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1. Stress by age at exposure - early childhood stress

1. Stress by age at exposure - early childhood stress

Early childhood stress increases susceptibility to mental health problems such as ADHD, depression, anxiety and addiction1

Early childhood stress causes changes in cortisol concentrations and cortisol metabolism.

  • Girls with a history of sexual abuse were found to have higher cortisol levels and altered cortisol concentrations in their saliva.
  • Early childhood stress (especially if chronic) can lead to increased cortisol concentrations in the blood.
  • Rats that were separated from their mothers at an early age or received less care still show an increased basal cortisol level as adults, an increased release of cortisol in response to acute stress, increased activity of the HPA axis (stress axis) and more stress symptoms.

Early childhood stress causes various changes in the brain that can last a lifetime. This particularly affects the areas of the brain that are responsible for stress response and emotional processing. The hippocampus, which is responsible for memory and the regulation of the stress hormone cortisol, shows an altered receptor density as a result of early childhood stress. Epigenetic changes in the glucocorticoid receptor gene NR3C1 can lead to a reduced number of cortisol receptors and thus to permanently increased cortisol levels in the brain.
The dopaminergic system, which is responsible for reward processing, is altered by early childhood stress. The motivation to pursue rewards can decrease along with dopamine levels in the striatum. The serotonin balance in the brain can be disrupted, which impairs neuronal development and emotion regulation. Early childhood stress can downregulate the sympathetic nervous system.
Prenatal maternal stress affects the migration and maturation of GABAergic cells and reduces the number of GABA-A and benzodiazepine receptors, which impairs cortical functions. A high level of maternal affection can reverse these changes.

Early stress causes further

  • an increased susceptibility to oxidative stress
  • an altered immunological stress response
  • epigenetic changes that influence gene expression
  • Shortened telomeres and reduced telomerase activity
  • a reduced brain volume in adulthood
  • Changes in the blood-brain barrier
  • an altered sensitivity to sedative hypnotics
  • increased startle reflex.

Stress in early childhood and adolescence (puberty) can also influence the remission of ADHD, with high levels of stress being associated with a more severe progression of ADHD into adulthood.

1.1. Stress during certain phases of brain development is particularly harmful

During the

  • prenatal development
  • Infancy
  • Childhood
  • Adolescence (puberty)2

people are particularly vulnerable to stressors. During these critical periods, stressors can have lifelong effects such as persistent cacostasis (dyshomeostasis). During these periods, individuals are also particularly susceptible to a favorable environment that can trigger hyperstasis and lead to the development of resistance to stressors in adulthood.3
Therefore, there is a considerable difference between stress occurring during a developmental phase of a brain region and stress occurring outside this phase (especially after the end of brain development, in humans at around 24 years of age).


  • Epigenetic demethylation of the FKPB5 gene, which modulates the sensitivity of glucocorticoid receptors4 is only mediated by stress during the differentiation and proliferation phase of neurons, but no longer in mature neurons.5
  • If excessive stress occurs during the developmental phase of the HPA axis, this increases the sensitivity of the HPA axis by permanently reducing the threshold values for the onset of the stress response.6 This impairs the ability to respond appropriately to stress7 and can lead to pathologically altered reactions to stressors later in life (including anxiety disorders, depression, autism and schizophrenia).

An example from the animal world: a certain species of bird lives by collecting and hiding nuts. For one year, an animal needs around 10,000 nuts, the hiding places of which it has to remember. These memory processes are carried out by the hippocampus. These birds have an above-average sized hippocampus. The hippocampus of birds experiences a developmental spurt between the 60th and 100th day of life. Animals that were only fed nut meal during these days were unable to take advantage of this developmental boost. Their hippocampus remained smaller than that of other specimens. In addition, they were unable to develop the ability to hide and find the required number of nuts for the rest of their lives, even if they were fed nuts from the 100th day of life.

The dopaminergic and noradrenergic systems, which are particularly important for attention, motor skills and stress resistance, develop especially in the first years of life (from conception to around 3 years of age) and again in middle adolescence. Negative environmental influences (stress) are therefore particularly harmful to the dopaminergic and noradrenergic systems during this period.

This is done in several ways, among others:

  • Early stress causes defective development of the dopaminergic pathways of the nucleus accumbens.8
  • Children who were exposed to a stressful environment or insecure attachment in the first 6 years of life suffer permanent damage in dopaminergic and serotonergic regions of the brain.9

Based on the description by Rensing et al. of the two-hit model, according to which mental disorders such as anxiety disorders, depression, autism and schizophrenia can be traced back to damage in adolescence that affects stress systems that have already been damaged,10 it would be conceivable to regard ADHD as the result of the first hit.
The assumption of ADHD as a first hit for other disorders may be contradicted by a study that found no increased specificity of symptoms of a disorder with increasing disorder severity.11

Stress levels during puberty can lead to an increase in early childhood stress levels.12 Another study shows that adults who reported more than five ADHD symptoms from their childhood were more likely than average to develop mental disorders or addiction.13

1.2. Age at exposure to stress determines type of mental disorder

It is not only the type and intensity of early childhood stress, but also the timing of the stress that determines the later disorder pattern. This is due to the fact that the development of the mammalian brain follows a specific chronological sequence. The individual brain regions do not develop simultaneously, but in their own time windows. In one phase of development, the respective brain regions are considerably more susceptible to external disorders.

  • Cortisol treatment during pregnancy reduced the sensitivity of corticoid receptors in the PFC of newborn monkeys, with the timing of cortisol administration determining in which parts of the PFC this occurred. In adult monkeys, reduced receptor sensitivity due to cortisol administration was no longer observed.14
  • Severe maternal anxiety in pregnancy during the 12th to 22nd week after the last menstrual period significantly increased the risk of ADHD-HI, while severe anxiety during the 32nd to 40th week did not increase the risk.15 In contrast, a study found no increased psychiatric disorders at age 9 in children of women exposed to one month of repeated civilian rocket fire during the 2006 Lebanon War.16 It is possible that one month of repeated stress is not a sufficiently intense stressor.
  • The developmentally oldest brain regions in the brain stem, which control the basic mechanisms of life and which develop first, are susceptible to very early disorders, which then often end fatally.
    Cortical areas of the brain that are not essential for survival and that develop later in time are susceptible to disorders that occur at slightly later stages of development.17
  • The specific effects of prolonged exposure to stress on the brain, behavior and cognition depend on the timing and duration of exposure to stress and, in part, on an interaction between gene effects and early childhood exposure to stress. These differences may explain why stress leads to different mental disorders at different times of life.18
  • Traumatic experiences before the age of 12 (such as the loss of a parent through death or permanent separation) increase the risk of a later depressive disorder, while traumatic experiences afterwards increase the risk of PTSD1920
  • Traumatic experiences before the age of 6 showed different dexamethasone/CRH test results than traumatic experiences at a later age.21
  • Prolonged emotional maltreatment in childhood correlated (as the only type of maltreatment) with a deviating (here: reduced) cortisol response to acute stressors with increasing adulthood.22
  • Sexual abuse at the age of 3 to 5 or at the age of 11 to 13 reduced the volume of the hippocampus, while sexual abuse at the age of 14 to 16 reduced the volume of the PFC.23
  • Extensive and long-term monitoring of 733 persons with ADHD with various personality disorders showed that the different intensity and timing of early childhood stress also contributes to the differentiation of the disorders.24 All of the people with ADHD were victims of early childhood stress: 73% of the 733 participants reported early childhood abuse, 82% early childhood neglect.
  • Changes in dopaminergic transmission in the mesolimbic, mesocortical and nigrostriatal systems caused by stress and high glucocorticoid concentrations prenatally and in the first years of life are probably determined by the ontogenetic developmental state of these brain regions at the time of stress exposure.25
  • The type and timing of early childhood stress exposure, for example, are likely to differentiate the environmental development of ADHD and borderline.26

The main developmental periods in which the respective brain regions are particularly vulnerable are (in years of life)27

  • Amygdala left: 0.5 to 2 years
  • Hippocampus: 3-528 and 11-14 years
  • Dorsal anterior cingulate cortex: 7-9 and 17-x years
  • Interiorer long fasciculus: from 7 years
  • Thalamus: 7-9 and 13-15 years
  • Corpus callosum: 9-10 years28
  • Ventromedial PFC: 8-10 and 14-16 years
  • Amygdala right: from 10 years
  • Visceral cortex: from 11 years of age
  • PFC (volume): 8-15 years29 14-16 years28

Gender-specific differences had to be taken into account. In girls, the amygdala developed much earlier than in boys, in whom an increase in amygdala volume could still be observed in adulthood.30

1.3. Early childhood stress

Early stress increases the risk of mental disorders.3132 Childhood emotional, physical or sexual abuse as well as trauma cause a long-lasting (beyond the period of abuse) profound disorder of stress regulation.33 There is some evidence that children whose mothers were exposed to particular stress during pregnancy have a persistently increased vulnerability to mental disorders.34
Children of women exposed to one month of repeated civilian rocket fire during the 2006 Lebanon War were not found to have increased psychiatric disorders at 9 years of age.16 This suggests that one month of repeated stress is not a sufficiently chronic stressor to damage the unborn child.

Rat pups separated from their mother at an early age have a long-lasting increased physiological and behavioral stress response to further stressors. The threshold for the onset of the stress response is reduced.35 The same applies to rat pups whose mothers showed weak nursing behavior.3637
A study of adopted persons with ADHD also addresses the question of how much of ADHD is inherited and how much is acquired.38

Even with early childhood stress, it depends on the degree to which it is beneficial or detrimental. Very brief handling (removing baby rats from their mother by holding them in the hand) is a beneficial stimulus, mainly because it increases the rate of maternal licking and grooming. Prolonged periods of separation of newborn rats from the mother are stressful, especially because they attenuate maternal licking and grooming,39 which is associated with oxytocin release.

1.3.1. Behavioral changes due to early stress

Early childhood stress affects the brain and body for a lifetime. For example, early physical or sexual abuse causes lifelong behavioral and pathophysiological problems.4041 Similarly, cold and indifferent families or chaos in the home environment lead to lasting emotional problems in children.4243 ADHD and PTSD most common disorders in childhood stress

ADHD and PTSD / PTSD are the most commonly diagnosed disorders in sexually abused children. There is a high degree of symptom overlap and comorbidity between ADHD, PTSD and sexual abuse.44
Early childhood stress, especially adverse care experiences such as child abuse (MALT), is a risk factor for ADHD4546 47 48 , but also other psychopathologies such as ASD48, anxiety, depression and addiction. Childhood abuse was found to triple the risk of ADHD.49 Risk of depression increased by early stress

Early childhood stress changes brain structure and brain function and increases the risk of depression later in life.5051 PTSD/PTBS risk increased by early stress

Early stress increases the risk of later post-traumatic stress disorder,5051 Obesity and cardiovascular disease risk increased by early stress

Early stress increases the risk of obesity and cardiovascular disease.5253 Risk of stress intolerance increased by early stress

Early stress increases the likelihood of increased subjective sensitivity to stress in adulthood, which is associated with an increased risk of anxiety disorders and depression.54

The development of increased sensitivity to stress appears to be gene-dependent. Early childhood stress increases stress resilience, exploration and less anxious behavior in male Cdh13 + / + - and Cdh13 +/- mice. In mice with Cdh13 - / -, however, early childhood stress caused delayed habituation, no reduction in anxiety-like behavior and reduced fear extinction.55 Risk of attention and learning problems increased by early stress

Early childhood (non-sexual) maltreatment impairs attention at the age of 14 and 21.56

Impaired latent learning and attention deficit due to early childhood stress correlates with changes in the cholinergic system in relation to the muscarinic and nicotinic receptors.57

Spatial learning and memory problems due to early childhood stress correlate with neurophysiological changes in the brain

  • NMDA receptor58
  • GABA-A receptor58
  • Serotonergic system59
  • Hippocampus: impairment of neurogenesis59 Risk of aggression disorder increased by early stress

The social isolation of rodents in the first few days after weaning causes increased aggression,58 linked to various neurophysiological correlates:

  • Noradrenergic system, beta-2-adrenoceptor6061
  • Neurosteroid system
    • Allopregnanolone6263
  • GABAergic system
    • GABA-B-1a receptor64
  • Serotonergic system
    • 5HT-2C receptor6566
  • Glutamatergic system
    • AMPA receptor66 Risk of hyperactivity increased by early stress

The social isolation of rodents in the first few days after weaning causes increased motor activity,6758 linked to various neurophysiological correlates:

  • Dopaminergic system
    • PFC68
    • Nucleus accumbens68
      • Reduced dopamine level in the tissue, increased dopamine turnover69
    • Striatum
      • Reduced dopamine level in the tissue, increased dopamine turnover69
  • Serotonergic system68
    • Nucleus accumbens
      • Reduced basal serotonin turnover67
  • Glutamatergic system
    • AMPA receptor70 Increased risk of anxiety disorders due to early childhood stress

Early childhood stress causes anxiety memory deficits,58, which are neurophysiologically linked to

  • Cholinergic system
    • Muscarinic receptor7172
  • Signaling systems associated with neuroplasticity71
  • Egr-1 system72 Impaired social behavior and early childhood stress

Early childhood stress causes deficits in social behavior that are neurophysiologically linked to the dopaminergic system and there to the D1 receptor.71

1.3.2. Neurophysiological changes due to early stress

Exposure to early childhood stress39

  • Activates the stress response systems and changes their molecular organization, which alters their sensitivity to response and reaction
  • Influences myelination, neural morphology, neurogenesis and synaptogenesis
  • Causes permanent functional consequences, such as
    • Attenuated development of the left hemisphere
    • Reduced feedback between right and left hemisphere
    • Increased electrical irritability within the circuits of the limbic system
    • Reduced functional activity of the cerebellar vermis.
  • Increased risk for the development of e.g.
    • PTSD
    • Depression
    • Borderline
    • Dissociative identity disorder
    • Drug abuse.

The various brain regions differ in their sensitivity, which depends in part on genetics, gender, time, development rate and density of the glucocorticoid receptor.39 Early stress makes the HPA axis (stress axis) more sensitive

Early childhood stress “programs” the HPA axis for life,7339 by means of epigenetic mechanisms.74

A comprehensive meta-analysis of 210 studies on biochemical substances (biomarkers) in ADHD indicated that the hypothalamic-pituitary-adrenal axis (HPA axis) is affected or dysregulated in ADHD (in addition to the brain’s monoamine system).75

Prenatal maternal stress affects the child’s brain and behavior. Stressful life events, natural disasters, maternal anxiety or depression increase the risk of emotional, behavioral and/or cognitive problems in the child, such as depression, anxiety, ADHD of conduct disorder. Studies on the biological correlates and mediators of these findings suggest that the HPA axis plays a role in mediating the effects of maternal stress on the fetal brain and that maternal stress is associated with changes in the limbic and frontotemporal networks and the functional and microstructural connections that link them. Maternal stress correlates with a thinner cortex and enlarged amygdala in children.76 Prenatal maternal stress increases the risk of premature birth and shortened telomere length. Early stress alters endocrine stress responses of the HPA axis

Permanent changes in the HPA axis in the unborn child may be the key mechanism that explains the link between prenatal stress, adverse birth outcomes (particularly low birth weight) and increased susceptibility to various diseases later in adulthood.

  • Stress before birth and into early childhood has a potentially lifelong impact on HPA axis responses in psychological and pharmacological terms.777879808182838485
  • In adulthood, there are significant correlations between childhood trauma, psychiatric symptoms in adulthood and HPA axis responses to psychological and pharmacological stress.868782
  • Interruptions in care during infancy and chronic stress alter the later stress response of the HPA axis and cause increased vulnerability to mental disorders.88
  • In humans, early experiences of stress also lead to permanent damage to the stress regulation systems, making them particularly susceptible to mental disorders as a result.8990 Change in the CRH system

Rats separated from their mother at an early age or less cared for by their mother showed91

  • More than doubled CRH levels on inflammation
  • Reduced density of CRH receptor binding in the anterior pituitary gland
  • Changes in extrahypothalamic CRH systems
    • 59% increase in CRH receptor binding sites in the raphe nuclei
    • Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86

Young monkeys that grew up under early attachment stress had increased CRH and decreased adrenaline levels at the age of 4 years.9293

The social isolation of rodents in the first days after weaning causes functional changes in the CRH system.94 Change in the ACTH stress response

In one study, sexually abused girls were found to have reduced basal ACTH levels and reduced ACTH responses to CRH stimulation, while the cortisol response was unremarkable.95

Disorders of the ACTH receptor systems can occur during early stress experiences, preventing the anxiety experience from being extinguished and thus causing long-term stress. This can be improved by administering ACTH.96 In our opinion, the change in ACTH receptor systems could possibly be a consequence of a down/upregulation response. ⇒ Downregulation / upregulation

Rats separated from their mother at an early age or less cared for by their mother show91

  • Elevated basal ACTH levels
  • Increased ACTH levels due to acute stress
  • More than doubled CRH levels to inflammation
  • Reduced density of CRH receptor binding in the anterior pituitary gland
  • Changes in extrahypothalamic CRH systems
    • 59% increase in CRH receptor binding sites in the raphe nuclei
    • Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86
  • Behavioral abnormalities such as97
    • Increased anxiety
    • Anhedonia
    • Increased alcohol preference
    • Sleep disorders
    • Cognitive impairments
    • Increased sensitivity to pain Changes in cortisol due to stress in early childhood Changes in corticoid receptors due to early stress
  • Rats that were separated from their mothers for a longer period of time at an early age had an increased messenger RNA density of the hippocampal mineralocorticoid receptor, while the glucocorticoid receptor messenger RNA density was reduced in the PFC as well as in the hippocampus.98 This shift causes impaired deactivation of the HPA axis by cortisol at the GR at the end of the stress response. This confirms that early childhood stress triggers the mechanism of downregulation in relation to the cortisol receptors relevant for responses to acute stress, while barely altering the diurnal feedback regulation of the HPA axis (which regulates basal cortisol levels outside of an acute stress response via the mineralocorticoid receptors).99

  • Intense stressful experiences in childhood cause epigenetic changes (methylation) in the glucocortioid receptor gene NR3C1. These changes result in a reduced number of docking sites for the hormone cortisol in the brain.100 Consequences are a permanently elevated cortisol level in the brain because the existing cortisol cannot dock. The brain is therefore in a permanent state of alert.

  • Early childhood stress permanently alters the expression of cortisol receptors in the hippocampus and the response of the HPA axis to acute and chronic stress **** .101102

  • Desensitized corticoid receptors also have an influence on other reaction chains, including the noradrenergic and adrenergic systems.103

  • Epidemiologic and preclinical studies have shown that the disorder of the HPA axis in ADHD may result from excessive cortisol exposure in the fetal and early postnatal period (early childhood stress). Glucocorticoid administration at this stage of life may permanently alter glucocorticoid receptors in the brain, causing dysregulation of HPA axis activity, disorders in the biosynthesis of neurotransmitters and their receptors, and alterations in intracellular pathways. Glucocorticoids (cortisol) enhance the activity of the dopaminergic system. Reduced expression of glucocorticoids could thus cause hypofunction of the dopaminergic system.104

  • Early stress alters the functionality of the glucocortioid (cortisol) receptors (here: in the hippocampus). This impairs the inhibition of the HPA axis after a stress reaction. The expression of glucocortioid (cortisol) receptors is enhanced by higher serotonin levels, which in turn is moderated by higher cAMP levels.105 This causes changes in the HPA axis into adulthood.106

  • Early childhood stress in mice alters stress coping behavior in adulthood and in adult male offspring. The behavioral changes are supported by increased glucocorticoid receptor (GR) expression and decreased DNA methylation of the GR promoter in the hippocampus. DNA methylation is also reduced in sperm of exposed males in adulthood. If animals with genetic exposure grow up without early childhood stress in a safe environment with many opportunities for social contact (enriched environment), no behavioral changes are observed. At the same time, the aforementioned changes in GR gene expression and DNA methylation in the hippocampus of the male offspring are reversed.107

  • Caring brood care in rat pups in the first week causes methylation of promoters involved in the expression of genes that influence stress responses and behavior throughout life (positive here).108
    In genetically identical rats, only different brood care showed a different expression of the stress systems:

    • Rat pups that received little grooming and physical attention from their mothers developed lower levels of the transcription factor NGFI-A (also known as EGR1) in the hippocampus. This resulted in increased methylation and thus lower expression of the glucocorticoid receptor gene (GR gene) in the hippocampus.109
      A lower GR expression level in the hippocampus correlates in adulthood with109
      • Increased basal glucocorticoid level (in mice: corticosterone, in humans: cortisol)
      • Increased glucocorticoid stress response
      • More anxious behavior
      • In females: less brood care of their own children
    • Rat pups that received a lot of grooming and physical care from their mother developed a higher level of the transcription factor NGFI-A (EGR1) in the hippocampus. This results in reduced methylation and thus higher expression of the glucocorticoid receptor gene (GR gene) in the hippocampus.109
      A higher GR expression level in the hippocampus correlated in adulthood with109
      • Lower basal glucocorticoid level (in mice: corticosterone, in humans: cortisol)
      • Lower glucocorticoid stress response
      • Less anxious behavior
      • In females: increased brood care of their own children
  • In adult rats that were separated from their mother once for 24 hours at the age of 6, 9 or 12 days, the cortisol feedback mediated by the GR was deficient and impaired.110 In addition to a simultaneous increase in MR and decrease in GR in the hippocampus, there was also increased activation of the adrenal gland as a result of increased ACTH levels.111

  • Intense stressful experiences in childhood cause epigenetic changes (methylation) in the NR3C1 glucocorticoid receptor gene. These changes result in a reduced number of glucocorticoid receptors (GR) in the brain.100 Consequences are a permanently elevated cortisol level because the existing cortisol cannot dock. The brain is therefore in a permanent state of alert.

  • Maternal neglect and chronic stress inhibit the development of glucocorticoid receptors in the hippocampus. This

    • Reduces the stress-dampening effect of cortisol at the end of the stress response of the HPA axis
    • Increases CRF and vasopressin mRNA levels in the hypothalamus
      • Production of the stress hormones ACTH and corticosterone was increased.

    The authors conclude that early stress programs stress regulation and primes the mammalian brain to be more anxious and to have an increased noradrenergic, corticosteroid and vasopressin response to stress.112113 Changes in the cortisol stress response due to early childhood stress
  • Rats that were separated from their mothers after birth showed an overactive stress hormone response of the HPA axis to acute stressors as adult animals,114115 while the response of the HPA axis outside acute stress situations showed no deviating stress hormone levels.99
  • Low birth weight correlates with aberrant salivary cortisol responses to acute psychosocial stress in male boys and adults.11611782
  • Salivary and plasma cortisol responses to pharmacologic stimulation are associated with birth weight and gestational age.11811982
  • Intense family problems in early childhood correlate with the cortisol response to unknown situations. This is understood as an indication of a gene-environment interaction.12082
  • There are significant (albeit only slight) correlations between infant attachment styles and salivary cortisol responses to acute stress in adulthood121122 123 82 and between attachment behavior in adulthood and salivary cortisol responses in relationship conflict situations.12482
  • Children whose mothers used cocaine during pregnancy showed an altered (usually flattened) cortisol response to stress. If experiences of violence were added, this effect intensified.125
  • Early childhood stress causes permanent changes in the HPA axis, which are reflected in altered basal and stress-induced cortisol levels. Children with internalizing problems often show elevated cortisol levels in response to acute stressors, while adults who have experienced early childhood psychological stress often show decreased basal cortisol levels and increased ACTH responses to acute stress.126
  • Monkeys that grew up in groups of peers without a mother showed more elevated cortisol levels in response to multiple 4-day isolation as a stressor than monkeys that had grown up with their mother. They also showed a greater affinity for addiction.127 Early stress changes basal daily cortisol levels
  • Children who grew up in an orphanage showed a cortisol level development throughout the day that showed almost no changes. Compared to children raised in families, the morning increase in cortisol levels (CAR) was absent, as was a decrease in cortisol levels throughout the day. The more pronounced the changes in cortisol levels were throughout the day, the greater the resilience to mental disorders.126
  • Flatter daily cortisol levels were associated with an increased risk of mental disorders. A higher amplitude of the cortisol curve throughout the day was associated with improved stress management.88
  • Prenatal stress increased the unborn child’s cortisol levels for the rest of its life.128
  • Childhood maltreatment led to striking changes in the HPA axis in macaques in the first six postnatal months45
    • Higher plasma cortisol levels
    • Higher cortisol accumulation in the hair
    • Increased HPA activity
    • Prolonged activation of the HPA axis
    • Increased level of emotional reactivity Changes in vasopressin (AVP) due to early childhood stress

Early stress experience in mice (on the 10th day of life) caused DNA hypo-methylation, which reduced the vasopressin release of the gene responsible for this throughout life and supported a permanent hyperactivation of the HPA axis.129 Dopamine system - permanent damage due to early childhood stress

Early childhood stress (e.g. postnatal deprivation, maternal separation) led to reduced motivation to pursue rewards and reduced mesolimbic dopamine levels in the striatum in adult rats and monkeys.130 Monkeys with early childhood stress experience also showed reduced interest in rewards. However, reward consumption remained unchanged. Increased noradrenaline degradation substances were found in the urine.131

In humans, early childhood stress is also associated with reduced reward-related activity in the ventral striatum132, which is associated with increased symptoms of anhedonia,133 although the data did not differentiate between reward expectation and reward receipt. It is conceivable that reduced reactivity to rewards received in particular correlates with anhedonia or depression.

Maltreated adolescents showed reduced dopaminergic activation of the pallidum (part of the striatum) during reward anticipation with simultaneously stronger symptoms of depression.134

Further studies confirm that early childhood stress (without a direct link to depression) correlates with reduced activation of the striatum during reward anticipation, but not during reward maintenance.135136 This is consistent with changes in ADHD in both reward anticipation and reward maintenance. Neurophysiological correlates of reward in ADHD

Stress and high glucocorticoid levels prenatally and in the first years of life appear to alter developmental programs that ensure dopaminergic transmission in the mesolimbic, mesocortical, and nigrostriatal systems. The induced changes are likely determined by the ontogenetic developmental state of these brain regions at the time of stress exposure, and their stability appears to be associated with increased lifetime susceptibility to psychiatric disorders, including drug addiction.25 A change in the mesolimbic dopamine system triggered by chronic (social) stress is also being discussed as a cause of schizophrenia.137 Early childhood neglect correlated with increased mesolimbic dopamine release in the ventral striatum in response to acute stress.138
With regard to ADHD, children whose mothers were treated with cortisol for longer periods during pregnancy have been shown to have lifelong changes in the dopaminergic system and the HPA axis (changes in the amount of MR and GR receptors that control activity and deactivation of the HPA axis).139 The ADHD symptoms described in these children are thus associated with changes in the HPA axis.

  • Early exposure to cortisol led to long-term changes in dopamine synthesis through adaptive responses. A cortisol receptor agonist (here: dexamethasone) promoted PACAP mRNA transcription, cell proliferation and DA synthesis, while a cortisol receptor antagonist inhibited this.140
  • Early stress caused defective development of the dopaminergic pathways of the nucleus accumbens.8
  • Children who were exposed to a stressful environment and insecure attachment in the first 6 years of life suffered permanent damage in dopaminergic and serotonergic brain regions.141
  • Early stress in combination with corresponding gene variants caused a sensitization of the dopamine system, making it more susceptible to acute stress, which leads to progressive dysregulation.142
  • Social stress in adolescence increased the number of dopamine transporters in mice.143 Increased DAT is typical for ADHD.
    • Mice that were separated from their mothers as newborns showed a reduced number of DAT in the nucleus accumbens and striatum as well as other changes in the dopamine system.144145
  • Altered function of the DAT is involved in ADHD and ASD. Within the first few months of life, environmental influences can epigenetically alter the expression of the DAT.146
  • Early childhood separation from the mother led to lifelong changes in the dopaminergic system in rats.147148

The social isolation of rodents in the first days after weaning from the mother causes reproducible, long-term changes58

  • Behavior:
    • Neophobia149
    • Disturbed sensorimotor gating149
    • Aggression149
    • Cognitive rigidity149
  • Neurophysiological:
    • Reduced PFC volume149
    • Reduced synaptic plasticity149
      • In the cortex
      • In the hippocampus
    • Hyperfunction of the mesolimbic dopaminergic system in the nucleus accumbens149
      • Increased presynaptic dopamine function
      • Increased serotonin function
    • Hypofunction of the mesocortical dopamine system149
    • Attenuated serotonin function in149
      • PFC
      • Hippocampus
    • Functional changes in the dopaminergic system in
      • Amygdala
        • Increased basal dopamine turnover150
      • Infralimbic mPFC
        • Reduced basal dopamine metabolism150

Rhesus monkeys that grew up without a mother and only with peers showed increased levels of the dopamine metabolite homovanillic acid (HVA) in response to social separation.151 Noradrenaline system - permanent damage due to early childhood stress

Separation of rat pups from their mothers increased GABA receptor-mediated release of norepinephrine in SHR rats (a model of ADHD-HI and ADHD-C), while this was decreased in Wystar-Kyoto rats (considered a control model of non-ADHD).152
Early childhood separation from the mother led to lifelong changes in the noradrenergic and dopaminergic systems in rats.147
Maternal stress (restriction for 1 h per day on day 15-21 of pregnancy) in rats led to a decrease in the hypothalamic noradrenaline and blood plasma corticosterone response to acute stress in adult male offspring.153

Monkeys separated from their mothers in early childhood showed a reduced basal noradrenaline level in the cerebrospinal fluid. This correlated with impaired social behavior, impulsivity, increased aggression and decreased interest in tasty rewards.154
Other monkeys with early childhood stress experience showed a reduced interest in rewards. However, reward consumption remained unchanged. Increased noradrenaline metabolites were found in the urine.131 Increased degradation substances in the urine indicate a reduced level in the brain.

Rhesus monkeys that grew up without a mother and only with peers showed reduced levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in response to social separation.151

Epigenetic environmental factors such as prenatal stress appear to be able to impair the development of the noradrenergic system. This can increase the risk of ASD.155
The catalytic enzyme HSD11B2 (11 β-hydroxysteroid dehydrogenase-2), which inactivates cortisol, is downregulated in the placenta in the middle of pregnancy. This increases the receptivity of the fetal brain to cortisol.156 While stress and nutritional deprivation can decrease HSD11B2 expression through increased methylation, hypoxia decreases HSD11B2 expression via other mechanisms.157158 This can result in significant changes in the noradrenergic system.

A further, but possibly non-causal, connection between stress and the noradrenaline system is established via MeCP2.
In the MeCP2 mutant mouse model of Rett syndrome, the HPA axis is overactivated, presumably due to increased expression of the CRH gene, leading to abnormal stress responses. MeCP2 binds the CRH promoter, which is normally enriched with methylated CpG dinucleotides.159 MeCP2 deficiency impairs the noradrenergic system and causes respiratory distress. The administration of noradrenaline improves this.160
Reduced MECP2 expression was found in 11 of 14 people with ASD and in 2 of 2 people with ADHD.161 One case study also reported an association with ADHD.162 SHR and PCB-contaminated rats showed changes in the MECP2 gene.163 Offspring of rat mothers given alcohol showed reduced MECP2 expression.164165 Alcohol during pregnancy massively increases the risk of ADHD. Serotonin system - permanent damage due to early childhood stress

Serotonin influences the developing brain. During certain stages of brain development, 5-HT, in conjunction with other transmitters, regulates brain cytoarchitecture and nodal connectivity by modulating a variety of developmental processes, including neuronal progenitor cell proliferation, migration and differentiation, maturation of postmitotic neurons, and apoptosis. Environmental factors that alter serotonergic modulation during development or variation in genes involved in 5-HT signaling can cause disorders associated with defective innervation, circuit formation, and network connectivity.166

Acute and chronic stress influences serotonergic communication:

  • Acute stress increased the gene expression of the 5-HT7 receptor in the CA1 region of the hippocampus,167 while the gene expression of the 5-HT1A receptor decreased168
  • Corticosterone dose-dependently influences 5-HT1A receptor-mediated responses in the rat hippocampus in vitro and in vivo: activation of only the high-affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated responses, while additional activation of lower-affinity glucocorticoid receptors enhances the effect of 5-HT.169
  • Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animals.169

Rhesus monkeys that grew up without a mother and only with peers showed151

  • Without stress
    • Lower 5-HIAA concentrations in the cerebrospinal fluid
  • As a reaction to social distancing
    • Higher 5-HIAA concentrations in the cerebrospinal fluid Changes in the vegetative nervous system (sympathetic / parasympathetic nervous system)

Early childhood stress experiences are associated with a down-regulation of the sympathetic nervous system, but probably not with a change in parasympathetic cardiovascular stress reactivity in adulthood.170 Changes in the cortex / PFC
  • Adults with early emotional maltreatment showed a reduced volume of mPFC.171
  • Animal experiments have shown that emotional experience in the first years of life causes structural neuronal changes (wiring patterns in the prefrontal-limbic circuits) in the brain that are retained throughout life.172173174
  • Maltreated children and adolescents show structural developmental damage, in175
    • Cortex
    • Orbifrontal cortex (reduced volume in institutionalized children)
      Disorders of the amygdala and the orbifrontal cortex correlate with social and emotional regulation disorders (including increased anxiety).
      Neuronal emotion processing and emotion regulation remain altered into adulthood.176177178
  • After stressing newborn rats, they showed developmental disorders of the neuronal systems of the PFC. These animals had a significantly higher stress response behavior with increased anxiety and orientation difficulties at an older age.179
  • Early sexual abuse caused a thinner cortex in the regions representing the genital area.180
  • Prenatal maternal stress correlates with a thinner cortex in children.181 A delay in the first cortex thickness maximum is considered a sign of developmental disorders. Early childhood stress alters connectivity of the thalamus

The spatial distribution of global connectivity is highest in the regions of salience and default mode networks, and the severity of early childhood stress experience predicted increased global connectivity of the left thalamus.182

Early childhood stress changes how the amygdala is addressed by the thalamus.183 Early childhood stress changes the amygdala

Maltreated children and adolescents exhibit structural developmental damage, e.g. in:175

  • Amygdala (increased volume in children at home)
    Disorders of the amygdala and the orbitofrontal cortex correlate with social and emotional regulation disorders (including increased anxiety).
  • Neuronal emotion processing and emotion regulation remain altered into adulthood.176177178
  • Prenatal maternal stress correlates with an enlarged amygdala in children.181 Hippocampus
  • Early stress reduces the amplitude of long-term potentiation in the hippocampus.
    Rodents exposed to early stress showed dendritic atrophy in hippocampal cells and reduced amplitude of long-term potentiation in the CA3 region of the hippocampus, leading to deficits in memory formation.184
  • Prolonged exposure to stress alters brain structures involved in cognition and mental health. In the prenatal period and the first years of life, the hippocampus (up to 2 years) and amygdala (up to 8 years) are particularly vulnerable to prolonged stress.18
  • Rats that were separated from their mothers for a longer period of time at an early age had an increased messenger RNA density of the hippocampal mineralocorticoid receptor, while the glucocorticoid receptor messenger RNA density was reduced in the PFC as well as in the hippocampus.98 This shift causes impaired deactivation of the HPA axis by cortisol at the GR at the end of the stress response. This confirms that early childhood stress triggers the mechanism of downregulation in relation to the cortisol receptors relevant for responses to acute stress, while barely altering the diurnal feedback regulation of the HPA axis (which regulates basal cortisol levels outside of an acute stress response via the mineralocorticoid receptors).99
  • Exposure to glucocorticoids (stress hormones) during hippocampal development in pregnancy influences the starting point of the stress response through epigenetic changes via mRNA and methylation.185
  • Another study also describes epigenetic changes in the hippocampus due to early childhood stress.186 Corpus callosum

Abused children and adolescents exhibited structural developmental damage, including in the corpus callosum.175

Like all myelinated regions, the corpus callosum is potentially susceptible to early childhood stress, as high concentrations of stress hormones suppress glial cell division, which is critical for myelination.187 The size of the corpus callosum is strongly influenced by early experience in a sex-specific manner. Handling led to a significantly larger width of the corpus callosum in male rats.188

When male monkeys are raised in isolation, this weakens the development of the corpus callosum and causes a4 reduced size, which correlates with defects in certain learning tasks.113

Childhood traumas such as severe neglect or abuse appear to correlate with a significant reduction in the mean proportions of the corpus callosum, particularly in boys.189190 The corpus callosum is said to be more susceptible to neglect in boys and more susceptible to sexual abuse in girls.113 Early childhood stress and GABA

Prenatal maternal stress delays the migration of GABAergic cell precursors from their site of origin in the medial ganglionic eminence (in the forebrain) to their destination in the cortex.191192 This GABAergic cell migration is crucial for later cortical function, e.g. in schizophrenia.191193194 The subsequent maturation of GABAergic cells is also influenced by prenatal stress and correlates with altered social and anxiety-like behavior after prenatal stress. An IL-6 antagonist was able to prevent a maternal stress-induced delay in the migration of GABAergic cell precursors in mice.191192195191

Social isolation of rodents in the first days after weaning causes functional changes in the GABAergic system5860196

Early childhood stress due to prolonged separation from the mother, endotoxins or neglect (e.g. due to less attentive breastfeeding) changes the molecular composition of the supramolecular complex of gamma-aminobutyric acid (GABA)-benzodiazepine and benzodiazepine. This had the following effects:197113

  • Reduced (high-affinity) GABA-A receptors in the amygdala and locus coeruleus
  • Reduced benzodiazepine receptors in the amygdala centrally and laterally, in the PFC, in the locus coeruleus and in the nucleus tractus solitaricus
  • Reduced mRNA levels for the GABA-A-gamma-2 receptor, which binds with high affinity to benzodiazepine, in the amygdala nuclei, locus coeruleus and nucleus tractus solitaricus.

Handling (briefly holding newborns), on the other hand, increased all three levels. It is known that brief handling leads to increased maternal care and affection, which causes increased oxytocin levels (instead of decreased oxytocin levels due to severe stress).

Here too, the offspring of mothers who showed a high level of affection also showed this as adults:198

  • More benzodiazepine receptors in the amygdala (central, lateral, basolateral) and locus coeruleus
  • More alpha2-adrenoceptors in the locus coeruleus
    • This reduces feedback inhibition of the noradrenergic neurons
  • Fewer CRH receptors in the locus coeruleus
  • A significantly lower level of anxiety in response to new stimuli
    Anxiety and fear are mediated by reduced GABAergic inhibition of the amygdala. GABAergic inhibition of the amygdala is influenced by, among other things
    • Noradrenergic projections from the locus coeruleus to the PFC
    • CRH projections from the amygdala to the locus coeruleus (anxiety-increasing)
    • Endogenous benzodiazepines (anxiolytic)

The authors conclude that maternal care during infancy serves to “program” behavioral responses to stress in the offspring by altering the development of the neural systems that mediate anxiety.198113 FKBP5

The glucocorticoid receptor (GR) is present in almost all cells and is a corticosteroid-dependent transcription factor. In the hormone-free state, it is present in the cell in a complex with heat shock protein 90 and a number of other helper proteins such as FKBP51, which influence steroid signal transduction. 199

  • Stress in the developmental phase of the HPA axis increases the activity of the FKBP5 gene through an epigenetic change (methylation). In adults, however, trauma does not cause methylation of this gene. FKBP5 is also thought to play a role in aggression.200201 The epigenetically altered variant of FKBP5 causes a permanent deterioration in stress regulation in people with ADHD.
  • Carriers of the FKBP5 genotypes rs1360780 or rs3800373 have a significantly increased risk of depression if they have been exposed to traumatizing events, such as physical violence, sexual abuse or serious accidents. Without such stressful events, the probability of depression is unchanged.202 In the case of such stress, the shutdown of the HPA axis normally triggered by cortisol at the end of the stress response is impaired. As a result, the HPA axis is not shut down properly and remains permanently activated.
    This effect is a phenotypic description of ADHD-HI (with hyperactivity). Increased susceptibility to oxidative stress

Early and long-term stress increases vulnerability to oxidative stress.203 Change in the immunological stress response (Kindling effect)

Moderate and severe childhood maltreatment (MAL) correlates positively with the overall change in the stress response of the cytokine IL-6 as well as the maximum IL-6 concentration during TSST.204

Traumatic experiences in childhood cause increased CRP levels.205
This could be due to the kindling effect. Earlier activation of cytokines (proteins that fight inflammation) leads to a more intensive cytokine response when they are activated again.
Kindling hypothesis of depression. Since cytokines can influence the neurotransmitter systems, early childhood cytokine intoxications cause long-lasting changes in the catecholamine systems (dopamine, noradrenaline, serotonin).
For example, even low doses of the cytokine IL-2 in newborn mice led to permanently reduced dopamine levels in the hypothalamus in adulthood.206 Epigenetic changes due to early stress

Epigenetic changes describe mechanisms by which the expression of genes and thus their activity are influenced. The effect of an epigenetic change can therefore occur in any of the ways described so far, e.g. a change in the cortisol receptors or a change in the dopaminergic system. Changes in DNA methylation

Early childhood stress experiences can contribute to the development of ADHD via DNA methylation. However, DNA methylation correlating with externalizing behaviors appears to be the Consequences of problematic behaviors reinforced by early childhood stress experiences rather than the epigenetic basis of such behaviors. Externalizing behavior methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices. These brain regions are associated with ADHD.207
Children who grew up in institutions show significant changes in DNA methylation compared to children who grew up in families. These changes in DNA methylation can explain around 7 to 14% of the changes in behavior.208 Shortened telomeres, reduced telomerase

Stress in the first 4 years of life, the time when the brain develops most rapidly, leads to shortened telomeres, the DNA repeats at the chromosome ends. Cortisol and oxidative stress increase telomere shortening and inhibit telomerase (the enzyme that repairs telomeres).209210211 Shortened telomeres cause altered behavior. However, it is less likely that certain behaviors later in life influence telomere length, as telomere shortening occurs primarily in the first years of life and barely occurs in adults. The length of telomeres significantly influences the expression of genes. A comprehensive and illuminating account can be found in Bateson, Nettle. Prenatal maternal stress correlates with shortened telomere lengths in children.21221321476

  • Behaviors that are promoted by shortened telomeres are214
    • Impulsiveness
      • Impatience
      • Devaluation of removed rewards
    • Willingness to take risks
    • Food
      • Higher BMI
      • Quantity
      • Frequency
    • Addictive behavior
      • Smoking
      • Alcohol consumption
    • Stress reactivity
      • Higher blood pressure
      • Higher basal cortisol level (in healthy children)
      • Higher cortisol stress responses
      • More internalizing symptoms
    • Neurotic personality traits
    • Pessimistic personality traits
    • Avoidance of physical activity
  • Behaviors that are promoted by longer telomeres are214
    • Physical activity Reduced brain volume in adulthood due to early deprivation

Deprivation in the first years of life (here: in Romanian children in institutions) resulted in a reduced brain volume in adulthood. This cannot be reversed even through an enriched environment (here: adoption).215 Altered development of the blood-brain barrier

Early childhood stress in rats led to an altered development of the blood-brain barrier by increasing caveolae-mediated transport in brain endothelial cells.216 Further neurophysiological changes due to early childhood stress
  • Reduced sensitivity to sedative hypnotics
    (shortened loss of the righting reflex)
    • CRH system
      • CRH receptor196
    • Noradrenergic system196
    • GABAergic system217
    • Allopregnanolone62218
  • Increased susceptibility to picrotoxin-induced convulsions
    • GABAergic system
      • GABA-A receptor219
    • Allopregnanolone219
  • Increased startle reflex67
  • Impaired prepulse inhibition67
  • Increased food collecting behavior (food hoarding)67
  • Reduced susceptibility to GABAergic drugs
    • Such as pentobarbital and diazepam
  • Histochemical changes in oligodendrocyte maturation and myelination220 and dendritic spine density in the mPFC221
  • Downregulation of the biosynthetic pathway of allopregnanolone
    • Allopregnanolone is a neurosteroid with positive allosteric modulatory activity against the GABA-A receptor.22262

1.4. Stress in childhood and adolescence prevents remission of ADHD

A study of stress levels in children with ADHD found that severe stress levels in childhood and adolescence were associated with more severe ADHD-HI or ADHD-I progression into adulthood, while children with low stress levels often showed remitting ADHD.223
Conversely, studies on the age-dependent effects of enriched environments in rodents show that youth is a very vulnerable age segment. Positive effects are already evident in childhood. However, the greatest benefit was observed in middle adolescence. Enriched environments resulted in improved selective and auditory sustained attention performance, increased exploration and food-gathering behavior as well as a significant decrease in corticosterone levels and reduced anxiety levels.224

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