Physiology and neurobiology of stress and adaptation: central role of the brain

The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.     

Chronic stress, allostatic load, and aging in nonhuman primates

Allostatic load is the "wear and tear" of the body resulting from the repeated activation of compensatory physiological mechanisms in response to chronic stress. Allostatic load can significantly affect the aging process and result in reduced longevity, accelerated aging, and impaired health. Although low socioeconomic status is associated with high allostatic load during aging, the effects of status-related psychosocial stress on allostatic load are often confounded by lifestyle variables. Chronic psychosocial stress associated with low dominance rank in nonhuman primates represents an excellent animal model with which to investigate allostatic load and aging in humans. Research conducted with free-ranging rhesus monkeys suggests that female reproduction can also be a source of stress and allostatic load. Female reproduction is associated with increased risk of mortality and hyperactivation of the hypothalamic-pituitary-adrenal axis. Reproduction is especially stressful and costly for aging females of low rank. Although many indicators of body condition and neuroendocrine and immune function are influenced by aging, there are marked and stable individual differences among aging females in body condition, plasma cortisol responses to stress, and cytokine responses to stress. These differences are consistent with the hypothesis that there are strong differences in chronic stress among individuals, and that allostatic load resulting from chronic stress affects health during aging. Comparisons between captive and free-ranging rhesus monkey populations may allow us to understand how differences in environmental stress and allostatic load affect rates of aging, and how these in turn translate into differences in longevity and health.     

Allostatic processes in the family

The concepts of allostatic load and allostatic processes can help psychologists understand how health trajectories are influenced by stressful childhood experiences in the family. This paper describes psychological pathways and two key allostatic mediators, the hypothalamic-pituitary-adrenal axis and the immune system, through which stressful early rearing conditions may influence adult mental and physical health. The action of meshed gears is introduced as a metaphor to illustrate how responses occurring within a brief time frame, for example, immediate reactions to stressors, can influence developmental and health processes unfolding over much longer spans of time. We identify early-developing psychological and biological response patterns that could link chronic stressors in childhood to later health outcomes. Some of these "precursor outcomes" (e.g., heightened vigilance and preparedness for threats; enhanced inflammatory and humoral responses to infectious microorganisms) appear to be aimed at protection from immediate dangers; they may reflect "adaptive trade-offs" that balance short-term survival advantages under harsh rearing conditions against disadvantages manifested later in development. Our analysis also suggests mechanisms that underlie resilience in risky family environments.     

Is burnout related to allostatic load?

Background: Burnout has a negative impact on physical health, but the mechanisms underlying this relation remain unclear. To elucidate these mechanisms, possible mediating physiological systems or risk factors for adverse health in burned-out employees should be investigated. Goal: The aim of the present study among 290 Dutch managers was to explore whether allostatic load mediates the relationship between burnout and physical health. Method: Burned-out managers, as identified with the Maslach Burnout Inventory General Survey (MBI-GS), were compared with a healthy control group with regard to their allostatic load. The allostatic load index included eight parameters: Body-mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), C-reactive protein (CRP), high-density lipoprotein (HDL), cholesterol, glycosylated hemoglobin (HbA1C) and glucose. Results: Contrary to expectations, burned-out managers did not differ from healthy managers with regard to their scores on the allostatic load index. An additional analysis, using groups of managers in the extreme deciles of exhaustion (the core symptom of burnout), did also not reveal differences in allostatic load. Conclusion: Burnout seems not to be associated with this proxy measure of allostatic load. The mediating physiological mechanisms between burnout and objective physical health remain to be elucidated.     

Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse—all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management (“mind–body”) interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS.     

Sex,stress and the hippocampus: allostasis,allostatic load and the aging process

The adaptive responses of the body that maintain homeostasis in response to stressors can be called "allostasis", meaning "achieving stability through change". Mediators produced by the immune system, autonomic nervous system (ANS) and hypothalamo-pituitary-adrenal(HPA) axis produce allostasis. The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters. When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body and brain that has been termed "allostatic load". Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Studies of the hippocampus as a target of stress and sex hormones have revealed a considerable degree of structural plasticity and remodeling in the adult brain that differs between the sexes. Three forms of hippocampal structural plasticity are affected by circulating hormones: (1) repeated stress causes remodeling of dendrites in the CA3 region; (2) different modalities of stress suppress neurogenesis of dentate gyrus granule neurons; (3) ovarian steroids regulate synapse formation during the estrous cycle of female rats. All three forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and NMDA receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, by ischemia and by severe and prolonged psychosocial stress. The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined. Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience. "Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging." This review discusses the current status of work on underlying mechanisms for protection and damage.     

Allostatic and environmental load in toddlers predicts anxiety in preschool and kindergarten

Psychobiological models of allostatic load have delineated the effects of multiple processes that contribute to risk for psychopathology. This approach has been fruitful, but the interactive contributions of allostatic and environmental load remain understudied in early childhood. Because this developmental period encompasses the emergence of internalizing problems and biological sensitivity to early experiences, this is an important time to examine this process. In two studies, we examined allostatic and environmental load and links to subsequent internalizing and externalizing problems. Study 1 examined relations between load indices and maladjustment, concurrently and at multiple times between age 2 and kindergarten; Study 2 added more comprehensive risk indices in a sample following a group of highly fearful toddlers from 2 to 3 years of age. Results from both studies showed that increased allostatic load related to internalizing problems as environmental risk also increased. Study 2, in addition, showed that fearfulness interacted with allostatic and environmental load indices to predict greater anxiety among the fearful children who had high levels of allostatic and environmental load. Taken together, the findings support a model of risk for internalizing characterized by the interaction of biological and environmental stressors, and demonstrate the importance of considering individual differences and environmental context in applying models of allostatic load to developmental change in early childhood.     

The effects of neonatal stress on brain development: implications for psychopathology.

Recent studies have focused on the behavioral and neurobiological sequella of exposure to early adverse events. We hypothesize that early adverse experiences result in an increased sensitivity to the effects of stress later in life and render an individual vulnerable to stress-related psychiatric disorders. This vulnerability may be mediated by persistent changes in corticotropin-releasing-factor (CRF)-containing neurons, the hypothalamic-pituitary-adrenal axis, and the sympathetic nervous system. We therefore present an overview of the CRF system and its role as a mediator in the development of the stress response, major depression, and posttraumatic stress disorder. The literature pertaining to behavioral and neurobiological alterations associated with exposure to early adverse life events in rodents, nonhuman primates, and humans is reviewed. We focus on animal models that precipitate depressive and anxiety symptoms while producing neuroendocrine alterations that mimic those seen in adults with those disorders. The literature integrating neurobiological and behavioral consequences of early life stress is also reviewed, focusing primarily on infants born to mothers with depression and on infants who were abused or neglected.     

Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models

Increasing evidence supports the view that the interaction of perinatal exposure to adversity with individual genetic liabilities may increase an individual's vulnerability to the expression of psycho- and physiopathology throughout life. The early environment appears to program some aspects of neurobiological development and, in turn, behavioral, emotional, cognitive, and physiological development. Several rodent and primate models of early adverse experience have been analyzed in this review, including those that "model" maternal separation or loss, abuse or neglect, and social deprivation. Accumulating evidence shows that these early traumatic experiences are associated with long-term alterations in coping style, emotional and behavioral regulation. neuroendocrine responsiveness to stress, social "fitness,' cognitive function, brain morphology, neurochemistry, and expression levels of central nervous system genes that have been related to anxiety and mood disorders. Studies are underway to identify important aspects of adverse early experience, such as (a) the existence of "sensitive periods" during development associated with alterations in particular output systems. (b) the presence of "windows of opportunity" during which targeted interventions (e.g., nurturant parenting or supportive-enriching environment) may prevent or reverse dysfunction, (c) the identity of gene polymorphisms contributing to the individual's variability in vulnerability, and (d) a means to translate the timing of these developmental "sensitive periods" across species.     

Child maltreatment and allostatic load: consequences for physical and mental health in children from low-income families

Child maltreatment and biomarkers of allostatic load were investigated in relation to child health problems and psychological symptomatology. Participants attended a summer research day camp and included 137 maltreated and 110 nonmaltreated low-income children, who were aged 8 to 10 years (M = 9.42) and racially and ethnically diverse; 52% were male. Measurements obtained included salivary cortisol and dehydroepiandosterone, body mass index, waist-hip ratio, and blood pressure; these indicators provided a composite index of allostatic load. Child self-report and camp adult-rater reports of child symptomatology were obtained; mothers provided information on health problems. The results indicated that higher allostatic load and child maltreatment status independently predicted poorer health outcomes and greater behavior problems. Moderation effects indicated that allostatic load was related to somatic complaints, attention problems, and thought problems only among maltreated children. Risks associated with high waist-hip ratio, low morning cortisol, and high morning dehydroepiandosterone also were related to depressive symptoms only for maltreated children. The results support an allostatic load conceptualization of the impact of high environmental stress and child abuse and neglect on child health and behavioral outcomes and have important implications for long-term physical and mental health.     

Early adversity and adult health outcomes

Adversity in childhood has effects on mental and physical health, not only in childhood but across the lifespan. A chief task of our research has been to define the pathways by which childhood experience has these surprising health outcomes, often decades later. The concept of allostatic load, which refers to dysregulations across major biological regulatory systems that have cumulative interacting adverse effects over time, provides a mechanism for understanding these relations and defining specific pathways. To chart these pathways, we examine early childhood socioeconomic status, family environment, and genetic predispositions as antecedents to socioemotional functioning/psychological distress; and neural responses to threat that have downstream effects on major stress regulatory systems, ultimately culminating in risks to mental and physical health outcomes. This integrative approach to investigating the impact of childhood experience on adult health outcomes illustrates the significance of multilevel integrative approaches to understanding developmental psychopathology more generally.     

A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development

The allostatic load (AL) model represents an interdisciplinary approach to comprehensively conceptualize and quantify chronic stress in relation to pathologies throughout the life cycle. This article first reviews the AL model, followed by interactions among early adversity, genetics, environmental toxins, as well as distinctions among sex, gender, and sex hormones as integral antecedents of AL. We next explore perspectives on severe mental illness, dementia, and caregiving as unique human models of AL that merit future investigations in the field of developmental psychopathology. A complimenting transdisciplinary perspective is applied throughout, whereby we argue that the AL model goes beyond traditional stress-disease theories toward the advancement of person-centered research and practice that promote not only physical health but also mental health.     

Adverse childhood experiences, allostasis, allostatic load, and age-related disease

How do adverse childhood experiences get ‘under the skin’ and influence health outcomes through the life-course? Research reviewed here suggests that adverse childhood experiences are associated with changes in biological systems responsible for maintaining physiological stability through environmental changes, or allostasis. Children exposed to maltreatment showed smaller volume of the prefrontal cortex, greater activation of the HPA axis, and elevation in inflammation levels compared to non-maltreated children. Adults with a history of childhood maltreatment showed smaller volume of the prefrontal cortex and hippocampus, greater activation of the HPA axis, and elevation in inflammation levels compared to non-maltreated individuals. Despite the clear limitations in making longitudinal claims from cross-sectional studies, work so far suggests that adverse childhood experiences are associated with enduring changes in the nervous, endocrine, and immune systems. These changes are already observable in childhood years and remain apparent in adult life. Adverse childhood experiences induce significant biological changes in children (biological embedding), modifying the maturation and the operating balance of allostatic systems. Their chronic activation can lead to progressive wear and tear, or allostatic load and overload, and, thus, can exert long-term effects on biological aging and health.     

The International Society for Developmental Psychobiology annual meeting symposium: Impact of early life experiences on brain and behavioral development

Decades of research in the area of developmental psychobiology have shown that early life experience alters behavioral and brain development, which canalizes development to suit different environments. Recent methodological advances have begun to identify the mechanisms by which early life experiences cause these diverse adult outcomes. Here we present four different research programs that demonstrate the intricacies of early environmental influences on behavioral and brain development in both pathological and normal development. First, an animal model of schizophrenia is presented that suggests prenatal immune stimulation influences the postpubertal emergence of psychosis-related behavior in mice. Second, we describe a research program on infant rats that demonstrates how early odor learning has unique characteristics due to the unique functioning of the infant limbic system. Third, we present work on the rodent Octodon degus, which shows that early paternal and/or maternal deprivation alters development of limbic system synaptic density that corresponds to heightened emotionality. Fourth, a juvenile model of stress is presented that suggests this developmental period is important in determining adulthood emotional well being. The approach of each research program is strikingly different, yet all succeed in delineating a specific aspect of early development and its effects on infant and adult outcome that expands our understanding of the developmental impact of infant experiences on emotional and limbic system development. Together, these research programs suggest that the developing organism's developmental trajectory is influenced by environmental factors beginning in the fetus and extending through adolescence, although the specific timing and nature of the environmental influence has unique impact on adult mental health.     

Psychosomatic medicine: emerging trends and perspectives

Developments have occurred in all aspects of psychosomatic medicine. Among factors affecting individual vulnerability to all types of disease, the following have been highlighted by recent research: recent and early life events, chronic stress and allostatic load, personality, psychological well-being, health attitudes and behavior. As to the interaction between psychological and biological factors in the course and outcome of disease, the presence of psychiatric (DSM-IV) as well as subclinical (Diagnostic Criteria for Psychosomatic Research) symptoms, illness behavior and the impact on quality of life all need to be assessed. The prevention, treatment and rehabilitation of physical illness include the consideration for psychosomatic prevention, the treatment of psychiatric morbidity and abnormal illness behavior and the use of psychotropic drugs in the medically ill. In the past 60 years, psychosomatic medicine has addressed some fundamental questions, contributing to the growth of other related disciplines, such as psychoneuroendocrinology, psychoimmunology, consultation-liaison psychiatry, behavioral medicine, health psychology and quality of life research. Psychosomatic medicine may also provide a comprehensive frame of reference for several current issues of clinical medicine (the phenomenon of somatization, the increasing occurrence of mysterious symptoms, the demand for well-being and quality of life), including its new dialogue with mind-body and alternative medicine.     

The effects of allostatic load on neural systems subserving motivation, mood regulation, and social affiliation

The term allostasis, which is defined as stability through change, has been invoked repeatedly by developmental psychopathologists to describe long-lasting and in some cases permanent functional alterations in limbic-hypothalamic-pituitary-adrenal axis responding following recurrent and/or prolonged exposure to stress. Increasingly, allostatic load models have also been invoked to describe psychological sequelae of abuse, neglect, and other forms of maltreatment. In contrast, neural adaptations to stress, including those incurred by monoamine systems implicated in (a) mood and emotion regulation, (b) behavioral approach, and (c) social affiliation and attachment, are usually not included in models of allostasis. Rather, structural and functional alterations in these systems, which are exquisitely sensitive to prolonged stress exposure, are usually explained as stress mediators, neural plasticity, and/or programming effects. Considering these mechanisms as distinct from allostasis is somewhat artificial given overlapping functions and intricate coregulation of monoamines and the limbic-hypothalamic-pituitary-adrenal axis. It also fractionates literatures that should be mutually informative. In this article, we describe structural and functional alterations in serotonergic, dopaminergic, and noradrenergic neural systems following both acute and prolonged exposure to stress. Through increases in behavioral impulsivity, trait anxiety, mood and emotion dysregulation, and asociality, alterations in monoamine functioning have profound effects on personality, attachment relationships, and the emergence of psychopathology.     

A developmental increase in allostatic load from ages 3 to 11 years is associated with increased schizotypal personality at age 23 years

Although allostatic load has been investigated in mood and anxiety disorders, no prior study has investigated developmental change in allostatic load as a precursor to schizotypal personality. This study employed a multilevel developmental framework to examine whether the development of increased allostatic load, as indicated by impaired sympathetic nervous system habituation from ages 3 to 11 years, predisposes to schizotypal personality at age 23 years. Electrodermal activity to six aversive tones was recorded in 995 subjects at age 3 years and again at 11 years. Habituation slopes at both ages were used to create groups who showed a developmental increase in habituation (decreased allostatic load), and those who showed a developmental decrease in habituation (increased allostatic load). Children who showed a developmental increase in allostatic load from ages 3 to 11 years had higher levels of schizotypal personality at 23 years. A breakdown of total schizotypy scores demonstrated specificity of findings to cognitive-perceptual features of schizotypy. Findings are the first to document a developmental abnormality in allostasis in relation to adult schizotypal personality. The relative failure to develop normal habituation to repeated stressors throughout childhood is hypothesized to result in an accumulation of allostatic load and consequently increased positive symptom schizotypy in adulthood.     

Kindergarten stressors and cumulative adrenocortical activation: the "first straws" of allostatic load?

Using an ethnically diverse longitudinal sample of 338 kindergarten children, this study examined the effects of cumulative contextual stressors on children's developing hypothalamic-pituitary-adrenocortical (HPA) axis regulation as an early life indicator of allostatic load. Chronic HPA axis regulation was assessed using cumulative, multiday measures of cortisol in both the fall and spring seasons of the kindergarten year. Hierarchical linear regression analyses revealed that contextual stressors related to ethnic minority status, socioeconomic status, and family adversity each uniquely predicted children's daily HPA activity and that some of those associations were curvilinear in conformation. Results showed that the quadratic, U-shaped influences of family socioeconomic status and family adversity operate in different directions to predict children's HPA axis regulation. Results further suggested that these associations differ for White and ethnic minority children. In total, this study revealed that early childhood experiences contribute to shifts in one of the principal neurobiological systems thought to generate allostatic load, confirming the importance of early prevention and intervention efforts. Moreover, findings suggested that analyses of allostatic load and developmental theories accounting for its accrual would benefit from an inclusion of curvilinear associations in tested predictive models.     

Mediators of allostasis and systemic toxicity in bipolar disorder

Bipolar disorder is associated with a high rate of medical and psychiatric comorbidities. This burden of illness, along with cognitive impairment, is seen particularly in late cases, after multiple episodes. These changes in clinical presentation that take place over time have been recently conceptualized as "neuroprogression". The concept of allostatic load is instrumental in understanding how the cumulative stress associated with psychiatric disorders translates into bodily wear and tear, thus providing an underlying explanation for illness progression. Allostatic load is engendered by several factors which interact in a nonlinear manner. Glucocorticoids are fundamental mediators; when chronically in excess, glucocorticoids initiate a series of bodily dysfunctions that may include cortisol-related mitochondrial dysfunction, oxidative stress, inflammation and decrease in the expression of neuroprotective factors. In the present review we examine the role of allostatic load in the illness progression that takes place in bipolar disorder.     

Maternal responsiveness moderates the relationship between allostatic load and working memory

A substantial amount of research has demonstrated the deleterious effects of chronic stress on memory. However, much less is known about protective factors. In the current study we test the role of maternal responsiveness in buffering the effects of childhood allostatic load on subsequent adolescent working memory. Allostatic load is a marker of cumulative stress on the body that is caused by mobilization of multiple physiological systems in response to chronic environmental demands. Results of the study suggest that allostatic load negatively affects working memory, but that this effect is significantly attenuated in children with responsive mothers.