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
(Originally posted on Virology Blog.)