By David Tuller, DrPH

Research into conditions categorized as “medically unexplained symptoms” (MUS) or “functional” disorders seems rife with studies that eagerly interpret associations and correlations as causal relationships. Not surprisingly, these proposed causal relationships tend to flow in the direction required by the investigators’ hypotheses, not in the direction that would undermine their arguments.

A classic example is when studies find an association between worse health outcomes and patients’ strong beliefs that their symptoms are a sign of organic disorder. Some investigators choose to interpret this link to mean that patients’ purportedly false ideations of having an organic disorder lead to the poor reported results. Observers less wedded to their own biases and hypotheses would recognize that the causation is often just as or even more likely to run in the opposite direction. If patients are correct in attributing symptoms to organic disease, it wouldn’t be surprising for them to experience further challenges and deterioration.

Now neurology researchers from New York University have applied similar logic to a study of postural orthostatic tachycardia syndrome (POTS), a form of orthostatic intolerance—a group of conditions in which standing makes people feel dizzy, nauseous, or otherwise crummy. In POTS specifically, patients’ heart rates spike when they get up from a reclining position. Patients with ME/CFS and now long Covid often experience orthostatic intolerance, including POTS. The causes have not been clearly elucidated.

The NYU paper, published last month by the journal Brain, is called “Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome.” The investigators try to make a case that POTS is a “functional psychogenic disorder.” Here’s their rationale: 

“We hypothesized that classic Pavlovian fear conditioning could mediate the pathogenesis of postural tachycardia syndrome. In fear conditioning, a well-known concept in the field of experimental psychology, subjects learn that a neutral stimulus predicts an aversive event. Pairing a neutral and an aversive event gives the former a frightful quality, so that even when the neutral stimuli is experienced alone, it elicits a fearful conditioned response, which is characterized by sympathetic arousal. This pairing can occur rapidly in humans and animals, even following a single conditioning trial, and can be maintained for extended periods.

“The conditioning event in patients with postural tachycardia syndrome could be a period of orthostatic intolerance with hypotension, light-headedness, and tachycardia upon standing. In normal subjects, such episodes frequently occur following viral illnesses, excessive fluid losses, or bedrest, all which have been reported before the onset of postural tachycardia syndrome. The episodes provoke fear (unconditioned stimuli), but in most subjects are transitory and leave no sequelae once the underlying disturbance resolves. In patients with postural tachycardia syndrome, however, the “neutral” act of standing up could become abnormally paired with the unpleasant sensations of orthostatic intolerance, thereby activating the neuronal circuit of fear just by standing (i.e., conditioned stimulus).”

David Putrino, a neuroscientist and physical therapist, is director of rehabilitation innovation at Mt Sinai Health System in New York City and an expert on long Covid. Here’s what he wrote about the NYU study in an e-mail:

“Essentially, research reporting that individuals with POTS experience an exaggerated stress response to being told they will be placed into a position that is KNOWN to exacerbate their symptoms is logical. If you told me that you were about to stab me with a knife, I would experience an exaggerated, measurable stress response. This doesn’t mean that I’m “afraid of knives”, it just means that I would rather not be stabbed at this time. At best, this research contributes almost nothing to our existing knowledge of POTS. At worst, it will contribute to gaslighting and psychologizing of patients with a known neurological condition.” 

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Details of the NYU study

To explore their hypothesis, the NYU researchers compared 28 POTS patients with 21 matched controls. The investigators documented that the POTS patients, compared to controls, were more anxious and engaged in more “somatic vigilance,” or monitoring their bodies for symptoms. This makes sense, given the stresses and concerns accompanying chronic illness.

While standing, the POTS patients had more signs of physiological abnormalities, compared to controls, including faster heart rate, reduced cerebral blood flow, higher plasma levels of catecholamines, and lower end-tidal CO-2. This also makes sense. The patients had POTS.

Finally, the POTS patients experienced more “anticipatory tachycardia”–in other words, an increased heart rate–when alerted that they would soon be positioned upright during a tilt-table test. This response should also have been expected. These POTS patients knew they were about to have an unpleasant experience. It shouldn’t be surprising if that knowledge triggered measurable signs of stress—like increased heart rate. The findings are completely consistent with the idea that the patients had ongoing cases of POTS.

To the investigators, however, these findings have a different and somewhat more circuitous meaning. They interpret the causal relationship as going the other way. Specifically, they postulate that “fear conditioning” from a prior transient episode of tachycardia continues to generate the physiological responses both in anticipation of and during a tilt-table test. This parallels the biopsychosocial position on ME/CFS—after an initial infection or other physiological insult, the patient’s own ideations, including fears of activity and belief in having an organic disorder, are presumed to maintain and perpetuate the condition.

As often happens, the NYU investigators over-interpret their findings of association. Here’s what they write in their abstract: “These findings suggest that the postural tachycardia syndrome 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…Our results have therapeutic implications.”

So what are these therapeutic implications? According to the investigators, “recasting postural tachycardia syndrome as a functional psychogenic disorder…opens the possibility of refocusing the therapeutic strategy, with greater emphasis on cognitive-behavioral approaches.”

Ok, then! Bring on the CBT!

In their discussion, the investigators do not appear to question or hedge on their argument that the data suggest POTS is a functional psychogenic disorder. Yet tucked in quietly at the end of the limitations section of the paper is a clue that the investigators are at least aware of the weakness of their position. Among the limitations, they note, is this: “We do not know if these findings are a cause or a consequence of the syndrome, but it is likely that fear conditioning contributes to the hyperadrenergic state when standing in affected patients and may serve to propagate or maintain the syndrome.”

Let’s pause for a second to consider this. The investigators acknowledge not having any idea “if these findings are a cause or a consequence of the syndrome.” That’s a crucial concession, and this phrase is arguably the most important in the paper—even though the investigators largely ignore its implications. The investigators know that this study does not document causality. That means they also know, or should know, that they have not presented convincing evidence that POTS is psychogenic.

That goes as well for the claim that fear conditioning is “likely” to “contribute to the hyperadrenergic state” and to “propagate or maintain” a patient’s case of POTS. What are the grounds for making this statement?

The investigators have documented that patients with POTS, when alerted that they will soon be positioned upright, are more likely than people without POTS to show signs that they anticipate having unwanted POTS-related symptoms. When they are in fact upright, patients with POTS are more likely to show physiologically abnormal signs than people without POTS. That’s about it. That’s what this study showed.

In other words, the investigators have presented associations as if they demonstrate the causal relationship that best fits their hypothesis, without weighing the logical counter-possibilities. Why didn’t peer reviewers or editors point out that the evidence for the NYU team’s assumptions and speculations is less than robust?