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

[Sid]

Authors’ reply to Tuller et al.

Dr Tuller and colleagues4 write that the finding of anticipatory tachycardia can be explained by patients knowing "that standing up during a tilt-table test could aggravate their symptoms¨. We agree with their statement as it describes fear conditioning. It is important to emphasize that the biological process of fear conditioning makes this neurological response unconscious and independent of will. Therefore, the fear conditioning that occurs in POTS should be treated. Extinguishing fear conditionings could improve symptoms; dismissing this would be a disservice to patients.

Extinguishing fear conditioning has already been tried. In fact it’s been the cornerstone of treatment of these patients for decades (CBT, GET) and it hasn’t worked.

Another letter pointed out that most patients have at some point been told their illness is psychiatric and many received psychiatric treatment with no success.

 

[Andy]

Authors’ reply to Tuller et al.



Extinguishing fear conditioning has already been tried. In fact it’s been the cornerstone of treatment of these patients for decades (CBT, GET) and it hasn’t worked.

Another letter pointed out that most patients have at some point been told their illness is psychiatric and many received psychiatric treatment with no success.

Wow. I can't wait for their next paper, "Everytime we turn on a blue light, we gave people an electric shock. These people have developed, for some reason, a fear of blue lights being turned on. If we convince them not to fear what happens when a blue light is turned on, this will mean they are invulnerable to electric shocks!".

 

[dave30th]

"Everytime we turn on a blue light, we gave people an electric shock. These people have developed, for some reason, a fear of blue lights being turned on. If we convince them not to fear what happens when a blue light is turned on, this will mean they are invulnerable to electric shocks!".

more or less, yes. How do you "extinguish" the normal response when you know you're going to undergo an unpleasant experience? It's a ridiculous statement. There is zero evidence that "extinguishing fear conditioning," if it were even possible, would have any effect on anything.

 

[Hutan]

Yes. And they don't seem to have understood the difference for most people between just standing up and undertaking a tilt table test. Most people with ME/CFS don't pass out when they stand up, and they will usually have the option to sit or lie down or move around to get the blood moving if orthostatic symptoms are bad. When you are strapped into a mechanism specifically designed to make you faint/suffer from unpleasant symptoms, and you know that you have to suffer those symptoms for long enough to show that you do actually have a medical condition, then the scope for inducing fear is fundamentally different to that of standing up in everyday life.

It's incredible that the authors don't understand that.

The tilt table test should be terminated at syncope or after protocol termination. Some patients have prolonged hypotension without loss of consciousness, and in this case, the termination of tilt testing during the pre-syncopal period may be considered, especially in elderly patients.

The tilt table test is a safe procedure. However, myocardial infarction or stroke may develop in persons with significant coronary or carotid artery stenosis. This is very rare. Arrhythmic complications may be represented by prolonged bradycardia, which may be treated with atropine. Ventricular fibrillation is extremely rare. Some patients may vomit after tilt testing or have severe weakness lasting for several hours. A headache is common, especially after nitroglycerine use. The patient should be informed about the risk of urinary incontinence or vomiting and have clothes to change into, if necessary.

 

[bobbler]

Authors’ reply to Tuller et al.



Extinguishing fear conditioning has already been tried. In fact it’s been the cornerstone of treatment of these patients for decades (CBT, GET) and it hasn’t worked.

Another letter pointed out that most patients have at some point been told their illness is psychiatric and many received psychiatric treatment with no success.

They also fail to note that conditioning requires quite a lot of closely repeated occurences of the 'nasty outcome' immediately following the stimulus. So it can't have been Pavlovian from numerous tilt tables - as noone would be signed off to do them daily just for safety reasons (as well as there being no point). And for it to apparently have been 'Pavlovian' then it would have required people to have had awful outcomes repeatedly and consistently from standing many times over in many consecutive, close-together situations, over a prolonged period of time.

EDIT: Here is a link: https://www.simplypsychology.org/classical-conditioning.html
Note that also the conditioned response would mellow if the symptoms reduced (ie POTS became better) because it would be stand up -> don't feel ill being repeated, even if there is a 'stress' in the middle. The idea that the stress continues when the POTS symptoms don't for much longer is suggesting a whole different ball game.

Ergo if you don't have POTS in the first place that isn't possible (hence not present in controls) - and if you have POTS that is the cause - and if someone anticipates that is because wherever you are you need to be on the lookout for safe landing spots.

How can someone get away with hurting patients for the sake of it, just to pretend the fact their stress went through the roof proves anything. Tell someone you are going to put them in a diabetic crisis by injecting with too much insulin and the ones who know what that means because they've been in one and know how dangerous it is will probably understandably show this too. Doesn't mean ethics should sign it off. And puts big red flags on ethics boards as to why this illness has been signed off for 'antagonise for no good means, but for quite malign purposes (if we are being frank)'.

What has the world come to on all this - it's weird

 

[bobbler]

Yes. And they don't seem to have understood the difference for most people between just standing up and undertaking a tilt table test. Most people with ME/CFS don't pass out when they stand up, and they will usually have the option to sit or lie down or move around to get the blood moving if orthostatic symptoms are bad. When you are strapped into a mechanism specifically designed to make you faint/suffer from unpleasant symptoms, and you know that you have to suffer those symptoms for long enough to show that you do actually have a medical condition, then the scope for inducing fear is fundamentally different to that of standing up in everyday life.

It's incredible that the authors don't understand that.

I horribly think that they do. It seems contrived of what they can 'get away with doing' that would obviously put someone's heart rate through the roof on a condition - and aren't allowed to do such vile tricks to any other type of patient, as it would seem only culture issues let this piece of nastiness slip through the ethics board.

Imagine them taking people who have heart issues that are tested by stress-tests that might be awful and someone signing off getting them in vs a bunch of people with no heart issue who've no idea what'll be involved in order to prove 'it's fear-conditioning not the test itself causing stress'. Or doing the X-factor long pauses on cancer check-ups and comparing the heart rate to a group who have never had cancer being made to take a blood test with a 0.001% likelihood and saying the former group were more stressed before it even started proves something. It's just outrageous ethics and idiocy to the point you wonder about missing modules in thinking these things up.

 

[RedFox]

Ask any patient with severe endometriosis, dense adhesions, fibromyalgia, large fibroids, multiple large ovarian cysts, untreated iron deficiency / B12 deficiency / anaemia, untreated thyroid disease, cancer that isn't diagnosed until a couple of days before death.

Hmm. Many of these conditions that doctors ignore seem to have something in common...

severe endometriosis, dense adhesions, large fibroids, multiple large ovarian cysts

I can't quite put my finger on it....

 

[Sid]

Letter to the editor by Bourne et al. cites an interesting study I had never heard of with much better methodology addressing the same research question (is POTS fear of standing).

Masuki et al.8 conducted an elegant study to tease out the role of anxiety versus gravitational fluid shifts as the cause of excessive tachycardia in patients with POTS. They simulated standing using lower body negative pressure (LBNP), in which negative pressure (suction) is applied to the lower body, causing blood to shift from the thorax into the abdomen and legs. LBNP simulates the intravascular fluid shifts that occur with the assumption of upright posture. This simulated orthostatic stress reduces stroke volume, unloads the baroreceptors and activates the baroreflex, resulting in increased sympathetic nervous system activation and increased HR. When Masuki et al. applied LBNP, patients with POTS had a significantly higher HR increase compared to the healthy controls, without a change in blood pressure.8 When the protocol was repeated with medical antishock trouser (MAST) pants inflated (to insulate the legs from suction), this HR increase was essentially eliminated. When the vacuum sound was applied without any negative pressure (negative control), the HR did not increase in patients with POTS.8 These data elegantly demonstrated that the increase in HR seen in patients with POTS was driven by the shift of fluids away from the thorax (baroreceptor unloading), and not the anticipation of LBNP.

Masuki S, Eisenach JH, Johnson CP, et al. Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety. J Appl Physiol. 2007;102(3):896-903.

 

[Hutan]

That is such a neat approach @Sid! Earlier I had a half drafted post for this thread with vague ideas on how the question could be answered, but I didn't think of an approach of replicating the gravitational effect of standing while the patients are still lying down. 2007, it's shocking that these questions were asked, and answered, so long ago.

 

[ahimsa]

I've seen other studies that use LBNP (lower body negative pressure) testing.

This video on Vimeo - Understanding Blood Volume and Hemodynamics in POTS, by Satish Raj - mentions a study that uses it:

​

Here's a screen shot showing what the machine looks like:



EDIT: This study showed "improved short-term orthostatic tolerance exhibited by the subjects with POTS following ORS administration. ORS is a convenient, safe, and effective therapy for short-term relief of orthostatic intolerance." [ORS = Oral Rehydration Solution]

https://pubmed.ncbi.nlm.nih.gov/31405524/

 

[Hutan]

We've made a thread for that Masuki 2007 study here:
Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety, 2007, Masuki et al

 

[SNT Gatchaman]

See Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome (2024, JACC: Basic to Translational Science) —

showed that postural reductions in stroke volume and cerebrovascular pulsatility, a marker of brain perfusion, were significant determinants of postural ventilation and sympathetic activity.

During head-up tilt, patients had larger reductions in stroke volume compared with control subjects, which was strongly correlated with the change in ventilation.

Note that they replicated findings in a partial animal model. Partial animal model here means no brain above brainstem, no heart, lungs or even blood; instead using artificial blood and pump. So there is categorically no requirement for fear conditioning.

Using an arterially perfused in situ preparation, we confirmed that changes in brain perfusion modulate respiratory and sympathetic activity independent of peripheral chemoreceptor and baroreceptor input. Together our findings suggest that in patients with POTS, reduced cerebrovascular pulsatility, likely driven by a reduction in stroke volume, may compromise brain perfusion resulting in increased ventilation and sympathetic activity.