This post, also a guest post on Cort Johnson’s Health Rising blog about chronic fatigue syndrome (aka ME/CFS), introduces the relationship between ME/CFS and freeze states. These occur in the nervous system, in our cells and in all kinds of tissues in the body (updated October 2020).
The science has finally arrived showing how it’s not “psychological” or “all in your head.”
This new paradigm of disease finds that chronic illness symptoms arise when a body gets stuck in a prolonged, physiological threat response that occurs
In this post I describe a 2016 study on the cell danger response as well as the clinically relevant and powerful science of polyvagal theory.
Both explain how a person with ME/CFS has a body that is caught in very real state that is a lot like hibernation or freeze.
As you’ll see, the science also applies to other chronic illnesses, including autoimmune diseases of all kinds.
Some diseases reflect bodies caught in survival states of fight and flight, while others, like ME/CFS, are from a body caught in a state of freeze.
The 2016 study is by Dr. Robert Naviaux, M.D, Ph.D, Professor of Medicine, Pediatrics and Pathology and director of the Mitochondrial and Metabolic Disease Center at UC San Diego identifying metabolic changes in ME/CFS and how it is a very real physiological state that is not psychological or “all in your head” (see Harvard physician, epidemiologist and professor specializing in ME/CFS Dr. Anthony Komaroff’s article in the July 5, 2019 volume of the medical journal JAMA which you can download for free a little farther down in this post).
Download Dr Naviaux’ freely available 2016 article on ME/CFS Metabolic State below (PDF):
A follow-up post cites research in epigenetics, brain development, embryology and more to explain how the cell danger response gets prolonged to affect risk for disease. The second post includes a FAQ and 4 surveys for people with ME/CFS.
The CDR mechanisms are relevant for over 100 diseases. I start here using ME/CFS as an example.
GET in FREE PDF or KINDLE
You can download the free pdf or kindle about the cell danger response using an example of ME/CFS. The new paradigm of disease applies to 100 other chronic illnesses including autoimmune diseases such as MS, type 1 diabetes, lupus, RA and more. The forms will appear momentarily.
Many health care professionals, family members, caregivers and researchers believe ME/CFS is a psychological illness despite the data that show otherwise.
When I write about the science of trauma in relation to disease in general, and to this disease in particular, many readers mistakenly interpret that I, too, am stating ME/CFS is in our heads or caused by a victim mentality.
This is the opposite of what I’m saying and I do not believe that chronic fatigue syndrome is in our heads, caused by negative thoughts, or run by psychological causes.
Many people with ME/CFS have at one time or another been blamed, shamed, judged and otherwise harmed by these mistaken beliefs, which suggest their illness is faked, due to personality flaws, caused by weakness, laziness, lack of will power or seeking attention, or for some other equally inaccurate reason. These views don’t believe or listen to what people are saying about their very real experiences of debilitating illness. And they don’t reflect the research. They are also deeply wounding.
As a result of these common misperceptions, I emphasize the fact and the scientific evidence explaining that ME/CFS is NOT PSYCHOLOGICAL throughout this post. This includes a quote from Dr. Robert Naviaux who also states this very clearly.
The following sections present some of the physiological underpinnings that drive ME/CFS. They also explain how and why the belief that it’s psychological is false and out of date.
ME/CFS: The Cause Remains Unknown
ME/CFS is a disease of extreme fatigue affecting an estimated 1-2.5 million people in the U.S. (and many more undiagnosed) that involves multiple organ systems, often results in profound disability, and has no unifying understanding of cause nor treatment.
In addition to fatigue, characteristic symptoms of ME/CFS include:
- worsening of fatigue and other symptoms with mental or physical activity
- difficulty recovering with rest
- symptoms not the result of excessive exertion (even if activity increases symptoms)
- problems with memory and thinking (cognitive dysfunction often referred to as brain fog)
- sleep disturbance
- worsening with standing or sitting (orthostatic intolerance)
- chronic or intermittent pain in joints, muscles; headaches
- interstitial cystitis
- irritable bowel syndrome
- subnormal body temperatures and cold extremities, intolerance of extremes of hot or cold
- sensitivities to foods, odors, chemicals, light, noise
- and more (see IOM / CDC diagnostic criteria, Canadian Consensus criteria)
- cerebral cytokine dysregulation
- increased cytokines with increased severity or duration of ME/CFS
- natural killer cell dysfunction
- microbiome abnormalities
- abnormalities in metabolism and metabolites (Naviaux, 2016)
- widespread inflammation in the brain (Younger)
- increased lactate in the brain (lactate occurs with anaerobic metabolism) (Younger)
- reduced brain blood flow and brain volume, small brain lesions
- Th1/Th2 Imbalance (see more here and here)
- a subset of people with ME/CFS have slightly low cortisol levels
- autoimmune activity (at 17:25) in cerebrospinal fluid against adrenergic receptors (often associated with epinephrine and norepinephrine in sympathetic nervous system activation) and acetylcholine receptors (often linked to parasympathetic activity)
See this clear, concise summary article by Harvard physician, professor and epidemiologist Dr. Anthony Komaraoff, who has believed in the very real nature of this disease and in looking for underlying causes since the 1980s. It’s an excellent article to give to your doctor if you are looking to give them practical, validating, respectable information about ME/CFS. It includes references to Naviaux’ cell danger response and ME/CFS research showing that it reflects a metabolic state of hibernation as well as some of the abnormalities mentioned above.
You can download the article to educate your doctor, family, friends, colleagues and others below:
ME/CFS Is Not Psychological
The perspective that ME/CFS is psychological is false and out of date
Because ME/CFS has no diagnostic test and remains diagnosed by symptoms that cannot be objectively measured, many doctors and other health care professionals still believe it is psychological and not a “real” disease.
Many with ME/CFS have been or are still told their illness is “all in their heads,” caused by mental health conditions such as depression, malingering, a personality flaw or unhelpful beliefs, and more.
Findings such as those delineated above, new studies in epigenetics and other fields of study, and metabolic abnormalities identified by Dr. Naviaux in the study presented here, explain how this perspective is inaccurate and out of date.
Graded Exercise (GET) & Cognitive Behavioral Therapy (CBT) are not appropriate
Following a single highly flawed and discredited study called the PACE trial, graded exercise (GET), pacing, and cognitive behavioral therapies (CBT) became the single dominant treatment recommendations for ME/CFS by the medical profession and the Centers for Disease Control (CDC).
While these approaches can be supportive in the management of life with any chronic illness, exercise is a characteristic trigger of flares and worsening of fatigue and other symptoms of ME/CFS. Together with CBT, graded exercise inaccurately suggests the underlying causes of ME/CFS and other diseases are psychological, psychosomatic or “functional.” ie: that the illness is not “real.”
These recommendations elicit an appropriate response of concern, anger, disbelief and distrust by people with ME/CFS, and rightly so.
As you’ll see, polyvagal theory, Naviaux’ cell danger response theory, and trauma science present a very different understanding as well as recommendations for working with and healing ME/CFS.
* Effects of trauma are not psychological
While any reference to psychological or physical trauma as a potential risk factor for ME/CFS and other chronic illnesses often leads health care professionals, patients, family members and western culture at large to believe a disease is likewise psychological, this perception is mistaken and no longer tenable. It is also traumatizing.
The science of traumatic stress, neurobiology, epigenetics and more demonstrate that subtle and overt types of trauma and adversity directly alter physiology, cell function, metabolism, immune and nervous system function and other organic and biological activities. Adverse life experiences increase risk for autoimmune and other chronic physical diseases, among many other effects. Psychological symptoms are a separate symptom of trauma and not the cause of these other effects (Ridout, 2018).
To restate this important distinction, the effects of trauma include psychological symptoms such as depression, anxiety and PTSD. Trauma ALSO independently affects risk for chronic physical diseases of all kinds.
Naviaux’ Study: Shattering the Myth That ME/CFS is Psychological
In 2016 Robert Naviaux, M.D, Ph.D, Professor of Medicine, Pediatrics and Pathology and director of the Mitochondrial and Metabolic Disease Center at UC San Diego and his team rocked the chronic fatigue syndrome (ME/CFS for myalgic encephalitis) world. They had just identified 20 metabolic pathways in people with ME/CFS that were markedly different from healthy controls (here’s his slide show).
In their study, Metabolic features of chronic fatigue syndrome, Naviaux explained how these biological pathways were those of the cellular defense response (CDR). This is the survival response of a healthy organism to threats such as infection, lack of food or oxygen, or cold and other dangers (Naviaux, 2016).
“The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis (Naviaux, 2014).
80% of the abnormal metabolites Naviaux found in ME/CFS were part of the CDR pathway. Intriguingly, they were in the opposite direction to the usual CDR response.
In the study, beautifully summarized by Cort Johnson at Health Rising (an ME/CFS blog), Naviaux explained how these metabolites in ME/CFS were similar to those found in very low metabolic states.
- Naviaux explains the particular state of “dauer” identified in the ME/CFS study is similar, although not exactly the same as hibernation
The metabolites of hibernation are well known from studies of c. elegans, a worm that adapts to life-threatening situations such as insufficient food or oxygen, drought, and other environmental stressors that cannot be overcome by mobilizing, with the death-like state called “dauer.”
Dauer, like hibernation, is a means of preserving survival by severely curtailing functions of ordinary life such as energy, digestion and movement (Naviaux, 2016, p. e5477).
Naviaux added that:
“Similar to dauer, CFS appears to represent a hypometabolic survival state that is triggered by environmental stress.
The study found that triggering events for ME/CFS fell broadly into five groups (p. e5473):
- biological (viral, bacterial, fungal/mold, and parasitic infections)
- chemical exposures
- physical trauma
- psychological trauma
The specific biological and chemical exposures and the precise nature of the physical and psychological traumas were diverse, numbering more than a dozen in just this small sample. Several patients had multiple triggers that converged in the same year.
Although biological triggers were most common, no single infectious agent or other stressor was statistically more prevalent (2016, p. e5473).
Naviaux explains that ME/CFS is not directly caused by these triggers, not even by toxins or infections as common as Epstein-Barr virus or Lyme. Rather, when a body is exposed to these triggers and goes on to develop ME/CFS, it’s is due to an activation of the cell danger response.
These different environmental stressors, in other words, trigger a similar hibernation / freeze cell danger response in people who go on to develop ME/CFS. Just like they do in c. elegans.
Only a small percent of people who are acutely infected with Epstein-Barr virus (EBV) or human herpes virus 6 (HHV6), or Lyme disease go on to develop chronic symptoms. If the CDR remains chronically active, many kinds of chronic complex disease can occur.
In the case of CFS, when the CDR gets stuck, or is unable to overcome a danger, a second step kicks in [after the body has worked to fight off the infection and you have maybe been sick for days, weeks or months] 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 (2016, FAQ).
Naviaux is saying that the effects of these infections and toxins are real but that they lead to ME/CFS because they trigger a particular pattern of the cell danger response in those who develop ME/CFS.
Despite the heterogeneity of triggers, 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 (2016, p. e5473).
So for anyone who developed ME/CFS after an infection or exposure to a toxin such as mold, their body may have been directly affected by the exposure, but the illness arose because of the CDR and all this entails, including potential difficulty getting rid of the infection or toxin.
As Naviaux described in their Q&A document, this is not because ME/CFS is psychological (2016):
Q1. Some people still argue that CFS is not a real illness but all in the mind. Does your discovery of a chemical signature help shatter this myth?
“Yes. The chemical signature that we discovered is evidence that CFS is an objective metabolic disorder that affects mitochondrial energy metabolism, immune function, GI function, the microbiome, the autonomic nervous system, neuroendocrine, and other brain functions. These 7 systems are all connected in a network that is in constant communication. While it is true that you cannot change one of these 7 systems without producing compensatory changes in the others, it is the language of chemistry and metabolism that interconnects them all [read more].
Q1.1. If you found that CFS is caused by chemical changes, why do you ask about childhood trauma in your new questionnaire for the expanded CFS metabolomics study? The questions made me think you were just like all the other doctors who told me that CFS was all in my head?
“The answer to this question has several layers. Perhaps the most important is founded on our discovery that the brain controls metabolism. Any factor that causes a chronic change in how the brain works will produce objective chemical changes in the blood.
Reciprocally, any chronic change in any of the 7 systems listed in Q1 will produce compensatory chemical changes in the blood that are coordinated by the brain, but can also change brain function.
Profound personal loss, grief, depression, fear, chronic pain, anxiety, and PTSD all cause chemical changes in the blood that we can measure with metabolomics …
We are trying to study this chemistry of risk objectively. The science behind the expanded CFS metabolomics study demands that we ask both CFS subjects and normal controls about psychological trauma to see if this can increase the susceptibility to CFS later in life, and to see how previous trauma might influence current metabolomics.
Here are insights into why people with ME/CFS can experience states of hibernation. How it is possible to have gotten to a state that feels death-like. And why it can be so very difficult to recover.
You’ll learn about science that supports and expands on Naviaux’ findings, which is that there is a deep, very real physiological basis for prolonged states of metabolic hibernation. And add more context into why ME/CFS is no more psychological, or all in our heads than the state of dauer is for c. elegans or states of hibernation are in bears.
I incorporate areas of study Naviaux refers to in his articles, which include brain development, neurobiology, and epigenetics.
I also reference the science of traumatic stress, which offers especially pertinent insights into the effects of environmental stressors such as infections, toxins as well as adversity on long-term health, including risk for states of hibernation. And how these effects are intelligent, biological, epigenetic and not about simple stress.
To restate this important distinction, the effects of trauma are not psychological. Even as it is possible to experience a chronic disease caused by physiological processes as the result of trauma. Even as it is possible to simultaneously also experience psychological symptoms such as depression, anxiety or PTSD from the same or different past trauma.
The science that has been overlooked in medicine offers insights that help explain why the cell danger response can go towards hypometabolism and get stuck there to cause ME/CFS in some people.
I never heard of this science as a doctor. It has helped me gain a new understanding and respect for autonomic nervous system function and made sense of my ME/CFS (as well as autoimmune diseases such as type 1 diabetes, MS, RA and other illnesses, including mysterious illnesses and what author Sarah Ramey compassionately and compellingly, with humor and insight, refers to as WOMIs and MOMIs – women with mysterious illnesses and men with mysterious illnesses – in her 2020 memoir that comes to similar conclusions as presented here).
Here’s what is being learned about how human bodies orient and respond to threat and how this can set individuals up with CDR pathways leading to states of dauer, hibernation, and freeze.
It starts with the autonomic nervous system and how its main goal is to maximize survival, even when the cost is high. This research is very slowly beginning to change the face of health care, even as it has a long way yet to go (National Research Council and Institute of Medicine, 2000; Shonkoff, 2012; Chitty, 2013).
Autonomic Nervous System Survival Strategies
As Naviaux explains, the CDR is not a new concept.
“The concept of the cell danger response … has evolved from a confluence of six rivers of scholarship that have developed in relative isolation over the past 60 years (2014, p.8).
Furthermore, the CDR is regulated by our autonomic nervous systems:
“The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem (2014, p. 8).
While individual cells and tissues can mount their own defensive responses to infection, physical wounds (such as surgery or physical trauma), toxins and other threats, the nervous system gets involved when the cell defense response becomes stuck and affects the whole body, such as in ME/CFS.
Our autonomic nervous system (ANS) manages and regulates physiological functions such as blood pressure, heart rate, temperature, immune activity, digestion, mitochondrial function, energy levels, metabolism and more. It supports these functions by directing cellular, metabolic and other underlying processes in our physiology in certain times, such as in those that involve many organ systems and chronic illness.
And it does so outside of our conscious control or awareness.
One of the branches of the autonomic nervous system (ANS) can cause hibernation-like states in humans. It originates in the brainstem, which is where the CDR is regulated.
It is one of three branches of autonomic nervous system, all of which interact with one another to influence short and long-term health. Here’s an overview of the three branches, starting with fight and flight of the sympathetic nervous system, which is linked to Naviaux’ CDR.
Naviaux also writes about these three branches of the nervous system, which are described below, and how the CDR is the source of over 100 diseases identified so far (see Table 1, including ME/CFS, POTS, fibromyalgia, MS, RA, Inflammatory bowel disease, Sjogren’s, diabetes and more). The italics are mine for clarification (Naviaux, 2018, p. 11):
When the CDR is chronically activated, the coordination between the two limbs of the vagus [VVC and DVC] is disrupted. This results in disinhibiting the sympathetic nervous system [ie: no longer inhibiting fight flight reactions] and the hypothalamic-pituitary-adrenal (HPA), which dominate during illness.
- Chitty: Chapter 6, (2013)
- Fredrickson (2013)
- Levine, Chapter 4, (2010)
- Ogden, Chapter 5, (2006)
- Porges (1992, 1995, 2001, 2004, 2009)
- Schore (1994, 2001)
Sympathetic Nervous System (SNS) Fight / Flight
We are most familiar with the sympathetic branch of the autonomic nervous system, which is the branch that can feel like having a foot on the gas pedal. The sympathetic nervous system enables us to take action in everyday life, and also in the event of threat.
In danger, we can fight, chase off the predator, or flee the hurricane.
In the first minutes and hours of a fight flight responses to stress, our bodies release adrenaline, increase blood pressure and heart rate, augment body temperature and breathing, enhance blood sugar availability to fuel muscles for fighting and fleeing, and increase our immune response (Dhabhar, 2018). This is all aimed at maximizing energy levels to support fight and flight.
And it is all part of the healthy cell danger response.
These changes optimize our ability to survive through escape mechanisms and by warding off infections, healing wounds by clotting more efficiently, and increasing speed and strength.
“[The CDR is a] coordinated set of cellular responses … that evolved to help the cell defend itself from microbial attack or physical harm … and at its most fundamental and most ancient role: to improve cell and host survival after viral attack (Naviaux 2014, p. 7).
The actions of the acute fight flight response are consistent with Naviaux’ acute cell danger response, which is the opposite of what he found in ME/CFS (paraphrased from his 2016 article on ME/CFS):
The acute CDR is found in acute infection, during acute inflammation and in the metabolic syndrome (a cluster of conditions that include high blood pressure, high cholesterol, insulin resistance and high blood sugar levels, and increased fat around the waist area. These symptoms, also known as Syndrome X, are associated with increased risk for heart disease, stroke and diabetes).
In this acute sympathetic nervous system response, our bodies also decrease or suppress functions that aren’t important for immediate survival, such as digestion and rest.
If stress continues for a long time, an increased degree of fight flight arises in which cortisol is released, the immune system is suppressed, inflammation rises and symptoms can occur.
In health, our bodies return to baseline when the stressor goes away or the threat disappears.
In health, at rest, and in play and safety, the sympathetic nervous system coordinates with the other branches of the autonomic nervous system to constantly tweak and maintain just the right levels of blood pressure, heart rate, oxygen consumption, mitochondrial function and other basics that support our ever changing activities of daily life.
In some circumstances, which I’ll discuss later, the sympathetic nervous system remains turned “on” and this acute CDR contributes to disease (Naviaux, 2014).
The Social Nervous System (“The Vagus”)
As introduced in an earlier post by Tim Vaughan on Health Rising, psychophysiologist Stephen Porges’ polyvagal theory shows that the parasympathetic portion of the autonomic nervous system is comprised of two branches rather than one.
This more evolved branch of the parasympathetic nervous system is present in mammals and humans and is called the social nervous system or the ventral vagus complex (VVC).
The social nervous system is regulated by the parasympathetic nervous system branch called the ventral vagus complex because of where it originates in the brainstem (in the nucleus ambiguous on the ventral or belly-like surface of the brain in the brainstem). Also known as Cranial Nerve X (Ten), the ventral vagus travels from the brain to the facial muscles down to the gut.
It is the faster of the two branches and supports safety and survival in the most metabolically energy efficient capacities we have: those of connection and communication.
If you’ve heard of the ventral vagus, it’s because it is “The Vagus” we refer to when we:
- incorporate mind body practices such as yoga nidra, mindfulness, or meditation to protect or improve our health
- use vagal stimulation as a treatment tool
- take up a hobby or other activity for pleasure
- go on a vacation to slow down and catch our breath
In health, our social nervous systems are in charge of autonomic nervous system functions and can inhibit fight, flight as well as freeze.
A healthy ventral vagus allows us to connect to ourselves and the world, and to empathize and bond with others, which supports safety through numbers and strength. It also enables people to read others’ facial expressions to assess whether they are safe to approach or should be avoided. This is all part of a highly evolved and built-in survival mechanism.
The ventral vagus allows us to sense into our gut feelings that warn us of safety vs danger, and to communicate using energy-sparing actions through our voices, gestures and facial muscles that show and express our feelings and boundaries.
Through the ventral vagus, for example, babies draw their parents towards them with their big, curious, beautiful eyes, their smiles, and their cries of hunger or discomfort. In health, babies pull at our heart strings to elicit bonds of love and the desire to nurture and protect them. This is all facilitated by the ventral vagus, which stimulates behaviors (cooing, smiling, eye contact), hormones (oxytocin and vasopressin), feelings (love, comfort, pleasure) and more that support feelings of love in both babies and their parents.
This is important because human babies and mammals are born at a very immature stage of development, when it is critical to draw in the proximity and care of adults as a requirement for survival.
Children and adults communicate affection and form protective, supportive alliances through touch, a smile or a conversation. These are actions of the ventral vagus. The social nervous system also supports our defenses with verbal boundaries like “no” or gestures, such as hand signals inviting approach or conveying “stop.”
The social nervous system facilitates all of these functions through the nerves that connect to our eyes, ears, mouths and facial muscles, to our hearts and voices, and through our endocrine, immune and other organ systems.
The ventral vagus makes survival and defense actions possible by placing a gentle brake on our baseline heart rates, which helps us feel more connected and relaxed. This occurs at the cellular and physiological levels and can often be enhanced through mind body practices.
Defenses that use words, eye contact and gestures are energy efficient.
Babies avert their gaze and look away when they are getting too much input, signaling the communicator to stop or slow down. When you talk someone down from raging at or firing you rather than fleeing the office, you are engaging your ventral vagus. The same is true when you stay present and engaged in the middle of a heated or painful argument with a spouse rather than attacking them physically, or disappearing (which would be sympathetic nervous system functions of fight and flight). Our ventral vagus also enables us to use the tone of our voices, such as to soothe a baby who is distressed or calm down a scared animal so that it doesn’t attack. And you may signal “stop” to a stranger who is approaching closer or faster than you are comfortable with before deciding if you need to flee.
This is the way of the social nervous system.
In health, the ventral vagus gently suppresses fight and flight unless it’s truly needed.
In health, our ventral vagus subtly immobilizes us so we can hold still long enough to make love, bond, or snuggle with and care for our babies and children – which is how the most vulnerable among us engage protection through connection.
In health, the ventral vagus can release its gentle brake so our heart rates can rise a little for activities such as standing, walking and playing. This enables us to shift gears without resorting to the higher energy functions of SNS fight and flight systems with releases of adrenaline or cortisol.
The ventral vagus is a critical player in keeping us healthy through energy efficient means.
When ventral vagus functions get interrupted, however, we can end up in states of prolonged fight and flight, hibernation and freeze, or some combination of both.
This is what happens when we have an illness like ME/CFS and feel as though we have one foot on the gas and one foot on the brake. It means that we each have our own, unique, individual version of the same disease. I’ll discuss this a little more after the next section on the freeze response.
The Parasympathetic Nervous System (PNS) Freeze / Hibernation
If you’ve ever gotten light-headed or fainted at the sight of blood or at the sight of a needle (Bracha, 2004), felt as though everything went into slow motion; felt rooted to the ground and unable to move, such as during or after a stressful or scary event (hearing a loud, unexpected sound; witnessing something horrifying; surviving a car accident), you’ve experienced a moment of physiological “freeze.”
As you know, this state was not something you did on purpose, through conscious control, or to “get attention.”
This state is facilitated by the branch of the PNS that acts as a brake in an even stronger manner than the ventral vagus.
Going into states of freeze happens when our other two forms of self protection, fight flight and tend and befriend, described above, are either unsuccessful or unlikely to succeed.
Like c. elegans and other living creatures, shutting down and going into hibernation and other freeze-like hypometabolic states is a CDR pathway designed to maximize survival when fighting, fleeing and connecting are not available options.
As Naviaux asserts in his 2016 article, the state of freeze
is an evolutionarily conserved, genetically regulated, hypometabolic state similar to dauer that permits survival and persistence under conditions of environmental stress but at the cost of severely curtailed function and quality of life (2016, p. e5477).
In other words, the option to freeze has persisted in life forms of all kinds as an evolutionary adaptation to maximize survival.
As mentioned in this video of an opossum in freeze, states of freeze are neither psychological nor manufactured.
In states of freeze, our bodies use the same physiology and produce the same metabolites as c. elegans when it goes into hibernation to wait out a threat it cannot successfully outrun or outgun.
States of freeze and hibernation are facilitated by the second branch of the parasympathetic nervous system, the dorsal vagal complex (DVC).
The dorsal vagus, like the ventral vagus, originates in the brainstem (Porges, Chitty).
The Dorsal Vagal Complex (DVC)
In health, the dorsal vagus interacts with the other branches of the autonomic nervous system and uses its braking function to gently decrease blood pressure, heart rate, and oxygen use. It supports digestion so that we are operating at maximum efficiency, just like an air conditioner that turns on and off to maintain a comfortable temperature rather than perpetually staying on and making it too cold.
In health, the dorsal vagus coordinates its functions with the social nervous system branch and the sympathetic nervous system to support changes in activity levels that takes us from activity to rest, eating to digesting, and back.
In health, the dorsal vagus functions to help us feel calm and available for play and work and rest.
Under threat, the dorsal vagus intensifies its brake.
Even more than fight and flight, the state of freeze is not a conscious choice. It is not a psychological ploy. It is an unconscious autonomic nervous system response of last resort in circumstances we are relatively helpless to address and towards threats that cannot be overcome.
In freeze, the opossum’s heart rate, blood pressure and body temperature actually go down (Gabrielsen, 1985).
These aspects of the freeze state are what the opossum and many other creatures have evolved as a primary defense strategy to fool predators into thinking they are already dead. Predators are less likely to attack when prey is unmoving and already looks dead.
In freeze, our own blood pressure, heart rate, temperature and oxygen levels can also go down. We may feel slow or foggy headed; we may disconnect and watch the event unfold as if we’re standing outside of our bodies or watching from the ceilng; or we may feel numb, limp or unable to move. We may also feel exhausted or too weak to stand.
Freeze states can also flood a body with feel-good hormones and numbness or even euphoria. This is nature’s way of supporting humans (and other animals) so that the pain of a broken bone or a physical assault do not prevent trying to escape and engaging fight and flight if an opportunity arises.
When humans experience states of freeze, our physiologies use the same CDR pathways as opossums and bears and c. elegans.
In freeze / hibernation, our bodies divert energy from eating and digesting to hunkering down and conserving as many resources as possible. Just like c. elegans.
As in c. elegans, the dorsal vagal complex takes humans into states of freeze when other options for survival in the face of threat aren’t available. Our bodies can also go “dorsal vagal” if we’ve had experiences of being unsuccessful at surviving or escaping using fight, flight or ventral vagal functions in the past.
Naviaux explains that dauer / freeze / hibernation physiology occurs as an intelligent strategy, not as a random mistake, mutation or a problem with faulty hardware or software:
- Entry into dauer confers a survival advantage in harsh conditions.
- Entering a hypometabolic state during times of environmental threat is adaptive, even though it comes at the cost of decreasing the optimal functional capacity.
- When the dauer response is blocked by certain mutations, animals are short-lived when exposed to environmental stress (p e5477).
In other words, when the freeze response is not an option, we don’t live as long.
This is the definition of Dauer, which means “persistence or long-lived in German” (Naviaux, 2016, p. e5477).
As Naviaux further explains, when we live in states of relative freeze for prolonged periods, it comes with a recognizable set of changes in our bodies and physiologies.
Dauer is comprised of an evolutionarily conserved and synergistic suite of metabolic and structural changes.
This state makes it possible to live efficiently by altering a number of basic mitochondrial functions, fuel preferences, behavior, and physical features.
Changes linked with hypometabolism run in the opposite direction of the acute CDR (Naviaux, 2016), which, as mentioned earlier, is consistent with sympathetic states of fight and flight.
The metabolites Naviaux identified in ME/CFS patients reflect a fundamental reset in our physiology (to use Cort’s term) that is consistent with freeze. This pathway, opposite to the acute CDR, includes the following:
- energy conservation and death-like states whose primary goal is survival despite the cost
- organism geared towards survival via inaction rather than action, to wait out overwhelming threat
- altered Th1/Th2 imbalance
- decreased immune system ability to fight infection
- loss of antibacterial and antifungal activity
- a “decrease in the ability to restore high-energy phosphate stores after exertion” (this relates to mitochondrial ATP and energy production)
- normal or low blood pressure
- aversion to glucose as a fuel with preference for fat as a fuel (Naviaux, 2016; Lant, 2010) [this suggests why people with ME/CFS may do better with ketogenic diets that use fat as the primary fuel]
- loss of intestinal mucosal integrity and leaky gut
- decreased gut absorption as part of a hypometabolic survival response
- changes in DNA methylation and histone modification that alter gene expression (epigenetic changes, Naviaux, 2014. p. 10)
- stress-induced cholesterol pathways, which are different from routes used in health
- altered mitochondrial function and the finding that:
Mitochondria represent the front lines in cellular defense and innate immunity … Their rapid metabolism makes [them] “canaries in the coal mine” for the cell.” (Naviaux, 2014, p. 9-10)
Low cortisol is another shift that happens as part of nervous system response to threat. Low cortisol is common in late phases of PTSD and in adults with a history of adversity in childhood as well as in their parents’ lives.
Cortisol is measured as part of a physiological / biological response. Like other physiological effects of environmental stressors including psychological trauma and adversity, it is not a psychological effect but a biological effect.
Low cortisol is seen in many chronic diseases such as fibromyalgia, cardiovascular and gastrointestinal diseases, rheumatoid arthritis, psoriasis, and thyroid disease (Lehrner, 2016, p. 268).
Low levels of cortisol are not a problem of adrenal exhaustion but the result of a body responding to prolonged threat in a directed rather than accidental way.
To reiterate, just like Naviaux’ findings, this physiological response is not a psychological effect of trauma. It is one that is driven by changes in the nervous system and linked to unconscious, unresolved perceptions of threat.
Naviaux explains that the high cost of being in a prolonged state of freeze, hibernation or dauer expresses itself as symptoms.
The changes in function listed above translate to many of the problems that are well-known characteristics of this disease.
The dorsal vagal survival state
- reduces energy levels to death-like states
- inhibits mobilization at cellular, mitochondrial, and other physiological levels.
- conserves energy by suppressing states of fight and flight.
Freeze states in humans also inhibit the social nervous system.
Low blood pressure, exhaustion, and other altered physiological processes are all NORMAL aspects and functions of the state of freeze. They are aimed at reducing the body’s energy consumption in order to preserve life as long as possible while we outwait the threat.
So what Naviaux is saying, and what research in the cell danger response and into polyvagal theory and hypometabolic states is saying, is that while the following signs and symptoms can occur in a chronic illness like ME/CFS and are all entirely real, these are not the CAUSE of ME/CFS.
In other words, a hypometabolic cell danger response is an intelligent, physiological, biological, chemical and epigenetic process that has gotten prolonged.
It is a state that has gone from a single location, group of cells, or tissue alarm to a system-wide state of defense that is guided and directed by the nervous system and by functions within our cells.
As a result, ME/CFS, like type 1 diabetes, POTS, fibromyalgia, celiac disease, MS, lupus, asthma, Parkinson’s, autism, Alzheimer’s and a 100 other diseases that Naviaux refers to, reflects a nervous system pattern that is deliberately inciting one or more different types of cell danger responses and all the changes this entails.
ME/CFS is therefore
- not caused by adrenal exhaustion even as adrenal function can be low (low adrenal function supports states of freeze while high function is supportive of fight/flight; both or alternating functions can be seen in ME/CFS)
- not due to a thyroid that is out of whack even as our thyroid activity may be low (low or high thyroid activity supports states of freeze and low energy or fight / flight for survival)
- not primarily from a lack of Vitamin D, nutrients or building blocks that enable mitochondria to function well even as these states can cause symptoms (we may have low building blocks because of poor absorption but many, such as Vitamin D, are intentionally low because the body is more or less sensitive to them in states of freeze, is conserving energy by not producing chemicals that are not absolutely necessary for survival, or is actively removing molecules and chemicals in order to create and preserve a freeze state that needs these factors to be low or absent for optimum function and self-protection) [Naviaux, 2014]
- not directly the result of leaky gut (cell walls in the body and gut are intentionally less boundaried during states of dauer / freeze / hibernation)
- and so on
The question in ME/CFS thus becomes, how do humans get stuck in a state of ME/CFS and freeze, especially if there’s no obvious threat in the present or at the time of onset?
This is where the science of traumatic stress offers important clues. This draws from research findings that most health care professionals and medical care have not yet caught up with – which includes the finding that ME/CFS and freeze are effects of environmental stressors even as they are not psychological.
Individual Expressions of Freeze and CDRs (“Tired” vs “Wired and Tired”)
There are many different versions of freeze and combinations in which freeze can be the dominant problem manifesting as disease and other symptoms.
Tired or more “Pure Dorsal Vagal”
Some types of freeze are the collapsy, death-like, shock-like states that Dr. Peter Levine refers to as “fold,”( p. 49) and that others describe as “faint,” along with many other terms such as shock etc. These states are characterized by feeling tired / exhausted / death-like , having low body temperature, low blood pressure etc, and are the more “pure” form of just the hypometabolic CDR or dorsal vagal state. There are additional variations of freeze I don’t go into here.
Some people with ME/CFS are more purely dorsal vagal.
In addition to the physiologic / immune / gut and metabolic abnormalities mentioned elsewhere, the dorsal vagal state can show up in behaviors, emotions, relationships, dreams as well as in other ways. This is, to be clear, not because it is psychological but because the effects of environmental stressors on nervous system function influence all types of health.
As one example, I regularly had dreams of being completely immobilized for many decades. These night terrors started in childhood long before the onset of my ME/CFS. I would awaken within the dream, thinking it was real, and feel terrified but unable to move, cry out, or wake myself up (dorsal vagal state). I had this dream regularly well into adulthood and it only gradually began to change as I began to heal my unconscious nervous system perceptions of threat. My sleep paralysis states started to shift in parallel with improvements in my ME/CFS.
After a while, in these dreams, I started being able to wake myself up with some effort. Over time, while still in the dream, I was able to sometimes make a sound (social nervous system) and eventually to begin to move. At first, these movements were slow, rubbery and without strength (still a dorsal vagal response).
Eventually I was able to mobilize and run in some dreams. In others I was actually able to strike the attacker in a solid, strong, effective way (sympathetic fight / flight). It’s been a long time now since I’ve had any versions of this dream and my ME/CFS is doing much better as well.
Wired and Tired: A Combination of Freeze and Underlying Fight/Flight
Other people experience a combination of both fight / flight AND freeze, in which freeze is the dominant and most visible form and set of symptoms, but suppresses an underlying state of heightened fight /flight.
This makes some people with ME/CFS feel both wired AND tired at the same time.
If you have ME/CFS and also have high blood pressure, diarrhea instead of or in addition to constipation, the metabolic syndrome with insulin resistance or high cholesterol or being overweight etc, or if you tend to feel more “wired and tired” than “tired,” this is consistent with a freeze state that dominates over a state of overactive fight/flight.
This is an example of a system that has components of both types of CDRs: both the hypometabolic and the acute CDR sympathetic nervous system response.
This is what is seen in the gazelle that suddenly shifts from running at full tilt (sympathetic flight) and collapses just before the cheetah pounces on her (dorsal vagal fold).
Her body shifts into parasympathetic when her nervous system perceives that she cannot survive the chase by running. Her nervous system tells her body to shut down, she collapses and immobilizes, and this provides a numbness and disconnection that make death painless, even if she gets munched.
Underneath this immobility, however, her body is primed to go from 0 to 60 in a moment’s notice should the cheetah get distracted long enough for her to escape (you see an example of this shift out of immobility to escape in this video of the gazelle).
Naviaux does not talk about this combination of CDRs in his 2016 article but does refer to 3 different types of disease states based on which type of CDR and which stage of healing the body is in (2018). Such mixed states are well known in the trauma literature.
Oscillating Between Freeze and Flight/Flight
While some people with ME/CFS have symptoms that are predominantly purely dorsal vagal or dorsal vagal combined with fight flight, some oscillate between various combinations of fight flight, and freeze / faint / fold.
This has been found in PTSD research, where a person can be in a state of fight flight (hypervigilance, high blood pressure, states of high blood clotting factors, or rage) in one moment, and in exhaustion, collapse, immobilization, low blood pressure, cold body temperature or depression, in the next. I’ve felt it in myself and seen it happen with clients when I was still learning how to catch early warning signs or anticipate this reaction that could happen very suddenly.
But the science is showing that such variations in symptoms are an effect of environmental stress and resulting perceptions of threat in the nervous system that are not psychological.
In other words, nervous system changes towards hibernation and freeze as well as fight flight are just as real in humans with ME/CFS and other chronic diseases as they are in c. elegans and other animals.
To offer another example, I have long had a predominantly dorsal vagal imprint with my own ME/CFS with a long history of low blood pressure as one example (varying between about 90/60 to 100/70 when normal is considered 120/80).
As I recover, my blood pressure has very gradually increased to within the more common ranges (It was 118/76 at my annual exam in September 2018, which is the highest it’s been in 20 years since the onset of ME/CFS). I also have had more and more irritability alongside the fatigue as my health has improved (emergence of an underlying state of fight flight).
Another impulse seen in the ME/CFS community is a profound impulse to escape, such as to some quiet place. I had such an impulse when I practiced medicine and life was too overwhelming and hectic and stressful.
The craving arose around the onset of my first fatigue attacks 20 years ago. I fantasized about finding a job in the middle of a national park somewhere, monitoring for forest fires and holing up in a tiny tower high up on stilts, away from everyone and everything except the quiet of nature.
This has components of flight but as a strong component of the health within the dorsal vagal freeze response that craves quiet, stillness and avoidance of social contact, which can support the process of healing (see Levine, 2010, Chapter 4).
What Causes Prolonged States of ME/CFS and Freeze / Hibernation?
Our defenses are adaptive and occur at multiple levels, including the cellular level and through physiology such as heart rate, energy levels and gut function. These mechanisms are meant to ensure our survival.
But while humans, like other animals, are designed to recover from infections, exposures to toxins and life’s other adversities given enough time and support, experiences severe enough to trigger a freeze response put people at risk of getting stuck and resetting into prolonged physiological states of survival. The result is a body caught in CDR pathways with symptoms that express themselves as chronic diseases such as ME/CFS.
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).
The field of trauma research in humans and animals has found that bodies and physiologies can get stuck in states of defense when the nervous system does not realize the threat is gone and the danger is past.
In the wild, animals that have just escaped their predators discharge their states of fight, flight and freeze, often by shaking or trembling. We experience this as humans too. It may be barely visible to the naked eye or overt as in this youtube video of a gazelle in a freeze state, emerging from the immobility with chaotic-looking shaking movements and then escaping by running away.
When this natural process of releasing a defense response is interrupted, delayed or prevented from happening – as frequently occurs in our human lives, such as when we fill out a police report after an accident, when childhood abuse or emotional neglect persists through many years, or when we undergo surgery and wake up to bright lights and bustling, efficient personnel that don’t quite connect with us – our brains may not get the message that we’ve survived the threat. In such events our bodies can default to freeze states as an adaptation response, just as c. elegans does in a drought or conditions of low oxygen:
These [prolonged metabolic CDR] pathways … suggest a postexposure adaptation in response to pathologically persistent or recurrent cell danger signaling (2016, p. e5477).
What we’ve learned from research in traumatic stress is that, when our brains don’t recognize that the threat is gone or the danger has passed, they maintain their states of defense to maximize self-protection and survival. This is what stimulates our brains to reset from healthy social nervous system functions to temporarily lose the ability to suppress and regulate fight, flight and freeze.
A symptom of this reset often includes a loss of our sense of connection to ourselves, to others or to our sense of belonging in the world. In other words, when our nervous systems shift into defense responses, our brains often disconnect and we feel alone.
These changes in physiology reflect a persistence of the CDR pathways. They don’t usually happen out of the blue but instead occur following a gradual accumulation of exposures throughout our lifetimes. The reset happens after one final “last straw,” which is the exposure that resets our nervous systems.
The CDR shows up in slightly different ways for each of us based on our accumulation of life exposures and adversities.
It may look like ongoing states of of fight and flight for some of us (metabolic syndrome, type 1 diabetes and others per Naviaux, 2014), as prolonged states of freeze for others (ME/CFS, depression, and other chronic illnesses), or as some combination of the two in which we either alternate between too much gas and too strong of a brake, or feel both at the same time even as the brake covers over symptoms of ready-for-fight-flight-in-the event-of-an-opportunity (also experienced in some of us with ME/CFS; Fibromyalgia? ).
In time, CDRs create symptoms of ME/CFS and other chronic diseases. We can have more than one set of symptoms and diseases based on the characteristics of the CDR our autonomic nervous system is expressing.
The CDR is initially adaptive and coordinated by the close interplay of mitochondria and the cell, but becomes maladaptive once the environmental danger is gone.
ME/CFS and Freeze are States of Adaptation That Come at High Cost in Humans
As Naviaux describes (2016), c. elegans expresses metabolites of hibernation in situations that it cannot outrun or successfully overcome through action – conditions such as cold, lack of food or oxygen, and other threats.
Our autonomic nervous systems use the same CDR pathway in situations we cannot escape or successfully overcome either. Experiences such as
- environmental stressors such as exposures to infections, toxins or chemicals, especially early in life are risk factors for many autoimmune and other diseases. They also trigger the cell danger response (Naviaux, 2014; 2016; 2018) and increase risk for autonomic nervous system perceptions of threat and the possibility of developing prolonged defensive responses (Naviaux; Chitty, 2013; Levine, 2010; Porges, 2004; Ogden, 2006; Schore, 2001, and others)
- a difficult environment in the womb (low oxygen, maternal emotional stress and fight flight freeze in her own system, or maternal physical illness, etc, which babies in the womb cannot escape by “connecting”, fighting, or fleeing, other than through premature birth) (Calkins, 2011; Sandman, 2018)
- a difficult or premature birth (these represent inescapable stressors that can be life threatening) (Sandman, 2018; Ridout, 2018)
- incubator care after birth and other events that increase separation of mothers from their babies (which can therefore interrupt the ventral vagus and elicit dorsal vagal complex responses in both individuals) (Hofer, 1994; Klaus & Kennell, 1976; Madrid, 2005; Moore, 2017;
- losing a parent in childhood (such as through divorce or death, which elicits feelings of loss and potential life threat to a child and cannot be fought or escaped) (Felitti, 1998; Hughes, 2017; Jackson Nakazawa, 2015)
- growing up with a depressed parent (depression is generally associated with significant distress that makes it difficult to offer the safety of nurturing, loving connection or even physical care)
- overt trauma, such as childhood physical, sexual, emotional abuse or parent who is an alcoholic (Dube, 2009; Romens, 2017)
- having a debilitating or life-threatening illness such as ME/CFS (Alonzo, 2000)
- and more.
In humans, the common factor that triggers the persistence of a survival state of fight, flight or freeze is initiated by experiences that elicit a degree of helplessness. This is the inherent definition of trauma that differentiates it from stress.
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
Experiences of relative helplessness elicit the freeze response since fight and flight and communication are not effective solutions.
The experience of an infection or exposure to a toxin can trigger a similar biological overwhelm and autonomic nervous system perception that fight flight and ventral vagus are insufficient methods for addressing the threat.
In health our autonomic nervous system responds to threats of all kinds by first using the most evolved survival mechanisms of connection and communication through our ventral vagus. If ineffective, it next implements states of mobilization through fight and flight. When neither are options or effective solutions, our autonomic nervous system resorts to states of freeze.
The science of traumatic stress explains how survival states of nervous system function can persist even after a toxin, infection or other environmental stressor is gone. And even when the threat seems small.
Why Exhaustion and Other Symptoms Persist in ME/CFS
When our brains believe we’re still in danger or under threat, they maintain survival states.
In the case of ME/CFS, this means our brains may insist on remaining in states of hibernation until our autonomic nervous system gets the message that it’s over, that the threat is gone, and that we’re safe.
At that point, our bodies can let go of survival states to come back to the responsive, moment-to-moment dance that reflects ongoing, fluctuating, adaptive interactions and balance between all three branches of the nervous system.
What both Naviaux and trauma science help to explain is that, while a serious disease like ME/CFS may begin after an environment stressor such as an infection, a vaccine or a stressful or traumatic event, this trigger is the final straw in a series of life long exposures rather than the single or actual cause of the disease.
As Naviaux reiterates, the symptoms of ME/CFS are not indications of broken mitochondria, faulty genes or nutrient deficiencies as much as they represent the effects of an organism hell bent on maintaining low energy states of hibernation and freeze in all ways available (cell function, physiology, behavior, emotions and more).
In my next post, I’ll build further on Naviaux’ work to describe what we now understand about how exposures and life experiences – infection, loss of a parent in childhood, abuse, a difficult birth, a vaccine – can lead to ME/CFS in some of us, and not in others. I’ll describe research that sheds light on why the stressor that triggers onset of ME/CFS can seem completely minor or not even threatening, and why flares can occur with similarly negligible stressors.
For more, here’s my story with ME/CFS and how this lens makes sense of my symptoms and is helping me to heal. You’ll find a sampling of books and therapies for working with the autonomic nervous system (it’s not because it’s in any way “your fault”). These are not cognitive behavioral therapies nor about will power and can help address effects of environmental stressors even if they happened decades in the past. I’ve also shared how healing complex PTSD (ACREs) helped me recover from food intolerances and how it affects my triggers and flares.
Find how to figure out which approaches to use from 11 tools I recommend. Take a look at the 2020 memoir by Sarah Ramey that skillfully, compassionately, clearly and with humor pulls it all together for those with all kinds of mysterious illnesses from a similar view, including how frequent infections and antibiotic use also contribute to risk, in The Lady’s Handbook for Her Mysterious Illness: A Memoir (which includes a vital perspective on the loss, suppression, blaming of the “softer,” sensitive, feeling, feminine aspect in all of us, men and women).
Alonzo, A. A. (2000). “The experience of chronic illness and post-traumatic stress disorder: the consequences of cumulative adversity.” Soc Sci Med 50(10): 1475-1484.
Calkins, K. and S. U. Devaskar (2011). “Fetal origins of adult disease.” Curr Probl Pediatr Adolesc Health Care 41(6): 158-176.
Chitty, J. (2013). Dancing with Yin and Yang. Boulder, Polarity Press.
Dhabhar, F. S. (2009). “Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology.” Neuroimmunomodulation 16(5): 300-317.
Dhabhar, F. S. (2018). “The short-term stress response – Mother nature’s mechanism for enhancing protection and performance under conditions of threat, challenge, and opportunity.” Front Neuroendocrinol 49: 175-192.
Dube, S. R., D. Fairweather, W. S. Pearson, V. J. Felitti, R. F. Anda and J. B. Croft (2009). “Cumulative Childhood Stress and Autoimmune Diseases in Adults.” Psychosom Med 71(2): 243-250.
Felitti, V. J., R. F. Anda, D. Nordenberg, D. F. Williamson, A. M. Spitz, V. Edwards, M. P. Koss and J. S. Marks (1998). “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 14(4): 245-258.
Fredrickson, B. (2013). Love 2.0: Finding Happiness and Health in Moments of Connection, Plume.
Gabrielsen, G. W. and E. N. Smith (1985). “Physiological responses associated with feigned death in the American opossum.” Acta Physiol Scand 123(4): 393-398.
Hofer, M. A. (1994). “Early relationships as regulators of infant physiology and behavior.” Acta Paediatr Suppl 397: 9-18.
Hughes, K., M. A. Bellis, K. A. Hardcastle, D. Sethi, A. Butchart, C. Mikton, L. Jones and M. P. Dunne (2017). “The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis.” Lancet Public Health 2(8): e356-e366.
Jackson Nakazawa, D. (2015). Childhood Disrupted: How Your Biography Becomes Your Biology, and How You Can Heal. New York City, Atria Books.
Klaus, M. H. and J. H. Kennell (1976). Maternal-infant bonding. St. Louis, Mosby.
Lant, B. and K. B. Storey (2010). “An overview of stress response and hypometabolic strategies in Caenorhabditis elegans: conserved and contrasting signals with the mammalian system.” International Journal of Biological Sciences 6(1): 9-50.
Levine, P. A. (2010). In an Unspoken Voice: How the body releases trauma and restores goodness. Berkeley, North Atlantic.
Madrid, A. (2005). “Helping children with asthma by repairing maternal-infant bonding problems.” Am J Clin Hypn 48(3-4): 199-211.
Moore, S. R., L. M. McEwen, J. Quirt, A. Morin, S. M. Mah, R. G. Barr, W. T. Boyce and M. S. Kobor (2017). “Epigenetic correlates of neonatal contact in humans.” Dev Psychopathol 29(5): 1517-1538.
National Research Council and Institute of Medicine (2000). From Neurons to Neighborhoods: the science of early childhood development. Committee on integrating the science of early childhood development. Board on children, youth, and families, Commission on behavioral and social sciences and education. Washington, D.C., National Academy Press.
Naviaux, R. K. (2014). “Metabolic features of the cell danger response.” Mitochondrion 16: 7-17.
Naviaux, R. K., J. C. Naviaux, K. Li, A. T. Bright, W. A. Alaynick, L. Wang, A. Baxter, N. Nathan, W. Anderson and E. Gordon (2016). “Metabolic features of chronic fatigue syndrome.” Proc Natl Acad Sci U S A.
Naviaux, R. (2018 (epub ahead of print). “Metabolic features and regulation of the healing cycle—A new model for chronic disease pathogenesis and treatment.” Mitochondrian.
Ogden, P., K. Minton and C. Pain (2006). Trauma and the Body: A sensorimotor approach to psychotherapy. New York, Norton & Co.
Porges, S. W. (1992). “Vagal tone: a physiologic marker of stress vulnerability.” Pediatrics 90(3 Pt 2): 498-504.
Porges, S. W. (1995). “Orienting in a defensive world: mammalian modifications of our evolutionary heritage. A Polyvagal Theory.” Psychophysiology 32: 301-318.
Porges, S. W. (2001). “The polyvagal theory: phylogenetic substrates of a social nervous system.” Int J Psychophysiol 42(2): 123-146.
Porges, S. W. (2004). “Neuroception: a subconscious system for detecting threats and safety.” Zero to Three May: 19-24.
Porges, S. W. (2009). “The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system.” Cleveland Clinic journal of medicine 76(Suppl 2): S86-S90.
Ridout, K. K., M. Khan and S. J. Ridout (2018). “Adverse Childhood Experiences Run Deep: Toxic Early Life Stress, Telomeres, and Mitochondrial DNA Copy Number, the Biological Markers of Cumulative Stress.” Bioessays: e1800077.
Romens, S. E., J. McDonald, J. Svaren and S. D. Pollak (2015). “Associations between early life stress and gene methylation in children.” Child Dev 86(1): 303-309.
Sandman, C. A. (2018). “Prenatal CRH: An integrating signal of fetal distress.” Dev Psychopathol 30(3): 941-952.
Scaer, R. (2005). The Trauma Spectrum: Hidden wounds and human resiliency. New York, W.W. Norton.
Scaer, R. C. (2001). The Body Bears the Burden: Trauma, dissociation, and disease. New York, Haworth Medical.
Schore, A. N. (1994). Affect regulation and the origin of the self: the neurobiology of emotional development. Hillsdale, NJ, Lawrence Erlbaum.
Schore, A. N. (2001). “The effects of secure attachment relationship on right brain development, affect regulation, and infant mental health.” Infant Ment Health J 22: 7-66.
Shalev, I., T. E. Moffitt, K. Sugden, B. Williams, R. M. Houts, A. Danese, J. Mill, L. Arseneault and A. Caspi (2013). “Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study.” Mol Psychiatry 18(5): 576-581.
Shonkoff, J. P., A. S. Garner, C. Committee on Psychosocial Aspects of, H. Family, A. Committee on Early Childhood, C. Dependent, D. Section on and P. Behavioral (2012). “The lifelong effects of early childhood adversity and toxic stress.” Pediatrics 129(1): e232-246.
Taylor, S. E., L. C. Klein, B. P. Lewis, Gruenewald, Tara L. , R. A. R. Gurung and J. A. Updegraff (2000). “Female responses to stress: Tend and befriend.” Psychological Review 107(3): 411-429.