**5. The diaeventological axis**

levels was statistically correlated to the ASIC1 common gene variant (rs1108923). This heritable variant thus segregated with a general anxiety and panic disorder-linked respiratory endophenotype [30]. Whether this gene variant would be either sufficient or necessary for respiratory distress-linked anxiety was not addressed. Upon consideration of the pathophysiological response and potential for genetic and epigenetic diaeventological interactions, it is at best a correlation that requires careful experimentation before validation of

Traumatic brain injury (TBI) is a tremendous health issue worldwide and is responsible for a considerable amount of brain-associated permanent disability and death. While physical

arterial pressure (MAP) within a short window (50–150 mmHg). When MAP falls above or below this range, the capacity for autoregulation collapses and either hypotensive ischemia or

These conditions can occur in utero and throughout the post gestational life. This effectively induces neuroimmune activation that can be modified via epigenetic mechanisms leading in some instances to a potential for predisposition to GAD and other neuropsychiatric disorders.

an increase in this parameter is associated with vasodilation of the cerebral blood vessels [31].

to neuronal and microglial activity. As neuronal action potentials fire, this increases biologi-

oxidative phosphorylation (ETC/OXPHOS) [31]. Both catecholamines and excitatory amino

concentration of neurotransmitters increases, thus potentiating neuronal damage and microg-

problem arises, and this involves the increase in intracranial pressure because of excessive blood flow. This is similar to stroke associated with edema that results in the extravasation of vessel contents into surrounding tissues, thus causing an increase in interstitial fluid which

lead to HPA axis stimulation and ultimately the endophenotypes linked to anxiety disorders. When this occurs chronically during gestation, the fetus may obtain epigenetic alterations in key metabolic, hormonal, and immune pathways leading to a predisposition to anxiety disorders in adulthood. Likewise, this can be repeated during early infant and childhood

demand and if blood flow is restricted due to the paCO<sup>2</sup>

effect is directed to control the paO<sup>2</sup>

because CO2

to drive ATP production via metabolism and the electron transport chain/

intoxication is also a contributing factor.

dissolves far better than O<sup>2</sup>

for cerebral oxygen demand

consumption in the brain is linked

in aque-

, the relative

is increased, another

, CO2, and pH, and mediate mean

in the blood (paCO2) alters the autoregulation of blood

effects on autoregulation, decreases cause vasoconstriction while

levels in the brain can result in neuroimmune activation that can

the argument.

blunt force trauma is a major source of TBI, CO<sup>2</sup>

flow to the brain [31]. Blood vessels in the CNS respond to O2

Clearly a case for a diaeventological mediated pathophysiological state.

lial activation to generate pro-inflammatory cytokines. When paCO<sup>2</sup>

Hyperbaric partial pressure of CO2

24 Anxiety Disorders - From Childhood to Adulthood

hypertensive edema can result [31].

This response is acutely sensitive to paCO2

will induce an immune response [31].

development, and into adulthood.

Increases or decreases in CO2

which is essential to prevent brain damage and death. O2

In the specific case of paCO<sup>2</sup>

ous. However, the paCO2

cal demand for O2

acids will increase O2

Living systems interact according to a three-dimensional biological trigonal plane according to the square of opposition:

A. Universal affirmative: No harm to host(s); maximum benefit to both; rare or occasional dependence.

E. Universal negation: Severe harm to hosts; benefit to only 1 host; 100% dependence.

I. Particular affirmative: benefit is disinterested; 50% dependence.

O. Particular negation: Some harm to neither; benefit to neither; no dependence for either.

This interplay involves the macrocosm, but it also appropriately describes the microcosm (human body and overall stress) imposed by the microbiome, invading pathogens, autoimmunity, cancer, autophagy, and senescence. This is the mechanism by which neuropathology is established in the CNS as described for example in glioblastoma [32].

Development, differentiation, and the signal transduction cascade network, including neuronal action potentials, neuroimmune mechanisms, and endocrine mediation, compose an opposing three-dimensional trigonal plane where the central element is the homeostasis of the existing individual.

Indeed, learning and the accumulation of memories and knowledge are all part of a massive internal interactome that can be understood compared to advantage, vectorial control, and constant failure and compensation. This is the basis for diaeventology as introduced in the introduction of this chapter.

There is a natural-native system that encompasses all of these features: the immune system.

Thus, the immune system has two roles in the human body. One is for defense and the other, in conjunction with epigenetic mechanisms, generates the existing individual with an ongoing neural network that can learn, via attention and ascent to stress on the system. This is accomplished via homologous recombination of variable regions of both the immunoglobulin family and the T-cell receptor in concert with chromatin remodeling [33], the histone code, and both the acetylome and methylome of cohering DNA [34].

If there is a link between the double aspect of mind and the body, at least one component is physical. This connection might be the molecular and cellular adaptive immunological interactome that serves to generate neural tracts according to developmental, endocrine, and peripheral stimuli, while maintaining repair processes in the CNS, by using the complex interactions between microglia and neurons.

It is well established that neuroinflammatory mediators play a critical role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair [35].

The immune response could function to generate the networked synaptic connections in the brain during development and throughout life. Soon after an ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells. This causes the adhesion and transendothelial migration of circulating neutrophils and monocytes [36]. These immune cells may accumulate in the capillaries, decreasing cerebral blood flow. They can further extravasate into the brain parenchyma, thus impacting neuropsychiatric states [37].

GM-CSF is a pro-inflammatory cytokine associated with enhancing the level of circulating leucocytes while decreasing fetal hemoglobin levels in sickle cell anemia patients, making it a potential target for blockade with pharmacological agents [43].GM-CSF is linked to decreased oxygenation in the blood and increased immune activity-associated inflammation. While GM-CSF was also linked to depression and anxiety score elevation in ARDS patients, corticosteroids, which reduce the inflammatory response, had the opposite effect on these disorders [41].GM-CSF expression is stimulated by pro-inflammatory cytokines and inhibited by anti-inflammatory cytokines and also serves to both stimulate and regulate pro-inflammatory cytokines, thus suggesting a direct role in the activation of type I macrophages, which have

The Diaeventology of Anxiety Disorders http://dx.doi.org/10.5772/intechopen.82176 27

Bioenergetic reprogramming is associated with macrophage polarization. The inflammatory macrophage cell type is fueled by aerobic glycolysis and can be triggered by LPS ± IFN-γ. With the anti-inflammatory lineage, IL-4 induces the expression of PPARγ, which in turn transcriptionally activates the urea cycle enzyme arginase 1 (Arg1), and the β-oxidation of fatty acids (Beta-OX) along with ETC/OXPHOS increased capacity via mitochondrial biogenesis. To fuel the anti-inflammatory bioenergetics, IL-4 also induces expression of CD36 which acts as a membrane receptor for circulating low-density lipoprotein (LDL) and VLDL-rich TAG. Finally, the unloading of TAG and associated fatty acid hydrolase activity is linked to Beta-OX, thus completing the anti-inflammatory polarization [40]. Inhibiting neuroinflamma-

A recent report examines the use of a potential probiotic bacterium, *Mycobacterium vaccae* NCTC 11659 [45]. *M. vaccae* could become a biological means to treat anxiety disorders and its mechanism may involve the enhancement of T regulatory cells (Treg) which act to curtail T-effector (Teff) cell-meditated inflammation via the stimulation of anti-inflammatory cytokines such as IL-10, and TGF-β regionally in the hippocampus. Whether biofuel switching plays a role in this response has not been fully addressed, but elsewhere it has been reported that Treg-cell metabolism toward Beta-OX and lipid utilization enhances the Treg control over Teff-cell-mediated inflammatory responses and further that Teff cells tend to use aerobic gly-

Besides neuronal firing, hormonal signaling, cell transduction cascades, cytokine and chemokine synthesis and release, and immune cell epigenetic patterning, this biofuel connection to anxiety disorders helps to explain how in utero dietary fluctuations can affect the developing fetus.

The pre-programming of the neuroimmuno epigenome may be one of the pillars of longitudinal psychiatric disease development. A diaeventological paradigm is thus developing to explain the biological patterning of anxiety disorders. **Figure 2** below provides a developmen-

tal time course for the molecular and cellular GAD patterning described in the text.

been linked to GAD and associated depressive disorders [44].

tion has become a new strategy in biological psychiatry.

colysis over Beta-OX [46].

**6. Conclusions**

Besides this, the infiltrating leukocytes, as well as resident brain cells, (neurons and macrophage-like microglia) may release pro-inflammatory agents like cytokines, chemokines, and oxygen/nitrogen radicals that result in tissue damage [38]. Moreover, recent studies have highlighted the involvement of matrix metalloproteinases in the propagation and regulation of neuroinflammatory responses to ischemic brain injury. These enzymes cleave protein components of the extracellular matrix such as collagen, proteoglycan, and laminin, but also process a number of cell-surface and soluble proteins, including receptors and cytokines such as interleukin-1β, thus promoting CNS inflammation and the potential for anxiety disorders [39].

The innate immune cells, macrophages, are classified into inflammatory or anti-inflammatory. Inflammatory macrophages differentiate in response to microbial and tumor antigens and interferon γ by producing pro-inflammatory cytokines at the site of nascent infection and cancerous lesions [40].

Anti-inflammatory macrophages differentiate via signaling by glucocorticoids or anti-inflammatory (type II) cytokines like IL-4, IL-13, and IL-10 where they promote TH2 immunity and mediate tissue remodeling, wound healing, and immune modulation.IL-4 and IL-13 drive anti-inflammatory macrophage polarization through the IL-4 receptor alpha chain (IL-4Rα), and anti-inflammatory polarization is also promoted by activation of several master regulators, including signal transducer and activator of transcription 6 (STAT6), Krüppel-like factor 4 (KLF4), and interferon regulatory factor 4 (IRF4), thus implicating all of these proteins in control over the generation of anxiety [40].

Macrophage polarity and activation are linked to neuropsychiatric conditions including GAD and MDD. A case in point is acute respiratory distress syndrome (ARDS) [41].

Acute respiratory distress syndrome (ARDS) is associated with an imbalance in the level of respiratory oxygen intake and CO2 release and thus is linked to known potential pathophysiological states and GAD. ARDS can be fatal if not treated appropriately. In adults, it is associated with stiffness of the respiratory system evident in the pulmonary oxygenation step. This results in both chronic and acute hypoxemia. ARDS pathology is characterized by injury to the capillary endothelia and subsequent damage to alveoli, severe arterial vasoconstriction, and pulmonary hypertension [42]. Subsequent to lung injury, ARDS patients are typically treated with granulocyte/macrophage colony stimulating factor (GM-CSF) as a component of their pharmacotherapy [41].

GM-CSF is a pro-inflammatory cytokine associated with enhancing the level of circulating leucocytes while decreasing fetal hemoglobin levels in sickle cell anemia patients, making it a potential target for blockade with pharmacological agents [43].GM-CSF is linked to decreased oxygenation in the blood and increased immune activity-associated inflammation. While GM-CSF was also linked to depression and anxiety score elevation in ARDS patients, corticosteroids, which reduce the inflammatory response, had the opposite effect on these disorders [41].GM-CSF expression is stimulated by pro-inflammatory cytokines and inhibited by anti-inflammatory cytokines and also serves to both stimulate and regulate pro-inflammatory cytokines, thus suggesting a direct role in the activation of type I macrophages, which have been linked to GAD and associated depressive disorders [44].

Bioenergetic reprogramming is associated with macrophage polarization. The inflammatory macrophage cell type is fueled by aerobic glycolysis and can be triggered by LPS ± IFN-γ. With the anti-inflammatory lineage, IL-4 induces the expression of PPARγ, which in turn transcriptionally activates the urea cycle enzyme arginase 1 (Arg1), and the β-oxidation of fatty acids (Beta-OX) along with ETC/OXPHOS increased capacity via mitochondrial biogenesis. To fuel the anti-inflammatory bioenergetics, IL-4 also induces expression of CD36 which acts as a membrane receptor for circulating low-density lipoprotein (LDL) and VLDL-rich TAG. Finally, the unloading of TAG and associated fatty acid hydrolase activity is linked to Beta-OX, thus completing the anti-inflammatory polarization [40]. Inhibiting neuroinflammation has become a new strategy in biological psychiatry.

A recent report examines the use of a potential probiotic bacterium, *Mycobacterium vaccae* NCTC 11659 [45]. *M. vaccae* could become a biological means to treat anxiety disorders and its mechanism may involve the enhancement of T regulatory cells (Treg) which act to curtail T-effector (Teff) cell-meditated inflammation via the stimulation of anti-inflammatory cytokines such as IL-10, and TGF-β regionally in the hippocampus. Whether biofuel switching plays a role in this response has not been fully addressed, but elsewhere it has been reported that Treg-cell metabolism toward Beta-OX and lipid utilization enhances the Treg control over Teff-cell-mediated inflammatory responses and further that Teff cells tend to use aerobic glycolysis over Beta-OX [46].

Besides neuronal firing, hormonal signaling, cell transduction cascades, cytokine and chemokine synthesis and release, and immune cell epigenetic patterning, this biofuel connection to anxiety disorders helps to explain how in utero dietary fluctuations can affect the developing fetus.
