Stressors refer to stimuli and context (e.g. losing a job). It is not the individual response to a stressor. There are positive stressors (1), tolerable stressors (2) and toxic stressors (3).

A positive stressor has the least impact on health (e.g. getting married). A stressor leads to change and can thus be positive. Toxic stressors are highly negative stressors (e.g. childhood adversity).

Childhood adversity refers to absence of nurturing stimulation or the presence of harmful stimulation. This is associated with maladaptive family functioning. This is highly predictive of mental disorders later in life and increases the need for early detection of childhood adversity. The effect of neglect can be measured using the still face experiment.

The stress system involves the amygdala, which signals the hypothalamus. This starts a cascade of hormonal reactions which is represented in the HPA axis. There is a fast and a slow stress response.

Chronic stress leads to a dysregulated HPA axis. The dysregulation can lead to a blunted cortisol response or a heightened cortisol response. Both are associated with impairments in executive functioning. A dysregulation of the HPA axis increases sensitivity to psychopathology and disease.

The 3-hit concept of vulnerability and resilience states that there are individual differences at the genetic level of the stress response. This influences the baseline stress response of a person. Thus, a negative genetic predisposition interacts with the early-life environment. The genetic predisposition is hit 1, the early life environment is hit 2 and hit 3 is the later life environment. Three negative hits would lead to negative health outcomes according to the model.

There are different methods to assess stress during different developmental periods.

HPA-axis dysregulations are apparent in stress-related psychiatric disorders. HPA-axis dysregulations appear to already be present during childhood adversity in children between the age of 0 and 5. There is a decrease in cortisol reactivity (1), increase in cortisol reactivity (2), decrease in baseline cortisol (3) and increase in baseline cortisol (4).

Childhood adversity could include maternal substance use during pregnancy (1), maternal mood and stress levels during pregnancy (2), maternal psychiatric and medication history (3), means of infant feeding (4), socio-economic status (5) and family structure and mother-infant attachment (6). These factors ideally should be studied in isolation, although this is often not possible.

Maternal care regulates the HPA-axis. The developmental theory of sensitive periods states that there are sensitive periods in which calibration of the HPA-axis is possible. In humans, HPA-axis regulation occurs due to breastfeeding (1), holding the child (2) and nurturing the child (3).

There are contextual adversities which are not as extreme as maltreatment but could still influence typical development (e.g. poverty). Parental behaviour mediates the effects of contextual adversity on child outcomes. There appears to be no connection between specific types of early adversity and HPA-axis hyper- or hypoactivity in early childhood.

It is likely that contextual adversity exerts influence on the HPA-axis through increasing experiences of direct adversity. The alterations in the HPA-axis, in turn, impairs development and functioning of brain structures which are important for self-regulation. The impairment in self-regulation increases the risk for psychopathology in the long-term.

During the early development of a child, there are dramatic developmental changes in frontolimbic circuitry involved in emotional reactivity and regulatory processes that may be particularly sensitive to early life experiences. Habituation in amygdala response to repeated exposures to threat cues is related to increased reports of anxiety symptoms. Without regulation after early life stress, there is a persistent effect of early life stress.

Early lie stress may lead to a premature closing of a sensitive period of neural development of frontolimbic circuitry. Early life stress can lead to persistent alterations in frontolimbic development and function. This highlights the importance of caregiver and early interventions in facilitating healthy brain development and emotional well-being.

The mother’s presence lowered the cortisol response to social stress for 12-year-old children in children who are adopted before 18 months. However, this does not occur for children that are adopted after 18 months. This provides evidence for the existence of a critical period of HPA-axis finetuning.

In development, there is a change from co-regulation (i.e. regulation together with the caregiver) to self-regulation. Mostly the reactivity aspect of the child’s behaviour needs to be regulated.

The perseverative cognition theory states that perceived stressors cause worry and physiological stress responses that ultimately lead to health problems. This means that the perceived stressors are the most important compared to the actual stressors. Thus, actual and perceived stressors lead to a chronic stress response.

The general unsafety theory of stress states that the stress response is a default response. According to the model, chronic stressors are caused by generalized unsafety, independent of their cognitive representation. The theory further states that people have the perception that they have no control over a stressor (i.e. no ability to cope).

The model states that the stress response is a default response and the response is inhibited by the perception of safety. Chronic stress responses are caused by the generalized perception of unsafety independent of stressors or their cognitive representation. The default response (i.e. stress response) may not be inhibited in modern society due to the failure to recognize situations as safe.

The default mode network refers to a network of brain areas which are activated when the brain perceives safety and is not involved in any particular task. The default stress response is inhibited during the default mode network. Safety signals are learned cues that predict the stress-free periods. The stress-reducing effect of predictability refers to the inhibition of the default response when stressors could be predicted. Low resting heart rate variability is an index of the chronically disinhibited default response.

It is important that people experience some stressors and develop experience with the control of stressors. There is enhanced stress vulnerability in later life as a result of chronic early life stress. Stress-related cognition is not necessary for a continued default response.

There are three conditions carrying health risks relevant to compromised unsafety:

1. Compromised bodies
   An unfit body (e.g. overweight; old) cannot fully be trusted and this leads to fewer perceptions of safety. Unfit bodies are unable to recognize safety signals with respect to the physical ability to deal with stressors.
2. Compromised social network
   This states that a social network which is not beneficial for the individual (e.g. loneliness) can lead to fewer perceptions of safety.
3. Compromised contexts
   This refers to daily contexts which are neutral by themselves which then are seen as unsafe after association with stressors via contextual conditioning.

Contexts are compromised (i.e. not perceived as safe) due to conditioning. A compromised context can be a neutral situation which has been paired with stressors.

Problem-solving skills are important because this allows worriers to relief their problems. However, while worriers are very good at defining problems, they are very poor at generating successful solutions or effective coping responses. Improving someone’s coping or problem-solving skills may reduce the impact of a dysregulated HPA-axis.