IIA. ME/CFS and The Cell Danger Response: How Adversity Triggers the Freeze Response and How the CDR Gets Stuck (Includes Surveys)

I’ve described how chronic fatigue syndrome (ME/CFS) is a disease driven by a cell danger response (CDR) and a nervous system caught in a threat response of freeze and some of us with an underlying fight/flight response (wired and tired) in Part 1. This second post describes how the CDR gets stuck to offer clues and potential tools for how to get  “unstuck.” I’ve developed surveys for anyone with ME/CFS to help get a better sense of risk factors based on the research. You can fill them out below or in the shorter companion post that contains only the surveys. The science provides a context for a future third post on how to approach treatment.

Note: This post is long enough to constitute an ecourse (or a book), so you can download it in a free kindle or pdf.  I want to lay out this information in one place so that the ME/CFS community can understand the series of arguments and science that support and further clarify Naviaux’ emerging new paradigm of disease. It explains why many of us may be more vulnerable to infections such as covid-19, why ME/CFS, like other chronic illnesses, is not psychological, and how infections may influence risk because they represent another form of a threat.

Read in Free PDFs

You can download this post or part I below – the forms will appear momentarily.

The view of ME/CFS as a metabolic state of freeze is supported by a new disease paradigm presented by Robert Naviaux, M.D, Ph.D, Professor of Medicine, Pediatrics and Pathology, who is also a geneticist and virologist conducting mitochondrial research in his Mitochondrial and Metabolic Disease Lab at UC San Diego.

In Part I, I introduced Dr. Naviaux’ study of patients with ME/CFS finding a body-wide cell danger response that has gotten stuck in a metabolic state of freeze. I integrated parallel research about how the nervous system responds to threat, drawing from polyvagal theory developed by Dr. Stephen Porges at the University of North Carolina at Chapel Hill.

Porges’ view of the nervous system describes how a system-wide CDR is regulated by the parasympathetic branch of the nervous system (the dorsal vagal complex or “DVC”), which operates the freeze-based survival response. In such physiology, the sympathetic branch that promotes fight or flight cannot inhibit, overcome or reverse the hibernation-like metabolism of immobility as it is designed to do. Neither can the second parasympathetic branch of the nervous system, called the social nervous system (ventral vagal complex or “VVC”).

I summarize Naviaux’ new paradigm of disease and ME/CFS in this way:

ME/CFS is a primarily hypometabolic state driven by a system-wide cell danger response (CDR). The CDR involves one or more survival oriented biochemical pathways that have been initiated, strengthened and prolonged by the additive effects of environmental stressors such as infections, chemicals, trauma and missing experiences. The autonomic nervous system drives the CDR of freeze to cause disease. When the social nervous system regains dominance it can inhibit fight, flight and freeze so our bodies can heal, rest, digest and play when threat is no longer present. The new paradigm of disease also explains how the disease process may therefore have some degree of reversibility.

Dr. Naviaux’ study identified 5 categories of stressors that trigger the onset of ME/CFS:

1. Biological (infections from viruses, bacteria, parasites; exposure to mold, fungus etc)
2. Chemicals (pesticides, fire retardants, etc)
3. Psychological trauma (loss of a loved one, separation or divorce, an accident, …)
4. Physical trauma (accident, surgery, breaking a bone, a fall, …)
5. Unknown

While biological factors were more common in Naviaux’ study, there was no single agent or type of infection that was more common for anyone and many of the patients in their study had experienced more than one of these stressors before the onset of their ME/CFS.

These risk factors are also seen to trigger the onset of many other chronic diseases. The science explains they are the “last straw” and not the actual cause.

***Survey 1: Adverse Pre-Onset Experiences (APOEs) in ME/CFS

This survey gives an idea of the kinds and number of adverse exposures that contributed to onset of ME/CFS. It includes a score of up to 15 for how many different triggers you may have experienced in the year before onset. I refer to these as adverse pre-onset experiences (APOEs).

• Note that many of us will have experienced similar environmental exposures for 2 or 5 or more years before onset. The effects of such events add up to affect risk. I hope to create a separate survey for exposures prior to one year before onset in the future and I’m using different surveys for different time periods to help me and each of us get a better sense of the wide range of contributing exposures (and what we can do about them). For this survey, I look at one year specifically to identify the potential role of infections and other “final” triggers of onset.

Onset triggers are events that occurred in the time period before you became sick. This is different from a survey of events that trigger flares after onset of ME/CFS.

 If you’d like to add an onset trigger that is not mentioned, check the box(es) for “Other” at the bottom of the questionnaire. There is one point for each kind of exposure.

There is a separate survey specifically about infections in question 7, section 7 of this post (under Frequently Asked Questions).

Note: in the PDF and Kindle versions of this post you will find the survey in the appendix.

Add up the exposures that played a role in your life (one point for each type and one point for other exposures). This is your ME/CFS Adverse Pre-Onset Score (APOE).

Introduction

A surprising amount of research in biology, brain and child development, physiology, epigenetics, adverse childhood experiences (ACEs), adverse babyhood experiences (ABEs), and in autoimmune and other chronic diseases help explain how the CDR gets stuck and support Naviaux’ new paradigm of disease. They also help make sense of it for those of us who aren’t cell biologists, geneticists and virologists. I introduce these scientific studies below.

Some of the research draws from the field of traumatic stress, which is a science that has evolved to include neuroscience and genetic studies. The belief that all effects of trauma are psychological is out of date and has yet to be taught in medical school.

So if you’ve ever been told that ME/CFS is in your head or that trauma means it’s not real, or due to a personality flaw, or that you are somehow at fault – know that this is false. It can also be traumatizing. As Harvard neurologist and neuropsychiatrist Matthew Burke puts it – this silent epidemic is causing harm and eroding doctor-patient relationships.

We are on the cusp of a new way of making sense of disease. The new science is changing medicine, leading to new guidelines at the American Academy of Pediatrics (AAP) and also beginning to shift some of the guidelines of the American College of Obstetricians and Gynecologists (ACOG) about pregnancy, delivery and care in the first weeks after giving birth.

The research is introducing possibilities for improvement, prevention and even healing in ways we’ve never thought of before.

Topics I’ll be discussing in this article include:

• a look at what prolongs the CDR to increase risk for disease
• examples of environmental stressors that can initiate or trigger disease onset
• characteristics of cell danger responses that begin to address many important questions in ME/CFS and other diseases.
• 4 surveys to specifically evaluate these risk factors in people, like me, who have or had ME/CFS.

I. Summary of ME/CFS (a State Like Hibernation)

The state of freeze is a built-in evolutionary defense mechanism that is expressed in all animals, including humans. It is not a conscious choice, a psychological ploy, or a sign of weakness or laziness. It is expressed by cells, the nervous and immune system, in other tissues and physiology, and through many other pathways.

Dr. Robert Naviaux’ research team came to four important conclusions in their study of ME/CFS:

1. The cell danger response (CDR) that drives symptoms in ME/CFS reflects a physiological state of hibernation aka “freeze”
2. ME/CFS is a state of low metabolic dysfunction and is not psychological
3. ME/CFS is triggered by 5 broad categories of exposures: infections, chemicals, psychological trauma, physical trauma and an unknown group
4. These different exposures all trigger the same cell danger response pathway

A State of Hibernation that’s Not Psychological

Naviaux’ research in the cell danger response (2014, 2016, 2017, 2018, Q&A 2016), which cites over 350 articles, states that cell danger responses lead to ME/CFS and a hundred other diseases:

The metabolic state of an individual at the time of illness is produced by both current conditions, age, and the aggregate history, timing, and magnitude of exposures to physical and emotional stress, trauma, diet, exercise, infections, and the microbiome recorded as metabolic memory (2016, p. 1).

Porges’ polyvagal theory and research in traumatic stress and other areas support and elaborate on these findings about the role of age, accumulated history, current conditions and triggers, as well as the timing and intensity of exposures. They explain similar patterns of response to threat at the nervous system level as Naviaux has described at the mitochondrial and cellular level.

In ME/CFS, the CDR shifts from a temporary, local, natural, mitochondrial cellular defensive response to a prolonged, system-wide function that does not switch off as it is designed to do in health. Instead, it actively and purposefully keeps the organism in a death-like state of shut-down as a means of surviving until an overwhelming threat goes away.

When human bodies, similar to the worm c. elegans, shift to the dorsal vagal states of relative immobilization and freeze to out wait a threat they can feel:

• exhausted and “death-like” with low heart rate, blood pressure or temperature
• jelly-limbed and unable to move or move with effort and fatigue
• dissociated and fuzzy-brained
• emotionally depressed or numb
• faint or weak
• unable to talk
• unable to digest
• more susceptible to infections
• and much more

Common features among the 5 types of exposures that trigger ME/CFS appear to be that they:

• are perceived as life-threatening just as low oxygen, low food, excessive heat or cold are life-threatening and trigger dauer in c. elegans
• cannot be overcome through parasympathetic social nervous system functions of communication, social interaction, negotiation, rest or patience
• cannot be escaped or resolved via sympathetic nervous system actions of fight flight
• elicit survival functions of parasympathetic dorsal vagal freeze responses
• are intelligent, physiological survival mechanisms that alter mitochondria, metabolism, cellular activity, immune function, nervous system patterns of regulation and many other physiological processes
• reflect a coordinated, purposeful shift in physiology to promote survival even at the cost of potential short or long-term losses of function (such as ME/CFS)

The research builds on Naviaux’ theory to explain that these triggers are not the cause of ME/CFS but the last in a series of exposures that have slowly been strengthening the CDR of freeze over years and often, over decades. Here’s how.

II. Introduction to The New Paradigm

CDR theory presents a completely new way of looking at causes of ME/CFS and 100 other diseases (2018).

Emerging evidence shows that most chronic illness is caused by the biological reaction to an injury, and not the initial injury, or the agent of injury itself.

For example, melanoma can be caused by sun exposure that occurred decades earlier, and posttraumatic stress disorder (PTSD) can occur months or years after a bullet wound has healed (emphasis added, Naviaux, 2018, p. 1).

Naviaux’ cell danger response paradigm looks at disease in a fresh way based on the latest research:

This study … reframes the pathophysiology of chronic illness as the result of metabolic signaling abnormalities that block healing and cause the normal stages of the cell danger response (CDR) to persist abnormally.

Reframing the pathogenesis of chronic illness in this way, as a systems problem that maintains disease, rather than focusing on remote trigger(s) that caused the initial injury, permits new research to focus on novel signaling therapies to unblock the healing cycle, and restore health when other approaches have failed (Naviaux, 2018, p. 1).

So what causes such an extreme biological reaction to injury or threat? What makes our cells and nervous systems so twitchy that they trigger ME/CFS after a sometimes mild infection, or a chemical that does not seem to be problematic for other people, or to what seems like a relatively non-life threatening stressor such as surgery or a fender bender or breaking a bone?

The rest of this post will begin to address this and the following questions:

1. How can we know if Naviaux’ paradigm is accurate?
2. Does other research support this view?
3. How does the CDR get stuck in freeze?
4. What kinds of exposures can cause ME/CFS?
5. Why does ME/CFS sometimes start immediately and other times months or years after a stressful or traumatic event?
6. What if there is no current threat in a person’s environment yet they still have ME/CFS?
7. What about infections?
8. What about toxins?
9. Why do some people develop ME/CFS after exposure to certain environmental stressors when others exposed to the same events and triggers do not?
10. How can a CDR cause so many different diseases?
11. What does this mean for treatment?

Naviaux looks at disease as a systems problem occurring at the cellular level. The following sections introduce other bodies of research that echo this perspective to address questions #1 & #2. They also expand on question #3, how the CDR gets stuck or prolonged to cause disease. Addressing this will begin to answer the remaining questions.

How Does the Cell Danger Response Get “Stuck in Freeze?”

Cell danger responses can occur in different organs and tissues without affecting the whole.

It is only when CDRs become systemic and widespread for long enough periods of time that disease occurs.

There are at least two important mechanisms that can prolong the CDR: exposures to threat, and missing experiences.

The first mechanism that can prolong the CDR involves the presence of threat significant enough to trigger an immobilization or freeze response. The second is the absence of early experiences needed to develop a fully engaged social nervous system that is strong enough to inhibit the freeze response and hypersensitivity to stress.

III. Mechanism 1: How Adversity & Trauma Trigger the CDR

In general, exposures to stress lead to threat responses in different organ systems, such as increases in heart rate when feeling afraid, increases in breathing when fleeing a bear, immune reactions in cells that isolate a virus or bacteria, or diarrhea and other changes in gut function that cope with an invading microbe.

When the stressors go away, these cell danger responses stop. In the normal cycle of healing, the CDR turns off when threat resolves.

When the CDR gets stuck, the healing cycle is interrupted and the cell danger response becomes a prolonged system-wide reaction associated with hypervigilance, shut-down, or disease.

In his talk, Dr. Naviaux explains that when we survive intense adverse experiences such as “running from a tiger,” our nerve connections and nervous systems form strong memories of the event. This is designed to maximize our chances of surviving similar circumstances in the future (watch from 1:38 to approximately 4 minutes). In such situations of danger, our ATP molecules exit the cell to send signals of danger (Dr. Naviaux citing his 2014 article on the cell danger response. Apologies, the video no longer exists as of 10/8/21).

Trauma research has also identified the process by which memories of adverse events or trauma become embedded in a way that symptoms ensue. It explains one core mechanism by which CDRs can become prolonged:

The kinds of threat that can turn a simple CDR into system-wide changes that lead to disease involve some degree of helplessness (neurologist Robert Scaer).

A. What Triggers the Freeze Response

Exposures that are overwhelming enough to elicit the freeze response can prevent recovery and healing at the cellular level and prolong the CDR.

As a result, it is the response to threat rather than the TYPE of threat or exposure that prolongs the CDR and leads to disease.

The cell danger response (CDR) is … activated when a cell encounters a … threat that could injure or kill the cell (Naviaux, 2014 p. 7).

When danger is detected, mitochondria alter cellular metabolism to help shield the cell from further injury (Naviaux, 2014, p. 10).

Psychologist Dr. Peter Levine, author of Waking the Tiger and other books on trauma, and founder of the somatically-based trauma therapy approach called Somatic Experiencing (SE), has spent time with game keepers of parks and national reserves in Africa. There, he discovered that freeze states happen when capture and death are imminent. It’s a defense response that arises naturally when the attempt to fight or flee is no longer viable. In such circumstances the animals’ nervous systems shift from sympathetic actions of flight or fight to sudden dorsal vagal shut-down that immobilize and numb them in preparation for death.

This state of freeze offers a window of opportunity for escape and survival. It is seen in c. elegans, the research worm that recovers from immobilized states of freeze known as dauer. C. elegans emerges from freeze and begins to function normally once oxygen rises to survival levels, or life-threatening levels of drought, heat or cold resolve.

This is the process Naviaux describes as the new understanding of disease. He explains that disease is not caused by broken mitochondria. It’s caused when the CDR gets stuck in either fight, flight, or freeze. Recovery is therefore potentially possible if the body can EXIT and recover from a CDR that hasn’t completed its natural healing cycle.

Here’s an example of how the CDR gets stuck.

B. How Threat Can Trigger Freeze

The following two youtube videos show impalas that have just been captured. One by a cheetah, the other by a leopard – and who successfully escape.

In both videos, the impalas enter a state of freeze or shock and look dead.

In states of freeze the body is inert, there is no movement or struggle even when the predator has one of them in its jaws, and there are no visible breathing movements or pulse.

This lack of movement is an inherent part of freeze. It happens even though an animal has just been running at full tilt with a massive surge of adrenaline, heart rate, breathing and blood pressure that are all increased to support flight and survival. It’s not psychological or faked, it’s a very real response to a very real life threat.

This shut-down is the same kind of state Naviaux found in patients with ME/CFS: a metabolic state of freeze.

As I described in Part I of this series, the freeze state actively changes and suppresses the actions of sympathetic and social nervous system function. It can do so almost instantaneously.

Note: Because these videos contain images of an animal under threat, they may evoke an activation of your own fight, flight or freeze response. So feel free to not watch them or to watch them with some support (such as in the company of a friend or supportive other person, or when you have the opportunity to talk it through with someone – both of which support social nervous system function, which is able to inhibit states of freeze).

In the first video below, the impala recovers from the freeze state very quickly and is able to run away before the hyena returns from chasing off the cheetah.

The freeze state has a built-in intelligence. It floods the system with endorphins, which numbs the body from physical pain of being eaten. It can numb our emotions to provide a sense of peace, calm or even euphoria to ease the process of death.

It is also designed to help an animal survive long enough to potentially escape.

The unexpected avenue for escape happens when the hyena chases off the cheetah.

This is what the freeze state is designed for. It is an innate survival strategy of last resort that provides an opportunity to survive a threat by out waiting it and anticipating the possibility that the danger will go away.

In the second video, the impala remains motionless for a longer period. The first sign of life takes some time to manifest, and is seen in the movements of breathing.

There is a delay in the second impala’s recovery and escape. It might be due to the added threat of having its mouth and nose held in the leopard’s jaws for a period of time, unlike in the first video. During that time the impala’s nervous system maintains a state of minimal (or perhaps no) breathing. Periods of low oxygen may compound the experience of life-threat, deepen the state of freeze, and require a longer period of recovery before the body could mobilize.

When the second impala begins to recover, it moves to a partly upright position and begins to make chaotic-looking shaking movements. This wasn’t seen in the first video and is one natural pattern of recovery from freeze. The process is referred to as “discharge” because it dissipates the enormous amount of fight flight energy that was running through the impala’s body when it was being chased and was suddenly suppressed by the state of freeze.

After a short period of rough shaking, the animal recovers and is able to engage flight energy to run away.

The two videos provide examples of exit and recovery strategies following threat and freeze that support health and healing.

They represent one way in which a cell danger response completes its functions of adequately escaping or thwarting overwhelming threat. This process happens in humans too.

As an example, if you’ve ever had a big shock – breaking a bone, receiving horrifying news, just barely avoiding a terrible accident – you may have felt a shakiness in your system. The trembling can be subtle or it can feel intense. It may have happened immediately after the event, or sometime later in the safety of your home or when talking to a supportive other. You, too, may have fully recovered and walked away unscathed.

But if it’s all that simple, why do we develop ME/CFS? And how can it be healed if we are indeed truly stuck in a metabolic state of freeze?

To begin with, people who develop ME/CFS or other diseases and symptoms of trauma may have CDRs and nervous systems that have not yet recovered from states of freeze.

C. If We Don’t Exit Freeze, It Prolongs the CDR

The two videos demonstrate how wild animals cope with daily experiences of life threat and relative helplessness. They do so by discharging during moments of safety.

Discharge is one way our bodies are designed to naturally exit states of freeze.

When this and other natural processes of releasing a defense response are interrupted, delayed or prevented from happening, the nervous system doesn’t get the message that we’ve survived. It doesn’t realize that the threat is over.

In this circumstance, ATP and the CDR continue to signal that there is danger. ATP levels can deplete the mitochondria and ATP’s other functions of energy production. This is also how the CDR pathway becomes prolonged to signal other cells and tissues, organ systems, emotions, behaviors and more to stay in the perceived safety of the freeze response.

These [prolonged metabolic CDR] pathways … suggest a post exposure adaptation in response to pathologically persistent or recurrent cell danger signaling (Naviaux, 2016, p. e5477).

If you have ME/CFS, another disease or other effects of trauma such as PTSD or depression, recovering from adverse exposures may have been interrupted in your past – by the police officer taking a report following an accident, when there was insufficient support during a painful or scary medical procedure, from living in an environment that felt threatening or unsafe, from being discriminated against for the color of your skin or your sexual orientation or for any other reason, or more.

As Naviaux describes:

When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results (Naviaux, 2014).

D. Helplessness and the CDR

The field of trauma research has come to additional conclusions similar to the ones Naviaux has reached.

Trauma science finds there is a common factor that contributes to risk for the persistence of a CDR. The CDR survival states can get stuck fight, flight or freeze – and therefore lead to different kinds of symptoms and different diseases.

The common factor that increases risk of a stuck CDR is any experience that triggers a state of relative helplessness.

To reiterate, experiences of relative helplessness are a mechanism that increase risk of the CDR becoming persistent rather than resolving or turning off.

Risk factors for prolonging CDRs are not about whether an adverse exposure is actually or overwhelmingly life-threatening.

They are not about whether physical damage occurs (the gazelles were physically unscathed), or whether experiences are clearly “traumatic” such as we commonly associate with war, assault or abuse. All of these types of exposures can prolong CDRs, but not all of these characteristics are required.

The definition of trauma I introduce below is useful because it identifies differences between some types of stress that cause no symptoms, and those that can.

Neurologist and traumatologist Dr. Robert Scaer, who specialized in rehab medicine during the 1990s and early 2000s using this paradigm of disease, has researched and written about the role of trauma in chronic illness (2001, 2005). He defines the effects of trauma in this way:

Any negative life event occurring in a state of relative helplessness—a car accident, the sudden death of a loved one, a frightening medical procedure, a significant experience of rejection—can produce the same neurophysiological changes in the brain as do combat, rape, or abuse.

What makes a negative life event traumatizing isn’t the life-threatening nature of the event, but rather the degree of helplessness it engenders and one’s history of prior trauma.

This definition of trauma goes far beyond psychological events. The research continues to deepen our understanding of its effects and who refine our understanding that it’s no longer mind OR body, nature OR nurture but both intertwined.

From this perspective, negative life events that can be significant enough to trigger helplessness include all kinds of environmental stressors – whether they are biological (such as viral and bacterial infections and fungus/mold), chemical (such as pesticides), physical and psychological trauma and more.

This definition also makes sense of what happens with c. elegans during encounters with drought, conditions of low oxygen, heat or cold too severe for survival and other life-threatening events it cannot outrun. In these instances it experiences a state of relative helplessness that shifts its functions into the state of dauer until the threat goes away.

In the past 20 years of studying the science of traumatic stress, I have used this comprehensive definition of trauma – a negative event significant enough to evoke relative helplessness –  to explore whether studies in different chronic diseases and across other bodies of research can make sense of illness.

The studies point to the same new paradigm of disease proposed by Naviaux.

Going forward, I will use this expanded definition of trauma that goes beyond psychological triggers and effects.

IV. Mechanism 2: Adverse Babyhood Experiences (ABEs)

The second type of life experience I’ve coined “adverse babyhood experiences” or ABEs. ABEs can lead to prolongation of CDRs and diseases such as ME/CFS through exposure to adversity during pregnancy, birth or in the first 3 years of life. ABEs include premature birth, incubator care, illness in the mom or baby, being born by cesarean or forceps, and more.

ABEs can also affect risk through what Dr. Gabor Mate and others refer to as “missing experiences.” And example of missing experiences are how a baby born prematurely does not get the important experiences of staying in the secure, protected space of the womb during developmental milestones and who this loss of the ideal environment, distinct from the trauma that may occur, has an impact. I’ve written a detailed summary of the science for ABEs and provided a free fact sheet and checklist to explore whether a history of ABEs may have contributed to risk of developing a chronic disease.

A. ABEs and Trauma Affect Gene Function (Epigenetics)

After my medical training in the early 1990s, I had an unconscious assumption that chronic physical diseases were all caused by genes and genetic risk factors.

It turns out that that genes contribute only 50% or less of the risk for most chronic diseases. In addition, genes generally require exposure to environmental factors to become active enough to contribute to disease (Rappaport, 2016; wikipedia). Stress and trauma appear to play a role in the age of onset of even genetically based diseases such as Huntington’s and to therefore accelerate or slow down the disease process.

Naviaux expounds on this view, explaining that the role of environmental stressors on metabolic function is much greater than genetic influences:

Our lab classifies all complex chronic disease as being the result of either mitochondrial underfunction or mitochondrial overfunction. Each type has both genetic and environmental causes, but environmental causes outnumber genetic causes in the clinic 10:1 . .. These disorders range from autism to asthma, depression and autoimmune diseases, to Parkinson and Alzheimer’s disease, and many more (Q&A, 2016).

Some of the science that has helped change this view so dramatically comes from studies in epigenetics.

The still relatively new science of epigenetics refers to the way in which life experiences become embedded in our biology. They do so by adding or removing chemicals to the surface of our DNA. These molecules tell our genes whether to turn on or off or do something in between. They guide gene function without changing the structure or sequence of DNA.

This is one way in which exposure to environmental stressors can trigger the onset of disease. It is also how missing experiences affect nervous system function and sensitivity to stress to also affect risk for disease later in life.

McGill University researcher Michael Meaney, a behavioral epigeneticist and neurobiologist and his colleague Moshe Szyf, a molecular biologist and geneticist, knew that rats in the lab who were handled by humans for 5 to 15 minutes a day were licked and groomed more by their mothers afterwards. These pups became calmer and less stressed in adulthood than their littermates who didn’t get extra touch. They wondered if the mechanism was epigenetic.

Journalist Dan Hurley wrote a detailed, easy-to-read article about their research called Grandma’s Experiences Leave a Mark on Your Genes. Meaney and Szyf’s work opens up a whole new understanding of disease:

Originally these epigenetic changes were believed to occur only during fetal development. But pioneering studies showed that molecular bric-a-brac could be added to DNA in adulthood, setting off a cascade of cellular changes resulting in cancer. Sometimes methyl groups attached to DNA thanks to changes in diet; other times, exposure to certain chemicals appeared to be the cause. Szyf showed that correcting epigenetic changes with drugs could cure certain cancers in animals (Hurley, 2015).

In their landmark study, Meaney and Szyf examined whether maternal behaviors could alter gene function.

They evaluated the role of maternal touch on the stress response by comparing two groups of rat pups. One group was raised by more nurturing dams who licked and groomed their pups more and arched their backs to make nursing easier and more accessible. These pups grew up to be calmer and less sensitive to stress (Weaver, 2004).

The rat pups who experienced less maternal contact and care were more sensitive to stress.

Meaney and Szyf’s big aha! came when they saw that these differences were indeed associated with measurable epigenetic changes. These changes occurred in genes and areas of the brain that are designed to help manage stress and regulate cortisol and stress responses.

What they identified was that experiences of contact and nurturing maternal behaviors aren’t just a “nice thing to have” but actually serve a vital purpose. Life experiences facilitate brain function by promoting resiliency and resistance to stress sensitivity later in life.

We see similar effects in human babies who are exposed to adversity before their 3rd birthday or whose mothers experience stress or trauma during this time (this is why I’ve created the construct of ABEs and written a journal article about for the summer edition of JOPPPAH in June 2020).

B. Timing of Exposure to ABEs Affects Risk

ABEs and missing life experiences impact function during sensitive periods of brain development. They also influence the direction of development of other organ systems.

The effects of missing (or adverse) experiences are particularly pronounced when they happen at times when cells, tissue receptors and brain pathways are developing at particularly fast rates very early in life. This means sensitivity to the environment of experience and exposures is especially high during prenatal life, at birth, during infancy, and throughout childhood and the teenage years. Furthermore, growth and development continues for some organ systems well into adulthood.

Interactions with the environment helps our bodies assess whether threat exists and whether to prepare by becoming more or less sensitive to stress.

Meaney and Szyf’s rat pups showed epigenetic changes only if they were exposed (or weren’t exposed) to these maternal behaviors during the first week of life.

This effect of timing of exposure is known as a critical period or sensitive period.

Naviaux refers to critical periods of exposure in early life as risk factors for prolonged CDRs and disease:

[CDR] pathways are immature in newborns and growing children, leading to effects that are not limited to inflammation and innate immunity in peripheral tissues, but can also alter neurodevelopment and increase the risk of other chronic childhood diseases (Naviaux, 2014, p. 10).

As in Naviaux’ paradigm, Meaney and Szyf also discovered that these changes were potentially reversible, even later in life long after these experiences had happened. Reversibility in the rat pups was even possible when patterns of high sensitivity to stress were well established at older ages.

C. Missing Experiences

We don’t think of experiences of low touch or contact – such as being held infrequently as a baby, not getting much physical contact or touch, having parents who were not particularly nurturing or emotionally connecting, not breastfeeding, being hospitalized as a baby or child, or needing incubator care as being traumatic. We don’t even think of them as particularly threatening.

Physical and emotional connection in early life, however, influence the developing nervous system and other organs.

A baby who has to “cry it out,” as many parents were taught to do in the 1960s and 1970s, actually learns they cannot depend on their caregivers to protect them, respond to their needs, or keep them safe. This is how a nervous system and other organ systems can interpret and experience their environment and assess them as unsafe even when there is no overt trauma or exposure to harm.

Missing experiences such as low contact are so important that the effects can persist for life and continue in the next generation. They also appear to be capable of initiating cell danger responses and strengthening them through repeated exposures that prime physiology in a direction of heightened sensitivity to stress.

Meaney, Szyf and their colleagues describe it this way:

Through … epigenetic processes, maternal effects influence the development of defensive responses to threat in organisms ranging from plants to mammals.

In the rat, such effects are mediated by variations in maternal behavior, which serve as the basis for the transmission of individual differences in stress responses from mother to offspring (Weaver, 2004, p. Z).

Similar epigenetic effects are also seen in human studies.

Dr. Sarah Moore’s 2017 study at the University of British Columbia’s Children’s Hospital Research Institute found that month-old infants who experienced less physical contact with their mothers showed changes in 5 areas of their genes when they were 4 years old. These epigenetic changes were different from those found in the control group of children who had experienced high contact.

One of the 5 genetic areas codes for immune system functions that regulates T-cells. T-cells are involved in many autoimmune diseases, including type 1 diabetes (Zhao, 2016). They are also altered in ME/CFS (Craddock, 2014; Jason, 2009). A second area of epigenetic change was seen in a gene that affects metabolism. 3 other areas have functions that aren’t yet known.

These types of studies are changing how we understand disease in the same way and in the same direction as Naviaux’ cell danger response paradigm.

Such studies also beg the question, “What kinds of experiences affect a mother or father’s behaviors and ability to nurture and connect with their baby?”

I’ll describe this in the following section.

This is where we begin to see how life experiences interact with one another on many levels to affect risk for disease and the prolongation of CDRs.

D. Mechanisms: Emotional and Physical Separation at Birth

If you have a chronic illness, chances are you (or your doctor) have never considered the possibility that infections or chemical exposures early in life or events such as being born cesarean, needing care in an incubator, or getting hospitalized as an infant could have anything to do with getting sick decades later.

The science, however, is finding that such events are risk factors for disease and that they initiate or promote CDRs.

Separation At Birth Increases Risk for Disease

In the 1970s, Columbia University researcher and professor Dr. Myron Hofer discovered that when rat pups were separated from their dams in their first days of life, they had lower heart rates, body temperatures and blood pressure levels. He learned that this brief period of separation could influence a rat pup’s physiology to such an extent that it developed chronic diseases such as high blood pressure later in life.

Hofer’s studies showed that close proximity to adults in early life served an important, as-yet-unrecognized function: adults were psychobiological regulators for their infants.

This term explains how the presence of the adult and his or her physiology helps regulate the developing brain and other organ systems to support and shape the immature physiology of young rats.

Hofer found that separation was an environmental stressor that guided the direction of body functions as the pups grew and matured. This corresponds with Meaney and Szyf’s finding that even a decrease in maternal contact and touch has an impact on long term biology, physiology and development.

Rat pups and human babies can express their needs and distress through crying, which is a social nervous system survival response. They cannot, however, force their mothers to stay close, nurture, feed, touch or protect them.

In addition, rat pups and babies aren’t physically able to chase their mothers to maintain proximity (a sympathetic flight response).

Separation and other missing experiences are greatly underestimated risk factors. They represent the type of threat that can elicit a state of relative helplessness if there is insufficient comforting, safety, nurturing and protection.

All of these characteristics are congruent with Naviaux’ description of how cell danger responses can arise early in life to shape long-term health:

Beginning in the first trimester, the brainstem is responsible for the chemosensory integration of whole body metabolism with neurodevelopment. After birth, the trajectory of normal development can be altered if the CDR and its attendant metabolic changes persist (Naviaux, 2014).

Additional research further clarifies our understanding of the effects of negative and missing events in early life.

Bonding Affects Short and Long-Term Health

In their 1976 book Maternal-Infant Bonding, pediatricians Klaus and Kennell presented similar discoveries with human babies that Hofer had made with rats. A mere hour of skin-to-skin contact between mothers and babies in the first 2 hours after birth had an astonishing impact in comparison with a control group of mothers who experienced the traditional hospital routine of briefly seeing their babies after birth and then receiving them from the nursery for feeding every 4 hours.

Early contact affected both mother and baby.

Mothers who had more early contact held, soothed, caressed, kissed, gazed at, and spoke to their babies more. They spent more time with their babies, were more protective during routine medical appointments, and were more resistant to leaving their babies to go back to work.

Like Meaney and Szyf’s rat pups, babies who experienced more contact were calmer and easier to soothe. They also cried less and breastfed more easily. In addition, they had

• fewer infections
• fewer deaths
• shorter hospital stays
• warmer body temperatures
• more stable heart rates
• more stable breathing rates
• greater language skills and higher IQs than their counterparts in childhood

Klaus and Kennell’s research is increasingly understood and continues to be validated 40 years after publication.

Positive effects of what is often referred to as kangaroo maternal care (KMC) with premature babies, as one example, are still observable 20 years later (Charpak, 2017).

This seemingly innocuous form of routine separation interfered with a mother’s innate capacity to bond with her baby. The bond itself affected how she felt and behaved toward her child not only in the first days or weeks of life, but also throughout childhood and beyond.

These missing and adverse experiences affect a baby’s developing nervous system, physiology and behavior over a period of months and often decades.

E. Mechanisms: Nervous System Regulation 

The example above begins to highlight the number of factors that interact with one another to influence health. It introduces the role of early life experiences in shaping whether our nervous systems develop strong social engagement systems that can regulate stress responses or whether our bodies orient through more predominant survival states of fight, flight or freeze.

It also provides an example of how infections are potentially fewer or easier to treat when the threat or potential for threat is decreased or removed through support such as physical proximity and nurturing maternal behaviors.

This offers insights into protective factors that can nip a CDR in the bud or build protections against the need for cell danger responses in the first place.

Mechanisms associated with early contact may also prevent existing CDRs from becoming prolonged or reverse them as a baby experiences safety and their system recovers and settles.

One of the mechanisms involved in early contact and missing experiences is the fact that touch, holding, gazing, caressing, cuddling, breastfeeding and other behaviors are all forms of social nervous system activity.

All of these behaviors provide a sense of safety through connection and contact.

They all strengthen the developing Smart Vagus – the branch that we often try to stimulate in order to help regulate our nervous systems when we have a chronic illness as an adult.

A mother who holds, gazes and caresses less is unconsciously expressing a disruption in her own social nervous system. This is a natural response to threat because fear increases states of self-protection such as fight, flight or freeze and interferes with our ability to feel safety and connection.

Threat, in other words, heightens sympathetic survival states of fight / flight energy.

Because babies are inherently so immature physically that they cannot use fight/flight strategies as effective survival mechanisms, they are particularly vulnerable to experiences of helplessness.

This means that prenates, babies, infants and toddlers are at greatly increased risk of defaulting to survival states of parasympathetic freeze when exposed to even seemingly small or “mild” threat.

Early bonding activities help shape and build the ventral vagus branch of the parasympathetic nervous system, which conveys protection through the eyes, the use of sounds and words, through facial expressions and through behaviors. Gazing, cooing and talking, mirroring facial expressions and nurturing through physical contact are ways in which parental behaviors and a baby’s life experiences interact with their genes to influence how their organs develop. It also strengthens the connections between neurons (Schore, 1994, 2001).

The social nervous system is the branch of the autonomic nervous system that is able to inhibit stress responses of fight or flight as well as freeze (Schore 1994, 2001).

The following example pulls together how adverse or negative life experiences, missing experiences, and gene function can all cascade upon one another to gradually strengthen pathways that lead to disease. It will give you an idea of how early life experiences influence risk for disease later in life. It also provides a mechanism for addressing CDRs that become prolonged.

F. Example of Asthma (and How Healing Can Happen)

Psychologist Dr. Antonio Madrid’s research builds on pediatricians Klaus and Kennell’s early contact studies.

Madrid found that children with asthma, and their mothers, had both experienced more separation, negative events and missing experiences in early life than healthy kids. He refers to these as non-bonding events (1991, 2000, 2004).

In his studies, Madrid learned that kids with asthma had more than double the non-bonding events compared to well children with an average of 2.8 events in asthmatics vs 1.2 episodes in well kids. Furthermore,

70% of asthmatic children experience more than one non-bonding event compared with 25% of healthy kids (1991, p. 351).

Examples of non-bonding events in Madrid’s study included

• physical separation, such as occurs with cesarean sections
• anesthesia or medications that make it hard for a mother to be mentally present
• infections or other illness in mother or baby
• incubator care

As mentioned earlier, physical separation is a risk factor for disease later in life.

Physical separation can also interfere with bonding.

Emotional separation is another risk factor Madrid identified. Difficult emotions can be so strong that they interfere with a mother’s ability to bond with her baby. Examples of events that can trigger emotional separation in mothers include

• a previous miscarriage
• intense fear
• not holding her baby in the first hours after birth
• having twins, because it can be a more complicated pregnancy or birth and because it can be more difficult to bond to two babies at once
• the loss of a parent, child or other loved one during pregnancy or in her child’s first year of life

Madrid, Klaus and Kennel all found that environmental stressors could interfere with bonding whether they occurred in the year or two before pregnancy (loss of a loved one, previous miscarriage), during pregnancy, labor, or delivery (preeclampsia, premature birth, difficult delivery), or in the first years of their children’s lives (divorce, job loss, marital conflict, assault, a fall).

Madrid found that kids with asthma had experienced higher numbers of non-bonding events regardless of whether they were emotional or physical (or both).

Naviaux references the role of additive effects of threat as risk factors for stuck CDRs:

Progressive dysfunction with recurrent injury after incomplete healing occurs in all organ systems, not just the brain.

Chronic disease then results when cells are caught in a repeating loop of incomplete recovery and re-injury, unable to fully heal. This biology is at the root of virtually every chronic illness known, including susceptibility to sequential or recurrent infections (Naviaux, 2018, p 1).

Furthermore, Naviaux explains that epigenetics are a way our bodies remember the past to influence risk for disease from CDRs that get stuck:

A metabolic memory of the exposure that led to the CDR is stored away similar to the way the brain stores memories, in the form of durable changes in mitochondrial biomass, and cellular protein, lipid and other macromolecule content, cell structure, and gene expression via somatic epigenetic modifications (Naviaux, 2014).

Madrid made another striking find.

This discovery is predicted by Naviaux’ paradigm, including Naviaux’ small pilot study of autistic kids. It is also predicted by Meaney and Szyf’s epigenetic research.

The finding is that chronic disease may be more reversible than we currently realize.

When Madrid helped mothers heal their distress from non-bonding events and other effects of past adversities or trauma, something unexpected happened. When the mothers’ symptoms improved, their kids’ asthma also improved or resolved completely, often in less than 24 hours (you can learn more about his work on his website Asthma-Busters, in this interview, and in a detailed description here on my blog).

The youngest children typically recovered fully and no longer needed their asthma medications.

Older kids, beginning at about 9 years of age, improved but did not always heal completely.

Madrid wondered if the effects of additional adversities and exposures in childhood might play a role in this process.

Naviaux and others also propose that reversal of CDRs and defense responses may be harder as brains get older.

Dr. Madrid also wondered how it was possible for improvement to happen so quickly, since it lies so far outside our understanding of health, disease and possibilities for recovery. I’ve been searching for research that might explain this since I first met Tony 20 years ago. Science that may explain it has begun to emerge.

G. Reversing Disease (and the Cell Danger Response)

Epigenetic studies and understanding the CDR both suggest mechanisms that could explain these rapid recoveries or improvements and shifts in health.

Naviaux’ pilot study with 4 autistic children, for example, showed dramatic improvement in some symptoms. One 12-year-old child started making more eye contact within an hour of receiving the infusion. Two of the kids started speaking for the first time.

These are activities of a more robust social nervous system. This is the branch of the autonomic nervous system that is able to inhibit fight, flight and freeze when a threat response is unnecessary. It’s the part of the nervous system that is in charge when we are healthy.

Naviaux and colleagues do not believe CDR is the cause of ASD [autism spectrum disorder], but rather a fundamental driver that combines with other factors, such as genetics or environmental toxins. And suramin, at this stage, is not the ultimate answer (UCSanDiego Health article, 2017).

Healing trauma can reverse epigenetic changes

Another finding supporting Madrid’s success in reversing asthma at all, let alone so quickly, is that healing trauma with psychotherapy can reverse epigenetic changes.

Dr. Rachel Yehuda is a professor of psychiatry and neuroscience and the director of the Traumatic Stress Studies Division at the Mount Sinai School of Medicine. She is most well-known for her studies showing that traumatic experiences such as the Holocaust affects sensitivity to stress and PTSD in the second generation (1998, 2014). One of her studies also shows that epigenetic changes occur in veterans who recover from PTSD with trauma therapy (2013). In other words, psychotherapy is a form of environmental regulation that heals visible or recognizable effects and symptoms of trauma at one level while reversing epigenetic changes associated with these effects at another. You can learn more about her work and perspectives in this interview.

The science of epigenetics is helping to identify how life experiences interact with our genes to shape health and why it’s not psychological. It’s because our experiences embed in our biology.

Maternal Stress is Mirrored in Epigenetic Changes in Her Baby

A study published by Michele Wright and her colleagues at NYU Rory Meyers College of Nursing in 2018 adds one more layer of support for this discussion about mechanisms for reversing the CDR and why treating mothers can shift a child’s health.

Their group found that stressed mothers had epigenetic changes compared with mothers with low parenting stress.

In other words, mothers who don’t bond with their babies or who are not as nurturing, caring, or protective aren’t just experiencing a lack of will power, laziness, or psychological problems. They, too, are being held hostage by epigenetic effects and changes in their genes that result from difficult, missing or traumatic experiences.

The study found that a baby’s epigenetic patterns mirrored the changes in their mothers’.

This appears to be another mechanism through which Tony’s work that helped mother’s heal from trauma and regain their sense of love and bonding to their children could lead to a resolution of asthma in their children: by changing a mother’s epigenetics, and therefore indirectly also affecting her child’s.

H. Adverse Babyhood Experiences (ABEs) Increase Risk for Disease

The cell danger response and epigenetic studies, among others, provide potent mechanisms that explain how threat in early life can be a risk factor for disease. I refer to this large body of research as adverse babyhood experiences (ABEs) to build on the increasingly recognized research studies called adverse childhood experiences (ACEs), which I will present in a separate upcoming section.

Adverse babyhood experiences also explain how events can add up and increase risk with time.

ME/CFS and Adverse Babyhood Experiences

While I don’t know of any studies yet examining adverse babyhood events in risk for ME/CFS, Drs. Dietert and Dietert have proposed that negative experiences in early life are likely risk factors just as they are for many other diseases (2008) ⁽³⁶⁾ .

The growing list of diseases impacted by negative events during pregnancy and birth includes the following. Some have been identified in relation to prenatal emotional or physical stress, others to birth complications and adversity or missing experiences in the first years of life. The fetal origins of disease (FOAD) group of studies also show risk from all kinds of maternal experiences of prenatal stress (Calkins, 2011).

Adverse babyhood experiences increase risk for:

• the presence of type 1 diabetes-related antibodies in toddlers
• type 1 diabetes at any age
• multiple sclerosis
• inflammatory bowel disease (Crohn’s, Ulcerative Colitis)
• asthma (studies other than Madrid’s)
• the metabolic syndrome of insulin resistance (high blood pressure, type 2 diabetes, high cholesterol, obesity, heart disease)
• Alzheimer’s
• COPD
• osteoporosis
• cancer
• depression
• and more

Additional studies suggest that events occurring during the prenatal time frame also increase risk for:

• lupus ⁽³⁴⁾
• rheumatoid arthritis / disease  ⁽³⁵⁾

Risk for many of these diseases was found to be higher in the next generation, just as it was in Meaney and Szyf’s studies with rat pups and Rachel Yehuda’s findings in kids whose parents survived the Holocaust. This multigenerational component can obscure risk factors and make it harder to identify since they occur in parents’ and grandparents’ lives.

As these numerous studies suggest (and there are many more), there is a vast and diverse body of research in different fields of study supporting Naviaux’ proposal that adverse and missing events can initiate or prolong CDRs during early development to affect risk for all kinds of different diseases.

Summary of ABEs Research and the New Disease Paradigm

1. Life experiences embed in our biology through epigenetics to shape health
2. Missing experiences and adverse events stimulate cell danger responses (CDRs)
3. Relative helplessness triggers a freeze response that may initiate CDRs
4. Relative helplessness is a risk factor for prolonging brain perceptions of threat
5. Missing experiences lead to a weaker ventral vagus aka social nervous system
6. In disease, the social nervous system cannot inhibit freeze as it is designed to do
7. Too many negative or missing events add up to increase risk of prolonged CDRs
8. A new paradigm of disease is that of the prolonged cell danger response
9. A new paradigm of disease is that life events embed in our biology via epigenetics
10. A new paradigm of disease is a nervous system caught in old perceptions of threat
11. One underlying mechanism for ME/CFS appers to be a CDR stuck in freeze
12. Another underlying mechanism for ME/CFS may be a CDR caught in fight / flight underneath the freeze
13. Stuck CDR pathways would be unique and slightly different for each of us to potentially explain
    1. the slight variations we each have in symptoms
    2. the many different findings that different researchers identify
14. Adverse and missing experiences in babyhood increase risk for disease
15. Maternal contact affects gene function (epigenetics) in babies and children
16. Early contact can be protective and even preventive of CDRs and disease
17. The CDR and epigenetics are reversible
18. Healing negative experiences from early threat can reverse epigenetic changes
19. Healing maternal threat responses can reverse asthma in children
20. Diet, exercise, and trauma therapy can all reverse epigenetic changes

This leads to the next question: Can healing threat responses reduce or improve diseases such as ME/CFS?

***Survey 2: ME/CFS and Adverse Babyhood Experiences (ABEs)

This ME/CFS ABE survey aims to give you a better sense of the types of experiences that affect risk for chronic disease.

These 30 questions are covered on three pages. They do not include all possible adverse experiences. 

You will see your score on the third page and a set of graphs after you click submit.

* These questions were drawn from Dr. Antonio Madrid’s Maternal Infant Bonding Survey (MIBS) included in his training manual, Klaus & Kennel’s book Maternal Infant Bonding, EMDR Therapy and Somatic Psychology and other sources such as listed above, among others.

Note: in the PDF and Kindle versions of this post you will find the survey in the appendix.

Add up the exposures that played a role in your life (one point for each type and one point for other exposures). This is your ABE Score.

V. Mechanism 3: Serious Life Events in Childhood

If you developed ME/CFS as an adult, you may have never thought events in childhood could have anything to do with your illness any more than you might have considered risk from events around your birth or in prenatal life. Or you may have worried that if you had had difficult experiences in childhood that doctors would say your disease was psychological or all in your head.

A. Adverse Childhood Experiences (ACEs)

The adverse childhood experiences (ACE) are the most well-known group of studies to have evaluated the effects of negative events in childhood on short and long-term health.

The first study, published in 1998 was conducted by Dr. Vincent Felitti, an internist and clinical professor of medicine at the University of California working at Kaiser Permanente in San Diego, and Dr. Robert Anda, an epidemiologist at the CDC at the time. They sent a questionnaire to over 17,000 adult, middle class, educated, mostly white Kaiser patients. They asked whether they had experienced 10 specific types of negative events between birth and their 18th birthday. Another 450,000 people have since been screened for ACEs with the same results.

The 10 ACEs

The original 10 ACEs included the loss of a parent from divorce or separation (but not death, which is now considered an ACE), mental illness in a parent such as depression, having a household member with drug or alcohol dependence or who spent time in jail, domestic violence between parents, and physical, emotional or sexual abuse or physical or emotional neglect.

Each ACE category gives 1 point towards a score. The ACE score can have up to a maximum of 10 points – 1 point for each type of adverse event.

ACEs Increase Risk for Disease

ACEs greatly increases risk for early death and all kinds of chronic diseases, including autoimmune diseases, heart disease, type 2 diabetes, cancer, stroke, dementia and many more. ACEs also increase risk for depression, anxiety, PTSD and have many other long-lasting negative effects. Felitti and Anda believe that ACEs are the leading public health issue of our time and that addressing the effects of ACEs would be like finding a vaccine that cured a major cause of illness in our society.

Hundreds of ACE studies have since found similar results in different populations, in different states in the U.S, and in other countries.

Dr. Joan Luby at the Washington University School of Medicine in St. Louis, Missouri also found that ACEs increase risk for physical health problems and chronic illness in children, which is much younger than was expected (Luby, 2017).

ACEs alter epigenetics.

In fact, the ACE of child abuse alters the same gene in a child –  NR3C1 – as low mothering behaviors does in rat pups. This adds yet one more confirmation for Naviaux’ paradigm and neurologist Robert Scaer’s finding that it is not a specific environmental risk factor or exposure that determines risk for disease, – but the fact that our nervous systems experience them as a source of threat.

Naviaux’ research is part of a wave of new science recognizing that events in childhood are more important in shaping our health than events that happen right before we get sick. He and others show that the effects of adverse childhood experiences (ACEs), even if the ACEs themselves are psychological or represent missing experiences, have an impact because they change how our genes and cell danger responses and nervous systems function, among other mechanisms.

Diseases associated with exposure to ACES are no more psychological than chronic illnesses linked to a history of adverse babyhood experiences (ABEs) described above.

B. Serious Life Events

Like ABEs, negative experiences in childhood can initiate, strengthen or prolong the CDR:

Unresolved CDR activation by adverse childhood experiences (ACEs) … may … play a role in many other adult illnesses like heart disease, cancer, and stroke (Naviaux, 2018, p. 14).

Psychological trauma, particularly during childhood, can also activate the cell danger response, produce chronic inflammation, and increase the risk of many disorders (Naviaux, 2014, p. 7).

An example comes from research in type 1 diabetes (T1D). The All Babies in Southeast Sweden (ABIS) study followed 10,000 babies in the general population from birth to 14 years of age (these babies were not at increased genetic risk for T1D). Parents were interviewed along the way in this prospective study looking at the potential role of serious life events (SLEs) (Nygren, 2015).

Nygren and her colleagues found that serious life events were three times more common in the children who developed type 1 diabetes than in kids who stayed healthy:

The risk of a child being diagnosed with diabetes before 14 years of age was estimated to be three times higher if the child had experienced an SLE than if they had not … [serious life events] including death and illness experienced by the child and including death, illness and accidents experienced by the parent were associated with a higher risk of diagnosis after adjusting for heredity and age at entry into the study, and remained so after adjusting for all potential confounders as well as BMI [body mass index] (Nygren, 2015, p. 6).

I cite this study because of its quality and also because it does not focus exclusively on physical or sexual abuse as the only types of adversities that might affect risk.

In contrast to common beliefs, risk factors for type 1 diabetes in the study listed above included common psychological stressors, such as the loss of a parent or a grandparent, moving, or having a parent with a serious illness.

As in the adverse babyhood experiences, the study authors also emphasized how negative experiences in parents’s lives had an impact on a child’s health.

Serious life events experienced by the child and the parent were highly correlated [to risk for type 1 diabetes] (Nygren, 2015, pp 6-7)

A large body of research shows the same kinds of risk factors for many other autoimmune diseases and chronic illnesses.

C. Mechanisms: Missing Experiences in Childhood

The 10 ACEs don’t address every type of trauma or adversity that affects long-term health. Instead, they provide a context to begin to understand the kinds of life experiences that affect health.

To give you an idea of how potent and sometimes subtle ACEs are, an ACE score of 2 could arise from having a parent who was depressed and got divorced before a child turned 18.

These are not what we typically think of as traumatic events for children. They are not a sign that parents are intentionally harming their kids. They aren’t a sign that parents don’t love their children.

What ACEs science reveals is that a depressed parent (or an anxious, or sick, or addicted or workaholic parent) has an impact on their child’s development. This is because depression and other states of stress make people less emotionally available to nurture, support and interact with their children as well as with others, including spouses, family and friends, work colleagues and others.

Parents who divorce generally experience conflict, grief and stress before signing the papers to separate. As a result, their children are also exposed to conflict, grief and stress even if it is not overtly expressed (see the study mentioned in ABEs on how parental stress is mirrored in epigenetic changes in their babies).

Parental separation represents the loss of a parent for a child, and consequently the loss of psychobiological regulation, psychological support and connection for a child even if they continue to have contact with both parents.

ACEs are indicators of overt trauma, such as abuse, as well as of missing experiences.

ACEs are also increased by adverse babyhood experiences, because bonding disruptions interfere with connection and all the related behaviors and interactions.

Like babies, kids are at risk for disease and other symptoms when they miss out on the degree and quality of contact, connection and nurturing support their nervous systems are designed to receive. This is because such experiences are a critical to the development of strong social nervous systems. They are keys to how bodies and physiologies learn to calm down and be less reactive to stress.

A 2009 study showed that an ACE score of 2 is enough to increase the risk of being hospitalized for an autoimmune disease by 70% (Dube, 2009).

Furthermore, for every additional 1-point increase in the ACE score, risk for developing an autoimmune disease such as type 1 diabetes, lupus, rheumatoid arthritis and many others goes up by 10% to 20%.

D. Childhood Physical, Sexual and Emotional Abuse are Risk Factors for ME/CFS

There is data showing that adverse experiences in childhood increase risk for ME/CFS.

A systematic review of 31 studies conducted over 20 years found that emotional abuse, childhood sexual abuse, and physical abuse are associated with increased risk for both ME/CFS and Fibromyalgia (FM):

There is a strong association between experiences of childhood stressors and the presence of CFS and FM, with rates of CFS/FM being two- to three-fold higher in exposed than in unexposed subjects.

We also found evidence for an increased risk for the development of additional symptoms, such as depression, anxiety and pain (Borsini, 2013, Abstract).

A 2020 UK study of 80,000 adults exposed to ACE-type traumas and 161,000 not exposed found that childhood maltreatment was twice as high in people with ME/CFS and Fibromyalgia. Childhood maltreatment was also associated with higher risk for IBS, restless legs, and chronic low back pain (Chandan). If anything, estimates were low because they excluded any conditions people had prior to entering the study and only evaluated adults in their early 20s, thus potentially missing illness that might be identified in an older population.

E. Mechanisms: It’s Not Psychological

When doctors treating those of us with ME/CFS or fibromyalgia learn we also have depression or anxiety they sometimes blame these symptoms on our disease, or say that our disease is all in our heads and caused by our emotions.

Depression and anxiety, however, are among the most common effects of unresolved trauma.

The above review study on ME/CFS and fibromyalgia, along with other ACE studies, suggest that depression, anxiety and pain associated with ME/CFS or fibromyalgia are largely due to the effects of trauma.

Another of way of saying this is that, while negative feelings can have an impact on our health they are not typically the cause of serious illnesses such as ME/CFS or fibromyalgia.

Rather, ME/CFS, fibromyalgia, depression and anxiety are often all due to the same history of accumulated exposures to adverse or missing events.

In addition, mental, emotional and physical symptoms in ME/CFS can all be driven by the same CDR of freeze. This is not because the illness is faked or not real, but because early adversity and missing experiences trigger CDR pathways that lead to these same kinds of symptoms.

Emotional symptoms such as depression and frustration can also reflect the trauma of having an incurable, debilitating, potentially life-threatening disease. Our feelings can stem from a loss (or fear of loss) of the ability to care for our daily needs, as well as to maintain our livelihoods, family relationships and much more. Like many diseases, ME/CFS can render a person relatively helpless due to its physical and other effects and can therefore be traumatic in and of itself.

F. Mechanisms: ACEs Alter Epigenetics

As with the ABEs research, epigenetic changes have also been found in children with a history of adversity such as ACEs.

Dr. Seth Pollak, a professor at the University of Wisconsin and head of the study, wanted to know how, exactly, abuse was changing these children’s bodies on a cellular level.

The change was actually in the same gene that Meaney and Szyf identified in their rat pups – NR3C1.

NR3C1 is the gene that regulates cortisol and the stress response. Pollak’s study looked for the gene in the white blood cells, which are part of the immune system:

The fact that these changes occur in the immune system is significant on its own. Having too few receptors for cortisol keeps the immune system from learning to manage inflammation and infections, helping explain why children in abusive homes seem to get sick more often, and are at a higher risk for chronic health problems.

While rat pups only developed epigenetic changes in this particular area when exposed to low maternal nurturing behaviors in the first week of life, other types of adversities or missing experiences influence this particular gene at different times in humans, including after infancy and into childhood.

G. ACEs are One Face of The New Paradigm

The science of ACEs is helping to shift our understanding of disease and leading us in the direct proposed by Naviaux and the cell danger response.

One of the ACEs pioneers is Dr. Nadine Burke Harris, a pediatrician and founder of The Youth Wellness Center. She is the author of one of the best books I have found on trauma and disease, The Deepest well, which describes how helpful this knowledge is in treating her young patients. She describes the role of epigenetics and risk for disease, mental illness and other effects of trauma. Burke-Harris was named the first surgeon general of California in January 2019. You can hear about the science in her compelling conversation about adversity and disease in an interview with Gwyneth Paltrow from April 2020.

Dr. Jack Shonkoff is also a pediatrician involved in alleviating and reducing the effects of ACEs. He is the founder of Harvard’s Center for the Developing Child, which is implementing strategies in schools and other environments to help prevent disease, mental illness and other effects of early, generally unrecognized trauma and missing experiences.

Shonkoff and Burke-Harris have spoken to congress about the toxic effects of separating kids and families at the border, which include increased risk for disease:

From a scientific perspective, the initial separation and the lack of rapid reunification are both indefensible. Forcibly separating children from their parents is like setting a house on fire. Prolonging that separation is like preventing the first responders from doing their job (Shonkoff, 2019).

Shonkoff and pediatrician colleague Andrew Garner have also facilitated the incorporation of this emerging paradigm of disease into the new guidelines for the American Academy of Pediatrics (AAP). Their article may be one of the best publications to give to your doctor in combination with Naviaux’ work:

The process of development is now understood as a function of “nature dancing with nurture over time,” in contrast to the longstanding but now outdated debate about the influence of “nature versus nurture.”

That is to say, beginning prenatally, continuing through infancy, and extending into childhood and beyond, development is driven by an ongoing, inextricable interaction between biology (as defined by genetic predispositions) and ecology (as defined by the social and physical environment) (Shonkoff, 2012, p. e234; here’s the full pdf to give to your doctor)

***Survey 3: ME/CFS and Expanded Adverse Childhood Experiences (ACEs+) 1.0

I’ve created this expanded version of the original ACE survey to provide a better sense of the types of experiences that affect risk for chronic diseases, including ME/CFS.

These 30 questions are covered in three pages. As with the original ACE survey, they do not include all possible adverse childhood experiences. They are designed to give you an idea of the kind of exposures that can increase risk for chronic disease and other health problems.

You will see your score on the last page and a set of graphs after you click submit.

* The original 10 Question ACE survey is included in this one. I’ve expanded some of the questions slightly. I’ve added the last question about other ACEs on Dr. Vincent Felitti’s recommendation. I’ve drawn additional questions from The Pediatric ACEs and Related Life-events Screener (PEARLS) developed by Dr. Nadine Burke-Harris and colleagues in the Bay Area Research Consortium on Toxic Stress and Health (BARC). Other sources for this expanded ACEs+ survey included other ACE surveys, Finkelhor’s research (2017), and additional sources. You can get your ACE score from the original ACE survey here.

Note: in the PDF and Kindle versions of this post you will find the survey in the appendix.

Add up the exposures that played a role in your life (one point for each type and one point for other adverse exposures). This is your ACE+ score.

VI. Putting it Together: Life Experiences Influence Health

Above, I’ve introduced some of the research that connects the dots on how trauma and more subtle types of adversity increase risk for chronic illness, including ME/CFS and Fibromyalgia. The studies show how exposures to different adversities affects the developing nervous system, the CDR, gene function and perceptions of threat.

In reality, I’ve only named a few examples of events and time periods that can affect risk for chronic diseases.

This is an artificial way of helping people understand how longstanding and lifelong the effects of adverse events and exposures can be.

I could say more about the research showing that multigenerational trauma affects health in kids and grandkids.

I could acknowledge in a more detailed way that many of us who get sick after our 18th birthdays have had additional adverse life experience (ALEs) between that age and the onset of our diseases, such as car accidents, loss of a loved one, surgery, divorce, bankruptcy, exposures to infections, vaccines, chemicals, the stress of medical training and other work environments, and more.

My goal is not to cover every type of threat (although I gave it a good try and gave you a long post to read)- which isn’t really possible anyway. Even with an expanded ACE survey containing 30 questions instead of 10, for example, it isn’t possible to name or list every type of event that may have affected our cell danger responses.

My intention, like that of the ACE studies, is to provide enough information so we can begin to recognize the kinds of environmental factors that influence health. It is also to demonstrate just how strong the evidence is.

Ultimately, I want to emphasize that chronic disease is affected by the balance of exposures we’ve had between negative experiences and supportive, nurturing experiences.

With this kind of awareness, it becomes possible to think differently about chronic disease and other effects of adverse exposures, which include mental illness, addictions, chronic pain, difficulty finding or maintaining satisfying long-term intimate relationships, and much more.

From a systems point of view, this information helps us think about treatment, prevention, and medical care with fresh eyes.

Can you imaging what it would be like if your doctor(s) believed you? If they understood why some medications work for some people but cause terrible side effects for others and didn’t blame people for it? If we recognized that helping parents heal their trauma could enable them to be more present and nurturing with their kids and at the same time prevent chronic health conditions in their children’s lives? If we implemented what we already know more widely, so as to support women in childbirth and prevent or nip potential CDRs and risk for disease in the bud?

With this context, a whole new paradigm emerges for understanding symptoms, triggers, flares and approaches to healing.

This is what Dr. Robert Naviaux is talking about.

We will all experience some kinds of adversity simply as part of being human.

Furthermore, a large number of people will emerge relatively and remarkably healthy, emphasizing just how resilient our bodies and nervous systems are.

But the rest of us who are affected and whose lives get derailed are the canaries in the gold mine. We know that it’s time for a new paradigm. We are looking for a context that can help us take back our lives, our futures and the lives of our children and grandchildren.

The next section briefly describes what the new paradigm implies for healing, which I will address in the next post of this series.

VII. Implications for Treatment

Here’s why it matters if you’ve had negative experiences in the past, and why understanding the cell danger response can make a difference if you have ME/CFS.

1. Existing Tools

The CDR, like epigenetics, may be at least partly reversible in ME/CFS (and in other diseases).

The good news is that the dauer state in the worm model is completely reversible. If dauer is a good model for ME/CFS, then there is hope that by studying the molecular controls of the dauer phenotype, new treatments might be discovered rationally to help stimulate the exit from the dauer-like state and begin the process of recovery (Naviaux, 2018, p. 13).

This means that tools other than medications that we so often hear about – diet, mindfulness, meditation and other mind body practices such as yoga and yoga nidra, sleep hygiene, satisfying relationships, among others – can be helpful because they

• can send signals of safety to the nervous system and to cells
• can reverse epigenetic threat and stress responses
• create more “space” in our bodies, nervous systems and lives to allow for the body’s own capacity to heal

These tools are more powerful than we’ve thought. They are not merely “lifestyle choices.” They actually support the healing of threat responses.

For many of us, we need to use as many of these tools as possible (one is often not enough). Many of these have helped me, for example, but I’ve had to go very slowly and  gently. Diet helped but did not cure me even with 4 years on a ketogenic diet (and only cheating half a dozen times). Starting with very gentle, short distances, I’ve been able to grow my ability to walk 1/2 hour and hike on occasions. But these have not been cures.

If the concept of adversity resonates as a risk factor, there is another tool that is often dismissed because it’s thought to be psychological tool for psychological illness. This is the approach of trauma therapy. There are specific types of psychotherapy that operate from the nervous system perspective, that understand freeze and other threat responses, and that recognize the need to work gently and at each person’s unique pace. I refer to these as somatic trauma therapies, which are different from cognitive behavioral therapies because they help access effects of trauma that we do not hold in our conscious awareness. Learn more and find a therapist in my post about therapies.

Potential Future Tools

As I mentioned earlier, Naviaux has begun testing the reversibility of the CDR by blocking the danger signal that is spread by adenosine triphosphate (ATP), referred to as “purinergic signaling”:

Antipurinergic drugs can treat the abnormal metabolic syndrome that causes autism by sending a cellular “all’s clear” or safety signal like the one that is announced when a fire is extinguished, telling you it is safe to return to school (2017)

The study tested suramin with 4 children who have autism. It showed extraordinary improvements. I’ll restate some of the changes that occurred after a single dose of suramin was given to these children:

The six-year-old and the 14-year-old who received suramin said the first sentences of their lives about one week after the single suramin infusion …  during the time the children were on suramin, benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, applied behavioral analysis and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.

This first test of antipurinergic therapy (APT) supports the existence of the CDR as well as the potential for reversibility.

The findings are preliminary with much more testing needed, however. There are 19 different purinergic receptors and medications are likely to be different for each disease, and there will be a need for “careful fine-tuning to identify appropriate doses” while monitoring for potentially serious side effects (Naviaux, 2017).

While suramin is not a medication ready to be tested on (or potentially even appropriate for) ME/CFS at this early stage, it offers hope as well as support for the possibility of improvement or even reversibility through a variety of different approaches.

I will be talking about the implications of the CDR along with trauma science and nervous system perspectives for working with ME/CFS in a future third part of this series.

VIII. Frequently Asked Questions About ME/CFS

1. Why do different types of exposures affect risk for ME/CFS?

Risk of prolonged CDRs increases when healing does not occur between exposures to environmental stressors.

Naviaux’ new paradigm explains that disease is caused by an accumulation of the effects of environmental stressors when healing fails to occur after the exposure – whether these are infections, chemical exposures, psychological or physical traumas or something else.

Soldiers who develop PTSD, another CDR state identified by Naviaux (2014), for example, are more likely to have a prior history of other trauma than their counterparts who do not (Lehrner, 2016).

This is also seen with adverse childhood experiences (ACEs), in which risk for disease and other symptoms increases exponentially with each additional ACE a person experiences (Dube, 2009; Felitti, 1998).

Naviaux proposes that the same occurs with the CDR in  ME/CFS and other diseases:

Mixtures of chemical and biological threats can have synergistic effects, and the total load of danger triggers can influence the magnitude and form of the CDR (Naviaux, 2014, p. 10).

The total load of triggers is integrated by metabolism and regulates the CDR (Naviaux, 2014, p. 7).

Naviaux, and others such as Bruce McEwen, Ph.D. (2005) who studied different types of stress and their effects in his neuroendocrinology lab at Rockefeller University in NY, refer to the term “allostatic load” as the way in which a particular physiology acts either in the direction of defense and survival or towards relaxation and health based on past and current exposures:

When stressors (psychosocial stress, food deprivation, infectious disease, environmental toxins and drugs, poor sleep, etc.) act upon a living organism, they can dysregulate adaptive processes (allostasis) that promote pathophysiology (allostatic load/overload) (Peters & McEwen, 2012, Abstract).

Under the healing cycle model for chronic disease, allostatic load initiates the CDR and the healing cycle. (Naviaux, 2018, pp 12-13).

As Naviaux alluded to in his video earlier in this article, the “load” and its effects accumulate because our mitochondria, cells and nervous systems remember negative experiences particularly well. Our bodies do this on purpose so we can unconsciously recognize and respond more quickly should similar events happen again in the future.

When the CDR does not resolve and heal as it is designed to do and instead becomes prolonged, these imbedded memories and their associated CDRs are strengthened with each additional negative event we experience in infancy, childhood and later in adulthood.

As Naviaux and neurologist Dr. Robert Scaer emphasize, negative experiences strengthen one (or more) CDRs over time.

It this is the case, do people with ME/CFS have a history of more exposures or a higher “load” than healthy folks?

The 20 year review of adverse childhood experiences in ME/CFS previously found that childhood experiences of physical and psychological trauma were 2 to 3 times more frequent in people with ME/CFS. The 2020 study found that experiences of maltreatment in childhood doubled the risk for ME/CFS.

Another series of studies conducted in Kansas in 2006 also found that people with ME/CFS had a higher allostatic load than controls. Allostatic load was measured with tests of metabolic function such as blood pressure, cortisol levels, IL-6 and other immune and metabolic tests. Allostatic load in people with ME/CFS was twice as high as in controls (Maloney, 2006), and was also greater in people with sudden onset and who had more severe symptoms of ME/CFS (Goertzel, 2006).

The influence of events that trigger states of relative helplessness is well-known in the field of traumatic stress for its different effects on risk for PTSD and other symptoms.

Greater intensity – degree of helplessness, severity of life-threat, frequency or duration of exposure, younger age at time of exposure – all increase risk for higher symptom severity as seen above in ME/CFS and are also risk factors for a younger age of onset (McFarlane 2015, 2017; Yehuda, 2015).

Naviaux’ team found that “decreases in these [dauer or freeze type of] metabolites correlated with disease severity” in ME/CFS (Naviaux, 2014, p. e5477).

To put it another way, people with the most severe symptoms of ME/CFS had deeper metabolic states of freeze-based CDRs.

2. Isn’t the event that triggers ME/CFS the cause of the disease?

Many people with ME/CFS can pinpoint a particular event or series of events that happened in the period before the onset of their disease or that seemed to trigger onset,

The event that triggers the onset of ME/CFS can seem far too trivial for such a serious illness. It can also seem unreasonable to think that a minor infection, a vaccine, exposure to mold that others live around with no problem, the stress of caring for a loved one who is sick, undergoing routine surgery or almost-but-not-quite-getting-into-a-serious car accident can trigger onset.

The new disease paradigm explains that this final event acts like “the last straw” rather than being the cause of the disease. It is a final exposure that makes the CDR reset and solidify into a system-wide pathway focused on survival through freeze.

Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content (Naviaux, 2014, p. .

Metabolic memory of past exposures primes the cellular response to future exposures, even when the original trigger or stress is no longer present (Naviaux, 2018, p. 11).

In multiple sclerosis research, Dr. Charles Poser observed that the onset of MS follows a long period during which certain pathways begin to change without it being obvious to the individual or to their doctors (1986).

He described this gradual evolution of disease as similar to the development of an “undersea volcano,” with symptoms peaking through and being obvious on occasion, months or years before the actual onset of disease, but then going dormant again and sinking below the surface.

The clinical course of MS, rather than the apparent [visible] one of exacerbations and remissions, is actually a continuous process, the clinical events resembling the tips of the undersea volcanoes that constitute the Hawaiian Islands (Poser, 1986. p. 2).

I had brief symptoms of intense fatigue when doing a bike tour in college more than 10 years before the onset of my first steady symptoms of ME/CFS. A history of brief symptoms is common in other diseases as well and is increasingly recognized as the way diseases evolve. In another example of the lengthy latency period during which a chronic illness or CDR slowly develops incognito is the presence of antibodies, which have been found years or decades before the onset of type 1 diabetes or lupus. The current problem is that we don’t know what to measure in ME/CFS even as many parameters are emerging, including Naviaux’ hypometabolic CDR and Porges’ polyvagal theory.

3. Is ME/CFS due to a current threat?

The idea that threats that have triggered the CDR of freeze leading to ME/CFS may be long gone and no longer present is a new concept in disease.

Now that I’ve provided more of the science to explain how this happens, I want to restate one of Naviaux’ most important quotes about this phenomenon:

In chronic illness, the original triggering event is often remote, and may no longer be present. Emerging evidence shows that most chronic illness is caused by the biological reaction to an injury, and not the initial injury, or the agent of injury itself. For example, melanoma can be caused by sun exposure that occurred decades earlier, and posttraumatic stress disorder (PTSD) can occur months or years after a bullet wound has healed (Naviaux, 2018, p. 1).

4. How can a relatively small stressor trigger such a severe disease?

As described above, the event that triggers disease is the last in a series of exposures. It stimulates a CDR that has been slowly strengthening and tips it or “resets” it so that it becomes the dominant state at a system-wide level.

Depending on a person’s prior history and current circumstances of support, stress and resiliency, the last straw can be a serious event that triggers the sudden onset of severe symptoms, or it may be a tiny stressor that contributes to a gradual worsening, or anything in between.

5. Why do some people develop ME/CFS after exposure to certain environmental stressors when others exposed to the same events and triggers do not?

The cell danger response paradigm as well as science in critical period programming, developmental trauma, epigenetics and traumatic stress offer at least 2 explanations.

Naviaux explains that the CDR only becomes prolonged if too many events happen without time for resolution, or if exposures are too severe. Other science I’ve mentioned above has identified the same facts.

People who develop ME/CFS after the same kinds of stressors their healthy peers experience without getting sick, such as an accident, a vaccine, or an infection – are likely to have a higher allostatic load. They likely have a greater history of adverse or missing events.

People who get sick therefore have an underlying CDR pathway that has been developing and strengthening and that becomes fully reset or “stuck” after this final exposure and tipping point. Their peers likely do not have strong CDR pathways or CDRs that are on the verge of becoming stuck with this particular exposure.

Resources and Support Can Buffer the Effects of Environmental Stressors

A second important influence that can determine whether a person develops ME/CFS or not is the concept of resource. In trauma science and in some diseases, it is referred to as a buffer (Daskalakis, 2013; Lehrner, 2016; Luby, 2017; Sepa, 2004; Thernlund, 1992).

Buffers are anything that help minimize risk of helplessness during negative experiences, that support healing of threat responses such as the CDR if they arise, or that prevent CDRs from becoming prolonged.

Buffers can come in the form of nurturing parents that help their child recover from an accident or a serious infection requiring hospitalization. A buffer might arise from having enough time in between exposures for the CDR to heal as it is designed to do. For a child with a high ACE score and the difficult family life this suggests, a buffer may equate to greater resilience because they have someone in their lives who they can talk to, and who sees and believes them, such as a grandparent, teacher, neighbor or other adult. Early contact between mothers and babies is a buffer against bonding disruptions and their effects.

Buffers may delay the onset of a disease by slowing down or weakening CDR pathways, or may prevent the onset of CDRs and disease altogether.

A 1989 study by Drs. Robinson and Fuller found that family members who had antibodies for type 1 diabetes but did not progress to the disease had more buffers in their lives than their relatives who did develop the disease over the 5 year period of the study (Robinson, 1989).

6. Why can the same trigger lead to ME/CFS in some of us and to a different disease in others?

The timing of exposure during early life shapes organ systems and other structures as they develop. This interaction guides the direction their patterns of regulation will take.

The chronic CDR disorders [autoimmune diseases, metabolic syndrome, Alzheimer’s, asthma and others]… produce abnormalities in a broad range of target tissues and cell types. The genotype and health of the host, the developmental timing and the nature of the exposure determine the risk of developing a particular disease (Naviaux, 2014, p. 9).

Michael Meaney and Moshe Szyf’s rat pups who were exposed to high or low nurturing mothers, for example, developed epigenetic changes in the cortisol pathway only if they experienced these behaviors within the first week of life.

In humans, the period of time when skin-to-skin contact carries the greatest protection against bonding disruptions and consequent risk of its effects on health in the first 2 hours after birth in particular and the first 24 hours in general (Bystrova, 2009; Klaus, 1972).

Critical Periods Influence Which Disease Can Develop

The following detailed example comes from the history of the drug thalidomide, which was given to pregnant women to treat nausea in the late 1950s. At the time it was believed that medications could not cross the placenta and would therefore have no impact on the baby.

Thalidomide turned out to cause a number of birth defects in babies depending on when the mother took it:

The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment.

Thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28.

Thalidomide did not damage the fetus if taken after 42 days gestation (wikipedia).

This very specific and poignant example illustrates how an environmental exposure influences tissues undergoing particularly large, rapid cycles of growth and refinement during early development.

It also brings up the question of whether there is a specific risk period for ME/CFS or other chronic diseases during pregnancy, infancy or childhood.

The coauthors of the in-depth overview of the fetal origins of disease (FOAD) research ask a similar question. They found that prenatal events could influence the size of the baby at birth. Some babies were smaller than expected for their birth age, and others were very large. Birth size was a risk factor for disease, not because it was a risk factor in and of itself, but because it reflected prenatal events that affected risk. They wondered what might be going on to influence long-term health:

Why would growth or other insults in early life alter one’s disease potential?

First, cell number and growth are exquisitely sensitive to their metabolic and hormonal milieu.

Undernourished animals and babies have reduced renal volumes and nephrons, which can result in hypertension. Autopsies of hypertensive humans who died in motor vehicle accidents have demonstrated reduced numbers of, but hypertrophic [larger], glomeruli.

Second, any stress can alter hormonal concentrations, hormone receptors, and hormonal responses. Receptors can be down- or up-regulated and mutations may result in structural transformations. Hormonal responses can be blunted, or exaggerated.

Consistent with this paradigm is the SGA [small for gestational age] child who later develops type 2 diabetes. These individuals have a reduced number and function of pancreatic β-cells resulting in decreased insulin production and consequently a high glucose/insulin ratio (Calkins, 2011, p. 5).

Critical period programming is one way in which early exposures steer particular organ systems, tissues and other physical systems in directions of relative dysregulation to support survival. Like Naviaux’ c. elegans that goes into freeze despite the cost, these shifts in regulation choose survival even though makes them more vulnerable to disease and future exposures to stress.

This is also what Naviaux refers to as the developmental timing factors that influence the type and direction CDR(s) can take during early development.

Brain function is another example of an organ system affected by prenatal stress and early stress. This includes the hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol and stress responses. The HPA axis is involved in the physiological abnormalities seen in ME/CFS and many other diseases:

Development of the fetal HPA axis …  is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit (Howland, 2017, abstract).

Timing of exposure during early life influences risk for specific health conditions and diseases. As seen with thalidomide, this means that timing of exposure influences risk for physical birth anomalies. It can also influence cell numbers, physiology and more to increase risk for chronic disease, mental health conditions, behavioral changes and more.

7. What about infections? Aren’t they a separate cause of ME/CFS (take the survey)?

Biological triggers (viral, bacterial, fungal/mold, and parasitic …) are among the most common triggers of ME/CFS, yet treating these infections is often not only difficult but even if seemingly successful, it often fails to cure the disease. What does this mean?

Why is it that some individuals get sick from common exposures, and cannot complete the healing cycle?

For example, Epstein-Barr virus (EBV) is a risk factor for ME/CFS. In the US, 82% of people have been exposed to EBV by the time they are 19 years old. If EBV is “the” cause, why do fewer than 1% of the US population have ME/CFS (Naviaux, 2018, p. 15)?

Naviaux explains that when infections trigger the onset of ME/CFS, symptoms arise because different bacterial, viral and other pathogens act as the final triggers that tip the body into a prolonged freeze-based cell danger response:

Although biological triggers were most common, no single infectious agent or other stressor was statistically more prevalent [in study patients with ME/CFS]…

Despite the heterogeneity of triggers [chemical, biological, as well as physical and psychological trauma], the cellular response to these environmental stressors in patients who developed CFS was homogeneous and statistically robust. These data supported the notion that it is the unified cellular response, and not the specific trigger, that lies at the root of the metabolic features of CFS (Naviaux, 2016, p. e5473).

Naviaux makes the case that even though infections are the most common trigger of ME/CFS, the onset of disease arises because of contributions from past exposures. These past events have already predisposed a hypometabolic CDR to become prolonged and these are the people who are at risk of developing chronic fatigue syndrome after further exposures:

[The] pre-exposure condition of the host determines a large fraction of the pathology of infection (Naviaux, 2014, p. 8).

Stress is a well-known risk factor for susceptibility to infection. We’ve also seen in the section on early experiences that greater contact between mothers and babies after birth is protective against infections. Early contact is also protective against infant deaths, duration of hospital stays when babies get sick, and more.

ACE studies also find that adversity in childhood may increase sensitivity to infections:

Childhood stressful events may increase [autoimmune diseases] independently as well as amplify the effect of other environmental factors, such as infections (Dube, 2009, p. 248).

In health, a virus, bacteria or other pathogen stimulates an acute CDR. It if successfully fights, defends and protects the body, the CDR goes through a healing cycle and resolves.

Naviaux explains that if the CDR is unsuccessful and unable to overcome the threat, it can get triggered into a prolonged hypometabolic state that leads to symptoms of ME/CFS:

Activation of the CDR sets in motion a powerful sequence of reactions that are tightly choreographed to fight the threat. These are tailored to defend the cell against either intracellular or extracellular pathogens, kill and remove the pathogen, circumscribe and repair the damage, remember the encounter by metabolic and immunologic memory, shut down the CDR, and to heal.

In most cases, this strategy is effective and normal metabolism is restored after a few days or weeks of illness, and recovery is complete after a few weeks or months.

In the case of CFS, when the CDR gets stuck, or is unable to overcome a danger, a second step kicks in that involves a kind of siege metabolism that further diverts resources away from mitochondria and sequesters or jettisons key metabolites and cofactors to make them unavailable to an invading pathogen, or acts to sequester toxins in specialized cells and tissues to limit systemic exposure. This has the effect of further consolidating the hypometabolic state (Naviaux, 2016, Question 2 in Q&A).

The role of past trauma, adversity and missing events or allostatic load may play a role in who is more vulnerable to infections, including to covid-19 and the process of recovery. But we have many unanswered questions.

Might people who develop ME/CFS after an infection have a history of more infections in early life and childhood rather than other environmental stressors? Might they be particularly sensitive to infections because of past exposures?  Research does not appear to have explored this question yet in any disease I am aware of.

This important topic can be further examined in Naviaux’ 2016 Question & Answers, especially in Questions 2 (which expands on the quote from above), 7 (potential negative effects of antibiotics on mitochondria), 8 (mitochondria can’t sustain 100% function towards defense against infections while also maintaining full energy production), 9 (Lyme), and 11 (doesn’t the positive impact of antivirals for some people prove ongoing latent infection and that viruses are the cause of ME/CFS?).

***Survey 4: When ME/CFS is Triggered by Infection

I’ve created this survey to get a sense of whether there are differences in exposure histories between people whose ME/CFS is triggered by infections and those whose disease is triggered by something else (or by unknown triggers).

* Please take the survey even if your ME/CFS was not triggered by an infection as it will help identify potential differences between groups.

You will see graphs of all the responses after you click submit.

Note: in the PDF and Kindle versions of this post you will find the survey in the appendix.

8. What about toxins?

Naviaux explains that chemicals and toxins act in the same way as infections and other environmental stressors in that they lead to ME/CFS because they trigger and prolong a hypometabolic CDR.

Physical disruption of gap junctions that connect and coordinate cell function in tissues can activate the CDR.

Other triggers include bacteria, viruses, fungi, protozoa, or exposure to biological or chemical toxins.

In all cases, extracellular ATP and other metabokines are released from the cell to signal danger. This happens through stress-gated pannexin/P2X7 channels in the membrane and through an increase in vesicular export of ATP through SLC17A9, the vesicular nucleotide transporter (VNUT), and related transporters (Naviaux, 2018, p. 4)

9. Why does ME/CFS sometimes begin immediately and other times months or years after an environmental exposure (or no known trigger at all)?

The CDR develops through repeated exposures to a variety of environmental stressors. The  exposures affect both the type of CDR that develops (hypometabolic or hypermetabolic) and the size and strength of the CDR.

There are at least 3 scenarios for onset of ME/CFS.

Rapid, Full Blown Symptom Onset Shortly After a Trigger. The sudden onset of ME/CFS implies a strong pre-existing CDR that is close to a tipping point of resetting to a system-wide CDR. This, in turn, suggests

1. a history of many exposures to stressors
2. a history of particularly strong or intense stressors in the past
3. a very significant final stressor that triggers ME/CFS
4. all of the above.

If the final trigger is relatively minor such as a small cold, a vaccine, or a slight fender-bender but ME/CFS starts very suddenly afterwards it suggests scenarios 1 or 2 above (or both).

If the final trigger is very severe, such as a car accident in which you are seriously injured or someone dies the prior history may not be as severe.

Gradual Onset. Those of us with gradual onset have likely had fewer exposures, exposures of lesser intensity, experiences of greater support and resources (which buffer effects of trauma and help the CDR resolve and heal), or a smaller trigger or set of triggers before onset. Symptoms may worsen slowly over time in such a situation in which the CDR is strong enough to cause symptoms but not so strong as to cause sudden, severe, debilitating effects. With continued exposures, however, the CDR may continue to strengthen and to simultaneously increase the severity of symptoms.

Delayed Onset. Sometimes ME/CFS develops months or years after exposure to an environmental stressor. The event(s) can be so long before onset that ME/CFS seems to come out of the blue. This is consistent with exposure to a combination of fewer or less intense prior exposures and triggers. It is consistent with a CDR that is evolving more slowly. Trauma science has recognized that such delays, seen in a small percentage of people who develop PTSD, occur because the defense response is still strengthening following the latest trigger (Yehuda, 2015).

Delays between exposures to environmental stressors and the onset of a chronic disease are common enough to have a name. They are referred to as latency periods. Latency periods are seen in type 1 diabetes, MS, Parkinson’s disease and other chronic illnesses.

In summary, the speed of onset of ME/CFS and the severity of symptoms is influenced by the aggregation of past experiences and how the status of the CDR at the time of exposure.

10. Are there Subsets of ME/CFS?

Naviaux does not answer this question directly but some of his findings suggest this to be possible and even probable. I make the following speculations based on some of Naviaux’ statements.

First, his team tested 63 metabolic pathways in his study of people with ME/CFS and the control group. 20 of the 63 pathways were abnormal and 80% of these pathways were found to be hypometabolic. But not all pathways were in the direction of freeze.

Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome (2016, Abstract).

Second, the abnormal hypometabolic pathways in people with ME/CFS showed a lot of variation between participants:

About 75% of the metabolite abnormalities were unique to the individual and useful in guiding personalized treatment (2016, p. e5478).

Third, there may be quite a number of pathways that combine to drive symptoms of ME/CFS:

The genotype and health of the host, and the developmental timing and the nature of the exposure determine the risk of developing a particular disease. In many cases, it appears that mixtures of cell danger exposures are required (Naviaux, 2014, p. 15).

The unique mixture of CDRs in each person with ME/CFS and the finding that 15% of the abnormal pathways are not hypometabolic, suggest that other CDR pathways exist. These may therefore be in any direction, including in the acute CDR, which is a hypermetabolic state of fight / flight.

Perhaps this explains why some people with ME/CFS have high blood pressure (a sympathetic nervous system response to threat), high resting heart rates, POTS, pain, brain fog etc, when others do not.

Another consideration may be that infections and other exposures that lead to ME/CFS stimulate other CDR pathways. Perhaps symptoms of ongoing infection, which do not occur in everyone with ME/CFS, are related to particular CDRs that have become prolonged to affect certain aspects of immune function in some individuals and not in others.

In Summary

The metabolic state of an individual at the time of illness is produced by both current conditions, age, and the aggregate history, timing, and magnitude of exposures to physical and emotional stress, trauma, diet, exercise, infections, and the microbiome recorded as metabolic memory (Naviaux, 2016, p. 1).

In Part III of this series about ME/CFS and Naviaux’ new paradigm of disease, I will present strategies on how to approach improvement and healing in ME/CFS. These approaches draw from the context gained by understanding factors that influence and prolong the CDR as well as what we are learning about what is needed for healing.

In the meantime, learn more about ways of healing the CDR and effects of trauma in my post 10 Tools and my list of therapies for healing nervous system perceptions of threat.

More of Naviaux’ research

Question and Answers 2016 (Updated Version)

Very Readable News Release about Naviaux CDR (2018)

Metabolic features of chronic fatigue syndrome (the 2016 ME/CFS study)’

Metabolic features of the cell danger response (2014 Introduction to the CDR)

Naviaux’ most detailed journal article about the CDR (2018)

Related posts on my blog

Part I; ME/CFS and Freeze: A Metabolic State of Hibernation That is Not in Your Head

The Cell Danger Response: The New Disease Paradigm

Adverse Childhood Experiences and Chronic Illness

#1 Early Trauma and Autoimmune Disease: Clues from Antibodies, Birth & Type 1 Diabetes

#2 Adverse Babyhood Experiences (ABEs): Clues from Asthma and Stress in Early Life

Healing Trauma, ME/CFS and Other Diseases

Therapies for Healing Nervous System Perceptions of Threat

Treating Chronic Illness: 10 Empowering Tools That Help You Heal

References

1. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 2016;113(37):E5472-80. doi: 10.1073/pnas.1607571113
2. Chandan JS, Keerthy D, Zemedikun DT, et al. The association between exposure to childhood maltreatment and the subsequent development of functional somatic and visceral pain syndromes. EClinicalMedicine 2020;2(42):1-9. doi: 10.1016/j.eclinm.2020.100392
3. Zhao LP, Alshiekh S, Zhao M, et al. Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes [abstract]. Diabetes 2016;65(3):710-8. doi: 10.2337/db15-1115 [published Online First: 2016/01/08]
4. Moore SR, McEwen LM, Quirt J, et al. Epigenetic correlates of neonatal contact in humans. Dev Psychopathol 2017;29(5):1517-38. doi: 10.1017/S0954579417001213
5. Burke MJ. “It’s all in your head”—Medicine’s silent epidemic. JAMA Neurolology 2019 doi: 10.1001/jamaneurol.2019.3043 [published Online First: 2019/09/17]
6. Dube SR, Fairweather D, Pearson WS, et al. Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med 2009;71(2):243-50.
7. Romens SE, McDonald J, Svaren J, et al. Associations between early life stress and gene methylation in children. Child Dev 2015;86(1):303-9. doi: 10.1111/cdev.12270
8. Wright ML, Yunfeng Huang, Qin Hui, et al. Parenting stress and DNA methylation among African Americans in the InterGEN Study. Journal of Clinical and Translational Science 2018 doi: 10.1017/cts.2018.3
9. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004;7(8):847-54. doi: 10.1038/nn1276
10. Naviaux R. Metabolic features and regulation of the healing cycle—A new model for chronic disease pathogenesis and treatment. Mitochondrion 2018;46:278-97. doi: 10.1016/j.mito.2018.08.001
11. Naviaux RK. Metabolic features of the cell danger response. Mitochondrion 2014;16:7-17. doi: 10.1016/j.mito.2013.08.006
12. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study [see comments]. Am J Prev Med 1998;14(4):245-58.
13. Mo C, Hannan AJ, Renoir T. Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington’s disease [abstract]. Neurosci Biobehav Rev 2015;52:178-92. doi: 10.1016/j.neubiorev.2015.03.003 [published Online First: 2015/03/15]
14. Madrid A, Morgan A, Taormina A, et al. The mother and child reunion bonding therapy: The four part repair. Journal of Prenatal and Perinatal Psychology and Health 2012;26(3):165-84.
15. Madrid A, Ames R, Horner D, et al. Improving asthma symptoms in children by repairing the maernal-infant bond. Journal of Prenatal and Perinatal Psychology and Health 2004;18(3):221-31.
16. Charpak N, Tessier R, Ruiz JG, et al. Twenty-year follow-up of Kangaroo Mother Care versus traditional care. Pediatrics 2017;139(1) doi: 10.1542/peds.2016-2063
17. Mahlknecht P, Seppi K, Poewe W. The Concept of Prodromal Parkinson’s Disease. J Parkinsons Dis 2015 doi: 10.3233/JPD-150685
18. Sepa A, Frodi A, Ludvigsson J. Mothers’ experiences of serious life events increase the risk of diabetes-related autoimmunity in their children. Diabetes Care 2005;28(2394-2399)
19. Shonkoff JP, Garner AS, Committee on Psychosocial Aspects of Child Family Health, et al. The lifelong effects of early childhood adversity and toxic stress. Pediatrics 2012;129(1):e232-46. doi: 10.1542/peds.2011-2663
20. McFarlane AC. One hundred years of lessons about the impact of war on mental health; two steps forward, one step back. Australasian Psychiatry 2015 doi: 10.1177/1039856215588211
21. Madrid A. The mother and child reunion: Repairing the broken bond. Monte Rio: Lulu Press 2010.
22. Lehrner A, Daskalakis NP, Yehuda R. Chapter 11: Cortisol and the hypothalamc-pituitary-adrenal axis in PTSD [uncorrected proof]. Posttraumatic stress disorder: From neurobiology to treatment: John Wiley & Sons, Inc 2016:265-90.
23. Yehuda R, Hoge CW, McFarlane AC, et al. Post-traumatic stress disorder. Nature Reviews Disease Primers 2015;October:150-57. doi: 10.1038/nrdp.2015.57
24. Calkins K, Devaskar SU. Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care 2011;41(6):158-76. doi: 10.1016/j.cppeds.2011.01.001
25. Sepa A, Ludvigsson J. Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation 2006;13(5-6):301-8. doi: 10.1159/000104858
26. Nygren M, Carstensen J, Koch F, et al. Experience of a serious life event increases the risk for childhood type 1 diabetes: the ABIS population-based prospective cohort study. Diabetologia 2015;58(6):1188-97. doi: 10.1007/s00125-015-3555-2
27. Tobi EWT, 1,2 Roderick C. Slieker,1 René Luijk,1,3 Koen F. Dekkers,1 Aryeh D. Stein,4, Kate M. Xu, 5 Biobank-based Integrative Omics Studies Consortium,* P. Eline Slagboom,1, Erik W. van Zwet LHL, 1,6† Bastiaan T. Heijmans1†‡. DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. 2018
28. Madrid A, Pennington D. Maternal-infant bonding and asthma. Journal of Prenatal and Perinatal Psychology and Health 2000;14(3-4 (Spring)):279-89.
29. Madrid A. Helping children with asthma by repairing maternal-infant bonding problems. Am J Clin Hypn 2005;48(3-4):199-211. doi: 10.1080/00029157.2005.10401517
30. Madrid A, Ames R, Skolek S, et al. Does maternal-infant bonding therapy improve breathing in asthmatic children? Journal of Prenatal and Perinatal Psychology and Health 2000;15(2):90-117.
31. Klaus MH, Jerauld R, Kreger NC, et al. Maternal attachment. Importance of the first post-partum days. N Engl J Med 1972;286(9):460-63.
32. Thernlund GM, Dahlquist G, Hansson K, et al. Psychological stress and the onset of IDDM in children. Diabetes Care 1995;18(10):1323-29.
33. Klaus MH, Kennell JH. Maternal-infant bonding. St. Louis: Mosby 1976.
34. Madrid A, editor. Repairing maternal-infant bonding problems. New York: John Wiley and Sons, 2007.
35. Yehuda R, Engel SM, Brand SR, et al. Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 2005;90(7):4115-8.
36. Hofer MA. Early relationships as regulators of infant physiology and behavior. Acta Paediatr Suppl 1994;397:9-18.
37. (BARC) BARCoTSaH. Pediatric ACEs and Related Life-Events Screener (PEARLS) [Available from: https://www.nppcacesmembers.org/screening-resources/pick-the-questionnaire/pediatric-aces-and-related-life-events-screener-pearls/ accessed February 6 2019.
38. Howland M, Sandman CA, Glynn LM. Developmental origins of the human hypothalamic-pituitary-adrenal axis. Expert Rev Endocrinol Metab 2017;12(5) doi: 10.1080/17446651.2017.1356222
39. Rappaport SM. Genetic Factors Are Not the Major Causes of Chronic Diseases. PLoS One 2016;11(4):e0154387. doi: 10.1371/journal.pone.0154387 [published Online First: 2016/04/23]
40. Finkelhor D. Screening for adverse childhood experiences (ACEs): Cautions and suggestions. Child Abuse Negl 2017 doi: 10.1016/j.chiabu.2017.07.016 [published Online First: 2017/08/09]
41. Luby JL, Barch D, Whalen D, et al. Association Between Early Life Adversity and Risk for Poor Emotional and Physical Health in Adolescence: A Putative Mechanistic Neurodevelopmental Pathway. JAMA Pediatr 2017 doi: 10.1001/jamapediatrics.2017.3009
42. McFarlane AC. Post-traumatic stress disorder is a systemic illness, not a mental disorder: is Cartesian dualism dead? Med J Aust 2017;206(6):248-49.
43. Bystrova K, Ivanova V, Edhborg M, et al. Early contact versus separation: effects on mother-infant interaction one year later. Birth 2009;36(2):97-109. doi: 10.1111/j.1523-536X.2009.00307.x
44. Wadhwa PD, Buss C, Entringer S, et al. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med 2009;27(5):358-68. doi: 10.1055/s-0029-1237424
45. Jason LA, Porter N, Herrington J, et al. Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Behav Neurosci Res 2009;7(2):1-17.
46. Craddock TJ, Fritsch P, Rice MA, Jr., et al. A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome. PLoS One 2014;9(1):e84839. doi: 10.1371/journal.pone.0084839
47. Daskalakis NP, Bagot RC, Parker KJ, et al. The three-hit concept of vulnerability and resilience: toward understanding adaptation to early-life adversity outcome. Psychoneuroendocrinology 2013;38(9):1858-73. doi: 10.1016/j.psyneuen.2013.06.008
48. Hurley D. Grandma’s experiences leave a mark on your genes: Your ancestors’ lousy childhoods or excellent adventures might change your personality, bequeathing anxiety or resilience by altering the epigenetic expressions of genes in the brain. Discover, 2013.
49. Peters A, McEwen BS. Introduction for the allostatic load special issue. Physiol Behav 2012;106(1):1-4. doi: 10.1016/j.physbeh.2011.12.019
50. McEwen BS. Brain on stress: how the social environment gets under the skin. Proc Natl Acad Sci U S A 2012;109 Suppl 2:17180-5. doi: 10.1073/pnas.1121254109
51. Hillenbrand L. A Sudden Illness: How my life changed. The New Yorker, 2003.
52. Maloney EM, Gurbaxani BM, Jones JF, et al. Chronic fatigue syndrome and high allostatic load. Pharmacogenomics 2006;7(3):467-73.
53. Poser CM. Pathogenesis of multiple sclerosis. A critical reappraisal. Acta Neuropathol (Berl) 1986;71(1-2):1-10.
54. Goertzel BN, Pennachin C, de Souza Coelho L, et al. Allostatic load is associated with symptoms in chronic fatigue syndrome patients. Pharmacogenomics 2006;7(3 %U http://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.485):485-94.
55. Sepa A. The stress hypothesis: Implications for the inducation of diabetes-related autoimmunity in children? Linkoping, 2004:89.
56. McEwen BS. Stressed or stressed out: what is the difference? J Psychiatry Neurosci 2005;30(5):315-8.
57. Hofer MA. Early stages in the organization of cardiovascular control. Proc Soc Exp Biol Med 1984;175(2):147-57.