The human stress system - the basics of stress

Chronic cortisolergic stress, i.e. prolonged severe (usually psychological) stress that is perceived as threatening or frightening, can cause all symptoms of ADHD. ⇒ ADHD symptoms are stress symptoms
Nevertheless, ADHD is different from chronic stress: stress symptoms go with the stressor, ADHD stays.
ADHD can have many different causes. Defects in the stress systems are one possible cause, which is why it is helpful to understand the human stress systems.

Humans react to stressful situations with a stress response that is controlled by various stress systems in the body. The most important of these are the CNS (brain and spinal cord), the HPA axis, the vegetative nervous system and the HSA axis. These stress systems regulate each other and form a fault-tolerant system that can also cope with the failure of individual components.
The brain can transmit signals both endocrine (chemical, slow) and neural (electrical, fast). The HPA axis (stress axis) is controlled endocrinally, while the autonomic nervous system (VNS) is controlled neurally. The HPA axis in particular plays an important role in the regulation of stress and is often overactivated in ADHD. People with ADHD often have a reduced basal cortisol level, while the phasic cortisol stress response can vary depending on the ADHD subtype.

Stress can be triggered psychologically or physically (infections, toxins, injuries). Uncontrollable stress and the risk of rejection or not belonging are particularly strong stressors. The stress response depends on various factors such as genes, epigenetic changes, environmental factors and the age of the individual.

The amygdala is a central instance for evaluating stressors and activates the various stress systems. The noradrenergic locus coeruleus regulates stress reactions as well as attention.

Stressors trigger a stress reaction chain that can escalate into four phases: Problem perception, alarm phase, resistance phase and exhaustion phase.
The pre-phase of stress is triggered by non-specific activation of neurons in the associative cortex of the PFC, which leads to noradrenergic activation of the central and autonomic nervous system.
During acute stress, the noradrenaline level in the brain rises, while chronic stress leads to a reduced release of cortisol.
The resistance and exhaustion phases of stress lead to permanent harmful changes in the stress systems.

• 1. The human stress system
  • 1.1. Central process and control of stress reactions
  • 1.2. Endocrine and neuronal signaling
  • 1.3. The most important stress regulation systems
    • 1.3.1. The central nervous system (brain and spinal cord, CNS)
      • 1.3.1.1. Noradrenaline 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 autonomic nervous system: sympathetic / parasympathetic nervous system
    • 1.3.3. The HPA axis (stress axis) of the body
    • 1.3.4. Cooperation between 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
      • 1.4.3.1. What is oxidative stress
      • 1.4.3.2. Oxidative stress and ageing
      • 1.4.3.3. Origin of ROS
      • 1.4.3.4. Positive and negative effects of ROS
      • 1.4.3.5. Oxidative stress and ADHD
      • 1.4.3.6. Methylphenidate and ROS
• 2. The stress reaction chain / stress phases
  • 2.1. Problem perception (pre-phase, stress phase 0)
  • 2.2. Alarm phase (stress phase 1: further increase in noradrenaline 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. Changed hormone and neurotransmitter levels depending on the stress phase
  • 3.1. Breakdown of the cortisol system during the stress phases
  • 3.2. Breakdown of neurotransmitter systems over the stress phases
    • 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 / not belonging
  • 4.3. Endocrine stress response and individual stress elements
• 5. Stress cessation

1. The human stress system¶

Descriptions of stress in various concepts have existed since the beginning 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) are listed by Pacák and Palkovit.²

Stress is a healthy reaction of the human organism to stressful situations. The stress reaction differs fundamentally according to whether the stressful situation is perceived as threatening/anxiety-provoking or not, as different stress systems are triggered.

Monoamines (dopamine, noradrenaline, serotonin) and neuropeptides play a decisive role 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 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 reaction is caused by the interaction of different areas of the brain.

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

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

1.2. Endocrine and neuronal signaling¶

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

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

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

More on this at ⇒ Neurotransmitters and stress

1.3. The most important 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 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 is to the neurotransmitters noradrenaline, CRH and cortisol, which are particularly relevant during stress: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 the sympathetic nervous system
• Dorsal raphe nuclei
  more on 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 boundaries
• Autonomic nervous system (VNS, also autonomous nervous system)
  • Sympathetic nervous system (sympathetic nervous system, 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 initially raised slightly. Both improve cognitive performance (ability to perceive and think).
If this does not solve the problem (the stressor is not eliminated), dopamine and noradrenaline levels continue to rise, which deactivates the PFC and transfers behavioral control to other brain regions. ⇒ Neurotransmitters during stress Noradrenaline 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 plays a central role in the regulation of the autonomic nervous system and controls it directly by means of¹⁰

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

This can have a direct impact:¹¹

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

The autonomic nervous system regulates:

• Adrenaline secretion
• Cortisol secretion
• Arterial blood pressure
• Heart rate
• Heart rhythm
• Stroke volume
• Cardiac output
• Vascular perfusion of the skeletal muscles
• Pupil reaction
• Salivation
• Breathing rate
• Breathing depth
• Renal blood flow
• Stomach movements
• Intestinal movements
• Systemic resistance in the cardiovascular system
• Structural myocardial damage to the heart

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

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

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

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

• Immune functions,¹³¹⁴ by means of
  • Direct neural influence on the parasympathetic and sympathetic nervous system (VNS)
  • Indirect neuroendocrine influence (e.g. the HPA axis)
• Heart disease¹⁵
  • ECG abnormalities
    • Disorders of the repolarization phase, identical to ischemic heart disease, but without any thrombotic occlusion of the coronary arteries
      • Prolongation of the QT interval
      • Lowering the ST line
      • Flattened or inverted (negative) T-waves
  • Cardiac arrhythmia
    frequently with
    • Intracerebral or subarachnoid hemorrhages
    • Ischemic cerebral infarctions
    • Epilepsy
  • Serum enzyme changes
  • Myofibril degeneration
    without stenosis of the coronary arteries, brain diseases are a common cause of sudden cardiac death due to myofibril degeneration
• Lung and respiratory diseases¹⁶
• Diabetes¹⁷
• Impairment of the perception of pain¹⁸

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

1.3.1.1. Noradrenaline and stress¶

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

• Slightly increased noradrenaline levels
  • Stimulate the function of the PFC
• Highly elevated noradrenaline levels
  • Switch off the PFC
    • Impaired analytical thinking
    • Impaired cognitive decision-making ability
    • 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 a reduction in dopamine levels in the nucleus accumbens in the striatum (reinforcement center).
• Long-term stress leads to a downregulation (reduction in the number of dopamine transporters and dopamine receptors in the PFC) and a deterioration in the effect of dopamine in the PFC.
• Long-term stress (despite reduced dopamine levels after downregulation) is associated 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 reactions.²²

More on this at ⇒ 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.

More on this at ⇒ Neurotransmitters and stress

1.3.1.3. Serotonin and stress¶

The dorsal raphe nuclei, in which serotonin is formed, have a stress-inhibiting function.²³

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

1.3.2. The autonomic nervous system: sympathetic / parasympathetic nervous system¶

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

• It is initially activated in the case of manageable stress without a threatening content (short-term stress, stressful situations or serious illness).
• The VNS mediates stress primarily through acetylcholine and adrenaline in the body. Adrenaline activates other areas of the body than cortisolergic stress. As adrenaline - like noradrenaline and unlike cortisol²⁴ - cannot cross the blood-brain barrier, adrenaline produced in the body acts solely on the body’s organs.
• Both short-term and long-term stress cause the
  • Release of arginine vasopressin (AVP).
  • Increase in prolactin in plasma
  • Increase in β-endorphin in the blood
    β-endorphin increases the release of dopamine. However, β-endorphin can only cross the blood-brain barrier to a small extent, which is why β-endorphin in the body can only have an indirect dopaminergic effect in the brain at best
• Oxytocin is an anti-stress hormone
• See here: ⇒ The autonomic nervous system: sympathetic / parasympathetic nervous system

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

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

The HPA axis is activated in uncontrollable stress situations. Several stress hormones (CRH, ACTH, cortisol) are released in succession through a network of the hypothalamus, pituitary gland and adrenal cortex, triggering the “ultimate” state of alert: now it’s a matter of sheer survival. The HPA axis triggers most stress symptoms. Stress symptoms are useful for the individual in the fight for survival.
⇒ Stress benefits - the survival-promoting purpose of stress symptoms

The cortisolergic response of the HPA axis occurs more slowly or later than the rapid adrenergic stress response of the autonomic nervous system. Its deactivation is also slower. The last of the three stress hormones released by the HPA axis, cortisol, also mediates the deactivation of the HPA axis at the end of the stress hormone chain. This is because stress is an exceptional state, a kind of turbo mode of the body and mind, which is only helpful in the short term and harmful in the long term.

As the HPA axis is essential for understanding stress and ADHD, we refer to the detailed description at ⇒ HPA axis The HPA axis / stress regulation axis Is referred to.

1.3.4. Cooperation between the VNS and HPA axis¶

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

The nucleus coeruleus, which contains most of the brain’s noradrenergic nerve cells and is part of the sympatho-adrenomedullary axis of the sympathetic nervous system (and thus the VNS), communicates intensively with the hypothalamus, which is the first increment of the HPA axis. The information travels 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 reactions.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 a high level of anxiety and fear. If the amygdala assesses situations as threatening, it gradually activates the various stress systems.

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 brain stem and / or forebrain.

• Activate limbic structures in the brain stem (bottom-up):
  • The HPA axis (HPA) via direct projections onto the paraventricular nucleus of the hypothalamus (PVN) and
  • The autonomic nervous system (ANS) via direct preganglionic projections.
• 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 the autonomic or neuroendocrine neurons (top-down regulation).
  Many of these intervening neurons are located in nuclei of the hypothalamus that also respond to homeostatic status, providing a mechanism by which descending limbic information can be modulated according to physiological status (middle management).²⁹
• Various 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 of these regions send to specific regions of
    • Brain stem
    • Hypothalamus
    • Bed nucleus of the stria terminalis (BST)
    • These regions in turn activate the medial paraventricular hypothalamus (PVN)
  • Limbic structures can modulate predicted stressors by prior activation of the PVN through interactions with reactive stress circuits. The superimposition of limbic input on brainstem and hypothalamic stress effects forms a hierarchical system that mediates both reflexive (reactive) and anticipated (anticipatory) 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 reactions.
It is activated by orexin and sends the noradrenaline it produces to a number of brain regions that are involved in stress systems.

• Stimulated by orexin
• Afferences (signals received) from:
  • MPFC
    • Constant stimulating input according to the activity level
  • Nucleus paragigantocellularis
    • Integrates autonomous stimuli and environmental stimuli
  • Nucleus prepositus perihypoglossalis
    • Controls horizontal and vertical eye movements, eye tracking movements and gaze fixation
  • Lateral hypothalamus
    • Produces orexin
• Produces noradrenaline
• Efferences (sends signals) to:
  • Amygdala
  • Hippocampus
  • Brain stem
  • 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 response of the HPA axis. However, after 4 weeks of chronic stress, the HPA axis response was fully restored despite deactivated LC.³² This indicates that the LC appears to mediate primarily 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

In the animal model, the HSA axis is activated in rats in enriched environments (EE), i.e. environments with a lot of social contact with other animals, plenty of stimulation through play opportunities and exercise (compared to socially isolated housing). However, EE also activate the VNS and the HPA axis without causing negative effects. This could possibly be due to the fact that short-term activation of the VNS and the HPA axis corresponds to a healthy lifestyle with activation/stimulation/relaxation. It is known that only permanent activation of the VNS and the HPA axis is harmful.

The activation of the HSA axis in the enriched environment caused a significant shrinkage of viral tumors.³⁴

1.4. Types of stress¶

There are different types of stressors.

1.4.1. Psychological stressors¶

Mental stressors can be divided into³⁶

• External stressors
  • Threat
  • New/Unusual/Unexpected
  • Uncertainty
  • Neglect
  • Exclusion
• Internal stressors
  • Patterns of thought
  • Negative reinforcement

1.4.2. Physical stressors¶

Physical stress is stress on the body, such as

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

1.4.3. Oxidative stress¶

1.4.3.1. What is oxidative stress¶

Oxidative stress is a condition caused by an excess of reactive oxygen species (ROS - reactive oxygen species) Characterized by an excess of reactive oxygen species. Oxidative stress is not triggered by psychosocial stress, but by illness or poor/unbalanced nutrition, for example.
Oxidative stress is involved in neurodegenerative processes in brain cells, among other things.³⁷³⁸

1.4.3.2. Oxidative stress and ageing¶

ROS are held responsible for the ageing of the body by the “Free Radical Theory of Ageing”^{3940 41 42 43 44} . This appears to be the most important of the hundreds of theories about ageing processes, although none of them has yet been generally accepted scientifically.⁴⁵
According to this theory, an increased metabolic rate leads to increased ROS formation, which causes cell damage that accumulates over time to the point where it overwhelms the antioxidant protection system and triggers dysfunction and apoptosis.

1.4.3.3. Origin of ROS¶

ROS are primarily produced by the mitochondrial respiratory chain and also as by-products of metabolic reactions in the cytoplasm, in the endoplasmic reticulum, in the plasma membrane and in peroxisomes. ROS can irreversibly damage vital cell molecules (e.g. DNA, proteins, lipids). If the natural redox balance is influenced in favor of oxidative conditions, this promotes ROS and thus molecular damage that can cause disease, aging and death. More oxidized proteins, DNA molecules and lipids are determined [Sohal et al. 1993, Stadtman 1992]. ROS are associated with the development of degenerative diseases [Alam et al. 1997a, Alam et al. 1997b, Coyle and Puttfarcken 1993]. Antioxidants [Vina et al. 1992] or overexpression of antioxidant enzymes [Orr and Sohal 1994] combat ROS and prolong life expectancy in Drosophila.⁴⁵
However, more recent publications show that antioxidants do not always achieve the expected positive results and sometimes even have unfavorable effects [Howes 2006, Le Bourg and Fournier 2004, Riccioni et al. 2007]

1.4.3.4. Positive and negative effects of ROS¶

In addition to harmful effects, ROS also have beneficial effects, e.g. in the case of cell degeneration to prevent cancer.⁴⁶

ROS and neurodegeneration
Positive effect of ROS: Fundamental importance for

• neuronal development
• synaptic plasticity
• Memory formation
• Energy supply
  Negative effect of ROS:
  Neurons have relatively low antioxidant activity and are therefore particularly susceptible to oxidative damage.
• Defects in the mitochondria can increase ROS generation and lead to an accumulation of lipid droplets that trigger neurodegeneration via activation of JNK and sterol-regulating element binding proteins (SREBP).⁴⁷
• Suppression of ROS via upregulation of the ferritin heavy chain by NF-kappa B inhibits TNF-α-induced apoptosis⁴⁸
• Reduction of ROS levels by PGC-1α increased antioxidant enzymes GPx1 and SOD2 could protect neurons from oxidative damage⁴⁸
• ROS can be increased by methylmercury⁴⁹ or manganese⁵⁰ and then have a neurotoxic effect
• In Down syndrome and Parkinson’s disease, increased ROS in the substantia nigra pars compacta lead to neuronal apoptosis of dopaminergic neurons. Antioxidants or catalase could prevent apoptosis ⁵¹

• Oxidative stress increases the expression of mRNA for acidic glial fiber protein, which leads to hyperactivation of astrocytes with subsequent damage to the astrocytes.³⁷⁵²

• NRROS could protect the central nervous system from EAE by reducing oxidative damage through the degradation of NOX2 at the endoplasmic reticulum⁵³
• CRH and mifepristone (the latter is a strong antagonist of glucocorticoid and progesterone receptors) protect neurons from cell death triggered by oxidative stress.⁵⁴⁵⁵

• CRH protects CRH receptor type 1 cells against cell death triggered by oxidative stress.⁵⁵ This protective function of CRH is achieved by an increase in the release of “nonamyloidogenic soluble amyloid β-precursor protein” and a suppression of “nuclear factor-κB”.⁵⁶

1.4.3.5. Oxidative stress and ADHD¶

An imbalance between oxidants and antioxidants with increased melatonin levels in the blood serum has been found in ADHD.⁵⁷ Melatonin is said to counteract oxidative stress.⁵⁸
One study found significant changes in oxidative stress and antioxidant proteins (MAD, SOD, PON1, ARES, TOS, TAS, OSI) in both children and adults with ADHD.⁵⁹⁶⁰

1.4.3.6. Methylphenidate and ROS¶

MPH promoted ROS formation in endothelial cells by activating Rac1-dependent NADPH oxidase (NOX) and c-Src activation at the plasma membrane.⁶¹
MPH at low doses reduced oxidative stress and thus protected against hypoxia-induced mitochondrial damage in human neuroblastoma cells⁶²
MPH reduced ROS in C. elegans mitochondria after 5 days, although ROS were still elevated in the first few days⁴⁵

2. The stress reaction chain / stress phases¶

Stressors trigger a stress reaction chain that can escalate in four phases.⁶³ 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 shown below depicts the successive increments 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 throughout the day (basal = tonic cortisol level) and the cortisol stress response (phasic change in the cortisol level in response to acute stress).
In ADHD - as is often the case with chronic stress⁶⁴ - the basal cortisol level is reduced (mild tonic hypocortisolism). This affects all ADHD subtypes.
The phasic (short-term) cortisol stress response is often excessive in ADHD-I and melancholic and psychotic depression (phasic hypercortisolism), while in ADHD-HI and atypical and 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 stop at the alarm phase of stress. In this respect, the following description should rather be seen as an example for the case of developing hypocortisolism.

2.1. Problem perception (pre-phase, stress phase 0)¶

• Perceptions that are not covered by experience (stored memory content)
• → cause non-specific 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 system
• → moderate release of noradrenaline
  • Activates PFC (thinking ability increased)
• → Even very mild stress increases the release of dopamine in healthy people in the PFC⁶⁵
  • Supports filtering of irrelevant information (focused attention = increased perceptual ability)
  • Supports the development/reinforcement of existing neuronal circuits that were helpful in solving problems
• If this does not solve the problem, further noradrenergic escalation occurs
  → Transition to alarm phase

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

• Further increase in noradrenaline levels in the brain
  • → thereby activating the hypothalamus (first increment of the HPA axis)
    • Hypothalamus activates several stress systems
      • CRH (corticotropin-releasing hormone) release from the hypothalamus
        • → activates anterior pituitary = second increment of the HPA axis
      • Oxytocin and vasopressin release from the hypothalamus
        • → Activates the vegetative nervous system
  • → Highly elevated noradrenaline levels disrupt the function of the PFC.⁶⁶⁶⁷ Severe stress impairs the function of the PFC.⁶⁸
• a. Vegetative nervous system:
  • Oxytocin and vasopressin release from the hypothalamus
  • Neuronal (via nerves = electrical = fast) to the pituitary gland
  • → activates the posterior lobe of the pituitary gland
    The posterior lobe is nerve tissue that temporarily stores the stress hormones oxytocin and vasopressin (ADHD) released by the hypothalamus and releases them into the blood at the appropriate time; vasopression is not relevant to stress, but regulates the body’s fluid volume via kidney function.
    • Increased thirst and the resulting increase in water intake are frequently observed symptoms of stress.⁶⁹ As 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.⁷⁰ Fluid intake significantly reduces the stress response.⁷¹
      However, thirst is not described as a typical ADHD symptom. Thirst is only sometimes described as a mild side effect of MPH in connection with ADHD.
• b. HPA axis:
  • Vasopressin and CRH release from the hypothalamus
  • Endocrine (via blood = slowly) to the pituitary gland
  • → thereby activating 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 the adrenal cortex (3rd increment of the HPA axis) to release cortisol
      • Β-endorphin:
        can manipulate dopaminergic excitatory conduction. Dopamine release in the synaptic cleft is increased.
      • In addition, release of non-stress-relevant hormones:
        • FSH (follicle stimulating hormone)
          promotes egg maturation in women, sperm development in men
        • TSH (thyroid stimulating hormone):
          stimulates thyroid function
        • LH (luteinizing hormone):
          regulates the female cycle together with FSH
        • Prolactin:
          stimulates growth of the mammary glands and milk production
        • Growth hormone (GH)
          promotes growth before puberty and growth of the organs.
    • Vasopressin, which is released during short-term and long-term stress, and the activated sympathetic nervous system also promote the release of ACTH
  • → thereby activating the adrenal cortex
    • Glucocorticoid release (stress hormones, especially cortisol)
      • Acute stress (alarm phase) increases the cortisol level in phase 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 term.⁷²
      • Uncontrollable stress leads to a sharp increase in dopamine and noradrenaline in the PFC in healthy people⁷³⁷⁴⁷⁵
        In life-threatening situations, the individual benefits more from the speed of reactions (as provided by the older, posterior brain areas) than from the accuracy of the slow analytical processes of the PFC for fight or flight. Behavioral control is therefore outsourced to these older posterior parts of the brain, which react instinctively, spontaneously and faster.
• Effects of the autonomic nervous system and HPA axis
  • → Destabilization of existing neuronal circuits through cortisol
    • Advantage:
      • Memory content that is less helpful for problem solving can be erased more easily (established paths can be abandoned)
    • Disadvantage:
      • Dissolution of existing successful problem-solving strategies
      • Possible solution finding is energy-intensive, as it has to be recreated and can no longer or not yet be retrieved automatically
  • → Short-term stimulation of gluconeogenesis
    • Increase in blood sugar level
  • → increased availability of carbohydrates
    • Increase in blood sugar level
  • → Activation of various peripheral organs
    • Increase in blood pressure
    • Oxygen-rich blood to skeletal muscles
    • Reduced blood supply to skin and intestines
    • Coagulation capacity of the blood is increased
      • Advantage: less blood loss in the event of injuries
      • Disadvantage: increased risk of thrombosis and heart attack
    • Suppression of inflammatory defense mechanisms by cortisol
      • Advantage: no short-term loss of energy 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 in different areas absorb glandotropic hormones from the blood, which causes the release of effector hormones.
      • Thyroid gland
        → Thyroxine release
      • Gonads
        → Release of oestrogen 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 A
        → Renin release
      • Gastrointestinal tract
        → Gastrin secretion
    • TH1/TH2 shift
      Suppression of inflammatory reactions (TH1)
      Strengthening the defense against foreign bodies (TH2)
  • If this does not solve the problem: Transition to resistance phase

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

• Increased release of mineralocorticoids as a late effect of constant ACTH release
• Glucocorticoid formation (cortisol) is suppressed
  • → Lack of suppression of the inflammatory reactions increased by CRH
    • Consequences: more frequent inflammatory problems
      e.g. stomach or intestinal ulcers, neurodermatitis, asthma etc.
  • → Lack of control of foreign bodies
    • Consequences: 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
  • Noradrenaline deficiency
  • Dopamine deficiency
  • Serotonin deficiency
• Shrinkage (atrophy) of the adrenal cortex
  • Cortisol deficiency (basal hypocortisolism)

This model is just one example of a 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. In our opinion, this is not a question of the stress phases, but a question of the direction in which the collapsing stress system falls.

Which stressors trigger which stress reactions in an individual and via which (neuronal/neurobiological) pathway depends on genes, epigenetic changes and environmental factors.⁷⁶ The age of the individual is also likely to play a role.

What they all have in common is that prolonged (chronic) stress in the resistance and exhaustion phase leads to profound and lasting harmful changes.
A detailed description of the various individual damage mechanisms can be found at
⇒ Stress damage - effects of prolonged stress.

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

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

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

Unloaded condition:⁷⁷

• In the morning: ∅ 7.5 ng/ml
• Midday: ∅ 3 ng/ml, short midday high of 4 ng/ml
• In the evening: ∅ 1.5 ng/ml

Acute stress (not permanent):⁷⁷

• In the morning: ∅ 12 ng/ml
• Midday: ∅ 3 ng/ml, short midday high of 4 ng/ml
• In the evening: ∅ 1.5 ng/ml

Chronic stress (not yet too long lasting, not yet adapted):⁷⁷

• In the morning: ∅ 9 ng/ml
• Midday: ∅ 8 ng/ml, short midday high of 10 ng/ml
• In the evening: ∅ 3 ng/ml

Chronic stress (long-lasting, already adapted - burnout):⁷⁷

• In the morning: ∅ 4 ng/ml
• Midday: ∅ 2.5 ng/ml, short midday high of 3 ng/ml
• In the evening: ∅ 1.5 ng/ml

Similar results were obtained in a study on changes in the cortisol stress response over the duration of depression in adolescents. New onset depression correlated with an increased cortisol response, while 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 is reversed when depressive problems persist over longer periods of time.⁷⁸

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 in ADHD at the same time: dopamine levels are systematically reduced in ADHD (compared to non-affected individuals). During acute stress, dopamine levels are initially elevated; prolonged exposure to too much dopamine (noradrenaline, serotonin) leads to downregulation, i.e. neurotransmitter levels fall - however, the stress symptoms not only remain, but intensify, as the stress regulation that healthy hormone and neurotransmitter systems can provide is impaired.

3.2. Breakdown of neurotransmitter systems over the stress phases¶

Similar changes to the cortisol levels over the various stress phases are apparently also evident in neurotransmitter systems. While acute stress correlates with increased dopamine and noradrenaline levels, chronic stress - at least for certain stressors - is associated with reduced noradrenaline 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, which impair the dlPFC.⁷⁹ Chronic stress causes reduced dopamine levels in the PFC, which impair the function of the working memory in the dlPFC and thus the executive functions.⁸⁰

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

An example of long-lasting changes in the noradrenergic system due to chronic stress is the noradrenaline receptor hypothesis of depression, which is described below by Fuchs, Flügge (2004):⁸¹

1. Stress increases the concentration of noradrenaline.
2. A permanently increased noradrenaline level initially reduces the number of alpha2-adrenoceptors in the target regions of the noradrenergic nerve cells (downregulation).
   Downregulation occurs presynaptically (at the noradrenergic terminals) and postsynaptically (e.g. glutamatergic neurons).
3. Presynaptic downregulation impairs the negative feedback inhibition of noradrenaline release. Therefore, noradrenergic neurons remain permanently activated during stress activation after downregulation of noradrenaline receptors.
4. The permanent activation leads to a depletion of the noradrenaline nerve cells, so that the amount of noradrenaline now decreases.
5. In response to this, the postsynaptic (noradrenergic) alpha2-adrenoceptors can upregulate again.

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

• New⁸²
• Unpredictable⁸²
• Uncontrollable⁸³⁸²
• Ambiguous⁸²
  or
• Is associated with the risk of social rejection.⁸³

4.1. Uncontrollable¶

In particular, a threat to self-esteem that is perceived as uncontrollable leads to stress and consequently to increased cortisol release.⁸⁴⁸⁵ Noise or films, on the other hand, trigger cortisolergic stress less frequently, as they are rarely uncontrollable and threaten self-image or existence.

Nowadays, uncontrollable stress can be caused, for example, by divorce (rejection, exclusion from the family), serious illnesses (which address exactly the same stress systems from the body side as psychological stress from outside), bullying (exclusion from the group) or serious problems at school or work. Children who are unable to make friends in their new school after moving 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 difference and find it more difficult to make friends who think the same way. Giftedness typically leads to the development of specific character traits, which can lead to a much more serious feeling of being different than the slightly faster thinking. Find out more at ⇒ Giftedness and ADHD.

4.2. Risk of rejection / not belonging¶

Not belonging or being rejected is the strongest stressor that can be reproduced in studies. (Meta-analysis of k = 208 studies)⁸⁶ The background is once again the millions of years of imprinting of our stress systems from the time before sedentarization. Being excluded from a nomadic group was associated with a high risk of death - even more so for women 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 reactions such as “Tend and Befriend”.

4.3. Endocrine stress response and individual stress elements¶

The cortisolergic and adrenergic stress response is strongest and most long-lasting when the factors of uncontrollability and the threat of social rejection are combined.⁸³

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 ability to influence it). The adrenaline stress level is also dependent on the activation factors mentioned, but unlike noradrenaline, which stabilizes blood pressure, it is susceptible to habituation.⁸⁷
Adrenaline and noradrenaline levels react not only to unpleasant excitement, but also to pleasant excitement. A stimulating comedy raises adrenaline levels in healthy people just as much as a horror movie, with a particularly anxiety-inducing film achieving the highest levels.⁸⁸ A winning game of bingo increases adrenaline levels even more than a cognitive performance test under time pressure.⁸⁹

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

A stress-induced increase in cortisol is most pronounced in the afternoon.⁸³

Psychological tests address (psycho)social stress (public speaking / loud mental arithmetic in front of a judgmental group), to which cortisol responds preferentially. This addresses the motive of affiliation. In the first test run, 80% of the test subjects have an elevated cortisol level. Repeated tests reduce the level by reducing novelty and unpredictability, so that by the 3rd to 5th round only a third of the test subjects still have an elevated cortisol level - but with identical subjective stress perception and identical other parameters (adrenaline, noradrenaline, pulse).⁹⁰

However, there was a significant difference in tests of vocabulary to be learned in this state. The test subjects without a cortisol increase had perfect memory performance, while the third of the test subjects with a cortisol increase (and of these again mainly the female members) also showed considerable memory losses.
This effect could be reproduced in other test subjects by administering cortisol.⁹⁰ Contrary to the assumption that this is due to an inhibition of recall processes⁹¹, there is barely any impairment of recall if the cortisol is given after the vocabulary has been learned or shortly before it is recalled, which is why it can be assumed that cortisol impairs the learning process / storage process.

The subjects with elevated cortisol levels were more insecure, less extroverted and tended to be more neurotic in personality questionnaires.⁹⁰ This also indicates a correlation between introversion and increased cortisol stress response, which seems to occur more frequently in ADHD-I.

5. Stress cessation¶

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

The stress hormone cortisol, which (after the stress hormones CRH and ACTH) is the last stress hormone to be released at the end of the chain of the HPA axis, has the task of activating certain emergency behaviors that make sense under stress (⇒ Stress benefits - the survival-promoting purpose of stress symptoms), cortisol also has another function: it shuts down the stress systems and thus ensures that cortisol itself is no longer released.
This termination is important because stress hormones are neurotoxic, i.e. poisonous, if exposed for too long.

In ADHD-HI, this termination of the stress state is impaired. People with ADHD-HI and ADHD-C (with hyperactivity) often have too low a cortisol response to acute stressors, which consequently does not switch off the stress axis properly.

In contrast, people with ADHD-I (without hyperactivity) have a cortisol response that is too high, which causes the stress systems to switch off too early / too often. The norepinephrine response, which is too high at the same time, causes the PFC to switch off too quickly/too frequently.

More about CRH, cortisol and the cortisol stress responses in ADHD at ⇒ The HPA axis / stress regulation axis.