By David Tuller, DrPH
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.
In “Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome” (2022), the investigators document a number of associations. They report that patients with postural tachycardia syndrome, or POTS, scored higher on anxiety and “somatic vigilance”–that is, paying attention to bodily sensations–than controls. They report that POTS patients, compared to controls, had a “more pronounced anticipatory tachycardia” when alerted to a coming tilt-table test that would position them upright. They report that, compared to controls, POTS patients positioned upright during the tilt-table test had faster heart rate, higher plasma catecholamine levels, lower end-tidal CO2, and reduced middle cerebral artery blood flow velocity.
The investigators explain the findings by positing that POTS patients have a “classic Pavlovian fear conditioning” response developed after a prior episode of having unpleasant symptoms upon standing. They describe the anticipatory tachycardia as “a physiologic indicator of fear conditioning to orthostasis”—an assertion presumably designed to bolster the argument that negative past experiences trigger current POTS symptoms. At the end of the limitations section, the investigators acknowledge, as if in passing, that they “do not know” if their findings “are a cause or a consequence of the syndrome.” Despite this significant and obvious knowledge gap, they nonetheless maintain that the results provide robust support for their characterization of POTS as a “functional psychogenic disorder.”
Notwithstanding the “more pronounced anticipatory tachycardia” found in the intervention than in the control group, a key challenge for the investigators’ hypothesis is the significant overlap between the two ranges of heart rates, as indicated in Figure 1B. As is also clear from Figure 1B, a subset of the POTS patients, like a subset of the healthy controls, experienced a decline rather than an increase in heart rate in anticipation of the tilt-table test. These salient details undermine the claim of psychogenic pathogenesis but are not addressed in the text of the paper.
Beyond that, the investigators conflate association and causation. In fact, the findings reported here can easily be explained by assuming causality runs in the other direction. As is common with chronic illness, many people with POTS are more likely than healthy controls to have anxiety and to measure higher on questionnaires assessing awareness of physical sensations. They would also be alert to factors or conditions that could aggravate their symptoms, including a tilt table test. Many people with POTS would therefore understandably experience a stress response upon knowing they were about to undergo the unwelcome process of being tilted upright. And it is not surprising that POTS patients, when in an upright position, have worse outcomes than controls in multiple domains.
The investigators are aware of the shortcomings of their data, but they nevertheless choose to interpret the research as if it favors their hypothesis—even though it does not. Their conclusion—that POTS is “a functional psychogenic disorder in which standing may acquire a frightful quality, so that even when experienced alone, it elicits a fearful conditioned response”—is unwarranted, appears to stem from the authors’ confirmation bias, and cannot be justified based on the results presented here.
Norcliffe-Kaufmann L, Palma JA, Martinez J, Camargo C, Kaufmann H. Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome. Brain. July 2022; online ahead of print. https://doi.org/10.1093/brain/awac249
School of Public Health, University of California, Berkeley; Berkeley, CA, USA
Dysautonomia Clinic, Department of Neurology, University of Buffalo Jacobs School of Medical Sciences; Buffalo, New York, USA
Department of Radiology, Starship Children’s Hospital; Auckland, New Zealand
Department of Medical Informatics and Decision Making, Imperial College London; London, England, UK
Department of Medicine, University College London; London, England, UK
Department of Epidemiology, Columbia University Mailman School of Public Health; New York, NY, USA
School of Psychology, National University of Ireland, Galway; Galway, Ireland
Department of Rehabilitation Medicine, Icahn School of Medicine, Mt Sinai; New York, NY, USA
Division of Infectious Diseases and Vaccinology, University of California, Berkeley; Berkeley, CA, USA
Another good and important letter. Many thanks to all involved.
Vijay Iyer says
Thank you for highlighting the fundamental flaw of downplaying the central problem of “cause or consequence”.
I don’t have ready access to the full manuscript, but judging from the abstract, there appear to be two additional notable flaws:
* They posit a mechanism of “fear” without mentioning any neurological or neuroscientific evidence of fear circuit engagement.
* Abstract notes an observation of anticipatory effects on two parameters (tachycardia & hyperventilation) but not all 4 parameters they found affected by tilt in POTS patients. If the underlying paper data matches this, this would actually seem to bolster consequence over cause: anticipating reduced cerebral blood flow sure would be a healthy thing to do!
Elizabeth Trebotich says
This thought process would never work with any condition bc it ignores the most basic principle of logic: if you have to out of your way to explain why you’re right, when you have to mould and manipulate & cajole the data to fit, you are being illogical. Unless you’re standing in the plains of Africa, the sound of hoofbeats should be assumed to be horses, not zebras. And unless you have evidentiary proof to the contrary, the most likely reason a POTS patient feels anxious before a tilt test is because NO ONE likes being made to feel sicker just to prove that they are sick at all. If you told these ppl they had to put their hand against a hot burner to test their nerve response, I highly doubt they’d be anything other than anxious or scared.
I just get SO… ANGRY.
Common sense is nowhere to be found with ppl like this. How do you argue with a fanatic? You can’t because evidence means nothing.
Brian Hanley says
Thanks. That paper is obvious, egregious, garbage that wouldn’t pass a junior high school science fair. The journal should launch an investigation into who passed it, and how? What did the reviews say? Did any editors even skim the reports or submission?
Richard Schoenbaum says
The comments are great! They brightened my morning after reading Dr. Tuller’s letter to yet another group of researchers trying to prove that diagnosis for a
frustrating malady is “it’s all in your head”.
Anne Kennedy says
David, what is your view of Lloyd and hickies recent article on the dubbo study? I sense that they are trying to give an impression that cfs is psychological
Anne Kennedy says
I realise now the Lloyd and hickie article is just part of a slew of articles being produced by the psyche lobby in response to the 2021 nice guideline
Anne Kennedy says
Lloyd and hickie article
A friend of mine says, ” people who are sicker have a worse mood, big deal”
Thank you, David. So appreciate having you articulating this stuff to these people.
David Tuller says
Anne, exactly–the baseline in Dubbo was already after onset of the acute infection. So at that point you’re only tracking what happened after they’re sick. Lenny Jason’s recent study, which tracks students from before they ever have the acute illness–in that case, mononucleosis/glandular fever–and he found not links between prolonged medical issues and pre-illness psychological correlates.
Anne Kennedy says
Alicia Butcher Ehrhardt, PhD says
Patients must be telepathic for these responses to be passed around to a bunch of sick people who almost never get out – and then see something to be gained from looking like idiots.
It always surprises me when, all of a sudden, the body declares: “You will sit me down NOW.” Because I have to obey the imperative – or feel like cr*p, again.
Otherwise, I have way too many other symptoms I’m dealing with to pay attention to this fuzzy one.
We lose so many things when we get sick – this kind of badly planned and executed research just rubs it in that even doctors think millions of people with THE SAME SYMPTOMS, worldwide, have chosen to play the victim – because the ‘doctors’ don’t know what’s going on, and that FEELING in a doctor must not be allowed to live.