamus and prefrontal cortex, was affecting autonomic nervous system functioning in ME/CFS.

Other Kinds of Brain Scans

Other kinds of brain scans, such as magnetic resonance spectroscopy (MRS), can pick up signs of neuroinflammation. Although almost 10 MRS studies of the brain in ME/CFS have been done, VanElzakker et. al. report that a clear and consistent picture of metabolite alterations in the brain has yet to emerge.

They believe that’s due largely to a common theme in medical research, found in this disease in particular – lack of standardization. Different diagnostic criteria, different types of healthy controls, different brain regions examined, and different metabolites targeted make it difficult to present a clear picture of the metabolic alterations in the brains of people with ME/CFS.

The Japanese Take

The Japanese probably couldn’t agree with Barnden more. Their studies indicate that, as the healthy controls became more fatigued, two core regions – both of which communicate with the brainstem ( the prefrontal cortex and the anterior cingulate cortex) – shut down.

As these regions begin to shut down, control of autonomic functioning becomes lost.  In particular, the ability to activate the parasympathetic nervous system (i.e. the vagus nerve) and tone down the sympathetic nervous system activity, is lost.

The Japanese believe a breakdown in what they call the facilitation system in the brain has occurred.  As we become fatigued, the facilitation system jumps in to increase the signals coming from the primary motor cortex to the muscles. This increased “drive” from the motor cortex prompts the muscles to work harder and activates more and more of them so that activity can proceed.

Fatigue – the Japanese Way: A Chronic Fatigue Syndrome Perspective

So long as new, fresh muscle fibers remain to be recruited, the activity can continue.  If no muscle fibers are left to be recruited or if the brain has a problem recruiting new muscle fibers, fatigue sets in.

A 2003 study suggested that reduced muscle recruitment due to reduced motor cortex output was indeed occurring in ME/CFS. That study suggested that, “… changing motor deficits in CFS has a neurophysiological basis [which] … supports the notion of a deficit in motor preparatory areas of the brain”.  That study titled, “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“, to my knowledge was never followed up on.

Fatigue Explained? Japanese Assert Brain Damage Causes Fatigue in Chronic Fatigue Syndrome

Conclusion

Several studies suggest significant brainstem issues may be present in ME/CFS. Problems with the brainstem could produce everything from autonomic nervous system problems to immune issues to problems with movement.

The authors critique past brain imaging studies and provide a “how to” guide to assess the brainstem in ME/CFS. Barnden’s Australian brainstem studies suggest that when done correctly, MRI imaging studies may indeed find extensive damage is present in ME/CFS including evidence of brainstem neuron demyelination, a compensatory remyelination in parts of the brain the brainstem connects with, and lastly, a reduced connectivity between these regions.

VanELzakker et. al.  assert that future imaging studies that focus on the specific functional connectivity pathways in the brain which are activated by inflammatory processes should be able to capture the neuroinflammatory processes occurring in ME/CFS.  (Two of the three pathways they cite include the brainstem.) The thalamus’s role in sensory stimuli activity presents another fruitful pathway to assess.  Lastly, the authors suggest that researchers target the nucleus of the solitary tract (NTS) where the vagus nerve enters the brainstem.

With help from an ME/CFS donor, VanElzakker has been employing brain imagining techniques to assess the brainstem in chronic fatigue syndrome (ME/CFS). He will be speaking at the NIH ME/CFS Conference in Baltimore in April.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Catching ME/CFS in the Act: The Collaborative on Fatigue Following Infection (COFFI)

It sounds like a great idea – combine all the post-infectious fatigue studies together into one database in order to find answers to one of the biggest questions in ME/CFS – why do some people stay ill after an infection while others recover?

infection - chronic fatigue

Every major infection has provoked a similar response – a significant number of people become chronically ill.

COFFI (Collaborative on Fatigue Following Infection) incorporates no less than 9 studies that have examined post-infective fatigue or illness. The Dubbo study – pioneered by Andrew Lloyd and funded by Australian Health Agencies and the Centers for Disease Control (CDC) in the U.S., still in some ways the best study – started it all off.

The most dramatic conclusion of the first Dubbo study was that somewhere around 10% of people exposed to a serious infection remained ill six months later. Remarkably, the kind of infection – viral or bacterial – didn’t matter. It seemed that being exposed to any serious infection left one at risk for a prolonged fatiguing illness.

Since the Dubbo studies began, eight other post-infectious cohort studies have finished up or are underway. The largest of these are the four Chicago cohort studies (about 1000 participants) under the direction of Ben Katz and Lenny Jason, which have been examining infectious mononucleosis college students for almost ten years. There’s also campylobacter gastroenteritis (n=600), Legionnaires disease (n=190), and Ross River Virus (n=60) cohorts. All told, about 3000 people have participated in 9 studies which have examined people who failed to recover from an infection.

COFFI believes that susceptible individuals develop prolonged fatigue after infection because of biological (immune system, autonomic nervous system, etc.), behavioral and/or environmental effects, which produce alterations in neurobehavioural, cardiovascular and/or immunological systems. The goal of the collaborative is to elucidate what went wrong in those with post-viral (and bacterial) illnesses.

On the face of it, the collaboration holds great promise. How better, after all, to learn about how an illness develops than to capture it in its earliest stages?

The Post-Infectious Illness Group

Different flavors of post-infectious illness exist. One set involving diseases like acute disseminated encephalomyelitis and Guillain-Barre Syndrome produces very dramatic symptoms (paralysis, coma) and is studied. The other produces less dramatic symptoms (fatigue, cognitive problems, PEM) etc., but despite the tremendous functional hits seen, has mostly skated under the scientific establishment’s radar.

The studies that have emerged in the second group look like the kind of studies you would expect from a niche topic. They tend to be underfunded, focus on more easily and cheaply assessed factors, are often light on biological analyses, and sometimes focus on behavioral factors.

Nevertheless, some foundational findings have emerged. First – any serious infection is going to incapacitate a significant subset of those afflicted. The results have been remarkably consistent across types of infectious onset, with most showing from 9-13% of those encountering a serious infection of any type are still ill at six months and 7-9% remain ill a year later.

That’s obviously not a small number of people.

Lloyd, the senior author of the collaborative, has enrolled a mishmash of partners. They include biologically oriented members (Ben Katz, Renee Taylor, Ute Vollmer-Conna, Knut-Arne Wensaas, Jeannine L.A. Hautvast), some in-betweener’s (Brun Wyller, Dedra Buchwald, Renee Taylor) and some behaviorists (Peter White, Esther Crawley, Gabrielle Murphy, Rona Moss-Morris).

The Epidemiological Efforts

Giardia

The Bergen Giardia studies demonstrate the funding woes present in this field. They’ve succeeded in documenting high rates of ME/CFS, chronic fatigue and/or irritable bowel syndrome (IBS) years after an extended Giardia outbreak in Norway.  The studies have established that the outbreak has had a significant health impact on a substantial number of people – an important finding for sure – but it’s been unable, until recently, to delve into any biological factors. (A genetic study is underway.)

The Biopsychosocial Efforts

Moss-Morris’s work shows that cognitive behavioral therapy (CBT) has moved into clearly defined biological illnesses such as MS and renal disease. She’s managed to study the behavioral aspects of fatigue and/or conducted CBT trials in no less than five diseases – ME/CFS, IBS, multiple sclerosis, renal disease and cancer. (The MS CBT trial was deemed successful.)

Moss-Morris assessed epidemiological and biopsychosocial factors in people who became ill following a campylobacter infection (food poisoning). Ironically, that study suggested that those who tried hardest to ignore or push past their illness (e.g. who felt “I must not let this get the better of me” and who engaged in all-or-nothing behavior) were most likely to get ill. (So much for the malingering hypothesis).

chaos

The biopsychological studies have failed to provide consistent theme

Psychologist Peter White must have been chagrined to find that his Bart cohort failed to indicate that mood disorders or negative life events contributed to a “fatigue syndrome” after an infection.

The results of Buchwald’s 2000 infectious mononucleosis study must have flummoxed everyone.

It suggested that a greater number of life events more than six months before the illness began and increased family support were predictive of those who remained ill.

The Q fever studies ended up with a similarly hard to understand mix of factors. Female gender, being younger, having a pre-existing health condition, and being hospitalized in the previous 3 months might make some sense, but why would consuming no alcohol and using medication contribute to a prolonged illness?

The Qure study found that long-term doxycycline treatment utterly failed to move the needle on the illness; i.e. a persistent bug is not responsible.  CBT, on the other hand, improved fatigue and symptoms somewhat but completely failed in the most important measure – improving functionality. (By reducing stress, behavioral therapies should provide some symptom reduction…)

The lack of a recognizable theme suggests that the biopsychosocial results are not getting at the root of anything.  If the goal is illness eradication, researchers need to dig into the biology, and biological efforts have indeed achieved better results.

Biological Efforts

The studies that have dug deeper into biology appear to have been more successful.  Blood tests in the Dubbo studies suggested that pathogen persistence was not the issue: in every case the pathogen appeared, at least, to have been vanquished.

The results of the Qure study on the effectiveness of long-term doxycycline treatment in those with prolonged Q fever suggested the same: it found that the standard treatment for the disease had no effect at all on those who remained ill.

Nor did immune activation over time – as measured by cytokine levels – appear to cause disease persistence in the Dubbo group.

The only risk factors identified occurred early in the illness. Higher levels of cytokines and symptom severity early in the illness appeared to set the stage for a prolonged illness. This suggested that the bug – whichever bug it was – did its damage early and then disappeared.

Genetic studies then suggested a reason why. Immune gene polymorphisms were found in this group which predisposed them to a heightened immune response when confronted with a pathogen.  With three studies confirming and extending that finding, it seems solid. It appears that people with polymorphisms in specific immune genes that heighten the inflammatory response are more likely to become and stay ill.

consistency

The biological studies have provided a more consistent theme of immune activation and autonomic nervous system activation.

The ongoing Chicago infectious mononucleosis studies have dug a bit deeper biologically and uncovered some interesting findings.  Autonomic symptoms and early illness severity were predictive of a prolonged illness (while perceived stress, stressful life events, family stress, difficulty functioning and attending school, and psychiatric disorders were not).

Six months of illness resulted in lower oxygen consumption and reduced peak oxygen pulse; i.e. problems utilizing oxygen – something that Hanson’s latest metabolomic study and others suggested may be happening. (The authors called this “reduced fitness” and “efficiency of exercise.”).  Plus, a network analysis was able to diagnose 80% of ill patients using immune factors, and at six months autonomic nervous symptoms stood out. The analysis suggested a powerful pro-inflammatory immune state persisted for as long as 24 months after the initial onset.

The new “Dubbo studies” (“The Sydney Infectious Outcomes Study (SIOS)) have found an early reduction in heart rate variability, suggesting autonomic nervous system involvement.

In contrast to the biopsychosocial-oriented studies, a theme may be emerging in the biological studies: immune activation and autonomic nervous system problems early, resulting possibly in problems with oxygen utilization, with autonomic nervous system problems persisting.

Wyller’s Weird Results Or Why a Poor Study is Worse Than No Study at All

Many of the post-infective studies have been confined to charting epidemiological factors. Only the initial Dubbo study and the Katz/Taylor Chicago studies have tried to dig deeply at all into biological factors. Even then the scope of the studies has been limited.

Brun Wyller’s CEBA studies (Chronic Fatigue Following Acute Epstein-Barr Virus Infection in Adolescents) appeared at first glance, to fix that. The three studies analyzed 149 factors including early illness severity, immune factors, neuroendocrine stress response, cognitive functioning, emotional disturbances, genetics/ epigenetics of candidate genes, personality traits, and critical life events during and after infectious mononucleosis (IM).

Steps Per Day

The first CEBA study (Lifestyle factors during acute Epstein Barr virus infection in adolescents predict physical activity six months later) assessed the effects of the 149 factors on the number of steps taken per day at six months in 200 individuals. None of the markers of infection or immune response studied affected activity levels.  (Nor did any psychological factors).

Instead, three factors – none of which showed up previously in the post-infectious studies – did. Baseline physical activity (steps per day), substance use (alcohol and illicit drugs), and human growth hormone were associated with reduced steps per day after six months. (Notice the opposing substance use results: low alcohol use was a risk factor for post-Q fever illness, while increased alcohol/substance use was a risk factor for post-infectious mononucleosis illness).

The results suggested that sedentary individuals with low HGH levels who were abusing alcohol/drugs and who became ill with IM are predisposed to be, guess what, more sedentary than usual six months after coming down with infectious mononucleosis.

That’s among the most underwhelming and just weird results I’ve ever seen, and one wonders why Wyller bothered to publish it.

Predictors of Chronic Fatigue

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.

Another study of Wyller’s cohort charted biological factors against fatigue at six months. The main finding that a bunch of symptoms (sensory sensitivity, pain severity, functional impairment, negative emotions) were associated with increased fatigue simply stated the obvious. The more fatigued a person was, the more negative emotions they had (what a surprise!), the more functionally limited they were (!!!!), and the more pain they were in (stunning!), etc.

The fact that viral load had no predictive value was in line with past studies. The slightly increased plasma C-reactive protein found (Wyller suggested it was caused by negative life events) and reduced plasma vitamin B12 levels were the only two biological factors that stood out.  Neither will move this field forward significantly.

Predictable Results?

So how did Wyller get such pitiful results?

It turned out the study was not as comprehensive as the 149 factors made it appear to be, and was rudimentary to boot.  Included in that 149 factor set were standard blood tests, demographic results, psychological testing, etc.

Wyller testing ME/CFS

Wyller’s testing regimen made a biological result unlikely.

Wyller used a Fatigue Scale – the Chalder Fatigue Scale – believed be problematic in ME/CFS.  His immune tests mostly consisted of immune cell counts which have historically not been particularly effective.  Natural killer cell cytotoxicity – which has consistently been found to be low in ME/CFS – was not done.

The one stressor used – during the autonomic nervous system testing (deep breathing while supine and during 3 minutes of standing) – was too mild (at least a 10 minute tilt table test is needed to diagnose POTS).

While changes in heart rate and blood pressure have been found in ME/CFS, heart rate variability is a more discerning factor and has been more commonly assessed and found altered in ME/CFS – but was not used in Wyller’s study. The cortisol blood test Wyller used has not been found effective in ME/CFS. (Blood cortisol awakening response and morning saliva cortisol tests (not done) have been more effective).

All in all, the study – with its lack of a significant stressor, its limited testing protocol and the use of measures which have not proved useful in ME/CFS – appears to have been almost doomed to failure.  One wonders why Wyller expected to find anything at all, and the results probably could have been predicted.

They also, not surprisingly, opened the door wide open to a biopsychosocial interpretation of ME/CFS that Wyller walked right through.  Wyller reported that,

“Taken together, the results seem to support a biopsychosocial rather than a biomedical perspective on the development of chronic fatigue and CFS.”

Lenny Jason’s Chicago Studies

The next Chicago studies, led by Lenny Jason, will examine many more biological factors in its next iteration. Unlike the Dubbo, Giardia, Wyller’s studies and others, Jason’s samples predate the illness onset, giving him the potential to uncover biological risk factors present before a person became ill.

He has blood samples from over 4,000 students, 4-5% of whom contracted infectious mononucleosis, which they are following. Papers should start appearing this spring/summer. As of October 2018, Jason was still in the process of applying for grants to study blood and saliva factors. They hope to study autonomic functioning, cytokine, metabolomic and saliva biological risk factors.

Jason’s preservation of his samples in a deep freeze means they’ll be able to be assessed as we learn more about ME/CFS over time.  They provide the potential for uncovering perhaps the greatest mystery of all in ME/CFS – what was going on before ME/CFS actually hit that put one at risk for it?

Conclusion

Time will tell if the The Collaborative on Fatigue Following Infection (COFFI) will help, hurt or do anything at all. If the embarrassingly rudimentary website with its weird ads is any indication, the group may not amount to much.

Wyller’s efforts indicate that rudimentary, poorly targeted efforts can do more harm than good if the authors decide to default to a historical norm: if you can’t find something biological, a biopsychosocial explanation must apply.  His results and other biopsychosocial study results are so bizarre, though, that one wonders if anyone will take them seriously.

trigger - post-infectious fatigue

The post-infectious studies have the possibility of catching the disease in the act.

The biological efforts are another story. These cohorts offer the enticing possibility of catching the disease in the act as it first manifests itself. The first post-infectious fatigue studies – the Dubbo studies – are still some of the best, and outlined some findings that have continued to stand: illness severity is a major risk factor and the bugs that triggered the illness in the first place don’t appear to play a role in prolonging it. The early cytokine and genetic results fit that picture: they suggest a stronger than usual early immune response may set the stage for ME/CFS.

Incorporating more sophisticated tests, the Chicago infectious immune studies add the possibility of long-term autonomic nervous system problems, further suggest immune issues play a role and, intriguingly, provide the first signs of impaired energy production during exercise.

Jason, if he can get the money to test his samples, has the opportunity, with his metabolomic, autonomic nervous system and immune testing, to provide more insights into how this illness got started in the first place and why it remains. Plus, his frozen samples provide the opportunity for future researchers to dig even deeper into these questions. They should prove invaluable.

 

 

Could the Gut Cure Neuroinflammation? An MS and ME/CFS/FM Inquiry

Gut Neuroinflammation Connection Revealed

“There is something very critical about how the gut and brain are connected, and we’re starting to unravel the molecular threads behind that clinical observation. It’s a great example of how fast science can move.” Jen Gommerman – co-author

Limiting our attention solely to chronic fatigue syndrome (ME/CFS), fibromyalgia (FM) and allied disorders might be a mistake. Recent studies indicate that ME/CFS and FM fit into the broad category of neuroinflammatory disorders which include multiple sclerosis (MS), Parkinson’s disease and others.

ME/CFS and FM neuroinflammatory

ME/CFS and FM may fit into a broad spectrum of neuroinflammatory disorders.

The same parts of the brain may not be affected in each disease, but it’s possible that each is undergirded by a similar inflammatory milieu. If the goal is to reduce neuroinflammation, then an approach that works in one disease could work in another.

The immense amount of research being devoted to these other neuroinflammatory disorders suggests they could provide critical insights into ME/CFS and FM as well.

A recent multiple sclerosis gut study provided a prime example of how progress in one neuroinflammatory disease may benefit others. It underscored the gut’s long reach and illuminated a potential treatment approach – not just for MS, but possibly also for other neuroinflammatory diseases.

It raised the possibility that manipulating one’s gut bacteria may at some point become an effective treatment approach in the fight against neuroinflammation.

Cell. 2018 Dec 21. pii: S0092-8674(18)31560-5. doi: 10.1016/j.cell.2018.11.035. [Epub ahead of print] Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10. Rojas OL1, Pröbstel AK2, Porfilio EA1, Wang AA1, Charabati M3, Sun T1, Lee DSW1, Galicia G1, Ramaglia V1, Ward LA1, Leung LYT1, Najafi G1, Khaleghi K1, Garcillán B4, Li A5, Besla R6, Naouar I1, Cao EY1, Chiaranunt P1, Burrows K1, Robinson HG7, Allanach JR7, Yam J1, Luck H5, Campbell DJ8, Allman D9, Brooks DG10, Tomura M11, Baumann R2, Zamvil SS12, Bar-Or A13, Horwitz MS14, Winer DA6, Mortha A1, Mackay F4, Prat A3, Osborne LC7, Robbins C15, Baranzini SE16, Gommerman JL17.

Their study started in the head and moved downwards. Researchers wondered where the heck the plasma cells (IgA antibody producing B-cells) showing up in the central nervous systems of MS patients were coming from. It turned out they were coming from the gut.  They found that B-cells were making their way to the gut where gut bacteria where flipping their switch – and turning them into IgA producing plasma cells. Now their one and only goal was to produce IgA antibodies.

IgA antibody gut chronic fatigue

IgA antibody producing cells that are formed in the gut appear to play a major role in tamping down inflammation in the brain

Eventually they made their way up the body to the brain, where (in the presence of IL-10) they were tamping down inflammation. Interestingly, the guts of the mouse model for MS were deficient in these cells. These plasma B-cells were so effective at reducing brain inflammation that boosting their levels in the mice’s guts returned them to health.

The levels of these plasma cells are also reduced in the guts of humans during MS relapses – presumably because they’re being recruited to the brain to fight the inflammation.

This finding cleared up a conundrum – why knocking out B-cells tended to help people with MS while knocking out only the IgA-producing cells made them worse. B-cells were believed to promote neuroinflammation and autoimmunity and they do. The B-cell inhibitors used are believed to reduce T-cell activation and suppress autoantibody production.

No one suspected, though, that specialized B-cells might also play a critical role in suppressing inflammation. Knocking those cells out resulted in the patients getting worse.

Gut Modification

“Showing that IgA-producing B cells can travel from the gut to the brain opens a new page in the book of neuroinflammatory diseases and could be the first step towards producing novel treatments to modulate or stop MS and related neurological disorders.” Sergio Baranzini – co-author

The next steps seem clear: find a way to increase the number of IgA-producing plasma cells in the guts of people with neuroinflammatory disorders in the hope that they will knock down inflammation in the brain. Because some bacteria – which ones is unknown at the moment – trigger B-cells in the gut to change to IgA producing plasma B-cells, the next step is to identify that microbe and find a way to increase its numbers.  In other words, find a way for the gut to naturally reduce inflammation in the brain.

“If we can understand what these cells are reacting to, we can potentially treat MS by modulating our gut commensals. That might be easier than getting drugs into the brain, which is a strategy that hasn’t always worked in MS.” Gommerman – senior author

Potential Relevance to Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, etc.

“As a clinician-scientist, it is exciting that our experiments linking preclinical animal models to the biology we see in real MS patients may have uncovered a general mechanism for how the immune system counteracts inflammation.” Pröbstel – co-author

Chronic fatigue syndrome (ME/CFS) is not MS but the two diseases might be more closely related than one might think. Having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and infections often trigger relapses in both diseases. The most disabling symptom in MS tends to be fatigue and both diseases mostly affect women. Plus pregnancy often brings a (temporary) respite in both diseases.

A Simmaron Research Foundation sponsored spinal fluid study found similar levels of immune alterations in ME/CFS and MS, and pointed to a major, almost MS-like, alteration of immune factors in ME/CFS.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

Jarred Younger, who knows neuroinflammation as well as anyone in this field, believes that MS and ME/CFS could turn out to be close cousins. Younger believes the neuroinflammation present in both diseases may be similar, with the notable distinction that the immune cells in MS have been tweaked to attack the neurons, while those in ME/CFS, thankfully, have not. (Younger has begun a low dose naltrexone trial in early stage MS patients to see if he can stop the neuroinflammation before it has irrevocably damaged the nerves.)

 

Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

What works in MS could work in ME/CFS and it already has – at least in two cases. A MS drug called Copaxone was very effective in two ME/CFS patients who’d been misdiagnosed with MS. In fact, it was much more effective in those patients – resulting in significant reductions in fatigue –  than it ever was in MS.

The really exciting thing about this study is its potential relatability to other diseases.  These researchers appeared to have stumbled upon a basic gut induced anti-inflammatory pathway that may help with other neuroinflammatory diseases including, who knows, perhaps ME/CFS and FM.

It’s clear that we can’t view MS as strictly a brain disease. Yes, the overt physical damage occurs in the brain, but gut issues play a role as well. In fact, this study suggests the possibility that gut damage – in the form of a dysregulated microbiome – might even play a critical role in allowing MS to progress.

Could the Gut Be a Potential Drug Factory?

Given the possibility that harnessing an as yet unknown microbe in the gut could reduce inflammation in the brain, one has to wonder if the gut, with its trillions of microbes, is a potential reservoir of drugs.  Could we tweak the microbes in the gut to provide other factors that reduce disease? Will gut manipulation ultimately play an important role in treating chronic diseases?

Immune Factor May Jump Start Chronic Fatigue Syndrome (ME/CFS)

December 31, 2018

“For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system. Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS.” Alice Russell

This British study is interesting in so many ways. Most importantly, it draws a link between an overactive immune system and CFS-like chronic illness in Hepatitis C patients who were studied before and after treatment with an immune stimulant. The authors believe it may tell us why some people come down with chronic fatigue syndrome (ME/CFS) after an infection. If so the Brits have found the first predictive blood factor for ME/CFS.

Psychoneuroendocrinology. 2018 Dec 14. pii: S0306-4530(18)30196-3. doi: 10.1016/j.psyneuen.2018.11.032. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Russell A1, Hepgul N2, Nikkheslat N3, Borsini A4, Zajkowska Z5, Moll N6, Forton D7, Agarwal K8, Chalder T9, Mondelli V10, Hotopf M11, Cleare A12, Murphy G13, Foster G14, Wong T15, Schütze GA16, Schwarz MJ17, Harrison N18, Zunszain PA19, Pariante CM20.

It is interesting in one way, because it comes out of King’s College London – the longtime home of Simon Wessely, the British psychologist who developed the cognitive behavioral therapy (CBT) and graded exercise therapy (GET) approach to chronic fatigue syndrome (ME/CFS). Wessely, a leader of the biopsychosocial approach to ME/CFS, championed the idea that psychological and social factors largely perpetuate ME/CFS.  Psychiatrists Trudy Chalder and Mathew Holtorf also hail from King’s College.  (Anthony Cleare, another psychiatrist from King’s College, has done substantial research into the HPA axis in ME/CFS over the past 20 years. Cleare’s 1995 paper used cortisol tests to differentiate ME/CFS from depression.)

Kings College Medicine

King’s College London has been the home of several prominent pyschiatrists studying ME/CFS (By Stephen Craven, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=13848828)

Six years ago Medical Express reported that the PACE Trial – which Kings College researchers participated in – proved that CBT/GET practices “provide good value for the money“. Three years ago Queen Mary College of London and King’s College London dug their feet in to prevent the release of the raw PACE data.  It was King’s College that called the attempt to get the data “vexatious,” which in legal terms basically means without merit. The PACE findings are now in the throws of being discredited.

The study is also interesting because it was funded by the Medical Research Council (MRC), a United Kingdom based governmental agency that funds medical research. The MRC, which helped fund the PACE trial, has been a mixed bag. Funded studies on ethnicity, risk factors (biopsychosocial risk factors) and CBT speak to a strong behavioral thrust. However, the MRC has also funded studies on the mitochondria, the autonomic nervous system and now on an immunological model of ME/CFS.

A new generation of psychiatrists from King’s College appear to be taking a different tack. Carmine Pariante, who has focused for years on the physiological roots of depression, has been using hepatitis C patients to try and understand how immune mediated fatigue and depression arise.

A Model for ME/CFS?

It turns out that when hepatitis C patients are given interferon-alpha (IFN-a) about a third of them develop severe fatigue and/or become depressed. The realization that an immune activating drug was causing fatigue and depression in those who were not fatigued or depressed before was a revelation to the medical community. That led to the idea of sickness behavior, which posits that during an infection, the brain and immune system induce symptoms (flu-like symptoms) that force individuals to isolate themselves, stopping the spread of the infection.

trigger ME/CFS

Did high IL-10 levels jump start ME/CFS?

Since many people with chronic fatigue syndrome (ME/CFS) are by definition caught in a chronic case of “sickness behavior” (a chronic illness state triggered by an infectious event), hepatitis C patients provide the possibility of real insights into ME/CFS.  If researchers can determine how immune activation triggers flu-like symptoms and/or depression in people being treated for hepatitis, they may get clues to what is going on with ME/CFS.

In an action that proved enormously helpful, the group took baseline measures of immune activation prior to the introduction of the interferon drug, and then afterwards. They also assessed psychological factors and metabolites associated with the kynurenine system.

THE STUDY

Psychological Factors Play No Role

In a finding that must have disappointed Trudy Chalder and Mathew Hotopf – who were also part of the study – psychological factors struck out on all counts. Neither a history of depression, stressful life events in the prior six months or early life trauma had any effect on  those who became ill following the IFN-a administration.

Cytokines Not Perpetuating Fatigue

Cytokines weren’t, strictly speaking, perpetuating fatigue in the ill hepatitis C group either. The cytokine levels in both the recovered and the still fatigued hepatitis C patient were similar.

They may, however, have triggered it.

Possible Predisposing Factor Identified

The hepatitis patients who came down with severe fatigue demonstrated increased IL-10 and IL-6 levels early on – very early on.  In fact, hepatitis C patients who became ill had high IL-10 levels BEFORE they received the drug. High levels of IL-6, a pro-inflammatory cytokine which has been associated with fatigue, were found early in the illness.

IL-10

High Il-10 levels at baseline may be a biological risk factor for coming down with ME/CFS.

The researchers speculated that patients’ immune systems were primed to take off prior to their receiving the drug – and it was this immune priming which lead them to become ill after taking the drug.

Six months later their IL-10 levels, interestingly, were normal – suggesting that IL-10 had done it’s work quickly and then faded into the background, leaving behind a chronic state of fatigue.

The beauty of this study is that it identifies possibly the earliest blood factor yet – increased IL-10 levels – that may set someone on the path to developing ME/CFS.

While the authors didn’t attempt to explain how these factors produce ME/CFS, some possibilities immediately present themselves. Higher than normal IL-10 levels could suppress one’s ability to quickly clear an infection.  High IL-10 levels and several IL-10 polymorphisms have also been associated with the development of lupus, an autoimmune disorder.

Andrew Miller of Emory University has some ideas of his own.

Miller Time

Andrew Miller, PhD also believes that the ‘sickness behavior’ he finds in hepatitis C patients given IFN-a is similar to what’s happening in ME/CFS.  Miller, however, came to that conclusion, by looking at the brain.

He found reduced activation of the striatum – a part of the basal ganglia that produces dopamine – in fatigued hepatitis C patients and people with ME/CFS. This finding suggested that reduced dopamine levels in ME/CFS may be producing problems with motor activation (physical activity) and fatigue. Indeed, primate studies indicate that immune activation in the presence of low dopamine levels results in enormous fatigue, motor slowing, and depression.

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome

Another study, taking a deeper look at what happens to a brain on IFN-a, found it took just four hours for IFN-a to produce microstructural changes in the left striatum – changes that were “strikingly correlated” with the development of fatigue. The authors reported that increased levels of lactate and altered pH – two problems found in ME/CFS –  may set the stage for these microstructural abnormalities.

Microstructural Havoc: The Immune System, Fatigue and the Brain – An ME/CFS and FM Scenario

Immune Hypersensitivity Syndrome?

This presents the possibility that infection-produced inflammation could knock out dopamine production permanently, leaving behind – and this may be the important part – a hypersensitized reaction to inflammation. Miller believes that dopamine deprivation causes the basal ganglia to over-respond to inflammatory signals, resulting in the fatigue and other symptoms associated with “sickness behavior”.

That sickness behavior includes mood changes. The British group found that a “biological sensitivity”, or over-reaction to IFN-a, predicted who would come down with depression while on the drug.

When Anthony Cleare of King’s College trashed Montoya’s cytokine findings last year because they didn’t show cytokine elevations, he missed the point that Montoya’s results may have pointed to a possible exquisite sensitization to cytokines in ME/CFS.

Conclusion

It was very good to see an MRC-funded physiological study pan out and get such abundant media coverage.  Thankfully, Lenny Jason is in a good position to follow up on this study result to see if IL-10 is indeed raised in young people who fail to recover from infectious mononucleosis. If that pans out, the first predisposing factor for ME/CFS in the blood will have been found.

That finding will then give us an entry point to determining how ME/CFS comes about. Avindra Nath’s and Derya Unutmaz’s studies of short-duration post-infectious ME/CFS patients would hopefully be able to piggyback on the British finding and begin to unravel the genesis of ME/CFS.

The basal ganglia/hepatitis connection is fascinating because it suggests that the Brits’ hypothesis, that fatigued hepatitis C patients present a good model for ME/CFS, may be correct. Andrew Miller’s and other studies suggests that the brain changes in ME/CFS replicate those of the fatigued hepatitis C patients. Interestingly, they affect the basal ganglia – a part of the brain involved in motor activation (physical movement), learning, cognition and fatigue.

Miller’s hypothesis that inflammation may knock out dopamine production in the basal ganglia resulting in a hypersensitization to immune signals in ME/CFS is compelling. Neuroinflammation has been linked to microglial activation and reduced dopamine levels.  Plus two studies have found reduced basal ganglia activation in FM. One study suggested the basal ganglia could be causing the movement problems in FM.

Spinning Fibromyalgia: Brain Findings Suggest Dopamine May Be Key

Given that the basal ganglia affects movement, fatigue and reward, it would seem to present a rich vein for ME/CFS researchers to mine.  In other fields, researchers would probably be vigorously digging away at a vein with this much potential ore in it, but in ME/CFS researchers are just scratching the surface. Getting  more out of the research community will require that the federal government fulfill its promise to invigorate this field.

In the meantime, it’s good to see the MRC and the Brits, psychiatrists most of them (!), make good on a physiological study, hopefully set the stage for more to come.

The Probiotic Paradox: When Probiotics Fail or Even Do Harm – an ME/CFS Perspective

December 18, 2018

Our guts are teeming, just teeming, with bacteria that provide many useful functions. They break down food, knock down pathogens, regulate the immune system and hormone release, and even affect brain functioning. Several serious diseases including cancer, diabetes and rheumatoid arthritis have been associated with what are considered unhealthful assemblages of gut bacteria.

probiotics

These studies indicated that pounding the gut with probiotics isn’t always a good idea.

Studies suggest that something is off, though, in the guts of people with chronic fatigue syndrome (ME/CFS). Pro-inflammatory and anaerobic species are more dominant and diversity -an important component of a healthy gut –  is low.  Plus bad gut bacteria may be gnawing away at our gut linings when we exercise, allowing the bacteria to spill into our blood, causing systemic inflammation.

The solution seems clear – pound the gut with good bacteria, get it back into balance, turn the immune activation off, and who knows, maybe even conquer ME/CFS and fibromyalgia (FM). Certainly it’s worked for some people but for many others it hasn’t. That’s really no surprise, nothing works for everyone in these diseases, but some people have experienced really negative effects from good bacteria. How could that have happened?

We’re beginning to learn how. Two studies that are turning upside down our notions of using probiotics to replenish our gut flora are indicating that the gut, like every other part of the body, is more complex than we knew, it seems.

The Studies

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, Kotler E, Zur M, Regev-Lehavi D, Brik RB, Federici S, Cohen Y, Linevsky R, Rothschild D, Moor AE, Ben-Moshe S, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Shapiro H, Pevsner-Fischer M, Sharon I, Halpern Z, Segal E, Elinav E. Cell. 2018 Sep 6;174(6):1388-1405.e21. doi: 10.1016/j.cell.2018.08.041.

These Israeli researchers did something rather simple – at least in design – which, in retrospect, should have been done long ago. They took 25 healthy people, used endoscopy and colonoscopy to assess the bacteria found in their upper and lower guts, then gave them a standardized dose of probiotics twice a day (Lactobacillus acidophilus, L. casei, L. casei sbsp. paracasei, L. plantarum, L. rhamnosus, Bifidobacterium longum, B. bifidum, B. breve, B. longum sbsp. infantis, Lactococcus lactis, and Streptococcus thermophilus) and measured the bacteria in their guts. Their stools were sampled throughout the study.

Resisters and Persisters

Two groups emerged: the persisters – a group whose guts accepted the new bacteria and changed in a positive way, and the resisters whose guts rejected the bacteria and didn’t change at all.

Their interest piqued, the researchers then transferred the bacteria from the resisters and persisters into mice with no gut bacteria, and then gave probiotics to them. The same thing happened – indicating that the bacterial makeup of a person’s gut, at least in part, determines whether probiotics will help them or not. Something about the ecological makeup of the resisters’ bacterial populations made it impossible for the good bacteria to catch hold.

That was an intriguing finding, but the Israeli researchers didn’t stop there. Adding the participants’ gene expression – which genes were active or not in the blood – into the mix, they hit a home run.  Even though they were healthy, the resisters had something extra going on – an autoimmune gene signature – that was somehow not allowing their gut to accept good bacteria.

If you’re not benefiting from probiotics, then, both your immune system and your gut bacterial makeup may be keeping the probiotic bacteria from taking hold. The problem may be worse than that, though.

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.

Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, Horn M, Cohen Y, Moor AE, Zeevi D, Korem T, Kotler E, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Pevsner-Fischer M, Shapiro H, Sharon I, Halpern Z, Segal E, Elinav E.Cell. 2018 Sep 6;174(6):1406-1423.e16. doi: 10.1016/j.cell.2018.08.047.

When gut problems are suspected, a standard protocol among some doctors is to wipe the slate as clean as possible by killing the bacteria with antibiotics and then re-populating the gut with probiotics. Of course no probiotic combination can approach the immense diversity found in our guts, but anecdotal reports suggest the protocol does seem to work in some people.

This study suggested, though, that there are much better ways to go about replenishing one’s gut after a nuclear attack by antibiotics. The researchers wiped out the guts of three sets of people, then recolonized one group with fecal transplants of their own gut bacteria, another with probiotics, and the last they let recover naturally.

The guts of the participants recolonized with transplants of their own fecal material recovered at lightning-speed: within a week their gut composition was back to normal. The participants whose guts were allowed to heal naturally took about three weeks to return to normal, but the people taking probiotics took up to six months for their gut composition to return to normal, and some of them were still not normal even then.

Any ecologist  (the gut is an ecological system) probably wouldn’t have been surprised at this result. Trying to reinstitute a complex ecosystem by giving a few species a boost can allow them to block others from establishing themselves, resulting in a low diversity ecosystem. That’s basically what happened. Even months later the guts of probiotic-receiving participants had low bacterial loads and dysregulated gut ecosystems. It turned out it was far better to let mother nature take its course and allow the gut ecosystem to repopulate naturally.

It’s possible, then, that taking probiotics when you have a dysregulated gut ecosystem could help, but it could also throw things off. One wonders if some of the negative responses to probiotics result from adding good bacteria into the wrong ecosystem.

Laboratory studies suggest that factors secreted by the Lactobacillus species often found in yogurt preparations might actually be inhibiting other bacteria from colonizing. The probiotic species found in store-bought preparations, it should be noted, are not necessarily the ones that are needed – they’re the ones easily grown in the lab.

“We’re talking about an entire rainforest in the gut that’s being affected in different ways by different antibiotics, and you can’t just patch that up by giving a probiotic. Because, let’s face it, a probiotic has maybe seven or eight strains. There’s a lot in the literature about some of these bacteria being beneficial, and it’s interesting, but they are really some of the few microbes in the gut that are fairly straightforward to culture. And I think that drives the probiotic industry more than it would like to admit.” Allen-Vercoe

The Poop on Stool Samples

But then came some more bad news. Putting stool samples in your body may not be your idea of fun, but at least it’s easy to do and relatively inexpensive. However, despite the fact that stool samples are regularly used to assess gut bacterial composition, they provide a pretty inaccurate snapshot of what’s going on in the gut.  The bacteria actually found in the gut (obtained through endoscopies and colonoscopies) were markedly different from those found in stool samples.

Lactobacillus bacteria

Factors secreted by some Lactobacillus bacteria may prevent other bacteria from colonizing

Finding the probiotics you took via your mouth in your stool was supposed to be a sign of success, but this study found that wasn’t necessarily true.  It’s quite possible for probiotics to show up in your stool without recolonizing your gut at all.

The stool samples failed at predictiveness as well. While the gut mucosal samples (and the gene expression results) could be used to determine whether someone was a “resister” or “persister” – the stool samples could not.

It turns out that the most widely used snapshot of the gut – the stool sample – is the least representative. Gut mucosal sampling – a sampling of the bacteria found in the gut lining via two invasive procedures (endoscopy and colonoscopy) is the only way to truly determine the state of your gut, because the samples are obtained from where the gut bacteria actually reside.

There are, of course, other less invasive ways to assess the effectiveness of probiotics or fecal transplant. Improvement in symptoms: gut issues, fatigue, mood, etc. could indicate that whatever gut manipulation you’re doing is working.

The news in these studies wasn’t all bad, though. The fact that the probiotics were better able to colonize the guts of the healthy controls who had lower levels of good gut bacteria suggested that people with poor gut flora – such as people with ME/CFS – have a better chance of benefiting from probiotics. (That has to be considered alongside the fact that people with autoimmune tendencies tended to resist probiotic colonization.)

Still, the fact that probiotics may be more effective in those with more impaired guts wasn’t really a surprise. There is certainly a place for probiotics in medicine. A recent review of two ME/CFS probiotic studies concluded that probiotics had a “significant effect on modulating the anxiety and inflammatory processes “. Repeated studies have found them helpful in irritable bowel syndrome (IBS), metabolic syndrome, diabetes and obesity. The situation is just a bit more complex now.

That we’re not at the prescriptive phase of treating most diseases with probiotics isn’t exactly shocking, either.  ME/CFS researchers Ian Lipkin and Maureen Hanson, a member of Simmaron Research’s Scientific Advisory Board, have been tackling the gut, and both have been wary about providing any prescriptions for gut manipulation in ME/CFS yet. Given the huge differences in gut bacteria from person to person, a personalized approach – matching personal gut weaknesses with specific probiotics – was always probably going to be necessary.

Ian Lipkin alluded to this earlier:

As we learn more about ME/CFS, we are beginning to define subtypes. This is critical to understanding how people become ill and developing practical solutions for management. The challenge is not unique to ME/CFS. It is representative of the Precision Medicine initiative that is sweeping clinical medicine and public health. Just as there is no one cause or cure for all cancers, all forms of heart disease, or all infections, there will be more than one path to ME/CFS and more than one treatment strategy.

The good news is that gut research is exploding in ME/CFS. Ian Lipkin introduced an  gut-associated subset (ME/CFS patients + IBS) with unique metabolic problems, and remarkably enough, found that differences in gut bacteria were more effective than metabolites in differentiating people with ME/CFS from health controls.  Derya Unutmaz – whom Lipkin is now collaborating with – has found strong evidence that T-cells  associated with bad bacteria are playing a role in ME/CFS.  Plus, a recent hypothesis put forth by Jonas Blomberg proposes that leaky gut may set the stage for ME/CFS. Finally, Maureen Hanson is overseeing the first fecal transplant trial in ME/CFS.

“The Subset Maker”: Lipkin Chronic Fatigue Syndrome Study Highlights Energy Issues In Gut Subset

Simmaron Research is an active collaborator in microbiome and immune-related studies with Dr. Lipkin, Dr. Hanson, Dr. Mady Hornig, Dr. Elizabeth Unger, and others to deepen the field’s understanding of disease subsets and to identify and study treatment options for patients.

Immune Study Adds to Evidence Of Body-Wide Problems With Energy Production in Chronic Fatigue Syndrome (ME/CFS)

Increased expression of CD24 …could thus reflect abnormalities in maintaining appropriate ATP generation (in ME/CFS). The authors

Numerous studies suggest problems with energy production exist in chronic fatigue syndrome (ME/CFS). The huge energy needs exertion places on the muscles and brain suggest they’re an obvious place for energy production problems to show up. Ramping up to fight off pathogens also places extreme demands on energy production in immune cells. Now comes a study which suggests that energy production problems in a subset of B-cells could be setting people with ME/CFS up for problems with inflammation and autoimmunity.

B-cells and ME/CFS

The first couple of successful Rituximab trials brought renewed interest in the immune cells most effected by the drug – the B-cells. The last, large Rituximab trial unfortunately failed – the drug does not work in ME/CFS – but the Rituximab effort succeeded in other ways.

First off, it brought two creative and dedicated researchers, Oystein Fluge and Olav Mella to the field and energized ME/CFS research in Norway.

B-cell

A B-cell producing antibodies to fight pathogens

Secondly, the B-cells – which play a huge role in immunity (and autoimmunity) – finally got some study in ME/CFS.  Keeping with ME/CFS’s time-honored tradition of falling between the cracks in medicine, several studies found no indication of altered levels of “classical B-cell markers”.

Something unusual did, however, pop up, in an extended analysis, which went well beyond the classical markers usually explored. In 2015 a study found that a molecule called CD24 was highly expressed in a group of B-cells.

CD24 is an adhesion molecule which turns on various signaling networks – it basically tells cells what to do. It is most highly expressed on early stage or transitional B-cells as they emerge from the bone marrow.

During the normal transition from immature to mature metabolically active B-cells, early B-cells are tested again and again for evidence that they may be turning into autoantibody producing cells and many are removed.  Over time, as these cells transform themselves into mature B-cells, the CD24 molecule gradually disappears from their surfaces. High levels of these molecules in people with ME/CFS suggested that a problem with B-cell maturation might be present.

Since antibody producing B-cells play a major role in fighting off infections, having a bunch of immature B-cells hanging around the immune systems of ME/CFS patients could constitute a problem.

Plus there’s evidence that the CD24 molecule plays a role in several diseases.  CD24 polymorphisms (genetic variants of CD24) have been associated with increased risk for and accelerated progression of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. CD24 can also be over‐expressed in many cancers, including B cell lymphomas.

In short, it’s not a molecule you want to ignore.

Energy Production Problems in the Immune System

Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Mensah FFK1, Armstrong CW2, Reddy V1, Bansal AS3, Berkovitz S4, Leandro MJ1, Cambridge G1.

In a 2018 study, a UK and Australian group took B-cells from ME/CFS patients and healthy controls, stimulated them and then monitored what happened.  As before, they found an increased frequency of CD24+ B-cells in ME/CFS patients.

What made the increased frequency of these naïve CD24 packed B cells in ME/CFS so interesting, though, was their mode of energy production.

Examining the metabolism of the ME/CFS patients’ cells, the researchers found a “strong(ly) positive” association between the amount of glycolysis and lactate produced and the expression of CD24 molecules on ME/CFS patients’ B-cells. Put another way, the more glycolysis was used to produce energy and the greater the lactate production (a by-product of glycolysis) – the more the CD24 molecule showed up on ME/CFS patient’s B-cells.

energy production me-CFS

Findings suggesting that a body-wide problem with energy production are present in ME/CFS are piling up.

Lower levels of mitochondria in these cells suggested one reason ME/CFS patients’ B-cells may be stuck in this mode.  Not surprisingly, the authors found this more prominent B-cell subset in ME/CFS was also largely unresponsive to stimulation.

That suggested that not only do the energy problems in ME/CFS extend to the immune cells but that they could be impacting immune functioning – in this case by keeping ME/CFS B-cells in a naïve state – that may be associated with disease.

Plus increased levels of the CD24 molecule have also been associated with a damaging state called “senescence”.  Instead of undergoing a process called autophagy during which a cell’s contents are safely recycled, during senescence – which is often associated with aging –  damaged mitochondria cause cells to slowly deteriorate while producing scads of pro-inflammatory factors.

An exercise physiologist, Graham Salmun, recently reported that his exercise study results suggest senescence is indeed occurring in ME/CFS.  He believes problems with aerobic energy production are a) impairing ME/CFS patients ability to produce energy and b) creating a senescent state that is causing chronic inflammation.

Anaerobic Thresholds, Fatty Acid Problems and Autophagy: Dr. Klimas’s Exercise Study

Conclusion

This study provided an intriguing metabolic snapshot of the immune system. The fact that increased expression of the CD24 molecule has been associated with autoimmune disorders and cancer makes the CD24 finding in ME/CFS interesting, but the metabolic connection the researchers found may be more important.

Their findings suggest that the same problems producing energy found elsewhere in ME/CFS may also be occurring in their immune cells.  Plus the findings suggest that a state of senescence, chronic inflammation and cellular unresponsiveness may be present as well. The possible penalties of having an immune system with a broken aerobic energy production system could go beyond fatigue and pain and extend to problems with autoimmunity, and perhaps in rare cases, cancer.

Studies finding an increased reliance on anaerobically produced energy in the muscles, the brain, in neutrophils and now in some of the B-cells all suggest that a body-wide disruption in energy production may be present in ME/CFS.