Researcher Interactions Question collection thread for S4ME Q&A with Dr Michael VanElzakker

Andy

Andy

Retired committee member
Dr VanElzakker and I haven't quite finalised exactly when this Q&A will take place but, famous last words, we are close to doing so, and it will probably be sooner rather than later, so I'm asking for your questions now.

[ETA: We are now booked in to talk on Fri 11th October].

Background:

From his profile at Tufts University, https://ase.tufts.edu/psychology/people/vanElzakker/index.htm
Dr. VanElzakker received a master's degree in behavioral neuroscience at the University of Colorado, working in Dr. Robert Spencer's neuroendocrinology laboratory, and a PhD in experimental clinical psychology at Tufts University, working in Dr. Lisa Shin's psychopathology neuroimaging laboratory. His postdoctoral fellowship is at Massachusetts General Hospital/ Harvard Medical School, at the Martinos Center for Biomedical Imaging, in the Division of Neurotherapeutics.

Dr. VanElzakker is interested in uncovering the mechanisms of post-traumatic stress disorder (PTSD), and of myalgic encephalomyelitis - also known as chronic fatigue syndrome (ME/CFS).

His PTSD research uses functional and structural brain imaging, behavioral attention tasks, blood, and genetic data to investigate what makes some individuals vulnerable to PTSD following trauma. He is interested in using non-invasive electroceutical medical devices to enhance safety learning, which may eventually serve as an adjunct to enhance exposure-based therapy for PTSD.

His ME/CFS research uses functional and structural brain imaging to look for abnormal patterns in brain metabolism and inflammation in this patient population. This research focuses on dysfunction at the intersection of the nervous and immune systems and posits that ME/CFS may be what happens when the nervous system detects an exaggerated and ongoing innate immune response. He is interested in using non-invasive electroceutical medical devices to enhance the anti-inflammatory vagus nerve reflex.
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His Researchgate profile, https://www.researchgate.net/profile/Michael_Vanelzakker

Recent papers:
Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods, discussed here
Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis, from 2013, Paywall, Scihub

And he can be found on Twitter here, https://twitter.com/MBVanElzakker

ETA: Date of Q&A
 
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Great, ty!

1.)

Would he advise to try transcutane vagus nerve stimulation?

If so, which product would he try and with which protocol?

If he would be interrested, I‘d maybe finance a small placebo controlled study for this. If he would be interested but has no time maybe he could redirect it to someone else he sees capable of doing it.

2.)

Why is nobody trying to get nerve tissue biopsy samples (from vagus nerve?) from patients? I am sure there would be enough patients to do so!

3.)

Does he think that Enteroviruses could play a role in me/cfs in a subset? The similarities with post polio syndrome are very apparent, also there were tissue biopsies showing Enteroviruses in me/cfs patients.


How will you come back to us?

Thank you!
 
Thanks Andy and thanks to Dr. VanElzakker.
1. How does he choose his cohorts and which criteria does he use, and does he see any differences/similarities in the results between criteria? Could this be used to sub group patients and ultimately treatment strategies?
2. Have you or will you be carrying out punch biopsy for SFPN and could he again look to see if there are any differences/similarities in the results using different criteria and also see if there is any correlation between those with extreme neuropathic pain and mast cell problems.
3. What would results of punch biopsy infer with regard possible treatment strategies?
4. Could he please explain why MIT/Mass Gen/ Harvard use punch biopsy over the new ‘machine’ (forget it's name) which supposedly can give just as good an interpretation of SFPN than using punch biopsy. Does he think the new technology is inferior to a punch biopsy?
 
A question I've had for a while and I think he's well-placed to comment on this.


The paralysis state sometimes experienced by ME patients is hard to describe. It doesn't feel so much that nerve signals are not being sent but rather that they are being resisted, a sort of feedback that kind of cancels it. You want to move and try to and it's usually possible but only by mere fraction, as if a perfect counterweight was resisting the action.

Personally, I find it a similar experience to the thing we commonly call "getting the wind knocked out of you", though I have no idea what the proper term is and what it has to do with breathing besides making it difficult. It feels like a shock to the system, a sort of forced hold to prevent any further damage in case the bodily trauma that caused it could be worse than it seems but hidden by adrenaline or whatever other responses create this state of shock.

An example of that would be falling from a certain height, being tackled or ramming into a wall. It's that initial moment after the hit when you can't really move or process what is happening. There is no nerve damage and yet it's nearly impossible to move, think or have much awareness.

I'd like to know what is that state and what is involved in its physiology. Do we know much about it? It sounds like something very hard to study since for accidents that state will be long gone by the time someone gets to a hospital and I doubt there would be approval for a study that includes intentional infliction of serious bodily harm, no matter how convincing the promises of not causing injury may sound. The TACKLE trial is unlikely to get approval.

I think it's likely that there is a common link between the two. A sort of protective state that is misfiring. Would there be a way to test this?
 
This is a similar question to one I wrote in the Karl Morten thread

In his NZ presentation Karl Morten showed a 6 fold increase in Glutamate and a reduction in Glutamine. (finding not replicated yet)
glutamineglutamate_karlmorten_slidespage59-jpg.8059


Here is his slide of data scatter
glutamateglutamine_karlmortenslide60-jpg.8060



In your Harvard talk you presented changes in Glutamate and Glutamine levels with PEM/changes in symptoms
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Elevated Glutamate or glutamate metabolic issues are thought to be involved in Catanonia (Wikipedia) and Catatonia symptoms share many elements with very severe ME.
https://en.wikipedia.org/wiki/Catatonia

Some quotes from Wikipedia:
Catatonia is a state of psycho-motor immobility and behavioral abnormality manifested by stupor.
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Though catatonia has historically been related to schizophrenia (catatonic schizophrenia), it is now known that catatonic symptoms are nonspecific and may be observed in other mental disorders and neurological conditions.
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It may also be seen in many medical disorders including infections (such as encephalitis), autoimmune disorders, focal neurologic lesions (including strokes), metabolic disturbances, alcohol withdrawal[2] and abrupt or overly rapid benzodiazepine withdrawal
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Initial treatment is aimed at providing symptomatic relief. Benzodiazepines are the first line of treatment, and high doses are often required. A test dose of intramuscular lorazepam will often result in marked improvement within half an hour.
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Excessive glutamate activity is believed to be involved in catatonia;
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Here is a recent Twitter thread that is worth a read on Catatonia by Dr. Mark Guthridge from Australia (tweets a lot about ME/CFS)


We have heard from patients that benzodiazepine can help severe or very severe ME and the Stanford ME/CFS clinic sometimes prescribes low dose Abilify. Both drugs are also used in Catatonia.

Q1. Could there be a high glutamate subset that exhibits particular symptoms at a high level (e.g. very severe ME)?
Q2. How do Glutamate levels in the blood correlate to Glutamate levels in the brain?
Q3. What could be the causes for high glutamate or glutamate changes with PEM? Problem with glutamate transport perhaps?
Q4. What are your thoughts on the topic of how glutamate can cause glial activation - are there other methods that can be used to quantify if this is happening in a subset of patients.
 
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In 2018 Prof Theoharides came out with a paper titled "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis?"
Thread here
https://www.s4me.info/threads/myalg...rbed-homeostasis-2018-theoharides-et-al.5257/
The ME/CFS phenotype has been associated with abnormalities in energy metabolism, apparently due to mitochondrial dysfunction, in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism, mitochondria may be further contributing to the ME/CSF symptomatology by extracellular secretion of mitochondrial DNA, which could act as an “innate” pathogen and create an auto-inflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental neuroimmune pathogenic and stress triggers activates microglia leading to focal inflammation in the brain and disturbed homeostasis.
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Is there anything in your work that suggests mast cells activating microglia in the brain may play a role in ME?
 
Jarred Younger received a grant from the NIH for brain scans in ME. Is there an opportunity to coordinate work between the two groups so that together the field moves forward faster? e.g. something you find, or a technique you use, would allow him to test your small sample observation in a larger cohort quickly.

Along similar lines, do you see an improvement in collaboration in ME/CFS research. We hear the words spoken, but are the words becoming reality?
 
@Andy Thank you so much for this upcoming Q&A.

I have a question regarding glutamate and excitotoxicity, since Glutamate is a key part of excitotoxic insults. If we assume that patients have increased glutamate levels, how can we identify excitotoxic events in the brain and / or other tissues of ME patients?

Also, since tinnitus is one common symptom of ME patients, could it be possible that this symptom can be attributed to excitotoxic events, given the below ?


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458046/

Pathophysiology
Most people with chronic tinnitus have some degree of hearing loss (Ratnayake 2009), and the prevalence of tinnitus increases with increased hearing loss (Han 2009; Martines 2010). The varying theories of tinnitus generation involve either changes in function or activity of the peripheral (cochlea and auditory nerve) or central auditory nervous systems (Henry 2005). Theories involving the peripheral systems include the discordant damage theory, which predicts that the loss of outer hair cell (OHC) function where inner hair cell (IHC) function is left intact leads to a release from inhibition of IHC and aberrant activity (typically hyperactivity) in the auditory nerve (Jastreboff 1990). Such aberrant auditory nerve activity can also have a biochemical basis, resulting from excitotoxicity or stress‐induced enhancement of IHC glutamate release with upregulation of N‐methyl‐D‐aspartate (NMDA) receptors
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NelliePledge said:
does he have any thoughts/opinions he wants to share about CCI being linked to ME?
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I will ask him about this but if it's a subject that he's not willing to address then I won't ask him about it in the video. Having said that he spoke about it at the IiME conference so at the moment I wouldn't want to predict if this is something we will be talking about or not.
 
@Andy thanks for this.

I’d like to ask:

1. What are your thoughts on thyroid involvement or hormone involvement in a subset of patients with ME.

2. What are your thoughts on cardiac involvement in a subset of people with ME. Not necessarily regular issues, Microvascular involvement.

3. What are your thoughts on how ME can fluctuate and how (sometimes) some patients (maybe a subset) have mini remission periods.
 
thanks for seeking our input with one of my favourite researchers @Andy
My quite basic questions not put well I doubt:

1) if there is microglial activation is there any supplements or diet with any effect patients can take and/or any drugs that he himself might recommend or try in trials.
2) I personally feel quite sure there will be neuroinflammation found. I’m guessing his cohort will be from the mild-moderate. If he finds correlates with level/extent of neuroinflammation and severity within that cohort would he expect the severely affected to Have higher and even “high” levels? . I’m aware of talk of “low grade neuroinflammation” but I don’t think that the levels will be the same across severity. Does he think massive brain dysfunction or microglia activation is going on in the severe to cause such knock out symptoms. I know he’s talked about post concussion symptoms, and concussion can be milder or knock out too I think..
 
Andy said:
I will ask him about this but if it's a subject that he's not willing to address then I won't ask him about it in the video. Having said that he spoke about it at the IiME conference so at the moment I wouldn't want to predict if this is something we will be talking about or not.
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Ok thanks @Andy i wasn’t sure if he’d already commented but as his area involves brain imaging it seemed to me like he might have something useful to say
 
Dr Leighton Barnden gave a talk at the Australian ME Conference on "Brain Stem Myelination & MRI Changes in ME/CFS"
https://mecfsconference.org.au/videos/leightonbarnden/

I believe Dr. Van Elzakker's interest is also the brain stem. I'd be interested to hear how the two groups are similar and different in what they are studying.

Are any of the current studies at Harvard able to look into myelination in the brain stem in order to replicate/extend Dr. Barnden's work in a small cohort? If not, is there an interest to do so in the future?
 
@Andy I know it was mentioned above the whole glutamate picture. I'm so interested in his thoughts. I'm severe and klonopin helps me, it helps me function a little longer and clears the fogginess. Without klonopin I'd be unable to attend GP. Klonopin also helps me sit upright for longer and can at times stave off a crash.
 
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