ME/CFS as a Breakdown in Homeostasis


Here I present a new theory of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling and complex illness affecting millions of people worldwide.

The Centers for Disease Control and Prevention (CDC) defines ME/CFS as follows:

People with ME/CFS are often not able to do their usual activities. At times, ME/CFS may confine them to bed. People with ME/CFS have overwhelming fatigue that is not improved by rest. ME/CFS may get worse after any activity, whether it’s physical or mental. This symptom is known as post-exertional malaise (PEM). Other symptoms can include problems with sleep, thinking and concentrating, pain, and dizziness.

There is no agreed scientific explanation of the disorder, no treatment and no cure. The most popular theory has been that the condition is psychosomatic. In my view, this theory is completely wrong.

Here I present a new theory suggesting that ME/CFS is a multi-system disorder in which the homeostasis of the body is broken. Homeostasis is a fundamental physiological principle that ensures equilibrium, stability and safety of the organism in a continuously changing and potentially life-threatening environment.

The featured illustration above is courtesy of Scientific American.

Bodily Homeostasis

The body uses three biological systems for the maintenance of equilibrium: the nervous system, the endocrine system and the immune system. The three systems communicate using electrical and chemical signals. They activate and de-activate tissues, organs and muscles to control and regulate the body, the emotions and the mind. The principal objective of the three systems is to preserve homeostasis. It is proposed that the complex multi-system disorder known as myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is caused by a breakdown of homeostasis. This Homeostasis Theory of ME/CFS is supported by a substantial number of studies in the recent literature.

The three systems and their relationships to the brain and behaviour are illustrated in Figure 1.

Figure 1 The nervous, endocrine and immune systems, and their relationships to brain and behaviour. Reproduced with permission from Marks, Murray and Estacio (2020, p. 26).

Continuous, reciprocal interaction between the brain, organs and gut is essential for smooth and efficient control and coordination of bodily functions, experience and behaviour. Endocrine substances directly affect the nervous and immune systems. The CNS innervates every organ and tissue of the immune system with reciprocal connections. The continuous interactions of the nervous, endocrine and immune systems was termed ‘neuroimmunomodulation’ by Spector and Korneva (1981). If a breakdown in homeostasis occurred, an individual would be in serious trouble. This may precisely be the case in people with ME/CFS (pwME/CFS).

The chronic nature of ME/CFS suggests that its pathogenesis involves a disruption of homeostasis leading to chronic inflammation and immunological dysfunction. Biomarkers of inflammation and leaky gut syndrome as a possible result of microbiome disturbance and bacterial translocation have been reported (Shukla et al., 2015; Cortes Rivera et al., 2019; Mandarano et al., 2018; Sweetman et al., 2019). According to this theory, an aberrant state of homeostasis is the central cause of ME/CFS (Hatziagelaki et al., 2018; Nacul et al., 2020; Sweetman et al., 2019).  To quote Sweetman et al. (2020):

In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium.” (Figure 2).

Figure 2. Homeostasis breakdown in three hypothetical stages of disease in ME/CFS. Reproduced by permission from Nacul et al. (2020).

In line with what is known about the typical course of the disease, it can reasonably be assumed that the hypothesized state of aberrant homeostasis can be aggravated by new stressors in the form of infection (Shepherd & Chaudhuri, 2019), physical exertion, cognitive effort such as reading or solving mental puzzles, triggering a post-exertional malaise (PEM), comorbid conditions such as sleep disturbances (Chu, Valencia, Garvert & Montoya, 2018) and other factors (Nacul et al., 2020). In people who happily do not develop ME/CFS or prolonged illness following an acute infection or other insult, external stressors initially cause short-term physiological changes but the usual state of homeostatic equilibrium that operated before the insult is quickly restored.  Hatziagelaki et al. (2018) suggested that the abberant state of homeostasis could be caused by inflammation in the hypothalamus, which I discuss next.

The Neuroimmune Hypothesis

Patients with ME/CFS often present with an acute onset of illness, with symptoms similar to an influenza infection, but these symptoms do not subside. Many of the symptoms are inflammatory, i.e. myalgia, arthralgia or joint pains, sore throat and tender lymphadenopathy. The immune system is a network of cells, tissues and organs that protects the body against disease or other potentially damaging foreign bodies. When properly functioning, the system identifies and attacks a variety of threats using billions of diverse antibodies, including viruses, bacteria and parasites, while distinguishing them from the body’s own healthy tissue. For each type of invader the body needs a distinct antibody. Antibodies are made by B cells using a combination of 20,000 genes and an enzyme called ‘RAG’, which is a DNA shuffler. This enables the immune system to create a vast diversity of antibodies and respond to diseases it has never encountered before.

Inflammation is a critical defence response in our innate immune system wherein white blood cells protect us from infection by foreign organisms, bacteria and viruses. Inflammation occurs following infection or tissue damage when a rapid and complex series of reactions takes place to prevent tissue damage, isolate and destroy the infective organism, conserve and protect some micronutrients and activate the repair processes to restore normal function (Thurnham, 2014). Inflammation is a homeostatic process that is only intended to last a few days but, if it is continued indefinitely, there is a poor prognosis in many conditions. Inflammatory responses take precedence over normal body metabolism with the objective of restoring normality as quickly as possible.

Immune activation indicated by elevated levels of cytokines in pwME/CFS have been studied since 2001 (Patarca, 2001). Recent studies have used immune system profiling to determine whether an abnormal profile of circulating cytokines could be identified in pwME/CFS and whether this profile correlated with disease severity and/or fatigue duration. In one study, serum cytokines of 192 pwME/CFS and 392 healthy controls were measured (Montoya et al., 2017). Seventeen cytokines showed a statistically significant upward linear trend that correlated with ME/CFS severity of which 13 were proinflammatory, which is likely to be a contributing factor to the symptoms.

Strawbridge, Sartor, Scott and Cleare (2019) carried out a systematic review and meta-analysis of 42 studies of circulating inflammatory proteins in pwCFS and non-affected control groups. Patients with CFS had significantly elevated tumour necrosis factor, interleukin-2, interleukin-4, transforming growth factor-β and c-reactive protein. The authors concluded: “These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder.”

The generic cause cause of the abnormal inflammatory response in pwME/CFS is a breakdown in homoeostasis. The precise mechanism is still unknown (Komoroff, 2019). But that inflammatory response is definitely present.

The Microbiome Hypothesis

The field of microbiome research studies the microbes within the gut and the effects of these microbes on the host’s well-being. The microbiome is the community of symbiotic and pathogenic microorganisms, that live on the skin and genitals and in the nose, ears, mouth and gut. Microbes influence metabolism, immunity and behaviour. One mechanism appears to involve hormones because specific changes in hormone levels correlate with the presence of the gut microbiota. The microbiota produce and secrete hormones, respond to host hormones and regulate expression levels of host hormones. Hormones and the microbiome are linked to immune responses under both healthy  conditions and autoimmune disease. There are many interconnections and the microbiome and hormones may work through shared pathways to affect the immune response (Neuman et al., 2015).

Zhang et al. (2018) illustrate the homeostasis system’s response to changes in diet and drug ingestions using this diagram (see Figure 3 below):

Figure 2. Graphical representation of the commensal homeostasis of gut microbiota-host under the intervention of diet and drugs. Diet and drugs can be digested, absorbed, and metabolized by the host and gut microbiota. The host and gut microbiota can interact synergistically to impact the physiological status of the human body. They not only support themselves directly by using nutritional substrates but also impact each other indirectly by enterotype, genotype, metabolites, and related functions. Ultimately, the host and gut microbiota achieve a commensal homeostasis of composition, interactions, metabolites, and energy utilization.

Organisms within the gut play a role in the early programming and response to stress. The gut contains 1013– 1014 micro-organisms, ten times the number of cells in the human body, and contains 150 – 360 times as many genes as our genome. That’s a heck of a lot. When a pathogen such as Escherichia coli (aka E coli) enter the gut, the HPA can be activated. Stress can induce increased permeability of the gut, allowing bacteria and bacterial antigens to cross the epithelial barrier and activate a mucosal immune response, which in turn alters the composition of the microbiome and leads to an enhanced HPA drive.

Patients with irritable bowel syndrome and major depression show alterations of the HPA which are induced by increased gut permeability. In the case of irritable bowel syndrome, the increased permeability can respond to probiotic therapy. The gut microbiota play a role in regulating the HPA. Verdino (2017) cautiously concludes his review of the connection between gut health and emotional well-being as follows: “… it is crucial not to oversimplify the idea that nutritional intervention and a healthy gut will be the panacea for profound psychological difficulties. Severe mood and paralyzing anxiety disorders are not going to be cured with probiotic yogurt and prebiotic fiber, alone” (Verdino, 2017: 4).

The immune and neuroendocrine systems share a set of hormones and receptors. Glucocorticoids, such as corticosterone and cortisol, regulate inflammation levels and have effects both on the innate and adaptive immune responses. Additionally, vitamin D affects immune cell responses by enhancing antigen presentation. Moreover, sex hormones affect the immune response in numerous ways.

Dysbiosis, an imbalance in the microbiome, seems to be involved in the pathophysiology of ME/CFS. Shukla et al. (2015) studied changes in the gut and plasma microbiome following exercise challenge in pwME/CFS.  In exercise challenge, changes occurred in the amount of bacterial phyla in the gut in pwME/CFS that were not observed in healthy controls. Also, bacteria clearance from the blood was delayed in pwME/CFS following exercise. Altered gut microbiome and increased bacterial translocation following exercise thus appear to play a role in ME/CFS that may account for the post-exertional malaise experienced by many pwME/CFS.

Mitochondrial Failure

Mitochondrial failure is another part of the jigsaw puzzle posed by ME/CFS (Myhill et al. 2009, 2013). Mitochondria generate cellular energy by manufacturing ATP (adenosine triphosphate). Infections with pathogens, including viruses, bacteria, parasites and toxins can cause changes in the function of mitochondria and deplete energy metabolism. Metabolomics, the systematic identification of metabolic products (the metabolome) of a biological system is revealing a possible chemical pattern of chemical abnormalities or metabolite abnormalities in pwME/CFS. Myhill, Booth and McLaren-Howard (2009) developed interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP, the energy currency for all body functions, and recycling ADP to replenish the ATP supply as needed. Patients attending a private medical practice specializing in ME/CFS were diagnosed using the Centers for Disease Control criteria. A correlation was obtained between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of 71 patients overlapped the normal region.

Figure 4. Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable whereas the inner membrane is permeable only to water and gases. Special carrier and Translocator proteins pass reactants through it. At the top are the proteins involved in the respiratory electron transfer chain (ETC) and in the transfer of ATP and ADP between the cytosol and mitochondrion. ADP and Pi are combined by ATP synthase to make ATP. The ADP/ATP Translocator opens OUT to transfer ADP into the matrix and opens IN to transfer ATP to the cytosol. Nicotinamide adenine dinucleotide plays a key role in its oxidised form NAD+ and its reduced form NADH + H+ in carrying and transferring protons (H+) and electrons (e). Reproduced from Sarah Myhill et al. 2009.

The authors concluded that “the “ATP profile” test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out” (Myhill et al., 2009).

Morris and Maes (2014) support Myhill et al.’s approach in arguing that mitochondrial dysfunctions in the form of lowered ATP production may play a role in the onset of ME/CFS symptoms and help to explain in part the central metabolic abnormalities observed in ME/CFS, e.g. glucose hypometabolism and cerebral hypoperfusion.

The results of a study by Sweetman et al. (2020) also “support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress.” 

Developing diagnostic biomarkers will be a significant next step.


Whatever the specific causal mechanism turns out to be – and whoever solves this problem will deserve the Nobel prize – homeostasis breakdown seems the most likely candidate as the underlying problem.

The reactive scope model—a new model integrating homeostasis, allostasis, and stress.

Romero, L. M., Dickens, M. J., & Cyr, N. E. (2009). The reactive scope model—a new model integrating homeostasis, allostasis, and stress. Hormones and behavior55(3), 375-389.


Allostasis, the concept of maintaining stability through change, has been proposed as a term and a model to replace the ambiguous term of stress, the concept of adequately or inadequately coping with threatening or unpredictable environmental stimuli. However, both the term allostasis and its underlying model have generated criticism. Here we propose the Reactive Scope Model, an alternate graphical model that builds on the strengths of allostasis and traditional concepts of stress yet addresses many of the criticisms. The basic model proposes divergent effects in four ranges for the concentrations or levels of various physiological mediators involved in responding to stress. (1) Predictive Homeostasis is the range encompassing circadian and seasonal variation — the concentrations/levels needed to respond to predictable environmental changes. (2) Reactive Homeostasis is the range of the mediator needed to respond to unpredictable or threatening environmental changes. Together, Predictive and Reactive Homeostasis comprise the normal reactive scope of the mediator for that individual. Concentrations/levels above the Reactive Homeostasis range is (3) Homeostatic Overload, and concentrations/levels below the Predictive Homeostasis range is (4) Homeostatic Failure. These two ranges represent concentrations/levels with pathological effects and are not compatible with long-term (Homeostatic Overload) or short-term (Homeostatic Failure) health. Wear and tear is the concept that there is a cost to maintaining physiological systems in the Reactive Homeostasis range, so that over time these systems gradually lose their ability to counteract threatening and unpredictable stimuli. Wear and tear can be modeled by a decrease in the threshold between Reactive Homeostasis and Homeostatic Overload, i.e. a decrease in reactive scope. This basic model can then be modified by altering the threshold between Reactive Homeostasis and Homeostatic Overload to help understand how an individual’s response to environmental stressors can differ depending upon factors such as prior stressors, dominance status, and early life experience. We illustrate the benefits of the Reactive Scope Model and contrast it with the traditional model and with allostasis in the context of chronic malnutrition, changes in social status, and changes in stress responses due to early life experiences. The Reactive Scope Model, as an extension of allostasis, should be useful to both biomedical researchers studying laboratory animals and humans, as well as ecologists studying stress in free-living animals.

Vividness, Consciousness, and Mental Imagery: Making the Missing Links across Disciplines and Methods

Guest Editor: Amedeo D’Angiulli

All articles can be accessed freely online.

Marks, D.F. I Am Conscious, Therefore, I Am: Imagery, Affect, Action, and a
General Theory of Behavior. Brain Sci. 2019, 9(5), 107;
Views: 2082, Downloads: 1277, Citations: 2, Altmetrics: 2

Lefebvre, E.; D’Angiulli, A. Imagery-Mediated Verbal Learning Depends on
Vividness–Familiarity Interactions: The Possible Role of Dualistic Resting
State Network Activity Interference. Brain Sci. 2019, 9(6), 143;
Views: 1537, Downloads: 645, Citations: 0, Altmetrics: 5

Pinna, B.; Conti, L. The Limiting Case of Amodal Completion: The Phenomenal
Salience and the Role of Contrast Polarity. Brain Sci. 2019, 9(6), 149;
Views: 1307, Downloads: 701, Citations: 2, Altmetrics: 1

Craver-Lemley, C.; Reeves, A. Taste Modulator Influences Rare Case of
Color-Gustatory Synesthesia. Brain Sci. 2019, 9(8), 186;
Views: 1041, Downloads: 907, Citations: 0, Altmetrics: 0

Haustein, S.; Vellino, A.; D’Angiulli, A. Insights from a Bibliometric
Analysis of Vividness and Its Links with Consciousness and Mental Imagery.
Brain Sci. 2020, 10(1), 41;
Views: 810, Downloads: 300, Citations: 0, Altmetrics: 1

van der Helm, P.A. Dubious Claims about Simplicity and Likelihood: Comment on
Pinna and Conti (2019). Brain Sci. 2020, 10(1), 50;
Views: 699, Downloads: 234, Citations: 1, Altmetrics: 0

Pinna, B.; Conti, L. On the Role of Contrast Polarity: In Response to van der
Helm’s Comments. Brain Sci. 2020, 10(1), 54;
Views: 657, Downloads: 243, Citations: 0, Altmetrics: 0

Thorudottir, S.; Sigurdardottir, H.M.; Rice, G.E.; Kerry, S.J.; Robotham,
R.J.; Leff, A.P.; Starrfelt, R. The Architect Who Lost the Ability to
Imagine: The Cerebral Basis of Visual Imagery. Brain Sci. 2020, 10(2), 59;
Views: 2817, Downloads: 972, Citations: 0, Altmetrics: 56

Brain Sciences (ISSN 2076-3425) is a journal published by MDPI AG, Basel,


Sleep function and synaptic homeostasis

Tononi, G., & Cirelli, C. (2006). Sleep function and synaptic homeostasis. Sleep medicine reviews10(1), 49-62.


This paper reviews a novel hypothesis about the functions of slow wave sleep—the synaptic homeostasis hypothesis. According to the hypothesis, plastic processes occurring during wakefulness result in a net increase in synaptic strength in many brain circuits. The role of sleep is to downscale synaptic strength to a baseline level that is energetically sustainable, makes efficient use of gray matter space, and is beneficial for learning and memory. Thus, sleep is the price we have to pay for plasticity, and its goal is the homeostatic regulation of the total synaptic weight impinging on neurons. The hypothesis accounts for a large number of experimental facts, makes several specific predictions, and has implications for both sleep and mood disorders

Consciousness without a cerebral cortex

Merker, B. (2007). Consciousness without a cerebral cortex: A challenge for neuroscience and medicine. Behavioral and brain sciences30(1), 63-81.


A broad range of evidence regarding the functional organization of the vertebrate brain – spanning from comparative neurology to experimental psychology and neurophysiology to clinical data – is reviewed for its bearing on conceptions of the neural organization of consciousness. A novel principle relating target selection, action selection, and motivation to one another, as a means to optimize integration for action in real time, is introduced. With its help, the principal macrosystems of the vertebrate brain can be seen to form a centralized functional design in which an upper brain stem system organized for conscious function performs a penultimate step in action control. This upper brain stem system retained a key role throughout the evolutionary process by which an expanding forebrain – culminating in the cerebral cortex of mammals – came to serve as a medium for the elaboration of conscious contents. This highly conserved upper brainstem system, which extends from the roof of the midbrain to the basal diencephalon, integrates the massively parallel and distributed information capacity of the cerebral hemispheres into the limited-capacity, sequential mode of operation required for coherent behavior. It maintains special connective relations with cortical territories implicated in attentional and conscious functions, but is not rendered nonfunctional in the absence of cortical input. This helps explain the purposive, goal-directed behavior exhibited by mammals after experimental decortication, as well as the evidence that children born without a cortex are conscious. Taken together these circumstances suggest that brainstem mechanisms are integral to the constitution of the conscious state, and that an adequate account of neural mechanisms of conscious function cannot be confined to the thalamocortical complex alone.

Keywords: action selection; anencephaly; central decision making; consciousness; control architectures; hydranencephaly; macrosystems; motivation; target selection; zona incerta

The conscious id

Solms, M. (2013). The conscious id. Neuropsychoanalysis15(1), 5-19.


Two aspects of the body are represented in the brain, and they are represented differently. The most important difference is that the brain regions for the two aspects of the body are associated with different aspects of consciousness. Very broadly speaking, the brainstem mechanisms derived from the autonomic body are associated with affective consciousness, and the cortical mechanisms derived from the sensorimotor body are associated with cognitive consciousness. Moreover, the upper brainstem is intrinsically conscious whereas the cortex is not; it derives its consciousness from the brainstem. These facts have substantial implications for psychoanalytic metapsychology because the upper brainstem (and associated limbic structures) performs the functions that Freud attributed to the id, while the cortex (and associated forebrain structures) performs the functions he attributed to the ego. This means that the id is the fount of consciousness and the ego is unconscious in itself. The basis for these conclusions, and some of their implications, are discussed here in a preliminary fashion. Keywords: affect; cognition; conscious; ego; id; unconscious

Mentalizing homeostasis: The social origins of interoceptive inference

Fotopoulou, A., & Tsakiris, M. (2017). Mentalizing homeostasis: The social origins of interoceptive inference. Neuropsychoanalysis19(1), 3-28.
Is the self already relational in its very bodily foundations? The question of whether our mental life is initially and primarily shaped by embodied dimensions of the individual or by interpersonal relations is debated in many fields, including psychology, philosophy, psychoanalysis, and more recently, cognitive neuroscience. In this interdisciplinary target article, we put forward the radical claim that even some of the most minimal aspects of selfhood, namely the feeling qualities associated with being an embodied subject, are fundamentally shaped by embodied interactions with other people in early infancy and beyond. Such embodied interactions allow the developing organism to mentalize its homeostatic regulation. In other words, embodied interactions contribute directly to the building of mental models of the infant’s physiological states, given the need to maintain such states within a given dynamic range despite internal or external perturbations. Specifically, our position rests on the following three propositions: (1) the progressive integration and organization of sensory and motor signals constitutes the foundations of the minimal self, a process which we have linked to contemporary, computational models of brain function and named “embodied mentalization”; (2) interactions with other people are motivated and constrained by the same principles that govern the “mentalization” of sensorimotor signals in the individual – and hence the mentalization of one’s body can include signals from other bodies in physical proximity and interaction, especially in interaction with particular bodies. (3) Crucially, given the dependency of humans in early infancy, there is a “homeostatically necessary” plethora of such embodied “proximal” interactions, especially as regards interoception. Collectively, such experiences of proximal intercorporeality “sculpt” the mentalization process and hence the constitution of the minimal self, including the progressive sophistication of mental distinctions between “subject-object,” “self-other” and even “pleasure-pain.” Finally, we explore notions of cardiac and more broadly interoceptive awareness as later, cognitive acquisitions that allow us to progressively solidify such distinctions, as well as understand and empathise with other people.
self; affect; emotion; awareness; social cognition; touch; interoception; intersubjectivity; embodiment; skin ego; minimal self

Homeostasis in Neuroscience


Some commentaries from the neurosciences point of view about the relations between citizens and public agencies

A. F. Rocha, State University of Campinas, Brazil

Research on Artificial and Natural Intelligence


The success story continues making Nudge well read and much applied. The key message is that people are irrational on their decision making and need to be guided by policy markers, which are able to have useful insights from Psychology and Behavioral Economics about how to elaborate choice structures to rationalize people’s financial behavior. Inertia is one popular of these insights and refers to the tendency of humans to procrastinate in making choices. This tendency is acknowledged but not understood and explained. The same occurs with other reported insights. In contrast, the present paper proposes any decision guaranteeing the individual biological; psychological and social homeostasis are rational despite being or not the expected decision supported by any formal model. Most of the important human decisions are about keeping homeostasis within boundaries promoting well being, hence resulting from complex analyses of benefits; risks and costs from both the personal and social point of view as carried out by two different Personal and Social Decision Networks. Rational choice selects, therefore, high beneficial goods or services for promoting homeostasis at lowest risk and cost from both personal and social point of views. A decision neural model for decision making is presented and used to illustrate how rational choices are computed to guarantee individual homeostasis, and to propose that individuals seem to be irrational because the proposed economic formal theories take into consideration just the policy maker point of view disregarding the individual needs.

Keywords: Decision Making, Brain, Economic Psychology, Behavioral Economy, Neurosciences, Nudge

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