INDIVIDUAL ASSIGNMENT

Neuropsychiatry
3 year / 5 Semester / 2022 / FMUI 2020
rd th

Mohamad Arbian Karim

2006489400 – Group C

PBL Trigger 1

How is The Physiology of Stress, Anxiety, and its Adaptation Mechanism? And How to
Diagnose it?

Introduction

Physiological stress is defined as any external or internal circumstance that disrupts a cell's or
organism's equilibrium. It is classified into three categories: environmental stress, intrinsic
developmental stress, and aging. Changes in the environment provide a challenge to all living
creatures throughout their lives. Changes in oxygen levels, temperature, and redox status, for
example, set off chemical processes that allow an organism to adapt, live, and reproduce.1

Fear is a stress-related involuntary neurophysiological state of alarm defined by a fight or

flight reaction to a cognitive evaluation of current or imminent danger (actual or imagined).
Anxiety is related to fear and emerges as a future-oriented emotional state comprised of a
complex cognitive, affective, physiological, and behavioral response system involved with
preparedness for expected dangerous events or circumstances. Pathological anxiety is
generated when there is an overestimation of the perceived threat or an incorrect risk
assessment of a scenario, resulting in excessive and inappropriate responses.2

In this LTM, I will be explaining about the the physiology of stress, anxiety, its adaptation
mechanism and the diagnosis that is needed to help further assessment.

Topics Discussion
A. Introduction of Stress
Stress is a natural component of the world that affects nearly all biological systems.
Biological stress refers to any circumstance that causes living systems to deviate from
a physiologically stable state, and its influence is strongly related to the nature of the
materials that shape live creatures. Because stress may refer to many distinct levels of
biological organization, it has been utilized in a variety of settings to date.
"Physiological stress" is the fundamental biological stress and may be defined as any
external or internal circumstance that disrupts a cell's or organism's equilibrium.
Taking into account the various potential sources of biological stress, we may divide
physiological stress into three categories: environmental stress, internal
developmental stress, and aging.1
Fig. 1 Different Aspects Of Physiological Stress. Aging and environmental stress are
present throughout life whereas intrinsic developmental stress applies only during
embryonic and post-embryonic development.1

Stress is a condition of threatened homeostasis caused by intrinsic or external

unfavorable influences (stressors) and is countered by a complex repertoire of
physiologic and behavioral responses aimed at maintaining/reestablishing optimal
bodily equilibrium (eustasis). The adaptive stress response is dependent on a complex
neuroendocrine, cellular, and molecular infrastructure known as the stress system.
The hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system
(ANS) are key components of the stress system that interact with other vital centers in
the central nervous system (CNS) and tissues/organs in the periphery to mobilize a
successful adaptive response against the imposed stressor (s). Dysregulation of the
stress system (hyper- or hypo-activation) in conjunction with intense and/or chronic
stress can significantly disturb physiological homeostasis, resulting in cacostasis or
allostasis, with a range of clinical symptoms.3

a. Environmental Stress
Biological systems are built to evolve and thrive in a wide range of changing
situations. Many various adaptations have evolved throughout time to allow
creatures to not only survive but also reproduce in a variety of sometimes
hazardous environments. These adaptations are linked to certain structures and
behaviors that are adapted to a given environment. Different techniques exist
at the molecular level that cells and systems utilize to respond and adapt to
environmental changes such as variations in oxygen supply and temperature
swings. Environmental fluctuations that surpass specified thresholds are
referred to as "environmental stress."1

b. Intrinsic Developmental Stress

Developmental events might be attributed as another source of physiological
stress. As living creatures grow, they encounter a number of problems related
to morphogenesis and changes in internal chemistry. Rapid embryo growth, in
fact, generates huge internal changes in an organism as it develops and
changes form. Different developmental events can result in varying degrees of
stress, with some being more severe than others. As a result, adaptability to
developmental stress is equally important for individual and species survival.1
 c. Aging
When development is complete and organismal maturity has occurred,
environmental stress is merely one component of the physiological stress that
individuals face. Aging is another additional hardship that living beings must
bear throughout their lives. Although aging is frequently viewed as the
deteriorative effect of many pressures, it may also be viewed as an additional
layer of stress throughout life due to the thermodynamic features of biological
materials, which contribute to the stochastic accumulation of molecular
damage over time. Each organism's ability to deal with aging and other
challenges determines its longevity. Thus, functional deterioration due to
aging, which happens even under medically optimal environmental conditions,
may contribute to the influence of entropy on organisms and highlight
potential flaws in homeostatic processes.1

B. Stress System and Stress Adaptation

All important physiologic systems of the body are intrinsically designed to maintain a
specified steady state (homeostasis or eustasis), which is crucial for life and well-
being, as a result of rigorous fine-tuning performed during evolution. This ideal
balance is continually threatened by stresses, which might be either inherent or
exogenous, actual or perceived. Thus, stress is characterized as a condition of discord
(cacostasis or allostasis) that is countered by a complex repertoire of physiologic and
behavioral reactions aimed at maintaining/reestablishing the threatened homeostasis
(adaptive stress response). This adaptive stress response is regulated by the stress
system's extensive and interrelated neuroendocrine, cellular, and molecular
infrastructure, which is found in both the central nervous system (CNS) and the
periphery. A variety of genetic, environmental, and developmental variables influence
each individual's adaptive response to stress. Changes in the ability to respond to
stresses effectively (e.g., insufficient, excessive, and/or extended responses) may
result in illness. Furthermore, very intense and/or persistent stresses can impair a wide
range of physiologic systems, including growth, metabolism, reproduction, and
immunological competence, as well as behavior and personality development.
Prenatal life, infancy, childhood, and adolescence are key periods in the process of
developing the matrix of the adaptive stress response, with the stress system being
highly flexible and vulnerable to stressors.3

The stress system receives and integrates a wide range of neurosensory (visual,
auditory, somatosensory, nociceptive, and visceral), blood-borne, and limbic signals
that arrive at different stress system centers/stations via different paths. Acute stress
system activation causes a series of time-limited behavioral and physical alterations
that are quite uniform in their qualitative presentation and are referred to as the stress
syndrome. Under normal circumstances, these modifications are adaptive and increase
one's chances of survival. Initially, stress system components are stimulated in a
stressor-specific way; however, as the strength of the stressor(s) grows, the specificity
of the adaptive response declines, resulting in the rather general stress syndrome
phenomenology that follows exposure to strong stressors.3

Behavioral adaptation comprises increased arousal, alertness, vigilance, cognition,

focused attention, and analgesia, whereas vegetative activities such as eating and
reproduction are inhibited. Physical adaptation, on the other hand, facilitates an
 adaptive redirection of energy and physiological resources. As a result, increases in
cardiovascular tone, respiratory rate, and intermediate metabolism (gluconeogenesis
and lipolysis) all work together to promote this redirection of vital substrates, while
energy-consuming functions (such as digestion, reproduction, growth, and immunity)
are temporarily suppressed. As a result, oxygen and nutrients are predominantly sent
to the CNS and stressed body sites where they are most needed.3

In addition to the adaptive stress response, restraining forces are engaged during stress
to prevent the various stress system components from responding excessively. The
capacity to produce restraining forces in a timely and exact manner is also required
for a good outcome against the imposed stressor(s), because prolonged the mobilized
adaptive stress response might turn maladaptive and contribute to disease
development.3

Surprisingly, the mobilization of the stress system is frequently of a size and kind that
permits the individual to perceive control. Stress may be rewarding and enjoyable,
even thrilling, under certain conditions, giving good impulses for emotional and
intellectual growth and development. As a result, it is not unexpected that stress
system activation during eating and sexual activity, both of which are necessary for
survival, is largely associated with pleasure.3

C. Stress System and Physiological Interactions

a. Neuroendocrine Effectors of the Stress Response- “The Stress System”

Although the whole CNS is engaged in maintaining and fine-tuning general
body homeostasis, certain parts of the brain play crucial and different roles in
orchestrating the stress response. As a result, the central components of the
stress system are located in the hypothalamus and the brainstem, and include
the parvocellular corticotropin-releasing hormone (CRH) and arginine-
vasopressin (AVP) neurons of the hypothalamic's paraventricular nuclei
(PVN), and the CRH neurons of the medulla's paragigantocellular and
parabranchial nuclei, as well as the locus coer (central sympathetic nervous
system). The peripheral limps of the hypothalamic-pituitary-adrenal (HPA)
axis, as well as the efferent sympathetic/adrenomedullary system, make up this
integrated system.3

b. Central Stress System - CRH, AVP, & Catecholaminergic Neurons

The central neurochemical circuitry that activates the stress response is a very
complex physiological system inside the CNS, comprised of both stimulatory
and inhibitory networks with various sites of interaction that control and fine-
tune the adaptive stress response. The hypothalamic CRH and AVP neurons,
in conjunction with the central catecholaminergic (LC/NE) neurons, are
critical components of these networks. The activation of the central stress
system is based on reciprocal reverberatory neuronal connections between
PVN CRH and catecholaminergic LC/NE neurons, with CRH and NE
boosting each other's production via CRH receptor-1 (CRH-R1) and 1-
noradrenergic receptors, respectively. It is worth noting that autoregulatory
ultrashort negative feedback loops exist in both PVN CRH and brainstem
catecholaminergic neurons, with collateral fibers reducing CRH and
catecholamine production via regulation of the corresponding presynaptic
CRH- and 2-noradrenergic receptors, respectively. Furthermore, both CRH
and catecholaminergic neurons get stimulatory innervation from the
serotoninergic and cholinergic systems, as well as inhibitory input from the
gamma-aminobutyric acid (GABA)/benzodiazepine (BZD) and opioid
neuronal systems of the brain, as well as glucocorticoids (the end-product of
the HPA axis). Interestingly, both 2-adrenoceptor and opiate agonists act on
neurons in the LC via distinct receptors, while sharing similar post-receptor
effector signaling mediated by Gi proteins.3

Vale et al. identified CRH, a 41-amino acid peptide, as the primary

hypothalamic stimulation to the pituitary-adrenal axis in 1981. The later
availability of synthetic CRH and inhibitory counterparts expanded the scope
of stress study significantly. Thus, CRH and CRH-receptors have been found
in a variety of extra-hypothalamic brain regions, including limbic system,
basal forebrain, anterior pituitary, and central arousal-sympathetic systems
(LC-sympathetic systems) in the brainstem and spinal cord. Furthermore,
central CRH treatment was demonstrated to initiate a coordinated sequence of
physiologic and behavioral reactions, including activation of the pituitary-
adrenal axis and the sympathetic nervous system (SNS), as well as typical
stress-related behaviors. As a result, it became clear that CRH plays a more
important role in stress response coordination than previously thought. In fact,
as detailed in Table 1, this neuropeptide appears to recapitulate the stress
response phenomenology.3

Table 1. Behavioral and Physical Adaptation During Stress.3

c. Fast and Slow Response of Physiological Stress
Stress response physiology is divided into two parts: a gradual reaction
mediated by the HPA axis and a quick response mediated by the SAM axis.
The rapid reaction caused by SAM activation leads in increased secretion of
norepinephrine (NE) and epinephrine (E) into the circulation, as well as
increased secretion of NE from the sympathetic nerves, resulting in raised
levels of NE in the brain. The released E and NE bind to -adrenergic and -
adrenergic receptors found in the central nervous system, smooth muscle cell
membranes, and various organs throughout the body. Once released,
norepinephrine (NE) and epinephrine (E) connect to particular membrane-
bound G-protein receptors, triggering an intracellular cAMP signaling cascade
that rapidly triggers cellular responses. Activation of these receptors causes
vasoconstriction, increased blood pressure, heart rate, cardiac output, skeletal
muscle blood flow, increased salt retention, increased glucose levels (owing to
glycogenolysis and gluconeogenesis), lipolysis, increased oxygen
consumption, and thermogenesis. It also reduces intestinal motility, causes
cutaneous vasoconstriction, and dilates the bronchi. Furthermore, SAM
activation causes behavioral activation (enhanced arousal, alertness, vigilance,
cognition, focused attention, and analgesia).4

The sluggish response is caused by activation of the HPA axis, which results
in the release of Corticotropin-releasing hormone (CRH) into the blood from
the hypothalamic paraventricular nucleus. The hypothalamic release of CRH
works on two receptors: CRH-R1 and CRH-R2. In animals, CRH-R1 is
extensively expressed in the brain. It is the primary receptor for the anterior
pituitary's stress-induced ACTH production. CRH-R2 is largely expressed in
peripheral tissues such as skeletal muscles, the gastrointestinal system, and the
heart, as well as subcortical brain areas. The cortisol releasing hormone
binding protein CRH-BP has a greater affinity for CRH than CRH does for its
receptors. The liver, pituitary gland, brain, and placenta all express CRH-BP.
CRH-significance BP's as a regulator of CRH bioavailability has been
supported by studies that show 40 to 60% of CRH in the brain is bound by
CRH-BP. When stressed, the expression of CRH-BP rises in a time-dependent
manner, which is assumed to be a negative feedback mechanism to reduce
CRH-R1 interaction. The total cortisol level in the body is described by serum
cortisol level, of which 80% is bound to cortisol binding globulin (CBG) and
10% is bound to albumin. Cortisol is physiologically active when it is
unbound.4

The CRH produced stimulates the anterior pituitary gland, which subsequently
releases adrenocorticotrophin hormone (ACTH) into the circulation. ACTH
activates the adrenal cortex, causing it to produce glucocorticoid hormones
such as cortisol into the bloodstream. Cortisone, the inactive form of cortisol,
is converted to cortisol, the active form, by 11 beta-hydroxysteroid
dehydrogenases.4

Pituitary adenylate cyclase-activating polypeptide regulates the HPA axis

(PACAP). PACAP may be involved in the synthesis of CRH as well as
modulating numerous levels of the HPA axis. PACAP may possibly have a
role in the autonomic response to stress by increasing catecholamine
 production. PACAP receptors are G-protein coupled, with PACAP-R1 being
the most prevalent in both central and peripheral organs. PACAP may
potentially influence the role of estrogen in the potentiation of the acute stress
response. Because CRH has a greater affinity for CRH-BP than for its
receptors, once released, it interacts with cortisol releasing hormone binding
protein (CRH-BP). The liver, pituitary gland, brain, and placenta all express
CRH-BP. CRH-significance BP's as a regulator of CRH bioavailability has
been supported by studies that show 40 to 60% of CRH in the brain is bound
by CRH-BP. When stressed, the expression of CRH-BP rises in a time-
dependent manner, which is assumed to be a negative feedback mechanism to
reduce CRH-R1 interaction. [2] The total cortisol level in the body is
described by serum cortisol level, of which 80% is bound to cortisol binding
globulin (CBG) and 10% is bound to albumin. Cortisol is physiologically
active when it is unbound.4

d. Organ Systems Involved in Stress and The Function of Stress

Stress has an impact on all physiological systems, including the
cardiovascular, respiratory, endocrine, gastrointestinal, neurological,
muscular, and reproductive systems. Acute stress induces an increase in heart
rate, greater heart muscle contractions, dilatation of the heart, and blood
diversion to major muscles in the cardiovascular system. The respiratory
system collaborates with the cardiovascular system to provide oxygen to the
body's cells while eliminating carbon dioxide waste. Acute stress narrows the
airway, causing shortness of breath and fast breathing. To trigger the body's
stress response, the endocrine system raises the production of steroid
hormones such as cortisol. Stress can influence the gastrointestinal tract by
slowing the passage of food through the intestines. It can also have an impact
on digestion and the nutrients absorbed by the intestines. In terms of the neural
system, stress stimulates the sympathetic nervous system, which then
stimulates the adrenal glands. The parasympathetic nervous system aids the
body's recuperation once the acute stress-induced crisis has passed. Stress
affects the musculoskeletal system by tightening the muscles to protect against
pain and damage. Chronic stress can have a deleterious influence on sexual
desire, sperm production/maturing, pregnancy, and menstruation in the
reproductive system.4

The increased autonomic reaction raises the heart rate and blood pressure.
Catecholamine release reduces GI tract blood circulation during serious
sickness. During times of stress, plasma levels of norepinephrine and
epinephrine redistribute blood volume in order to conserve the brain's blood
supply. The sympathetic nervous system is stimulated by a variety of stressors
to the body, including hypoglycemia, hemorrhagic shock, exertion beyond the
anaerobic threshold, and asphyxiation. Epinephrine is also linked to active
flight, aggression, and immobility fear.4

The increased autonomic reaction raises the heart rate and blood pressure.
Catecholamine release reduces GI tract blood circulation during serious
sickness. During times of stress, plasma levels of norepinephrine and
epinephrine redistribute blood volume in order to conserve the brain's blood
supply. The sympathetic nervous system is stimulated by a variety of stressors
 to the body, including hypoglycemia, hemorrhagic shock, exertion beyond the
anaerobic threshold, and asphyxiation. Epinephrine is also linked to active
flight, aggression, and immobility fear. Increased arterial pressure, more blood
flow to active muscles and less blood flow to organs not required for rapid
motor activity, increased rate of blood coagulation, increased rates of cellular
metabolism throughout the body, increased muscle strength, increased mental
activity, increased blood glucose concentration, and increased glycolysis in the
liver/muscle are all physiologic changes caused by this mass discharge effect.
The aggregate result of all of these impacts permits a person to engage in more
intense activities than usual. The body recovers to pre-arousal levels once the
perceived threat has passed.4

e. General Adaptation Syndrome

General adaptation syndrome describes the various stress-induced
physiological changes in three stages, with the final two stages demonstrating
the pathological changes of prolonged stress. This condition is separated into
three stages: alarm reaction, resistance, and fatigue. The alarm reaction stage
refers to the body's first indications of acute stress and the "fight or flight"
response. The body begins to mend itself after the first shock of the stressful
experience by reducing cortisol levels and restoring physiologic responses (i.e.
blood pressure and heart rate). During this period of recuperation, the body
stays on high alert until the traumatic incident has passed. If the stressful event
lasts for a lengthy period of time, the body will adjust to deal with the
increased degree of stress. The body will continue to release stress hormones,
which will maintain the body's physical response to stress. This initiates the
resistance stage, which is characterized by symptoms such as poor attention,
impatience, and frustration. The body will enter the fatigue stage if the
stressful event persists. Burnout, exhaustion, sadness, anxiety, and a lower
stress tolerance are all symptoms of this stage. As the stressful event
continues, the body's immune system weakens. This is due to the suppressive
effects of stress hormones on immune system cells.4

D. Introduction of Anxiety
Fear is an instinctive neurophysiological alert state defined by a fight or flight
reaction to a cognitive assessment of current or impending threat (real or perceived).
Anxiety is related to dread and emerges as a future-oriented emotional state
comprised of a complex cognitive, affective, physiological, and behavioral response
system involved with preparedness for expected dangerous events or circumstances.
Pathological anxiety is generated when there is an overestimation of the perceived
threat or an incorrect risk assessment of a scenario, resulting in excessive and
inappropriate responses.2

Norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid are regarded to

be important anxiety mediators in the central nervous system (GABA). Most
symptoms are mediated by the autonomic nervous system, particularly the
sympathetic nervous system.2

The amygdala is vital in regulating fear and anxiety. Patients suffering from anxiety
disorders have a heightened amygdala reaction to anxiety stimuli. The amygdala and
 limbic system are linked to prefrontal cortical areas, and anomalies in prefrontal-
limbic activity can be rectified by psychological or pharmaceutical therapies.2

E. Behavioral and Structural Adaptations to Stress and What Leads to Anxiety

Survival under harsh situations requires both behavioral and physiological stress
reactions. Rapid reactions to acute stress assist organisms in avoiding real damage as
well as coping with injuries if the threat cannot be averted. These quick responses,
however, have the potential to be deleterious if they are required to be repeated
regularly over lengthy periods of time in response to prolonged exposure to stressors
in risky circumstances. Chronic stress management will most likely necessitate
alternative approaches. Fear learning, for example, can improve prediction and
planning, boosting the chances of avoiding future stresses. Anticipated bodily
adaptations to better cope with harm can also be enabled by anticipatory danger.
Avoidance behaviors and recurrent physiological preparation, on the other hand,
might have negative bodily implications if prolonged or repeated for an extended
length of time. The ability to modify stress responses to changing contexts is crucial
for resilience, or the ability to recover from difficulties or stresses.5

Rapid learning is essential in unpleasant contexts because it allows an organism to

avoid or respond properly to previously encountered hazards (Do-Monte et al., 2015;
Ghosh and Chattarji, 2015). Fear learning generalization is similarly adaptive, since it
allows for the avoidance of hazards that have not before been encountered. Excessive
generalization, on the other hand, is maladaptive if it results in overly strong fear
reactions or occurs in unsuitable settings, interfering with more rewarding acts. Fear
of unfamiliar situations, for example, may be protective. However, it may increase
freezing and decrease exploration in rats to the point where it interferes with effective
food foraging, and it may diminish involvement in enjoyable activities or events in
people. Anxiety disorders are distinguished by a reduction in rewarding activities as a
result of inappropriate fear (Dunsmoor and Paz, 2015; Lissek, 2012; Luyten et al.,
2011). There is, thus, a balance or ideal degree of fear generalization for a specific
scenario, which is determined by the chance of experiencing adversity and reward
within the environment (Figure 2). Understanding and treating stress-related diseases
such as generalized anxiety disorder, post-traumatic stress disorder, and depressive
illness requires elucidating the brain circuits and processes that govern the extent of
fear generalization and mediate stress response optimization.5
 Fig. 2 To behave effectively in unfamiliar or unknown settings, reward seeking and
cautious or anxiety-like behavior must be harmonized. Signals indicating safety and
reward push behavior toward reward seeking, whereas cues indicating real or possible
dangers tilt the balance toward defensive or cautious responses such freezing or
approach-avoidance exploration. Based on the predictability of previous threats, new
neurons created in the adult dentate gyrus can tip the balance in either direction.
Stress and the anatomical alterations that ensue in the hippocampus bias the system
toward caution.5

Extreme threats, such as very powerful negative stimuli (e.g., intense shocks), which
may mimic the sort of traumatic event that might lead to PTSD, result in high degrees
of generalization, i.e., freezing to signals that are not linked with the shock (Ghosh
and Chattarji, 2015). This impact is non-associative, generalizing to stimuli that are
significantly distinct from those present during the painful experience, and it can be
evident even after only a few mild footshocks (Kamprath and Wotjak, 2004; Seo et
al., 2015).5

F. Diagnosis of Anxiety
Anxiety is a natural and necessary basic emotion that is required for individual
survival. Pathologically heightened anxiety can occur in numerous forms of mental
disease, not only anxiety disorders. Anxiety can also be a warning indication of
impending harm in somatic disorders such as myocardial infarction or hypoglycemia
in a diabetic patient; in such cases, a whole new treatment strategy is required. A
complete psychological and somatic assessment is required for any patient presenting
with pathologically high anxiety so that an underlying pulmonary (e1), cardiovascular
(e2), neurological (e3), or endocrine condition (eg, of the thyroid gland) (e4) may be
ruled out.6

The International Classification of Diseases (ICD-10) (3) classifies anxiety disorders

as phobic disorders, which include agoraphobia with (F40.00) or without panic
 disorder (F40.01), social phobia (F40.1), and specific phobias (F40.2), as well as other
anxiety disorders, which include panic disorder (F41.0), generalized anxiety disorder
(F41.1), and mixed anxiety and depression (F41.2) (table 1). Separation anxiety
disorder and selective mutism are now defined as anxiety disorders in the current
version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (e6),
which is the basic reference document for the taxonomy of mental diseases in the
United States. These were traditionally thought to be childhood and adolescent
ailments, but are now thought to be significant in adults as well.6

Table 2. Clinical manifestations of anxiety disorders according to ICD-10.6

Summary
We are subjected to a variety of stresses, including physical, environmental, physiological,
and psychological stressors. These stresses generate a variety of stress reactions in the body,
including psychological, physiological, and behavioral responses. When such stress persists
for an extended period of time, it creates a variety of health problems that impact the majority
of the body's systems. Fear and anxiety have biological roots, and the primary brain regions
and neural circuits involved in emotional information processing and behavior have been
identified. Even when dealing with such a fundamental feeling as fear, emotional and
cognitive processes cannot be separated. The cognitive fear of events and situations plays an
important role in emotional experiences and determines coping methods or defensive
mechanisms.

References

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https://www.tandfonline.com/doi/full/10.31887/DCNS.2002.4.3/tsteimer
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