The human stress systems - basics of stress

All ADHD symptoms are “completely normal” stress symptoms. Acute cortisolergic stress, i.e. severe (usually psychological) stress that is perceived as threatening or frightening, can cause all symptoms of ADHD.
⇒ ADHD symptoms are stress symptoms

• 1. The stress systems of humans
  • 1.1. Central process and control of stress reactions
  • 1.2. Endocrine and neuronal signal transduction
    • 1.2.1. Endocrine information transmission
    • 1.2.2. Neural information transmission
  • 1.3. The main stress regulation systems
    • 1.3.1. The central nervous system (brain and spinal cord, CNS)
      • 1.3.1.1. Norepinephrine and stress
      • 1.3.1.2. Dopamine and stress
        • 1.3.1.2.1. Dopamine level changes due to stress
        • 1.3.1.2.2. Different dopamine level changes depending on the stressor
        • 1.3.1.2.3. Dopaminergic neurological correlates of various stress responses
      • 1.3.1.3. Serotonin and stress
    • 1.3.2. The vegetative (autonomic) nervous system: sympathetic / parasympathetic nervous system
    • 1.3.3. The HPA axis (stress axis) of the body
    • 1.3.4. Collaboration of the VNS and HPA axis
    • 1.3.5. The amygdala in the limbic system: the stress conductor
      • 1.3.5.1. Limbic system activates the stress systems
    • 1.3.6. Locus coeruleus
    • 1.3.7. Hypothalamic-sympathetic-adipocyte axis (HSA axis)
  • 1.4. Types of stress
    • 1.4.1. Psychological stressors
    • 1.4.2. Physical stressors
    • 1.4.3. Oxidative stress
• 2. The stress response chain / stress phases
  • 2.1. Problem perception (preliminary phase, stress phase 0)
  • 2.2. Alarm phase (stress phase 1: further noradrenaline increase activates VNS and HPA axis - acute stress)
  • 2.3. Resistance phase (stress phase 2 - chronic stress)
  • 2.4. Exhaustion phase (stress phase 3 - stress that has become chronic)
• 3. Altered hormone and neurotransmitter levels depending on the stress phase
  • 3.1. Breakdown of the cortisol system over the stress phases
  • 3.2. Breakdown of neurotransmitter systems over the stressful periods
    • 3.2.1. Changes in the dopaminergic system due to chronic stress
    • 3.2.2. Changes in the noradrenergic system due to chronic stress
• 4. Stress triggers (stressors)
  • 4.1. Uncontrollable
  • 4.2. Risk of rejection / of not belonging to the group
  • 4.3. Endocrine stress response and individual stress elements
• 5. Stress Termination

1. The stress systems of humans¶

Descriptions of stress in a wide variety of concepts have existed since the dawn of medical science.¹ The various stress theories and the most important contributions to their further development by Bernard (1878), Cannon (1929), Selye (1974), Mason (1971), Hennesy and Levine (1979), Krantz and Lazar (1987), Munck and Guyre (1986), Levine and Ursin (1991), Weiner (1991), Chrousos and Gold (1992), Goldstein (1995), McEwen (1998) list Pacák and Palkovit.²

Stress is a healthy reaction of the human organism to stressful situations. The stress reaction basically differs according to whether the stressful situation is perceived as threatening/anxious or not, as different stress systems are addressed in the process.

Monoamines (dopamine, norepinephrine, serotonin) and neuropteptides in particular are crucially involved in the human stress response.³

The human body has several systems that regulate stress. These form a complex network that complements and influences each other. This creates a fault-tolerant system that can also cope with the failure of individual genes or parts of the stress regulation systems in such a way that the survival of the individual is not endangered.

1.1. Central process and control of stress reactions¶

A stress response occurs through an interaction of different areas of the brain.

The first step is an integration of sensory information by the PFC to cognitively evaluate its meaning and importance and provide the appropriate coping strategies.
This triggers emotional responses via the limbic system, which in turn activate physiological stress systems such as the HPA axis and the autonomic nervous system.⁴⁵⁶

A summary of the brain regions involved is given below under 1.3.

1.2. Endocrine and neuronal signal transduction¶

The brain can trigger signals in two different ways: endocrine (slow) and neural (fast).

1.2.1. Endocrine information transmission¶

Endocrine information is transmitted by hormones that are transported via the blood. This transmission path is slow.⁷
The HPA axis is endocrine driven.

1.2.2. Neural information transmission¶

Neural information is transmitted through direct nerve connections. Within the nerves, information is transported as electrical signals and amplified or weakened (inhibited) by neurotransmitters at the junctions of the nerves, the synapses. This transmission path is fast.⁸
The autonomic nervous system (VNS) is controlled neurally.

For more on this topic see ⇒ Neurotransmitters and stress

1.3. The main stress regulation systems¶

The human body has several systems that regulate stress. These form a complex network that complements and influences each other. This creates a fault-tolerant system that can also cope with the failure of individual genes or parts of the stress regulation systems in such a way that the survival of the individual is not endangered.

The strongest binding to the neurotransmitters norepinephrine, CRH and cortisol, which are particularly relevant in stress, is shown:⁹

• MPFC
• PVN, paraventricular nucleus
  • Produces oxytocin
  • Produces antidiuretic hormone (low)
  • Produces CRH
• Amygdala
  • ⇒ The amygdala - the stress conductor
• Lateral septum
  • Is inhibited by GABA
  • Is stimulated by glutamate
• Hippocampus
• Locus coeruleus
  more about the locus coeruleus see below
  • Is stimulated by orexin
  • Produces noradrenaline
  • Stimulates sympathetic nervous system
• Dorsal raphe nuclei
  more about the dorsal raphe nuclei see below
  • Produces serotonin
• Nucleus tractus solitarii

The human nervous system is divided into

• Central nervous system (CNS, brain and spinal cord) and peripheral nervous system (PNS, body)
  The PNS is a spatially delimited part of the CNS without functional delineation
• Autonomic nervous system (VNS, also autonomic nervous system)
  • Sympathetic nervous system (sympathetic, activating)
  • Parasympathetic nervous system (vagus or parasympathetic nervous system, inhibitory)
• Somatic nervous system (voluntary nervous system, enables conscious perception)
• Enteric nervous system (ENS, digestive nervous system

Of these, the CNS and VNS are particularly involved in stress regulation.

1.3.1. The central nervous system (brain and spinal cord, CNS)¶

In the case of mild challenges, the dopamine level in the PFC and the noradrenaline level are raised slightly at first. Both improve cognitive performance (ability to perceive and think).
If this does not solve the problem (does not remove the stressor), dopamine and norepinephrine levels continue to rise, which deactivates the PFC and transfers behavioral control to other brain regions. ⇒ Neurotransmitters during stress Norepinephrine activates the other stress systems, in particular the autonomic nervous system and the HPA axis (stress axis).
Deactivation of the PFC further disinhibits the HPA axis, which is controlled by the PFC.

The cortex has a central role in the regulation of the autonomic nervous system and directly controls it by means of¹⁰

• Anterior cortex
• Posterior cortex
• Orbitofrontal cortex
• Island bark (insula)
• MPFC
• Motor cortex
• Somatosensory cortex

This can directly influence:¹¹

• Sympathetic nervous system
  • Activating
  • Inhibiting
• Parasympathetic
  • Activating
  • Inhibiting

The autonomic nervous system regulates:

• Adrenal secretion
• Cortisol secretion
• Arterial blood pressure
• Heart rate
• Heart rhythm
• Beat volume
• Cardiac output
• Vascular perfusion of skeletal muscles
• Pupil response
• Salivation
• Breathing rate
• Breathing depth
• Kidney blood flow
• Stomach movements
• Bowel movements
• Systemic resistance in the cardiovascular system
• Structural myocardial damage of the heart

Psychological stress alters the functional connectivity of the vmPFC with different brain areas involved in stressor processing:¹²

• Increased functional connectivity of the vmPFC during psychological stress:
  • Insula
  • Amygdala
  • Anterior cingulate cortex
  • Dorsal attention center
  • Ventral attention center
  • Frontoparietal network (continuing to increase during the recovery phase)
• Decreased functional connectivity of the vmPFC during psychological stress:
  • Posterior cingulate cortex
  • Thalamus
  • Default-Mode-Network

Except for connectivity to frontoparietal networks, this corresponded to pre-stress values in the post-stressor recovery phase.

Brain injuries can therefore cause not only sensory, motor and cognitive disorders, but also a wide variety of physical disorders, e.g.

• Immune functions,¹³¹⁴ using
  • Direct neural influence on parasympathetic and sympathetic nervous system (VNS)
  • Indirect neuroendocrine influence (e.g. the HPA axis)
• Heart disease¹⁵
  • ECG Abnormalities
    • Disturbances of the repolarization phase, identical to ischemic heart disease but without any thrombotic occlusions of the coronary arteries
      • QT interval prolongation
      • Lowering of the ST line
      • Flattened or inverted (negative) T-waves
  • Cardiac arrhythmias
    often with
    • Intracerebral or subarachnoid hemorrhage
    • Ischemic cerebral infarctions
    • Eplilepsy
  • Serum enzyme changes
  • Myofibril degeneration
    without stenosis of coronary arteries, brain diseases are a common cause of sudden cardiac death due to myofibril degeneration
• Lung and respiratory diseases¹⁶
• Diabetes¹⁷
• Impairment of pain perception¹⁸

In addition, the cognitive assessment of situations by the cortex at the same time causes emotional reactions, which indirectly control the autonomic body processes via the amygdala and the hypothalamus.¹⁹

1.3.1.1. Norepinephrine and stress¶

In the CNS, stress is primarily modulated by norepinephrine:²⁰

• Slightly elevated norepinephrine levels
  • Stimulate the function of the PFC
• Strongly elevated norepinephrine levels
  • Switch off the PFC
    • Analytical thinking impaired
    • Cognitive decision-making ability impaired
    • Control of the HPA axis impaired
  • Strengthen the sensorimotor and affective regions of the brain (which intensifies perception and emotion)

1.3.1.2. Dopamine and stress¶

Stress directly activates the dopaminergic system in the brain (CNS),²¹ which is centrally impaired in ADHD.

1.3.1.2.1. Dopamine level changes due to stress¶

• Short-term stress massively increases the dopamine level in the PFC.
• Increased dopamine levels in the PFC probably lead to decreased dopamine levels in the nucleus accumbens in the striatum (reinforcement center).
• Long-term stress leads to a deterioration of the effect of dopamine in the PFC via downregulation (reduction in the number of dopamine transporters and dopamine receptors in the PFC).
• Long-term stress is associated (despite reduced dopamine levels after downregulation) with overexcitation of the PFC, which leads to a reduction in dopamine levels in the nucleus accumbens in the striatum (reinforcement center).

1.3.1.2.2. Different dopamine level changes depending on the stressor¶

Different stressors cause different dopamine responses.²²

For more on this topic see ⇒ Neurotransmitters and stress

1.3.1.2.3. Dopaminergic neurological correlates of various stress responses¶

Different stress responses have different dopaminergic neurological correlates.
This applies to ADHD as well as comorbid disorders.

For more on this topic see ⇒ Neurotransmitters and stress

1.3.1.3. Serotonin and stress¶

The dorsal raphe nuclei, where serotonin is produced, have a stress-inhibiting function.²³

• Limiting excessive stress response
• Via 5-HT-1a autoreceptor inhibition of
  • Fear
  • Panic
  • Appetite
  • Emesis
  • Addiction
  • Impulsivity
• Via 5-HT-2a receptor stimulation of
  • Mood
  • Perception
  • Sexuality
  • Sleep
  • Regeneration
  • Vascular tone
  • Breathing
  • Body temperature

1.3.2. The vegetative (autonomic) nervous system: sympathetic / parasympathetic nervous system¶

Sympathetic (stimulating) and parasympathetic (inhibiting) nervous systems together regulate a balance of activation and relaxation.

• It is initially activated during manageable stress without threat content (short-term stress, exertion situations or severe illness).
• The VNS mediates stress primarily through acetylcholine and epinephrine in the body. Adrenaline activates different areas of the body than cortisol stress. Since adrenaline - like noradrenaline and unlike cortisol²⁴ - cannot cross the blood-brain barrier, adrenaline generated in the body acts solely on the body’s organs.
• Short-term as well as long-lasting stress cause the
  • Release of arginine vasopressin (AVP).
  • Increase of prolactin in plasma
  • Increase of β-endorphin in the blood
    β-Endorphin increases dopamine release. However, β-endorphin can only cross the blood-brain barrier to a small extent, which is why β-endorphin in the body can at best have an indirect dopaminergic effect in the brain
• Oxytocin is an anti-stress hormone
• See for this: ⇒ The autonomic nervous system: sympathetic / parasympathetic nervous system

1.3.3. The HPA axis (stress axis) of the body¶

The HPA axis is the most involved stress system in ADHD.

The HPA axis is activated during uncontrollable stress situations. Through a network of hypothalamus, pituitary gland and adrenal cortex, several stress hormones (CRH, ACTH, cortisol) are released one after the other, triggering the “ultimate” state of alarm: now it’s a matter of naked survival. The HPA axis triggers most stress symptoms. Stress symptoms are useful in the fight for survival for the individual.
⇒ Stress utility-the survival-promoting purpose of stress symptoms

The cortisolergic response of the HPA axis is slower or later than the rapid adrenergic stress response of the autonomic nervous system. Its deactivation is also slower. The last of the 3 stress hormones secreted by the HPA axis, cortisol, also mediates the reactivation of the HPA axis at the end of the stress hormone chain. This is because stress is a state of emergency, a kind of turbo mode of the body and mind that is only helpful in the short term and harmful in the long term.

Because the HPA axis is essential for understanding stress and ADHD, we refer to the detailed discussion at ⇒ The HPA axis/stress regulation axis Referred to.

1.3.4. Collaboration of the VNS and HPA axis¶

The two stress systems, the VNS and the HPA axis, have different tasks due to their different temporal response (VNS: neuronally driven = fast, HPA axis: hormonally driven = slow) and complement each other.

The nucleus coeruleus, which contains most of the noradrenergic neurons in the brain, and which is part of the sympato-adrenomedullary axis of the sympathetic nervous system (and thus the VNS), communicates intensively with the hypothalamus, which is the first stage of the HPA axis. In this process, the information runs in both directions.²⁷

1.3.5. The amygdala in the limbic system: the stress conductor¶

The amygdala (part of the limbic system) is the central instance for evaluating stressors for their threat and triggers the brain’s stress responses.²⁸ The amygdala receives information from the entire body and brain and evaluates it for its threat potential. Damage to the amygdala in the direction of hypersensitivity causes high anxiety and fearfulness. If the amygdala evaluates situations as threatening, it activates the various stress systems in stages.

Parts of the amygdala are:

• Lateral amygdala (LA)
• Basolateral amygdala (BLA) → calculated action
• Central medial amygdala (CMA) → impulse-driven emotional behavior

If the amygdala is inhibited by medication, the stress/ADHD symptoms also disappear.

The amygdala receives information from many organs and systems about current stressors.
⇒ The amygdala - the stress conductor.

1.3.5.1. Limbic system activates the stress systems¶

Stressors activate limbic structures in the brainstem and/or forebrain.

• Activate limbic structures in the brainstem (bottom-up):
  • Via direct projections to the nucleus paraventricularis of the hypothalamus (PVN) the HPA axis (HPA) and
  • Via direct preganglionic projections the autonomic nervous system (ANS).
• Limbic regions of the forebrain, on the other hand, have no direct connections with the HPA axis or the ANS. They use intervening synapses to control autonomic or neuroendocrine neurons (top-down regulation).
  Many proportion of these intervening neurons are located in nuclei of the hypothalamus that also respond to homeostatic status, yielding a mechanism by which descending limbic information can be modulated according to physiological status (middle management).²⁹
• Different limbic brain regions influence the activation of the HPA axis³⁰
  • MPFC
  • Central amygdala (CeA)
  • Ventral subiculum (vSUB)
  • Medial amygdala (MeA)
  • Lateral septum (LS)
    None of these regions directly address the paraventricular hypothalamus (PVN). All projections from these regions send to specific regions of
    • Brainstem
    • Hypothalamus
    • Bed nucleus of the stria terminalis (BST)
    • These regions, in turn, activate the medial paraventricular hypothalamus (PVN)
  • Limbic structures can modulate predicted stressors through prior activation of the PVN via interactions with reactive stress circuits. The superposition of limbic input on brainstem and hypothalamic stress effects forms a hierarchical system that mediates both reflexive (reactive) and anticipatory (anticipated) stress responses via direct PVN projections.
    The projections of these limbic areas overlap considerably, although not completely. The overall stress response therefore depends on the interaction of these structures. ³⁰

1.3.6. Locus coeruleus¶

The locus coeruleus regulates attention and is an important mediator of stress responses.
It is activated by orexin and sends the norepinephrine it produces to quite a few brain regions involved in stress systems.

• Stimulated by orexin
• Afferents (received signals) from:
  • MPFC
    • Constant stimulating input according to the activity level
  • Nucleus paragigantocellularis
    • Integrates autonomous and environmental stimuli
  • Nucleus prepositus perihypoglossalis
    • Controls horizontal and vertical eye movements, gaze following movements and gaze fixation
  • Lateral hypothalamus
    • Produces orexin
• Produces noradrenaline
• Efferences (sends signals) to:
  • Amygdala
  • Hippocampus
  • Brainstem
  • Spinal cord
  • Cerebellum
  • Cortex
  • Hypothalamus
  • Tectum (dorsal mesencephalon)
  • Thalamus
  • Ventral tegmentum

Chronic activation of the locus coeruleus appears to reduce the stress response³¹

Chemical deactivation of the locus coeruleus acutely and briefly reduced the HPA axis response. However, after 4 weeks of chronic stress, the HPA axis response was fully restored despite deactivated LC.³² This suggests that the primarily appears to mediate acute stress responses.

1.3.7. Hypothalamic-sympathetic-adipocyte axis (HSA axis)¶

The HSA axis is activated during eustress, i.e. positively perceived stress (flow).³³³⁴³⁵

The HSA axis is addressed in animal models of rats in so-called enriched environments (EE), i.e. environments with a lot of social contact with other animals, ample stimulation through play opportunities and exercise (compared to socially isolated housing). However, EE also activate the VNS and HPA axis, but without causing negative effects. This could possibly be because short-term activations of the VNS and HPA axis correspond to a healthy lifestyle of activation/demand/relaxation. It is known that only a permanent activation of the VNS and the HPA axis is harmful.

In any case, activation of the HSA axis in the enriched environment caused significant shrinkage of virally induced tumors.³⁴

1.4. Types of stress¶

There are different types of stressors.

1.4.1. Psychological stressors¶

Psychological stressors are divided into³⁶

• External stressors
  • Threat
  • New/unfamiliar/unexpected
  • Uncertainty
  • Neglect
  • Exclusion
• Internal stressors
  • Thinking patterns
  • Negative reinforcement

1.4.2. Physical stressors¶

Physical stress is strain on the body, such as.

• Cold
• Heat
• Noise
• Physical action
• Injuries
• Chemical effects
  • Poisons

1.4.3. Oxidative stress¶

Another form of stress is so-called oxidative stress. This is triggered less by psychosocial stress than, for example, by illness or poor/unbalanced nutrition. Oxidative stress is a metabolic condition in which an excess of reactive oxygen compounds (ROS - reactive oxygen species) Is formed or present. Oxidative stress is also involved in neurodegenerative processes of brain cells.³⁷³⁸

• Expression of mRNA for glial acidic protein is increased by oxidative stress, leading to hyperactivation of astrocytes with subsequent astrocyte damage.³⁷³⁹
• CRH and mifepristone (the latter is a potent antagonist of glucocorticoid and progesterone receptors) protect against neuronal cell death due to oxidative stress.⁴⁰⁴¹
• CRH protects CRH receptor type 1 cells against cell death caused by oxidative stress.⁴¹ This protective function of CRH occurs through an increase in the release of “nonamyloidogenic soluble amyloid β-precursor protein” and suppression of “nuclear factor-κB”.⁴²

In ADHD, an imbalance between oxidants and antioxidants has been found with increased levels of melatonin in the blood serum.⁴³ Melatonin is thought to counteract oxidative stress.⁴⁴
One study found significant alterations in oxidative stress and antioxidant proteins (MAD, SOD, PON1, ARES, TOS, TAS, OSI) in both children and adults with ADHD.⁴⁵⁴⁶

2. The stress response chain / stress phases¶

Stressors trigger a stress response chain that can escalate in four phases.⁴⁷ If a stressor exceeds a certain level of intensity, the next higher level is activated.¹

• Problem perception (preliminary phase)
• Alarm phase
• Resistance phase
• Exhaustion phase

The model presented below depicts the successive temporal stages of the stress response in a schematic, model-like manner.
However, the statement that a breakdown of the stress systems is accompanied by hypocortisolism must be viewed in a differentiated manner. A distinction must be made between the cortisol level over the day (basal = tonic cortisol level) and the cortisol stress response (phasic change in cortisol level to acute stress).
In ADHD - as is often the case with chronic stress⁴⁸ - basal cortisol levels are reduced (mild tonic hypocortisolism). This affects all ADHD subtypes.
The phasic (short-term) cortisol stress response is often excessive in ADHD-I and melancholic as well as psychotic depression (phasic hypercortisolism), whereas in ADHD-HI and atypical as well as bipolar depression there is often a flattened cortisol stress response (phasic hypocortisolism).
ADHD-I, melancholic and psychotic depression are, according to this understanding, not disorders that would have stopped at the alarm phase of stress. In this respect, the following presentation is rather to be seen as an example for the case of an emerging hypocortisolism.

2.1. Problem perception (preliminary phase, stress phase 0)¶

• Perceptions that are not covered by empirical values (stored memory contents)
• → cause nonspecific activation of neurons of the associative cortex of the PFC
• → Propagation into the limbic system
• → noradrenergic activation of the central (CNS) and autonomic (sympathetic) nervous systems
• → moderate noradrenaline release
  • Activates PFC (thinking ability increased)
• → Even very mild stress increases dopamine release in healthy individuals PFC⁴⁹
  • Supports filtering of irrelevant information (focused attention = perceptual ability increased)
  • Assists in the regeneration / reinforcement of existing neuronal circuits that were helpful in problem solving
• If this does not solve the problem, further noradrenergic escalation will occur
  → Transition to alarm phase

2.2. Alarm phase (stress phase 1: further noradrenaline increase activates VNS and HPA axis - acute stress)¶

• Further increased norepinephrine level in the brain
  • → thereby activation of the hypothalamus (first stage of the HPA axis)
    • Hypothalamus activates multiple stress systems
      • CRH (corticotropin-releasing hormone) release by the hypothalamus
        • → activates anterior pituitary = second stage of the HPA axis
      • Oxytocin and vasopressin release from the hypothalamus
        • → activates vegetative nervous system
  • → Strongly increased norepinephrine level interferes with the function of the PFC.⁵⁰⁵¹ Severe stress impairs the function of the PFC.⁵²
• a. Vegetative nervous system:
  • Oxytocin and vasopressin release from the hypothalamus
  • Neuronal (via nerves = electrical = fast) to pituitary gland
  • → activates posterior pituitary lobe
    Posterior lobe is nerve tissue that caches the stress hormones oxytocin and vasopressin (ADH) released by the hypothalamus and releases them into the blood at the appropriate time; vasopression is not stress-related, but regulates the body’s fluid volume via renal function.
    • Increased thirst and a resulting increase in water intake are frequently observed symptoms of stress.⁵³ Since stress aims to increase blood pressure in order to optimally prepare the body for fight or flight, increased fluid intake is an immediately useful tool.⁵⁴ Fluid intake significantly reduces the stress response.⁵⁵
      However, thirst is not described as a typical ADHD symptom. Thirst is only sometimes described as a mild side effect of MPH in the context of ADHD.
• b. HPA axis:
  • Vasopressin and CRH release from the hypothalamus
  • Endocrine (via blood = slow) to pituitary gland
  • → thereby activation of the anterior lobe of the pituitary gland
    Anterior lobe is glandular tissue that produces and releases hormones
    • Release of glandotropic hormones into the blood
      • ACTH
        → Activates adrenal cortex (3rd stage of HPA axis) to release cortisol
      • Β-Endorphin:
        can manipulate dopaminergic excitation conduction. Dopamine release in synaptic cleft is increased.
      • In addition, the release of hormones that are not relevant to stress:
        • FSH (follicle stimulating hormone)
          promotes oocyte maturation in women, sperm development in men
        • TSH (thyroid stimulating hormone):
          stimulates thyroid function
        • LH (luteinizing hormone):
          together with FSH regulates the female cycle
        • Prolactin:
          stimulates growth of mammary glands and milk production
        • Growth Hormone (GH)
          promotes growth before puberty and growth of organs.
    • Vasopressin, which is released during short-term and long-term stress, and the activated sympathetic nervous system also promote ACTH release
  • → thereby activation of the adrenal cortex
    • Glucocorticoid release (stress hormones, especially cortisol)
      • Acute stress (alarm phase) increases cortisol levels phasically to activate problem-solving behavior
      • Chronic stress increases the level of cortisol and other stress hormones tonically and phasically (hypercortisolism)
        • Cortisol is neurotoxic in the long run.⁵⁶
      • Uncontrollable stress leads to large increases in dopamine and norepinephrine in the PFC in healthy individuals⁵⁷⁵⁸⁵⁹
        In life-threatening situations, for fight or flight, the individual benefits more from the speed of responses (as provided by the older, posterior brain areas) from the accuracy of the slow analytical processes of the PFC. Behavioral control is therefore outsourced to these older posterior brain parts, which respond instinctively, spontaneously, and more quickly.
• Effects of Vegetative Nervous System and HPA Axis
  • → through cortisol destabilization of existing neuronal circuitry
    • Advantage:
      • Memory contents that are less helpful for problem solving can be deleted more easily (well-worn paths can be left)
    • Disadvantage:
      • Dissolution of existing successful problem solving strategies
      • Possible solution finding is energy-consuming, since it has to be created anew and can no longer or not yet be retrieved again automatically
  • → short-term stimulation of gluconeogenesis
    • Increase in blood glucose level
  • → increased availability of carbohydrates
    • Increase in blood glucose level
  • → Activation of various peripheral organs
    • Blood pressure increase
    • Oxygenated blood to skeletal muscles
    • Blood supply skin and viscera reduced
    • Blood clotting ability is increased
      • Advantage: less blood loss in case of injuries
      • Disadvantage: increased risk of thrombosis and heart attack
    • Suppression of inflammatory defense mechanisms by cortisol
      • Advantage: no short-term energy loss due to immune reaction
      • Disadvantage: weakening of the cell-bound specific immune defense (increased risk of infection); still detectable weeks after stress experience
    • Hormone receptors of different areas take up glandotropic hormones from blood, which causes release of effector hormones.
      • Thyroid gland
        → Thyroxine release
      • Gonads
        → Release of estrogen and progesterone (women) or testosterone (men)
      • Adrenal cortex
        → Cortisol release
      • Pancreas
        → digestive secretion (pancreatic juice), glucagon, insulin, somatostatin, pancreatic polypeptide, ghrelin
      • Thymus
        → Release of thymosin, thymopoietin I and II
      • Kidneys
        → Renin release
      • Gastrointestinal tract
        → Gastrin release
    • TH1/TH2 shift
      Suppression of inflammatory reactions (TH1)
      Strengthening of the foreign body defense (TH2)
  • If this does not solve the problem: Transition to resistance phase

2.3. Resistance phase (stress phase 2 - chronic stress)¶

• Increased secretion of mineralocorticoids as a late effect of constant ACTH secretion
• Glucocorticoid formation (cortisol) is suppressed
  • → Lack of suppression of inflammatory responses increased by CRH
    • Consequence: more frequent inflammatory problems
      e.g. stomach or intestinal ulcers, neurodermatitis, asthma etc.
  • → Lack of foreign body control
    • Consequence: Allergies can now occur more frequently
• If this does not solve the problem: Transition to exhaustion stage

2.4. Exhaustion phase (stress phase 3 - stress that has become chronic)¶

• Breakdown of hormonal control
  • Norepinephrine deficiency
  • Dopamine Deficiency
  • Serotonin Deficiency
• Shrinkage (atrophy) of the adrenal cortex
  • Cortisol deficiency (basal hypocortisolism)

This model is merely an example of one possible type of stress system breakdown. In some people, a breakdown of the stress systems is accompanied by a flattened endocrine stress response (as shown here) and in others by an exaggerated endocrine stress response. It is our impression that this is not a question of the stress phases, but a question of which direction the collapsing stress system falls.

Which stressors trigger which stress responses in an individual through which (neuronal/neurobiological) pathway depends on genes, epigenetic changes and environmental factors.⁶⁰ In addition, the age of the individual is likely to play a role.

Common to all pathways is that prolonged (chronic) stress in the resistance and exhaustion phase leads to profound permanent harmful changes.
A detailed description of the manifold individual damage mechanisms can be found under
⇒ Stress damage - effects of prolonged stress.

3. Altered hormone and neurotransmitter levels depending on the stress phase¶

3.1. Breakdown of the cortisol system over the stress phases¶

Stress has different phases. Young (acute) stress has a different cortisol diurnal pattern (basal cortisol levels) than chronic or long-lasting adapted stress.

Unloaded condition:⁶¹

• Morning: ∅ 7.5 ng/ml
• Noon: ∅ 3 ng/ml, short midday peak to 4 ng/ml
• Evening: ∅ 1.5 ng/ml

Acute stress (not permanent):⁶¹

• Morning: ∅ 12 ng/ml
• Noon: ∅ 3 ng/ml, short midday peak to 4 ng/ml
• Evening: ∅ 1.5 ng/ml

Chronic stress (not yet too long lasting, not yet adapted):⁶¹

• Morning: ∅ 9 ng/ml
• Noon: ∅ 8 ng/ml, short midday peak to 10 ng/ml
• Evening: ∅ 3 ng/ml

Chronic stress (long lasting, already adapted - BurnOut):⁶¹

• Morning: ∅ 4 ng/ml
• Noon: ∅ 2.5 ng/ml, short midday peak to 3 ng/ml
• Evening: ∅ 1.5 ng/ml

Identical results were obtained in a study of changes in the cortisol stress response over the duration of depression in adolescents. New-onset depression correlated with an increased cortisol response, whereas chronic depression correlated with a flattened cortisol stress response. The results of this study suggest that depressive problems initially increase cortisol responses to stress, but that this pattern reverses when depressive problems persist over longer periods of time.⁶²

The development of cortisol levels in adapted long-term chronic stress shows a downregulation of the cortisol system. This is likely to correspond to what happens to the dopamine system at the same time in ADHD: dopamine levels are systematically reduced in ADHD (compared to non-affected individuals). In acute stress, dopamine levels are initially elevated; prolonged exposure to too much dopamine (norepinephrine, serotonin) leads to downregulation, i.e., neurotransmitter levels drop - the stress symptomatology, however, not only remains but intensifies because the stress regulation that healthy hormone and neurotransmitter systems can provide is impaired.

3.2. Breakdown of neurotransmitter systems over the stressful periods¶

Comparable changes as with cortisol levels over the different stress phases are apparently also evident in neurotransmitter systems. While acute stress correlates with increased dopamine and norepinephrine levels, chronic stress - at least for certain stressors - is associated with decreased norepinephrine and dopamine levels.

3.2.1. Changes in the dopaminergic system due to chronic stress¶

Acute stress causes limitations in executive functions via increased dopamine levels that impair the dlPFC.⁶³ Chronic stress causes decreased dopamine levels in the PFC, which impair working memory function in the dlPFC and thus executive functions.⁶⁴

3.2.2. Changes in the noradrenergic system due to chronic stress¶

An example of long-lasting changes in the noradrenergic system caused by chronic stress is the noradrenaline receptor hypothesis of depression, which is presented below based on the description by Fuchs, Flügge (2004):⁶⁵

1. Stress increases the concentration of norepinephrine.
2. When norepinephrine levels are permanently elevated, the number of alpha2-adrenoceptors in the target regions of noradrenergic neurons is initially reduced (downregulation).
   Downregulation occurs presynaptically (at noradrenergic terminals) as well as postsynaptically (e.g., glutamatergic neurons).
3. Presynaptic downregulation impairs negative feedback inhibition of norepinephrine release. Therefore, noradrenergic neurons remain permanently activated during stress activation after downregulation of noradrenaline receptors.
4. Sustained activation leads to depletion of the norepinephrine neurons, so that the amount of norepinephrine now decreases.
5. In response, postsynaptic (noradrenergic) alpha2-adrenoceptors may upregulate.

4. Stress triggers (stressors)¶

Stressors can be infections or injuries, as well as psychological stress.
Environmental influences are primarily perceived as stressors when a situation is

• New⁶⁶
• Unpredictable⁶⁶
• Uncontrollable⁶⁷⁶⁶
• Ambiguous⁶⁶
  or
• Is associated with the risk of social rejection.⁶⁷

4.1. Uncontrollable¶

In particular, a threat to self-esteem that is perceived as uncontrollable leads to stress and subsequently to increased cortisol release.⁶⁸⁶⁹ Noise or movies, on the other hand, trigger cortisolergic stress less frequently, since they are rarely uncontrollable and threaten self-image or existence.

In today’s world, uncontrollable stress can be caused, for example, by divorce (rejection, exclusion from the family), serious illnesses (which from the body side address exactly the same stress systems as external psychological stress), bullying (exclusion from the group) or serious problems at school or work. Children who do not fit in after moving to a new school or who are bullied in their class experience themselves existentially as outsiders and not belonging. (Unrecognized) gifted children are often bullied because of their specific otherness and find it harder to think alike and therefore less likely to connect. Highly giftedness typically leads to the expression of specific character traits, which can lead to a much more serious sense of otherness than slightly faster thinking. For more, see ⇒ Giftedness and ADHD.

4.2. Risk of rejection / of not belonging to the group¶

Not belonging, being excluded is the strongest stressor there is. The background is once again the million-year-old imprint on our stress systems from the time before sedentarization. Being excluded from a nomadic group was associated with a high risk of death - for women even more than for men, who were more often trained as hunters and warriors and could therefore live alone for a few days. This is probably why women have specific stress responses such as “tend and befriend.”

4.3. Endocrine stress response and individual stress elements¶

The cortisolergic and adrenergic stress response is strongest and longest lasting when the factors of uncontrollable and threatened social rejection combine.⁶⁷

The release of adrenaline by the sympathetic nervous system correlates linearly with the subjective perception of stress in healthy subjects and passively received stress (without the possibility of influencing it oneself). The adrenaline stress level is also dependent on the activation factors mentioned. but unlike the blood pressure-stabilizing norepinephrine, habituation-sensitive.⁷⁰
Adrenaline and noradrenaline levels respond not only to unpleasant excitement but also to pleasant excitement. A stimulating comedy raises adrenaline levels in healthy individuals just as much as a horror film, with a particularly anxiety-provoking film achieving the highest levels.⁷¹ A profitable bingo game raises adrenaline levels even more than a cognitive performance test under time pressure.⁷²

Novice skydivers have a 10-fold increase in cortisol levels immediately before their very first jump. With further jumps, this level decreases, but remains elevated before each jump.

In the afternoon, a stress-induced increase in cortisol is most pronounced.⁶⁷

Psychological tests address social stress (public speaking/loud mental arithmetic in front of a group judging this) to which cortisol responds preferentially. This addresses the motive of affiliation. On the first test run, 80% of subjects have elevated cortisol levels. Test repetition reduces novelty and unpredictability, so that only one third of the subjects have an elevated cortisol level in the third to fifth test run - but with identical subjective stress perception and identical other parameters (adrenaline, noradrenaline, pulse).⁷³

However, a significant difference was found in tests of vocabulary to be learned in this state. The subjects without cortisol increase had a perfect memory performance, while the third of the subjects with cortisol increase (and of these again mainly the female members) also showed considerable memory losses.
This effect could be reproduced in other subjects by cortisol administration.⁷³ Contrary to the assumption that this was due to an inhibition of retrieval processes⁷⁴, hardly any retrieval impairments are shown when cortisol is given only after the vocabulary has been learned or shortly before it is retrieved, which is why it can be assumed that cortisol impairs the learning process / memorization process.

The subjects with elevated cortisol levels were more self-confident, less extroverted, and tended to be more neurotic in personality questionnaires.⁷³ This also suggests a correlation between introversion and elevated cortisol stress response, which seems to be more common in ADHD-I.

5. Stress Termination¶

Human stress systems are designed to cope with short-term emergency situations. For this purpose, power reserves are activated and emergency measures are set in motion.
However, activating the stress systems for too long is harmful. Anyone who runs at “130%” permanently will break down from this overload.

The stress hormone cortisol, which (after the stress hormones CRH and ACTH) is secreted as the last stress hormone at the end of the chain of the HPA axis, has, in addition to the task of activating certain emergency behaviors that are useful during stress (⇒ Stress utility-the survival-promoting purpose of stress symptoms), it also has another task: cortisol shuts down the stress systems again, thereby causing cortisol itself to stop being secreted as well.
This termination is important because stress homones are neurotoxic, i.e. toxic, when exposed for too long.

In ADHD-HI, this termination of the stress state is impaired. ADHD-HI and ADHD-C sufferers (with hyperactivity) often have too low a cortisol response to acute stressors, which subsequently fails to properly shut down the stress axis.

ADHD-I sufferers (without hyperactivity), on the other hand, have too high a cortisol response, which causes the stress systems to shut down too early / too often. The parallel too high norepinephrine response causes a too fast / too frequent shutdown of the PFC.

For more on CRH, cortisol, and the cortisol stress responses in ADHD, see ⇒ The HPA axis/stress regulation axis.