Neurobiological Programming of Early Life Stress- VanTieghem & Tottenham - 2017 - Article

Summary with the article: Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for Stress-Related Psychopathology - VanTieghem & Tottenham - 2017

Numerous experiments have shown the influence of early adverse experiences on vulnerability for stress-related mental illnesses. The research focusses on the effects on neurobiology in adulthood and outcomes in long-term mental health. In this review, the role of emotion regulation involved in stress-related syndromes is discussed from a transdiagnostic -and developmental perspective. The evidence that multiple adverse experiences impact functional development of the amygdala-prefrontal circuity. These alterations in development are associated with dysregulation of emotions symptoms. Potential mediating mechanisms of this process are examined as well. Protective factors may shield the consequences of adversities on amygdala-prefrontal development and cause more adaptive outcomes. The objective is to gain further insight in mechanisms linking early adversity, neurobiology and emotional phenotypes. This could facilitate the implementations of successful interventions created to reduce the risk for psychopathology in youth exposed to early life stress.

What is the connection between childhood adversities and mental health outcomes?

Several mental health problems in adulthood are associated with early life stress (ELS). These childhood adversities include maltreatment, neglect, parental stress, family conflict, trauma or poverty-related stressors. Experiences as such cause neurobiological changes that can cause mental illness across the lifespan. Especially adaptive processes are important for the link between ELS and mental health. The dynamic systems theory explains development in terms of experiences, it emerges via the interaction with the environment. Thus, the role of adaptation in response to ELS must be promoted. The stress-acceleration hypothesis states neurobiological changes caused by ELS can have long-term trade-offs in the neuro-affective circuitry and functional integrity. These neurobiological adaptive short-term responses are associated with maladaptive mental health outcomes later in life.

In the current review, the effects of early adverse experiences on neuro-affective development is researched. The risk for dysfunctional stress-related emotion regulation is discussed. Multiple forms of ELS are defined by functional phenotypes of neuro-affective circuitry across development. There are three forms in functional development and stress-induced changes.

1. There is an increased activity of the amygdala.

2. The amygdala-prefrontal activity is higher.

3. Developmental changes in the amygdala-prefrontal cortex circuitry will predict differences in stress-related mental dysfunctionality.

What is the role of the amygdala-prefrontal circuitry in emotion regulation?

Symptoms of dysregulation of emotions are associated with amygdala-prefrontal circuitry. The links between amygdala and prefrontal cortex are involved in emotion regulation and learning. The amygdala detects salient information and triggers psychological responses when a potential threat comes along. Patients with internalized stress disorders, including anxiety, PTSD and depression show functional alterations of amygdala reactivity and amygdala-prefrontal connectivity. The amygdala-prefrontal circuitry endures sustained development containing age-related changes. The amygdala is more active in response to emotional cues at a young age. Its integrity strengthens during adulthood. Paediatric disorders, such as depression, PTSD and anxiety are defined by increased amygdala reactivity and atypical amygdala-prefrontal cortex connectivity while processing emotions.

How is the plasticity of amygdala-PFC circuitry in early life?

The amygdala-PFC circuitry is sensitive to environmental input, especially in early life. Corticotrophin releasing hormone (CRH) and mRNA concentrations shape stress-response in early life. Furthermore, the development of the amygdala relies on the hypothalamic-pituitary-adrenal (HPA) axis function, this determines onset of reactivity and fear-learning. Evidence is found that ELS causes long-term effects on the amygdala and its function, regulatory connections and structure. There are two crucial considerations that outline the state of current research.

1. Timing and duration of exposure to ELS is often unclear. As many forms of ELS are chronic, it is difficult to depict the effects of stressors during specific periods.

2. Certain dimensions of ELS may have different effects on neurobiological development.

What are the effects of ELS on amygdala reactivity and amygdala-PFC connectivity?

Emotional neglect, lower perceived social status and maltreatment is associated with heightened amygdala reactivity. Childhood stressors combined with socioeconomic status show lasting effects on the functioning of the amygdala in response to emotional stimuli. Previously internalized (PI) youth show increased amygdala reactivity. This indicates that the increased reactivity of the amygdala is a neural marker of previous exposure to stress. Also, there seems to be a connection between onset of maltreatment and amygdala reactivity.

Besides increased amygdala reactivity, the connectivity with prefrontal regions is also altered by ELS. Evidence shows connectivity patterns of amygdala-PFC connections are altered after exposure to ELS. Modulating effects of family income were found, which shows prefrontal dysregulation is caused by chronic stress. The increased emotional reactivity is caused by top-down prefrontal regulation of amygdala reactivity as a response to emotional cues. Youth that experienced trauma show weaker connectivity between the amygdala and PFC. It also predicts performance on the emotional conflict task showing an impaired regulation of emotional distractors. The resting state of the amygdala-PFC connection is altered by ELS as well. The effect of ELS can start as early as infantry, altered patterns of resting-state amygdala have been found at 6 months, caused by maltreatment.

Are there individual differences in psychopathology caused by ELS?

Different types of ELS could have converging effects on the development of emotion regulation circuitry. This can cause an atypical amygdala-prefrontal circuit function. On the other hand, heterogeneity in long-term mental health outcomes has been discovered. Similar adverse experiences contain risks for different pathology types in adults. The stress acceleration hypothesis states that environmentally driven changes in neurobiology show an ontogenetic response to ELS and cause maladaptive behavioural outcomes. It is important to consider individual trajectories to be able to predict the risk of exposure is childhood maltreatment.

What are individual differences in amygdala reactivity and psychopathology?

Typically, increased amygdala reactivity causes internalizing -and depressive symptoms. Evidence shows greater amygdala reactivity after exposure to trauma and PTSD to emotional stimuli. It was found that early trauma and levels of psychopathology predict amygdala response. Increased amygdala reactivity also predicts negative affect in both depressed and healthy children. Thus, amygdala reactivity is a neural marker for current -and future levels of stress-related mental dysfunction.

What are long-term effects of amygdala-PFC connection and psychopathology?

An abnormal amygdala-PFC connection can represent a neurobiological risk for the development of a psychopathological syndrome. The strength of resting-state amygdala connectivity is a mediator between childhood stress and the internalization of symptoms. A weaker connectivity causes higher anxiety and depressive symptoms. Furthermore, weaker amygdala-ACC connectivity mediates the effect of trauma and stress on anxiety symptoms. Amygdala-PFC connection and symptom-levels were both able to predict anxiety symptoms one year after measurement. Thus, stress-related changes in functioning of the amygdala-PFC circuitry causes stress-related psychopathology.

Another important predictor is the cortisol hormone. Maternal stress influences the cortisol hormone levels during resting state amygdala-PFC connection. Greater childhood stress equals increased cortisol (stress-hormone) during resting state. Higher baseline cortisol levels are associated with altered amygdala-PFC connection in resting state. Maternal stress does not directly influence amygdala-PFC connections, but mediates the relation between heightened cortisol levels and depressive symptoms. A weaker amygdala-PFC connection predicts more anxiety, whereas a stronger connection predicts more depressive symptoms. Stress-related changes are associated with atypical amygdala-PFC connections and therefore cause an increased vulnerability for internalizing psychopathology followed by early childhood stress.

What have cross-sectional studies discovered about the amygdala-PFC connection?

Several cross-sectional studies were executed to examine the effects of ELS on age-related alterations in the development trajectory of the amygdala-PFC circuit function. For example, previously PI youth showed an atypical age-related amygdala-PFC connectivity when presented with fearful stimuli. The amygdala-PFC connection was more negatively focussed, compared to people from the same age that had not been institutionalized. Cortisol levels mediated the relationship between ELS and amygdala-PFC connection. This supports the role of the HPA-axis in stress-related alterations in neuro-affective development. Furthermore, amygdala-PFC connections predicted the current psychopathology levels of participants in the PI-group. People with a more mature connection, showed more anxiety. According to the stress acceleration hypothesis, earlier functional maturation of the amygdala-PFC connection is an adaptation to previous exposure to stress.

According to another study, atypical amygdala-PFC functional is important in PTSD caused by childhood maltreatment. Threat-related connectivity of the amygdala-PFC predicted severity of avoidant symptoms in young people suffering from PTSD. Also, changed patterns of connectivity related to age was found in people with PTSD. The amygdala-PFC connection increased with age and children show a more matured pattern of this connection compared to others the same age. On the other hand, adults with PTSD show a less mature amygdala-PFC connection. According to the stress-acceleration hypothesis adaptation in childhood may result in reduced maturity in adulthood. No effects were found of the time of diagnosis and amygdala-PFC connection. It does not mean traumatic effects at earlier versus later stages of development have different effects on neuro-affective development.

What are protective factors of neuro-affective development following ELS?

Not everyone who is exposed to stress-related childhood experiences develops a psychopathologic dysfunctionality. Many individuals do not develop a clinical disorder. Moreover, people that experienced ELS might show better functioning in some domains. Both cognitive -and environmental factors contribute to individual differences in mental well-being following ELS. Protective factors of the social environment are discussed here.

• Quality caregiving and family stability mediates the effect of exposure to early adversities. Also, interventions at a young age caused lower levels of internalizing symptoms.

• Social buffering effects, such as maternal presence blocks stress relativity and learning of fear. It reduces cortisol levels in result to social stress and enhances emotion regulation abilities. However, some evidence for parental presence during a socio-emotional functioning task shows that it has no greater regulatory effect on cortisol reactivity. It is suggested that social-buffering mechanisms are diminished following atypical caregiving experiences.

What are limitations and future research suggestions of this study?

The authors state several limitations with corresponding suggestions for further research on this subject, these are described here.

1. There is not enough research on the effects of timing and chronicity of stressors on neuro-affective development. In future research animal studies could be useful in examining the effect of age and allow for greater conclusions about causality. This is because in animal studies, age of onset can be experimentally manipulated.

2. Different childhood adversities can cause different aspects of neurobiological development. A distinction should be made between for example, threat, anxiety and neglect. Other dimensions may target other neural circuits.

3. Genetic factors may also be important in neuro-affective development followed by ELS. Epigenetic factors should be considered as they influence depressive symptoms.