Below I will link Canadian document headings of symptoms with an exploration of this theory.

1. Fatigue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level. (Also include post exertional malaise )

The defining symptom of CFS/ME is disabling physical and mental exhaustion(26). In many respects this gross fatigue shares characteristics with hypoglycaemia(27) for example, profound exhaustion could be caused by hypothalamic "glucostat" dysfunction in the following way; blood sugar is regulated in the brain via sympathetic neurons. In the adrenal medulla a long pre-ganglionic fibre (via a splanchnic nerve)(28) stimulates the chromaffin cells to release catecholamines (adrenaline) if blood sugar is low. Also, excitatory fibres from the hypothalamus descend the spinal chord stimulating the pre-ganglionic sympathetic neurons. Fibres of these neurons innervate the visceral organs and skin. Noradrenaline is released following stimulation.

Below as a summary of catecholamine function with regard to energy/energy production/manifestation.

Noradrenaline Adrenaline.

Glycogenolysis Glycogenolysis

Lipolysis Lipolysis

Blood pressure up Blood pressure up

Increased heart activity Increased heart activity

Brain arousal Brain arousal

Increased BMR

Bronchiole dilation (30)

Notably, in CFS/ME, low brain arousal and low blood pressure feature strongly in symptomatic patients.

Catecholamine activation increases energy availability in the liver and promotion of lipolysis in adipose tissue (31). Glycerol is converted to glucose in the liver following the lipolysis of fat. The liver glucose pool is boosted directly by glycogenolysis (32). I speculate that if the hypothalamic "glucostat" is dysfunctional, then it cannot respond appropriately to energy demands.

A potentially linked factor in disruption of energy production from fatty acids and glycerol is deranged liberation of GRH from the hypothalamus resulting is possible lack of stimulation in the pituitary gland to produce GH. GH targets fat cells (33).

Furthermore, in this state of low/no energy the hypothalamic involvement is of note with regards to activation of the CRH -ACTH axis which leads to release of cortisol from the adrenal cortex(34). Cortisol can function in the proper activity of GH on fat cells (35). Cortisol also mobilises amino acids from muscle and connective tissue. It also stimulates their utilization for gluconeogenesis in the liver (36).

Under conditions of hypoglycaemia there are manifestations of disturbed nervous, cognitive and conscious activity, movement may become uncoordinated and speech slurs. There is also fatigue, dizzyness, weakness, confusion and pallor (37).

Patients suffering from CFS/ME are very familiar with these symptoms yet the key question remains how could this mechanism be accurate and yet we find within normal range glucose blood test results in CFS/ME patients?

The issue of measurement is also pertinent in the area of thyroid activity. Hypothalmic dysfunction(38) can lead to symptoms of low base metabolic rate (BMR). Secretion of Thyroid Releasing hormone (TRH) from the hypothalamus stimulates release of Thyroid stimulating hormone (TRH) from the anterior pituitary which results in release of T3 and T4 from the Thyroid(39). TH increases metabolic rate by boosting the oxygen consumption rate and heat production. Heart rate, contractility and vascular responsiveness to catecholamines are also affected resulting in an increase in blood pressure (BP). Low BP is a feature of CFS/ME.

Sleep dysfunction - There is unrefreshed sleep or sleep quality or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.

A hallmark symptom of CFS/ME is gross unrefreshed sleep(41). It has been speculated that this part of the syndrome is the catalyst for all the other symptoms(42).

Normal sleep patterns consist of 3 non REM phases. Each phase is characterized by specific changes in Electroencephalography (EEG) (43). There follows a period of Rapid Eye Movement (REM) sleep. The four phases in total makes up one cycle of normal sleep of approximately 90 minutes duration.(44).

The phase of sleep that is most relevant to normal functioning is N3 deep sleep(45). This phase is characterized by slow, large delta waves (previously denoted as stage 4 sleep). It is concomitant with "refreshing sleep"(46). The N3 stage is considered to be of greatest physiological importance(47) because deprivation of N3 leads to physical, mental and emotional fatigue and diminished ability to perform higher level cognitive functions.(48). Lack of refreshed sleep has been shown to course neuronal degradation from the activity of free radicals (and an increase in glucocorticoids)(49).

During sleep, most body systems are in a heightened anabolic state - accentuating the growth and rejuvenation of immune, nervous and muscular skeletal systems(50). Further, secretion of Growth Hormone, which is pulsatile with episodic bursts, occurs in N3 stage sleep. This is precisely the phase of sleep which is deregulated in CFS/ME(51). There is evidence that Alzheimer's disease may be the result of chronic sleep debt(52).

Patients suffering from CFS/ME report refreshed sleep deprivation being the norm, suffered continuously not occasionally. Profound fatigue results(53).

Warwick University studies (54) indicate lack of sleep can double the risk of death from cardiovascular disease. Direct results of sleep deprivation include memory lapse, impaired judgement, impaired immune system, risk of Type 2 diabetes developing, increased reaction time in muscle and tremor(55).

Studies of sleep deprivation in CFS/ME clearly show disruption of N3 stage sleep.(56). Hence, the metabolic benefits of refreshed sleep are lost, for example increased glymphatic clearance of metabolic waste products produced by neural activity in the brain (57). Sleep combats the accumulation of free radicals in the brain, in which glial cells are restored with glucose (via activity of GH)(58). N3 stage sleep is necessary for survival. (59)

Does dysregulation of N3 stage sleep implicate disruption of hypothalamic function? Sleep is highly dependent on the activity of the hypothalamus and reticular formation (RF) (60). The RF cholinergic system is linked to the hypothalamus and and has active involvement in the generation, timing and execution of sleep and the regulation of transition between the different sleep stages.(61).

Projection neurons in the RF modulate EEG waves(62). The hypothalamic suprachiasmatic nucleus (brain's biological clock) controls diurnal cycles thus regulating the timing of sleep and wakefulness(63). Prostaglandins are released to generate sleep(64). Also of note is that the adrenergic system (medulla) generates wakefulness (65). If the hypothalamus is indeed damaged in its normal functioning capacity this "wakefulness" system could be compromised.

Hypothetically, then, dysfunctional hypothalamic activity can affect sleep regulation. Sleep deprivation is N3 stage could be the direct cause of neurological/cognitive manifestation, such as "brain fog" in CFS/ME. "Confusion, impairment of concentration and short term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perception and sensory disturbances -eg spatial instability and disorientation and inability to focus vision. There many be overload phenomenon (hypersensitivities to stimuli that have changed from pre-illness status).

Cognitive, sensory eg photophobia and hypersensitivity to noise and /or emotional overload. HM may lead to "crash" periods (temporary period of immobilising physical/cognitive fatigue)and /or anxiety." From Canadian document.

The hippocampus is located under the cerebral cortex in the brain in an area which intersects lymbic system and hypothalamus(66) The hippocampus is thought to function in a variety of ways including short term memory, information processing, categorizing, word retrieval and spatial navigation.(67). Of note is that damage to this area is found in the early stages of Altimeter's disease. Could damage to this area of the brain via pathogen/immune interaction result in such a manifestation as a type of CFS ataxia?

Neuroendocrine manifestations such as loss of thermostatic stability- Subnormal body temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities,intolerance of extremes of heat and cold, marked weight change, anorexia or abnormal appetite, loss of adaptability and worsening of symptom with stress.

The hypothalamus acts as the body's temperature regulator(74), stimulation of the anterior section of the gland activates the heat loss mechanism, i.e. it acts as a cooling centre. Stimulation of the posterior section of the gland activates heat conservation ( it acts as a heating centre(75) .Deranged hypothalamic function could be the reason for loss of thermostatic activity in CFS/ME.

Conclusion.

The brain is susceptible to infection by pathogen. Immune system activation and ensuing interaction with foreign protein can damage brain tissues and persist as chronic disease.

I have attempted to correlate established symptoms of CFS/ME with posited hypothalamic dysfunction. There is, I believe supportive evidence to suggest that the variety of symptoms in this disease are related to the disruption .of this gland's normal functioning.

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