Elsevier

NeuroImage

Volume 97, 15 August 2014, Pages 236-244
NeuroImage

Sensitive periods of amygdala development: The role of maltreatment in preadolescence

https://doi.org/10.1016/j.neuroimage.2014.04.025Get rights and content

Highlights

  • Adults with childhood maltreatment show increased amygdala volume.

  • Severity of adversity accounts for 27% of variance in right amygdala volume.

  • Adversity at age 10–11 contributes to larger right but not left amygdala volume.

  • Results suggest a potential sensitive period of the amygdala in preadolescence.

  • Clinical interventions during sensitive periods may help limit sequelae of abuse.

Abstract

The amygdala is vulnerable to stress-dependent disruptions in neural development. Animal models have shown that stress increases dendritic arborization leading to larger amygdala volumes. Human studies of early stress and amygdala volume, however, remain inconclusive. This study compared amygdala volume in adults with childhood maltreatment to that in healthy controls. Eighteen participants from a longitudinal cohort and 33 cross-sectional controls (17 M/34 F, 25.5 ± 3.1 years) completed a structural magnetic resonance imagining scan and the Maltreatment and Abuse Chronology of Exposure scale. Random forest regression with conditional trees was used to assess relative importance of exposure to adversity at each age on amygdala, thalamic or caudate volume. Severity of exposure to adversity across age accounted for 27% of the variance in right amygdala volume. Peak sensitivity occurred at 10–11 years of age, and importance of exposure at this time was highly significant based on permutation tests (p = 0.003). The regression model showed that exposure during this sensitive period resulted in steep dose–response function with maximal response to even modest levels of exposure. Subjects in the highest exposure quartile (MACE-11, range = 11–54) had a 9.1% greater right amygdala volume than subjects in the lowest exposure quartile (MACE-11, ≤ 3.5). No associations emerged between age of exposure and volume of the left amygdala or bilateral caudate or thalamus. Severity of adversity experienced at age 10–11 contributed to larger right but not left amygdala volume in adulthood. Results provide preliminary evidence that the amygdala may have a developmental sensitive period in preadolescence.

Introduction

Childhood adversity is a major risk factor for psychopathology associated with 30–70% of the population attributable risk fraction for depression, suicide attempts, anxiety disorders and substance abuse (see Teicher and Samson, 2013 for review). Early adversity may increase risk through excessive release of glucocorticoids and epigenetic modifications that alter critical developmental processes such as neurogenesis, synaptogenesis and myelination (Lupien et al., 2009). The amygdala may be particularly vulnerable due to high glucocorticoid receptor density (Peiffer et al., 1991) and postnatal developmental trajectory characterized by rapid initial growth followed by more sustained growth to peak volumes between 9 and 11 years and gradual pruning (Payne et al., 2010, Uematsu et al., 2012). Aberrant amygdala volume and function have been reported in psychiatric disorders marked by affective dysregulation (Rauch et al., 2006, Saleh et al., 2012, Lange and Irle, 2004, Schmahl et al., 2003a).

Translational studies show that psychological stressors (i.e., immobilization) and administration of stress hormones stimulate dendritic arborization and formation of new spines in the amygdala and increase volume (Mitra et al., 2005, Vyas et al., 2006). Using a parallel human-mice model, Cohen et al. (2013) showed that manipulating type and timing of stressor to parallel early orphanage experiences in humans led to early and persistent alterations in amygdala development and function. Interestingly, this pattern is opposite to stress-induced hippocampal atrophy and is less reversible even when the stressor is removed (Cohen et al., 2013, Vyas et al., 2004). The consequences of early life stress on the human amygdala and the underlying causes (e.g., dendritic arborization), however, remain inconclusive. In fact, many studies have reported no differences in amygdala volume following adversity (Bremner et al., 1997, Brambilla et al., 2004, van Harmelen et al., 2010, Andersen et al., 2008, Ansell et al., 2012, Cohen et al., 2006, Dannlowski et al., 2012, De Bellis et al., 2001, De Bellis et al., 1999, De Bellis et al., 2002, Carrion et al., 2001). Yet, increased amygdala volume was found in children who had experienced prolonged institutional deprivation (Mehta et al., 2009, Tottenham et al., 2010) or rearing by chronically depressed mothers (Lupien et al., 2011). In contrast, smaller amygdala volumes were reported among adults with childhood trauma and diagnoses of Borderline Personality (Driessen et al., 2000, Schmahl et al., 2003b) or Dissociative Identity Disorders (Vermetten et al., 2006, Weniger et al., 2009).

Several factors may contribute to these inconsistencies. First, stress-related effects on the amygdala may change over development, leading to hypertrophy in childhood followed by shrinkage in adolescence or adulthood. Second, the amygdala may show a differential response to stress, enlarging in the face of neglect or insufficient human interaction, as with prolonged institutional deprivation, or shrinking with exposure to the types of intense abuse often reported by individuals with borderline personality or dissociative identity disorders. Third, the timing of adversity may be critical (Andersen et al., 2008, Tottenham and Sheridan, 2009). Given the amygdala's developmental trajectory, it may be particularly sensitive to structural changes during early childhood when it is growing at a rapid rate and again during preadolescence when growth peaks and pruning takes over, as observed in the hippocampus (Andersen and Teicher, 2008).

To explore these factors, we recruited adults from a 30-year longitudinal sample who were followed since infancy and had experienced significant levels of childhood adversity during different developmental stages to take part in a magnetic resonance imaging (MRI) study. Control subjects were healthy adults with no or very low levels of childhood adversity. It was hypothesized that adults who experienced childhood adversity would show: (1) increased stress-related symptoms, and (2) increased amygdala volume. We also explored whether exposure to adversity during particular developmental windows was associated with larger effects on amygdala volume.

Consistent with previous research (e.g., Tottenham et al., 2010), the caudate and thalamus were selected a priori as control structures that should be less susceptible to periadolescent stress due to their developmental trajectory and lower glucocorticoid receptor density (Patel et al., 2000, Giedd et al., 1996a, Hasan et al., 2011).

Section snippets

Participants

The study was approved by the Harvard Medical School, Cambridge Hospital, and McLean Hospital IRBs. Subjects provided informed written consent and were reimbursed $100 for their time. Two groups were enrolled: 18 longitudinal participants with early and continued life stress (ELS: 8 M/10 F, 29.33 ± 0.49 years) and 33 cross-sectional healthy controls (HC: 9 M/24 F, 23.43 ± 1.45 years) with no or very low exposure to childhood maltreatment and no history of psychopathology.

HC subjects were participants

Maltreatment exposure and current symptomatology

As expected, ELS subjects reported more severe exposure to childhood maltreatment across development than HC (F(1,611) = 48.89, p < 10 11) (Fig. 1). Exposure was slightly higher in females than males (F(1,611) = 4.46, p < 0.04). ELS subjects reported at least a moderate degree of exposure to 2.8 ± 2.1 different types of maltreatment (range = 0–8) versus 0.4 ± 0.5 types in HC (range = 0–1) (t(18.078) =  4.93, p = 0.0001). Compared to HC subjects, ELS subjects experienced greater severity of exposure to emotional

Discussion

This study provides initial evidence for enlarged amygdala volume associated with ELS in an adult sample. In particular, in relation to the right amygdala, we found a dose–response relation between severity of exposure and volume. The results further add to our understanding by identifying important differences in right versus left amygdala sensitivity to the type and timing of ELS.

Previous studies have also observed a specific association between ELS and anatomical changes in the right

Conclusion

To explore sensitive periods during which the amygdala is susceptible to early and continued life stress, we recruited adults from a 30-year longitudinal sample who were followed from infancy and who experienced adversity during different developmental stages. Random forest regression revealed that severity of adversity experienced at age 10–11 contributed to a larger right but not left amygdala volume in adulthood. Results provide preliminary evidence that the amygdala may have a developmental

Acknowledgments

This research was supported by funding received from the Harvard Catalyst/Harvard Clinical and Translational Science Center (NIH Award # UL1 RR 025758) and the Frederick Leonhardt Foundation awarded to KLR, MHT, and PP and R01 MH091391 awarded to MHT. The authors would like to sincerely thank Sarah Richardt and Cynthia McGreenery for their important contributions to participant recruitment and data collection. Preliminary data from this research was presented as a poster at the 68th Annual

References (76)

  • M.D. De Bellis et al.

    Developmental traumatology. Part II: brain development

    Biol Psychiatry

    (1999)
  • M.D. De Bellis et al.

    A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder

    Biol. Psychiatry

    (2001)
  • M.D. De Bellis et al.

    Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study

    Biol. Psychiatry

    (2002)
  • B. Fischl et al.

    Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system

    Neuroimage

    (1999)
  • B. Fischl et al.

    Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain

    Neuron

    (2002)
  • M.M. Grant et al.

    Childhood trauma history differentiates amygdala response to sad faces within MDD

    J. Psychiatr. Res.

    (2011)
  • E.J. McCrory et al.

    Heightened neural reactivity to threat in child victims of family violence

    Curr. Biol.

    (2011)
  • R.A. Morey et al.

    A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdala volumes

    Neuroimage

    (2009)
  • P.D. Patel et al.

    Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain

    J. Psychiatr. Res.

    (2000)
  • A. Peiffer et al.

    Age-related changes in glucocorticoid receptor binding and mRNA levels in the rat brain and pituitary

    Neurobiol. Aging

    (1991)
  • S.L. Rauch et al.

    Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future

    Biol. Psychiatry

    (2006)
  • K. Saleh et al.

    Impact of family history and depression on amygdala volume

    Psychiatry Res.

    (2012)
  • C.G. Schmahl et al.

    Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder

    Psychiatry Res.

    (2003)
  • C.G. Schmahl et al.

    Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder

    Psychiatry Res. Neuroimaging

    (2003)
  • M.H. Teicher et al.

    Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens

    Brain Res. Dev. Brain Res.

    (1995)
  • A.L. van Harmelen et al.

    Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment

    Biol. Psychiatry

    (2010)
  • A. Vyas et al.

    Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior

    Neuroscience

    (2004)
  • A. Vyas et al.

    Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala

    Neuroscience

    (2006)
  • S. Yoshimura et al.

    Self-referential processing of negative stimuli within the ventral anterior cingulate gyrus and right amygdala

    Brain Cogn.

    (2009)
  • S.L. Andersen et al.

    Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development

    J. Neuropsychiatry Clin. Neurosci.

    (2008)
  • J.M. Bland et al.

    Statistical methods for assessing agreement between two methods of clinical measurement

    Lancet

    (1986)
  • L. Breiman

    Random forests

    Mach. Learn.

    (2001)
  • C. Browne et al.

    The effect of childhood trauma on later psychological adjustment

    J. Interpers Violence

    (2007)
  • C. Buss et al.

    Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems

    Proc. Natl. Acad. Sci. U. S. A.

    (2012)
  • S. Cohen et al.

    A global measure of perceived stress

    J. Health Soc. Behav.

    (1983)
  • M.M. Cohen et al.

    Early-life stress has persistent effects on amygdala function and development in mice and humans

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • D.R. Cutler et al.

    Random forests for classification in ecology

    Ecology

    (2007)
  • U. Dannlowski et al.

    Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala

    Hum. Brain Mapp.

    (2013)
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