Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2021, Xia Li et al

Even if it could not distinguish that, if the reduced blood flow proves a significant ME/CFS characteristic, then that would presumably still be of major import. Pathfinding for further research maybe.

 

I don't know about RA but this sort of thing seems to have happened to me.

I can be in significant pain for a long time, with pain killers right next to me, and not take them, even when I remember that - as moving involves lots of processes that I know won't stop the pain for a long time.

So it doesn't happen.

Which is why I rely on a schedule, sort of, when it works.

 

Me too.

 

I don't have any additional info about this study, sorry.

But yes, I admire Per Julin and I deeply appreciate his work I dare say he's the best ME expert in Sweden. He's definitely not a BPS proponent.

Julin is a senior research physician: MD, PhD, specialist in rehabilitation medicine (focus on brain injuries), with clinical research in cognitive disorders, especially neuroimaging, including 6 years at Astrazeneca R&D. He's got clinical experience with ME since 2010.

He worked as a senior consultant and researcher at the Stora Sköndal ME/CFS clinic (biomedical, situated at the neuro rehab clinic) until it was closed down earlier this year. For years before that, he was the head of research at the ME/CFS project at Danderyd.

On top of his role as a ME specialist physician (which included doing home visits to severely ill pwME) and researcher, he has done invaluable work over the years through giving educational talks to the Parliament (Riksdagen), healthcare professionals, patients & carers as well as the public; written opinion pieces in medical publications, served as a medical and scientific expert for several projects related to national clinical guidelines for ME including SBU and the National Board of Health and Welfare (Socialstyrelsen), written articles about ME for official public healthcare information websites like 1177.se and VISS, served on the scientific advisory board of the patient organisation, and contributed to advocacy work in other countries as well. I could go on and on...

I haven't been able to find any linkable sources to confirm, but I've heard rumours that he's currently working at a long covid clinic.

About Per Julin on the staff pages at Karolinska Institutet, including list of publications:
https://staff.ki.se/people/per-julin

Per Julin, list of publications on PubMed:
https://pubmed.ncbi.nlm.nih.gov/?term=julin+p

I'm afraid I don't know much at all about MRI physicist professor Tie Qiang Li. I'm aware he and Julin has known each other for many years, and that they have previously collaborated on development of new MRI techniques, among other things.

There's also the ME study about kinetic oscillatory stimulation (KOS) in the nasal cavity that Julin and Li did together a while ago:

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
https://www.biorxiv.org/content/10.1101/2020.02.20.958249v2

Forum threads on the KOS study here and here. (I'm honestly not sure what to think about this one... it's a bit of a weird one, but Julin appears to be excited about it, so I can't help feeling curious.) One of the main aims of the study was to find out, with the help of fMRI, if KOS can affect neurophysiological mechanisms, for example changing the connectivity between different brain areas in pwME, and if so what are the neurophysiological mechanisms behind the effect?

Here's a related study by Tie Qiang Li:

Li TQ, Wang Y, Hallin R, Juto JE. Resting-state fMRI study of acute migraine treatment with kinetic oscillation stimulation in nasal cavity. Neuroimage Clin. 2016 Aug 15;12:451-9. doi: 10.1016/j.nicl.2016.08.014. PubMed PMID: 27622142; PubMed Central PMCID: PMC5008046.
https://www.sciencedirect.com/science/article/pii/S2213158216301504

I'm not familiar with Xia Li either, sorry. It's not his only collaboration with Swedish researchers though. Here's one recent example, also together with Tie Qiang Li:

Dataset of whole-brain resting-state fMRI of 227 young and elderly adults acquired at 3T
https://www.sciencedirect.com/science/article/pii/S235234092100617X?via=ihub

 

There are some MRI techniques that are used to measure hypoperfusion due to vascular problems/mild hypoxia, for example in acute stroke, or in newborns. The one I've heard of before is MRPI which is used to assess blood flow in the regions surrounding the stroke infarct. Another is DWI (diffusion weighted imaging).

This one used here, PCASL, is new to me. But the method seems to be commonly used to measure brain activity in response to some task (or at rest), in much the same way as fMRI.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821165/
https://www.sciencedirect.com/science/article/pii/S016503271400216X
https://www.sciencedirect.com/science/article/pii/S0920996414000589

There's also this PCASL study on MECFS:
https://www.sciencedirect.com/science/article/pii/S0730725X15003033

The other reason I'm interpreting this as a functional study, not a study of vascular abnormalities, is because the significant regions are not associated in terms of their vascular supply, they're not brain regions that are super vulnerable to mild hypoxia (like the hippocampus) and they're not in "watershed" areas (regions that sit in between two vascular territories that may be particularly vulnerable to mild hypoxia). The regions are functionally associated.

 

Yes!

Yes, that's my take on it. Just a guess, though. These sorts of studies can't support very strong inferences about what mental functions might be going on.

 

I wonder whether they might be a mistake with the references:

The study on ASL in healthy controls is probably not reference 21 as the text indicates, but reference 20, namely:
Imaging brain fatigue from sustained mental workload: an ASL perfusion study of the time-on-task effect - PubMed (nih.gov)

Similarly, the ASL study in ME/CFS patients that found no difference with healthy controls is probably not 22 but 21, namely:
Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study - PubMed (nih.gov)

 

My take on this is the observation of limbic hypoperfusion in PWME is consistent with the oft reported symptoms of emotional lability and cognitive dysfunction.

So I welcome this as an empirical observation of what strikes me as a real phenomenon, i.e. a validation.

Not sure where we go from there but I guess the questions on p1 of this thread about the causes of hypoperfusion are worth asking and answering.

It could be an aspect of an evolutionarily adaptive system which is downregulating the brain to favour immune activity over brain activity and may relate to the observations regarding hibernating genes I recall from a while ago.

Alternatively it could be some kind of circulatory pathology in which case if it was assisted it could help.

Or a bit of both.

At a practical level I have tried circulatory assistance and still eat celery every day as it is a mild blood thinner and I feel it helps, possibly by reducing blood thickening / volume reduction in ME previously observed as high ESR (erythrocyte sedimentation rate) in PWME. I find regular celery makes me feel less like a zombie.

2c

 

Just some rambling thoughts. This study shows that ME patients are different from controls but it does not tell us if that is due to a pathology preventing blood flow or oxygen release, if it is a consequence of the whole process of being tested exhausting the patients or if it is a protective response by the patients to prevent further damage.

I would add it could be because the damaged aerobic system in patients puts the brain under pressure so it prioritises important regions.

There have been many studies which have shown differences in the brains of people with ME, though in older ones it is hard to know how many actually had PEM. Nothing has been conclusive but they point the way to a cause and what is generating our symptoms.

It is inevitable that the body makes adjustments in chronic diseases. It will always optimise survival which is why we must be wary of "treatments" which force us to live like a healthy person without the knowledge to know if we are causing damage.

These differences in brain perfusion could easily be the cause of the "incongruent" symptoms that the FND people go on about finding and all those weird little things that are so hard to describe.

 

How often are they testing? A dear friend w/ME showed evidence of hypoperfusion on a PET/SPECT one year for disability application, and no hypoperfusion several years later when retested.

 

It could be the reason why symptoms are hard to describe. A brain that is having symptoms due to a deficit in oxygen could also have difficulties creating descriptive memories of what is happening. Later, it's then difficult to describe what exactly happened.

 

Exactly, there a few things that I know happen but I cant access what it is that is going on.

 

I find the study very important as a psychiatrist and I am also aware of a lot of my own cognitive problems having the illness. Most particularly, there is a relationship between hypoperfusion and illness severity. It would be interesting to have neuropsychological testing for the cognitive function in this group especially on attention and working memory (which utilises the ACC). It appears they might look at microvascular changes which will be very interesting.

 

Basically yes. A key point is we cannot measure the microvascular flow or the micro-delivery of oxygen, because the skin (and bone) provide a barrier that prevents such imaging (the one exception being through the eye). The imaging techniques discussed are just aggregates for particular areas.

@Woolie mentions the regulation is based 'level of need' (a process scientists still don't properly understand the mechanisms of) but perhaps the tissue not getting the oxygen delivery it needs is the problem. I have had a permanent headache for the last 20 years, which is why I still wonder about this possibility.

 

The late Dr Paul Cheney said that he measured a problem with well oxygenated blood in PWME not desaturating at tissues, meaning the oxygen is not released by the blood to enter the tissues. He thought this is pH regulated. Dr Cheney considered this problem was due to blood alkalosis compensating for cellular acidosis but I have not seen any recent follow up on this.

Ron Davis also published a paper suggesting the deformability of red blood corpuscles is reduced in ME CFS but this had a small sample size and was not replicated by Brenu et al in Australia and the issue has not been settled. The ME Association did a helpful summary with several references to other brain blood flow studies in ME CFS.
https://meassociation.org.uk/2018/1...ced-ability-to-change-shape-04-december-2018/

These other potential factors affecting oxygen transfer and utilisation are in addition to the flow rate issue, so potentially quite a lot going on for PWME not covered by this method. As the WIKI was good enough to explain to me this MRI experiment does not measure any of this as it just measures bulk flow rates by magnetising water and measuring its displacement.
https://en.wikipedia.org/wiki/Arterial_spin_labelling

-

The personal relevance of this is it makes sense to always try to keep good hydration. Though this is a known problem for PWME due to a tendency to increased diuresis and lowered blood volumes and ESRs, so its a rock vs hard place situation as per usual.

I feel Dr Cheney's observations may correspond with the "air hunger" many PWME report and which I experienced for a long time. This also may explain the problem with carbs making them feel rougher which many PWME report, possibly because of carb foods creating more acidosis.

Because of Dr Cheney's discussion I tried adding bicarb to my food and this made air hunger worse whereas acidifying my diet helped relieve the air hunger, so to this day I try to keep bicarbonate intake low and drink dilute apple cider vinegar as my first drink of the day!

It also helps to breath more slowly i.e. the techniques used to treat hyperventilation, as this raises blood CO2 which makes it more acidic.

I also have tried ketogenic diets to reduce carb intake and found I could not tolerate a zero carb diet but that reducing carb as a proportion of my food did help a little.

 

I just did a trial run yesterday and the results showed a potential for formal study. I used a NIRS device (near-infrared spectroscopy). This lies somewhere between "magic" and Star Trek and overcomes the problem noted by @Snow Leopard. I was able to measure the ratio of oxygenated Hb to deoxygenated Hb in the micro-circulation in my superficial frontal lobes. It plots at around 20 second temporal resolution.

It showed a perfectly reasonable 87% when lying, that quickly dropped to 77% on standing (within a minute). We didn't check against a normal control yesterday because the device wasn't quite optimised for the two of us, which we would need to do. However, we expect that there should be no, or very little, change in normals.

 

Here's a paper from 2019, looking at "POTS" patients, using NIRS with head-up tilt testing.

Paper: Monitoring of cerebral oximetry in patients with postural orthostatic tachycardia syndrome

I don't have any significant cognitive dysfunction symptoms, although I will formally test that soon. My pretty decent parenchymal O2 levels (at least as they are this week) would seem to correlate.

ETA: Thread posted here

 

Useful to be a radiologist! Not sure about the magic but these technologies are becoming the most useful imaging techniques for trying to understand cognition, neuroanatomy and disease processes. Is there a good review article that you have found most informative that covers the current knowledge in this area suitable for my level of specialisation?

So your scientific process is to study brain vasculature in the most accessible place, i.e. on front of your head. Do you do anything cognitively during this process? Are you at rest? Sounds like a good start. Also having my clinical hat on, knowing the history you have provided within this forum I have read, is that you have ME with POTS with PEM, brain fog or whatever one chooses to describe it, but no other prominent symptom cluster? I will always be considering you have particularly sensitive cardiovascular pathways but may be irrelevant as this enquiry maybe the universal underlying process in ME.

 

Thank you @hibiscuswahine. I'm POTS/PEM/fatigue/sound hypersensitivity/sleep disturbance range of symptoms. I have syncope and pre-syncope and my head has felt "fragile", "full", "fuzzy" and other nebulous "not right" feelings, but I haven't really had brain fog in terms of cognitive dysfunction.

My mind has remained active and my wit has been on its usual (terrible) form. What was very clear though was something of a psychomotor slowing (?) of speech. I hope I'm using the terminology correctly. My voice was quiet and weak and I spoke more slowly. I'm not normally loud but I am enthusiastic, with confident verbalisations and used to talking to a room. I attributed this to a generally low energy state on the basis that my internal thinking itself was still fast and clear. I may be mistaken with this subjective assessment though and this may have been modest brain fog. Family and friends could tell how I was day to day just when I answered the phone.

I also quickly looked at liver and quadriceps muscle perfusion, but didn't see any overt changes there. That may be explained by the liver being downhill from the heart and so orthostatically tolerant. Also, in the available time I only did some very modest unweighted leg extension against gravity for a few minutes, so not a reasonable exercise challenge.

(My wife has vetoed me doing any self-experiments that risk significant PEM - at the moment I seem to be in a recovery phase and quite reasonably feels it should not be jeopordised. She's been through hell and despite my academic enthusiasm, she has the casting vote here.)

For the brain, the NIRS device attaches to "somewhere on the forehead", with no hair to spoil the contact — and I haven't been able to have a haircut for 3 months! It measures superficial tissue oxygenation so will be targetting cortex and sub-cortex. Without shaving, it would be limited to anterior frontal convexities and of course wouldn't be able to get to the inferior frontal lobes. This might be hard to target specific areas of interest as per the article under discussion. I'm not sure the spatial resolution could work with various specific cognitive challenges either, but I'm sure researchers will be wanting to see if it could complement fMRI. I suspect even with advancements, this technique will be limited due to inaccessibility of deep brain structures.

What I started out being interested in was whether there was diurnal variation in many of our symptoms — I strongly suspect there are and that mechanisms might be suggested by some investigations. This was during normal (paced) daily activities, rather than post exercise challenge. I was interested particularly in brain and muscle, e.g. MRI spectroscopy for lactate in the cerebral ventricles and thigh.

However, yesterday I also ran a venous oxygen saturation at rest and it is 45%. Still very much lower than it should be, but much better than the 22% I had when initially crashed. I'm 11 months in and evidence would suggest that long-term ME patients normalise or go high with this reading. So for me, it could mean anything, but coupled with clear improvements in my daily functioning (still being very carefully paced), I suspect this represents real improvement. As per my other posts I have theories as to why, but won't pollute this thread by re-iterating.

So that leaves me changing tack again. I might actually not be a good candidate as a representative ME patient, and perhaps I'm on a recovery trajectory. That makes me favour doing a set of investigations say a month apart, rather than tracking through the day.

Instead now I'm thinking of formal cognitive assessment (eg the BrainCheck system), SF36, Bell disability scale, 10m walk test, transcranial Doppler, NIRS, lying/standing P/BP, fingerprints and some other very cutting edge medical imaging (PET and MRI) if possible.

---
If I am trully slowly repairing then I can absolutely confirm it was nothing to do with talking myself out of it or a Paul Garner-like power-of-one victory.

 

I can only go from my experience of myself, my close whanau’s observation of living with me and my ME and my training. You have had it for a year and presumably improves if more rested or “successfully” paced your day, an almost impossible goal for me currently as I am in a major relapse but seem to be able to pull some learnt material out, some very dusty, and use deeply embedded motor skills (typing) which is considerably less stressful than when I speak, (major word finding difficulty, slurred speech and very noticeable to my partner). I am fully aware that this forum is cognitive stress for me but whatever, I live to my values and interests. Recovery or finding the often mythical baseline is a process and I am waiting for the neural up and down regulation of oestrogen and progesterone receptors to see if they will improve my sleep using MRT. Early days. I appreciate my circadian and diurnal rhythms but still not been able find the right thing to twig them yet but ever hopeful (but yes, not the LP/switch therapy, change your dysfunctional beliefs and behaviour from whatever the latest psychological therapy prevalent in psychiatry).

If you are self-funding, I think formal neuropsychological testing would be optimal as a baseline, perhaps by the supportive psychologist you saw. It is the gold standard and also useful to help guide your own cognitive rehab, lists, no multitasking…. I had neuropsychological testing about 20 years ago, when I was going into relapse every time I tried to sit my writtens for fellowship. I passed once they changed the format. They should also be able to do meaningful and well recognised functioning and disability scales, gets around the self administered bias you may encounter. This will also be useful when considering return to work and fitness to practice, if that ever becomes an issue.