The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function and Pineal Melatonin-Producing Function in Healthy People

*Irina Labunets*

## **Abstract**

The circadian and circannual rhythms play the main role in the adaptation of human immune and pituitary-adrenal systems functioning to the changing photoperiod. The rhythmicity of thymus endocrine function is an important part of the chronobiological organization of immune system. The pineal hormone melatonin is the central regulator of rhythms of healthy human organism functions and involves thymus hormones (namely FTS/thymulin) in synchronizing influence on the immune system functioning. Age-related changes of thymus hormone and melatonin rhythms in healthy people are linked and precede the aging desynchronosis of immune and pituitary-adrenal system functions. In healthy male versus female the above changes occur at earlier life periods and are more pronounced. The thymus endocrine function does not completely disappear in the elderly/old people and is able to respond to the synchronizing influence of melatonin with part of the adrenal gland. Age-related changes in the circadian and circannual rhythms of the thymus hormone, melatonin, immune system, and adrenal gland functions become more pronounced at the development of age-associated diseases (neurodegenerative, cardiovascular, oncological). Melatonin can be perspective medicine for restoration of disturbed rhythmicity of thymus, immune system, and adrenal glands in accelerated human aging and in patients with age-dependent diseases.

**Keywords:** thymus hormones, pineal gland melatonin, human biorhythms, age, age-related diseases

## **1. Introduction**

Time-dependent rhythmicity in the organization of physiological processes is an important property of living organisms [1]. Circadian (daily) and circannual (seasonal) rhythms play the main role in human organism adaptation to such changing environmental factors as light, temperature, geomagnetic field, and humidity [1, 2]. Among the above factors, the photoperiod has the most stable synchronizing properties for circadian and circannual rhythms of different human organs and system functions. The circadian rhythms provide fast adaptation of organism functions to the day-night shifts, whereas the circannual rhythms control potential possibilities of functions and differentiation processes.

The control system of these rhythms includes the next components: (a) generator (pacemaker) of endogenous rhythms of functions (suprachiasmatic nucleus (SCN) of the hypothalamus), (b) afferent way to the pacemaker and (c) efferent pathway from the pacemaker to peripheral organs [1, 3]. The pineal gland hormone melatonin plays a key role in the regulation of human circadian and circannual rhythms of organism functions through the coordination of endogenous rhythms that are generated in SCN [4, 5]. In adult organisms melatonin production during the dark period and with the shortening season photoperiod increases.

The circadian and circannual rhythms of immune system indices in healthy young/adult human subjects are found [6–9]. Human immune system functions are under the influence of thymus hormones [10]. The thymus endocrine function is characterized by circadian rhythm and melatonin is responsible for its nocturnal increase [11].

In aging there occurs dyscoordination of rhythms and disturbance of adaptive capacity of the immune and neuroendocrine systems which are associated with the development of age-related diseases [12]. Age-dependent changes in the thymus and pineal gland functioning precede the aging disturbances of the above systems and influence lifespan [4, 10]. At the same time, the administration of melatonin and thymus hormones to aging people leads to a decrease not only in age changes in immune and neuroendocrine system functions but also in the incidence of age-related diseases [13, 14].

This chapter of the monograph reviews the published and our own data about circadian and circannual rhythms of the thymus hormonal function and the pineal melatonin-producing function in young/adult healthy human, their changes in aging, and link with disturbances in rhythmicity of immune and neuroendocrine systems. A connection was shown between age desynchronosis of the thymus and pineal gland functioning, on the one hand, and the development of some age-related diseases, on the other hand. The significance of the maintenance of rhythmicity of immuneneuroendocrine interactions involving thymus and pineal gland in the activation of adaptive features of the human organism is substantiated.

## **2. Thymus as a regulator of immune system functions in healthy human organism**

## **2.1 Young/adult people**

## *2.1.1 Cytocrine and endocrine thymus functions*

## *2.1.1.1 T cells differentiation*

Different subpopulations of T lymphocytes with certain functional properties (T effectors/suppressors, T helpers) are formed in the thymus [15–19]. "Maturation" of T cells in thymus begins from the migration of their progenitors (prothymocytes) from bone marrow. After "maturation" T cell subpopulations (CD4+ and CD8+ T cells) *The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

migrate from thymus to T-dependent zones of spleen and lymphoid nodes and bone marrow [18, 19]. Small amounts of immature T cells also migrate from thymus to peripheral lymphoid organs where they can differentiate into mature cells. A more detailed description of thymus cytocrine function is presented in the book review [20].

Along with cytocrine function, the thymus acts as an endocrine organ. It is known that true hormones, including the thymus hormones, must meet the following criteria:


Only a few of the numerous peptides of the thymus meet the criteria for true hormones. It was shown that the thymus produces the next hormones: thymosin-α1, thymopoetin II, and thymulin/thymic serum factor (FTS) [15, 21–24].

#### *2.1.1.2 Thymosin-α1*

Thymosin-α1 was found in medullary epithelial cells and Hassal's bodies of the human thymus just like in blood [21, 25]. Besides, thymosin-α1 is formed in other lymphoid and non-lymphoid tissues of humans [26]. Hormone blood content decreases after thymus removal and with age [27]. Thymosin-α1 influence on T lymphocytes differentiation in the thymus and the activity of mature peripheral immune cells (antibodies production, change in lymphocytes proliferation) increases interleukin (IL)-10 production and decreases the content of blood tumor necrosis factor α (TNF-α) and IL-6 [21]. Thymosin-α1 due to its immunomodulatory properties is already used in the clinical treatment of infectious diseases, immunodeficiency, and cancer [28].

#### *2.1.1.3 Thymopoietins*

The discovery of thymopoietins was associated with the study of neuromuscular transmission in severe myasthenia gravis and significant therapeutic effect after thymectomy [22]. Along with its influence on neuromuscular transmission, thymopoietins modulate the expression of membrane molecules on immature T cells (induction differentiation of prothymocytes to thymocytes) and enhance manifestations of T-immune defense [22, 29]. Thymopoietins are ubiquitously produced, mainly by

immune system organs (including thymus) and are determined in the blood [27]. Its serum content begins to decrease around 10 years of age [27].

So, thymosins and thymopoietins can be attributed to the true thymus hormones, since they are secreted by the epithelial cells of the thymus, are found in the blood, and influence differentiation of T-lymphocytes and their activity. A more detailed description of these hormones' properties is presented in a number of reviews [21, 22, 30].

### *2.1.1.4 Thymulin/FTS*

Among the thymus hormones, of particular interest is the highly biologically active FTS/thymulin with a Zn2+-dependent activity. It is formed exclusively in the thymic epithelial cells of humans and animals, circulates in the blood, disappears from circulation after thymectomy and shows biological properties of all known thymus hormones [23, 31, 32]. FTS influences all stages of differentiation of T lymphocytes (bone marrow, thymus, peripheral lymphoid organs). Thus, in the bone marrow suboptimal doses of FTS act on the expression of CD90 (Thy-1 antigens), CD2, CD5, and CD7 markers on the progenitors of T lymphocytes [15]. Expression of these markers on T cells progenitors characterizes an increase in their ability to migration and adhesion [16]. FTS also acts as a chemotactic signal that plays a role in the migration of bone marrow T-cell progenitors into thymus.

In the thymus FTS affects thymocyte antigen-1 (Thy-1) and cluster of differentiation 3 protein (СD3) expression and influences the balance of regulatory T lymphocytes, cytokine production by CD4+ thymocytes, and transformation of cortisol-sensitive thymocytes into cortisol-resistant ones [15]. Besides, under the FTS influence, there appear markers of mature T lymphocytes on immature cells in the lymph nodes.

FTS affects the functional activity of "mature" T-lymphocytes in peripheral lymphoid organs. Thus, it enhances the proliferative response of T cells to mitogen (phytohemagglutinin) and keeps the regulatory T cells balance, namely helper T cells type 1 and type 2, and increases the number of cytotoxic T cells [33]. FTS enhances the production of interferon γ (ІFN-γ) and ІL-2 by T helpers type 1 [34]. FTS effects on immune cells can be mediated via high-affinity specific membrane receptors [23, 31]. Besides, FTS stimulates the activity of natural killer cells and the response of peritoneal macrophages to activating effect of IFN-γ [33].

#### *2.1.2 Thymus and bone marrow functioning*

Bone marrow is the central organ of the immune and hematopoietic systems. Bone marrow lymphoid and myeloid lineages of hematopoiesis are derived from the common progenitor—hematopoietic stem cells (HSCs) [35, 36]. Progenitor cells of hematopoiesis in bone marrow differentiate into granulocytes, monocytes/ macrophages, thrombocytes, and erythrocytes. Bone marrow cells of the microenvironment, namely stromal fibroblasts, macrophages, T helpers, and B cells play an important role in directed differentiation of HSCs [37, 38]. In particular, T lymphocytes (CD4+) of thymus origin can function as regulatory elements of hematopoiesis producing such cytokines as IL-3,4,5,6,13,17 and granulocyte macrophage colonystimulating factor (GM-CSF) [18, 37]. In human patients with combined immunodeficiency, recovery of impaired differentiation of bone marrow stem cells in the granulocyte-macrophage direction was observed after injections of bioactive thymus factors [24].

*The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

As shown, the thymus is involved in the differentiation of multipotent mesenchymal stromal cells (MMSCs) in the bone marrow. These cells differentiate into osteoblasts, adipocytes, chondrocytes and have immunosuppressive action [39]. Reduced proliferative and osteogenic potentials of MSCs after thymus removal coincides with the decreased amount of bone marrow CD4+ T-cells and lack of thymulin in the blood [40]. At the same time, the above properties of bone marrow MSCs were restored after *in vitro* addition of synthetic FTS [40]. The immunosuppressive effect of bone marrow MSCs was enhanced after thymus removal or after a decrease in its endocrine function [40].

So, the thymus functions are important for the normal functioning of the peripheral immune system and the realization of biological properties of bone marrow HSCs and MSCs in adult organisms. Thymus acts on the bone marrow functions through its hormones and T-lymphocytes. Therefore, thymus dysfunction affects immune defense of the organism against damaging factors of different origins and efficiency of cell therapy using these stem cells.

#### **2.2 Elderly/old people**

#### *2.2.1 Cytocrine and endocrine thymus functions*

Age-related processes in the thymus play a crucial role in changes of immune system functioning in aging [41, 42]. Thymus involution depends on the intra- and extrathymus influences. Intrathymus changes include the degenerative alterations of the epithelial thymus cells, decreased proliferation and enhanced apoptosis of the thymocytes, imbalance in the production of intrathymus cytokines (leukemia inhibitory factor, IL-6, IL-7), blockade of the rearrangement of T cell receptor genes and attenuation of the keratinocyte growth factor production, etc. Age-related deterioration of the thymus epithelial cells structure leads to a decrease in its endocrine function. Age-dependent decrease of the blood serum thymulin level is the most pronounced compared to other thymus hormones [23, 27]. Extrathymus factors of thymus involution may be associated with age-related changes in the neuroendocrine system [41].

The pathways of intrathymus differentiation of thymocytes change with age [43]. Diminished expression of CD3 receptors on the thymocyte membrane may result in age-related changes in T cell selection in the thymus [41]. The peripheral T cell functions (proliferation, cytotoxicity, lymphokine production, etc.) in old humans are worsening [41]. There occurs an imbalance not only between helper and suppressor T cells but also between helper T cells type 1 and type 2 [44]. The range of cytokines being synthesized by these cells is altered thereby stimulating humoral immune response. Besides, the functional activity of neutrophils and mononuclear phagocytes is reduced.

#### *2.2.2 Bone marrow functioning*

The proliferative and differentiation potential of HSCs and lymphoid progenitor cells in the bone marrow decreases with age [35, 45]. Alterations of the hematopoiesis are explained by the deterioration of the regulatory mechanisms, accumulation of mutations in cell genome, deoxyribonucleic acid damage and oxidative stress. The shift in the hematopoiesis, namely from lymphopoiesis to myelopoiesis affects blood system functioning and leads to the higher frequency of myeloproliferative disorders.

The proliferative capability of stromal elements in the old bone marrow is changed and an imbalance in their differentiation towards active adipocyte generation can be observed [46]. Aging human MMSCs secrete other cytokines and trophic factors displaying a reduced differentiation potential.

## *2.2.3 Administration of thymus active factors in aging organism*

The positive effect of thymosin-α1 on immune system is most pronounced in immunodeficiency states (aging, cancer, use of immunosuppressants) [21, 28]. In old patients, following injections of thymus factor thymalin (its structure has sequences that are homologous to thymulin) was observed the increase of diminished blood thymulin level and number of peripheral T cells and neutrophil phagocytic activity [14]. There is evidence that the development of osteoporosis may be linked to an imbalance of regulatory T cells in bone marrow and thymus dysfunction [47]. After thymus factor thymalin administration the reduced spongy bone mineral density increased and bone structure improved in old human subjects [14]. In the old human subjects with thymus endocrine hypofunction, thymus factor administration enhances the differentiation of bone marrow stem cells into macrophages and activates liver macrophages [24], which is associated with a decrease in blood content of small circulating immune complexes [14]. As a result of the long-term circulation of these complexes, the vascular walls are damaged promoting the development of vascular diseases.

In summing up, the thymus biologically active factors produce geroprotective effects in elderly people thereby influencing positively age-related changes in immunological indices and bone marrow functioning.

## **3. Biorhythms of thymus and immune system functions and their age-related changes in healthy people**

### **3.1 Circadian rhythms**

### *3.1.1 Thymus*

Studies on the circadian rhythm of thymus endocrine function revealed higher nocturnal thymulin/FTS and thymosin-α1 levels in the blood of healthy young human subjects compared to daytime content [11, 21]. According to our data, the thymus endocrine function in young healthy humans (20–29 years old) is characterized by increased blood FTS content at 21.00 and its highest value at 1.00 am [6, 7, 48, 49]. In elderly healthy people (after 60 years), the nocturnal rise FTS level is less compared to young subjects or the hormone rhythm is monotonous [48–50].

### *3.1.2 Bone marrow*

The human bone marrow hematopoietic and microenvironment cells have a circadian rhythm [51, 52]. Human HSCs taken for transplantation at evening hours (during thymus function activation) have shown better positive effects compared to morning hours [52].

*The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

#### *3.1.3 Peripheral immune system*

In healthy young human subjects, the circadian rhythms in the peripheral blood contents of CD4+ and CD8+ T cells, granulocytes, imunoglobulins (Ig), and some cytokines were observed [6, 53, 54]. Age-related changes in circadian rhythms of immune cells show themselves both in their number and functional activity. Thus, in elderly humans, the nocturnal amplitude of the number of blood T cells and its T helper subpopulation is decreased and daily acrophase of neutrophils content is shifted [12, 54]. At the same time, the nocturnal amount of activated T cells and cell production of ІL-1, TNF-α, and IFN-γ are increased. So, the response of certain immunological indices to changed light regimens in old organisms can be linked with thymus dysfunction and is not only diminished but also enhanced.

#### **3.2 Circannual rhythms**

#### *3.2.1 Thymus*

There are no literature data on age-related changes in the thymus endocrine function in healthy people in different seasons of the year. According to our results, the FTS production by thymus in young healthy men and women is characterized by circannual rhythms [6, 55]. We found that the FTS level in healthy humans at age 20–29 years in summer and autumn is higher compared to other seasons (**Table 1**). FTS levels in women higher compared to men (**Table 1**).

In 30–39 old men the FTS blood content in summer decreases and at the age of over 40 its fluctuations become monotonous. In men, after 60 years the highest FTS level is observed in spring. The season changes in FTS level in elderly women mostly look like those in young women although its values decreased in summer and autumn.

So, age-associated changes in the circannual rhythm of FTS level have sex differences. Thus, the first signs of thymus dysfunction are found in men over 30 years old and become more pronounced with age. Age-related changes in thymus hormonal rhythmicity in healthy women are less significant compared to men. It is important that in elderly people the thymus endocrine function does not completely disappear.

#### *3.2.2 Bone marrow*

In the human bone marrow, season-dependent fluctuations of proliferative activity in hematopoietic progenitor and stromal cells have been established [51, 56]. In healthy young individuals, the highest number of colony-forming unit


*\*p < 0.05—winter.*

*\*\*p < 0.05—autumn.*

*# p < 0.05—summer.*

*&p < 0.05—men (our data [55]).*

#### **Table 1.**

*FTS level in blood of healthy 20–29-year-old subjects in different seasons, M ± SE.*

granulocyte-macrophage (CFU-GM) was at the end of summer, and the least MSCs possibility for colony formation in the spring and autumn [56]. According to the authors, the annual changes in the number of bone marrow colony-forming unit fibroblasts (CFU-F) should be considered in cell therapy of patients with bone tissue disturbances. After thymus removal in adult organisms, the number of CFU-GM and CFU-F decrease in seasons of their maximum content in bone marrow [57].

#### *3.2.3 Peripheral immune system*

According to the below authors and our data, in healthy young human subjects the amount of blood CD3+, CD4+, and CD8+ T cells; B cells; and content of Ig have maximal values in autumn [6, 53, 54]. In old healthy human subjects, age-related changes of annual fluctuations of immune indices coincide with seasonal desynchronosis of thymus endocrine function and they are characterized by shifting seasonal peaks of the number of blood CD3+, CD4+T cells, and Ig level from autumn to spring [6, 55].

So, age-related immune system response to photoperiod changes is largely associated with age-dependent desynchronosis of thymus functions and can be explained by the disturbance of interactions with the pineal gland which coordinates such reaction [5, 12].

## **4. Role of the pineal gland in the regulation of thymus and immune system biorhythms in healthy people**

### **4.1 The pineal gland biorhythms and their changes in aging**

The pineal gland and its hormone melatonin is the main regulator of circadian and circannual rhythms not only in mammals but also in the human organism [5, 58]. Production of melatonin during light period is suppressed whereas in the dark hours is increased. Besides, with shortening of the seasonal photoperiod melatonin production is enhanced [59]. Melatonin regulates endogenic rhythms of organisms that are generated in the SCN of the hypothalamus [5, 58]. Melatonin acts on the activity of the hypothalamus-pituitary system and peripheral endocrine glands through its binding with nucleus and membrane receptors which are identified in various brain and endocrine structures. There is a link between pineal gland functioning, organism adaptation, and lifespan [60].

The circadian rhythm of pineal gland function and its changes in aging were found in humans [4, 61]. In the majority of elderly and old human subjects, the nocturnal peak of blood melatonin level is diminished compared to young people [4, 13]. Elderly human subjects with saved pineal gland melatonin-produced function have higher physical and psychomotor activity as well as expressed circadian rhythms of some functions and lifespan [13, 62]. We also observed a nocturnal peak of blood melatonin concentration in young people and its decrease in aging [48, 63, 64]. Age-related decrease of the nocturnal peak of melatonin content in the pineal gland and blood is explained by the diminished activity of the key enzymes of its synthesis (N- acetyltransferase, hydroxyindol-O-methyltransferase), decrease both in the density of β-adrenergic receptors on the pinealocyte membrane and in the capability of postganglionic sympathetic fibers for synthesis and noradrenaline release [4, 61].

The circannual rhythm of blood and pineal gland melatonin content in old humans is characterized by the decrease of the winter peak of hormone level or the

### *The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

shift of its seasonal acrophase to the spring compared to young people [4]. We also found that melatonin level in the blood of young (20–29 years old) healthy men and women was maximal in winter [55]. According to our data, age-related changes in melatonin blood level rhythmicity have sex differences. Thus, in healthy men aged 30-49 years the seasonal peak of blood melatonin content was in summer and in men after 60 years it was in spring. In men, after 30 years melatonin blood level decreases in winter. In elderly women, the spring increases and the winter decrease of blood melatonin was less than in men.

So, the circannual rhythm of melatonin level changes in the blood of healthy men after 30 years. Desynchronosis of this hormone increases with age. Age-related dysfunction of the pineal gland is less pronounced in women compared to men.

## **4.2 Age-related changes of pituitary-adrenal system biorhythms and its link with pineal gland disfunction in healthy people**

The rhythmicity of pituitary-adrenal system functioning undergoes changes due to the modulation of the pineal melatonin-producing function [4, 62, 65, 66]. Thus, in young people, the highest blood contents of such adaptive hormones as adrenocorticotrophic hormone (ACTH) and cortisol are observed in the light period of the day compared to evening and night. According to our data, the blood cortisol level in the elderly healthy people does not differ in the morning and evening [48]. At the same time, the altered circadian rhythms of endocrine glands (in particular, adrenal gland) in old human subjects were improved after melatonin injections [4, 48].

The authors found the seasonal fluctuations of cortisol in the blood of healthy people and its age-related changes [4]. We studied annual fluctuations of blood ACTH and cortisol levels in healthy men and women of different ages [55]. We found that in young healthy men and women (20–29 years old), the highest ACTH level was in spring-summer periods of the year and cortisol in autumn. In 30–39 old men, ACTH level increases in winter and such changes in hormone level were also observed in 40–59 old men. In healthy women (30–59 years old) age-related increase in ACTH level is less intensive and forms later compared to men.

In young healthy men (20–39 years old), the blood cortisol level increases in autumn and winter. After 40 cortisol level significantly increases in spring and its annual rhythm becomes monotonous. The seasonal increase of cortisol content in autumn observed in 20–29-year-old healthy women remains unchanged up to the age of 50. The blood cortisol content in spring and summer is lower in women after 40 than in men of the same age.

So, changes in circannual rhythms of blood melatonin and ACTH levels are seen in men as early as the age of 30–39 years. These changes are ahead of age-related activation of the glucocorticoid function of the adrenal cortex and the formation of its seasonal desynchronosis in elderly people. In healthy men changes in the pituitaryadrenal system are more intense compared to women and are formed earlier [55]. Sex differences in age-related changes of the above system functioning can be explained not only by higher blood melatonin levels in women but also by the neuroprotective and neurotrophic effects of estrogens. Melatonin stimulates neurotransmitters exchanged in the hypothalamus and promotes brain sensitivity to peripheral regulatory signals [5].

Thus, the age pineal gland dysfunction is the pathogenetic link of age-related desynchronosis of the pituitary-adrenal system. Gender and age-related changes in the pineal gland and pituitary-adrenal system functions may be explained by certain sex-related differences in the development of some age-associated diseases (cardiovascular diseases, cancer, osteoporosis, diabetes, etc.) as well as in the medicine pharmacodynamics during treatment.

## **4.3 Melatonin, other hormones, and the immune system functions in healthy people**

 Immune system functioning is in close interaction with the neuroendocrine system [ 30 , 67 ]. Melatonin effects on the immune system functions include not only direct ways via own receptors in immune cells but also indirect ways via changing endocrine glands functions [ 67 ].

## *4.3.1 Thymus*

 Thymus is the first target for melatonin [ 67 ]. Melatonin is capable to influence directly on the synthesis and secretion of thymus hormones [ 67 , 68 ]. Melatonin action on the thymus endocrine function can pass through changes in hypothalamuspituitary-adrenal axis functioning [ 69 , 70 ]. High concentrations of glucocorticoids suppress thymus endocrine function [ 70 ]. The efficiency of thymus hormone administration is increased under the condition of short-term hypocorticism. Fluctuations of the expression and/or sensitivity of glucocorticoid receptors on the thymus epithelial cells are controlled by melatonin [ 71 ]. The lymphocytes and epithelial cells of the thymus have receptors for glucocorticoids and androgens [ 68 ]. Corticosteroids influence the differentiation of thymus epithelial cells and sex hormones act on the differentiation of thymocytes via FTS synthesis [ 72 , 73 ]. Besides, glucocorticoids influence the distribution of mature T-lymphocytes in the organism and their accumulation in bone marrow [ 18 ].

 The authors' data and our own findings have shown that in young human subjects, the nocturnal peaks of blood thymus hormones level (thymulin/FTS, thymosin-α1) and melatonin are similar [ 6 , 11 , 48 ]. We found that in young healthy men aged 20–29 years, the increase of blood melatonin and FTS levels was at 21.0 p.m. with a peak at about 1.0 a.m. ( **Figure 1** ), whereas the level of cortisol was lowest at 21.0 p.m. and highest at about 5.0 a.m. and 9.0 a.m. [ 6 , 48 ].

#### **Figure 1.**

 *FTS and melatonin blood levels in healthy young people (aged 20–29 years) during 24 hours (our data [ 48 ]). \* p < 0.05–9.00; \*\* p < 0.05–17.00, # p < 0.05–21.00; ## p < 0.05–1.00; & p < 0.05–5.00.* 

#### *The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

In young organisms, pineal gland hypofunction (removal, prolonged lighting) is accompanied by the disappearance of nocturnal peaks of blood thymulin content. On the contrary, melatonin treatment enhances the expression of prothymosin-α1 in the thymus epithelium and restores circadian changes of T cell composition in the thymus after its damage by constant lighting [74].

The daily fluctuations of thymulin and melatonin blood levels coincide and are characterized by increased values in the evening and highest values at 1.00 a.m. In the morning, the content of these hormone decreases compared to the night period.

In aging organisms, following melatonin injections the nocturnal peak of thymulin blood level, the blood zinc and IL-2 contents were increased and the number of thymus apoptotic cells and the glucocorticoid blood levels were decreased [75, 76]. According to our data, in the elderly subjects, the circadian rhythm of blood FTS was ambiguous and correlated with the patterns of melatonin blood rhythmicity [48, 49, 63]. Thus, an increase in FTS level during dark hours (21.0 p.m. or 3.0 a.m.) coincides with a more pronounced nocturnal increase of blood melatonin content compared to elderly people without thymus activation in dark hours. Besides, our own finding of two-week melatonin injections to elderly human healthy subjects demonstrates an increase in FTS levels in the evening and at night and a decrease in blood cortisol and testosterone levels in the evening [48–50]. In the comparison with our younger patients, this effect was registered with lesser melatonin doses [50]. A melatonin-like synchronizing effect on blood FTS and cortisol levels in elderly people was shown by us for pineal gland peptides [77]. The melatonin level after administration of pineal gland peptides (epithalamin, epithalon) increases in the body [14].

#### *4.3.2 Bone marrow*

Melatonin influence on hematopoiesis is realized directly via the receptors in monocytes/macrophages cells and owing to an increased response of these cells to activating hematopoiesis cytokines, namely ІL-3, 4, 6 or GM-CSF [74]. Bone marrow T cells progenitors and T helpers type 1 are the main targets for melatonin [67]. Melatonin synthesized by human bone marrow cells protects *in situ* cells against oxidative stress and enhances the functional activity of the lymphocytes [74]. Pineal gland hypofunction is accompanied by diurnal desynchronosis in the bone marrow functioning.

Our studies have established thymus involvement in melatonin influence on circannual changes of the number of MMSC, CFU-GM as well as CD3+, CD4+, and CD8+ T cells in the bone marrow of young and old organisms [78]. In adult organisms, exogenous melatonin acts on bone marrow cells of the microenvironment and this action is realized via thymus hormone. In old organisms, the participant of thymus hormone in action of melatonin is mainly linked with bone marrow CFU-GM changes*.*

#### *4.3.3 Peripheral immune system*

Under the influence of exogenous melatonin (evening injections) the number of СD3+ and СD4+ T lymphocytes increased and that of СD8+ T cells decreased in the blood and lymphoid organs; balance not only of СD3+ and СD4+ T cells but also of T helpers type 1 and type 2 was changed and the number of mature B cells in the lymphoid organs and functional activity of the macrophages increased [67, 74]. Melatonin also influences circannual rhythms of the immune system. We have

shown that in elderly human subjects after melatonin injections FTS blood level, the amount of blood CD3+ and CD4+ cells, and the phagocytic activity of neutrophils are increased in autumn, being similar to those being seen in the younger subjects [48]. Adrenal and sex hormones also influence cellular and humoral immune responses and phagocytosis.

So, the above data show the pathogenic significance of pineal melatonin-producing dysfunction for age-related changes of thymus and immune system rhythmicity and involvement of adrenal glands and gonads in the synchronizing effect of melatonin.

It is important that along with produced hormones, a number of cytokines are formed in the thymus, for example, TNF-α, IL-1,3,6,7,8,15, ІFN-γ, and GM-CSF [79]. All types of thymus cells are able to produce cytokines both spontaneously and after stimulation. But the main producers of cytokines in the thymus are epithelial cells and thymocytes [80]. Intrathymic cytokines are important at various stages of activation, proliferation, and differentiation of thymocytes [80].

Some intrathymic cytokines are involved in the interactions between the thymus and pineal gland. Among such intrathymic cytokines, TNF- α is of particular interest. This cytokine has pronounced pro-inflammatory properties and is considered as a key factor in the pineal-immune axis [30]. TNF-α is secreted by cultured mouse thymocytes, indicating its importance for the development and/or regulation of the immune response [81]. The ability of TNF-α to influence melatonin secretion by the pineal gland has been shown in Ref. [82]. Thus inhibitory effects of this cytokine *in vitro* are realized at the level of transcription factors and manifest themselves in a decrease of N-acetylserotonin and N-acetyltransferase synthesis. The disappearance of the inhibitory effect of TNF-α after its prolonged incubation with the pineal gland suggests the involvement of melatonin in the different phases of the inflammatory process.

In addition, there are data on the stimulating effect of ІFN-γ and CSF-GM *in vitro* on the secretion of melatonin by the pineal gland [83].

Therefore, the interaction of melatonin and thymus can be realized not only through thymus hormones but also intrathymic cytokines.

### **4.4 Reverse effects of thymus hormones on neuroendocrine system**

Regarding the immune-endocrine interactions, the lymphokines and monokines act as afferent signals for the hypothalamus-pituitary-adrenal axis. Besides, thymulin, thymopoetin, thymosin, and thymic humoral factors are believed to link the immune and central nervous systems [69, 84]. Thus, after injections of thymulin and thymosin fraction 5, the blood ACTH and corticosterone levels increase in adult organisms [68]. In conditions of thymus hypofunction, thymulin gene therapy restores the decreased blood follicle-stimulating hormone and luteinizing hormone (LH) levels, whereas thymosin-β4 stimulates the production of LH in the pituitary gland [85, 86]. Thymulin is believed to be the pituitary trophic peptide [86]. Thymus factors can directly change corticosteroid secretion by adrenal glands in organisms of different ages.

We found the reverse influence of the thymus hormone on the pineal functioning in young organisms [87]. The *in vivo* and *in vitro* studies showed that this influence depends on season and age. Thus, the seasonal dependence of blood melatonin level on thymus factor administration is absent in old *versus* adult organisms. The *in vitro* studies show that the activating effect of synthetic FTS on melatonin production by the pineal gland is also absent in old organisms [87]. Age-related decrease in the

### *The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

pineal gland response to thymus hormone can be associated with the development of structural disturbances in the gland [61]. Moreover, the endocrine balance of aging organisms may play a role in the appearance of changes in the seasonal reaction of pineal melatonin-producing function to thymus factor injections. In aging the excess of glucocorticoids diminishes the melatonin-producing function of the pineal gland and the activating influence of thymus factors on this gland.

So, thymus hormones are an important component in immune-neuroendocrine interactions in adult organisms. In aging the reverse effects of thymus hormones on the neuroendocrine system are disturbed.

## **5. Age-related changes in the thymulin/FTS and melatonin biorhythms in human age-associated pathologies**

As was shown in previous sections, circadian and circannual rhythms play an important role in the adaptive reactions of human neuroendocrine and immune systems to changing photoperiods. The rhythms of these systems are disturbed in human aging and are linked with altered rhythmicity of melatonin and thymus hormone production. The development of age-dependent diseases may be associated with the intensification or acceleration of age-related changes in the immune and neuroendocrine systems functions.

## **5.1 Neurodegenerative diseases**

The frequency of age-related neurodegenerative pathology, such as Parkinson's disease (PD), Alzheimer's disease (AD), brain ischemia, and multiple sclerosis (MS) increases worldwide and has great socio-economic implications. Progressive neurons loss was shown in neurodegenerative diseases. Their development includes enhancement of oxidative stress, neuroinflammation along with microglia activation, mitochondrial dysfunction, disturbances of brain neurogenesis, sleep-wake cycle, and immune system functions. It is important that along with its influence on the neuroendocrine system functions, thymus hormone thymulin has anti-inflammatory effects on the central nervous system, reducing the synthesis of pro-inflammatory cytokines [88].

## *5.1.1 Alzheimer's disease*

A more pronounced age-related decrease of the nocturnal blood melatonin content in AD elderly patients compared to the control group are coincided with the development of daily desynchronosis of blood ACTH and cortisol levels and cognitive disturbances [66, 89]. Circadian changes in organism functions often occur at early stages of AD and may precede the appearance of cognitive symptoms. Infiltration of active T lymphocytes and mononuclear phagocytes into the injured brain was shown in AD [90]. Melatonin treatment improves disturbed sleep rhythm and produces synchronizing, antioxidant anti-inflammatory and immunomodulatory effects in this pathology [89].

## *5.1.2 Parkinson's disease*

PD is characterized by circadian disturbances in blood melatonin and cortisol levels compared to the elderly healthy control group as well as the disturbed sleep rhythm [91]. PD development is slowed after melatonin administration which may be linked with its chronobiological, antioxidant and anti-inflammatory effects [92]. Active peripheral T cells, macrophages, and neutrophils infiltrate the brain and damage dopaminergic neurons [93]. In our study, the immune disturbances in parkinsonism were connected with the decrease of blood thymulin level which is restored after melatonin administration [94]. The gender differences in the frequency and clinical symptoms were found in neurodegenerative diseases. Thus, more men than women suffer from PD. These sex differences may be linked with estrogen neurotrophic influence on brain, in particular neurons in SCN. In our data, the women had less intensive and slower age-related development of circannual rhythms disorders in blood FTS, melatonin, ACTH, and cortisol levels compared to men [55].

## *5.1.3 Brain ischemia*

In the elderly ischemic stroke patients the nocturnal melatonin content is decreased compared to the age control group and is associated with elevated blood cortisol levels and altered sleep-wake rhythm [95]. Peripheral T cells may migrate into the injured brain, release pro-inflammatory cytokines and chemokine and cause further injury to the ischemic brain [96]. In cerebral ischemia, exogenous melatonin reveals antioxidant, anti-apoptotic, and anti-inflammatory properties [95]. In our experimental brain ischemia, the decreasing blood FTS and melatonin levels coincided [97].

## *5.1.4 Multiple sclerosis*

In MS patients, the decrease in melatonin level at night is associated with circadian rhythm sleep disturbances and daily blood cortisol level rhythmicity [98, 99]. The higher frequency of MS relapses in the spring/summer period against the winter season is linked with a more marked decrease in nocturnal melatonin levels in these seasons [99]. Melatonin treatment improves the life quality of MS patients. Activation of immune cells leads to damage of myelin and neurons in MS. At the same time melatonin decreases the formation of pathogenic T helper 17 and stimulates the formation of protective Tr1 regulatory cells and anti-inflammatory cytokine IL-10 [99]. We have shown that exogenous melatonin has neuroprotective, anti-inflammatory, antioxidant, and immunomodulatory effects in demyelinating pathology [100]. It is important that melatonin activates the thymus endocrine function in adult and old organisms with demyelinating pathology and restores thymulin blood levels in autumn.

## **5.2 Cardiovascular diseases**

Cardiovascular diseases (ischemic heart disease (IHD), essential hypertension, and myocardial infarction) are the most common causes of disability and mortality worldwide. Risk factors of these diseases (metabolic and alimentary disturbances, hypodynamia, unhealthy habits, psycho-emotional tensions, and inheritance) occur preferably in elderly humans and coincide with changes in the neuro-endocrine and immune systems functions [14]. Thus, in elderly patients with IHD and essential hypertension, the nocturnal blood melatonin content is lower compared to the healthy control group [13]. The degree of pineal gland dysfunction correlates with disturbances in rhythmicity of cardiovascular system indices.

### *The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

Clinical data indicate an acceleration of age-related changes in peripheral immune system functioning and their role in the development of cardiovascular diseases [13, 14]. The cytokines, activated leucocytes, circulating immune complexes, and macrophages are able to damage artery walls, alter endothelium and change vessel permeability that, in turn, can cause plaque formation in the damaged areas. Positive effects of biologically active thymus factors on some of the above immunological indices were shown [14]. According to our data, in elderly patients with cardiovascular diseases, the types of FTS circadian rhythms were similar to those recorded in the healthy control group [48, 50, 77]. However, the number of patients with monotonous and inverted FTS blood level rhythms was significantly greater than in the age control group in which the people with reduced nighttime hormone levels predominated. Taking melatonin in the evening led to thymus activation and appearance of daily differences in the FTS blood levels due to its increase in the evening. In these patients, the circadian rhythm of blood cortisol levels also improved. So, melatonin administration in the evening delays the onset of aging changes in the rhythmicity of thymus, immune system, and adrenal glands functioning in elderly patients with IHD. Besides, in cardiovascular pathology melatonin produces antioxidant and antiinflammatory effects [13].

#### **5.3 Oncological diseases**

The frequency of tumors increases every 5 years in people after 40 years of age. According to the below authors, circadian rhythms the number of blood lymphocytes and their T-populations are destroyed in tumor organisms and seasonal changes in tumor growth are linked with the seasonal fluctuations of immune system functions [101]. In oncological patients, the nocturnal peak of melatonin blood level is decreased and the circadian rhythm of blood cortisol content is monotonous [102].

We have shown that in oncological patients over 50 years of age, the features of the circadian rhythm of blood FTS and cortisol levels are associated with the character of blood melatonin rhythmicity and point to an increase in their age-related changes [6, 7]. In particular, under conditions of increased melatonin blood level at 21.00 compared to 9.00, the FTS level and the amount of T cells also increased in the evening. When melatonin blood rhythm was inverted, the rhythmicity of FTS blood level and T-lymphocyte content was monotonous. In such patients, the scope of daily changes in blood cortisol content exceeded that observed in patients with activation of pineal gland function in the evening.

In the oncological patients aged 20–40 years, the seasonal peak of blood melatonin level was observed in spring but not in winter as in age-matched controls [6, 7, 103]. The rhythm of blood FTS content becomes monotonous compared to the age control subjects and rhythmicity of the number of blood T-lymphocytes inverted with the highest values in the spring. It is important that the features of rhythmicity of pineal gland and thymus functions in cancer patients till 40 years old are similar to those of healthy older people. These results suggest a possible acceleration of age-related changes in the circannual rhythms of the pineal gland and thymus functioning in oncological patients [104].

The interaction of the thymus and pineal gland may appear during the rhythmical activity of the ovaries (menstrual cycle). The authors showed the link between ovarian dysfunction, on the one hand, and reduced longevity and increased tumor incidence in aging organisms, on the other hand [60]. At the same time, administration of melatonin improves ovarian cyclicity, increases immune system functions,

and decreases tumor development. We found that in healthy women under 40, the melatonin blood levels were increased during the follicular and luteal phases of the menstrual cycle and those of FTS during the luteal phase [103]. Unchanged blood levels of melatonin and decreased FTS content in the luteal phase of the cycle were typical for women over 40 [103]. So, the thymus is involved in the ovarian cyclicity regulation by melatonin which can be changed in aging.

Thus, age-related changes in the rhythmicity of immune and neuroendocrine systems functions in patients suffering from neurodegenerative, cardiovascular, and oncological diseases are linked with dysfunction of their central regulators, thymus hormones, and melatonin.

## **6. Conclusion**


*The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

effect of melatonin on thymus hormones is also manifested in elderly/old people, but the reverse effects of thymus hormones on the neuroendocrine system are disturbed.


In conclusion, we hope that this review has shown pathogenic significance of pineal melatonin-producing dysfunction for age-related changes in the thymus and immune and endocrine systems rhythms and pointed to the importance of supporting immune-neuroendocrine interactions rhythmicity in aging and pathology development.

## **Acknowledgements**

The author thanks her colleague Turta Maya for her assistance in the preparation of an English version of the given review article.

## **Conflict of interest**

The authors declare no conflict of interest

*Sleep Medicine – Asleep or Awake?*

## **Author details**

Irina Labunets1,2

1 Experimental Modeling Laboratory, Cell and Tissue Technologies Department, Institute of Genetic and Regenerative Medicine, National Scientific Center "M.D. Strazhesko Institute of Cardiology, Clinical and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine

2 Laboratory of Pathophysiology and Immunology, D. F. Chebotarev State Institute of Gerontology of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

\*Address all correspondence to: irina\_labunets@ukr.net

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Relationships of Age-Related Changes in the Biorhythms of the Thymus Endocrine Function… DOI: http://dx.doi.org/10.5772/intechopen.112433*

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#### *Sleep Medicine – Asleep or Awake?*

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## **Chapter 3**

## The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders

*Jorge Garza-Ulloa*

## **Abstract**

Many conditions that can cause "sleep disturbance" for many different health conditions, where normal constant sleep is interrupted since altering falling asleep to a frequent disturbance for a long time duration, usually implicit for a wide range of causes including environment alteration, health problems that affect physical or mental body functions, and others. Finding causes for "*sleep disturbances or sleep disorders*" is not an easy task, even for medical professionals. At this time, where humanity is confronting a huge amount of disasters due to climate change, bacteria and viruses of different kinds have been evolving as a treat with a long pandemic time, and economic impacts do not present a near sign of stabilization; technological advances based on artificial intelligence are making frequent changes in our way of living, which usually widen the amount of information that we receive and process. These factors and others are misdirecting the basic survival needs of human beings, such as food, water, air quality, and the necessary and confronting need to sleep. These altered facts overuse our brains and, as a consequence, maximize their normal functions. Including natural biology tools such as the "circadian clock" that regulate all brain substructures, the nervous system expresses its frustration as a progressive brain structural deterioration.

**Keywords:** sleep disturbance, sleep disorders, circadian clock, anxiety, stress, depression, sleep change patterns, neurological disorders, sleep/wake cycles, brain waves

## **1. Introduction**

There are many conditions that can cause "sleep disturbance" for many different health conditions where "normal constant sleep" is interrupted since altering "falling asleep" to a "frequent disturbance for a long duration of time" usually implicit for a wide range of causes including environment alteration, health problems that affect physical or mental body functions, and others. Typically, the affected person with a "sleep disorder" tries to resolve the problem by paying attention to the "effect," and intending to avoid the disturbing conditions with temporal reachable solutions such as "traditional home remedies," that is, tea. If the situation continues, then they use "offthe-counter drugs" as sleep pills, that is, melatonin, and finally, when the situation is getting worse, they request professional medical help to find the "cause" of their unmanageable and possible "sleep disorder." Finding the cause of "sleep disturbance" and/or "sleep disorders" is not an easy task, even for medical professionals. In this time where humanity is confronting a huge amount of disasters due to "climate changes" with environmental changes that even have increased earth temperature, bacteria and viruses of different kinds have been evolving as a treat with a long pandemic time, and economic impacts do not present a near sign of stabilization; technological advances based on artificial intelligence that are making frequent changes in our way of living usually widen the amount of information that we receive and have to process. All these factors and many others are misdirecting the "basic survival need for the human being as amount and food, water, air quality, and the necessary and confronting need to sleep." All these facts have altered the pressure of the process and tried to find solutions to stabilize our situation, overusing our "brain and, by consequence, maximizing its normal functions." Including our natural biology tools, such as the "circadian clock," that regulate all the brain sub-structure is needed to process all the information and situations ASAP. Our nervous system by itself expresses its frustration as "progressive brain structural deterioration" generating different abnormal behaviors as "stress" (a physical, mental, and emotional factor), "anxiety" (an additional factor to stress reflecting as an emotion such as tension, excessive nervousness, fear, increased blood pressure), and many others as "depression."

All these factors are evolving into "sleep disorders," where frequently genetic factors are altered by "sleep change patterns" due to adjustments of shift of our own "circadian clock" by a big diversity of alteration as stress, and its response is detectable as anxiety and many others, including but not limited to aging, hormonal level changes, mood, sleep apnea, snoring, lifestyles, environment changes, restless leg syndrome, and many other reasons. If all these brain responses are not attended to, the possibility of permanent and destructive changes in our neuronal circuits can explain many abnormal behaviors in "neurological disorders" [1]. The research of all these factors is the main objective of this book chapter, "Sleep Medicine - Asleep or Awake."

## **2. Circadian clock, circadian rhythms, and physiological functions**

The "circadian clock" is a biochemical oscillator clock or internal pacemaker in most living things that cycles with a stable phase and is synchronized with the solar time, It helps organisms and humans anticipate daily environmental changes of the day-night cycle and adjust their daily biology routines and behavior accordingly. "Circadian clock" is the central mechanism to drive "circadian rhythms." Some examples of circadian rhythms are sleep and wake cycles, hormonal activity, body temperature rhythm, eating, and digesting.

In humans, the "circadian clock" is slightly greater than 24 hours, and, earth's 24-hour rotation creates temporal variations, including light/dark cycles with temperature oscillations, which forces humans and other organisms to adapt to the cyclic environmental changes activate compensatory mechanisms and

## *The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*

redundancy to maintain the function of the clock, providing "circadian rhythms," for many behaviors and physiological functions [2]: "sleep/wake cycle," "endocrine system," "metabolism," "immunity," and "mood." Where:

	- a. "hypothalamus," which connects your endocrine system with your nervous system.
	- b. "Pituitary gland," which is attached to the "hypothalamus," indicates when the pituitary gland starts or stops making hormones, and
	- c. "Pineal glands" make a chemical hormone called "melatonin" in response to darkness that helps your body get ready to go to sleep, and it has been linked to the regulation of circadian rhythms.

**REMARK:** In a general way, we can say that if we alter the "circadian clock" as the central mechanism that drives "circadian rhythms," the alteration is reflected on the "sleep/wake homeostasis," driven by the "endocrine system" glands as the "hypothalamus" that connects the endocrine system with the nervous system, and is attached to the "pituitary gland," indicating when to start or stop making hormones. This alters the release of "melatonin" to initiate the normal "sleep cycle," and by consequence, this alters the release of "melatonin" to initiate the normal "sleep cycle," altering the nervous system that can be detected with "mood swing" showing as stress, anxiety, and other moods.

## **3. Brain waves and sleep stages**

Our brain is always producing bursts of electrical activity identified as "electrical pulses" in the brain cell nerves known as "neurons." The "electrical pulses "are the way the neurons communicate to each other in their neuronal pathways to send orders or receive information, generating "wave activity" that can be detected and measured with a device known as an "electroencephalogram (EEG)" that evaluates the electric activity in the brain and records it in waves measured in cycles per second identified as "hertz (Hz)." Basically, the brain waves have a different speed from the fastest to the slowest frequency. There are five different types: gamma, beta, alpha, theta, and delta, as shown in **Table 1**.

"Sleep" is defined as the normal condition of body and mind, such as that which typically recurs for several hours every night, in which the nervous system is relatively inactive, the eyes are closed, the postural muscles are relaxed, and consciousness is practically suspended. The normal "sleep stages" are four, three of them with "non-rapid eye movements (NREM)" and one with "rapid eye movements (REM)" as indicated in **Table 1**, where the duration for each step is different at different ages.



**Table 1.**

*General brain wave types and brain states.*

*The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*


Initially falling asleep, a "rapid eye movement (REM)" is observed, where the eyes make sudden movements in different directions, heart rate and blood pressure increase, and breathing becomes fast, irregular, and shallow. "REM" can last up to an hour, and an adult can have five or six of these cycles with intervals: "REM" and "nonrapid eye movement (NREM is also known as "progressive rapid eye movements (pREM))," where the brain consolidates and processes information from the day before so that it can be stored in your long-term memory; these "pREM intervals are very important to maintain the brain in good standing." Besides, "sleep spindles" are a type of brainwave that come in bursts, and they are described as an oscillatory activity of the brain that is mostly said to happen during stage 2, which is identified as "nonrapid eye movement NREM sleep," indicated as sleepy stages 1–2 in **Table 1**, and additionally occurs during deep sleep stages 3–4. "Sleep spindles" are described based on the frequency of waves as slow or fast: "slow spindles" occur between 9 and 12 Hz and originate in the frontal brain areas, and "fast spindles" have a range of 12 to 16 Hz from the central nervous system and peripheral parts.

**REMARK**: The "circadian clock" generates the "sleep circadian rhythm" initiated by the release of "melatonin" for the "sleep cycle" that has four stages: in the first 2 from awake to sleepy generating "alpha" and "theta" brain waves, and in the last 2 with "deep sleep generating Delta" brain waves where the brain consolidates, and processes information accumulated during the day and moves from a short-term memory to a long-term memory through "pREM intervals" are very important to maintain the brain restored.

## **4. Introduction to neuroscience and circadian neuroscience**

"Neuroscience" is the scientific study of the nervous system, including the brain, spinal cord, and peripheral nervous system, and its functions. "Circadian neuroscience" is a branch of neuroscience and chronobiology that looks at the neurological mechanisms that maintain "circadian rhythms" and investigates their subsequent effects on processes in the nervous system [5].

The human internal clock is controlled by the "Suprachiasmatic Nucleus (SCN)" located in a forward region of the brain area identified as the "hypothalamus" that connects your endocrine system with your nervous system, as explained in the last section. "SCN" contains a group of "neurons or nerve cells" that control the human body's "circadian rhythm." When the morning light is received by the eyes, an optical nerve senses it and sends the signal through neurons in the "SCN" that are sensitive to the light and release hormones such as "cortisol" that make an order for wake-up. At night, darkness is detected in the eyes, and the SCN sends a signal to the "pineal gland" that releases the chemical hormone that initiates the process of sleep, making our body feel sleepy [6].

## **5. Stress-anxiety take to sleep alteration**

*"Stress"* is defined as a physical, mental, or emotional factor that causes bodily or mental tension. Stress can be external or internal. Where:


**REMARK**: "Stress" is unavoidably something that everyone experiences throughout their lives. While some stress can pass quickly or feel acute, the most important thing is how we handle it.

"Anxiety" is an emotion characterized by feelings of tension, worried thoughts that lead to excessive nervousness, fear, apprehension, and inclusive physical symptoms such as increased blood pressure and others that may seriously affect day-to-day living.

**REMARK:** "Anxiety" is the human brain's natural response to the "stress" accumulated.

Sleep alteration is an evolution of stress into anxiety, and this can be triggered by internal and external factors, as shown in **Figure 1**.

"Sleep Internal Alteration": Some frequent examples that cause "sleep change patterns" are: "inflammation," "injuries," "pain," "aging," "and other factors."


*The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*


#### **Figure 1.**

*Sleep alteration is an evolution of the stress to anxiety, this can be triggered by internal and external factors as indicated.*

metabolism with changes such as glucose intolerance, nutrient sensing dysregulation, and mitochondrial dysfunction [2].

**REMARK:** Aging body declination functions are reflected in metabolic disorders [7], such as obesity, diabetes, hypertension, and other changes that cause the human body to develop "sleep disorders."

"Sleep external alteration" examples that cause "sleep change patterns" could be in many ways, the most common are "artificial intelligence algorithms inspired by behaviorist psychology," "smart device screens and their blue light," and prescribed medicine side effects." Where:

	- "Search engines online" such as Google, Microsoft Bing, Yahoo, Baidu, Ask.com, and many more to search information on webpages, images, news, research papers, books, etc.
	- "Social media," such as Instagram, Facebook, Snapchat, Twitter, TikTok, YouTube, and many others, are controlling the lives of their users. On a daily basis, they frequently control users by checking their notifications and

sighing in dissatisfaction because they have not gotten enough likes on your profile picture or comments.

◦ "News websites" are always updating, generating, and adding new news to meet the need to be informed. These websites analyze the traffic and your activities and, with statistics, detect what is of more general interest, and if they have your username, they personalize the news for them, to maintain their attention and force them to check frequently for updates that are important for them, such as stock prices, public health, to accomplish user awareness.

**REMARK:** "Artificial intelligence algorithms inspired by behaviorist psychology" running on smart devices create "addiction," which is handled by the need to stay up-to-date to try to relax the anxiety generated by "stress." The main problem is that we expend part of our energy on unimportant things that do not benefit our important daily duties, at the end of the day, we feel more nervous, and these thoughts alter our daily sleep [8].

• "Smart devices Screen and their blue light." The problem with the display on smart devices LED (light-emitting diode) flat panel that emits blue light beside others from small displays and more large-scale video displays. It uses an array of LED units known as modules, consisting of many small LED chips placed on a printed circuit board (PCB) substrate. On a natural rainbow, we see the visual light spectrum; these are the colors visible to the human eye and include red, blue, and green "wavelengths." All light we see is a combination of these wavelengths, including light from the sun and exposure to blue light from the sun as well as our screens, which boost mood and alertness, that is, sunrise signals to our brain that it is time to wake up. In the evening, these flat screens can disrupt "our body's natural sleep cycle," known as the "circadian rhythm," which synchronizes the "sleep-awake cycle" with night and day. By slowing the natural production of "melatonin." It is a natural hormone that is produced by the "pineal gland in the brain" and then released into the bloodstream to make us follow the natural "circadian rhythm" cycle [9].

**REMARK:** Almost everyone has an occasional night with little or low-quality sleep. But when sleep problems start to affect your "quality of life," you may develop a "sleep disorder." The most common sleep disorder caused by too much exposure to "smart device screen blue light" is "insomnia," which refers to habitual sleeplessness, and it is the most common "sleep disorder" in the world. Besides, "insomnia" is more common as you get older, and it can affect your life in a number of ways, including daytime fatigue, poor concentration, and low mood.

• "Medicines side effects": many of them may cause "sleep deprivation" as "antiarrhythmic," "beta-blockers" for high blood pressure, or heart rhythm problems or angina; "chemotherapy" for cancer; "clonidine" for high blood pressure; "corticosteroids" for inflammation or asthma; "diuretics" for high blood pressure; "medications containing drugs" as headaches or pain relievers; "sedating antihistamines" for cold, allergy, or motion sickness; "selective serotonin reuptake inhibitors" for depression or anxiety; "sympathomimetic

stimulants" for attention deficit disorder; "theophylline" for asthma; "thyroid hormone" for hypothyroidism, and many others [10].

	- a. Class I sodium channel blockers to slow electrical impulses in heart muscles include disopyramide, flecainide, mexiletine, propafenone, and quinidine.
	- b. Class II beta blockers slow down the heart rate, often by blocking hormones such as adrenaline. that is, acebutolol, atenolol, bisoprolol, metoprolol, nadolol, and propranolol.
	- c. Class III potassium channel blockers slow down electrical impulses in all of the heart's cells, that is, amiodarone, bretylium, dofetilide, dronedarone, ibutilide, and sotalol.
	- d. Class IV, nondihydropyridine calcium channel blockers to decrease heart rate and contractions, such as diltiazem and verapamil,
	- e. Other antiarrhythmic drugs not included in the VW classification are adenosine, digoxin, and blood thinners.

your blood, decreasing the amount of fluid flowing through your veins and arteries. This reduces blood pressure. As shown in [14].


**REMARK:** If prescribed medicines are affecting your "sleep pattern," it is strongly recommended to inform your healthcare provider to correct this issue ASAP.

**IMPORTANT:** Never take medicine for sleep without a medical prescription and follow-up medical supervision.

## **6. Sleep-wake and circadian disorders and neurological disorders**

"Central nervous system (CNS)" lesions appear by disrupting continuously the "sleep-wake cycle" based on constant alteration of the human "circadian clock" developing into "circadian disorders." These are identified as "sleep-wake and circadian disorders (SWCD)," leading primary to lesioning specific cell types or structures generating or regulating sleep, wake, and circadian functions or through nonspecific lesioning of diffuse neural networks. In addition, "SWCD" can arise secondarily from complications of "CNS" lesions such as spasticity, "muscle stiffness and spasms," "pain," and even "depression."

As explained in Section: Introduction to Neuroscience and Circadian Neuroscience, "Circadian rhythms" signals from the "Suprachiasmatic Nucleus (SCN)" are distributed in the brain and the entire body by two main cell-brain connections identified as pathways: the "Hormonal rhythms control pathway" and the "Euro humoral pathway" [15]. These are:

*The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*

	- a. "Heart rate rhythm" is a healthy "sinoatrial (SA) node" a special cardiac muscle in the upper back wall of the right atrium made up of cells known as "pacemaker cells." It has an intrinsic heartbeat generation rate of 60 to 80. If the atrium fails to generate a heartbeat, then a healthy "atrioventricular node (AV)" can do so at a rate of about 40, and if needed, the ventricles themselves can generate heartbeats at a rate of about 20 per minute.
	- b. "Muscular strength rhythm" is the "circadian rhythm" in muscle force that has also been described for maximal dynamic contractions and isometric contractions. The "acrophase" (time of the maximal level of the rhythm) of the muscle capacity to develop maximal force has been found in the evening compared with the morning. The diurnal variations in muscle performance can be influenced by several factors, such as core temperature, sleep deprivation, warm-up duration, and hormone concentrations such as cortisol and catecholamine [17].
	- c. "Insulin rhythm": levels of both insulin and the counterregulatory hormones, which work against the action of insulin, are influenced by a "circadian rhythm." The counterregulatory hormones, which include glucagon, epinephrine (adrenaline), growth hormone, and cortisol, raise blood glucose levels when needed [18].
	- d. "Leptin rhythm," where leptin is a pleiotropic protein hormone produced mainly by fat cells, regulates metabolic activity and many other physiological functions. The intrinsic circadian rhythm of blood leptin is modulated by gender, development, feeding, fasting, sleep, obesity, and endocrine disorders [19]
	- e. "Glycemia rhythm" refers to the concentration of sugar or glucose in the blood. Glycemia is measured by a number called the glycemic index, which reflects how much an individual's blood sugar level rises after consuming 50 grams of carbohydrate compared with someone without diabetes who has consumed 50 grams of carbohydrate.

In many cases, the "sleep-wake and circadian disorders" may worsen over time, leading primary to lesioning specific cell types or structures on the brain. That could present the first manifestations of an underlying neurologic disorder such as "dream enactment behavior in Parkinson disease (PD)," "excessive daytime sleepiness (EDS) in hypothalamic disorders," or "insomnia in Alzheimer disease (AD)" [20]. Finally, through time it is evolving as an identifiable "progressive neurologic disease."

**REMARK:** The brain is the one that drives sleep and wakefulness through the "circadian clock," which acts as a natural pacemaker, adjusting our daily lives with day-night based on the detection of solar light, allowing us to do our routines and behaviors that are driven by "circadian rhythms." Their continuous alterations are reflected in "sleep-wake and circadian disorders," which sooner or later affect neural brain networks, memory, circadian preferences, neural development, and unresponsiveness to outside events. All these changes are ways to develop and could be associated with "progressive neurologic diseases" with abnormalities such as insomnia, schizophrenia, epilepsy, mental retardation, and mental health issues observed in Parkinson's, Alzheimer's, and other diseases.

## **7. How to analyze sleep-wake and circadian disorders**

The "sleep-wake-circadian pathologies" are generally underdiagnosed in neurologic patients despite their major impact on the onset, evolution, and outcome of neurodevelopmental disorders in the sense of an illness that disrupts normal physical or mental functions, including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), Prader-Willi syndrome (PWS), and Smith-Magenis syndrome (SMS), and diseases as progressive disorders with abnormal conditions that negatively affect the structure or function of all or part of an organism, and that is not immediately due to any external or internal injury, such as Parkinson's, Alzheimer, and many more. The main key in this research paper is to focus on accessible technologies and methodologies that are necessary for the periodic evaluation of "sleep-wake and circadian disorders." These are summarized in **Figure 2**. With the purpose of measuring the progression effect or efficacy of their therapeutic interventions and helping to evaluate the progression of "sleep-wake and circadian disorders" that could lead to neurologic disorders and diseases, separated on four instrument types: "personal home monitor," "lab studying testing," and "neuroimaging."

#### **Figure 2.**

*Sleep-wake cycle circadian disorders instruments for evaluation of progression and sleep-wake cycle circadian pathologies.*

*The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*

	- "Actigraphy" or "actometer" is worn on the nondominant wrist or ankle to record acceleration or deceleration of body movements. It is worn for days or weeks and complements a daily sleep log for the diagnostic "circadian rhythm sleep disorders" and other primary sleep disorders such as insomnia and idiopathic hypersomnia.
	- "Smart watches." Today, some smart watches include a clinical-grade "actigraph" used for sleep and activity home monitoring, showing an easyto-follow and understand graph with automatic daily recordings, with high accuracy and sensitivity, very useful as primary personal feedback, that allows you to take the information collected to the medical doctor with valid information on your personal "sleep/wake cycle" for an initial diagnostic of "circadian rhythm sleep disorders." Please be sure to buy a clinically validated smart watch for sleep monitoring [21].
	- "Electroencephalogram (EEG)" to measure electrical activity in the brain using electrodes attached to the scalp, for detecting and analyzing several polygraphic physiologies during sleep.
	- "Chin electromyogram (EMG)" to assess the health of muscles and the nerve cells that control the chin and allow determination of sleep stages.
	- "Limb EMG" for leg muscle evaluation, detecting and analyzing periodic leg movements that may disrupt sleep as "restless legs syndrome," and other evaluations.
	- "Oronasal thermal airflow sensors" use thermistors or thermocouples to measure and analyze thermal airflow, reading the difference between the temperature of exhaled and ambient air to estimate airflow and detect mouth breathing. Interrupt during sleep as "sleep apnea," and other issues.
	- "Electrocardiography" is the process of producing an electrocardiogram (ECG or EKG) recording the heart's electrical activity.
	- "Electrooculogram" for measuring the cornea-retinal standing potential that exists between the front and the back of the human eye and detection of eye movements.
	- And many other instruments, such as "pulse oximetry" for measuring arterial oxygen saturation and "audiovisual recordings," enhance the diagnostic utility of polysomnography.

"Polysomnography" is used to diagnose sleep-disordered breathing, movement disorders, and abnormal behavior during sleep, such as "REM sleep behavior disorder" and arousal disorders.

**REMARK**: "Polysomnography" is very useful to analyze the sleep architecture process for the wakefulness stage, Stage W, and NREM and REM sleep stages, as shown in **Table 1**.

	- "Structural imaging," which visualizes brain anatomy and pathology and measures volume and other tissue characteristics,
	- "Functional neuroimaging," measuring brain activity, blood flow, and glucose metabolism; and
	- "Molecular imaging" focuses on information on biologic processes, including protein aggregation, neuroinflammation, and related processes.

The development of "functional neuroimaging" consists of all techniques that can generate images of brain activity. In humans, such techniques usually include "single photon emission computed tomography (SPECT)," "positron emission tomography (PET)," "functional magnetic resonance imaging (fMRI)," "optical imaging," "diffusion tensor imaging (DTI)," "multichannel electroencephalography (EEG)," "magnetoencephalography (MEG)," and others. Each technique has its own advantages and drawbacks in terms of spatial and temporal resolution, accessibility, safety, and cost [23]. Applying AI algorithms detected following:

	- "Regional brain activity" identifies them when they are influenced by incoming stimuli as well as by previous waking experience.
	- "Neural correlates of sleep-wake regulation tend toward a relatively stable equilibrium between interdependent elements for sleep pressure and the non-visual effect of light."
	- "Functional imaging of patients with sleep disorders: studying their neural system changes across the sleep-awake cycle."

Many researchers applying "neuroimaging techniques" have discovered the relation of the "sleep-wake cycle" with neurological diseases such as: "REM sleep behavior *The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*

disorder," "isolated rapid eye movement (REM) sleep behavior disorder," "type 2 diabetes mellitus and sleep disorders,"

	- "Obesity," Neuroimaging analysis demonstrated that there were altered interactions in the brain networks of obese individuals in response to food cues [26], particularly in the frontal-mesolimbic network [27].
	- In "insomnia," the main affected brain areas are the "ascending reticular activating system," "hippocampus," "amygdala," "insular cortex," and "medial prefrontal cortices" [28].

"Molecular Imaging (MI)" is a growing biomedical research discipline that enables the visualization, characterization, and quantification of biologic processes taking place at the cellular and subcellular levels within intact living patients in their own psychological environment. Examples of progressive neurologic diseases are "Parkinson's disease," "Alzheimer's disease," "frontotemporal dementia," "multiple system atrophy," and many more related to disturbances in the "sleep/wake cycle."

	- "α-synuclein or synuclein alpha" is also known by the alias "SNCA or NACP or PARK1 or PARK4 or PD1." "α-synuclein" is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, mainly in the axon terminals of presynaptic neurons, and
	- "Tau or tubulin," also known by the alias "MAPT (microtubule-associated protein tau) or DDPAC or FTDP-17 or MAPTL or MSTD or MTBT1 or MTBT2 or PPND or PPP1R103 or microtubule-associated protein tau ortau-40," is a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the "central nervous system (CNS)," where the cerebral cortex has the highest abundance. It is found in atypical Parkinson's known as "Progressive Supranuclear Palsy," which often shows "midbrain" and "superior cerebellar peduncular atrophy" and cell loss in a specific distribution, particularly affecting the "subthalamic nucleus," "globus pallidus," "substantia nigra," and "pretectal area of the midbrain" [30].

inspiratory sighs that are considered a diagnostic red flag for the parkinsonian form of MSA [33].

And many other neurologic diseases usually present sleep disturbances.

**REMARKS:** Sleep and mental health are closely connected. Sleep deprivation affects our psychological state and mental health. And they are particularly common in patients with anxiety, depression, bipolar disorder, and attention deficit hyperactivity disorder, and also have connections with neurologic disease.

## **8. Conclusions and comments**

"Sleep quality" is critical for the maintenance of a stable equilibrium of body function driven by "circadian function," especially for "neuronal cells and pathways" in the brain, endocrine system, metabolism, immunity, and others. If we leave unattended the importance of normal "sleep/wake cycles," our human body is taken to the next step, presenting "chronic sleep disturbances" through the increment of undesirable "mood swings," presenting symptoms of stress, anxiety, and many others. People who regularly experience "mood swings" are more likely to experience "psychiatric disorders" such as "anxiety," "depression," "post-traumatic stress disorder," "bipolar disorder," and "borderline personality disorder." And with time, the same situations grow to have significant "cognitive" and "physical health" consequences that likely exacerbate disease severity as "neurological disorders." Today, there are technologies that can detect and evaluate "sleep-wake and circadian disorders," measuring and tracking the severity of the damage with "specialized lab tests," such as "polysomnography," that combine specialized monitor instruments for evaluation of sleep tests, breathing, movements, and others. Technologic advances based on "neuroimaging analyzing," "functional neuroimaging," and "molecular imaging" that allow the discovery of new "genetic mutations" as well as the development of "potential biomarkers" may serve to further expand knowledge to help with "sleep quality" that is affecting millions of people and continues growing around the world.

The odds of being "sleep deprived with less than 6 hours a night for adults" have increased significantly over the past 30 years as the lines between work and home have become blurred and digital technology has firmly become part of our lifestyles [34].

**FINAL REMARK:** "Sleep quality" is affecting millions of people and continues to grow around the world. Today, there are technologies that can detect and evaluate "sleep-wake and circadian disorders" before they cause chaos on our neuronal circuits, creating endless multiple neurologic responses that could take us to "degenerative diseases that still have no cure."

Please sleep well. Thanks. Dr. Jorge Garza- Ulloa. More information: https://garzaulloa.org

#### *Sleep Medicine – Asleep or Awake?*

Notices: Knowledge and best practice in this field are constantly changing as new research and experience broaden our understanding, and changes in research methods, professional practices, or medical treatment may become necessary. To the fullest extent of the law, neither the publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence, or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

## **Author details**

Jorge Garza-Ulloa Research Consulting Service, El Paso, Texas, USA

\*Address all correspondence to: jorge@garzaulloa.org

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders DOI: http://dx.doi.org/10.5772/intechopen.111749*

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Section 2
