The rubber meets the road for mindfulness practices with biology. Can altering one’s thought patterns actually change one’s biology? That’s one of the questions that Spanish researchers asked in the recent study, “Mindfulness-Based Program Plus Amygdala and Insula Retraining (MAIR) for the Treatment of Women with Fibromyalgia: A Pilot Randomized Controlled Trial“, which employed Ashok Gupta’s Amygdala and Insula Retraining Program. The study was published in the Journal of Clinical Medicine.

If there’s no evidence, and there isn’t any, of a psychological predisposition to ME/CFS/FM (chronic fatigue syndrome/fibromyalgia), then if people with ME/CFS/FM report that they feel exhausted, are in pain, are less able to relax, less able to concentrate, more on edge, are more prone to mood swings, etc. it stands to reason some biology is involved.

That would seem to make mindfulness/neuroplasticity practices the odd man out. Biology is biology and the mind is the mind – right? Examples abound, though, of instances where an accident or infection literally changed the kind of person a person was. In those cases, an altered biology clearly affected “the mind”.

Her Brain Was On Fire: A Neuroinflammation Story

Mindfulness/neuroplasticity therapies for ME/CFS/FM believe they can get at the problem from the other end. Most revolve around the same thesis – that the stress response in the brain is jacked up to the hilt – causing pain, hypervigilance, hypersensitivity issues, difficulty sleeping, energy depletion, etc. You can’t heal, they believe, because your body can’t really rest.

These practitioners generally attempt to reduce the unceasing barrage of alarm messages the brain is automatically (and unconsciously) pumping out when it’s in that state. A wide variety of methods – from meditation (to desensitize the system) to visualization (to inculcate peaceful scenarios) to catching negative thoughts (to tame the alarm signals) – just to mention a few – are employed to do this.

The big question is whether mindfully turning down the arousal can give the body enough room to start healing? Is that enough to make a dent in difficult diseases like fibromyalgia?

Different Angles – Similar Scenario?

Both scenarios propose that an overactive stress response plays a key role in ME/CFS.

It’s interesting that while Gupta and Komaroff/Lipkin approach chronic fatigue syndrome (ME/CFS) from different angles – one focused on neuroplasticity, and the others from a more physiological approach – their conception of the core problem is not all that different. The study reports that:

“The Amygdala and Insula Retraining Program (AIR) hypothesizes that “chronic over-sensitization and heightened fear response of the amygdala … keep the nervous system and the immune system in a state of heightened arousal.”

In the AIR workbook, Gupta states that he believes ME/CFS/FM is:

“caused by an over stimulation of these survival responses, these defense responses … (as a result) of the immune system, the sympathetic nervous system is overstimulated and it all results in too much inflammation … this uses up all our energy and leads to exhaustion.”

This is not so different from Komaroff and Lipkin’s proposal that in ME/CFS (and perhaps long COVID):

“the ‘unchecked persistence of a response’ to a stressor had triggered a cell danger response at the cellular level, and an ‘integrated stress response’ at the organism level.” That ongoing response left ME/CFS patients in a hibernation-like state where “essential energy-consuming processes” were “throttled down” – leaving only small amounts of energy left to be used for the basics of maintaining life.”

Experts Assert Insights From ME/CFS Needed to Understand Long COVID


The question remains, though, can mindfulness techniques change the brain’s functioning enough so that it shows up on a brain scan or some other biological instrument? The answer is pretty clear here too. John Kabat-Zinn’s Mindfulness-Based Stress Reduction (MBSR) protocol has been shown to improve prefrontal cortex activity as well as other parts of the brain, including the amygdala.

Fibromyalgia, though, is a complex and difficult-to-treat disease. Besides pain, it also causes fatigue, sleep, cognitive and sensory problems. It appears to affect more parts of the brain and is probably a harder nut to crack than most conditions.

A small 2012 study did attempt to assess the effectiveness of the Amygdala Retraining Program using a variety of questionnaires in ME/CFS and FM. The study found that while the program did provide statistically “significant improvements” in physical health, energy, pain, symptom distress, and fatigue scores, only about a third of the participants who started the program completed it. (Ashok Gupta stated that the program was “delivered by the study’s own therapists who were not trained in AIR, and who had only a cursory understanding (of it))

The Gupta study went further. It attempted to determine if mindfulness techniques could actually change the biology in people with fibromyalgia.

The Gist

  • Mindfulness/neuroplasticity practices aimed at ME/CFS/FM generally assert that an overactive stress response is causing pain, fatigue, cognitive and sleep problems, etc. These practices tend to use things like meditation, mindfulness, breathing and relaxation exercises to turn the stress response down and hopefully allow the body to heal.
  • A small Spanish study assessed the effectiveness of relaxation therapy and Ashok Gupta’s Amygdala and Insula Retraining (AIR) program in fibromyalgia using a variety of questionnaires and by measuring the levels of a factor called BDNF which has been associated with pain hypersensitivity states.
  • The 8-week trial included daily homework, a weekly meeting with a therapist trained in these techniques, and a monthly meeting as well.
  • The study found that Gupta’s mindfulness/neuroplasticity AIR program was far more effective than relaxation therapy in improving functionality, reducing symptoms and improving well-being. The AIR program also significantly reduced BDNF levels returning them to near normal.
  • Over 80% of the AIR participants reported a 30% jump in functionality and about 1/3rd received a 50% increase in functionality. Anxiety and catastrophizing, etc. levels declined markedly as well. The participants still appeared to have fibromyalgia but they were generally much improved.
  • Surprisingly, the effects of the program largely remained intact in a 3-month follow-up. In some areas, the participants continued to improve.
  • While the authors called the AIR program an “innovative and effective treatment for improving several outcomes in patients with FM”, they also noted that the study was too small for “strong conclusions” to be drawn. Ashok Gupta reported that he was hoping to do larger-scale studies in fibromyalgia and chronic fatigue syndrome (ME/CFS)
  • In an interview, Gupta noted that he believes the term “mind-body” is inaccurate as he believes the brain is largely responsible for the symptoms found in ME/CFS/FM.

The Study

The parallel pilot, randomized, eight-week controlled trial (RCT) assessed symptoms and levels of brain-derived neurotrophic factor (BDNF) and inflammatory cytokines in two groups of people with fibromyalgia (FM). Thirty-four people participated in the small study.

One side of the study focused more on relaxation techniques while the other focused more on mindfulness/neuroplasticity techniques.

The two groups were well supported. One group did relaxation training (visualizations, autogenic relaxation, progressive relaxation, and breathing exercises), which consisted of daily homework assignments of about 15-20 minutes, plus 8 weekly 2-hour sessions, and 3 monthly sessions given by a therapist skilled in relaxation techniques.

The MAIR group did the mindfulness and meditation exercises in the Amygdala and Insula Retraining program, plus some techniques used in Mindfulness-Based Stress Reduction (MBSR)* protocol. This group also had daily 15–20-minute homework assignments, as well as eight weekly 2-hour sessions, and three-monthly sessions with a therapist trained in MBSR and Amygdala and Insula Training (AIT).

(Ashok Gupta reported that he believed the most recent incarnation of the Gupta program is functionally equivalent to the MAIR program the researchers used. The older version was already quite similar as well.)

The study’s results were assessed using a variety of questionnaires – with a widely used functional questionnaire – the Fibromyalgia Impact Score (FIQ) – as the primary endpoint. Other questionnaires included the Clinical Global Impression-Severity Scale (CGI-S), the Pain Catastrophizing Scale (PCS), the Hospital Anxiety and Depression Scale (HADS), the Visual Analogue Scale (VAS), Acceptance and Action Questionnaire (AAQ-II), The Five Facets of Mindfulness Questionnaire (FFMQ), and the Self-Compassion Scale (SCS).

Brain-Derived Neurotrophic Factor (BDNF)

BDNF has been linked with pain hypersensitivity states and may play a key role in pain modulation, pain transduction, nociception, and hyperalgesia (pain hypersensitivity).

Since 2007, no less than 20 studies have assessed BDNF in different ways in FM. Increased BDNF levels have found in the blood and the cerebral spinal fluid of FM patients and two studies have identified a small genetic change called a polymorphism in the BDNF gene in FM. Several other studies, however, have not found evidence of altered BDNF levels in FM.

Study Results

The authors reported that the Gupta program:

“had moderate-to-large effect sizes—for improving a wide range of outcomes: functional impairment, clinical severity, and quality of life along with the cognitive processes … such as mindfulness, and self-compassion.”

Three months after the study was complete, most of the gains remained, with the participants posting – to the researchers’ surprise – continued improvements in clinical severity, perceived health, pain catastrophizing and psychological flexibility.

BDNF levels decreased significantly, and, in fact, approached normality. While a downward trend was seen in some cytokine levels, they did not decrease significantly. The authors noted that a recent fibromyalgia cytokine meta-analysis concluded that cytokines likely had only a small to moderate effect on FM.

Dropout rates were low in each group, with 86% and 84% completing the Gupta and RT arms respectively.

While the Gupta group didn’t reach normal functionality by the end of the study they were significantly improved.

The Gupta program was far more effective in improving functionality as 84% of the Gupta participants reduced their Fibromyalgia Impact Scores (FIQ) by 30%, while only 19% of the Relaxation Therapy (RT) participants did. With 36% of the Gupta participants achieving a greater than 50% reduction in their FIQ scores, the “number needed to treat (NNT)” was 3.

According to Wikipedia, an NNT of 2.5 indicates an “Effective treatment with moderate improvement over control”; i.e. the treatment was effective in producing a moderate improvement.

The numbers bore that out. The all-important functional impact (FIQ) scores dropped from 68 to 43 in the Gupta group (but didn’t drop at all for the Relaxation group.) (The 68 FIQ score at baseline in this study was similar to that found in a large European FM study.) Note that a completely healthy person would have an FIQ of zero.

None of the RT participants achieved a greater than 50% reduction in their FIQ scores. The other scores followed a similar pattern:

  • Gupta – 47% Increase in Perceived Health (EQ-VAS) vs 16% in the RT group
  • Gupta – 46% Reduction in Pain Catastrophizing (PCS) vs 9% in the RT Group
  • Gupta – 45% Reduction in Anxiety (HADS-A) vs 15% in RT group
  • Gupta – 41% Reduction in Depression (HADS-B) vs 6% in RT Group

Both techniques employed meditation and visualization, but the Gupta program’s approach – which emphasized mindfulness and identifying negative thought patterns – was significantly more effective than the muscle relaxation, visualization, and breathing techniques employed in the RT control group.

The authors noted that the study was too small (n=34) to reach strong conclusions, and larger studies are needed. The study differed from a standard Gupta protocol in that it employed therapists (but see below), but it was also much shorter (8 weeks) than the standard Gupta program, which is designed to produce its effects over six months.

Summing up, they reported that they found the Gupta program “to be an innovative and effective treatment for improving several outcomes in patients with FM”.

Talking with Ashok Gupta


Gupta eschews the mind/body dichotomy, preferring to focus, instead, on the brain.

I know that Ashok Gupta has been wanting to test his AIT program in a study for years. I asked him what role he played in it. He replied:

“I did not have any involvement in the initiation or running of the trial. It was initiated by the University of Zaragosa in Spain, as they had seen improvements in patients and therefore wanted to independently test the protocol. I did provide the active treatment arm materials.”

The program added some components of MBSR (walking meditation, body scan?). I asked if the effort used differed much from that now offered by the Gupta program. Ashok replied that:

“The research team used the previous incarnation of the Gupta program which was not so heavy on mindfulness (although included meditation and exercises), whereas the updated program includes much more on it. So, the updated Gupta program is “MAIR”.”

The regular sessions with a therapist trained in these approaches must have helped. I asked Ashok if anything similar was available.

He reported that 30 trained Gupta Program Coaches are available to support people. He noted that while that is “important for some patients, others find the online materials and webinars enough to move forward.”

The program used to be the Amygdala Retraining Program. Now it’s the Amygdala and Insula Retraining Program. What is it you’ve learned about the insula that had you add to the title? 

There is plenty of evidence that the insula in ME/CFS and fibromyalgia are impacted, and are no longer playing their role in modulation of the autonomic nervous system, the pain network, and the immune system, following the bombardment of internal signaling from the viscera. Furthermore, animal studies in the last 10 years have shown that conditioning of the immune system to otherwise neutral events has its base in the amygdala and insula. This has been proven by Dr. Pacheco-Lopez’s groundbreaking work. Therefore, the insula is where we hypothesize the conditioning of the immune reaction is stored in chronic illnesses.

It’s been a long time since I tried the program but it seemed to me that the while core parts of the program (“soften and flow”, the retraining technique, meditation) are similar to the one I tried over a decade ago, the program has been considerably expanded. The Manual looks to be about double the size of the former one and contains numerous modules and techniques. Some of the aspects that seemed new to me, at least, included a technique called “the accelerator”, sections on “retraining the protector”, the “slow-motion technique”, the “Groove technique” and others.

Gupta asserted that the new program is easier to use and more comprehensive, and includes more information on mindfulness. He also believes it works better for people who are bedbound than the old program did and includes more information on staying well after getting better.

I asked Ashok why he thought the mindfulness/neuroplasticity approach was more effective than relaxation therapy. 

The relaxation of a general system does not target the specific network that is over responding, and it may not respond to a general calming of the overall brain and body. Neuroplasticity is about engaging with a specific neuronal network that is over-responding and retraining it, which naturally allows the whole system to calm down. But the other way around doesn’t work half as well!

Finally, I asked him about the controversy regarding mind/body protocols and ME/CFS.

“The reason for this controversy is that it is modern medicine that creates this artificial cartesian dichotomy. That somehow there is a separation between mind and body. We have one nervous system which is like the electrical system of a car, and connects to all organs and functions in the body. And the brain is the head of the nervous system.


That one nervous system is responsible for physical, mental, and emotional processing and survival. For instance, the amygdala was before only implicated in emotional responses before, however, now it has been implicated in everything from pain responses to immune responses.


Therefore, we do not call ourselves a “mind-body” approach nor a psychological approach. This is a neuroplasticity approach, indicating that the reason for these conditions is based in faulty neural wiring that can be corrected. And that brain retraining/neuroplasticity is a whole new branch of modern medicine that has crossovers with the term “Bio-electrical” medicine (Something you referred to in a recent article).


So, we hope that gradually as people realize the impact of the “brain” on the body, they will not see these approaches as controversial anymore. The controversy comes because patients have previously been dismissed as it “being in the mind” and therefore we are seen as undermining the mainstream advocacy of these illnesses amongst patient groups.


But we say it is not in the mind, but “in the brain”. It is unconscious and usually beyond conscious awareness, with real physical symptoms. But these unconscious processes can be influenced and gradually retrained. It is similar to brain retraining techniques used for phantom limb pain. So, I hope that over time the controversy will ease and people will embrace this approach.”


This small study found an 8-week course of the Amygdala and Insula Retraining program (AIR) when supported by a therapist trained in the technique – effectively improved functionality and symptoms in many people with FM.

Over 80% of FM patients improved their functionality scores by at least a third, and a third of the participants improved their functionality by at least 50%. Some improvements continued to increase three months after the 8-week study had been completed. The levels of a neurotrophic factor (BDNF) associated with pain hypersensitivity fell to near normal by the end of the study.  Cytokine levels were not significantly affected. The participants had not recovered from FM but they were clearly improved.

Parleying the results of the study to someone doing the online Gupta program is a bit problematic. The fact that the course was supported by a therapist trained in the program probably boosted results. On the other hand, the Gupta course is designed to produce its effects in 6 months, not the 8 weeks of this study. Gupta believes the longer course done online can produce more results.

While the dropout rates for both practices were low, the relaxation therapy approach was not nearly as effective as the AIR program. Functionality – the prime endpoint in the study – was not improved, and no significant declines in BDNF were seen.

The authors warned that larger studies are needed to validate these findings, but for now, Gupta’s approach – developed using practices that he used to recover from ME/CFS/FM – seems to be, if you’re interested in trying neuroplasticity approaches, the more effective track. Find out more about the AIR here.

Gupta reported that he’s is actively seeking to partner with researchers and institutions to initiate a larger-scale phase 3 trial on ME/CFS and/or Fibromyalgia.”

About 8 months ago I received a gratis copy of the AIR program. (I have not tried it yet.) Other than that Health Rising is not associated in any manner with the Amygdala and Insula Retraining Program. 


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