By David Tuller, DrPH
Update: I have sent the following letter to the responsible person listed on the clinical trial registration for the Finnish study of “amygdala and insula retraining”:
Dear Dr Lira–
I am a public health researcher and journalist with the Center for Global Public Health, part of UC Berkeley’s School of Public Health. I frequently comment on research in the field of ME/CFS and related diseases, now including long Covid. Much of this commentary appears on Virology Blog, a popular science site hosted by Professor Vincent Racaniello, Higgins Professor of Microbiology at Columbia University. (I have cc’d Professor Racaniello here.)
I have recently seen the clinical trial registration for “Amygdala and Insula Retraining (AIR) Program and HUS Internet Therapy Compared to Treatment as Usual in Bodily Stress Syndrome, Fibromyalgia, Long Covid, and Chronic Fatigue Syndrome (ME/CFS).” Yesterday, I posted a Virology Blog commentary in which I criticized the research on a couple of fronts.
If you would like to send a response to the concerns I have raised, I would be happy to post it on Virology Blog, alongside my critique. If you do so, perhaps you could address these questions:
1) Given the interventions, the study is of course unblinded. However, all the outcomes are subjective. This combination of elements—being unblinded and relying solely on subjective outcomes—is a recipe for generating bias. Participants who know they have received interventions that promise significant benefits are understandably more likely for any number of reasons to report benefits than participants who do not receive the interventions.
Are you concerned about the bias inherent in the study design, and that this issue could create doubt about the accuracy of the results? If not, why not? Did you consider including any biomarkers or objective outcomes of physical function or movement? If not, why not?
2) The study is presented as investigating “amygdala and insula retraining” even though it is not assessing participants’ amygdalae and insulae in any way, much less whether they have been “retrained.” As I assume you understand, the use of this sort of language by so-called “brain rewiring” programs is a marketing strategy designed to enhance their appeal and imply they are grounded in sound science.
Beyond hypothetical musings, can you provide any serious evidence that the intervention in fact involves “amygdala and insula retraining”? (Modest and hard-to-interpret changes in BDNF levels in a small pilot study do not justify use of the phrase; moreover, this trial is not measuring BDNF levels.)
Are you concerned that giving an intervention an unwarranted scientific-sounding name could lead to bias and unrealistic expectations among participants? Did anyone involved in the design or approval of the study raise concerns that adoption of the phrase “amygdala and brain retraining” was deceptive and perhaps unethical?
As mentioned, I would be happy to post any response you would like to send. Thank you!
David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley
I have written a couple of times about a Dutch trial of internet-delivered cognitive behavior therapy to prevent severe fatigue in long Covid patients. The goal is to address factors like “dysfunctional beliefs about fatigue,” “perceived low social support, “problems with processing the acute phase of COVID-19, and “fears and worries regarding COVID-19″ that are purportedly driving the prolonged symptoms. My posts—here and here–were not favorably disposed toward the research and suggested the design was biased toward producing positive results.
Last month, advocates from three Dutch patient organizations published their own report about the study. The researchers, from the Dutch Knowledge Center for Chronic Fatigue (NKCV), were awarded €308,000 by ZonMw, a major health care research agency. The lead investigator, psychologist Hans Knoop, is a well-known proponent of the CBT/GET treatment paradigm for ME/CFS. In 2011, he and a Dutch colleague wrote a commentary for The Lancet that accompanied the PACE trial and declared that participants had met “a strict criterion of recovery”—a demonstrably untrue statement.
The three patient organizations–Group ME The Hague, ME and Disability Support Group, and the ME/CFS Association—explained in their report why they decided to conduct their review:
“Our goal was to prevent that in the future grants will be awarded to a treatment that is not based on scientific knowledge about the nature and cause of the disease, but on the assumption that the patient maintains his own fatigue through unhelpful thoughts and wrong behaviour. The treatment in the ReCover study has the same principles as ‘CBT for CFS’. The British NICE [National Institute for Health and Care Excellence, which published new ME/CFS guidelines last October] has determined that the quality of the scientific evidence for this treatment is low to very low. It is also clear from Dutch and foreign patient surveys that this form of CBT does not help the majority of patients and leads to deterioration in a considerable number of patients. We aim to prevent this for longCOVID patients too.”
The report also included the transcript of a somewhat testy exchange between representatives of the three organizations and Professor Knoop. Here’s a revealing slice:
“[Organizations] It is known that measuring only subjective outcome parameters in such an open trial has a high risk for bias. Therefore, objective outcome parameters must be used also. How do you handle that?
(K) Why are patient organizations so obsessed with objective measures? Objective measures are subjective too. They depend on how you interpret them.
[Organizations] It is well known that the outcomes on subjective measures such as fatigue are directly influenced by the treatment (we have used the term ‘manipulated’ in the conversation).
(K) So you’re basically saying you don’t trust the outcomes reported by the patients themselves? How does that relate to the fact that you as a patient organization represent these patients while you do not take their answers seriously?
[Organizations] We take patients very seriously. But with regard to your research, we indicate that the treatment is aimed directly at influencing the patient’s thoughts about fatigue, the main outcome measure. That leads to bias.
(K) We have only subjective primary and secondary outcome parameters. In medical research, more and more researchers are moving away from objective outcomes and they are looking at what is relevant for the patient and how he feels…In previous research, we have shown that there is no correlation between the objective and subjective outcome parameters.“
Professor Knoop’s argument that medical researchers are “moving away from objective outcomes” is a new one to me. Apart from that, his apparent rejection of objective outcomes in his studies because they have “no correlation” to subjective outcomes is hard to justify. What’s the rationale for dumping the objective findings instead of the subjective ones?
I don’t get it.
Finnish Study of “Amygdala and Insula Retraining”
And now here’s a clinical trial of a self-management program grandiosely called Amygdala and Insula Retraining (AIR). The trial is officially titled “Amygdala and Insula Retraining (AIR) Program and HUS Internet Therapy Compared to Treatment as Usual in Bodily Stress Syndrome, Fibromyalgia, Long Covid, and Chronic Fatigue Syndrome (ME/CFS).”
This Finnish trial, which is currently recruiting and seeks a total of 360 participants for three arms, is being conducted by the HUS Clinic for Functional Disorders at the Helsinki University Central Hospital. Per the clinical trial registration information, BSS includes fibromyalgia, irritable bowel syndrome, multiple chemical sensitivities, and other functional disorders.
Besides the AIR arm, a second arm is receiving another self-management program. Both groups will also receive treatment as usual. The third group will only get treatment as usual. The primary outcome of “functional ability” and seven secondary outcomes are all subjective. No objective measures of function or physical ability appear to be included. To be clear, no one is measuring the impact of the interventions on anyone’s amygdala and insula—the nominal targets of the interventions.
Given that the treatments are necessarily unblinded, the study presents enormous opportunity for bias. After all, people enrolled in a program claiming to retrain their amygdala and insula will undoubtedly be motivated to provide answers that support the notion that such retraining has occurred. Unblinded studies relying on subjective outcomes simply cannot be considered reliable evidence of anything other than that such trial provide unreliable results.
Like the Lightning Process, the Gupta Program, and the Dynamic Neural Retraining System, AIR falls into the category of so-called “braining rewiring” programs. Of course, the program creators have no evidence that anyone’s amygdala and insula are being retrained. This is a hypothesis—nothing more—and the scientific-sounding words are marketing ploys based on the buzzy concept of neuroplasticity.
It is disturbing that a clinical trial would highlight such an unevidenced claim for an intervention and even include such hype in its formal title. It is also disturbing that any ethics committee would approve a trial with such an obviously bogus and unevidenced promise.
Here’s information about AIR from the trial registration:
“The Amygdala and insula retraining program consists of novel brain retraining approaches focused on hypothetically interrupting and retraining the conditioned defensive hyper-stimulation of the sympathetic nervous system and aspects of the immune system by the amygdala and insula, to bring the brain and body back to homeostasis. It includes supportive techniques such as breathing, meditation, and neurolinguistic programming.”
And here’s information about the other self-management program:
“The HUS internet therapy for bodily stress syndromes (iHUSbss) includes psychoeducation about autonomic nervous system and of the effects of patient’s own thinking and action on the nervous system. The exercises aim at relaxing the body, at novel ways to observe the symptoms, and at developing acceptance and self-compassion. The program includes exercises that are done regularly in everyday life.”
To repeat what I have written before: Some of the strategies used in these programs are likely helpful for many people. Meditation, relaxation exercises, breathing strategies, positive affirmations—these modalities all have their place and can help prompt positive changes in thought and behavior. Unfortunately, beyond personal anecdotes from devoted fans, there is no legitimate scientific evidence that they cure chronic medical diseases. To create a study that is bound to generate attractive results for so-called “brain rewiring” because of its poor design is a farce.