Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome, Norcliffe-Kaufmann et al, 2022

Other questions I have on this paper —
  1. Authors make little acknowledgement of the anticipatory tachycardia seen in HCs. That HC tachycardia could be to the same level as pats. And that some pats had an anticipatory bradycardia.
  2. No discussion of lack of hyperventilation in the supine anticipatory phase.
  3. No mention that I could see of the time course of end-tidal CO2 and reduced MCA velocity. Their conjecture is that fear -> hyperventilation -> dec. CO2 -> cerebral vasoconstriction -> inc. cerebral vascular resistance -> dec. cerebral blood flow. If the drop in MCA velocity occurs immediately on standing rather than following the slower onset of respiratory alkalosis - that knocks down their theory.
Screen Shot 2022-08-07 at 12.38.16 PM Medium.jpeg Screen Shot 2022-08-07 at 12.38.41 PM Medium.jpeg
 
SNT Gatchaman said:
Authors make little acknowledgement of the anticipatory tachycardia seen in HCs. That HC tachycardia could be to the same level as pats. And that some pats had an anticipatory bradycardia.
Click to expand...
That the authors could draw their conclusion so confidently on the basis of that Figure B is amazing. That's a really substantial overlap. A control could easily have as much 'anticipatory tachycardia' as the POTS patient, although presumably the outcome on the tilt table was quite different.

Hutan said:
Also, perhaps the increased heart rate of the people with POTS, can be at least partly attributed to the orthostatic and exertional challenge of coming into the clinic, and waiting to undergo the test.
Click to expand...
Now I see the paper, I see that this possibility is incorrect. The test subjects rested for 30 minutes before being told they would soon be tilted.

Physiologic signals were acquired during 30 minutes of supine rest. Following this, and while still in the supine position, following a standardized clinical protocol, subjects were told that the table would immediately move upright, and that they might feel unwell. This auditory warning was precisely timed 30 seconds prior to actual tilt. The 30-second time window from the auditory warning to the actual tilt was used to assess the anticipatory (i.e., cortical) tachycardia.
Click to expand...
Mean cerebral blood flow velocities and end-tidal CO2 concentrations were averaged over a minimum of 10-beats.... The anticipatory tachycardia was defined as the finalheartbeat prior to the table moving minus the heart rate averaged over 5 beats prior to the oral tilt warning.
Click to expand...
It's hard to believe, but it seems that, during the 30 seconds between being told the tilt would happen and the tilt actually happening, the 'anticipatory tachycardia' was calculated by subtracting the average heart rate just before the warning (with the average based on 5 heart beats) from the heart rate just before the table moved (with this measure based on 1 heart beat). The cerebral blood flow velocities and end-tidal CO2 concentrations were averaged over 'a minimum' of 10 beats (so might have been averaged over a number of beats larger than 10 for some participants).

That is all sounding pretty arbitrary to me; I wonder if the methodology was logged in a trial registry before the study started. Why wouldn't you use the same method of measuring heart rate for the before and after measures? Why wouldn't you use a longer period to average the heart rate over e.g. why not the 20 seconds before the warning and the 20 seconds before the tilt started? A single heart beat seems a ridiculously short time to measure average heart rate over and requires a great deal of precision in aligning the timing of the start of the tilting with the selection of the correct single heart beat.
 
Last edited:
subjects were told that the table would immediately move upright, and that they might feel unwell. This auditory warning was precisely timed 30 seconds prior to actual tilt.
Click to expand...

It seems to me that most anybody in that situation would be wondering over the 30 seconds if something had gone wrong with the mechanism, am I about to be jerked upright to catch up because it's supposed to be immediate? etc etc.
 
Screen Shot 2022-08-07 at 5.47.25 pm.png

This figure, which is supposed to be the average of all of the data for the two groups, is a bit odd.

Table 1 tells us that the heart rate for the controls during supine rest averaged 68, and the heart rate for the POTS patients averaged 71 bpm.

Screen Shot 2022-08-07 at 5.54.03 pm.png

But, look at Figure A, in the first section before the warning (limbic stimulation). The controls' heart rates average is never less than 68 bpm, with a mean more like 69 bpm. The POTS patients' average resting heart rate is never 71 bpm - it's more like 75 bpm.

And then, look at Figure A again. The crucial bit with the heart rates just before (5 beats) and just after (1 beat) the tilt table moves (i.e. the heart rates used to calculate the difference in anticipatory heart rate increase) is missing. If you look at the scale, you can see that the data really is missing. Why?

Also, the x axis is heart beats. And yet we were told that the time between the auditory warning and the tilt was precisely 30 seconds. Given that the two groups had different heart rates, surely the timing of the various measures should be shown at different points on the x axis?

The x axis only runs out to 175 heart beats. That's only a couple of minutes. It would have been good to see the entire 10 minutes of the tilt table test.
I'm not sure about the figures given in Table 1 for the 10 minute tilt test - I can't see any description of how they are calculated.

The report seems a bit messy and vague (as well as making fundamental errors in interpretation of course).
 
Last edited:
The paper said:
We did not measure cardiac output.
Click to expand...

They measured MCA velocity at 10 minutes. I expect cerebral blood flow actually drops on orthostatic challenge in association with decreased cardiac output and that this occurs quickly. But, I can't find information about expected timeline for MCA velocity drop in experimentally hyperventilating normals or in patient evaluations (eg. van Campen/Visser/Rowe).

However, as a first approximation to cerebral blood flow, last year I recorded my frontal lobe SpO2 dropping by 10% within 10-20 seconds of standing — to the surprise and lack of delight of my intensivist colleague. I think we both would have noticed if I was hyperventilating sufficient to blow off the required amount of CO2 to achieve that...

---
Hyperventilation is used in neuro-ICU to try and reduce cerebral blood flow and thereby intracranial pressure. See Hyperventilation in Adult TBI Patients: How to Approach It? (2021). Also pCO2 and pH regulation of cerebral blood flow (2012) is probably worth referencing for this part of the discussion. The overview for respiratory alkalosis is here.
 
SNT Gatchaman said:
  • No discussion of lack of hyperventilation in the supine anticipatory phase.
Click to expand...
Interestingly, Wessely et al, and separately Bazelmans et al, showed in the mid-90s that hyperventilation is not an issue in ME (CFS).

There was no association between level of functional impairment and degree of hyperventilation. There is only a weak association between hyperventilation and chronic fatigue syndrome.

https://pubmed.ncbi.nlm.nih.gov/8140219/

Physiological evidence of hyperventilation was found significantly more often in CFS patients than in healthy controls. However, no significant differences between CFS patients with and CFS patients without hyperventilation were found on severity of fatigue, impairment, number of complaints, activity level, psychopathology, and depression. It is concluded that hyperventilation in CFS should probably be regarded as an epiphenomenon.

https://pubmed.ncbi.nlm.nih.gov/9330236/
 
SNT Gatchaman said:
  1. No mention that I could see of the time course of end-tidal CO2 and reduced MCA velocity. Their conjecture is that fear -> hyperventilation -> dec. CO2 -> cerebral vasoconstriction -> inc. cerebral vascular resistance -> dec. cerebral blood flow.
Click to expand...

We already know that isn't true (hyperventilation is not the cause of the cerebral vasoconstriction). But I think the hypothesis is the fear leads to sympathetic activation that leads to increased cerebral vasoconstriction in parallel with the hyperventilation.

But in POTS the increased vasoconstriction is a central/body-wide symathetic response to increased venous blood pooling. Their study is meaningless unless they measure the kinetics of this pooling.
 
Trial By Error: A Letter to Journal Brain About Paper Claiming POTS Is a “Functional Psychogenic Disorder” by @dave30th

I recently criticized a study from New York University’s neurology department. The investigators wildly over-interpreted their findings in order to argue that postural orthostatic tachycardia syndrome, or POTS, is a “functional psychogenic disorder.” This morning, I sent a letter to Brain, the journal that published the paper, on behalf of several colleagues as well as myself. I have also posted the letter on a pre-print server, and below as well.
Click to expand...

Jonathan Edwards, Mady Hornig and Brian Hughes among the signatories.

https://www.virology.ws/2022/08/17/...ng-pots-is-a-functional-psychogenic-disorder/
 
Is it just me or has this been an experiment in taking 2 unrelated things and putting them in the same sentence, or on this occasion experiment, in the hope that some people will fall for the fallacy that means the two are connected?

I just can't understand the ethics of how they got POTS patients onto a tilt test that is known to make them really ill and be very challenging to even get through (ends with passing out) if they did not hide the reason for this being to do this. It clearly offers no medical benefit to those with POTS so there must have been industrial-sized lies as far as I would believe ethics goes.

They could easily have done such an experiment without the actually setting off the table part - because neither design would mean anything. It has no connection to POTS and the next part whatsoever from what I can see. They maybe had some call for those who didn't have POTS ie HCs to put them on the table and set it off in order to check they weren't in the group and show that in normal people scaring them vs tilting them has a x proportionate effect but I don't get the point..

But for this design, with POTS patients... it's just comparing those who knew what was coming, are objectively made more ill by it, and had been through the same thing before where there was no pause would be more puzzled by it - as they knew that delay was abnormal - than those to whom a tilt test was novel. And to be fair they might at that point, some of them, realised they'd been tricked into something they would never have signed up to and now strapped in to something that will damage their health to no good avail.

Why doesn't someone report that? This is just into the realms of someone signing off toying with subjects for the sake of it. Given there would surely be room for 'other ways of obtaining this information' to be achieved how on earth did someone sign this off?

Or am I missing something
 
bobbler said:
Or am I missing something
Click to expand...
Nope. Biopsychosocial is not serious, a return to old style pre-science medicine where someone tries a bunch of stuff and says "good enough for me", explicitly set out with a conclusion to prove and do the rest around it.

It turns out that trying to solve a problem without bothering to understand it leads to very silly and incompetent nonsense. Who knew?!
 
rvallee said:
Nope. Biopsychosocial is not serious, a return to old style pre-science medicine where someone tries a bunch of stuff and says "good enough for me", explicitly set out with a conclusion to prove and do the rest around it.

It turns out that trying to solve a problem without bothering to understand it leads to very silly and incompetent nonsense. Who knew?!
Click to expand...

Indeed.

What is strange is that someone with responsibility for ethics and patient safety - and with that the risks being 'worthwhile' is signing these things off.

I find it impossible to see how this was sold to anyone from an ethics perspective as justifiable, and who on earth as a POTS patient would voluntarily put themselves on a tilt table without having been led to believe there was some serious medical help/progress/good to come from it. Only bad answers come to my mind for that second one

What does: (31 ± 12 years old, 25 women) mean in the POTS sample? what is the + above the - and what does it mean in relation to the 12 years old after it?
 
Yes I think you're right, that makes more sense. It's an odd way of writing it that I haven't seen before. I had presumed they did not have patients under the age of 19. Now I look back, I see they've used the "±" in all their tabulated data too, so yes: it must be mean / standard deviation. Thanks for clarifying.
 
You must log in or register to reply here.
Back
Top Bottom