1. Stress by age at exposure - early childhood stress.

• 1.1. Stress during certain brain development phases particularly harmful
• 1.2. Age at stress exposure determines type of mental disorder
• 1.3. Early childhood stress
  • 1.3.1. Behavioral changes due to early stress
    • 1.3.1.1. ADHD and PTSD most common disorders in childhood stress
    • 1.3.1.2. Depression risk increased by early stress
    • 1.3.1.3. PTSD/PTBS risk increased by early stress
    • 1.3.1.4. Obesity and cardiovascular disease risk increased by early stress
    • 1.3.1.5. Stress intolerance risk increased by early stress
    • 1.3.1.6. Attention and learning problems risk increased by early stress
    • 1.3.1.7. Aggression disorder risk increased by early stress
    • 1.3.1.8. Hyperactivity risk increased by early stress
    • 1.3.1.9. Anxiety disorder risk increased by early childhood stress
    • 1.3.1.10. Impaired social behavior and early childhood stress
  • 1.3.2. Neurophysiological changes due to early stress
    • 1.3.2.1. Early stress makes HPA axis (stress axis) more sensitive
      • 1.3.2.1.1. Early stress alters endocrine stress responses of the HPA axis
      • 1.3.2.1.2. Change of the CRH system
      • 1.3.2.1.3. Alteration of the ACTH stress response
      • 1.3.2.1.4. Changes in cortisol due to early childhood stress
      • 1.3.2.1.4.1. Alterations in corticoid receptors due to early stress
      • 1.3.2.1.4.2. Changes in the cortisol stress response due to early childhood stress
      • 1.3.2.1.4.3. Early stress alters basal cortisol day levels
      • 1.3.2.1.5. Alterations in vasopressin (AVP) due to early childhood stress
    • 1.3.2.2. Early childhood stress permanently alters the dopaminergic system
    • 1.3.2.3. Early childhood stress and norepinephrine
    • 1.3.2.4. Early childhood stress disturbs serotonin balance
    • 1.3.2.5. Changes in the vegetative nervous system (sympathetic / parasympathetic)
    • 1.3.2.6. Changes in the cortex / PFC
    • 1.3.2.7. Early childhood stress alters connectivity of the thalamus
    • 1.3.2.8. Early childhood stress alters amygdala
    • 1.3.2.9. Hippocampus
    • 1.3.2.10. Corpus callosum
    • 1.3.2.11. Early childhood stress and GABA
    • 1.3.2.12. FKBP5
    • 1.3.2.13. Increased susceptibility to oxidative stress
    • 1.3.2.14. Alteration of the immunological stress response (Kindling effect)
    • 1.3.2.15. Epigenetic changes due to early stress
      • 1.3.2.15.1. Changes in DNA methylation
      • 1.3.2.15.2. Shortened telomeres, reduced telomerase
    • 1.3.2.16. Reduced brain volume in adulthood due to early deprivation
    • 1.3.2.17. Altered development of the blood-brain barrier
    • 1.3.2.18. Other neurophysiological changes due to early childhood stress
• 1.4. Stress in childhood and adolescence prevents remission of ADHD

1.1. Stress during certain brain development phases particularly harmful¶

During the

• prenatal development
• Infancy
• Childhood
• Adolescence

people are particularly vulnerable to stressors. During these critical periods, stressors can have effects, such as persistent cacostasis (dyshomeostasis), that last a lifetime. At the same time, during these periods, individuals are particularly susceptible to a favorable environment that can trigger hyperstasis and lead to the development of resistance to stressors in adulthood.¹
Therefore, there is a significant difference whether stress occurs during a developmental phase of a brain region or outside of it (especially after the end of brain development, in humans at about 24 years of age).

Examples:

• Epigenetic demethylation of the FKPB5 gene, which modulates glucocortioid receptor sensitivity², is mediated only by stress during the differentiation and proliferation phase of neurons, but no longer in mature neurons.³
• If excessive stress occurs during the developmental phase of the HPA axis, this increases the sensitivity of the HPA axis by permanently lowering the thresholds for the onset of the stress response.⁴ This deteriorates the ability to respond appropriately to stress.⁵ This can lead to pathologically altered responses to stressors later in life (including anxiety disorders, depression, autism, schizophrenia).

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 about 3 years) and again in middle adolescence. Therefore, negative environmental influences (stress) during this period are particularly harmful for the dopaminergic and noradrenergic systems.

This is done in several ways, including:

• Early stress causes defective development of the dopaminergic pathways of the nucleus accumbens.⁶
• Children exposed to stressful environments or insecure attachment in the first 6 years of life suffer permanent damage in dopaminergic and serotonergic brain regions.⁷

Based on Rensing et al.’s description of the two-hit model, according to which mental disorders such as anxiety disorders, depression, autism, and schizophrenia result from damage in adolescence that hits already pre-damaged stress systems,⁸ it would be conceivable to consider ADHD as the result of the first hit.
Against the assumption of ADHD as a first hit for other disorders there is a study that could not find an increased specificity of symptoms of a disorder with increasing severity.⁹

Stress in adolescence can cause a potentiation of early childhood stress.¹⁰ Another study shows that adults who reported more than five ADHD symptoms from childhood were more likely than average to develop mental disorders or addiction.¹¹

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

Not only the type and intensity of early childhood stress, but also the timing of the stress determines the later disturbance pattern. This results from the fact that the development of the mammalian brain follows a specific time 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 disturbances.

• Cortisol treatment during pregnancy decreased the sensitivity of corticoid receptors in the PFC in newborn monkeys, and the timing of cortisol administration determined in which parts of the PFC this occurred. In adult monkeys, decreased receptor sensitivity due to cortisol administration was no longer observed.¹²
• Severe maternal anxiety in pregnancy during weeks 12 to 22 after the last menstrual period significantly increased the risk for ADHD-HI, whereas severe anxiety during weeks 32 to 40 did not.¹³ In contrast, a study found no increased psychiatric disorders at age 9 years in children of women exposed to one month of repeated rocket fire on civilians during the 2006 Lebanon War.¹⁴ It is possible that one month of repeated stress is not a sufficiently intense stressor.
• The developmentally oldest brain regions in the brainstem, which control the basic mechanisms of life, and which develop first, are prone to very early disorders that are then often fatal.
  Cortical brain areas that are not essential for survival and that develop later in time are susceptible to perturbations that occur at somewhat later stages of development.¹⁵
• The specific effects of prolonged stress exposure on brain, behavior, and cognition depend on the timing and duration of stress exposure and, in part, on an interaction between gene effects and early childhood stress exposure. These differences may explain why stress leads to different mental disorders at different times of life.¹⁶
• Traumatic experiences before age 12 (such as loss of a parent through death or permanent separation) increase the risks of depressive illness later in life, while traumatic experiences thereafter increase the risk of PTSD¹⁷¹⁸
• Traumatic experiences before 6 years of age showed different dexamethasone/CRH test results than traumatic experiences later in life.¹⁹
• Prolonged emotional maltreatment in childhood correlated (as the only type of maltreatment) with an aberrant (here: decreased) cortisol response to acute stressors with increasing adulthood.²⁰
• Sexual abuse at age 3 to 5 or at age 11 to 13 decreased hippocampal volume, whereas sexual abuse at age 14 to 16 decreased PFC volume.²¹
• An extensive and long-term follow-up of 733 affected persons with different personality disorders showed that the different intensity and timing of early childhood stress also contributes to the differentiation of the disorder patterns.²² All affected individuals 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.²³
• The nature and timing of early childhood stress exposure, for example, are likely to distinguish the environmental origins of ADHD and borderline.²⁴

The main developmental periods in which the respective brain regions are particularly vulnerable are (in life years)²⁵

• Amygdala left: 0.5 to 2 years
• Hippocampus: 3-5²⁶ and 11-14 yrs
• 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 years²⁶
• Ventromedial PFC: 8-10 and 14-16 years
• Amygdala right: from 10 years
• Visceral cortex: 11 years and older
• PFC (volume): 8-15 years²⁷ 14-16 years²⁶

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.²⁸

1.3. Early childhood stress¶

Early stress increases the risk for mental disorders.²⁹³⁰ Childhood emotional, physical, or sexual maltreatment, as well as trauma, causes a long-lasting (beyond the time of maltreatment) profound disruption of stress regulation.³¹ Evidence suggests that children whose mothers were exposed to particular stress during pregnancy have a persistent increased vulnerability to mental disorders.³²
Children of women exposed to one month of repeated rocket fire from civilians during the 2006 Lebanon war were not found to have increased psychiatric disorders at age 9.¹⁴ This suggests that one month of repeated stress is not a sufficiently chronic stressor to harm the unborn child….

Baby rats separated early from their mothers have long-lasting increased physiological and behavioral stress responses to further stressors. The threshold for the onset of the stress response is reduced.³³ The same is true for baby rats whose mothers showed poor nursing behavior.³⁴³⁵
A study of adopted ADHD sufferers also addresses the question of how much of ADHD is inherited and how much is inherited.³⁶

Even with early infant stress, the degree to which it is beneficial or detrimental matters. Very brief handling (removing baby rats from their mothers by taking them in hand) is a beneficial stimulus, primarily because it increases the rate of maternal licking and grooming. Prolonged periods of separation of newborn rats from their mothers are stressful, primarily because they attenuate maternal licking and grooming,³⁷ which is associated with oxytocin release.

1.3.1. Behavioral changes due to early stress¶

Early childhood stresses affect the brain and body throughout life. For example, early physical or sexual abuse causes lifelong behavioral and pathophysiological problems.³⁸³⁹ Likewise, cold and indifferent families or chaos in the home environment lead to lasting emotional problems in children.⁴⁰⁴¹

1.3.1.1. 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.⁴²
Early childhood stress, particularly adverse caregiving experiences such as child abuse (MALT), is a major risk factor for ADHD and other psychopathologies such as anxiety, depression, and substance abuse⁴³

1.3.1.2. Depression risk increased by early stress¶

Early childhood stress alters brain structure and function and increases the risk for depression later in life.⁴⁴⁴⁵

1.3.1.3. PTSD/PTBS risk increased by early stress¶

Early stress increases the risk for later post-traumatic stress disorder,⁴⁴⁴⁵

1.3.1.4. Obesity and cardiovascular disease risk increased by early stress¶

Early stress increases the risk of obesity and cardiovascular disease.⁴⁶⁴⁷

1.3.1.5. Stress intolerance risk increased by early stress¶

Early stress increases the likelihood of increased subjective stress sensitivity in adulthood, which is associated with increased risk of anxiety disorders and depression.⁴⁸

The development of increased stress sensitivity seems to be gene-dependent. Early childhood stress increased stress resilience, exploration, and less anxious behavior in male Cdh13 + / + - and Cdh13 +/- mice. In contrast, in Cdh13 - / - mice, early childhood stress caused delayed habituation, no reduction in anxiety-like behavior, and reduced fear extinction.⁴⁹

1.3.1.6. Attention and learning problems risk increased by early stress¶

Early childhood (nonsexual) maltreatment impairs attention at age 14 as it does at age 21.⁵⁰

Impaired latent learning and attention deficit due to early childhood stress correlates with changes in the cholinergic system related to the muscarinic and nicotinic receptors.⁵¹

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

• NMDA receptor⁵²
• GABA-A receptor⁵²
• Serotonergic system⁵³
• Hippocampus: impairment of neurogenesis⁵³

1.3.1.7. Aggression disorder risk increased by early stress¶

Social isolation of rodents in the first days after weaning causes increased aggressiveness,⁵² linked to various neurophysiological correlates:

• Noradrenergic system, beta-2-adrenoceptor⁵⁴⁵⁵
• Neurosteroid system
  • Allopregnanolone⁵⁶⁵⁷
• GABAergic system
  • GABA-B-1a receptor⁵⁸
• Serotonergic system
  • 5HT-2C receptor⁵⁹⁶⁰
• Glutamatergic system
  • AMPA receptor⁶⁰

1.3.1.8. Hyperactivity risk increased by early stress¶

Social isolation of rodents in the first days after weaning causes increased motor activity,⁶¹⁵² linked to various neurophysiological correlates:

• Dopaminergic system
  • PFC⁶²
  • Nucleus accumbens⁶²
    • Decreased dopamine level in the tissue, increased dopamine turnover⁶³
  • Striatum
    • Decreased dopamine level in the tissue, increased dopamine turnover⁶³
• Serotonergic system⁶²
  • Nucleus accumbens
    • Decreased basal serotonin turnover⁶¹
• Glutamatergic system
  • AMPA receptor⁶⁴

1.3.1.9. Anxiety disorder risk increased by early childhood stress¶

Early childhood stress causes deficits in fear memory,⁵², which are neurophysiologically linked to

• Cholinergic system
  • Muscarinic receptor⁶⁵⁶⁶
• Signaling systems linked to neuroplasticity⁶⁵
• Egr-1 system⁶⁶

1.3.1.10. 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.⁶⁵

1.3.2. Neurophysiological changes due to early stress¶

Exposure to early childhood stress³⁷

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

Different brain regions differ in their sensitivity, which depends in part on genetics, gender, timing, developmental rate, and density of the glucocorticoid receptor.³⁷

1.3.2.1. Early stress makes HPA axis (stress axis) more sensitive¶

Early childhood stress “programs” the HPA axis for life,⁶⁷³⁷ via epigenetic mechanisms.⁶⁸

A comprehensive meta-analysis of 210 studies on biochemical substances (biomarkers) in ADHD indicated that the hypothalamic-pituitary-adrenocortical (HPA) axis is affected or dysregulated in ADHD (in addition to the brain monoamine system).⁶⁹

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 of 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 corelates with thinner cortex and enlarged amygdala in children.⁷⁰ Prenatal maternal stress increases the risk of preterm birth and shortened telomere lengths.

1.3.2.1.1. Early stress alters endocrine stress responses of the HPA axis¶

Permanent alterations in the HPA axis in the unborn may be the key mechanism explaining the link between prenatal stress, adverse birth outcomes (especially low birth weight), and increased susceptibility to various diseases later in adulthood.

• Stress before birth into early childhood potentially has a lifelong impact on HPA axis responses psychologically and pharmacologically.^{717273747576777879}
• In adulthood, significant associations exist between childhood trauma, psychiatric symptoms in adult life, and HPA axis responses to psychological and pharmacological stress.⁸⁰⁸¹⁷⁶
• Interruptions in care during infancy and chronic stress alter the later stress response of the HPA axis and result in increased vulnerability to mental disorders.⁸²
• In humans, early experiences of stress also lead to permanent damage to stress regulation systems, making them particularly susceptible to mental disorders as a result.⁸³⁸⁴

1.3.2.1.2. Change of the CRH system¶

Rats separated early from the mother or less cared for by the mother showed⁸⁵

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

Young monkeys raised under early attachment stress had elevated CRH and decreased epinephrine levels at 4 years of age.⁸⁶⁸⁷

Social isolation of rodents in the first days after weaning causes functional changes in theCRH system.⁸⁸

1.3.2.1.3. Alteration of the ACTH stress response¶

In one study, sexually abused girls were found to have decreased basal ACTH levels and decreased ACTH responses to CRH stimulation, whereas the cortisol response was unremarkable.⁸⁹

Early experiences of stress can result in disruptions of the ACTH receptor systems that prevent extinction of the fear experience, causing long-term stress exposure. This can be ameliorated by ACTH administration.⁹⁰ In our opinion, the alteration of ACTH receptor systems could possibly be a consequence of a downregulation/upregulation response. ⇒ Downregulation/upregulation

Rats separated early from the mother or less cared for by the mother show⁸⁵

• Elevated ACTH levels basal
• Elevated ACTH levels on acute stress
• More than doubled CRH levels on inflammation
• Reduced density of CRH receptor binding in the anterior pituitary
• Alterations in extrahypothalamic CRH systems
  • Increase in CRH receptor binding sites in the raphe nucleus by 59%
  • Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86%
• Behavioral problems such as⁹¹
  • Increased anxiety
  • Anhedonia
  • Increased alcohol preference
  • Sleep disorders
  • Cognitive impairments
  • Increased sensitivity to pain

1.3.2.1.4. Changes in cortisol due to early childhood stress¶

1.3.2.1.4.1. Alterations in corticoid receptors due to early stress¶

• Rats separated from their mothers for prolonged periods early had increased hippocampal mineralocorticoid receptor messenger RNA density, whereas glucocorticoid receptor messenger RNA density was decreased in the PFC as well as in the hippocampus.⁹² This shift causes a worsened shutdown 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 with respect to cortisol receptors relevant to responses to acute stress, whereas diurnal feedback regulation of the HPA axis (which regulates basal cortisol levels outside of an acute stress response via mineralocorticoid receptors) is barely altered.⁹³

• Intense stress experiences in childhood cause epigenetic changes (methylations) at the glucocortioid receptor gene NR3C1. These changes result in a reduced number of docking sites for the hormone cortisol in the brain.⁹⁴ As a result, cortisol levels in the brain are permanently elevated because the existing cortisol cannot dock. As a result, the brain is in a constant state of alert.

• Early childhood stress alters the expression of cortisol receptors in the hippocampus and the response of the HPA axis to acute and chronic stress permanently.⁹⁵⁹⁶

• Desensitized corticoid receptors also influence other response chains, including the noradrenergic and adrenergic systems.⁹⁷

• Epidemiological and preclinical studies have shown that HPA axis dysfunction 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, disturbances in the biosynthesis of neurotransmitters and their receptors, and alterations in intracellular pathways. Glucocorticoids (cortisol) enhance the activity of the dopaminergic system. Decreased expression of glucocorticoids could thereby cause the underactivity of the dopaminergic system.⁹⁸

• Early stress alters the functionality of glucocortioid (cortisol) receptors (here: in the hippocampus). This impairs inhibition of the HPA axis following a stress response. Glucocortioid (cortisol) receptor expression is enhanced by higher serotonin levels, which in turn is moderated by higher cAMP levels.⁹⁹ This causes changes in the HPA axis into adulthood.¹⁰⁰

• Early childhood stress alters stress coping behavior in mice during adulthood and in adult male offspring. The behavioral changes are accompanied by increased glucocorticoid receptor (GR) expression and decreased DNA methylation of the GR promoter in the hippocampus. DNA methylation is also decreased in sperm from exposed males in adulthood. If animals with genetic exposure grow up without early childhood stress in a safe environment with many social contact opportunities (enriched environment), no behavioral changes are observed. At the same time, the aforementioned changes in GR gene expression and DNA methylation are reversed in the hippocampus of male offspring.¹⁰¹

• Caring brood care in rat pups during the first week causes methylation of promoters involved in the expression of genes that influence stress responses and behavior throughout life (positive here).¹⁰²
  In genetically identical rats, different brood care alone showed different expression of stress systems:

  • Rat pups that received little grooming and physical attention from their mothers developed lower levels of the transcription factor NGFI-A (also called EGR1) in the hippocampus. This caused increased methylation and thereby lower expression of the glucocorticoid receptor gene (GR gene) in the hippocampus.¹⁰³
    A lower GR expression level in the hippocampus correlates in adulthood with¹⁰³
    • Elevated basal glucocorticoid levels (in mice: corticosterone, in humans: cortisol)
    • Increased glucocorticoid stress response
    • More anxious behavior
    • In females: lower brood care of own children
  • Rat pups that received a lot of grooming and physical attention from their mothers developed higher levels of the transcription factor NGFI-A (EGR1) in the hippocampus. This causes reduced methylation and thereby higher expression of the glucocorticoid receptor gene (GR gene) in the hippocampus.¹⁰³
    Higher GR expression level in the hippocampus correlated in adulthood with¹⁰³
    • Lower basal glucocorticoid levels (in mice: corticosterone, in humans: cortisol)
    • Lower glucocorticoid stress response
    • Less anxious behavior
    • In females: increased brood care of own children

• In adult rats separated from the mother once for 24 hours at 6, 9, or 12 days of age, GR-mediated cortisol feedback was deficient and impaired.¹⁰⁴ In addition to a concomitant increase in MR and decrease in GR in the hippocampus, increased activation of the adrenal gland also occurred as a result of increased ACTH levels.¹⁰⁵

• Intense stressful experiences in childhood cause epigenetic changes (methylations) at the glucocortioid receptor gene NR3C1. These changes result in a reduced number of glucocorticoid receptors (GR) in the brain.⁹⁴ As a result, cortisol levels are permanently elevated because the existing cortisol cannot dock. As a result, the brain is in a perpetual state of alert.

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

  • Decreases the stress-attenuating effect of cortisol at the end of the stress response of the HPA axis
  • Increases CRF and vasopressin mRNA levels in the hypothalamus
    • Was increased production of the stress hormones ACTH and corticosterone.

  The authors conclude that early stress programs stress regulation and primes the mammalian brain to be more anxious and to have increased noradrenergic, corticosteroid, and vasopressin responses to stress.¹⁰⁶¹⁰⁷

1.3.2.1.4.2. Changes in the cortisol stress response due to early childhood stress¶

• Rats separated from mothers after birth showed an overactive stress hormone response of the HPA axis to acute stressors as adults,¹⁰⁸¹⁰⁹ whereas the HPA axis response outside acute stress situations did not show aberrant stress hormone levels.⁹³
• Low birth weight correlates with aberrant salivary cortisol responses to acute psychosocial stress in male boys and adults.^11011176
• Salivary and plasma cortisol responses to pharmacological stimulation are associated with birth weight and gestational age.^11211376
• Intense familial problems in early childhood correlate with cortisol response to unknown situations. This is understood to indicate a gene-environment interaction.¹¹⁴⁷⁶
• There are significant (albeit slight) associations between childhood attachment styles and salivary cortisol responses to acute stress in adulthood^{115116 117 76} and between attachment behaviors in adulthood and salivary cortisol responses in relationship conflict situations.¹¹⁸⁷⁶
• Children whose mothers used cocaine during pregnancy showed an altered (most) flattened cortisol response to stress. If violent experiences were added, this effect was intensified.¹¹⁹
• Early childhood stress causes permanent changes in the HPA axis, as evidenced by altered basal and stress-induced cortisol levels. Children with internalizing problems often show elevated cortisol levels to acute stressors, whereas adults who have suffered early childhood psychological stress often show decreased basal cortisol levels and increased ACTH responses to acute stress.¹²⁰
• Monkeys raised in groups of peers without a mother showed greater elevated cortisol levels in response to multiple 4-day isolation as a stressor than monkeys raised with their mother. They also showed greater addiction affinity.¹²¹

1.3.2.1.4.3. Early stress alters basal cortisol day levels¶

• Children raised in an orphanage showed a cortisol level trend throughout the day with almost no changes. Compared with children raised in families, the morning increase in cortisol levels (CAR) was absent, as was a decrease in cortisol levels over the day. The more pronounced the changes in cortisol levels over the day were, the greater was the resilience against mental disorders.¹²⁰
• A flatter daily cortisol level trajectory was associated with an increased risk of mental disorders. A higher amplitude of the cortisol course over the day was associated with improved stress coping.⁸²
• Prenatal stress increased cortisol levels in the unborn for life.¹²²
• Childhood maltreatment resulted in striking changes in the HPA axis during the first six postnatal months in macaques⁴³
  • Higher plasma cortisol levels
  • Higher cortisol accumulation in the hair
  • Increased HPA activity
  • Prolonged activation of the HPA axis
  • Increased level of emotional reactivity

1.3.2.1.5. Alterations in vasopressin (AVP) due to early childhood stress¶

Early stress experience in mice (at day 10 of life) caused DNA hypomethylation that reduced vasopressin release from the gene responsible for it throughout life and supported sustained hyperactivation of the HPA axis.¹²³

1.3.2.2. Early childhood stress permanently alters the dopaminergic system¶

Early childhood stress (e.g., postnatal deprivation, maternal separation) resulted in decreased motivation to pursue rewards and decreased mesolimbic dopamine levels in the striatum in adult rats and monkeys.¹²⁴ Monkeys with early childhood stress experience also showed decreased interest in rewards. However, reward consumption remained unchanged. Increased urinary norepinephrine degradation was found.¹²⁵

In humans, early childhood stress is also associated with decreased activity in relation to reward in the ventral striatum¹²⁶, which is associated with increased symptoms of anhedonia¹²⁷, although the data did not differentiate between reward expectation and reward receipt. It would be conceivable that reduced reactivity to received rewards in particular correlates with anhedonia or depression.

Maltreated adolescents showed reduced dopaminergic activation of the pallidum (part of the striatum) in reward expectancy concomitant with more severe depression symptoms.¹²⁸

Further studies confirm that early childhood stress (with no direct link to depression) correlates with decreased activation of the striatum during reward expectancy but not during reward maintenance.¹²⁹¹³⁰ This is consistent with changes in ADHD in both reward expectancy 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 dependence.²³ In relation to schizophrenia, an alteration of the mesolimbic dopamine system triggered by chronic (social) stress has also been dircussed as a cause.¹³¹ Early childhood neglect correlated with increased mesolimbic dopamine release in the ventral striatum in response to acute stress.¹³²
With respect to ADHD, children whose mothers were treated with cortisol for prolonged periods during pregnancy have been shown to have lifelong alterations 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).¹³³ Thus, the ADHD symptoms described in these children are associated with changes in the HPA axis.

• Early exposure to cortisol resulted in long-term changes in dopamine synthesis through adaptation responses. A cortisol receptor agonist (here: dexamethasone) promoted PACAP mRNA transcription, cell proliferation, and DA synthesis, whereas a cortisol receptor antagonist inhibited this.¹³⁴
• Early stress caused defective development of the dopaminergic pathways of the nucleus accumbens.⁶
• Children exposed to stressful environments and insecure attachment during the first 6 years of life suffered permanent damage in dopaminergic and serotonergic brain regions.¹³⁵
• Early stress in combination with corresponding gene variants caused sensitization of the dopamine system, making it more susceptible to acute stress, leading to progressive dysregulation.¹³⁶
• Social stress in adolescence increased the number of dopamine transporters in mice.¹³⁷ Increased DAT is typical in ADHD.
  • Mice separated from their mothers as newborns showed reduced numbers of DAT in the nucleus accumbens and striatum, as well as other changes in the dopamine system.¹³⁸¹³⁹
• Altered function of DAT is implicated in ADHD and ASD. Within the first months of life, environmental influences can epigenetically alter the expression of the DAT.¹⁴⁰
• Early childhood separation from the mother led to lifelong changes in the dopaminergic system in rats.¹⁴¹¹⁴²

Social isolation of rodents in the first days after weaning from the mother causes reproducible, long-term changes⁵²

• Behavior:
  • Neophobia¹⁴³
  • Disturbed sensorimotor gating¹⁴³
  • Aggression¹⁴³
  • Cognitive rigidity¹⁴³
• Neurophysiological:
  • Reduced PFC volume¹⁴³
  • Decreased synaptic plasticity¹⁴³
    • In the cortex
    • In the hippocampus
  • Hyperfunction of the mesolimbic dopaminergic system in the nucleus accumbens¹⁴³
    • Enhanced presynaptic dopamine function
    • Enhanced serotonin function
  • Hypofunction of the mesocortical dopamine system¹⁴³
  • Attenuated serotonin function in¹⁴³
    • PFC
    • Hippocampus
  • Functional changes dopaminergic system in
    • Amygdala
      • Increased basal dopamine turnover¹⁴⁴
    • Infralimbic mPFC
      • Decreased basal dopamine turnover¹⁴⁴

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.¹⁴⁵

1.3.2.3. Early childhood stress and norepinephrine¶

Separation of rat pups from their mothers increased GABA receptor-mediated release of norepinephrine in SHR rats (a model for ADHD-HI), whereas it decreased it in Wystar-Kyoto rats (considered a control model for non-ADHD).¹⁴⁶
Early childhood separation from the mother resulted in lifelong changes in the noradrenergic and dopaminergic systems in rats.¹⁴¹
Maternal stress (restriction for 1 h per day on day 15-21 of gestation) decreased hypothalamic norepinephrine and blood plasma corticosterone responses to acute stress in adult male offspring in rats.¹⁴⁷

Monkeys separated from their mothers in early childhood showed decreased basal norepinephrine levels in cerebrospinal fluid. This correlated with impaired social behavior, impulsivity, increased aggression, and decreased interest in palatable rewards.¹⁴⁸
Other monkeys with early childhood stress experience showed reduced interest in rewards. However, reward consumption remained unchanged. Increased urinary norepinephrine breakdown substances were found.¹²⁵ Increased urinary catabolites indicate decreased levels in the brain.

Rhesus monkeys that grew up without a mother and only with peers showed decreased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in response to social separation.¹⁴⁵

1.3.2.4. Early childhood stress disturbs serotonin balance¶

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.¹⁴⁹

Acute and chronic stress affects serotonergic communication:

• Acute stress increased 5-HT7 receptor gene expression in the CA1 region of the hippocampus,¹⁵⁰ while 5-HT1A receptor gene expression decreased¹⁵¹
• Corticosterone dose-dependently affects 5-HT1A receptor-mediated responses in rat hippocampus in vitro and in vivo: activation of only the high-affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated responses, whereas additional activation of lower affinity glucocorticoid receptors enhances 5-HT effects.¹⁵²
• Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animals.¹⁵²

Rhesus monkeys that grew up without a mother and only with peers showed¹⁴⁵

• Without stress effect
  • Lower 5-HIAA concentrations in the CSF
• In response to social separation
  • Higher 5-HIAA concentrations in the CSF

1.3.2.5. Changes in the vegetative nervous system (sympathetic / parasympathetic)¶

Early childhood stress experiences are associated with downregulation of the sympathetic nervous system but probably not with alteration of parasympathetic cardiovascular stress reactivity in adulthood.¹⁵³

1.3.2.6. Changes in the cortex / PFC¶

• Adults with early emotional maltreatment exhibited decreased volume of mPFC.¹⁵⁴
• 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 maintained throughout life.^155156157
• Maltreated children and adolescents exhibit structural developmental disabilities in¹⁵⁸
  • Cortex
  • Orbifrontal cortex (reduced volume in institutionalized children)
    Amygdala and orbifrontal cortex dysfunction correlate with social and emotional regulation disorders (including increased anxiety).
    Neural emotion processing and emotion regulation remain altered into adulthood.^159160161
• After stress on newborn rats, they showed developmental abnormalities of the neuronal systems of the PFC. These animals had a significantly higher stress response behavior in old age with increased anxiety and orientation difficulties.¹⁶²
• Early sexual abuse caused thinner cortex in regions representing the genital area.¹⁶³
• Prenatal maternal stress correlates with thinner cortex in children.⁷⁰ A delay of the first cortex thickness maximum is considered a hallmark of developmental disorders.

1.3.2.7. 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.¹⁶⁴

Early childhood stress alters how the thalamus addresses the amygdala.¹⁶⁵

1.3.2.8. Early childhood stress alters amygdala¶

Maltreated children and adolescents exhibit structural developmental disabilities, including in:¹⁵⁸

• Amygdala (increased volume in institutionalized children)
  Amygdala and orbitofrontal cortex dysfunction correlate with social and emotional regulation disorders (including increased anxiety).
• Neural emotion processing and emotion regulation remain altered into adulthood.^159160161
• Prenatal maternal stress correlates with enlarged amygdala in children.⁷⁰

1.3.2.9. 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 decreased amplitude of long-term potentiation in the CA3 region of the hippocampus, resulting in deficits in memory formation.¹⁶⁶
• Prolonged exposure to stress altered 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.¹⁶
• Rats separated from their mothers for prolonged periods early had increased hippocampal mineralocorticoid receptor messenger RNA density, whereas glucocorticoid receptor messenger RNA density was decreased in the PFC as well as in the hippocampus.⁹² This shift causes a worsened shutdown 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 with respect to cortisol receptors relevant to responses to acute stress, whereas diurnal feedback regulation of the HPA axis (which regulates basal cortisol levels outside of an acute stress response via mineralocorticoid receptors) is barely altered.⁹³
• 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.¹⁶⁷
• Another study also describes epigenetic changes in the hippocampus due to early childhood stress.¹⁶⁸

1.3.2.10. Corpus callosum¶

Maltreated children and adolescents showed structural developmental damage in the corpus callosum, among other areas.¹⁵⁸

The corpus callosum, like all myelinated regions, is potentially vulnerable to early childhood stress because high concentrations of stress hormones suppress glial cell division critical for myelination.¹⁶⁹ The size of the corpus callosum is strongly influenced by early experience in a sex-specific manner. Handling resulted in a significantly larger width of the corpus callosum in male rats.¹⁷⁰

When male monkeys are raised in isolation, this weakens the development of the corpus callosum and causes a4 reduced size that correlates with defects in certain learning tasks.¹⁰⁷

Childhood trauma, such as severe neglect or abuse, appears to correlate with a marked reduction in the mean proportions of the corpus callosum, especially in boys.¹⁷¹¹⁷² The corpus callosum is said to be more vulnerable to neglect in boys and more vulnerable to sexual abuse in girls.¹⁰⁷

1.3.2.11. 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.¹⁷³¹⁷⁴ This GABAergic cell migration is critical for subsequent cortical function, e.g., in schizophrenia.^173175176 Subsequent maturation of GABAergic cells is also affected by prenatal stress and correlates with altered social and anxiety-like behavior after prenatal stress. An IL-6 antagonist was able to prevent maternal stress-induced delay in the migration of GABAergic cell precursors in mice.^173174177173

Social isolation of rodents in the first days after weaning causes functional changes in the GABAergic system^5254178

Early childhood stress due to prolonged separation from the mother, endotoxins, or neglect (e.g., less attentive breastfeeding) alters the molecular composition of the gamma-aminobutyric acid (GABA)-benzodiazepine supramolecular complex. This caused:¹⁷⁹¹⁰⁷

• Decreased (high-affinity) GABA-A receptors in amygdala and locus coeruleus
• Decreased 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 amygdala nuclei, locus coeruleus, and nucleus tractus solitaricus.

In contrast, handling (briefly holding the newborn in the hand) increased all three values. It is known that brief handling leads to increased maternal care and attention, which causes increased (instead of decreased due to high stress) oxytocin levels.

Again, offspring of mothers who applied high levels of care showed as adults:¹⁸⁰

• More benzodiazepine receptors in amygdala (central, lateral, basolateral) and locus coeruleus
• More alpha2-adrenoreceptors in the locus coeruleus
  • This reduces feedback inhibition of noradrenergic neurons
• Fewer CRH receptors in the locus coeruleus
• A significantly lower anxiety to new stimuli
  Anxiety and fear are mediated by reduced GABEergic 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 caregiving during infancy serves to “program” behavioral responses to stress in offspring by altering the development of neural systems that mediate anxiety.¹⁸⁰¹⁰⁷

1.3.2.12. 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 complex with heat shock protein 90 and a number of other helper proteins, such as FKBP51, through which steroid signal transduction is influenced. ¹⁸¹

• Stress during 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.¹⁸²¹⁸³ The epigenetically altered variant of FKBP5 causes a permanent deterioration of stress regulation in affected individuals.
• 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 severe accidents. In the absence of such stressful events, the probability of depression is unchanged.¹⁸⁴ In the presence of such stress, the HPA axis shutdown normally triggered by cortisol at the end of the stress response is impaired. As a result, the HPA axis is not shut down cleanly and remains permanently activated.
  This effect is a phenotypic description of ADHD-HI (with hyperactivity).

1.3.2.13. Increased susceptibility to oxidative stress¶

Early as well as prolonged stress increases vulnerability to oxidative stress.¹⁸⁵

1.3.2.14. Alteration of the immunological stress response (Kindling effect)¶

Moderate and severe childhood maltreatment (MAL) positively correlates with the overall change in cytokine IL-6 stress response and maximum IL-6 concentration during TSST.¹⁸⁶

Traumatic experiences in childhood cause elevated CRP levels.¹⁸⁷
This could be due to the Kindling effect. Earlier activation of cytokines (proteins that fight inflammation) leads to a more intense cytokine response when activated again.
⇒ Kindling hypothesis of depression. Because cytokines can affect neurotransmitter systems, early childhood cytokine intoxications cause long-lasting changes in catecholamine systems (dopamine, norepinephrine, serotonin).
Thus, even low doses of the cytokine IL-2 in newborn mice caused permanently reduced levels of dopamine in the hypothalamus in adulthood.¹⁸⁸

1.3.2.15. 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 cortisol receptors or a change in the dopaminergic system.

1.3.2.15.1. Changes in DNA methylation¶

Early childhood stress experiences may 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 behavioral methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices. These brain regions are associated with ADHD.¹⁸⁹
Children who grew up in the home show significant changes in DNA methylation compared to children who grew up in families. These changes in DNA methylation can explain about 7 to 14% of the behavioral changes.¹⁹⁰

1.3.2.15.2. 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 hinder telomerase (the enzyme that repairs telomeres).^191192193 Shortened telomeres cause altered behavior. In contrast, it is less likely that certain later behaviors influence telomere length, because shortening of telomeres occurs primarily in the first years of life and is unlikely to occur in adults. Telomere length significantly influences gene expression. For a comprehensive and illuminating account, see Bateson, Nettle. Prenatal maternal stress correlates with shortened telomere lengths in children.^19419519670

• Behaviors promoted by shortened telomeres are¹⁹⁶
  • Impulsivity
    • Impatience
    • Devaluation of removed rewards
  • Risk appetite
  • 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 promoted by longer telomeres are¹⁹⁶
  • Physical activity

1.3.2.16. Reduced brain volume in adulthood due to early deprivation¶

Deprivation in the first years of life (here: in Romanian institutionalized children) caused a reduced brain volume in adulthood. This is not reversible even by an enriched environment (here: adoption).¹⁹⁷

1.3.2.17. Altered development of the blood-brain barrier¶

Early childhood stress resulted in altered blood-brain barrier development in rats by increasing caveolae-mediated transport in brain endothelial cells.¹⁹⁸

1.3.2.18. Other neurophysiological changes due to early childhood stress¶

• Decreased sensitivity to sedative hypnotics
  (shortened loss of the righting reflex)
  • CRH system
    • CRH receptor¹⁷⁸
  • Noradrenergic system¹⁷⁸
  • GABAergic system¹⁹⁹
  • Allopregnanolone⁵⁶²⁰⁰
• Increased susceptibility to picrotoxin-induced convulsions
  • GABAergic system
    • GABA-A receptor²⁰¹
  • Allopregnanolone²⁰¹
• Increased startle reflex⁶¹
• Impaired prepulse inhibition⁶¹
• Increased food gathering behavior (food hoarding)⁶¹
• Reduced susceptibility to GABAergic drugs
  • Such as pentobarbital and diazepam
• Histochemical changes in oligodendrocyte maturation and myelination²⁰² and dendritic spine density in mPFC²⁰³
• Downregulation of the biosynthetic pathway of allopregnanolone
  • Allopregnanolone is a neurosteroid with positive allosteric modulatory activity against the GABA-A receptor.²⁰⁴⁵⁶

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 a more severe ADHD-HI or ADHD-I course into adulthood, whereas children with mild stress levels often showed remitting ADHD.²⁰⁵
The fact that youth is a very vulnerable age segment is conversely shown in studies on the age-dependent effects of enriched environments in rodents. It is true that positive effects are already evident in childhood. However, the greatest benefit was observed in middle adolescence. Enriched Environment caused improved selective and auditory sustained attention, increased exploratory and foraging behavior, as well as a significant decrease in corticosterone levels and reduced anxiety levels.²⁰⁶