Neural mechanisms of social homeostasis

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Annals of the New York Academy of Sciences

Gillian A. Matthews and Kay M. Tye First published: 15 March 2019 

https://doi.org/10.1111/nyas.14016

Originally published as a REVIEW

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Abstract

Social connections are vital to survival throughout the animal kingdom and are dynamic across the life span. There are debilitating consequences of social isolation and loneliness, and social support is increasingly a primary consideration in health care, disease prevention, and recovery. Considering social connection as an “innate need,” it is hypothesized that evolutionarily conserved neural systems underlie the maintenance of social connections: alerting the individual to their absence and coordinating effector mechanisms to restore social contact. This is reminiscent of a homeostatic system designed to maintain social connection. Here, we explore the identity of neural systems regulating “social homeostasis.” We review findings from rodent studies evaluating the rapid response to social deficit (in the form of acute social isolation) and propose that parallel, overlapping circuits are engaged to adapt to the vulnerabilities of isolation and restore social connection. By considering the neural systems regulating other homeostatic needs, such as energy and fluid balance, we discuss the potential attributes of social homeostatic circuitry. We reason that uncovering the identity of these circuits/mechanisms will facilitate our understanding of how loneliness perpetuates long‐term disease states, which we speculate may result from sustained recruitment of social homeostatic circuits.

Introduction

The twenty‐first century has unleashed a tsunami of opportunities for social engagement and accelerated the flow of social information. Yet as our outlets for social sustenance proliferate, along with the global population,1 there is a paradoxical increase in social isolation within society.2 The proportion of the population who live alone has risen3 and an increasing number of people experience loneliness.45 Social isolation presents itself in multiple forms including social rejection, exclusion, ostracism, discrimination, social loss, or neglect—all of which have a significant negative impact on emotional state. Across the animal kingdom, social isolation can threaten survival—individuals lack protection from predators, assistance foraging, support raising offspring, opportunities for social play, and mating prospects. Similarly, in humans, deficits in objective quantity and/or subjective quality of social relationships can compromise longevity.6 Lower social integration (assessed by network size/participation, living arrangements, and frequency of close social contact) is predictive of elevated mortality,69 and even just the perception of isolation (colloquially referred to as loneliness) is associated with poor physical and mental health1011 and higher mortality rates.1213

However, beyond just constituting an unwelcome emotional side effect of social isolation, loneliness is theorized to represent an “adaptive predisposition” providing the motivational drive to maintain social contact and prevent the aversive consequences of isolation.1415 This adaptive response to deviation from an expected quantity/quality of social connections is reminiscent of negative feedback mechanisms triggered by challenges to physiological homeostasis, such as energy balance or thermoregulation.

In our review, we introduce the idea that coordinated adaptations across discrete neural circuits function to maintain “social homeostasis.” The term social homeostasis has previously been applied to the maintenance of stable organization within a large group of animals, typically social insects, such as ants, termites, and bees. This “supraorganismal” structure requires tight regulation to maintain stable social organization when met with changes in the environment or internal composition.1617 Here, we propose to extend this concept to the individual level in order to encourage a mechanistic understanding of how deficiencies in social connection are detected and evaluated, and how effector systems are activated to compensate for perturbations.

Social homeostasis: a widespread phenomenon

Homeostasis classically refers to physiological processes wherein stable states are maintained through compensatory mechanisms.18 Homeostatic systems are known to exist for a number of physiological needs essential to survival such as thermoregulation, energy balance, and osmoregulation. These rely upon detection of a deviation from a defined homeostatic “set point,” followed by central coordination of a response in a “control center,” and the recruitment of “effector systems” that interact with the environment to correct the deviation (Fig. 1). Challenges to physiological homeostasis can also elicit motivated behaviors associated with strong negative “drive” states, such as overheating, thirst, and hunger, designed to appropriately adapt/direct behavior.1921

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Figure 1Open in figure viewerPowerPointProposed model for social homeostasis. Based on Cannon’s classic model for homeostatic regulation,18 we propose that a social homeostatic system consists of a detector to sense a change in overall quantity/quality of social contact, a control center to compare this deviation to the individual’s set point, and effector systems to correct the change. (A) Detection of social signals (both their quantity and quality) would require social recognition in order to facilitate recall of previous social encounters and determine the expectation for interaction. Information relevant to the identity of the social agent (recognizing that individual as such) as well as estimation of their relative social rank would be required for appropriate evaluation of a deviation. Integration of this information may occur at the level of the detector (model A) or the control center (model B) stage of processing. Identity and rank information may be represented in an overlapping or nonoverlapping fashion (callout box). For a familiar animal, both these variables may be incorporated to set social expectation, but for an unfamiliar animal, only rank perception would be available. (B) Deviations from the set point would be evaluated within the control center by comparing the current social input to the homeostatic set point for quantity and/or quality of social contact. The social control center may integrate information pertinent to other homeostatic needs (e.g., energy balance, fluid balance, and thermoregulation) in a “hub and spoke” fashion (model A), or the social control center may be subservient to other homeostatic control systems (model B). Alternatively, integration of homeostatic needs may occur in a convergent arrangement onto shared effector systems (model C), with interconnections between control centers (model D). (C) If a deviation from set point is determined, effector systems may be engaged to correct the change. This process could include activation of “external” effectors to promote behavioral adaptation (e.g., social approach/avoidance) along with “internal” effectors to adjust internal/emotional state (model A). Alternatively, engagement of internal effector systems, and a change in emotional state, may itself promote behavioral adaptation (model B).

While a change in social connection may not appear to constitute an immediate challenge to internal stability, individuals on the social perimeter are vulnerable and becoming isolated can threaten survival. Even in controlled laboratory environments (where external threats to survival are absent), the presence of social contact is associated with increased life span across a range of social species including honeybees, ants, Drosophila melanogaster,2223 mice,2425 and rats,2628 as well as in free‐ranging groups of macaques29 and baboons.30 Therefore, an emerging social neuroscience model posits that evolutionarily conserved neurophysiological mechanisms underlie the adaptive, short‐term, self‐preservation mode triggered by a lack of social connections/mutual protection.1431 This model proposes that loneliness operates as an aversive signal designed to promote adaptation to the vulnerabilities of being alone and motivate reconnection.32 Thus, the long‐term disease states perpetuated by chronic loneliness may result from the prolonged engagement of neural systems that were intended for short‐term preservation.

To begin unraveling how the chronic state of loneliness emerges, it is necessary to first understand the neural response to social deficit. Conceptualizing this as the response of a homeostatic system would apply certain defined principles (Fig. 1). A social homeostatic system would be required to (1) monitor social conditions; (2) detect deviation from a homeostatic “set point” in control centers; and (3) activate effector systems to elicit an appropriate response (e.g., strategies to promote social contact). A deficit in social connections (whether perceived or actual) would be predicted to engage this system. In animals, one way to create a social deficit is to remove social contact entirely. While this only captures the objective component of social isolation, it offers controlled conditions for assessing rapid neurophysiological adaptations. Chronic social isolation, particularly in rodents, has been used as a developmental model of early life stress since many of the long‐term maladaptive changes resemble features of human neuropsychiatric disease.33 This rich body of work has been comprehensively reviewed elsewhere for both rodents3337 and nonhuman primates.3840

Alternatively, here we examine the response to acute social isolation (using under 1 week as an arbitrary operational definition of “acute” for the purpose of the review) in order to identify candidate neural circuits involved in the rapid response to social deficit. We focus primarily on experiments in social rodents, including laboratory mice (Mus musculus), rats (Rattus norvegicus), and prairie voles (Microtus ochrogaster), which are social species, adapted to group living, but with different styles of social behavior. The wild species of mice and rats from which laboratory strains were derived are promiscuous and territorial, but show greater social tolerance in high‐density living environments and adopt linear dominance hierarchies that promote group stability.41 In a laboratory setting, mice and rats prefer social company (even that of other males) over a solitary existence.4243 They show conditioned preference for regions previously associated with social contact,44 make nests in close proximity to conspecifics when partially separated,4345 and will actively work to obtain social contact.4647 Alternatively, prairie voles are socially monogamous and form an enduring, selective bond with their partner following mating. They show biparental care toward offspring, tend to live in extended families,4849 and are well utilized in the study of social bonding and isolation.

Here, we evaluate social isolation–induced adaptations in these rodents, in light of the phenotype of human loneliness, which may also represent a state of activation of “social homeostatic systems.” We have categorized the behavioral and neural adaptations into three broad themes: (1) hypervigilance/arousal; (2) social motivation; and (3) passive coping. We propose that parallel, overlapping circuits mediate the response to social deficit (the output of homeostatic “effector” systems) in an effort to heighten attention to environmental stimuli, motivate social reconnection, and limit emotional distress (Fig. 2). While we can only speculate as to the neural identity of the detector, control, and effector systems in a social homeostatic network, we anticipate that a cohesive understanding of the response to social deficit will help unmask candidate neural substrates.

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Figure 2Open in figure viewerPowerPointNeural circuit components implicated in the response to social deficit. Pathways, neuromodulators, neuropeptides, and receptors showing modifications following acute social isolation in rodents. Circuit components are colored based on their involvement in hypervigilance, social motivation, and passive coping. Other prominent projections/connections are shown in gray. Coordinated activity across these parallel, overlapping circuits may function to maintain social homeostasis by heightening attention to environmental stimuli, motivating social reconnection, and limiting emotional distress. 5‐HT, 5‐hydroxytryptamine (serotonin); ACTH, adrenocorticotropic hormone; AT1, angiotensin II receptor 1; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CRF, corticotropin‐releasing factor; CRFR1/2, corticotropin‐releasing factor receptor 1/2; DA, dopamine; D1/2, dopamine D1/2 receptor; DRN, dorsal raphe nucleus; Hp, hippocampus; KOR, ĸ‐opioid receptor; LC, locus coeruleus; MeA, medial amygdala; MOR, μ‐opioid receptor; NAc, nucleus accumbens; NE, norepinephrine; OT, oxytocin; PFC, prefrontal cortex; PVN, paraventricular hypothalamic nucleus; VMH, ventromedial hypothalamus; VTA, ventral tegmental area.

Homeostatic response to social deficit: promoting hypervigilance

An evolutionary perspective on the origins of loneliness proposes that the vulnerabilities of isolation promote hypervigilance to guard against potential threats.50 Lonely individuals often show high levels of anxiety,5152 and hypervigilant responses to negative social stimuli, suggesting heightened recruitment of attentional and self‐preservation mechanisms.53 In rodents, acute isolation can promote behaviors that indicate enhanced arousal and heightened vigilance. For example, adult rats show an increase in escape‐related behaviors over 1–7 days of isolation,54 along with a reduction in exploratory behavior and an increase in self‐grooming.5557 Targeted manipulations in rodents have unveiled that anxiety‐related behaviors arise from activity across distributed, interconnected corticolimbic circuitry, which interpret and evaluate incoming environmental stimuli (reviewed in Ref. 58). One major output system is the hypothalamic–pituitary–adrenocortical (HPA) axis, which regulates arousal, vigilance, and attention, in concert with central arousal circuits including the lateral hypothalamic (LH) orexin/hypocretin system, locus coeruleus (LC) noradrenergic neurons, basal forebrain cholinergic neurons, dorsal raphe nucleus (DRN) serotonergic neurons, and midbrain dopaminergic neurons.5960 Several of these neural circuits exhibit rapid adaptations following acute social isolation. Here, we briefly outline the nature of these changes and their potential role in the response of a social homeostatic system.

HPA axis

Glucocorticoid production is initiated by paraventricular hypothalamic nucleus (PVN) secretion of corticotropin‐releasing factor (CRF) into the hypophyseal portal system, triggering adrenocorticotropic hormone (ACTH) release by the anterior pituitary that in turn acts on the adrenal cortex to secrete glucocorticoids. The HPA axis is regulated by a negative feedback loop, wherein glucocorticoids bind to receptors in the pituitary and other brain regions including the hippocampus, which subsequently inhibits CRF and ACTH production. While acute activation of the HPA axis can be an adaptive physiological response to salient events, chronic activation of this system, particularly by continued psychosocial stressors, is implicated in the progression of multiple disease states and psychopathologies.61 Consistent with this, high self‐reported loneliness in humans has been associated with elevated daily cortisol output6266 and a flattening of diurnal cortisol rhythm,65 suggesting poor regulation of the HPA axis.67

Heightened HPA axis activity (evidenced by a robust increase in circulating corticosterone and ACTH) is observed after 1–5 days of social isolation in juvenile (3–5 weeks old)6869 or pair‐bonded adult7072 prairie voles. Peripheral corticosterone levels are also reportedly increased in male mice isolated for 12 h,73 and both pituitary ACTH and adrenal corticosterone are increased in male rats isolated for 24 h in a novel environment.7475 This recruitment of the HPA axis during acute periods of isolation may reflect the increased need for vigilance and attention to salient stimuli.

CRF signaling

CRF pathways are a prominent point of convergence for isolation‐induced adaptations. Aside from their role in initiating the neuroendocrine response to stress, PVN CRF neurons are pivotal in orchestrating the rapid, complex behavioral adaptations that occur following acute stress (potentially via glutamate coreleasing projections to neighboring hypothalamic regions).76 CRF‐producing neurons are also widely distributed in extrahypothalamic regions, including the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), nucleus accumbens (NAc), and hippocampus,7779 which have, likewise, been implicated in the behavioral and physiological responses to stress. Isolation of preadolescent female (but not male) mice for <24 h decreased the excitability of PVN CRF neurons in a glucocorticoid‐dependent manner.80 This finding may reflect glucocorticoid feedback–induced suppression of CRF activity. Consistent with this interpretation, a 24‐h isolation of adult rats decreased CRF mRNA and protein in the PVN75 and decreased cortical CRF1 receptor levels.81 Moreover, these changes in CRF were accompanied by enhanced angiotensin II (ATII) AT1 receptor expression in the PVN.74 ATII is a circulating endocrine factor that can trigger CRF production in response to stress.82 This factor may be necessary for isolation‐induced adaptations within the hypothalamic CRF system, as the isolation‐induced decrease in CRF mRNA in male rats could be prevented by an AT1 receptor antagonist.75 Conversely, a shorter period (1 h) of social isolation in adult male and female prairie voles housed with same‐sex siblings, resulted in increased hypothalamic and hippocampal CRF mRNA.83 This discrepancy may reflect the shorter duration of isolation or the different species under study. However, it highlights the growing need for a thorough understanding of the timeline of adaptations following social isolation.

LC noradrenergic system

The LC is the sole source of noradrenergic innervation to the central nervous system, best known for its role in arousal and vigilance, but more broadly thought to be recruited to combat environmental challenges.8485 In adult rats, a 24‐h isolation increased tyrosine hydroxylase (TH; the rate‐limiting enzyme in catecholamine synthesis) mRNA in the LC, an effect that could be blocked by an AT1 receptor antagonist.81 Thus, the acute response to isolation involves coordination across both peripheral and central neuromodulatory systems.

Homeostatic response to social deficit: engaging social motivational systems

In humans, a deficit in social connections is conceptualized to engage the “social monitoring system”86 with the purpose of directing attention toward socially relevant information. Accordingly, individuals that either self‐identified as lonely or expected a lonely future showed enhanced sensitivity to social cues and increased socially affiliative motivation.8690 Enhanced social motivation is similarly evident in acutely isolated rodents: when given the opportunity, previously isolated (2‐ to 48‐h duration) juvenile and adult rodents spend more time engaged in social behaviors.9198 It is suggested that up to 7 days of isolation promotes affiliative social behavior and social interest in rats,5792 whereas in adult mice, a significant increase in aggressive behavior was observed after 48 h, but not 24 h of social isolation.99

For many social species, the inherently rewarding nature of social interactions is a major driving force for social contact. In rodents, one method to evaluate the positive reinforcing properties of social interaction is the social conditioned place preference (social CPP) assay—an adaptation of a test traditionally employed to measure the rewarding properties of drugs of abuse.44 In this task, animals typically demonstrate preference for a place previously paired with social housing over one paired with isolate housing (∼24‐h duration44). Notably, therefore, the conditioned approach to a socially conditioned context may be a product of both “social reward” and “isolation aversion.”44 Several neuromodulatory systems (including dopamine, oxytocin, and opioid circuits) are posited to underlie the motivation for social reward. These circuits are also prominent sites of rapid adaptation following social isolation, which we discuss below. The degree to which neural circuits for “social reward” and “isolation aversion” overlap and diverge remains to be determined.

Ventral tegmental area dopamine system

The midbrain dopamine system has a long‐standing role in reward processing100 and affiliative social behavior,101 and is frequently reported as a site of isolation‐induced adaptation. The ventral tegmental area (VTA) dopamine neurons project to multiple regions including the striatum, prefrontal cortex (PFC), and basolateral amygdala (BLA), with the VTA–NAc pathway being particularly well associated with social reward.102103 In juvenile rats, isolation‐induced social play was suppressed by D1‐ or D2‐receptor blockade in the NAc,104 while in adult rats, 24 h or 4 days of isolation decreased striatal D2‐receptor density105 and increased mesostriatal TH activity,106 respectively. Isolation‐induced changes do not appear to be limited to the mesostriatal pathway, however, as adolescent mice isolated for 1–7 days showed an increase in cortical dopamine metabolism.107 Additionally, in the PFC, decreased GABAA‐stimulated chloride influx was evident in a membrane preparation from 24‐h isolated rats108 along with reduced benzodiazepine binding,81 indicating a decrease in cortical GABAA expression and/or function. Given the functional diversity of dopamine input to striatal subregions109110 and dopamine’s divergent effects on cortical projector populations,111 further work is necessary to elucidate precisely how these rapid isolation‐induced changes to dopamine neurotransmission influence downstream activity.

DRN dopamine system

Another component of the midbrain dopamine system—the DRN dopamine neurons—also exhibits acute isolation‐induced adaptations. These dopamine neurons were historically considered a caudal extension of the VTA, but accumulating evidence has revealed distinct downstream projections and functional roles.112118 In adult male mice, 24‐h social isolation potentiated glutamatergic synapses onto DRN dopamine neurons, and also heightened their activity in vivo in response to a novel mouse.118 Artificially enhancing activity of DRN dopamine neurons with optogenetic stimulation was sufficient to increase social preference. However, in the absence of a social stimulus, mice chose to avoid receiving stimulation of DRN dopamine neurons (demonstrated by real‐time and conditioned place avoidance), which suggests the induction of a negative affective state.118 DRN dopamine neurons may, therefore, be recruited following acute isolation to elicit “negative drive”–induced social motivation, in a manner distinct from the reward‐related social motivation mediated by the VTA–NAc dopaminergic pathway.103 Consistent with this assertion, optogenetic inhibition of the DRN dopamine population had no effect on sociability in group‐housed animals, but it suppressed social preference following 24 h of isolation.118

The DRN dopamine neurons lie directly upstream of several regions, most notably the BNST and CeA.116118 While the explicit role of dopamine in these regions in social behavior remains to be determined, dopamine receptor signaling can modulate synaptic transmission and activity in both the BNST and CeA.115118120 Specifically, in the dorsolateral BNST blunting of long‐term potentiation (LTP) is evident after 24 h of social isolation in male mice.121 Given that dopamine in the BNST can facilitate glutamatergic transmission, via a CRF‐dependent process,119 it is tempting to speculate that increased dopamine neurotransmission following acute isolation may occlude LTP.

Interestingly, it was recently revealed that an intermediate duration of isolation in mice (2 weeks) is associated with upregulation of the neuropeptide tachykinin 2 (TAC2; also known as neurokinin B) in several regions including the anterodorsal BNST (adBNST), CeA, and dorsomedial hypothalamus (DMH), with levels gradually increasing from just 30 min post‐isolation.122 Behavioral changes observed following 2 weeks of isolation appeared to be mediated by TAC2 upregulation in discrete sites, as chemogenetic silencing of TAC2‐expressing neurons in the adBNST, CeA, or DMH selectively prevented persistent freezing, acute freezing, or aggression, respectively.122 Notably, ∼50% of TAC2‐expressing neurons in the adBNST and CeA co‐expressed CRF,122 which again highlights the involvement of CRF circuits in isolation‐induced adaptation. A substantial body of work supports a role for the BNST in mediating sustained responses, and the CeA in mediating rapid responses, to potential/unpredictable threats.123 This behavioral control is enabled by the far‐reaching connections of the BNST and CeA, particularly with hypothalamic and brainstem structures, which underlies their ability to influence autonomic and neuroendocrine functions.124125 These regions are therefore well positioned to drive isolation‐induced adaptive responses, under modulatory control from upstream regions, including the DRN dopamine neurons.

This collection of findings compels the hypothesis that dopaminergic signaling may be involved in the initial response to social isolation, but that downstream regions (including the BNST and CeA) might exhibit longer term remodeling/plasticity following chronic isolation. Indeed, there is considerable evidence to support a similar model for the stages of drug‐evoked plasticity in the mesocorticolimbic dopamine system. Specifically, a single dose of cocaine is sufficient to potentiate glutamatergic transmission onto VTA dopamine neurons after 24 hours.126 Synaptic strength returns to baseline levels within a week, however, this VTA plasticity is required for the persistent changes that occur downstream in the NAc following prolonged cocaine exposure127 (reviewed in Ref. 128). This permissive role of synaptic plasticity in VTA dopamine neurons could similarly be a feature of DRN dopamine neurons in the response to social isolation. Such a feature would predict that acute isolation‐induced synaptic changes in DRN dopamine neurons precede, and are necessary for, chronic isolation‐induced adaptations in downstream regions. In this way, the myriad of maladaptive behavioral changes associated with long‐term social isolation37 might result from chronic engagement of neural circuits mediating the acute response to social isolation and persistent remodeling in downstream regions.

Opioid system

The opioid system exerts a broad influence on neural activity through widespread expression of opioid peptides and receptors, most notably within regions connected to positive reinforcement (reviewed in Ref. 129). Opioid signaling plays well‐documented roles in regulating pain/analgesia,130 reward processing,129 and social bonding,131 and has also been implicated in isolation‐induced social behavior. In vivo autoradiography revealed changes to opioid receptor binding, with 7 days of isolation in juvenile rats associated with upregulation of opioid receptor number or affinity in the PFC.57 Additionally, isolation‐induced social play in juvenile rats was attenuated by systemic administration of a μ‐opioid receptor (MOR) antagonist97132 or a ĸ‐opioid receptor (KOR) agonist,132 but enhanced by administration of a MOR agonist.97 Furthermore, in the CeA, infusion of an ACTH analog suppressed isolation‐enhanced social interest in 7‐day isolated rats, but this was prevented by administration of naltrexone (a MOR and KOR antagonist).56133 Therefore, both opioid and dopamine receptor signaling may be necessary for the heightened sociability evoked by acute isolation.

Hypothalamic oxytocin system

Oxytocin‐producing neurons of the PVN, along with the closely related vasopressin (AVP) neurons, are intimately involved in the regulation of social affiliation134 and have been particularly well studied in the monogamous prairie vole, as they play a pivotal role in pair bonding.135 Oxytocin neurons project not only to the posterior pituitary where they release oxytocin into the bloodstream but also to distinct targets within the brain for direct modulation of neuronal activity. One important site for oxytocin action is the NAc, which is a critical hub for the integration of motivationally relevant information and relays information to elicit motor responses.136 In male prairie voles, 3 days of isolation from a bonded female partner, but not a male sibling, decreased oxytocin mRNA in the PVN and oxytocin receptor binding in the NAc shell.137 Notably, oxytocin signaling in the NAc is reportedly essential for the expression of social CPP in adult male mice.138 Specifically, it was elegantly demonstrated that social CPP required activation of oxytocin receptors on presynaptic terminals in the NAc arising from DRN serotonergic neurons—facilitating serotonin release.138 Social CPP was further shown to be dependent on the PVN oxytocin projection to the VTA.139 Either suppressing activity in the PVN–VTA pathway or VTA dopamine–specific knockout of oxytocin receptors prevented social CPP in male mice.139 Collectively, these findings illustrate the dynamic balancing of dopamine, oxytocin, and serotonin signaling that is required for the reinforcing properties of social interactions.

Acute isolation has also been demonstrated to disrupt social recognition memory.140 Rodents possess an innate tendency to investigate novel rather than familiar social stimuli and typically reduce their investigation of a familiar conspecific on repeated exposure.141 This effect is absent in mice isolated for 24 h or 7 days, who display equivalent investigation of a familiar juvenile compared with the first exposure.142143 This lack of social recognition memory is associated with a suppression of oxytocin‐dependent synaptic plasticity in the medial amygdala (MeA) following 7 days of isolation in rats.144 Impaired social recognition memory may also result from elevated hippocampal Rac1 (a small GTPase), which is evident in male mice isolated for 24 h or 7 days.145 Thus, isolation‐induced modifications to oxytocin signaling, in a pathway‐specific manner, may contribute to changes in both social motivation and social recognition memory.

Homeostatic response to social deficit: a self‐protective coping strategy?

Individuals that self‐identify as lonely frequently exhibit features of negative affective state or depression.1050146149 Furthermore, individuals swayed toward feelings of future loneliness (by receipt of false feedback following a questionnaire) show a reduction in physical pain sensitivity and emotional sensitivity.89 This suggests the adoption of self‐protective strategies to minimize further emotional distress. While we cannot directly measure emotional state in rodents, we can assay motivated behavior as a proxy.58150 In rodents, immobility in the forced swim and tail suspension tests is thought to reflect passive coping and/or behavioral despair151152 (but see Ref. 153). There is a general lack of agreement over whether acute isolation alters immobility in these assays in mice.5573154 However, more consistent results have been obtained in monogamous prairie voles, wherein females or males isolated from their bonded partner for 3–5 days show an increase in immobility time.7071137

There is also evidence for disruption of reward‐related behavior in acutely isolated rodents, specifically in the response to addictive drugs. In rats, a 24‐h social isolation increased preference for ethanol and opioid intake, which was reversed with social housing.155156 Reduced pain sensitivity has also been reported, with male mice and juvenile rats exhibiting higher thermal and mechanical pain thresholds following 2–7 days of social isolation.157158 The prominent role of dopamine and opioid signaling in mediating the effects of drugs of abuse159 and analgesia130160 makes them strong contenders for underlying these adaptations. In particular, chemogenetic activation of ventrolateral periaqueductal gray (vlPAG)/DRN dopamine neurons can promote antinociception,117 while lesion of these neurons suppresses both the antinociceptive161162 and rewarding163 properties of exogenous opioids. Furthermore, inhibition of VTA dopamine signaling in mice can induce depression‐related behaviors,164 while KOR antagonists are proposed to have antidepressive effects in rodents (see Refs. 165167). In this way, interaction between the dopamine and opioid systems may underlie isolation‐induced changes to reward processing, pain sensitivity, and emotional affect.

In addition to dopaminergic and opioidergic mechanisms, isolation‐induced depressive‐like behavior may result from changes in the balance of CRF and oxytocin neurotransmission. Specifically, the passive coping behavior observed in pair‐bonded prairie voles isolated for 3 days was prevented by NAc shell infusion of a CRF2 receptor antagonist, or oxytocin, throughout the period of isolation.137 Microdialysis experiments suggest a mechanism by which this effect is mediated via presynaptic CRF2 receptor activation on oxytocin terminals in the NAc, which serves to reduce oxytocin release.137 These findings point toward a confluence of isolation‐induced adaptations in the NAc. The NAc receives strong glutamatergic input from thalamic and cortical regions, enabling it to integrate motivationally relevant information from neuromodulatory nuclei with higher cognitive and sensory input.168 Thus, this region is aptly poised to adapt goal‐directed behavior in response to social deficit.

Proposed attributes of components within a social homeostatic system

Flexibility

Animals are frequently faced with conflicting signals in the environment, which can elicit competing motivational drives. To ensure survival, animals must appropriately weigh environmental cues and evaluate them in light of current homeostatic need state. Selecting the appropriate behavioral response under these conditions requires dynamic coordination of neural activity.169 Thus, a key requirement for a social homeostatic system is its capacity for flexibility. Specifically, a change in environmental conditions and/or need state (e.g., hunger and thirst) may require a shift in the “set point” for social contact in the control center (Figs. 1B and 3). This will be heavily influenced by dynamic factors, such as resource availability, predator threat, mating prospects, and the presence of offspring.

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Figure 3Open in figure viewerPowerPointLong‐term integration of social experience within a homeostatic system. (A) Under normal conditions, appropriate functioning of a social homeostatic system would maintain social contact quantity/quantity within an acceptable dynamic range. Experienced social interactions may be assimilated and assessed (compared with set point) in a sliding window fashion across time (e.g., days/months). Social quality and quantity information might be weighted differently depending on the individual (traits) and current environmental conditions. The set point could be determined by a combination of factors including age, sex, species‐typical behavior, and past history of social encounters. (B) Failure of homeostatic system to correct deviations in social contact quantity/quality might result in a chronic deficit. This deficit (whether perceived or actual) may be associated with chronic engagement of homeostatic effector systems, and experienced as a state of loneliness. (C) Major life or environmental changes, such as moving away from home, or switching jobs, might provoke the need for a shift in set point. A stable shift in set point, and acceptance of a new expected quantity/quality for social contact, could represent an adaptive change. This shift may prevent social homeostatic effector systems from being chronically recruited and promote continued balance.

For example, in a state of hypernatremia (elevated plasma sodium, which is associated with the perception of thirst), rats exhibit greater social investigation of a novel intruder.170 This effect is proposed to have evolved to suppress anxiety in social situations, such as those encountered at a communal source of water, in order to promote social approach and allow drinking behavior.170 This observation suggests that social motivation can be altered by other physiological needs. Intriguingly, acute hypernatremia in rats is associated with increased plasma oxytocin, increased c‐Fos expression in magnocellular PVN oxytocin neurons, and suppression of ATII production.170 Given that ATII signaling can drive HPA axis activity, these data suggest that hypernatremia concomitantly suppresses activity within stress‐related circuitry, while promoting activity in social reward‐related oxytocin pathways, thereby inhibiting stress/anxiety‐related behavior and facilitating social interaction. This relationship illustrates overlap and coordination across homeostatic systems and also demonstrates the flexibility of effector systems.

The motivational state of hunger is another essential homeostatic drive that promotes rapid neural adaptations.171172 Specifically, the agouti‐related protein (AgRP) neurons in the arcuate nucleus of the hypothalamus are essential in the maintenance of energy balance, and increasing their activity can rapidly drive feeding behavior.173 Interestingly, in isolated mice, optical stimulation of AgRP neurons, or physiological hunger, provoked feeding, even in the presence of a novel male or female mouse.171 This finding suggests that AgRP activity in a state of hunger is sufficient to override a competing social motivational drive. Conceptually, it is possible that competing homeostatic drives are integrated into a social homeostatic system at the level of the control center in a “hub‐and‐spoke” fashion, or they may form an interconnected hierarchical arrangement that converges on effector systems (Fig. 1B). While it is possible that one homeostatic system may be subservient to another, an interconnected network would permit flexible control in a state of motivational need competition, prior to convergence on effector systems. Precisely how these homeostatic systems interface with one another remains to be elucidated.

Maintaining physiological variables, such as core body temperature and energy levels, within an appropriate dynamic range relies heavily upon a functioning immune system. Inflammation is theorized to be a unifying feature of homeostatic perturbation: providing a protective response to extreme deviations from the homeostatic set point.174175 Adverse conditions, including social isolation, can provoke a shift in immune function: enhancing expression of proinflammatory genes and reducing expression of antiviral/antibody‐related genes in circulating leukocytes.176 Social isolation may recruit this response to appropriately prepare an individual for the susceptibilities of being alone, which might include an increased need for a rapid inflammatory response to combat bacterial infections sustained through physical injury, but reduced need for protection against socially transmitted viral infections.15176 This immune response also appears to be recruited in a state of perceived isolation—humans with high self‐reported loneliness show enhanced proinflammatory activity but reduced antiviral response.66177179 Immune system changes can also predict subsequent loneliness, suggesting a reciprocal relationship between these two phenomena.64 Remarkably, classifying rhesus macaques as putatively high in loneliness (by sociability levels and social initiation attempts)180 revealed leukocyte gene expression changes similar to those observed in lonely human subjects.64 The recruitment of inflammatory processes under conditions of actual or perceived social isolation31 suggests that this state is recognized as a threat to an essential variable. As such, this supports the assertion that social contact may be regulated in a homeostatic manner.

Mixed selectivity

Considering the neural processing of “social homeostatic” information, one possibility is the existence of dedicated neural circuitry. An alternative model would feature overlap between neural systems governing social homeostasis and other highly conserved neural circuitry. This scenario would predict that certain nodes in a social homeostatic network display “mixed selectivity,” similar to neurons underlying other complex cognitive processes.181 In particular, this is conceivably a feature of “effector” regions in a homeostatic system. The disinhibition of VTA dopamine neurons, for example, has been shown to enhance motivation toward a variety of stimuli ranging from social stimuli to novel objects.182183 Furthermore, activation of BLA input to the ventral hippocampus or medial PFC (mPFC) not only induces robust anxiety‐like behavior in exploratory assays but also suppresses social investigation in the resident–intruder assay.184186 Perturbations in social behavior are often, but not always, co‐expressed with anxiety‐related behaviors, and there is significant overlap in their neural correlates, which suggests a tight relationship between these two forms of behavioral expression.58187

The DRN dopamine system is another prime example of overlapping circuit function. Monitoring fluorescent calcium activity in vivo revealed that these neurons are active in response to social stimuli, and this activity is heightened following acute isolation.118 However, these neurons are also responsive to other salient stimuli, including palatable food and unexpected foot shock, and show greater activity during wakefulness compared with sleep, suggesting an arousal‐promoting function.112115188 This diversity of sensitivities is consistent with the notion that neural circuits regulating social homeostasis may promote attention to a variety of salient stimuli, in an effort to scan the environment for potential threats or opportunities for social engagement. It was also recently reported that optogenetic or chemogenetic inhibition of DRN dopamine neurons during fear conditioning suppressed freezing in response to a footshock‐predictive cue, suggesting an additional role in aversive responding.115 Taken together, these findings illustrate the existence of multiple mechanisms through which DRN dopamine neurons may limit the vulnerabilities of being alone: increasing social motivation, promoting vigilance/arousal, and enhancing responsivity to aversive stimuli.

Considering the potential for mixed selectivity, the recent observation that activation of DRN dopamine neurons not only increases social preference118 but can promote antinociception117 could be reconciled in a number of ways. One possibility is that functional heterogeneity exists within this cell population. Another possibility is biological convergence in the representation of emotional pain and nociceptive pain in DRN dopamine neurons. In accordance with this notion, an emerging hypothesis posits that social pain and physical pain are processed by overlapping neural circuitry.189 This is supported by human imaging studies revealing that social disconnection engages brain regions including the dorsal anterior cingulate cortex and anterior insula cortex,190 which also process the affective component of physical pain.191 This dual role of DRN dopamine neurons also points toward a potential mechanism through which acute isolation reduces pain perception.157158 It is also interesting to note that inflammatory pain is suppressed by activation of AgRP neurons, suggesting a general reduction of chronic pain perception by strong motivational drive states.192 Mixed selectivity may, therefore, be a common feature within neural circuits regulating homeostatic needs, and cross talk between these systems might facilitate the activation or suppression of appropriate “effector” systems (Fig. 1).

Subjective nature of social experience

A third element in conceptualizing a social homeostatic system is the integration of subjective experience. There is mounting support for the notion that subjective or “perceived” isolation (the quality of social relationships) is a stronger predictor of poor health and emotional state in humans than objective isolation (the number/frequency of social contacts).1162146 Consistent with this, loneliness—independent of social network size—is associated with higher mortality13193 increased blood pressure,11194 higher rate of diabetes, hypertension, arthritis, emphysema,195 and Alzheimer’s disease,196 along with poor health habits stemming from a lack of self‐control.197198 Thus, in evaluating social needs, a homeostatic system would need to incorporate a subjective assessment of social experience, in addition to its overall objective nature), which may be heavily influenced by interoceptive signals and internal state (Figs. 1 and 3).

There is an ongoing debate as to whether animals experience emotions in the same way as humans.150199 However, it has been reasoned that emotions constitute an internal state, encoded by specific neural circuits, which can give rise to externally observable behaviors.150 These internal brain states may be subjectively perceived as feelings by the individual.150 Although the traditional concept of homeostasis refers to a purely automatic physiological control system, motivational drive states (guided by “homeostatic feelings”) play a significant role in maintaining homeostasis.200 Homeostatic feelings act as “informative regulatory interfaces”—providing means for an animal to sense its physiological state and guaranteeing attention to relevant stimuli.200 While this process can be adaptive and introduces greater flexibility into homeostatic regulation, it also passes an element of control to the individual, taking homeostatic regulation beyond purely automatic mechanisms.200

In order to understand the neural mechanisms of social homeostasis, a major hurdle lies in the ability to infer subjective social experience in animals.14 Although we can never truly know the emotional experience of a rodent, one method of differentiating between individuals is by exploiting the natural variability introduced by social hierarchy. Grouped living can lead to the establishment of social hierarchies in multiple species including fish, birds, rodents, and primates.201204 Hierarchies create a scenario in which grouped individuals might have divergent perceptions of their social experience. Social rank can influence access to essential resources including food, territory, and mates,205 and thus a more dominant rank is often a coveted position associated with higher quality of life. Although subordination in animal societies is not always directly related to low social connectedness or unmet social needs, social rank bestows variability in subjective social experience without removing support structure for safety, warmth and other nonsocial benefits of a group.

Strikingly, studies on social hierarchy in mice and rats have revealed underlying neural correlates in the same circuits implicated in the response to social deficit (Fig. 2). These findings include differences between subordinates and dominants in CRF expression in the BNST, CeA, MeA, and medial preoptic area;206 mitochondrial function and dopamine signaling in the NAc;207208 and glutamatergic synaptic strength in the mPFC.209 The mPFC, in particular, is frequently implicated in the representation of social rank. Most recently, “winning”‐induced plasticity in the tube test was localized to a mediodorsal thalamic (MDT) projection to the dorsomedial PFC (dmPFC), as phasic optogenetic stimulation of the dmPFC, or the MDT–dmPFC projection, immediately induced winning against a previously dominant cagemate.210 Notably, social rank also predicted the magnitude of behavioral effects elicited upon DRN dopamine manipulations in mice.118 Optogenetic activation of these neurons promoted social preference and real‐time place avoidance, whereas inhibition reduced isolation‐induced social preference. However, the behavioral change observed in these assays was greater in dominant animals relative to subordinates.118 This observation suggests that prior social experience may influence the ability of the DRN dopamine neurons to modulate behavior. Collectively, these findings illustrate that rank‐related information may be integrated into multiple neural circuits that respond to social deficit (Fig. 1A). This organization would permit flexible control over homeostatic regulation and adjustment of goal‐directed behavior depending on the social opportunities available.

Moving forward, several questions remain in elucidating how social information might be processed through a homeostatic system. For example, is the individual’s “expectation” for social contact encoded upstream in detector regions, or at the level of the control center? And how are different categories of social contact represented? To speculate on this last point, one possibility is that a social homeostatic system is category blind. Another potential arrangement would involve separate processing streams for the regulation of different social relationships, such as same‐sex, opposite sex, mother–offspring, or unfamiliar conspecifics. Indeed, specialized circuits, within discrete hypothalamic nuclei, underlie the expression of parental behavior,211 aggression,212 male intruder–specific behavior,213 opposite‐sex approach,214 and mating.212 If we conceptualize these as discrete “effector systems,” then this raises the possibility that decentralized processing of different social “needs” may occur in separable nodes.215 However, the precise organization of social homeostatic elements remains a topic of conjecture.

Valence of motivational drive

A fourth consideration is the valence of motivational drives that direct social interaction.216 Motivated behaviors regulating food intake are often distinguished as homeostatic (essential for maintaining energy balance and survival) or hedonic (driven by sensory perception or pleasure in the absence of a need state).217 Feeding behavior, therefore, is directed by motivational drives of opposing valence: the negative sensation of hunger and the positive hedonic value of palatable food. In extrapolating to social behavior, equivalent opposing motivational drives may promote social interaction: the aversive state of isolation and the hedonic value of social reward. However, while mechanistic differences exist, the neural systems mediating homeostatic and hedonic feeding are proposed to be intertwined, and highly overlapping with reward circuitry.217218 Similarly, social reward circuitry is heavily recruited in isolated animals. Engagement of reward circuitry in situations of social deficit may enhance the rewarding value of social contact—potentially similar to how food deprivation enhances the rewarding properties of food.219222 In support of this concept, functional magnetic resonance imaging (fMRI) in humans has revealed that more lonely individuals show greater activation of the ventral striatum in response to familiar social cues,223 but contrastingly reduced activation in response to unfamiliar social cues.224 Similarly, ventral striatal activity is initially high in response to palatable food but diminishes as individuals consume beyond satiety.225

The coordination of social behavior to meet homeostatic needs may, therefore, recruit both positive and negative motivational processes. The DRN dopamine system might be one source of negative motivational drive in response to social deficit.118 Recruitment of this system aligns with the “drive reduction” hypothesis, in which internal state elicits goal‐directed behaviors in order to reduce the intensity of an aversive/negative motivational drive (e.g., hunger and thirst)226 (Fig. 1C). A potentially similar function has been described for arcuate nucleus AgRP neurons and nitric oxide synthase 1 (NOS1) neurons in the subfornical organ (SFO). These neurons show heightened activity during hunger (AgRP) and thirst (NOS1), their activity elicits an aversive state (place avoidance), and they are essential for driving feeding and drinking behaviors, respectively.21227

However, the role of valence processing in homeostatic feeding behavior is complex. AgRP neurons are activated in a state of energy deficit,228 and their optical stimulation can voraciously promote food consumption, but also elicits real‐time place avoidance (indicative of an aversive state) in the absence of food.173227229 However, AgRP activity is rapidly suppressed on sensory detection of food,227228230 which, surprisingly, suggests that ongoing AgRP activity is dispensable for food consumption. This paradox is potentially reconciled by the observation that brief optical stimulation, as little as 1 min, prior to food availability was sufficient to promote robust, sustained feeding in well‐fed mice once food was made available.231 Furthermore, mice performed operant responses to stimulate AgRP neurons in the presence, but not the absence of food, suggesting that AgRP activity can be positively reinforcing.231 Therefore, an alternative hypothesis proposes that AgRP activity provides a sustained positive valence signal that potentiates the incentive value of food, and supports transition from foraging to feeding behavior via persistent changes in downstream circuitry.231 Intriguingly, this is not a feature of SFO NOS1 neurons, as prestimulation was insufficient to drive drinking behavior when water was subsequently made available.231 Therefore, the relationship between neuronal activity and behavioral regulation may depend on the specific homeostatic need.

While the precise role of DRN dopamine activity in social motivation and valence processing remains to be fully elucidated, drawing insight from other neural circuits that participate in maintaining homeostatic balance provides mechanistic clues into their mode of operation. However, an important consideration for social behavior is that (unlike food detection) initial social contact does not necessarily guarantee a rewarding social experience. Therefore, immediate suppression of neural activity on social contact may be inappropriate for DRN dopamine neurons, and activity might persist until a stable relationship has been achieved. Moving forward, it will be important to determine the temporal dynamics of activity within and across neural circuits during the response to social deficit and to understand how valence is represented in these systems.

Outlook

Moving forward, we propose that improving the evaluation of subjective social experience, and standardizing parameters used in studies of social behavior (Table 1), will accelerate the assembly of a cohesive model for social homeostasis. Studies in rodents are continuing to move toward approaches that capture larger, more naturalistic group living,206 and the incorporation of automated tracking is permitting a deeper longitudinal analysis of complex social interaction dynamics.232 Great promise has arisen from detailed behavioral observations on groups of nonhuman primates, facilitating classification of social relationship quality in females chacma baboons30 and putative loneliness in male rhesus macaques.180 Across the animal kingdom, we may see conservation in neuromodulatory systems for social behavior all the way to invertebrate systems, as recent groundbreaking work in the octopus demonstrates.233Table 1. Experimental conditions to report in the methodology of studies on social behavior and/or social isolation to facilitate informative interpretation and reproducibility

Grouped/Control AnimalsIsolated Animals
Housing conditions
Number of cage matesPrior number of cage mates
Cage mate relationship (siblings/age‐matched etc.)Cage mate relationship (siblings/age‐matched etc.)
Sexual experienceSexual experience
Age at isolation
Duration of isolation
Extent of experimenter handlingExtent of experimenter handling
Housing type (size, bedding material etc.)Housing type (size, bedding material etc.)
Social rank (if known)Social rank (if known)
Environmental enrichmentEnvironmental enrichment
Proximity of other animals
Normal or reverse light/dark cycleNormal or reverse light/dark cycle
Measurement of behavioral/neurophysiological parameters
Time of testing
Age at testing
Conditions of behavioral assays
Stress exposure
Food/water restriction
Timeline of conducted experiments

Current technological approaches in rodents now provide unprecedented temporal and spatial resolution with which to scrutinize neural circuits and have already yielded fascinating results identifying discrete systems mediating specific social behaviors including parental behavior,211 social reward,103138139 and social observational learning.234 The new millennium has brought with it a rapid rise in opportunities for social nourishment together with a growing prevalence of loneliness and social isolation. Given the protective effects of social contact on a vast array of physical and mental health measures, there has never been a more important time to understand the neural mechanisms underlying the need for social connection.

Acknowledgments

This article was prepared by invitation of the New York Academy of Sciences for publication in a special issue of Ann. N.Y. Acad. Sci. presenting work from winners and finalists of the Innovators in Science Award; K.M.T. was an Early‐Career Scientist finalist in 2017. Takeda Pharmaceutical Company Limited sponsors the Innovators in Science Award, as well as open access of this paper.

We thank Gwendolyn G. Calhoon and Ruihan Zhang for comments on the manuscript and all members of the Tye Lab for helpful discussion. K.M.T. is a New York Stem Cell Foundation–Robertson Investigator and McKnight Scholar and supported by funding from the JPB Foundation, the Picower Institute Innovation Fund (PIIF), the Picower Neurological Disorder Research Grant, the Picower Junior Faculty Development Program, the Alfred P. Sloan Foundation, the New York Stem Cell Foundation, the McKnight Foundation, and by the following Grants from the National Institutes of Health: NIMH R01‐MH102441‐01, NIMH R01‐MH115920, NIA RF1‐AG047661‐01, the NIH Director’s New Innovator Award DP2‐DK‐102256‐01 (NIDDK), and the NIH Director’s Pioneer Award DP1‐AT009925 (NCCIH). G.A.M. was supported by a fellowship from the Charles A. King Trust Postdoctoral Research Fellowship Program, Bank of America, N.A., cotrustees.

Competing interests

The authors declare no competing interests.

Consciousness as a Delusion

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In Chasing the Rainbow: The Non-conscious Nature of Being, David Oakley and Peter Halligan (2017) present the theory that consciousness is a delusion.

At the time of publication, the paper in Frontiers has received 107,012 views.

According to their theory, consciousness is a specially engineered delusion; let’s call it the ‘CAD theory’. Because, to them at least, consciousness is only a delusion, O&H place the word inside scare quotes, as ‘consciousness’. Here, I leave the word as it should be left: consciousness it is and consciousness it stays.

According to the CAD theory, the ‘epiphenomenon’ of consciousness evolved to provide humans a false belief that they are actors with agency. In reality, so O&H claim, all psychologically meaningful and functional processes occur within an unconscious ‘Central Executive Structure’ (CES).

The CES is an amazing cortical device that craftily creates a fake experience of consciousness to deceive naïve humans into the false belief that they have the power to voluntarily control their individual destinies with agency and selfhood. All other psychological products are manifested in Personal Awareness a brief ‘Libet’ unit of time after their production by the CES. Consciousness does not control any behavior. It serves a passive, narrative function as an excrescence. Humans are simply automatons. In 1999, the editor of an American Psychologist special issue entitled “Behavior— It’s Involuntary” wrote: “We perceive ourselves to have far more control over our everyday behavior than we actually do. . . . [T]he source of behavioral control comes not from active awareness but from . . . mental activations of which we are unaware and environmental cues to which we are not consciously attending that have a profound effect on our behavior (Park, 1999, p. 461). The CAD theory is illustrated in Figure 1.

The CAD Theory

Figure 1. The Oakley-Halligan CAD model. The schematic diagram shows all current CES functions and other psychological activities as non-conscious processes and their products. The most task-relevant of these psychological products are selected by a Central Executive Structure (CES) to create an ongoing personal narrative via the process of Internal Broadcasting. This personal narrative is passively accompanied by personal awareness – a by-product of Internal Broadcasting. Some components of this narrative are selected by the CES for further transmission (External Broadcasting) via spoken or written language, music, and art to other individuals. The recipients in turn transmit (internally then externally) their own narrative information, which may contain, or be influenced by, the narrative information they have received. The CES also selects some contents of the current personal narrative for storage in autobiographical memory. The contents of external broadcasts contribute (via Cultural Broadcasting) to an autonomous pool of images, ideas, facts, customs, and beliefs contained in folklore, books, artworks, and electronic storage systems (identified as “Culture” in the Figure) that is accessible to others in the extended social group but is not necessarily dependent on direct interpersonal contact. The availability of culturally based resources is a major adaptive advantage to the social group and ultimately to the species as a whole. The CES has access to self- and other-generated externally broadcast content as well as to cultural information and resources, all of which have the potential to provide information that supports the adaptedness of the individual and to be reflected in the contents of their personal narrative. As a passive phenomenon, personal awareness exerts no influence over the CES, the contents of the personal narrative or on the processes of External and Cultural Broadcasting. In the Figure non-conscious process are identified in green and personal awareness (subjective experience) in blue. (From Oakley & Halligan, Front. Psychol., 14 November 2017).

The simplistic automaton of the epiphenomenonalist view, in this reviewer’s opinion, is an inadequate and flawed scientific theory, which, ultimately, offers a false doctrine. Alternative positions that warrant more serious consideration include the emergence theory that views phenomenal ‘consciousness’ as a naturally emergent feature of life and complex brains (e.g. Sperry, 1990; Feinberg & Mallatt, 2020). IMHO, in spite of its rhetorical merits, this interesting and provocative paper does not ‘unmask consciousness’ but manages to conceal and obscure its true nature in obfuscation.

Merits and Demerits of the CAD Theory


Overall, the paper provides a clear statement of a well-known epiphenomenonalist view of consciousness, namely that consciousness is a superfluous carbuncle in the scientific analysis of behavior. The paper is concise and mainly internally consistent but it presents a highly incomplete and misleading analysis of consciousness and the associated cortical structures.

If it is to be given serious attention as a scientific theory, the authors need to specify not only (A), the axiomatic assumptions and ancillary propositions of the theory, but also (B), refutable and novel predictions evaluated with robust empirical evidence. However, to date they have only succeeded in producing A, the ‘pudding’, but there is no B, ‘proof of the pudding’. Unless refutable predictions can be added, this paper and theory will remain a flight of fancy about what might be so that is lacking any defined empirical tests to assess its veracity one way or the other. The current iteration of the theory, crafted and polished over several decades, remains a scientifically weak, descriptive theory of consciousness.


Unless the claims sketched out by O&H can be substantiated with hard evidence, the theory will remain a quaint ‘straw man’ on the hinterlands of the scientific study of consciousness. To be fair, the authors do mention in passing a few speculative hypotheses about brain mechanisms but they are vague (e.g. Figure 3) and I can find no substantive hypotheses that can be tested in non-brain-damaged subjects. The Casarotto et al. (2016) study described by the authors appears to this reviewer to have questionable relevance and should perhaps be removed.

There have already been several criticisms of the CAD paper. How are these known criticisms to be rebutted? What new research will follow from the claim that consciousness is a delusion? Does the CAD claim not have a stultifying impact on new investigation if there is nothing worth discovering about the consciousness delusion?

There are some well-known limitations and shortcomings of the CAD theory that need to be addressed.

Consciousness as an Unnecessary Epiphenomenon

As the authors must be aware, there are established objections to their type of epiphenomenalist account of consciousness that they have not addressed. For example, Meese (2018) raises the first technical objection with these words: “…the simple fact is, we can talk about consciousness. This is not trivial; it means the thing we call consciousness can influence the underlying system (by causing it to speak), and in philosophy of mind, epiphenomena do not have causal feedback (e.g., Megill, 2013), so consciousness cannot be epiphenomenal (Blackmore, 2004; Bailey, 2006; Robinson, 2015)”. So how do O&H answer this objection? To date, they have given no answer.


O&H believe that consciousness is not required. Yet, they write about consciousness throughout the article as (a) process(es) that they and readers all perfectly understand as universally available phenomenal consciousness. However, different people often mean different ‘things’ when they talk about consiousness. Also following Meese (2018): “we can envisage a machine that is programmed to store only some of its internal operations in memory, and call that a personal narrative, but it does not follow that this will imbue the machine with consciousness.”


A significant point overlooked in O&H’s manuscript is the fact that, in one or more of its different states, consciousness has demonstrable adaptive value. Consciousness convincingly delivers selfhood to ‘actors’ who set global, behavioral priorities and goals, life choices, career, country and region of residence, sexual preferences, gender assignment and choice of mate, beliefs, values, opinions, and significant communication, social, artistic and cultural functions. According to O&H’s theory, these ‘choices’ are all delusory products of an unconscious CES. Yet, in delegating all of developmental, personal, social and behavioral adaptations to the CES with a stroke of the pen, gaping holes are evident, straining the theory with severe limitations.


First Missing-Link: Motivation


According to O&H’s theory, the unconscious CES is responsible for the ‘what’ and ‘when’ of behavior – thinking, choosing, planning, remembering, problem solving, acting – in their entirety. However, the all-important ‘how’ and ‘why’ and associated ‘feelings’, emotions, drives and cravings that underly behavior are in another department of unconscious processing not considered relevant in the theory. Motivation, needs, wants are nowhere to be found. If ‘free will’ really is a delusion, then surely it remains necessary to formulate how and why the CES decides which actions are momentarily beneficial to survival and need to be prioritized? The authors do not say. Perhaps O&H could consider the following sources:

Maslow (1943): “”Thus man is a perpetually wanting animal.” Thwarting, actual or imminent, of these basic needs provides a psychological threat that leads to psychopathy”;

Rogers (2008): “The directional tendency in every living organism of maintaining, enhancing, and reproducing itself is seen as fundamental to the question of motivation. This “actualizing” tendency involves development toward autonomy and away from heteronomy, or control by external forces”;

Fanselow (2018):”Fear has the ability to overwhelm consciousness so that that nothing but phylogenetically selected action occurs. By filling consciousness fear prevents flexible behaviors and that is one reason why anxiety disorders can be so debilitating. Anxiety, fear and panic are states within the emotion that correspond to different levels of threat.”

If consciousness as a delusion is overwhelmed by fear, then the feeling of fear itself must be a delusion. Yet this ‘fear delusion’ is necessary for survival. In which case, consciousness is necessary for survival. QED.


Second Missing Link: Arousal, the Waking State, and Sleep


The well-known circadian alterations in consciousness that fall under the ‘arousal’ umbrella range from the fully awake state through intermediate states of inattention and drowsiness to sleep are all missing from O&H’s theory of consciousness. Self-evidently, these dramatically different, scientifically well-established states of conscious awareness are not delusory, nor are they figments of the CES ‘broadcasting station’. They exist. They are real. They are universal across many species apart from humans.


Third Missing Link: Mental Imagery/Imagination


Another notable absentee from the CAD theory is mental imagery/imagination. In this respect, O&H differ from Jorion (1999), who equated the alleged ‘consciousness delusion’ with ‘imagination’. O&H talk instead about ‘internal broadcasting’, the scripted narrative provided by the CES, serving the function of keeping the deluded and unconsciously controlled human content with their little lot by listening to especially scripted messages broadcast by an all-powerful inner structure. Thus, the internal broadcasting is like a ‘mental radio station’. O&H appear to have missed a trick here. They could just as easily have inserted a ‘multi-channel mental TV’ into the CES which could include fantasy fiction, travel, series, horror, thrillers, erotica/’adult’ material for instant replay whenever required by waking daydreams, dreams and nightmares, and even a ‘playstation’ for hypnotic and hypnagogic mental games such as counting sheep as people are drifting off to sleep. This ‘modernisation’ of the CES would make it immensely more powerful by enabling ‘broadcasting’ of a vast range of imaginative material into what the lay person calls the ‘mind’s eye’ unavailable on steam radio. Other sensory modalities could be added to the broadcasting of the CES to bring it into line with the quasi-perceptual qualities of taste, olfaction, touch, somatic sensations and synaesthesia. The current version allows only narratives ‘propaganda’ conjured up for innocents who believe the delusion that they are fully conscious with agency, selfhood, integrity, and a moral compass.

Figure 2 mentions the right cortex having ‘visuo-spatial ability’ so a rudimentary ‘mind’s eye’ is present in the theory but needs to be elaborated if the full range of known ‘internal broadcasting’ is to be captured by the theory. A more minor point: Figure 2 suggests a division of the two cortical hemispheres (‘verbal’ vs ‘visuo-spatial ability) in line with 1960s and 1970s neuropsychology with ‘sequential’ processing on the left side and ‘simultaneous’ processing on the right side. Is this classification still viable? Also, the arrow at the top of Figure 2 labelled “suppresses” requires clarification.


Fourth Missing Link: Adaptive Benefits of Consciousness


O&H’s proposition that consciousness should be abolished from science would gain more credence if there did not exist multiple, well-established, demonstrable evolutionary benefits of consciousness. Evidence of biologically adaptive benefits of consciousness has been reviewed in several articles (e.g. see Earl, 2014, 2019; Feinberg & Mallatt, 2020).

Consider these 12 categories of evidence :


1) The complexity and enormous range of altered states of consciousness need to be explained. O&H lump all of the processes and states of consciousness together as a single entity yet this is manifestly incorrect, viz. sleep, dreams, hypnagogic/hypnopompic state, hypnotic state, hypnotic analgesia, meditation, trance, trance logic, dissociative states, etc. Why do these empirically identifiable ASCs all exist and why are they necessary? Are these states all delusional? Do none have beneficial advantages to survival? Why does sleep and/or dream deprivation have such strongly detrimental effects on wellbeing? Lacking any consideration or acknowledgement of the complexity of consciousness, the O&H theory falls at the first post.


2) It is known that ancillary systems have evolved in association with consciousness, e.g. two perceptual systems, two memory systems, explicit vs implicit memory. In each case, why would two systems be necessary? Are both systems delusory – in spite of decades of supportive empirical evidence that they have functional relevance?


3) Whenever one is actively involved with events, one experiences representations of them, which aids selection of pleasurable vs non-pleasurable stimuli. If consciousness had no effect on behaviour, then it could indicate something quite different to what was actually happening, and it wouldn’t actually matter because, according to the theory, the CES would still control all human actions, so ‘consciousness’ must be adaptive.


4) Clearly, pleasure and pain are not delusory, yet they are an essential part of conscious experience. Consciousness ranks sensed stimuli by importance, enabling decisions on how to respond (Cabanac, 1996).


5) Self-related information, very relevant to survival, is treated differently from non-self-related information. This consciously experienced ‘personal self’ appears to be anything but a delusion. The selfhood/identity of a person is associated with a unique life history, kith and kin relationships, legal identity and set of morals, values and beliefs. The sense of selfhood is palpable and real.Self-protective behaviors in the face of danger trigger near-instantaneous “freeze, flight, fight, or fright” (4 F’s) behaviors with millisecond rapidity. A dog walks towards me barking aggressively. I freeze before moving away rapidly. It is me the dog approaches not the person on the other side of the road. I take preventive action accordingly. No internal broadcast here, just an instantaneous physiological and conscious choice.


6) Consciousness can directly influence behavior. Feelings and perceptions re-direct one from one activity to another without any significant delay. One can make immediate ‘changes of mind’ with fast adjustments to new stimuli. The few 2-300ms delay suggested by Libet’s contentious work is neither here nor there in the bigger picture of adapting to life’s slings and arrows.


7) Consciousness includes qualia, which convey information at a subjective level from a particular point of view. Why would qualia have evolved without adaptive purpose? The use of qualia increases with experience in specialized tasks, e.g. sommelier training for wine tasting. “An experienced taster obtains an initial, visual impression, potentially signals unappealing smells, and decides whether the eyes were right, indeterminate, or wrong. He/she then decides whether the wine is a good exemplar of the premium quality category or not. Taste representations may only provide confirmation, in combination with the representations available from the other senses (e.g., taste balance)” (Caissie, A. F., Riquier, L., De Revel, G., & Tempere, S. (2021). Representational and sensory cues as drivers of individual differences in expert quality assessment of red wines. Food Quality and Preference, 87, 104032.) Without qualia, such fine distinctions among trained experts would be impossible. The CES alone is not sufficient to explain human sensory discrimination ability. Chefs, composers, conductors, designers, engineers, surgeons, and artists rely on qualia in their creative work, which would be poorer in their absence.


8) Consciousness perceives and organizes sensory information into a detailed, unified simulation of the world, so that a person can choose the most efficacious and desirable responses based on simulations and conscious mental maps. Geographical space serves as a mental framework for an individual’s experiences of the world. Immensely significant life choices do not happen using only the unconscious CES. They require the entirety of the conscious imagination in communication with connected others. Consider migration: “Quintessential human migration occurs when people deliberately abandon one home in favor of a distant and unseen goal. In the nineteenth century many Europeans left their homes for remote parts of the world of which they had no direct experience. They did not go blindly: the move was a calculated risk. They had images of their new homes based on hearsay, letters from relatives, and immigration literature. Indeed these attractive images were a cause of their desire to move.” (Tuan, 1975).


9) Memories and thoughts are triggered by consciously experienced feelings, a process that is utilized beneficially in multiple kinds of psychotherapy and in nostalgic episodes when recalling earlier experiences, childhood memories and occasions. The conscious ‘reliving’ of life experiences with nostalgia provides joy for the self and affirms social identity (Sedikedes et al., 2015). The CES cannot achieve the positive outcomes achieved by memory work without the beneficial outcomes of conscious recall.


10) O&H insist that scientific psychology rests exclusively on a third-person perspective. However a complete science of psychology requires the first-person perspective also. One cannot be reduced to the other. Neither has priority in a proper science of ‘consciousness’. In accordance with Velmans (1991b): “information processing models which view humans only from a third-person perspective are incomplete…first-person and third-person accounts are complementary, and mutually irreducible. A complete psychology requires both.”


11) Again, following Velmans (1991b), from a third-person perspective, consciousness does not enhance adaptive functioning. Rather, the brain functions, in part, to produce experience. From a first-person perspective, the difference this makes is obvious. Without consciousness there would be no experienced world.”


12) In the domain of health-related behavior, people often act in non-optimal ways. Individuals would like to quit smoking, eat healthily, get enough sleep, and exercise, but they do not engage in these behaviors as often as they wish. Individuals also engage in risky behaviors such as drinking too much, unprotected sex, and the like, that can compromise health, either acutely or over the long-term. Issues of this type often result from failures to transcend the moment in the service of long-term goals. Impulsive tendencies (controlled by the CES in O&H’s theory) tend to favor behaviors, such as eating fatty food, that provide immediate pleasures, but can be problematic if repeated. Something like an ‘ego centre’ for control based in consciousness is needed to represent long-term goals of restraint to align current behaviors with courses of action that tend to be health-promoting (de Ridder & de Wit, 2006). See also point 3 above.


Conclusion


The CAD theory fails on a number of counts. Major revision is necessary to rebut the criticisms and to fill the void left by the numerous gaps identified above. Perhaps O&H will claim points 1-12 above are all, like consciousness itself, delusional. Owing to the flaws inherent in the approach, it seems doubtful that a rebuttal can be successfully achieved.

“Doctors can commit scientific fraud and financial fraud and not be punished”

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Press Release by Dr Myhill concerning Dr Myhill’s Virtual Hearing 22 MARCH 2021 – vs ICO & GMC

Doctors can commit scientific fraud and financial fraud and not be punished. This is the conclusion of Dr Sarah Myhill following her recent hearing vs the ICO and GMC.

Dr Sarah Myhill tells us “That is official General Medical Council policy”.

The PACE study of 2011, which concluded that patients with CFS and ME could be effectively treated with graded exercise and cognitive behaviour therapy, has been proven to be scientifically fraudulent. This fraud is so profound that PACE recommendations have been dropped by NICE. We now know that graded exercise makes patients with CFS, ME and Long Covid much worse. CBT is of little benefit, only as a supportive measure.


In response to this fraudulent study, Dr Myhill reported the authors of PACE, and its directors, to the General Medical Council in January 2018. The GMC has a duty, and is empowered by Parliament, to regulate doctors and this includes research misconduct. Despite taking six months to consider Dr Myhill’s request, the GMC refused to investigate. Dr Myhill supplied extensive scientific proofs but in its refusal the GMC failed to supply its scientific defence.


So, Dr Myhill, through FoI legislation, asked that the GMC supply her with the scientific references on which it relied in coming to its decision not to investigate the PACE authors. The GMC refused. It gave no reasons whatsoever.


Consequently, Dr Myhill reported the GMC to the Information Commissioner who in a ruling of 30 September 2019 agreed with her. The ICO informed the GMC that it must supply her with the scientific references on which it relied in deciding not to investigate the PACE authors. This was because Dr Myhill was asking simply for scientific references already in the public area. This was only fair to the thousands of patients who have been damaged by graded exercise and who have a right to a proper explanation as to why.


At this point you would think the GMC had to comply. However, it is suspected that the GMC refusal arose for reasons of cronyism – it did not want ex-Presidents of Royal Societies up in
front of the GMC and the Police. It did not want to admit that actually it held NO scientific evidence, and it had no good reason to proceed as it did.


So, the GMC had to think up some sort of legal argument for refusal. Hitherto it had no argument – simply blunt refusal. The GMC consulted with its legal beavers within and outside the GMC and came up with the argument that to comply with the ICO demands would infringe the personal privacy of the PACE authors. What a nonsense! Dr Myhill has no interest in the personal data of the PACE authors. She simply requested scientific references which should all be in the public arena!


This was the subject of the ICO Hearing on 22 March 2021: Myhill vs GMC and ICO.


The outcome was a split decision. It boiled down to the Public Interest test. Tribunal member Mr Malcolm Clarke agreed with Dr Myhill. He stated:


“I conclude that Dr Myhill’s legitimate interest in seeking this information, if it exists, as a practising doctor with patients, who has a deep professional interest in ensuring that national recommended treatments in this area of medicine are evidence-based, is a very strong one …Dr Myhill’s legitimate interest in knowing whether the information she requests is held by the GMC is a very strong one. I therefore conclude that ……Dr Myhill’s legitimate interests are not overridden by the rights and freedoms of the data subjects.”

Ref paragraphs 42-47,EA-2020-0018 Myhill v IC & GMC


Luckily for the GMC, the Judge Hazel Oliver and Panel member Gareth Jones disagreed. They decided the other way round.


This Ruling sends a very clear message to doctors who commit scientific fraud – it is easy to get away with it, you can easily hide behind Data Protection issues and the General Medical Council will assist. Cronyism works.


………and so now to round 4. Dr Myhill will not give up.


See https://www.drmyhill.co.uk/wiki/My_Complaint_to_the_GMC_about_the_PACE_authors for more detail

Towards a comprehensive theory of obesity and a healthy diet: The causal role of oxidative stress in food addiction and obesity

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Review published in Behavioural Brain Research

Volume 384, 20 April 2020, 112560

written by: Tobore Onojighofia Tobore

Independent Scholar, San Diego 92110, United States

ShareCite https://doi.org/10.1016/j.bbr.2020.112560

Get rights and content

Abstract

Background

Obesity is a major public health problem whose prevalence has been rapidly increasing in the United States (U.S), and globally. It is one of the leading causes of preventable deaths globally and contributes to the development of many diseases.

Methods

The search was limited to studies published in English and other languages involving both animal and human subjects. Articles selected included preclinical studies, randomized clinical trials RCTs, observational studies, meta-analyses, narrative and systemic reviews providing primary quantitative data with a measure of obesity or food addiction as an outcome. Over 5000 articles were found in the first round of search which was filtered to 506 articles.

Results

Oxidative stress plays a critical role in food addiction and is both a cause and mediator of obesity. Reactive oxygen species play a direct role in adipogenesis and oxidative stress modulates all factors involved in obesity including genetics, sleep, gut microbiome, insulin, ghrelin, inflammation, adipokines, leptin, stress, HPA axis, and the hypothalamus.

Conclusions

The idea of thinking of combating obesity from the lens of calorie count, low carbohydrate, high or low-fat, vegetarian, vegan, plant-based, or animal-based diet is fundamentally wrong. The best way to look at obesity is through the framework of systemic redox homeostasis. Since redox homeostasis is tilted towards increased reactive oxygen species production, and excessive antioxidant intake can result in oxidative stress, an antioxidant and prooxidant food ratio of 2:3 per meal is the ideal nutritional ratio for good health and ideal weight. A ratio of 3:4 is ideal for obese individuals because of their state of chronic oxidative stress and inflammation. Physical activity, sleep quality, psychological stress, maternal prenatal diet and oxidative stress promoting disease conditions are important modulators of oxidative stress and obesity.

Illustration from: Savini I., Gasperi V., Catani M.V. (2016) Oxidative Stress and Obesity. In: Ahmad S., Imam S. (eds) Obesity. Springer, Cham. https://doi.org/10.1007/978-3-319-19821-7_6

How is obesity associated with happiness? Evidence from China

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Abstract

Yiwei LiuLing XuAaron Hagedorn

First Published October 11, 2020 

Research Articlehttps://doi.org/10.1177/1359105320962268

Liu Y, Xu L, Hagedorn A. How is obesity associated with happiness? Evidence from China. Journal of Health Psychology. October 2020. doi:10.1177/1359105320962268rticle information 
No Access

Abstract

Happiness is a universal goal that people pursue. Studies of the relationship between obesity and happiness have shown mixed findings. It is uncertain whether an optimum BMI level exists and at what level obesity interferes or interacts with happiness. Guided by the Circle of Discontent Theory, we examined the relationship between obesity and happiness among Chinese residents using the 2014 China Family Panel Studies data. The results reveal an inverted U-shaped relationship between BMI and happiness, with obesity associated with happiness through physical appearance, health, and income. The socioeconomic conditions for the appropriate weight to achieve happiness are discussed.

Keywords Chinacircle of discontent theoryhappinesshealthincomeobesityphysical appearance

Figure 2. Relationship between BMI and happiness.

Body mass index trajectories during mid to late life and risks of mortality and cardiovascular outcomes: Results from four prospective cohorts

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Yun-JiuChengab1 Zhen-GuangChenc1 Su-HuaWuab1 Wei-YiMeiab Feng-JuanYaod MingZhange Dong-LingLuof

ShareCite https://doi.org/10.1016/j.eclinm.2021.100790 Get rights and content

Citation: Cheng, Y. J., Chen, Z. G., Wu, S. H., Mei, W. Y., Yao, F. J., Zhang, M., & Luo, D. L. (2021). Body mass index trajectories during mid to late life and risks of mortality and cardiovascular outcomes: Results from four prospective cohorts. EClinicalMedicine33, 100790.

Note: This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

open access

Abstract

Background

Our understanding of the weight-outcome association mainly comes from single-time body mass index (BMI) measurement. However, data on long-term trajectories of within-person changes in BMI on diverse study outcomes are sparse. Therefore, this study is to determine the associations of individual BMI trajectories and cardiovascular outcomes.

Methods

The present analysis was based on data from 4 large prospective cohorts and restricted to participants aged ≥45 years with at least two BMI measurements. Hazard ratios (HR) and 95% confidence intervals(95%CI) for each outcome according to different BMI trajectories were calculated in Cox regression models.

Findings

The final sample comprised 29,311 individuals (mean age 58.31 years, and 77.31% were white), with a median 4 BMI measurements used in this study. During a median follow-up of 21.16 years, there were a total of 10,192 major adverse cardiovascular events (MACE) and 11,589 deaths. A U-shaped relation was seen with all study outcomes. Compared with maintaining stable weight, the multivariate adjusted HR for MACE were 1.53 (95%CI 1.40–1.66), 1.26 (95%CI 1.16–1.37) and 1.08 (95%CI 1.02–1.15) respectively for rapid, moderate and slow weight loss; 1.01 (95%CI 0.95–1.07), 1.13 (95%CI 1.05–1.21) and 1.29 (95%CI 1.20–1.40) respectively for slow, moderate and rapid weight gain. Identical patterns of association were observed for all other outcomes. The development of BMI differed markedly between the outcome-free individuals and those who went on to experience adverse events, generally beginning to diverge 10 years before the occurrence of the events.

Interpretation

Our findings may signal an underlying high-risk population and inspire future studies on weight management.

Funding

National Natural Science Foundation of China, Guangdong Natural Science Foundation.

Keywords

Trajectories Body mass index Cardiovascular events Mortality Mid-to-late life

Research in context

Evidence before this study

We searched Pubmed for articles published in English assessing risk of cardiovascular disease and all-cause mortality in relation to BMI and BMI trajectories, using the search terms “BMI”, “change in BMI”, “BMI trajectories”, “cardiovascular diseases”, “major adverse cardiovascular events”, “death”, “mortality”, “coronary heart disease”, “stroke”, “heart failure”, “myocardial infarction” and “risk”, from the inception to December 15, 2020. We found numerous studies discussing the associations of single time BMI measurements and cardiovascular risks, but few of them explored the associations of individual change trajectories and adverse outcomes.

Added value of this study

In this large population-based study, a U-shaped relation was observed between BMI trajectories and subsequent risk of different health outcomes. Both weight gain and weight loss conferred increased risks for cardiovascular events and all-cause mortality. In addition, we found for the first time that falling off the BMI trajectory could be a warning sign for future occurrence of adverse events.

Implications of all the available evidence

Our findings may signal an underlying high-risk population and underscore the importance of maintaining body weight over the middle to late adulthood.

1. Introduction

In light of the obesity epidemic [1,2], it is imperative to understand the relationship of weight to the risks of mortality and cardiovascular diseases (CVD). Although this relation is well documented in previous researches, most of them were based on single-time assessment of body weight (or body mass index, BMI) [3][4][5][6][7][8]. As noted, the relation of single-time BMI measurement to adverse outcomes changed during the observation period [9]. Specifically, the magnitude of this association weakens among middle-aged and elderly populations [10,11].

Further, using single-time BMI may fail to recognize the effect of weight change on the associated risks. Weight changes are highly variable over the life course [12][13][14][15]. Both weight loss and gain in middle-aged adults rendered increased risk of all-cause and CVD mortality [4,[16][17][18][19]]. However, the patterns of BMI change may differ among individuals; thus, a life-course perspective is essential. Mapping the longitudinal trajectory of BMI may directly capture the within-person change in BMI, and better characterize the associated risks.

Although increasing number of studies have investigated the relationship of BMI trajectories and cardiovascular outcomes, most were assuming the population lies within a mixture of latent groups, using either growth curve model or group-based latent model [11,[20][21][22][23][24][25][26][27][28][29]]. These models are largely based on subgroup means over a specific period of time and might be imprecise. Till now, there are at least 2 to 6 different BMI trajectory patterns being reported [11,[20][21][22][23][24][25][26][27][28][29][30]], even using the same dataset [20,26].

Therefore, in order to obtain a more precise association between BMI trajectory and cardiovascular outcomes, we here used the original BMI slope from each individual to represent individual BMI change trajectory. As far as we know, less than ten papers have reported the value of BMI slope in cardiovascular system [13,14,[31][32][33][34][35][36][37]]. Most of them investigated the association of BMI slope and change in cardiovascular risk factors [14,31,[33][34][35][36]]. Only two researches illustrated its association with cardiovascular outcomes [13,32]. However, models were not fully adjusted and differences on weight change direction were not taken into consideration.

Therefore, in our current study, we separated weight gain and weight loss by different degrees of change to comprehensively illustrate the relation of individual BMI trajectory to diverse study outcomes. As a second aim, we explored and characterized the developmental paths of BMI prior to individual outcomes.

…..

Model 1, adjusted for age, gender and race; Model 2, adjusted for age, gender, race, smoking status, current alcoholic use, education level, marital status, income, physical activity, consumption of fruits and vegetables, history of hypertension, diabetes, HF, CHD, cancer, COPD and stroke, baseline BMI, serum level of glucose, total cholesterol, LDLCHDLC and triglyceride.

Abbreviation: MACE, major adverse cardiovascular events; MI, myocardial infarction; CHF, chronic heart failure; CVD, cardiovascular disease; Non-CVD, non-cardiovascular disease; CHD, coronary heart disease.

3.2.1. Primary outcomes

Compared with maintaining stable weight, the multivariate adjusted HRs for MACE were 1.53 (95%CI 1.40–1.66), 1.26 (95%CI 1.16–1.37) and 1.08 (95%CI 1.02–1.15) respectively for rapid, moderate and slow weight loss; 1.01 (95%CI 0.95–1.07), 1.13 (95%CI 1.05–1.21) and 1.29 (95%CI 1.20–1.40) respectively for slow, moderate and rapid weight gain. Models examining the associations with outcomes of MI and CHF yielded similar results as MACE. While for stroke, the hazard was significantly increased in participants with moderate-to-rapid weight loss and moderate weight gain, but for slow weight loss or slow weight gain, the association was insignificant (Table 2). Consistently, Fig. 1-A shows a U-shaped relation of the entire range of annual BMI change to individual cardiovascular outcomes in the cubic spline models.

Fig 1

3.2.2. Secondary outcomes

Similarly, the HRs for all-cause mortality were 1.98 (95%CI 1.83–2.13), 1.38 (95%CI 1.28–1.49) and 1.18 (95%CI 1.12–1.25) respectively for rapid, moderate and slow weight loss; 0.99 (95%CI 0.93–1.04), 1.08 (95%CI 1.01–1.15) and 1.29 (95%CI 1.20–1.38) respectively for slow, moderate and rapid weight gain, when compared to maintaining stable weight. Identical patterns of association were observed for CVD, non-CVD and CHD death (Table 2). Likewise, in the restricted cubic spline models, we detected a U-shaped relationship between annual BMI change and mortality risk, with a nadir around 0 kg/m2/year (Fig. 1-B).

3.3. BMI trajectories prior to different outcomes

Fig. 2 is an illustrative drawing to represent the general developmental patterns of BMI prior to different outcomes. We found that the development of BMI differed markedly between the outcome-free individuals and those who went on to experience adverse events. Trajectories appeared similar for the outcomes of MACE, all-cause, CVD and non-CVD death. The outcome-free participants followed a trajectory where the average BMI levels rise initially, remain stable or steadily decreased throughout follow-up. Those who went on to experience events generally showed lower baseline levels of BMI, steeper rise initially and faster fall before the occurrence of the events. With regards to MI and CHD death, the average BMI level was comparable in participants with or without the outcomes, but an accelerated decline was observed in those who died or experienced the events. Interestingly, although the developmental trend was identical among participants with and without CHF, those who experienced CHF had a generally higher BMI level during their life. With respect to the outcome of stroke, the BMI trajectories were less distinctive between groups.

Fig 2

3.4. Additional information and stratified analysis

We repeated the primary analyses in a series of sensitivity analyses. Excluding participants with missing values on baseline covariates (supplementary Table 3 in Appendix 3), with preexisting illnesses at baseline (supplementary Table 4 in Appendix 3), or with highest weight variability during follow-up (supplementary Table 5 in Appendix 3) did not appreciably change the results. In terms of percent change of BMI, the association patterns for cardiovascular outcomes were identical to our primary analysis (supplementary Table 6 in Appendix 3). But for the death outcomes, we only found significant increased risk in weight loss quintiles (quintile 1 and 2). When separating the primary analysis by individual cohort, consistent findings were observed (supplementary Table 7 in Appendix 3).

As depicted in Fig. 3, the associations of BMI trajectories and MACE were generally consistent in stratified analyses by sex, race and smoking status. It should be noted that the BMI-MACE association was significantly modified by age and borderline by baseline BMI. The hazards for MACE were significantly higher in those younger than 60 years, but lower in those who were initially with obesity. For all-cause mortality, the associations with BMI trajectories were generally consistent in white or non-white population and significantly modified by age, sex, and smoking status. It’s revealed that male and individuals younger than 60 years had higher hazards for death. But surprisingly, the hazards were lower in the smoker subgroups. Similar to the MACE outcome, the hazards for death were lower in subgroup with obesity, but the modification effect by baseline BMI was insignificant. The association of BMI trajectories and other outcomes across the predefined subgroups are provided in supplementary Table 8 and Table 9 (Appendix 3).

4. Discussion

In our analyses of the overall cohort of 29,311 participants, a U-shaped relation was observed between BMI trajectories and subsequent risk of cardiovascular events and all-cause mortality. Significant increase of risks for MACE and all-cause death were noted for people assigned in weight loss or weight gain categories. The hazard risks for adverse outcomes were consistently lowest among individuals maintaining their body weight. Although effect modification was observed in several subgroups, our findings were generally robust in a number of sensitivity analysis. Furthermore, our study for the first time delineates the characteristics of BMI trajectories prior to different health outcomes, showing an accelerated decline in BMI almost ten years before the occurrence of the events.

More than 38.9% of US adults have obesity [1]; however, much of our understanding of the BMI-mortality association comes from single-time BMI measurement, without considering within-person variation over the long term. Since weight change is highly variable across adulthood, more studies are now focusing on BMI trajectories and different health outcomes [11,13,[20][21][22][23][24][25][26][27][28][29][30],32]. However, most of these studies were grouping people using growth curve model or group-based latent model [11,[20][21][22][23][24][25][26][27][28][29]]. Using the above models, one can identify individuals with distinct BMI trajectories from the available data [25,48]. However, class membership is not determined with certainty for each individual since it relies on the selected models (linear, curvilinear, cubic and other forms) and probability of belonging [20,49]. Thus, misclassification is possible and the associated risk of adverse outcomes could be invalid. In articles published by Zeng H.et al. and Zajacova et al., the authors used the same data but identified different patterns of BMI trajectory [20,26]. As of now, at least two to six patterns of BMI trajectories have been reported in the general population and majority of them were depicting an ascending trend or paralleling with each other [21,26,28,[50][51][52]]. It is unrealistic that all participants were going the same way over the life course. There must be some groups of individuals experiencing gradual weight loss or even rapid loss in their weight. Furthermore, most of the existing studies differentiate the curves by studying changes in pre-defined BMI categories: defining a change within normal weight as “normal-stable” [28], or a change from overweight category to category with obesity as “overweight obesity” trajectory [26]. This crude categorization of BMI trajectories would probably yield over- or under-deterministic results. It should be noted that a variety of changes could occur within the same categories; even a small change in BMI would pose a significant deleterious effect on health [26]. Furthermore, the rate of change, the direction of change, or the slope of the trajectory was all likely to make a difference in the negative outcomes [13,53].

Thus, from the current study, we derived an overall BMI trajectory (annul change in BMI or BMI slope) for each individual, giving further support to the associations of long term trajectories and diverse health outcomes. In our study, the slope of BMI throughout middle and older age, either positive or negative, rendered increased risks of MACE and mortality: the larger the changes the greater the risk. More specifically, BMI falling faster than 0.1 kg/m2 per year resulted in at least 8% higher risks of MACE and 18% of death. On the other hand, increasing BMI by 0.3 kg/m2 per year was associated with at least 13% higher hazards for MACE and 8% for death. Although several prior studies were conducted with a similar method, findings were mixed and inconsistent. As demonstrated in Framingham Heart Study, BMI slopes were inversely associated with the outcome of total mortality and morbidity due to CHD [13]. On the contrary, in the study of Chicago Western Electric Company, weight loss slope was significantly associated with total and cardiovascular mortality, while the weight gain slope showed nonsignificant increased risk of each endpoint for 25-year follow-up [32]. These inconsistencies may result from inadequate adjustment for potential cofounders and not considering the weight change direction.

Identical pattern of association was noted in subgroups of the population, after stratification for age, sex, race, smoking status and baseline BMI. However, effect modification of these stratification variables varied with respect to different outcomes. Generally, the hazardous effects of weight change and adverse outcomes were more pronounced in male participants and at younger age (<60 years). Two additional results should be noted. First, although previous studies have suggested that smoking status is a crucial modifier on the association of BMI and cardiovascular risks, we reveal that the hazards of cardiovascular outcomes were generally consistent in the three categories of smoking status. While for all-cause and non-CVD death, the association with weight loss were inconclusively modified by smoking status. The inconsistent observed relation could be the result of diverse weight change patterns associated with smoking or accounted for the unmeasured confounders [12,33]. Second, decreased weight in individuals with higher BMI (overweight or with obesity) may result in a better outcome when compared to those with normal weight at baseline, which could partially explain the phenomenon of “obesity paradox” [54]. The risk differences for weight gain among normal, overweight or individuals with obesity were less obvious.

In this study, we not only captured the characteristics of individual BMI change trajectory, but also directly evaluated the average BMI trajectories for those with and without specific outcomes. We found for the first time that patterns of change in BMI prior to different outcomes were different. Overall, the BMI trajectories appeared similar for most of the study outcomes: the outcome-free participants followed a trajectory where the average BMI levels remained relatively stable, while for those who went on to experience adverse events, the trajectories began to fall 10 years before the event. Although it’s unclear whether the observed weight loss was the antecedent cause or the consequence of the outcome, these findings may signal an underlying high-risk population and underscore the importance of maintaining body weight over the middle to late adulthood.

The major strengths of this study include the availability of multiple BMI measurements within identical time interval and using the linear mixed model, which entails a more accurate assessment of individual BMI trajectory. Furthermore, although distinguishing intentional and unintentional weight loss is challenging, we try to separate them by using weight variability, in which the highest variability subgroup represents intentional weight loss subcategory. As a result, in weight loss participants with high weight variability, moderate and rapid weight loss was not significantly correlated with increased risk of cardiovascular events. But likewise, we did not observe a beneficial effect in this group of population. One possible explanation for this is that weight rebound following intentional weight loss may offset the positive effect brought by losing weight [55]. Therefore, for weight loss individuals, it is imperative to first examine the reasons for weight loss: intentional or unintentional. If someone is losing weight intentionally, avoiding weight regain or achieving sustained weight loss may be the cornerstone of the accrued benefits brought by losing weight from a high BMI.

Despite of the strengths provided above, several limitations should be noted. Firstly, our findings relate solely to changes in BMI while the changes of fat mass, muscle mass and the general change of the body composition were unknown. In addition, since majority of the study participants were white US people, the results could not be generalized to more heterogeneous populations. Secondly, although we are trying to distinguish whether weight loss was intentional or unintentional in our sensitivity analysis, data on the causes of weight loss were unavailable in the current study. And thus, we could not confirm the above speculation and further studies are warranted.

In this large population-based study, a U-shaped relation was observed between BMI trajectories and subsequent risk of different health outcomes. Both weight gain and weight loss conferred increased risks for cardiovascular events and all-cause mortality. In addition, we found for the first time that patterns of change in BMI prior to different outcomes were different. Falling off the BMI trajectory could be a warning sign for future occurrence of adverse events; thus, maintaining body weight during the middle to late adulthood may be essential. Despite the observational nature of the current study, the trajectories and risk patterns identified here may inspire future studies on the cause and potentially weight management guidelines.

The ARIC, CHS, MESA and FHS studies are carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts. The study was also financially supported by the grants from National Natural Science Foundation of China (81600260), Guangdong Natural Science Foundation (2016A030313210), the Science and Technology Planning Project of Guangdong Province (2017A020215174), the Fundamental Research Funds for the Central Universities in Sun Yat-Sen University (18ykpy08), and the project of Kelin new star of the First Affiliated Hospital of Sun Yat-Sen University (Y50186).

Declaration of Competing Interest

We declare no competing interests.

Contributors

All authors contributed to the study concept and design. YC, CZ and WS contributed equally to this work. DL and YC are senior and corresponding authors who also contributed equally to this study. DL, YC, CZ and WS have full access to all the data in this study and take full responsibility as guarantors for the integrity of the data and the accuracy of the data analysis. CY, LD, CZ and WS contributed to the study design. CZ and WS contributed to analysis and data interpretation. CY and LD drafted the manuscript and contributed to the final approval of the manuscript. MW, YF and ZM contributed to critical revision of the manuscript for important intellectual content.

Data sharing statement

The cohort data sets were obtained from the NIH Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) and could be applied to the corresponding author upon reasonable request.

Appendix. Supplementary materials

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These authors contributed equally to the work.View Abstract© 2021 The Authors. Published by Elsevier Ltd.

Total Wake: Natural, Pathological, and Experimental Limits to Sleep Reduction

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New Mini Review Article in Frontiers in Neuroscience by:

Yuri Panchin1,2 and Vladimir M. Kovalzon1,3*

  • 1Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
  • 2Department of Mathematical Methods in Biology, Belozersky Institute, Lomonosov Moscow State University, Moscow, Russia
  • 3Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Moscow, Russia

Front. Neurosci., 07 April 2021 | https://doi.org/10.3389/fnins.2021.643496

Abstract

Sleep is not considered a pathological state, but it consumes a third of conscious human life. This share is much more than most optimistic life extension forecasts that biotechnologies or experimental and medical interventions can offer. Are there insurmountable physical or biological limitations to reducing the duration of sleep? How far can it be avoided without fatal consequences? What means can reduce the length of sleep? It is widely accepted that sleep is necessary for long-term survival. Here we review the limited yet intriguing evidence that is not consistent with this notion. We concentrate on clinical cases of complete and partial loss of sleep and on human mutations that result in a short sleep phenotype. These observations are supported by new animal studies and are discussed from the perspective of sleep evolution. Two separate hypotheses suggest distinct approaches for remodeling our sleep machinery. If sleep serves an unidentified vital physiological function, this indispensable function has to be identified before “sleep prosthesis” (technical, biological, or chemical) can be developed. If sleep has no vital function, but rather represents a timing mechanism for adaptive inactivity, sleep could be reduced by forging the sleep generation system itself, with no adverse effects.

 Dedicated to Michel Valentin Marcel Jouvet (1925–2017)

www.frontiersin.org
Michel Jouvet, 2005 (Photo by Vera Nezgovorova)

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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HYPOTHESIS AND THEORY ARTICLE

Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.62802

Dominic Stanculescu1Lars Larsson2 and Jonas Bergquist3,4*

  • 1Independent Researcher, Sint Martens Latem, Belgium
  • 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
  • 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
  • 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

Introduction

Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (156). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (710). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (1213).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology (1415). The most common peri-onset events reported by patients are infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%) (16). “Impaired function, post-exertional malaise (an exacerbation of some or all of an individual’s ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep” are considered to be core symptoms (14). The severity of the symptoms varies: “very severely affected patients experience profound weakness, almost constant pain, severe limitations to physical and mental activity, sensory hypersensitivity (light, touch, sound, smell, and certain foods), and hypersensitivity to medications” (17). We have listed a few hall mark symptoms that are often found in critically ill patients in chronic intensive care (ICU) patients and ME/CFS patients (Table 1).TABLE 1

Table 1. Comparison of the typical clinical picture of ICU patients and patients with ME/CFS.

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. These mechanisms characterize prolonged critical illness regardless of the nature of the initial severe injury or infection (3810); similarly, we propose that these mechanisms could underlie the perpetuation of illness in ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins, or other). We provide an overview of these mechanisms in ICU patients and discuss their relevance for understanding ME/CFS. We also bring findings from fibromyalgia into the discussion here because ME/CFS and fibromyalgia are often jointly considered in the literature (2021); fibromyalgia is similarly a syndrome that is medically unexplained, often comorbid with ME/CFS, and “shares the core symptoms of fatigue, sleep problems and cognitive difficulties” (22). Additional research projects are required to investigate the validity of this hypothesis building on the findings from critical illness and ME/CFS summarized here.

This hypothesis may be particularly relevant in light of the current COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms despite successfully defeating the virus—termed “post COVID-19 syndrome” or “long COVID-19”—that resemble ME/CFS (2326).

Suppression of Pulsatile Pituitary Secretions

Endocrine patterns observed during the initial acute phase of critical illness (in the first few hours or days) differ markedly from those observed during prolonged critical illness (after a few days) (2728). Indeed, the acute phase is characterized by increased release of pituitary hormones; the prolonged phase is characterized by suppression of the release of pituitary hormones. Simultaneously, hormone half-life and hormone up-take by the peripheral tissues differ markedly between these two phases (429). This biphasic pattern of the endocrine system during critical illness, however, is not readily observable in single or average measurements of circulating tropic and non-tropic hormone concentrations—which are a function of both hormone release and elimination from the blood stream. This pattern was thus only discovered in the early 1990s with measurements of the frequency and amplitude of pituitary secretions (i.e., pulsatility) performed as often as every 10 min over 24 h on ICU patients (29). The pulsatility of tropic hormone secretion is part of the signaling to the peripheral glands and thus considered a determining factor of hormone function (i.e., impact on target glands or tissues), in addition to overall volume of hormone release (3031). The finding that pulsatile pituitary secretions are suppressed during prolonged critical illness was critical in understanding the physiology of the syndrome and the curious failure of patients to recover (32). We describe the biphasic endocrine patterns during acute and prolonged critical illness for each of the main endocrine axes in further detail below, as well as the implications for the autonomic nervous system, metabolism and the immune system. We also provide evidence suggesting that the endocrine patterns observed in prolonged critical illness also underlie ME/CFS.

The Adreno-Cortical Axis (HPA Axis)

The adreno-cortical axis—also called hypothalamic-pituitary-adrenal (HPA) axis—is the body’s primary stress management system. The HPA axis responds to physical and mental challenges in part by controlling the body’s glucocorticoids levels, notably cortisol (33). Cortisol in turn modulates inflammation response, cardiovascular function and glucose metabolism (34). An inability to deal with stress, proneness to exaggerated immune responses and weight loss are associated with hypocortolism or poor HPA axis function (3538). The HPA axis also regulates mineralocorticoids that, in turn, regulate water and electrolyte balance (i.e., blood pressure). Low blood pressure and dizziness upon standing up are associated with a compromised HPA axis (35). Finally, the HPA axis (in addition to the gonadotropic axis not covered here) also contributes to the production of androgens, notably DHEA and testosterone, which are steroids that impact muscle mass, fat storage, pain, brain function and many other physiological traits. Low androgens are associated with muscle fatigue, joint pain, and noise intolerance (3942).

In normal conditions, the adrenal gland secretes cortisol during the day in pulses, with the highest amounts in the early morning hours and lower amounts at night. The hypothalamus signals to the pituitary with corticotrophin-releasing hormone (CRH), and to a lesser extent, arginine vasopressin (AVP), to produce adrenocorticotropic hormone (ACTH). This is in turn signals the adrenals to release cortisol and other hormones. Most cortisol circulating in the blood is bound to carrier molecules (2943). Production of cortisol is regulated by an inhibitory feedback loop. When free circulating cortisol attaches to glucocorticoid receptors on the hypothalamus and pituitary, these glands reduce production of CRH and AVP, and ACTH, respectively. The number and affinity of glucocorticoid receptors is thus considered one of the most important determining factors in the regulation of the HPA axis (43)

In Critical Illness

During the acute phase of critical illness, plasma cortisol concentrations rise rapidly. Increased cortisol availability is considered a vital response that allows for fluid retention, increased cardiac output and blood pressure, and induces an appropriate immune response while protecting against excessive inflammation (294445). Until recently believed to be the result of increased cortisol production by the adrenals, it is now known that high cortisol availability during this phase of critical illness is in fact largely driven by two peripheral mechanisms: a decrease in the abundance and affinity of the cortisol carrier molecules in circulation, and a slowing of cortisol breakdown in the liver and kidney (2934444647). Via inhibitory feedback loops, these higher cortisol concentrations suppress the HPA axis at the central level: the secretions of CRH and AVP by the hypothalamus and of ACTH by the pituitary fall, leading to an eventual drop in plasma cortisol levels (48).

Whereas, in critically ill patients that begin to recover, the HPA axis essentially normalizes within 28 days of illness, in cases of prolonged critical illness ACTH levels (surprisingly) continue to be depressed despite dropping cortisol levels (4950). Why and how this central suppression of ACTH is maintained is not clear and continues to be debated. Pro-inflammatory cytokines and O&NS likely play a leading role. Cytokines can mediate tissue-specific changes in the abundance and affinity of glucocorticoid receptors—which are major factors determining the activity of the HPA axis (244). Specifically, the cytokine IL-1β is known to modulate CRH release by the hypothalamus; TNF-α is known to impair ACTH release by the pituitary; and TNF-α is also known to impair cortisol production by the adrenal glands (2).

Without sufficient pulsatile stimulation by the tropic hormone ACTH, adrenal glands begin to atrophy and lose zonational structure. This is evidenced in the post-mortem dissection of patients that had been critically ill for a few weeks, but not in the patients that quickly died from their illness or trauma (3451). The weakening of adrenal glands not only compromises patients’ ability to cope with external stressors but also permits excessive inflammatory responses. In sum, the initial beneficial increase in cortisol availability induced by peripheral mechanisms during the acute phase of critical illness leads to a suppression of the HPA axis at the central-level from which a subset of patients appears unable to escape (Figure 1).FIGURE 1

Figure 1. The adreno-cortical axis (HPA axis) during normal conditions and prolonged critical illness.

In ME/CFS

Dysfunction of the HPA axis has been documented extensively in ME/CFS patients since the early 1980s (5263). Researchers have observed decreased baseline cortisol levels, blunted HPA axis responses to physical and psychological stressors, reduced HPA axis responsivity to provocation tests (such as CRH and ACTH administration), and a heightened inhibitory feedback loop (consistent with a higher abundance and affinity of glucocorticoid receptors at the level of the pituitary and hypothalamus). Strikingly, the magnitude of HPA axis dysfunction becomes more pronounced with illness duration and is associated with symptom severity (4364). Very few have studied pulsatility of ACTH release: one study of 36 study-pairs found no statistically significant differences in ACTH pulsatility between ME/CFS and matched controls (65), while another found a differential pattern of ACTH release over 24-h periods (66). Variations in the study-participants’ severity of illness—and methods used to control for these—may explain these apparently contradictory findings. Several studies have found the morning peak of ACTH is missing or weak in ME/CFS patients (43). A recent study assessing secretory events of cortisol found that CFS/ME patients have the same number of secretory events but secrete lower quantities in early morning hours (67). Significantly, a group of ME/CFS patients were found to have 50% smaller adrenals than controls (68), resembling adrenal atrophy in prolonged critical illness.

ME/CFS researchers have also proposed models to explain the persistence of a suppressed HPA axis (336970). Essentially, a short stress (i.e., a burst of cortisol) will produce a small perturbation in the glucocorticoid receptor concentration on the central glands that quickly returns to normal levels. However, long, repeated stress—from which the system doesn’t have time to recover—leads to a persistent high glucocorticoid receptor concentration, forcing the HPA axis to an alternate steady state. More recent models of the HPA axis have also included non-genomic feedback-controls (71), the endogenous effects of circadian rhythm (72), and interactions with the gonadotropic axis and the immune system (7374) to explain how HPA axis suppression is maintained even after the initial stress is gone.

HPA axis dysfunction is also present in the majority of fibromyalgia patients (7577). Various mechanisms have been suggested, including depressed secretion of CRH by the hypothalamus, a deficiency of CRH receptors on the pituitary, and adrenal atrophy due to chronic under-stimulation by reduced ACTH levels (78).

Moreover, the dysfunction of the HPA axis in ME/CFS and fibromyalgia has also been associated with pro-inflammatory cytokines and O&NS (43557980). A recent paper considering the bidirectional relationship between the function of the HPA axis and inflammation finds that immune-inflammatory and O&NS pathways induce HPA axis dysfunction in ME/CFS (81); the direction of causality is analogous to inflammatory pathways inducing endocrine dysfunctions in critical illness. Others have similarly theorized that local inflammation in the hypothalamus leads to a disturbed HPA axis in ME/CFS (82).

In sum, the HPA axis dysfunctions in ME/CFS are not unlike the dysfunctions in prolonged critical illness. However, to our knowledge a comprehensive study of the pituitary pulsatile secretions of ACTH in ME/CFS patients—which proved revelatory in understanding prolonged critical illness—does not yet exist. The relationship between the pituitary’s pulsatile ACTH secretions, severity of illness, the integrity and function of adrenal glands and resulting physiological alterations in ME/CFS thus remains largely unexplored.

The Somatotropic Axis (HPS Axis)

The somatotropic axis—also called hypothalamic-pituitary-somatotropic (HPS) axis—plays important roles in growth and development of children, but also contributes to a variety of physiological pathways in adults, including balancing catabolic (i.e., the break-down of molecules and tissues) and anabolic activities (i.e., the building of molecules and tissue) (4). An HPS axis dysfunction is known to cause loss of muscle and bone mass, induces weakness (29), and impacts gut mucosa integrity as well as glucose and fat metabolism (83). Low energy, exhaustion, mental fatigue, weak muscle strength as well as poor recovery after physical activity are associated with an inhibited HPS axis function (428485).

Uniquely, in the case of the HPS axis, the hypothalamus sends both stimulating (+) and inhibiting (-) signals to the pituitary for the production of growth hormone (GH): these are, respectively, the GH-releasing hormone (GHRH) and the GH-inhibiting hormone (GHIH, also called somatostatin) (4). In addition, ghrelin, mostly produced by the gut, also stimulates GH production by the pituitary. In normal conditions, GH is released by the pituitary in a pulsatile fashion under the control of these three signals, with peaks of GH levels alternating with virtually undetectable valleys in 3- to 5-h intervals over the course of the day (29). GH in turn has direct effects on some tissues and also stimulates the production of insulin-like growth hormone-1 (IGF-1), mostly by the liver. Nearly all of the IGF-1 hormones in the plasma are bound to IGF-binding proteins (IGFBP). IGF-1 and GH exert inhibitory feedback on the hypothalamus and the pituitary to maintain homeostasis. The half-life of GH is only 10 to 20 min, whereas the half-life of IGF-1 is more than 12 h. Thus, IGF-1 plasma concentrations are regularly used as proxies for GH secretion in clinical settings. This, however, overlooks the function of the pulsatile secretion of GH on the balance of anabolic and catabolic activities in the body (4).

In Critical Illness

In the acute phase of critical illness, the pituitary produces more GH: higher peaks, lower valleys and increased pulse frequencies (86). The rapid onset of two main peripheral mechanisms explain this finding: First, under the influence of cytokines, the liver expresses fewer GH receptors (i.e., becomes resistant to GH) and thus produces less IGF-1. Second, alterations in IGF binding proteins results in IGF-1 being cleared out faster from the system (i.e., IGF-1 has a shorter half-life) (87). The lower IGF-1 concentrations resulting from these two peripheral mechanisms will—via the feedback loop inherent to the axis—spur more GH production (29). The resulting increase in catabolic activity during the acute phase of critical illness serves to mobilize amino acids derived from the breakdown of peripheral tissues, such as skeletal muscle and bone, for use by the central organs (4).

However, if a critically ill patient fails to recover within a few days, GH secretion becomes erratic and almost non-pulsatile. Experiments have demonstrated that this is largely due to a lack of stimulation of the hypothalamus and pituitary by the hormone ghrelin. There is also evidence for changes in the relative amounts of GHIH and GHRH signals from the hypothalamus (4). As for the peripheral hormone, IGF-1, its levels are low or normal in prolonged critical illness. The liver’s resistance to GH (which previously suppressed IGF-1 production during the acute phase of critical illness) does not persist during prolonged critical illness (2987). However, without a concomitant pulsatile release of GH, the anabolic function of IGF-1 becomes inhibited (4).

In sum, although the increase in catabolic activity during the acute phase of critical illness may initially be beneficial because it serves to mobilize amino acids, the perpetuation of the imbalance in catabolic vs. anabolic activity (due in part to the loss of the pulsatile function of GH) during prolonged critical illness may be considered maladaptive (Figure 2). The imbalance in catabolic relative to anabolic activity in prolonged critical illness leads to protein break-down in skeletal muscle, liver, kidney and heart, reducing their cell mass and leading to impaired function (7). These processes are ultimately reflected in muscle and bone wasting typically present in prolonged critical illness (8889).FIGURE 2

Figure 2. The somatotropic axis (HPS axis) during normal conditions and prolonged critical illness.

In ME/CFS

GH regulation in ME/CFS has been studied since the 1990s. The findings are mixed, but almost none addresses the question of the pulsatility of GH release. Some described low nocturnal GH secretion (9091), while others have found normal levels of 24-h urinary GH excretion (92). Some have found reduced response to induced hypoglycemia (9091), while others describe normal GH responses to stimulation (93). One study describes unaffected diurnal patterns of GH release in ME/CFS, but it focused on assessing basal levels rather than the nature of secretory patterns (i.e., pulsatile vs. erratic) and may not have accounted for variations in the severity of illness of patients (66). In terms of IGF-1, there are no consistent differences between ME/CFS patients and controls (9394), which is consistent with findings from prolonged critical illness.

Studies in fibromyalgia show relative GH deficiency (76789599) and low or low-normal IGF-1 levels (9596100). Interestingly, some studies showed that fibromyalgia patients “failed to exhibit a GH response to exercise” (97101), consistent with a loss in pulsatility of GH release.

In sum, endocrine observations in ME/CFS are not unlike HPS axis dysfunctions found in prolonged critical illness. To our knowledge the pituitary pulsatile secretions of GH in ME/CFS patients has not been comprehensively studied. The relationship between the pituitary’s pulsatile GH secretions, severity of illness and the balance between catabolic and anabolic activities in ME/CFS thus remains largely undiscovered.

The Thyrotropic Axis (HPT Axis)

The thyrotropic axis—also called hypothalamic-pituitary-thyroid (HPT) axis—regulates the basal rate of our metabolism. Dysfunctions of the HPT axis are associated with tiredness, stiffness, constipation, dry skin and weight gain, among a myriad of other hypothyroid-like symptoms (3542).

In normal conditions, an inhibitory feedback loop works to maintain stable circulating thyroid hormone concentrations according to a daily rhythm (102). When unbound circulating thyroid hormone concentrations dip below a certain threshold, the hypothalamus produces thyrotropin-releasing hormones (TRH) in order to signal the pituitary to produce thyroid stimulating hormone (TSH), which in turn signals the thyroid gland to produce more thyroid hormones.

In Critical Illness

Dysfunctions of the HPT axis during critical illness have been studied extensively. Starting in the early 1970s, clinicians working in ICUs observed that patients with a wide range of critical conditions had low plasma concentrations of the active form of thyroid hormones (T3) relative to plasma concentrations of inactivated thyroid hormones reverse T3 (rT3) (103105). They gave this condition the name “non-thyroidal illness syndrome” (NTIS), also called “euthyroid sick syndrome” or “low T3 syndrome.” While NTIS was initially considered to be beneficial in critical illness—i.e., a state of “protective” down-regulation of metabolism during times of duress (106) —it is increasingly seen as maladaptive and hampering the recovery of patients in the case of prolonged critical illness (91029103104107108).

During acute and early stages of critical illness, peripheral mechanisms involving cytokines (notably IL-1β, IL-6, TNF-α) lead to the quick depression of thyroid hormone activity (104105109111) to help conserve energy resources (48104). The mechanisms include the alterations in the amount and affinity of thyroid hormone binding globulines in the blood (112114); modifications in the expression of the transporters that carry the thyroid hormone into the cells (115116); the down- and up-regulation of deiodinase enzymes that convert the thyroid hormone into active and inactive forms, respectively (113117); and the variation in the quantity and isoforms of cellular thyroid hormone receptors present (notably in the liver, adipose tissue and muscle) (118120). An alteration in any of these steps—which determine thyroid hormone function—can lead to large time- and tissue-specific adjustments in cellular metabolism (121122)—even without, or with only minor, changes in the blood concentrations of thyroid hormones (121123124).

During prolonged critical illness these peripheral mechanisms are supplemented by central mechanisms that also depress thyroid hormone function (125126). Cytokines (notably IL-12 and IL-18), in association with other signaling factors (including leptin, glucocorticoids, etc.), are believed to up-regulate the deiodinase enzymes D1 and D2 in the hypothalamus resulting in higher local levels of T3 that inhibit TRH release irrespective of circulating thyroid hormone concentrations (10127128). Moreover, cytokines (notably IL-1b and TNF-α) also suppress the release of TSH by the pituitary (129130). Finally, by reducing iodine uptake and thyroid hormone excretion, cytokines (notably IL-1) also impact the activity of the thyroid gland itself (103113). Together, these mechanisms can alter the inhibitory feedback mechanisms of the HPT axis (i.e., its “set-point”) during prolonged critical illness. Single measurements of circulating TSH, however, are ineffective in revealing such alterations in the set-point of the HPT axis.

In sum, an initial beneficial alteration of thyroid hormone activity in the periphery during acute critical illness is followed by a cytokine-mediated central suppression of the HPT axis resulting in a virtual complete loss of pulsatile TSH secretion (29). Peripheral mechanisms (notably variations in the conversion and transport of thyroid hormones) may further modulate thyroid hormone function in time- and tissue-specific ways resulting in complex physiological alterations in these patients (Figure 3) —not readily observable in blood concentrations of thyroid hormones. How these alterations of the HPT axis persist as well as their broader implications on metabolism and the immune system are further described below (see section A “Vicious Circle” Perpetuating Illness).FIGURE 3

Figure 3. The thyrotropic axis (HPT axis) during normal conditions and prolonged critical illness.

In ME/CFS

Dysfunctions of the HPT axis have long been suspected to play a role in ME/CFS (77131134) and fibromyalgia (135140). A recent study showed that ME/CFS patients had similar TSH levels as controls, but lower Free T3, Total T4, and Total T3, which the authors suggest resembles NTIS (141)—the typical feature of critically ill patients in ICUs described above.

In sum, alterations of the HPT axis in ME/CFS resemble dysfunctions found in prolonged critical illness. However, there does not to our knowledge exist a thorough study of the pulsatility of pituitary TSH secretion events in ME/CFS patients, nor a study of the tissue-specific alterations in thyroid hormone function—which proved revelatory in understanding prolonged critical illness. The relationship between the TSH axis dysfunctions, severity of illness, hypometabolic state and organ/tissue specific symptoms in ME/CFS thus remains largely unexplored.

Intermediate Conclusions

The endocrine axes control many of the most fundamental physiological processes; their suppression is associated with a myriad of symptoms (see Table 2). Essentially, the suppression of pulsatile pituitary secretions of ACTH, GH, and TSH are central to prolonged critical illness. Inflammatory pathways play a role in inducing and maintaining this suppression irrespective of the nature of the original illness or trauma (see Table 3). The resulting endocrine patterns may be considered maladaptive and have wide ranging implications, including dysfunction of the balance between anabolic and catabolic processes, metabolism, and the regulation of the immune system. The physiological parallels between ME/CFS and prolonged critical illness would suggest that the suppression of pulsatile pituitary secretions of these tropic hormones might also underlie ME/CFS, and that the severity of ME/CFS might be a function of the strength of the mechanism; this however remains largely unstudied. In the next section we provide an overview of a model from critical illness that explains the perpetuation of these endocrine dysfunctions and we describe the relevance of the model for understanding ME/CFS.TABLE 2

Table 2. Summary of endocrine axes and function of the main hormones in adults.TABLE 3

Table 3. Summary of endocrine dysfunctions and mechanisms in critical illness and ME/CFS.

A “Vicious Circle” Perpetuating Illness

Based on nearly five decades of research, critical illness researchers have proposed a model that describes how NTIS is maintained by reciprocal relationships between inflammation (notably pro-inflammatory cytokines), O&NS and reduced thyroid hormone function, forming a “vicious circle” (910) (Figure 4). This model can help to explain the perplexing failure to recover of some critically ill patients in ICUs that survive their initial severe illness or injury. We describe the main elements of this model in a simplified manner below, as well as the implications for metabolism and the immune system. We also provide evidence suggesting that the “vicious circle” observed in prolonged critical illness also underlies ME/CFS.FIGURE 4

Figure 4. Simplified model to explain the perpetuation of prolonged critical illness: a “vicious circle”.

In Prolonged Critical Illness

The key elements of the suggested “vicious circle” in prolonged critical illness include the following mechanisms:

(a) Cytokines depress thyroid hormone function: As described above [see section The thyrotropic axis (HPT Axis) In Critical Illness], in acute and early stages of critical illness, various peripheral mechanisms involving cytokines lead to the quick depression of thyroid hormone activity in tissue-specific ways. In prolonged critical illness, cytokines in association with other signaling factors targeting the hypothalamus, as well as the pituitary and the thyroid glands, also inhibit thyroid hormone production. The relative sequence and importance of these various mechanisms in depressing the HPT axis and thyroid hormone function in different tissues and phases of critical illness are the subject of most NTIS publications (10104105). Notwithstanding the effect of other mechanisms, alterations in the activity of the deiodinase enzymes lead to a decrease in T3 and an increase in rT3 and thus a reduction in thyroid hormone function in peripheral tissues during prolonged critical illness [based on biopsies on ICU patients who died (142) and studies on mice (143144)]. Circulating thyroid hormone concentrations, however, only reveal the “tip of the iceberg” of the alterations occurring at the tissue level (141145), which thus are often missed altogether in clinical settings (146).

(b) Low thyroid hormone function contributes to oxidative and nitrosative stress: The relationship between thyroid hormone function and O&NS is complex, and both hyperthyroidism and hypothyroidism have been associated with oxidative stress (147). Nonetheless, it seems clear that depressed thyroid hormone function hinders tissue cells from maintaining a healthy O&NS balance. Mechanisms include alterations to the lipid concentration of the cell membranes that maintain the cell’s O&NS balance (148), and reduced function of two proteins (Uncoupling Proteins-2 and -3) with anti-oxidant properties (149). Moreover, in low thyroid hormone function conditions, mitochondria damaged by O&NS are not cleared out of cells (9). In turn, it appears that oxidative stress depletes the glutathione required by the abovementioned deiodinase enzymes for the conversion of T4 into T3 (104). Similarly, competition for, and the resulting depletion of the trace mineral selenium—a component of both the deiodinase and the anti-oxidant enzymes (150) —may amplify the self-perpetuating link between increased oxidative stress and low thyroid hormone function.

(c) Oxidative and nitrosative stress stimulate the production of pro-inflammatory cytokines: The final mechanism which completes the “vicious circle” in prolonged critical illness is the link between O&NS and inflammation. O&NS stimulates the production of pro-inflammatory cytokines, notably leptin, resistin, TNF-α and IL-6 (151). In turn, pro-inflammatory cytokines (notably IL-6) further increase O&NS by triggering the production of superoxide radicals (104152). There is thus a tendency for O&NS and pro-inflammatory cytokines to perpetuate each other as well.

In sum, according to a model proposed by critical illness researchers, a “vicious circle” involving O&NS, pro-inflammatory cytokines, and low thyroid hormone function—as well as reciprocal relationships across these elements—can perpetuate a hypometabolic and inflammatory state, and thus help to explain why some critically ill patients fail to recover.

In ME/CFS

Similar patterns of O&NS, cytokines, and low thyroid hormone function have recently been documented in ME/CFS patients providing the elements for a similar “vicious circle.” We briefly summarize the findings from ME/CFS research relevant to each of these elements.

Reduced thyroid hormone function: An immune-mediated loss of thyroid hormone function in ME/CFS has long been suspected (132). As mentioned above [see section: The thyrotropic axis (HPT Axis) In ME/CFS], a recent study confirmed that CFS patients have lower circulating levels of Free T3, Total T4, and Total T3 than controls (141). Moreover, this study found a significantly higher ratio of rT3 to T3 hormones. These findings imply a depressed thyroid hormone function resembling NTIS. Given the possible tissue-specific alterations in thyroid hormone activity resulting from peripheral mechanisms, the authors suggest these circulating levels only reflect the “tip of the iceberg” of genuine T3 deficits in target tissues.

Oxidative & nitrosative stress: Numerous studies have found increased O&NS in ME/CFS and identified this as a factor in the observed metabolic dysfunction (153154). Indeed, Pall proposed a model that describes a “vicious circle” involving oxidative stress and cytokines in ME/CFS a decade ago (cf. the “NO/ONOO-Cycle”) (155). Researchers also suggest that high lactate and low glutathione levels found in the brains of ME/CFS patients likely derive from similar mechanisms involving oxidative stress (156). A recent study described the relationship between O&NS and immune-inflammatory pathways in ME/CFS (80).

Pro-inflammatory cytokines: Neuro-inflammation is central to ME/CFS, and many researchers have tried to develop diagnostic biomarkers for ME/CFS based on cytokine profiles of patients (157158). Montoya et al. found that some 17 cytokines were positively correlated with the severity of ME/CFS, of which 13 are pro-inflammatory. Similarly, circulatory levels of pro-inflammatory cytokines are altered in fibromyalgia patients (159). However, others have argued that given the innumerable sources of potential variance in the measurement of cytokines, it is “unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered” for ME/CFS (160). It may therefore be ineffectual to compare the cytokine profiles of ME/CFS and prolonged critical illness patients.

In sum, given the presence of reduced thyroid hormone function, O&NS and pro-inflammatory cytokines in ME/CFS, the “vicious circle” model proposed by critical illness researchers to explain prolonged critical illness may also help to understand why ME/CFS patients fail to recover.

Implications of the “Vicious Circle” and Its Elements

Reduced thyroid hormone function, increased O&NS and pro-inflammatory cytokines discovered in prolonged critical illness as well as in ME/CFS have important implications notably on metabolism, organ function, immune responses and the endocrine system. These are further described below:

Reduced thyroid hormone function: The prolonged down-regulation of thyroid hormone activity certainly has implications for the immune system. Authors describe the profound effects of circulating thyroid hormone levels on the activity of monocytes, lymphocytes macrophages, neutrophils, dendritic cells and natural killer cells; as well as cytokines (161170). Notably, depressed thyroid levels appear to depress the activity of natural killer cells (171)—a signature finding in ME/CFS (172). Such immune dysfunctions might explain other pathologies, such as viral reactivation observed in ICU patients (173175) and suspected in ME/CFS patients (176177). Experimenting on rats, researchers have shown that depressed thyroid hormone levels occur in a specific sequence, manifesting (from first to last) in the liver, kidney, brain, heart and adipose tissues (145). An implication of a tissue-specific down-regulation of thyroid hormone activity is differential impact on organ function. Some ME/CFS practitioners have argued that tissue-specific modulation of T3 can help explain the disparate and evolving symptoms in ME/CFS and fibromyalgia (133134138140). In aggregate, depressed thyroid hormone function would engender a general hypometabolic state. Finally, thyroid hormone function also impacts other endocrine axes as well (178179)—notably the HPA axis—setting the stage for further complex interactions between the various endocrine axes and the immune system.

Oxidative & nitrosative stress: The implications of chronic oxidative stress in the body are widely documented. In addition to inducing inflammation, oxidative stress causes cell damage and disrupts normal cellular transcription and signaling mechanisms (9). O&NS has been shown to cause mitochondrial damage during critical illness (180) and ME/CFS (153).

Pro-inflammatory cytokines: Researchers are finding that the more than 100 different cytokines play a part in determining the function of hormones through both central and peripheral mechanisms (32). As described in the previous section, cytokines are likely culprits in the central (i.e., hypothalamic and pituitary) suppression of the HPA, HPS and HPT axes in prolonged critical illness (29). Pro-inflammatory cytokines and inflammation also hinder normal mitochondrial function during critical illness (181). The alterations in cytokines found in critical illness likely have many further implications that have yet to be fully understood (182) which is also the case for ME/CFS (183).

Intermediate Conclusions

In sum, critical illness researchers have proposed that the self-perpetuating relationships between inflammation (notably pro-inflammatory cytokines), O&NS and low thyroid hormone function explains the maintenance of illness in some ICU patients following severe injury or infection. Given that the same elements of such a “vicious circle” have also been documented in ME/CFS, we suggest that the model can also explain the failure of ME/CFS patients to recover. Moreover, these elements have been shown to have profound implications on metabolism, as well as on the function of the immune and endocrine systems—which in in turn could explain the myriad of symptoms in prolonged critical illness and ME/CFS.

Relationship to Other Hypotheses of ME/CFS Pathogenesis

Our hypothesis that maladaptive mechanisms which prevent recovery in prolonged critical illness also underlie ME/CFS complements several other hypotheses of ME/CFS pathogenesis. In this section we provide an initial and non-exhaustive discussion of some of these complementarities.

Allostatic overload: Some researchers consider ME/CFS to be a maladaptive response to physical, infectious, and/or emotional stressors. They describe an “allostatic overload” (i.e., the cumulative effect of stressful situations exceeding a person’s ability to cope) or a “‘crash’ in the stress system” (184185). Our hypothesis fits into this theoretical framework and offers an explanation for the possible underlying physiological mechanisms by drawing on the research from critical care medicine.

Hypothalamic endocrine suppression: Researchers have suggested that hypothalamic endocrine suppression could explain ME/CFS (132186) and fibromyalgia (187189). Our thesis upholds this hypothesis and seeks to strengthen it by suggesting that the controversy around the existence of central endocrine suppression in ME/CFS may be resolved by studying the pulsatile secretions of the pituitary—rather than single or average measurements of circulating tropic and non-tropic hormone concentrations, which can fail to discern the dysfunctions of the endocrine axes.

Anomalies in thyroid hormone function: Numerous clinical practitioners and researchers believe that anomalies in thyroid hormone function—including changes in the conversion of thyroid hormones, a resistance of thyroid hormone receptors at cellular level, etc. —contribute to ME/CFS and fibromyalgia (133141). Indeed, practitioners have written about their successes in treating ME/CFS patients with thyroid hormone supplements (4277188190194); and patients have published books on their experiences (195197). Our hypothesis complements this reasoning: we propose that both the central and peripheral mechanisms altering thyroid hormone function during critical illness (c.f. NTIS, euthyroid sick syndrome or “low T3 syndrome”) also occur in ME/CFS. Moreover, by applying a model from critical illness, we suggest that low thyroid hormone function is one element of a “vicious circle” perpetuating illness in ME/CFS.

Viral Reactivation: It has long been suggested that viral reactivation plays a role in ME/CFS, particularly reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) (176177). Similarly, high incidences of viral reactivation have also been observed in ICU patients, notably in patients with sepsis and prolonged critical illness. ICU researchers propose that this viral reactivation is a result of immune suppression occurring during critical illness (173175). Thus, critical illness research would suggest that viral reactivation is a secondary pathology in ME/CFS—except in cases in which the viral infection was the onset event.

Viral infection: Viral infection is recognized to be a leading onset event of ME/CFS (16198201). This is particularly concerning in the context of the COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms after defeating the virus that resemble ME/CFS. Building on our hypothesis, we would suggest that post COVID-19 syndrome is evidence of a maladaptive response to the stress of infection akin to that experienced in prolonged critical illness and ME/CFS.

Chronic inflammation: Researchers have found that chronic inflammation—auto-immune, allergic or bacterial/viral—underlies ME/CFS (194202203). Others also ascribe the perpetuation of ME/CFS to the relationship between inflammation and O&NS (80155). Our hypothesis is largely complementary to these findings and associated theories. Indeed, following a cytokine surge during the acute phase of critical illness, inflammation is believed to persist in the case of prolonged critical illness (4). Moreover, pro-inflammatory cytokines and O&NS are elements in the “vicious circle” model of prolonged critical illness, which we propose also serves to understand the perpetuation of illness in ME/CFS patients.

Neuroinflammation of the brain: ME/CFS is associated with inflammation of the brain (hence the name myalgic encephalomyelitis) (204205). Some have specifically proposed that inflammation of the hypothalamus underlies ME/CFS (8182). Similarly, alterations of the endocrine axes through mechanisms mediated by pro-inflammatory cytokines which impact the hypothalamus and pituitary are central to prolonged critical illness (see section Suppression of Pulsatile Pituitary Secretions).

Energy metabolic defect: Researchers have found impairment in energy production (205206), reduced mitochondrial activity (207209) and irregularities in the metabolites of ME/CFS patients (210211) —suggesting that they experience a hypometabolic or “dauer” state (212). Our hypothesis is compatible with analyses that emphasize metabolic defects in ME/CFS. Indeed, the suppression of pituitary secretions, depressed thyroid hormone function, O&NS and immune system dysfunction—hallmarks of prolonged critical illness—have severe impacts on metabolism, including on glucose utilization and mitochondrial activity (see section A “Vicious Circle” Perpetuating Illness). Certainly, prolonged critical illness resembles a hypometabolic “dauer” state as well.

Genetic predisposition: Research also suggests there may a genetic element in the pathogenesis of ME/CFS (213216). Our hypothesis is compatible with a possible genetic predisposition for ME/CFS. Indeed, it is not known why some critically ill patients succumb to prolonged critical illness while others begin recovery (217218); genetics may play a role. The findings from the field of ME/CFS in the area of genetics might inform the field of critical illness in this regard.

In sum, our hypothesis is largely complementary to hypotheses that emphasize metabolic, hormonal and/or immune dysfunctions in the pathogenesis of ME/CFS. Our hypothesis—drawing from research on critical illness—integrates these dysfunctions into a single framework and provides arguments for the direction of causality between them.

Conclusion

Decades of research in the field of critical medicine have demonstrated that in response to the stress of severe infection or injury, endocrine axes experience profound alterations. An assessment of the pituitary’s pulsatile secretions reveals that in the subset of patients which survive their severe infection or injury but do not begin recovery (i.e., prolonged critically ill patients), the suppression of endocrine axes is maintained irrespective of the initial severe infection or injury. Recent pathological models propose that mechanisms involving pro-inflammatory cytokines, O&NS and low thyroid hormone function explain the perpetuation of these endocrine dysfunctions (i.e., a “vicious circle”).

The symptoms, physiological abnormalities and endocrine patterns observed in severe ME/CFS are not unlike those of prolonged critical illness. Moreover, the same elements of a “vicious circle” also exist in ME/CFS. However, unlike in critical illness, the pituitary’s pulsatile secretion and its relationships to metabolic and immune functions remain largely unstudied in ME/CFS.

Without excluding possible predisposing genetic or environmental factors, we propose the hypothesis that the maladaptive mechanisms that prevent recovery of prolonged critically ill patients also underlie ME/CFS. The severity of ME/CFS illness may be a function of the strength of these mechanisms; very severe ME/CFS most resembles prolonged critical illness. We further argue that this hypothesis should be investigated through collaborative research projects building on the findings from critical illness and ME/CFS. If this hypothesis is validated, past trials to break the “vicious circle” that perpetuates critical illness, and the early successes to reactivate the pulsatile secretion of the pituitary in ICU patients, may provide avenues for a cure for ME/CFS—including cases onset by infections. Certainly, given the similarities described above, active collaboration between critical illness and ME/CFS researchers could lead to improved outcomes for both conditions.

Finally, we suggest that immediate collaborative efforts should be sought among the researcher community in order to conduct longitudinal studies with the aim of identifying similarities and differences across prolonged critical illness, post-ICU syndrome, ME/CFS, fibromyalgia and long-COVID in relation to the hormonal axes, O&NS and pro-inflammatory response with the objective of discovering diagnostic and therapeutic targets mitigating the functional disability that these conditions induce.

Data Availability Statement

The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

DS wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding

Open Medicine Foundation and Swedish Research Council (2015-4870 (JB)) are acknowledged for support.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Text throughout this hypothesis is reproduced from DS’s blogposts on Health Rising (219221) licensed Creative Common–Attribution CC BY.

Abbreviations

ACTH, Adrenocorticotropic hormone; ARV, Arginine vasopressin; CRH, Corticotrophin-releasing hormone; DHEA, Dehydroepiandrosterone; GH, Growth hormone; GHIH, Growth hormone inhibiting hormone; GHRH, Growth hormone releasing hormone; HPA, hypothalamus-pituitary-adrenal axis: “Adreno-cortical axis”; HPS, Hypothalamic-pituitary-somatotropic axis: “Somatropic axis”; HPT, Hypothalamic-pituitary-thyroid: “Thyrotropic axis”; ICU, Intensive Care Unit; IGF-1, Insulin like growth hormone-1; IGFBP, Insulin like growth hormone binding proteins; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NTIS, Non-thyroidal illness syndrome; O&NS, oxidative and nitrosative stress; PICS, Post-intensive care syndrome; POTS, Postural Orthostatic Tachycardia Syndrome; TRH, Thyrotropin-releasing hormone; TSH, Thyroid stimulating hormone.

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Keywords: myalgic encephalomyelitis, critical illness, non-thyroidal illness syndrome, low t-3 syndrome, pituitary, cytokines, oxidative and nitrosative stress, post-intensive care syndrome

Citation: Stanculescu D, Larsson L and Bergquist J (2021) Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front. Med. 8:628029. doi: 10.3389/fmed.2021.628029

Received: 10 November 2020; Accepted: 08 January 2021; Published: 28 January 2021.

Edited by:Nuno Sepulveda, Charité–Universitätsmedizin Berlin, Germany

Reviewed by:Jose Alegre-Martin, Vall d’Hebron University Hospital, Spain
Klaus Wirth, Sanofi, Germany
Jonathan Kerr, Norfolk and Norwich University Hospital, United Kingdom

Copyright © 2021 Stanculescu, Larsson and Bergquist. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jonas Bergquist, Jonas.Bergquist@kemi.uu.se

MECFS: evidence for an autoimmune disease

Featured

Autoimmunity Reviews

Volume 17, Issue 6, June 2018, Pages 601-609

Autoimmunity Reviews

ReviewMyalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

FranziskaSotznya

JuliàBlancobc

EnricaCapellide

JesúsCastro-Marrerof

SophieSteinera

ModraMurovskag

CarmenScheibenbogena on behalf of the European Network on ME/CFS (EUROMENE)

Citehttps://doi.org/10.1016/j.autrev.2018.01.009Get rights and content

Under a Creative Commons license open access

Highlights

The pathogenesis of ME/CFS is multifactorial, and immunological and environmental factors play a role.•

Autoimmune mechanisms can be linked with ME/CFS at least in a subset of patients.•

Autoantibodies mostly against nuclear and neurotransmitter receptors are found in a subset of ME/CFS patients.•

Immunomodulatory therapeutic strategies targeting autoantibodies may be beneficial and should be pursued.

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MECFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients MECFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for MECFS. Immune dysregulation in MECFS has been frequently described including changes in cytokine profiles and immunoglobulin levelsT- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in MECFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of MECFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in MECFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of MECFS in order to better understand and properly treat this disease.

Abbreviations

AdRadrenergic receptorBAFFB-lymphocyte activating factordUTPasedeoxyuridine 5′-triphosphate nucleotidohydrolaseEBVEpstein-Barr virusFMfibromyalgia5-HT5-hydroxytryptanimeHHVhuman herpes virusIFNγinterferon gammaKIRkiller cell immunoglobulin-like receptorM AChRmuscarinic acetylcholine receptorME/CFSMyalgic Encephalomyelitis/Chronic Fatigue SyndromeMSmultiple sclerosisNKnatural killer cellsPBMCperipheral blood mononuclear cellsPOTSpostural orthostatic tachycardia syndromepSSprimary Sjögren’s syndromeRArheumatoid arthritisSLEsystemic lupus erythematosusSNPsingle nucleotide polymorphismsTCAtricarboxylic acidTfhT follicular helper cellsThT helper cellsTNFαtumor necrosis factor alphaTregregulatory T cells

Keywords

Autoimmune Biomarker Myalgic Encephalomyelitis Chronic Fatigue Syndrome Autoantibodies

1. Introduction

With an estimated prevalence of 0.2–0.3%, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem disease with unknown etiology. Patients suffer from persistent exhaustion, cognitive impairmentautonomic dysfunction, chronic pain and flu-like symptoms, leading to a substantial reduction of life quality [1].

ME/CFS disease onset is often reported to be triggered by infections and the link between infections and autoimmune diseases is well established [2]. Although the exact pathogenesis is still unknown, the most plausible hypothesis is that dysregulation of immune system, autonomic nervous system and metabolic disturbances contribute to this complex syndrome, in which severe fatigue and cognitive impairment are a central feature (Fig. 1). Stressful life events are frequently associated with disease onset concomitantly with a history of frequent recurrent infections, immune deficiency and autoimmunity [1,3]. There are numerous studies showing immunological, genetic and metabolic alterations consistent with an autoimmune mechanism. Further, the identification of autoantibodies in ME/CFS patients and the clinical benefit associated with B cell depleting therapy provide strong evidence that, at least in a subset of ME/CFS patients, the disease has an autoimmune etiology.

Fig. 1

2. Evidence for autoimmunity in ME/CFS

2.1. Role of infection

Infection by various pathogens, including the Epstein-Barr virus (EBV), the human herpes virus (HHV)-6 and the human parvovirus B19, but also intracellular bacteria, are known as triggers of disease [1,[4][5][6]]. In a subset of patients, ME/CFS begins with infectious mononucleosis and evidence for a potential role of EBV in ME/CFS comes from many studies [4,[7][8][9]]. In 1984, DuBois et al. first described patients with mononucleosis syndrome suffering from long-lasting fatigue and serological evidence of EBV reactivation [4] followed by a number of studies describing ME/CFS patients with serological evidence of chronic active EBV infection [[7][8][9]]. Infectious mononucleosis is known as a risk factor for various autoimmune diseases [2,10]. Several studies show homologies of EBV sequences with human autoantigens such as myelin basic protein for multiple sclerosis (MS) [11]. In a study from our group enhanced IgG reactivity against an EBNA-6 repeat sequence was found in ME/CFS patients [9]. Homologous sequences of various human proteins with an EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

Detection of anti-HHV-6 IgM antibodies and HHV-6 antigen in peripheral blood mononuclear cells (PBMC) and mucosa as evidence for HHV-6 reactivation is more frequent in patients with ME/CFS compared to healthy donors, showing that reactivation of persistent HHV-6 infection could be a trigger factor for ME/CFS [[12][13][14][15]]. In studies from our group evidence for an active HHV-6, HHV-7 or B19 infection was found in a subset of patients and was associated with subfebrility and lymphadenopathy [16]. Others, however, showed no difference between severity of symptoms and viral load of HHV-6 and HHV-7 in DNA from saliva and PBMCs among ME/CFS patients and controls [17]. It should be noted that HHV-6 and HHV-7 infect immune cells, preferentially CD4+ T cells, but also CD8+, monocytes/macrophages and natural killer (NK) cells involved in cellular, humoral and innate immune response [18,19]. Infection of immune cells by these viruses lead to changes in cell surface receptor expression, pro-inflammatory and anti-inflammatory cytokine and chemokine expression level modulating local inflammation and immune response. A role for HHV-6 has been proposed in several autoimmune diseases, including MS, autoimmune connective tissue diseases, and Hashimoto’s thyroiditis [20]. Molecular mimicry between myelin basic protein and an HHV-6 cell membrane protein is suggested to explain this link in MS [21]. Further, for ME/CFS and Gulf War Illness antibodies against the human dUTPase were reported by Halpin et al. [22]. These autoantibodies mainly occur together with antibodies against at least one of multiple HHV-encoded dUTPases suggesting an antigenic mimicry.

Parvovirus B19 infection has been shown to lead to development of ME/CFS. B19-triggered ME/CFS may be associated with a persistent viremia or may occur without viremia [23] and increased circulating TNF-α and IFN-γ were shown [24]. B19-associated ME/CFS was, in some cases, effectively treated with intravenous IgG [5,25,26]. Documented mechanisms in the pathogenesis of B19-associated autoimmunity include cross reaction of anti-B19 antibodies with human proteins, B19-induced apoptosis which results in presentation of self- antigens to T lymphocytes, and the phospholipase activity to the B19 unique VP1 protein region [23].

2.2. Immune cell alterations

Enhanced levels of immunoglobulins and alterations in B cells are frequently found in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) [[27][28][29][30]]. Further frequencies of CD21low B cells are frequently increased in these autoimmune diseases [27]. Consistently, alterations of B cell subsets are reported in ME/CFS. Elevated numbers of CD21+ as well as CD19+ and activated CD5+ B cells were described in ME/CFS patients [31,32]. Bradley et al. showed enhanced frequencies of naïve and transitional B cells and diminished plasma blasts [33]. Differently, Brenu et al. did not observe an altered frequency of plasma blasts, but an increase of memory B cells [34]. However, no major alteration of major B cell subpopulations was observed in other studies [3,35]. Mensah et al. reported an increase in CD24+ B cells, a fraction found to be elevated in autoimmune diseases [35]. Further elevated IgG levels in a subset of ME/CFS patients were shown in several studies [3,35,36]. Recently, a whole blood gene expression study discovered a downregulation of genes being involved in B cell differentiation and survival in ME/CFS [37].

T cell activation by infections could play an important role in the onset of autoimmune diseases [38]. In ME/CFS individuals, an increased frequency of activated T cells expressing the activation marker CD26 and HLA-DR has been shown, concomitant to lower levels of CD45RA+CD4+ T cells [31]. Similarly, ME/CFS was associated with higher frequencies of CD38 and HLA-DR co-expressing CD8+ T cells [39]. However, other authors found similar or lower expression of these markers in ME/CFS patients compared to healthy individuals [40,41]. Similarly, there is also evidence for a decreased cytotoxicity of CD 8+ T cells in a subset of ME/CFS patients [[42][43][44][45]]. Of particular interest in autoimmune diseases are T follicular helper cells (Tfh) that induce humoral responses at the germinal centers [46], the anti- inflammatory regulatory T cells (Treg) and the inflammatory T helper 17 (Th17) cells that modulate the activity of autoimmune responses [47]. The frequency of Treg has been addressed by several authors, most of them reporting a paradoxical higher frequency of this cell population in ME/CFS [40,42,48]. However, no studies on the potential role of Tfh and Th17 cells are available in ME/CFS yet.

In contrast to inconsistent B and T cell alterations reported in ME/CFS, diminished numbers of circulating NK cells and reduction of their cytotoxic activity were uniformly shown [31,40,49]. However, enhanced secretion of IFNγ and TNFα by the immunoregulatory CD56 bright NK cell subset was described in ME/CFS [49,50].

In summary, immune dysfunction in ME/CFS, as for other autoimmune disease, is a multifaceted hallmark that requires further studies using new technologies, standardized assays and well defined cohorts to clearly define common patterns.

2.3. Autoantibodies in ME/CFS

Several studies described autoantibodies in ME/CFS mostly against nuclear and membrane structures and neurotransmitter receptors (Table 1).

Table 1. Autoantibodies in ME/CFS.

AutoantigenCohorts of patients/control (n)Autoantibody positive
patients/control (%)
Refs.
Nuclear structures
ANA60/5168/15[51]
22523[53]
6057[54]
6068[55]
139/1497/5 (BioPlex ANA screen) 4/6 (IIF)[57]
Nuclear envelope60/5152/2[51]
60/3052/3[55]
Reticulated speckles60/3025/0[55]
68/48 kDa protein114/3713/0[52]
dsDNA8112[56]
Membrane structures
Phospholipids4238[58]
Cardiolipin2692 (IgM)[59]
4095 (IgM)[60]
814[56]
Phosphatidylserine815[56]
Gangliosides42/100 (FM)43[58]
Neurotransmitter receptors and neurotransmitter
M AChR5/11PET: binding to brain
M AChR in ME/CFS
[61]
M1 AChR60/3053/0[54]
M3/4 AChR and ®2-AdR268/108significantly elevated compared to
healthy controls
[53]
5-HT4262[58]
819[56]
Other autoantibodies
Cytoplasmic intermediate filaments60/3035/13[55]
dUTPase55/15115/5[22]
Neopitopes formed by oxidative or nitrosative damage14/11Significantly elevated compared to healthy controls (IgM titers)[66]
16/17[67]

Abbreviations: ANA: antinuclear antibodies; 5-HT: 5-hydroxytryptamine; IIF: indirect immunofluorescence; dUTPasedeoxyuridine 5′-triphosphate nucleotidohydrolase; FM: fibromyalgia.

2.3.1. Autoantibodies against nuclear and membrane structures

Antinuclear antibodies (ANA) were found in one study in 68 % of ME/CFS patients with the majority directed against the nuclear envelope [51]. Further studies showed ANA in 68%, 57%, 23% and 13% of ME/CFS patients [[52][53][54][55]]. Ortega-Hernandez et al. found dsDNA antibodies in 12% of patients [56], but another study failed to show such antibodies in ME/CFS (0.7%) [57].

Klein and Berg described anti-ganglioside antibodies in ME/CFS patients, but not in healthy controls [58]. In addition, they and others found phospholipid autoantibodies in ME/CFS patients [56,58,59] and antibodies against cardiolipin were described in 92–95% of ME/CFS patients in two studies [59,60] but only in 4% in another study [56]. Further autoantibodies against endothelial and neuronal cells were described in 30% and 16% of patients, respectively [56].

2.3.2. Antibodies against neurotransmitter receptors and neurotransmitter

Antibodies against the muscarinic M1 acetylcholine receptor (AChR) were reported in ME/CFS patients and were associated with muscle weakness [54]. Evidence for a functional role of these antibodies comes from a PET study showing reduced binding of a M AChR ligand in brain in antibody positive ME/CFS patients [61]. Antibodies against ß1 and ß2 adrenergic receptors (AdR) and M2/3 AChR were described in postural tachycardia syndrome, characterized by an increased heart rate in the absence of significant hypotension, as well as in orthostatic hypotension. This finding is of relevance for ME/CFS as 11–40% of ME/CFS patients concurrently suffer from postural orthostatic tachycardia syndrome (POTS) [[62][63][64][65]]. In a study from our group, elevated autoantibodies against both ß2-AdR and M3/4 AChR were found in a subset of ME/CFS patients compared to healthy controls [53]. A high correlation was found between levels of ß2 AdR autoantibodies and elevated IgG1–3 subclasses, activated HLA-DR+ T cells and thyroid peroxidase autoantibodies and ANA. The association of ß2 AdR autoantibodies with immune markers suggests an activation of B and T cells expressing ß2 AdRs. Further, disturbance of the AdR and M AChR function may explain symptoms of autonomic dysregulation in ME/CFS.

No differences between ME/CFS patients and controls were found in levels of autoantibodies directed against receptors for angiotensinendothelinmu-opioid, serotonin and dopamine [53,54]. However, autoantibodies against serotonin have been associated with ME/CFS [56,58].

2.3.3. Other autoantibodies

The IgM response against autoantigens formed by oxidative or nitrosative damage was studied by Maes et al. [66]. Autoantibodies directed against these neo-antigens, comprising oleic, palmitic and myristic acidS-farnesyl-l-cysteine, by-products of lipid peroxidation, e.g. malondialdehyde, and N-oxide modified amino acids, e.g. nitro-tyrosine and nitro-tryptophan, were significantly higher in ME/CFS patients than in controls. In addition, they observed that the level of these autoantibodies correlates with severity of illness and symptoms. Although increased IgM antibodies against these oxidatively damaged antigens were shown in major depression, too, a higher immune response was found in ME/CFS [67].

2.4. Soluble markers of autoimmunity

Autoimmunity is associated with enhanced levels of circulating inflammatory cytokines playing an important role in the pathogenesis of autoimmune diseases [68]. Elevated levels of cytokines related to Th1- as well as Th2-driven responses were reported for ME/CFS in several studies [42,[69][70][71][72][73][74]]. Further cytokine levels in ME/CFS were associated with severity and duration of illness [[72][73][74]]. However, alterations in cytokine profiles in ME/CFS were not found in all studies [75,76].

Elevated levels of B lymphocyte activating factor (BAFF) were described in a variety of autoimmune diseases including RA, SLE and pSS [77]. BAFF regulates the survival and maturation of B cells and mediates the IL-10 production of regulatory B cells [78,79]. Elevated levels of BAFF were shown in a subset of patients with ME/CFS in comparison to healthy controls [80]. As the gene expression of the BAFF receptor (TNFRSF13C) is reduced in ME/CFS, increased serum BAFF levels may represent a compensatory mechanism [37]. Interestingly, elevated serum BAFF levels correlated with the autoantibody production in RA, SLE and pSS [81]. In ME/CFS an association between BAFF and autoantibodies was not described so far.

Activin A and B, members of the Transforming Growth Factor β family, are involved in the control of inflammation and muscle mass [82]. Elevated levels of activin B as well as an elevated ratio of activin A or B to the binding protein follostatin in ME/CFS patients were demonstrated in a recent study [83]. An association of increased activin A with inflammatory bowel disease, RA, and asthma was already shown [82].

CD26 is a peptide-cleaving enzyme associated with immune regulation. In various autoimmune diseases, such as MS, Grave’s disease, and RA increased numbers of CD26 T cells were found in inflamed tissues and peripheral blood [84]. Fletcher et al. reported a higher frequency of CD26 expressing CD2+ lymphocytes in ME/CFS, but a decreased expression level on T and NK cells [85]. Further, they observed a reduction of the soluble CD26. Reduced serum CD26 levels were also reported for SLE and RA showing an inverse correlation with disease activity [84]. Low CD26 expression on PBMCs in ME/CFS was shown to correlate with reduced post-exercise muscle action potential, increased exercise- mediated lipid peroxidation, reduced quality of life and enhanced pain [86].

Other serum factors, frequently elevated in autoimmune disease like sCD30, sCD23, soluble cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4) or the soluble IL-2 receptor (sIl-2R) are not described in ME/CFS so far [[87][88][89][90][91][92]].

2.5. Genetic variants associated with autoimmunity

It is well established that certain HLA alleles are associated with autoimmune diseases. Smith et al. showed an increased prevalence of the class II major histocompatibility complex HLA-DQB1  01 allele in ME/CFS patients [93]. Two others variants of HLA-DQB1 in combination with two RAGE-374A variants were associated with ME/CFS [94]. In another study the interaction of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I epitopes were studied. An excess of KIR3DL1 and KIR3DS1 missing their HLA-Bw4Ile80 binding motif was shown in ME/CFS, leading potentially to an ongoing activation [95].

In the last years, genome-wide association studies revealed variants of various genes with either gain- or loss-of-function that are associated with the risk to develop autoimmune diseases. These single nucleotide polymorphisms (SNP) in receptors, enzymes or transcription factors play a role in B cell activationT cell development, activation and proliferation, and cytokine signaling which are crucial in autoimmune diseases [[96][97][98][99][100]]. Further, it is becoming increasingly clear that elements of the non-coding genome regulate a variety of normal immune functions and that dysregulation of enhancer elements or long non- coding RNA may play a key role in autoimmunity [101]. So far only polymorphisms in cytokine as well as toll-like receptor signaling pathways and complement cascade were studied showing an association with ME/CFS [102,103]. Due to its regulation of the inflammatory response the glucocorticoid receptor gene NR3C1 has gained interest. Several variants (SNPs) within NR3C1 gene were shown to be significantly associated with ME/CFS [104,105].

2.6. Energy metabolism and autoimmunity

Immunometabolism represents the interface between immunology and metabolism and is an exciting emerging field of research in autoimmunity [[106][107][108]]. The metabolic requirements of immune cells depend on their state of resting or activation and differentiation. Their activation results in a metabolic switch to aerobic glycolysis in order to provide enough energy and bio-precursors to meet the requirements for supporting rapid cell proliferation and immune functions. A growing body of evidence suggests that energy metabolism is crucial for the maintenance of chronic inflammation, not only in terms of energy supply but also in the control of the immune response through metabolic signals [106,107]. It has been suggested that disturbances in this intricate metabolic-immune cross-talk may be closely linked with and contribute to autoimmunity, although the precise pathomechanisms involved still remain to be elucidated [107,108]. It is also striking that several glycolytic enzymes act as autoantigens in rheumatic inflammatory disorders [109], although their role in ME/CFS remains unclear.

The profound and debilitating fatigue experienced by ME/CFS individuals led to the hypothesis that energy metabolism may be dysregulated. Defects in mitochondrial function in ME/CFS were shown in various studies from our group and others [[110][111][112][113]]. Metabolic profile had revealed disturbances related to energy, amino acids, nucleotidesnitrogen metabolism and oxidative stress in ME/CFS [[114][115][116][117][118][119]]. A metabolic shift toward aerobic glycolysis resulting in insufficient tricarboxylic acid (TCA) cycle and inadequate ATP production was reported recently, although the underlying basis has yet to be established [116,119]. Interestingly, the 2016 Fluge et al. study points to a secondary metabolic change driven by a serum factor in ME/CFS patients [116].

As dysfunctional metabolic pathways can directly influence and exacerbate defective immune responses, establishing the bioenergetic metabolism status of the different subsets of immune cells in ME/CFS has become a topic of increasing interest.

2.7. Comorbidity with autoimmune diseases

Comorbidity of ME/CFS with various autoimmune or immune-mediated diseases including fibromyalgia (FM), Hashimoto’s thyroiditis and POTS is observed (Fig. 2). Especially for FM there is considerable overlap with up to 77% of patients fulfilling disease criteria for both ME/CFS and FM [120]. FM is characterized by chronic widespread pain and is common in autoimmune diseases with around 50% of prevalence in patients with RA and SLE [121,122]. According to the modified ACR 2010 criteria FM has an overall estimated prevalence of 5.4%. In a recent study from our group analyzing clinical subgroups in a large Spanish ME/CFS cohort was reported FM comorbidity ranging from 26% to 91% [123]. In another study including patient cohorts from Norway, UK and USA, a comorbidity for ME/CFS and FM of 30% was observed [124]. In a similar manner Hashimoto’s thyroiditis characterized by elevated antibodies against thyroid peroxidase is frequent in autoimmune disease, whereas the overall prevalence is around 0.8% in the general population [125]. Hashimoto’s thyroiditis is found in 17–20% in ME/CFS patients [53,123]. Moreover, 11–40% of ME/CFS patients suffer from POTS [[62][63][64][65]]. Interestingly, for both disorders elevated frequencies of autoantibodies directed against AdRs and M AChRs were shown [53,[126][127][128]]. Furthermore, a substantial number of ME/CFS patients have a family history of autoimmune diseases [129,130].

Fig. 2

3. Therapies targeting autoimmunity in ME/CFS

First clear evidence for a pathogenic role of autoantibodies in ME/CFS comes from two clinical trials with the monoclonal anti-CD20 antibody rituximab [129,131]. Upon depletion of CD20+ B cells with rituximab, a monoclonal antibody directed against the B cell surface protein CD20, approximately 60% of patients experienced a partial or complete, and in some patients sustained clinical remission (Table 2). The delayed onset of response with a median of approximately 4 months in both trials suggests that clinical effects are not directly mediated by depletion of CD20+ B cells, but by diminishing short-lived antibody-producing plasma cells arising from CD20+ memory B cells, followed by subsequent wash-out of autoantibodies. Results from a multicenter controlled trial with rituximab are awaited in spring 2018.

Table 2. Clinical trials targeting autoimmunity in ME/CFS.

DosageStudy designPatients (n)EvaluationOutcomeRefs.
Intravenous IgG
1 g/kg/m2

RCT28FI & SRNo difference[133]
2 g/kg/m2

RCT49FI & SRFollow-up m3: 43% vs. 12%[134]
0.5 g/1 g/2 g/kg/m2

RCT99FI & SRNo difference[135]
1 g/kg/m2

RCT70 (adolescents)FIFollow-up m6: 72% vs. 44%[136]
Rituximab
500 mg/m2

RCT30FI & SRImprovement 67% vs. 13%[131]
500 mg/m2 6×Single arm29FI & SRImprovement 62%[129]
Ongoing Trials
Cyclophosphamide (Endoxan®)Fluge et al., unpub.
Immunoadsorption[137]

Abbreviations: RCT = Randomized controlled trial; FI=Functional Improvement; SR = Symptom reduction, assessed by questionnaires; unpub.: unpublished data.

Few other treatment modalities targeting autoimmunity were evaluated in clinical trials in ME/CFS (Table 2). High dose intravenous IgG therapy is efficacious in autoantibody-mediated diseases. Several intravenous IgG studies were performed in ME/CFS during the 80’s with two randomized controlled trials with positive and two with a negative outcome [132]. Preliminary data from an ongoing trial in Norway with cyclophosphamide suggests therapeutic efficacy of this broadly immunosuppressive drug (Fluge et al., unpublished data). Immunoadsorption is an apheresis in which IgG is specifically removed from plasma resulting in clinical improvement in various types of autoimmune disease. We performed a pilot trial in 10 patients with ME/CFS and observed first evidence for efficacy [137].

4. Conclusion

There is compelling evidence that autoimmune mechanisms play a role in ME/CFS. However clinical heterogeneity in disease onset (infection versus non-infection triggered), presence of immune-associated symptoms, and divergent immunological alterations point to the existence of subgroups of ME/CFS patients with possibly different pathomechanisms. Therefore, it is important to identify clinically useful diagnostic markers to select patients with autoimmune-mediated disease for clinical trials. The search for autoantibodies is of great importance enabling to develop potential biomarkers for diagnosis and providing a rationale for therapeutic interventions. Encouraging results from first clinical trials warrant larger studies with rituximab and other strategies targeting autoantibodies.

Funding

This review is based upon work from European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) as part of Cost Action CA15111 supported by the EU Framework Program Horizon 2020. Website: http://www.cost.eu/COST_Actions/ca/CA15111.

Author contributions

FS and CS were responsible for the first draft of the protocol, which was critically reviewed, further developed and approved by all authors.

Declaration of competing interests

JB reports personal fees from ALBAJUNA THERAPEUTICS, S.L., outside the submitted work; CS has received grant support for clinical trials and research from Fresenius, Shire, Lost Voices, SolveME, MERUK, IBB, and speaking honoraria from Octapharma and Shire. FS, EC, JCM, SS and MM have no conflict of interest to declare.

Acknowledgements

Not applicable.

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