Severe stress and the development of the amygdala in youth: A theory and its statistical implications

doi:10.1016/j.dr.2017.08.001

Developmental Review

Volume 46, December 2017, Pages 44-53

https://doi.org/10.1016/j.dr.2017.08.001 Get rights and content

Highlights

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Development of amygdala volumes may be altered under conditions of severe stress.
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Stress may delay, accelerate, or prolong typical growth patterns.
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Theory may help address inconsistencies in the literature.

Abstract

An empirical understanding of normal developmental variation in the amygdala is emerging. However, studies examining volumetric differences in the amygdala among patient populations, particularly individuals with posttraumatic stress disorder (PTSD), have not produced a consistent pattern of findings. One reason for this may be the failure to effectively address age variation in study design and data analysis. Findings on age related variation in human amygdala volumes as well as the role of stress on amygdala development are reviewed. A theory is developed which posits that normal developmental variation in amygdala volumes may be altered under conditions of severe stress. Specifically, that stress may delay, accelerate, or prolong typical growth patterns. The theory highlights identifying the factors related to either delayed, accelerated, or a prolonged period of growth. The theory also points to systematically testing age as an interactive (moderator) variable in pediatric and psychiatric neuroimaging research. This is because the theory implies that disorder status/exposure to severe stress may influence the relationship between age and amygdala volumes.

Introduction

The amygdala is a brain region of the anterior portion of the temporal lobes. Its main functions are thought to be involved in the evaluation of the emotional significance of incoming stimuli (Tottenham, 2012, Tottenham and Sheridan, 2010). The amygdala projects to several brain structures in the frontal cortex, the hippocampus, the striatum, the hypothalamus, and brain stem (see Gordon and Hen, 2004, LeDoux, 2000, Tottenham, 2012, Tottenham and Sheridan, 2010). Because of its structural connections and functionally identified roles, the amygdala is considered to have critical involvement in behavioral activation (approach) and inhibition (withdrawal) systems underlying emotional responses such as fear and anxiety and their regulation (Gray, 1994, Gray and McNaughton, 2000). Activation of the behavioral inhibition system is associated with fear, anxiety, and negative emotionality. Because of this link, the amygdala has received particular attention in biological theories of anxiety and stress related disorders such as posttraumatic stress disorder (PTSD) as well as other disorders involving emotion dysregulation (e.g., Davis, 1998, LeDoux, 2000).

Understanding the development of the amygdala has implications for emotional health and emotional disorder research given its role in the evaluation of the emotional significance of stimuli. While the empirical data is emerging, several factors may shape brain development in youth. Identifying developmental influences, such as parenting and stress, which may be associated with differential brain development is an important task (Belsky & de Haan, 2011). A number of perspectives suggest there may be differences in amygdala volumes among individuals exposed to severe or traumatic stress (Karl et al., 2006, Morey et al., 2012, Tottenham and Sheridan, 2010, Tottenham et al., 2010, Woon and Hedges, 2008, Woon and Hedges, 2009). However, studies examining volumetric differences in the amygdala among individuals with PTSD have not produced a consistent pattern of findings. For example, Morey et al. (2012) reviewed 12 studies on amygdala volumes among individuals (9 adult samples and 3 youth samples) with posttraumatic stress and reported four studies indicating relatively smaller volumes (in both sides); one relatively smaller in the left, but larger in the right; one study relatively smaller in the right, larger in left; and six relatively larger in both sides (compared to control participants). Only 1 of these 12 reported p-values reached the typical 0.05 alpha to indicate a statistically significant difference and so one conclusion might be that there is a consistent picture of non-statistically significant differences.

In this paper, findings on age related variation in human amygdala volumes as well as the role of stress on amygdala development are reviewed. A theory is developed which posits that normal developmental variation in amygdala volumes may be altered under conditions of severe stress. Specifically, that stress may delay, accelerate, or prolong normal growth. The theory highlights identifying the factors related to either delayed, accelerated, or a prolonged period of growth. The theory also points to systematically testing age (and other indices of maturation like pubertal development) as an interactive variable in pediatric and psychiatric neuroimaging research.

Section snippets

Normal developmental variation

There is fairly clear evidence that the amygdala develops (neuronal connections and structurally grows in size) until late childhood. Table 1 summarizes fourteen studies found in a literature search (using Medline, PsycINFO, Google Scholar, & review of references in previous publications) that have examined normal developmental variation in amygdala volumes or otherwise correlated age with amygdala volumes in various patient and control samples. Thirteen of these fourteen studies reported a

The role of stress on amygdala development

Tottenham and Sheridan (2010) have argued that adverse experiences can produce long-term changes in the amygdala structurally. In their view there is a stress-induced kindling of the amygdala where repeated stimulation produces greater future excitability and this implies potential differences in morphology. For example, among children adopted from orphanage care, Tottenham et al. (2010) reported a significant linear association between amygdala volumes and the amount of time spent in the

Future directions and statistical implications

The developmental theory presented here and findings from Weems et al. (2015, 2013) help contextualize research on youth with a history of traumatic stress and offer suggestions for the use of age in other patient populations. In particular, the model augments the work of Tottenham and colleagues (Tottenham, 2012, Tottenham and Sheridan, 2010) linking exposure to stress with atypical developmental variation in amygdala volumes in institutionalized children. Moreover the theory and findings are

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Traumatic experiences during childhood significantly impact the developing brain and contribute to the development of numerous physical and mental health problems. To date, however, a comprehensive understanding of the functional impairments within the brain associated with childhood trauma histories does not exist. Previous functional magnetic resonance imaging (fMRI) meta-analytical tools required homogeneity of task types and the clinical populations studied, thus preventing the comprehensive pooling of brain-based deficits present in children who have trauma histories. We hypothesized that the use of the novel, data-driven Bayesian author-topic model approach to fMRI meta-analyses would reveal deficits in brain networks that span fMRI task types in children with trauma histories.
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Adverse Childhood Experience (ACE) has been shown to have detrimental impact on amygdala structure. Prior research found that adaptive psychological changes after Mindfulness-Based Interventions (MBI) were associated with amygdala volumetric changes. The present study aims to further investigate whether such effects also occur among ACE survivors and whether the effects are unique to MBI.
A total of 64 young adult childhood adversity survivors were randomized to an eight-week MBI or Stress Management Education (SME) as an active control condition. Anatomical MRI and questionnaires on mindfulness, stress and psychological health were collected at baseline and post-intervention. Due to subject dropout, the final sample included 39 subjects (MBI:20, SME:19).
Both groups showed increased mindfulness levels, reduced stress, and improved psychological symptoms (depression, anxiety, and somatization), with no significant group by time interaction effect. There was no significant group difference on amygdala volumetric changes. Within the MBI group, childhood maltreatment severity was a significant mediator between changes of mindfulness levels and right amygdala volumetric changes. Across pooled sample of both groups, childhood maltreatment was a significant moderator for the effect of trait anxiety level changes on left amygdala volumetric changes.
Modest sample size, relatively low retention rates, suboptimal monitoring of home practice.
MBI did not demonstrate overall better clinical effects than SME. Psychological-change-dependent amygdala volumetric change was not specific to MBI. Childhood maltreatment severity modulated the relationships between adaptive psychological changes and amygdala volumetric changes.
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However, this finding contradicts the current hypotheses, which anticipated faster development of the right amygdala. Weems’s (10) synthesis of the literature reveals that the right amygdala may be more susceptible to effects of stress exposure. Notably, the typically developing participants in the current sample were unlikely to have endured such extreme forms of stress.
There is evidence that the amygdala undergoes extensive development. The exact nature of this change remains less clear, with evidence suggesting linear, curvilinear, and null effects. The aim of this study was the identification of a normative reference of left and right amygdala development by parceling variance into separate effects of age and longitudinal growth.
Data came from the National Institutes of Health MRI Study of Normal Brain Development. Participants in this sample were 54% female and ranged in age from 5 to 18 years (mean = 11.37 years) at study entry.
As predicted, the age at initial scan moderated the slope of both left and right amygdala volumes, demonstrating that the nature of longitudinal growth varies across age (i.e., steeper slopes observed among those first scanned at an early age). Follow-up analysis showed that the positive longitudinal growth slope becomes nonsignificant at 13.1 years of age for the left amygdala and at 14.5 years for the right amygdala, suggesting that growth of the left amygdala peaks earlier than growth of the right amygdala.
Findings suggest that rapid increases in volumes at early ages decline as youths enter adolescence and may turn to minor declines in volume during late adolescence or early adulthood.
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Previous reviews of this literature (6,17) have proposed that a lack of significant findings regarding amygdalar volume in pediatric PTSD (9–11,15,19) may stem from developmental changes in limbic structures (38–40) that have not been taken into consideration. That is, the association between amygdalar volume and PTSD may vary depending on age, such that an effect could be obscured in studies that do not examine age-related changes (17,41). Although we find that age is a significant moderator of variability for hippocampal but not amygdalar regions in our primary analysis, age does emerge as a significant moderator for amygdalar regions when only tracing studies are included in the meta-analysis.
Findings on structural brain volume associated with pediatric posttraumatic stress disorder (PTSD) have been variable, and it is unclear whether any structural differences are specific to pediatric PTSD in comparison with adult PTSD or other co-occurring pediatric psychiatric conditions.
We tested volumetric brain differences between pediatric groups with and without PTSD in a region-of-interest meta-analysis. We conducted meta-regressions to test the effects of age and sex on heterogeneous study findings. To assess specificity, we compared pediatric PTSD with the following: adult PTSD, pediatric trauma exposure without PTSD, pediatric depression, and pediatric anxiety.
In 15 studies examined, pediatric PTSD was associated with smaller total gray matter and cerebral, temporal lobe (total, right, and left), total cerebellar vermis, and hippocampal (total, right, and left) volumes, compared to peers without PTSD. In the pediatric PTSD group, but not the comparison group, we found a trend toward smaller total, right, and left amygdalar volumes. In an external comparison, smaller hippocampal volume was not significantly different between adult and pediatric PTSD groups. Qualitative comparisons with a pediatric trauma exposure without PTSD group, a pediatric depression group, and a pediatric anxiety group revealed differences that may be unique to pediatric PTSD, and others that may be convergent with these related clinical conditions in youth.
Pediatric PTSD is associated with structural differences that parallel those associated with adult PTSD. Furthermore, pediatric PTSD appears to be distinct from other related pediatric conditions at the structural level. Future studies employing longitudinal, dimensional, and multimodal neuroimaging approaches will further elucidate the nature of neurobiological differences in pediatric PTSD.
Does distress tolerance interact with trait anxiety to predict challenge or threat appraisals?
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Citation Excerpt :
Given the developmental shifts in emotion regulation and cognitive processes pertinent to risk or threat assessments occurring in early adulthood (Casey, Jones, & Somerville, 2011), future longitudinal efforts may also lend strength to this field by describing the stability of stress appraisals over time. This is particularly warranted given neurodevelopmental evidence of age-related changes in the maturation of structures associated with behavioral activation and inhibition crucial in the regulation of fear, anxiety, and negative emotions (Weems, 2017). Paired with evidence of similar age-related developments in assessing risk and decision-making (e.g., Rudolph, Miranda-Domínguez, Cohen, et al., 2017), future longitudinal studies should test stress appraisals as a mechanism that links DT and aspects of psychological functioning such as engagement in risky behaviors (e.g., Beck et al., 2013).
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ReviewSevere stress and the development of the amygdala in youth: A theory and its statistical implications

Highlights

Abstract

Introduction

Section snippets

Normal developmental variation

The role of stress on amygdala development

Future directions and statistical implications

Biological Psychiatry

Biological Psychiatry

Biological Psychiatry

Biological Psychiatry

Biological Psychiatry

Biological Psychiatry

Neuroscience & Biobehavioral Reviews

Neuron

Neuroscience and Biobehavioral Reviews

Neuroimage

Biological Psychiatry

Psychiatry Research

Neuroscience & Biobehavioral Reviews

Biological Psychiatry

Physiology & Behavior

Behavioural Brain Research

Brain Research

Abnormal functional architecture of amygdala-centered networks in adolescent posttraumatic stress disorder

Human Brain Mapping

Diagnostic and statistical manual of mental disorders

The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations

Journal of Personality and Social Psychology

Variation in susceptibility to environmental influence: An evolutionary argument

Psychological Inquiry

Differential susceptibility to rearing influence: An evolutionary hypothesis and some evidence

Origins of the Social Mind: Evolutionary Psychology and Child Development

For better and for worse differential susceptibility to environmental influences

Current Directions in Psychological Science

Annual research review: Parenting and children’s brain development: The end of the beginning

Journal of Child Psychology and Psychiatry

Beyond diathesis stress: Differential susceptibility to environmental influences

Psychological Bulletin

An operational definition of epigenetics

Genes & Development

The role of puberty in the developing adolescent brain

Human Brain Mapping

A theory of the epigenesis of neuronal networks by selective stabilization of synapses

Proceedings of the National Academy of Sciences of the United States of America

Review
Severe stress and the development of the amygdala in youth: A theory and its statistical implications