Insomnia, mood disorders, anxiety, melancholy, depression, MUS, panic attacks

Persistent activation of the HPA axis and presence of MUS

Circadian rhythm of the HPA axis and stress factors

In principle, the physiological circadian rhythm of the HPA axis is regulated at the level of the hypothalamus [7], specifically by the region of the suprachiasmatic nucleus (SCN), located immediately above the optic chiasm and connected to the retina through the retinohypothalamic tract. This region is linked to the paraventricular nucleus (PVN), the main site of CRH (Corticotropin Releasing Hormone) synthesis. CRH receptors in the adenohypophysis (anterior nucleus of the pituitary gland) control the synthesis and release of ACTH (AdrenoCorticoTropic Hormone or corticotropin) into the bloodstream. ACTH acts on the membrane receptors of corticoadrenal cells, stimulating the production of several hormones, predominantly cortisol (as well as other glucocorticoids, mineralocorticoids, dehydroepiandrosterone, and sex hormones) [HPA axis index - BIA-ACC].

Figure 1: Diagram of HPA axis interactions

In the brain, mineralocorticoid receptors (MC) in the hippocampus bind cortisol with high affinity, while there is lower affinity for cortisol binding to glucocorticoid receptors (GC) in the hypothalamus, the hypophysis and in other areas of the brain structure. The type of receptors involved in cortisol binding is a factor which is directly involved in maintaining the circadian rhythm of CRH release: bindings to mineralocorticoid receptors prevail early in the night (during the phase of lower cortisol levels), whereas bindings to glucocorticoid receptors (in both the hypothalamus and hippocampus) are predominantly occupied in the acrophase of cortisol levels, thus increasing the inhibitory effect of cortisol on CRH and, consequently, ACTH secretion.

Figure 2: Physiological circadian rhythm of cortisol

One of the possible problems related to excessive cortisol concentration is the activation of glucocorticoid receptors in the amygdala [1,2,7] (causing a similar reaction to that due to excessive emotional stress), which occurs precisely when the level of cortisol is such as to have already somehow saturated hippocampus and hypothalamus receptors: this situation leads to a reversal of the physiological feedback of cortisol, stimulating the synthesis of CRH (proinflammatory at the peripheral level), with the extreme consequence of further stimulating the adrenal cortex to release cortisol – hence the loss of the physiological rhythm of the HPA axis as well as the modification of its homeostatic regulation.

Figure 3: Cortisol bindings in the brain

Sleep disorders

Recent studies report that increased CRH secretion is associated with a decrease in the deepest sleep stage [6,7] and an increase in wakefulness. Electroencephalographic measurements have shown that, when CRH increases, δ (delta) frequencies [HF, LF, ANS-PPG Stress Flow], i.e., the lowest and most typical frequencies of the deepest sleep stages (called SWS, Slow-Wave Sleep), decrease.
The stressful activity due to the excess or loss of cortisol rhythmicity, which can easily correlate with chronic inflammatory states or poor nutrition [13] (see PPG Stress Flow, BIA-ACC and TomEEx diagnostic devices) – similarly to psychological or emotional stress factors involving strong reactions of the amygdala – thus leads to a drastic worsening of rest (and to the related chronic fatigue symptoms). This process represents a severe problem because the lower sleep quality increases in turn the activation of the HPA axis.

Figura 4: HPA, sleep disorders and MUS

Several sources have confirmed that chronic sleep deprivation is accompanied by elevated cortisol levels, particularly during the evening and the early night sleep. The evening cortisol level is also correlated with the number of nocturnal awakenings in both insomniacs and non-insomniacs.
A gradual recovery of the patient, aiming at lowering the evening cortisol level and restoring the circadian rhythm of the HPA axis through several methods (see RegMatEx and Biofeedback PPG Stress Flow devices), can therefore bring significant benefits, up to the disappearance of sleep-quality-related symptoms.

Mood disorders, MUS anxiety, melancholy, depression, panic attacks

Many studies have emphasized the link between HPA axis dysfunction and several psychiatric syndromes [10,12], particularly evident in the case of depression. The stress reaction system basically consists in the release of CRH and noradrenaline (or norepinephrine), with the consequent stimulation of related systems, i.e. HPA axis [HPA axis index - BIA-ACC] and sympathetic nervous system [ANS - PPG Stress Flow] (increased heart rate, inhibition of insulin secretion, altered thermoregulation, etc.). The release of CRH (hypothalamus) and noradrenaline (locus coeruleus) in the brain are closely linked processes that can stimulate each other in order to prepare the body’s stress response. This involves, in addition to adrenal gland stimulation and the establishment of an unfavorable relationship between the secretion of cortisol and DHEA (dehydroepiandrosterone), the inhibition of insulin secretion. Interactions also closely involve the amygdala region [14,15], that acts as a mediator of emotional memory and of anxiety and fear behaviours.

Figure 5: Hyperactivity of the HPA axis and sympathetic nervous system in anxious and depressive subjects

Many studies show the hyperactivity of the HPA axis [BIA-ACC - Flat Low/High HPA axis index], and the consequent neuroendocrine dysfunction, as a hallmark of anxiety-depressive disorders, to such an extent that it is considered a real method to distinguish between general melancholic states and clinical diseases [3,4,5]. The assessment of the impact of the stress level on the HPA axis (see TomEEx device in terms of functional impact, BIA-ACC device in terms of quantitative impact and PPG Stress Flow device in terms of impact in regulatory systems), the assessment of nutritional habits [13], and the gradual modulation of glucocorticoid levels (see RegMatEx device) remain therefore key aspects in the physiological approach to this type of disorders.

Authors: Dario Boschiero - Date: 04/11/2020

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  1. van Stegeren AH, Wolf OT, Everaerd W, Scheltens P, Barkhof F, Rombouts SA, Endogenous cortisol level interacts with noradrenergic activation in the human amygdala, Neurobiol Learn Mem. 2006 Jul 31;
  2. Urry HL, van Reekum CM, Johnstone T, Kalin NH, Thurow ME, Schaefer HS, Jackson CA, Frye CJ, Greischar LL, Alexander AL, Davidson RJ, Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults, J Neurosci. 2006 Apr 19;26(16);
  3. Halbreich U, Major depression is not a diagnosis, it is a departure point to differential diagnosis -- clinical and hormonal considerations, Psychoneuroendocrinology. 2006 Jan;31(1):16-22;
  4. Antonijevic IA, Depressive disorders -- is it time to endorse different pathophysiologies?, Psychoneuroendocrinology. 2006 Jan;31(1):1-15;
  5. Stewart JW, Quitkin FM, McGrath PJ, Klein DF, Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions, J Affect Disord. 2005 Jun;86(2-3):161-7;
  6. Buckley TM, Schatzberg AF, Aging and the role of the HPA axis and rhythm in sleep and memory-consolidation, Am J Geriatr Psychiatry. 2005 May;13(5):344-52;
  7. Buckley TM, Schatzberg AF, On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep – normal HPA axis activity and circadian rhythm, exemplary sleep disorders, J Clin Endocrinol Metab. 2005 May;90(5):3106-14;
  8. Turner-Cobb JM, Psychological and stress hormone correlates in early life: a key to HPA-axis dysregulation and normalisation. Stress. 2005 Mar;8(1):47-57;
  9. McBeth J, Chiu YH, Silman AJ, Ray D, Morriss R, Dickens C, Gupta A, Macfarlane GJ, Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents, Arthritis Res Ther. 2005;7(5):R992-R1000;
  10. Tafet GE, Smolovich J, Psychoneuroendocrinological studies on chronic stress and depression, Ann N Y Acad Sci. 2004 Dec;1032:276-8;
  11. Kudielka BM, Buske-Kirschbaum A, Hellhammer DH, Kirschbaum C, HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender, Psychoneuroendocrinology. 2004 Jan;29(1):83-98;
  12. Mello Ade A, Mello MF, Carpenter LL, Price LH, Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis, Rev Bras Psiquiatr. 2003 Oct;25(4):231-8. Epub 2004 Jan 15;
  13. Gonzalez-Bono E, Rohleder N, Hellhammer DH, Salvador A, Kirschbaum C, Glucose but not protein or fat load amplifies the cortisol response to psychosocial stress, Horm Behav. 2002 May;41(3):328-33;
  14. Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME, Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels, Pharmacol Biochem Behav. 2002 Mar;71(3):431-47;
  15. Posener JA, DeBattista C, Williams GH, Schatzberg AF, Cortisol feedback during the HPA quiescent period in patients with major depression, Am J Psychiatry. 2001 Dec;158(12):2083-5;
  16. Schule C, Baghai T, Zwanzger P, Minov C, Padberg F, Rupprecht R, Sleep deprivation and hypothalamic-pituitary-adrenal (HPA) axis activity in depressed patients, J Psychiatr Res. 2001 Jul-Aug;35(4):239-47;
  17. Gerra G, Zaimovic A, Mascetti GG, Gardini S, Zambelli U, Timpano M, Raggi MA, Brambilla F, Neuroendocrine responses to experimentally-induced psychological stress in healthy humans, Psychoneuroendocrinology. 2001 Jan;26(1):91-107;
  18. Doering S, Wedekind D, Pilz J, Bandelow B, Adler L, Huether G, Cortisol in night-urine: Introduction of a research method in psychoneuroendocrinology, Z Psychosom Med Psychother. 2001;47(1):42-57.