Megan R. Gunnar

Effects of stress throughout the lifespan on the brain, behaviour and cognition

Chronic exposure to stress hormones, whether it occurs during the prenatal period, infancy, childhood, adolescence, adulthood or aging, has an impact on brain structures involved in cognition and mental health. However, the specific effects on the brain, behaviour and cognition emerge as a function of the timing and the duration of the exposure, and some also depend on the interaction between gene effects and previous exposure to environmental adversity. Advances in animal and human studies have made it possible to synthesize these findings, and in this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.

Social regulation of the cortisol levels in early human development

Other papers in this special edition provide evidence to implicate activity of the limbic hypothalamic-pituitary-adrenocortical (L-HPA) system in the etiology of drug and alcohol abuse. Furthermore, studies in rodents and primates suggest that responsivity and regulation of this system later in life may be shaped by social experiences during early development. Cortisol is the major hormonal product of the L-HPA system in humans. Although it provides only a partial understanding of the activity of this neuroendocrine axis, its regulation may bear importantly on human growth and development. We review developmental studies of cortisol and behavior in human children, birth to approximately 5 years of age. We describe the development of social buffering of cortisol responses that produces a functional analogue of the rodent stress hyporesponsive period by the time children are about 12 months of age. We further describe the sensitivity of cortisol activity to variations in care quality among infants and toddlers, along with evidence that children with negative emotional temperaments may be most likely to exhibit elevations in cortisol under conditions of less than optimal care. Finally, the few studies of cortisol activity under conditions of neglectful and abusive care of young children are considered, noting that these often have yielded evidence of reduced rather than increased cortisol levels.

Low cortisol and a flattening of expected daytime rhythm: Potential indices of risk in human development

Since the work of Hans Selye, stress has been associated with increased activity of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis. Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under conditions of trauma and prolonged stress presently challenges basic concepts in stress research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking. We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis. We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol under adverse early life conditions in humans adds to the importance of understanding the implications of hypocortisolism for health and development.

Child maltreatment and the developing HPA axis

The developing HPA axis is under strong social regulation in infancy and early childhood and is vulnerable to perturbation in the absence of sensitive, responsive caregiving. Child maltreatment has complex, long-term influences both on basal cortisol levels and on HPA responsivity to pharmacological and psychological stressors, depending on current psychiatric status, current life adversity, age, and most likely, genetic factors. Among the more consistent findings, maltreated children with internalizing problems have elevated basal cortisol most often detected in early AM concentrations, whereas adults maltreated as children often exhibit low basal cortisol levels and elevated ACTH response to psychological stressors. To disentangle these complicated interactions, future research must take the above qualifiers into account, study the transition to puberty, explore the moderating role of candidate genes, and utilize animal models and pharmacological challenges, when ethical, to localize changes in the HPA axis. Post-institutionalized children may provide a model to separate early adverse care histories from current adversity.

Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation.

Early adversity, for example poor caregiving, can have profound effects on emotional development. Orphanage rearing, even in the best circumstances, lies outside of the bounds of a species-typical caregiving environment. The long-term effects of this early adversity on the neurobiological development associated with socio-emotional behaviors are not well understood. Seventy-eight children, who include those who have experienced orphanage care and a comparison group, were assessed. Magnetic resonance imaging (MRI) was used to measure volumes of whole brain and limbic structures (e.g. amygdala, hippocampus). Emotion regulation was assessed with an emotional go-nogo paradigm, and anxiety and internalizing behaviors were assessed using the Screen for Child Anxiety Related Emotional Disorders, the Child Behavior Checklist, and a structured clinical interview. Late adoption was associated with larger corrected amygdala volumes, poorer emotion regulation, and increased anxiety. Although more than 50% of the children who experienced orphanage rearing met criteria for a psychiatric disorder, with a third having an anxiety disorder, the group differences observed in amygdala volume were not driven by the presence of an anxiety disorder. The findings are consistent with previous reports describing negative effects of prolonged orphanage care on emotional behavior and with animal models that show long-term changes in the amygdala and emotional behavior following early postnatal stress. These changes in limbic circuitry may underlie residual emotional and social problems experienced by children who have been internationally adopted.

Salivary cortisol levels in children adopted from romanian orphanages.

Six and a half years after adoption. 6- to 12-year-old children reared in Romanian orphanages for more than 8 months in their first years of life (RO. n = 18) had higher cortisol levels over the daytime hours than did early adopted (EA, < or = 4 months of age, n = 15) and Canadian born (CB, n = 27) children. The effect was marked, with 22% of the RO children exhibiting cortisol levels averaged over the day that exceeded the mean plus 2 SD of the EA and CB levels. Furthermore, the longer beyond 8 months that the RO children remained institutionalized the higher their cortisol levels. Cortisol levels for EA children did not differ in any respect from those of CB comparison children. This latter finding reduces but does not eliminate concerns that the results could be due to prenatal effects or birth family characteristics associated with orphanage placement. Neither age at cortisol sampling nor low IQ measured earlier appeared to explain the findings. Because the conditions in Romanian orphanages at the time these children were adopted were characterized by multiple risk factors, including gross privation of basic needs and exposure to infectious agents, the factor(s) that produced the increase in cortisol production cannot be determined. Nor could we determine whether these results reflected effects on the limbic-hypothalamic-pituitary-adrenal axis directly or were mediated by differences in parent-child interactions or family stress occasion by behavioral problems associated with prolonged orphanage care in this sample.

Developmental changes in hypothalamus–pituitary–adrenal activity over the transition to adolescence: Normative changes and associations with puberty

Home baseline and laboratory stressor (Trier Social Stress Test for Children) measures of salivary cortisol were obtained from 82 participants (40 girls) aged 9, 11, 13, and 15 years. Measures of pubertal development, self-reported stress, parent reports of child depressive symptoms and fearful temperament, and cardiac measures of sympathetic and parasympathetic activity were also obtained. Significant increases in the home cortisol baselines were found with age and pubertal development. Cortisol stress reactivity differed by age group with 11-year-olds and 13-year-old boys showing blunted reactivity and 9-year-olds, 13-year-old girls, and 15-year-olds showing significant cortisol reactions. Cortisol reactivity correlated marginally with sexual maturation. Measures of sympathetic activity revealed increased sympathetic modulation with age. Higher sympathetic tone was associated with more fearful temperament, whereas greater cortisol reactivity was associated with more anxious and depressed symptoms for girls. The importance of these findings for the hypothesis that puberty-associated increases in hypothalamic-pituitary-adrenal axis activity heightens the risk of psychopathology is discussed.

Stressor paradigms in developmental studies: what does and does not work to produce mean increases in salivary cortisol.

The stress response system is comprised of an intricate interconnected network that includes the hypothalamic-pituitary-adrenocortical (HPA) axis. The HPA axis maintains the organisms capacity to respond to acute and prolonged stressors and is a focus of research on the sequelae of stress. Human studies of the HPA system have been facilitated enormously by the development of salivary assays which measure cortisol, the steroid end-product of the HPA axis. The use of salivary cortisol is prevalent in child development stress research. However, in order to measure childrens acute cortisol reactivity to circumscribed stressors, researchers must put children in stressful situations which produce elevated levels of cortisol. Unfortunately, many studies on the cortisol stress response in children use paradigms that fail to produce mean elevations in cortisol. This paper reviews stressor paradigms used with infants, children, and adolescents to guide researchers in selecting effective stressor tasks. A number of different types of stressor paradigms were examined, including: public speaking, negative emotion, relationship disruption/threatening, novelty, handling, and mild pain paradigms. With development, marked changes are evident in the effectiveness of the same stressor paradigm to provoke elevations in cortisol. Several factors appear to be critical in determining whether a stressor paradigm is successful, including the availability of coping resources and the extent to which, in older children, the task threatens the social self. A consideration of these issues is needed to promote the implementation of more effective stressor paradigms in human developmental psychoendocrine research.

Stress reactivity and attachment security

Seventy-three 18-month-olds were tested in the Ainsworth Strange Situation. These children were a subset of 83 infants tested at 2, 4, 6, and 15 months during their well-baby examinations with inoculations. Salivary cortisol, behavioral distress, and maternal responsiveness measures obtained during these clinic visits were examined in relation to attachment classifications. In addition, parental report measures of the childrens social fearfulness in the 2nd year of life were used to classify the children into high-fearful versus average- to low-fearful groups. In the 2nd year, the combination of high fearfulness and insecure versus secure attachment was associated with higher cortisol responses to both the clinic exam-inoculation situation and the Strange Situation. Thus, attachment security moderates the physiological consequences of fearful, inhibited temperament. Regarding the 2-, 4-, and 6-month data, later attachment security was related to greater maternal responsiveness and lower cortisol baselines. Neither cortisol nor behavioral reactivity to the inoculations predicted later attachment classifications. There was some suggestion, however, that at their 2-month checkup, infants who would later be classified as insecurely attached exhibited larger dissociations between the magnitude of their behavioral and hormonal response to the inoculations. Greater differences between internal (hormonal) and external (crying) responses were also negatively correlated with maternal responsiveness and positively correlated with pretest cortisol levels during these early months of life.

Early experience and the development of stress reactivity and regulation in children.

Children who spend early portions of their lives in institutions or those maltreated in their families of origin are at risk for developing emotional and behavioral problems reflecting disorders of emotion and attention regulation. Animal models may help explicate the mechanisms producing these effects. Despite the value of the animal models, many questions remain in using the animal data to guide studies of human development. In 1999, the National Institute of Mental Health in the United States funded a research network to address unresolved issues and enhance translation of basic animal early experience research to application in child research. Professor Seymour Levine was both the inspiration for and an active member of this research network until his death in October of 2007. This review pays tribute to his legacy by outlining the conceptual model which is now guiding our research studies.