Whatever happened to Harold Smith Peaches

Stress damage from early / prolonged stress

Stressors activate the different, parallel acting stress systems of humans. The most important are the autonomic nervous system (sympathetic / parasympathetic), which is quickly controlled by electrical nerve impulses, and the HPA axis, which is slowly controlled chemically by hormones. The HPA axis releases stress hormones in a series, starting with CRH and vasopressin, then ACTH and finally cortisol. These trigger stress symptoms at higher levels (which is healthy up to this point). However, if they are prolonged, they have a neurotoxic effect.(1)(2)(3)(4) If the levels are too low, the stress symptoms and reactions are not sufficiently formed and if the cortisol release is too low, the HPA axis cannot be shut down again properly in the end.
⇒ The HPA axis / stress regulation axis

The neuroplastic effect of long-term stress was described as an allostatic concept as early as 1988.(5)(6)
Prolonged exposure to stress leads to an allostatic overload(7) (acute pathological consequences of allostatic reactions), which causes changes in the following brain regions, among others, which in turn changes behavior and physiological reactions:

  • Hippocampus (decrease in volume)
    • cognitive impairment
    • depressions
    • Self-esteem impairment
  • Amygdala
  • PFC

Stress exposure has very different effects depending on the age of the individual.(8)(9)(10)

1. Stress by age when exposed

1.1. Stress is particularly harmful during active brain development phases

There is a considerable difference between whether stress occurs during a development phase of a brain region or outside it (especially after the end of brain development, in people around the age of 24).


  • The epigenetic demethylization of the FKPB5 gene, which modulates the sensitivity of the glucocortioid receptors(11) is only mediated by stress during the differentiation and proliferation phase of the neurons, but no longer in mature neurons.(12)
  • If excessive stress occurs during the development phase of the HPA axis, this increases the sensitivity of the HPA axis by permanently lowering the threshold values ​​for the occurrence of the stress reaction.(13) This worsens the ability to respond adequately to stress.(14) This can lead to pathologically altered reactions to stressors in later life (including anxiety disorders, depression, autism, schizophrenia).

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

This is done in several ways, including:

  • Early stress causes defective development of the dopaminergic pathways of the nucleus accumbens.(15)
  • Children who were exposed to a stressful environment or unsafe attachment in the first 6 years of life suffer permanent damage in dopaminergic and serotonergic regions of the brain.(16)

Based on the description by Rensing et al. to 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 encounter already damaged stress systems,(17) it would be conceivable to consider AD (H) S as the result of the first hit.
An examination that could not determine an increased specificity of symptoms of a disorder with increasing severity of the disorder may speak against the assumption of AD (H) D as the first hit for further disorders.(18)

Stress in puberty can increase stress levels in early childhood.(19) Another study shows that adults who reported more than five AD (H) D symptoms from their childhood developed mental disorders or addictions at an above-average rate.(20)

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

Not only the type and intensity of early childhood stress, but also the point in time of the stress determines the later disorder. This results from the fact that the development of the mammalian brain follows a certain timeline. The individual brain regions do not develop at the same time, but in their own time windows. In a phase of development, the respective brain regions are considerably more susceptible to external disturbances.

  • Cortisol treatment during pregnancy decreased the sensitivity of the corticoid receptors in the PFC in newborn monkeys, with the timing of cortisol administration determining in which parts of the PFC this occurred. In adult monkeys, decreased receptor sensitivity due to administration of cortisol was no longer observed.(21)
  • Severe anxiety in the mother in pregnancy during the 12th to 22nd week after the last rule significantly increased the risk of ADHD, while severe anxiety in the 32nd to 40th week did not increase the risk.(22) In contrast, a study in children of women who were exposed to repeated rocket fire at the civilian population for one month in the 2006 Lebanon war found no increased psychiatric disorders at the age of 9 years.(23) Repeated stress for a month may not be a sufficiently intense stressor.
  • The developmentally oldest regions of the brain in the brain stem, which control the basic life mechanisms and which develop first, are susceptible to very early disturbances, which are then often fatal.
    Cortical areas of the brain that are not essential for survival and that develop later in time are susceptible to disorders that occur at a slightly later stage in development.(24)
  • The specific effects of long-term stress exposure on the brain, behavior and cognition depend on the time and duration of the stress exposure and, in part, on an interaction between gene effects and early childhood stress. These differences can explain why stress at different times in life leads to different mental disorders.(25)
  • Traumatic experiences before the age of 12 (such as loss of a parent through death or permanent separation) increase the risk of later depressive illness, while traumatic experiences afterwards increase the risk of PTSD(26)(27)
  • Traumatic experiences before the age of 6 showed different dexamethasone / CRH test results than traumatic experiences at a later age.(28)
  • Persistent emotional abuse in childhood correlated (as the only type of abuse) with a different (here: decreased) cortisol response to acute stressors with increasing adulthood.(29)
  • Sexual abuse at ages 3 to 5 or ages 11 to 13 decreased the volume of the hippocampus, while sexual abuse between ages 14 and 16 decreased the volume of PFC.(30)
  • Extensive and long-term support for 733 people with various personality disorders showed that the different intensity and timing of early childhood stress also contributed to the differentiation of the disorders.(31) All those affected were victims of early childhood stress: 73% of the 733 participants reported early childhood abuse, 82% reported 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 state of development of these brain regions at the time of stress.(32)
  • For example, the type and timing of early childhood stress should differentiate between the environmental development of AD (H) D and borderline.(33)

The main development times in which the respective brain regions are particularly vulnerable are (in years of life)(34)

  • Amygdala on the left: 0.5 to 2 years
  • Hippocampus: 3-5(35) and 11-14 years
  • dorsal anterior cingular cortex: 7-9 and 17-x years
  • Internal long fasciculus: from 7 years
  • Thalamus: 7-9 and 13-15 years
  • Corpus callosum: 9-10 years(35)
  • Ventromedial PFC: 8-10 and 14-16 years
  • Amygdala on the right: from 10 years
  • visceral cortex: from 11 years
  • PFC (volume): 8-15 years(36) 14-16 years(35)

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.(37)

1.3. Early childhood stress

Early stress increases the risk of mental disorders.(38)(39) Emotional, physical or sexual abuse in children as well as trauma cause a long-lasting (beyond the time of abuse) profound disturbance of the stress regulation.(40) There is some evidence that children whose mothers were exposed to particular stress levels during pregnancy have a persistent increased vulnerability to mental disorders.(41)
Children of women who were exposed to repeated rocket fire by civilians within one month of the 2006 Lebanon War were not found to have increased psychiatric disorders at the age of 9.(23) This suggests that a month of repetitive stress is not a sufficiently chronic stressor to harm the unborn child.

Baby rats separated from their mother at an early stage have a long-term increased physiological and behavioral stress reaction to other stressors. The threshold value for the occurrence of the stress reaction is reduced.(42) The same applies to baby rats whose mothers showed poor care behavior.(43)(44)
A study of adopted AD (H) D sufferers also deals with the question of how much of AD (H) D is inherited and how much is acquired.(45)

Even with early childhood stress, it depends on whether it is beneficial or disadvantageous. Very brief handling (removing baby rats from mother by hand) is a beneficial stimulus, largely because it increases the rate of maternal licking and grooming. Prolonged periods of separation of newborn rats from the mother are stressful, mainly because they weaken maternal licking and grooming,(46) associated with the release of oxytocin.

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.(47)(48) Likewise, cold and indifferent families or chaos in the home environment lead to permanent emotional problems in children.(49)(50) AD (H) D and PTSD most common disorders in childhood stress

AD (H) D and PTSD / PTSD are the most commonly diagnosed disorders in sexually abused children. There is a high degree of symptom overlap and comorbidity between AD (H) D, PTSD, and sexual abuse.(51) Early stress increases the risk of depression

Early childhood stress changes the structure and function of the brain and increases the risk of depression later on.(52)(53) PTSD / PTSD risk increased due to early stress

Early stress increases the risk of later post-traumatic stress disorders,(52)(53) Obesity and cardiovascular disease risk increased by early stress

Early stress increases the risk of obesity and cardiovascular disease.(54)(55) Increased stress intolerance risk due to early stress

Early stress increases the likelihood of increased subjective stress sensitivity in adulthood, which is associated with an increased risk of anxiety disorders and depression.(56)

The development of an increased sensitivity to stress seems 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 fear-like behavior and less fear extinction.(57) Increased risk of attention and learning problems due to early stress

Early childhood (non-sexual) abuse affects alertness at ages 14 and 21.(58)

Impaired latent learning and attention deficit due to early childhood stress correlate with changes in the cholinergic system related to the muscarinic and nicotinic receptor.(59)

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

    • NMDA receptor(60)
    • GABA-A receptor(60)
    • serotonergic system(61)
    • Hippocampus: impairment of neurogenesis(61) Risk of aggression disorder increased due to early stress

The social isolation of rodents in the first days after weaning causes increased aggressiveness,(60) linked to various neurophysiological correlates:

  • noradrenergic system, beta-2 adrenoceptor(62)(63)
  • Neurosteroid system
  • GABAergic system
  • serotonergic system
  • glutamatergic system Increased risk of hyperactivity due to early stress

The social isolation of rodents in the first days after weaning causes increased motor skills,(69)