A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS

Perpetuation of ME/CFS

The literature provides a compelling account of how a range of physiological and emotional ‘stressors’ can stimulate the hypothalamic PVN through separate but convergent pathways. Sensory information (‘stress’ signals) is received by the PVN from physiological changes in the body, including respiratory and cardiovascular changes, pain and elevated levels of circulating inflammatory mediators via both neural (involving the ascending vagus nerve) and humoral pathways. Emotional ‘stress’ signals, however, are received by the PVN directly from the limbic system, such as the amygdala and hippocampus. The PVN integrates and processes these incoming ‘stress’ signals before activating the ANS and HPA-axis, to mount a homeostatic response.^3,4

A dysfunctional hypothalamic PVN, in ME/CFS, might help to explain the significantly lowered tolerance level to stressful events that is well recognised in ME/CFS patients. Ongoing ‘stressors’ to which ME/CFS patients are particularly vulnerable, and perpetuate the disease, include physical or mental overexertion, experiencing of emotional or financial stress, sleep deprivation and exposure to environmental stressors, including chemical toxins, infections and vaccinations. ⁵ The concept that such a diverse range of ‘stressors’ can all affect ME/CFS patients, independently or in a combined manner, by converging on an already dysfunctional hypothalamic PVN is represented by Figure 2.

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Figure 2.

A diverse range of ‘stressors’ are known to affect ME/CFS patients, who are also known to be hypersensitive to ‘stress’ of any kind. Hypothetically, these multiple, but divergent ‘stress’ signals appear to converge by known or by plausible, but unconfirmed routes, into the hypothalamic paraventricular nucleus (PVN).

Some of these ‘signal pathways’ to the hypothalamic PVN have been documented, others are more conjectural but highly plausible. The following sequence of events is suggested to occur in ME/CFS patients. When a certain stress ‘tolerance level’ or ‘threshold’ is exceeded, then an already compromised PVN (from neuroinflammation) becomes overloaded, causing a debilitating ‘relapse’, or perhaps more aptly termed (in the light of neuroinflammation) a ‘flare-up’ (Figure 1). This could signify a dramatic increase in glial cell (microglia and astrocytes) activity, and its associated neuroinflammation, throughout the CNS, but particularly centred within the limbic system of ME/CFS patients and with a correspondingly dramatic increase in the severity of their symptoms. ⁶

‘Inflammatory marker’ studies, including magnetic resonance imaging (MRI) pre- and post-exercise studies, support the concept that symptom severities likely ‘wax and wane’ in tandem with fluctuating levels of chronic neuroinflammation in the brains and CNS of ME/CFS patients, and this is an important feature of this paradigm.^1,6–9 Following a relapse, chronically activated glial cells, as mediators of inflammation, would gradually return to their quiescent states and allow the hypothalamic PVN to attain, once more, a higher threshold of ‘stress’ tolerance, decreasing the likelihood of relapses. Chronic but fluctuating neuroinflammation of the hypothalamic PVN, in ME/CFS, might certainly help to explain why the ‘stress’ tolerance levels appear to be constantly changing in ME/CFS patients: the more severe the neuroinflammation of the PVN, the lower the level of ‘stress’ required to trigger a relapse. The defining symptom of ME/CFS, post-exertional malaise (PEM), ⁶ can also be explained by this paradigm (Figure 1); in this case, through physical (or mental) overexertion- induced ‘stress’ signals targeting a compromised hypothalamic PVN in ME/CFS patients. Interestingly, a recent MRI study indicated that PEM could be correlated to a reduction in cognitive function of ME/CFS patients, and with increased brain activity, which was detected within the inferior and superior parietal and cingulate cortices – a region of the limbic system. ⁸

Onset of ME/CFS

This paradigm (Figure 1) supports the concept that an initial triggering event, in conjunction with predisposing factors, such as being of ‘female gender’ and a likely ‘genetic susceptibility’, leads to a sustained and chronic ‘innate immune response’ within the brains and CNS of ME/CFS patients. Common ‘triggers’ include several different viruses, especially from the Herpes virus family, Lyme Disease, chemical toxins, multiple vaccinations and emotional trauma. ⁵ These independently acting physiological ‘stressors’, of a sustained and particularly severe nature, could target the hypothalamic PVN by the same physiological routes that perpetuaute the disease (and as illustrated in Figure 2). Emotional trauma, for example, would emanate within the limbic system and, therefore, could send a persistent and intensive neurological ‘stress’ signal directly at the PVN. Viral infections that trigger ME/CFS such as glandular fever (Epstein–Barr Herpes virus) are severe enough, in their own right, to send a sustained and intensive ‘stress’ signal at the hypothalamic PVN, but by a different route, using a combination of humoral and neural pathways.^3,4 The mechanism of how the PVN could be affected, in ME/CFS susceptible people, is of course highly conjectural, but perhaps it might cause a form of ongoing disturbance within its complex neurological circuitry. As a consequence of this ‘assault’, the PVN might send out distorted neural (‘stress response’) signals, which in turn stimulate localised neuroinflammatory responses throughout the brain and CNS of ME/CFS patients.

A possible ‘neuroinflammatory’ response mechanism in ME/CFS

An initial ‘neuroinflammatory’ response, due to persistently activated microglia and astrocytes, is reported to occur across ‘early-stage’ neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Intriguingly, what appears to differentiate their pathological outcomes are the presence of disease and (CNS) location-specific ‘endogenous factors’ that help stimulate and sustain each of these uncontrolled ‘inflammatory’ responses: ‘amyloid-beta’ for AD, ‘α-synuclein’ for PD, ‘mutant SOD1’ for ALS and ‘myelin-peptide-mimetic’ for MS. ¹²

Different triggers and predisposing factors, in combination with a disease-specific ‘endogenous factor’, for ME/CFS, inducing a similar type of initial ‘neuroinflammatory’ response, but at different locations within the CNS and with different pathological outcomes, seems plausible. A resultant chronic, but lower level activation of microglia and astrocytes in the CNS of ME/CFS patients, as suggested here, might also be the defining factor in the development of a variety of other ‘neuroinflammatory’ diseases and, as has been implicated, in mental disorders, migraines and epilepsy, for example. This paradigm (Figure 1) proposes that the ‘neuroinflammatory’ response, which likely occurs in ME/CFS, follows a similar process to that which occurs in ‘early-stage’ neurodegenerative diseases and is outlined below.

Microglia can sense the presence of these alien forms (‘endogenous factors’) in their local environment, and the cells transform from sedentary, neuro-protective states into more active, neuroinflammatory responsive cells. In particular, ‘pattern recognition receptors’ expressed on microglia play a significant role in the initial detection and inflammatory response. This is amplified by downstream signal transduction pathways present in microglia and astrocytes, resulting in the production of proinflammatory cytokines, such as tumour necrosis factor (TNF)-α, IL-1β, and IL-6, as well as neurotoxic reactive oxygen species (ROS) and nitric oxide (NO). These may cause further amplification of the immune response, as well as neuroinflammation and neuronal damage, and become progressively more damaging if the process continues unabated. Adenosine triphosphate (ATP) released by necrotic neurones, during apoptosis, might also contribute to this process by further activation of microglia through positive feedback loops. Both microglia and astrocytes possess purinergic receptors that can bind ATP present in the interstitial fluid. ¹²

Microglia when activated can also release the neurotransmitter glutamate in a sustained form which is thought to have a deleterious effect on neuronal mitochondria (mitochondrial respiratory chain complex IV becomes inhibited). Mitochondrial dysfunction then could be a key component in the neuroinflammatory process and accounts for the reports of lactate, produced by anaerobic respiration, as mentioned earlier, being found in the CSF of ME/CFS patients.

Possible ‘endogenous factors’ for ME/CFS

Such a hypothetical factor specific to ME/CFS pathophysiology would likely be different in nature and operate more dynamically than those more ‘permanent forms’ associated with the neurodegenerative diseases. The ‘endogenous factor’ itself could then increase or decrease in proportion to any ongoing neural (‘stress response’) signals from a dysfunctional hypothalamic PVN and account for fluctuating levels of neuroinflammation and severity of symptoms in ME/CFS. One possibility for such an ‘endogenous factor’ is suggested from the observation that reactivation of viruses like Herpes Simplex from latent neuronal infection occurs in response to psychological stress, which is a known ‘stressor’ to impact on ME/CFS patients. Then, viral ‘pathogen-associated molecular patterns’, present within the CNS, could be the (dynamically changing) ‘endogenous factor’ that stimulates localised microglial activation and neuroinflammation. A number of studies have shown that psychological chronic stress can also affect mitochondrial function and morphology in the brains of animals. In ME/CFS such dysfunction could lead to the release of ‘alarmins’ in the form of (alien) mitochondrial DNA (potentially another form of ‘dynamically’ changing ‘endogenous factor’) stimulating localised microglial activity and a neuroinflammatory response. Nevertheless, there could be many other potential candidates as ‘endogenous factors’ involved in ME/CFS pathophysiology, and as described in the literature involving other neuroinflammatory pathways.

A dysfunctional limbic system

Almost all of the specific areas of the brain highlighted as affected in this PET/MRI study, such as the amygdala, hippocampus, thalamus and cingulate cortex, ⁶ are found to be within a region of the brain termed the limbic system. Sensitive emotions, mood swings, cognitive dysfunction, memory loss and increased anxiety all commonly experienced by ME/CFS sufferers ⁵ might therefore be explained by inflammation (and dysfunction) of the limbic system. The ‘feeling’ of profound fatigue ⁵ could also be partially accounted for by inflammation of the limbic system, not dissimilar to that proposed for major depressive disorder (MDD). Classic symptoms of ME/CFS–heightened and distorted senses of sound, light, touch, smell and taste ⁵ –could all emanate from a dysfunctional limbic system. While the five sensory centres are located outside of the limbic system, they all feed signals into it.

A dysfunctional hypothalamus

The hypothalamus, located centrally within its limbic system, was not highlighted specifically in the imaging study, ⁶ but a more recent MRI study which correlated autonomic dysfunction, measured by heart rates and blood pressure readings, for ME/CFS patients and healthy controls found abnormalities in the brain stem and hypothalamus itself. It seems highly plausible that the hypothalamus might be directly or indirectly compromised by the proximal inflammation of its other closely connected limbic system components, and if so could account for many of the diverse symptoms experienced in ME/CFS.

The hypothalamus contains the sleep, appetite and thermostatic control centres and regulates the HPA-axis and the ANS, thereby indirectly controlling clarity of vision, heart rate, blood pressure and gastrointestinal motions, for example. Lack of refreshing sleep, insomnia, fluctuations in appetite control often leading to dramatic weight changes, abnormal thermostatic control and hypersensitivity to extremes of temperature, blurred vision, heart arrhythmias and hypotension–itself plausibly linked to orthostatic intolerance–as well as sluggish peristalsis and bloating are all common symptoms experienced by ME/CFS patients. ⁵

Hypothalamic-ANS dysfunction might even provide an explanation for the subtle ‘downstream’ immune system changes in the blood reported in numerous ME/CFS studies ⁵ (and summarised in Figure 3). ‘Psycho-neuro-immunological’ studies provide support to the concept of glial cell activation in the brains of psychosocial stress-affected subjects, leading to further immune system changes ‘downstream’, which may also be of some relevance in the elucidation of ME/CFS pathophysiology.

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Figure 3.

Consequences of a dysfunctional hypothalamus on the autonomic nervous system (ANS) and possible outcomes (symptoms) as reported in ME/CFS patients. Th1 = T-Helper Cell type 1 (humoral immune response) and Th2 = T-Helper Cell type 2 (cell-mediated immune response).

A dysfunctional hypothalamus, causing HPA-axis disruption, might account for aberrant neuroendocrine messages to the pituitary gland and adrenal glands and help to explain the increased frequency of urination experienced by ME/CFS patients and ‘hypocortisolism’ often reported in ME/CFS.^2,5

It is hoped that the paradigm presented here (and Figure 1) will provide a useful ‘framework’ for scientific debate to facilitate better understanding of the neurological pathophysiology in ME/CFS. Critical investigative research to test out the hypotheses put forward here and to fill the gaps in the mechanistic detail required is desired. If activated glial cells are detected in the hypothalamus, and in particular, the hypothalamic PVN of ME/CFS patients, then this would strengthen the evidence for PVN involvement. Then, mechanistic detail of how multiple ‘triggers’ for onset and multiple ‘stressors’ for perpetuation of ME/CFS translate into amplification of glial cell activity in the CNS in ME/CFS via plausible ‘endogenous factors’ would need to be resolved. Within the recent studies on ME/CFS, there has been insufficient focus on the involvement of the CNS in its pathophysiology. However, it is encouraging to learn that neuroimaging technology is advancing rapidly and is being used increasingly to investigate the whole range of neurological brain disorders and diseases. In particular, rapid advances are being made in the range, sensitivity and effectiveness of ligands and potential cellular receptors for PET/MRI, which should significantly enhance ME/CFS neuroimaging as well. Indeed, it is to be hoped that a diagnostic ‘brain-signature’ for neuroinflammatory diseases (like ME/CFS) using advanced, more sensitive MRI technology may not be too far away.