Supported by NIMH grants K24 MH071434 (PI: Dr. De Bellis) and R01 MH063407 (PI: Dr. De Bellis).
Introduction
Child abuse and neglect are forms of interpersonal violence that can have lasting impacts on a child’s socioemotional development. Maltreated children are at increased risk for a host of behavioral and emotional difficulties including posttraumatic stress disorder (PTSD), mood disorders, and disruptive behavioral disorders, particularly attention deficit hyperactivity disorder (ADHD) and substance use disorders. It is thought that child maltreatment could be the single most preventable and intervenable contributor to child and adult mental and medical illness. Although it is clear that child maltreatment increases the risk for the development of psychopathology, the neurobiological substrates that mediate the relation between maltreatment and psychopathology are not well understood. Given that child abuse and neglect tend to be chronic and co-morbid, the array of adverse psychological outcomes that are associated with child maltreatment can be regarded as an environmentally induced complex developmental disorder with identifiable neurobiological substrates.
The main goal of this chapter is to synthesize and summarize the available literature on these neurobiological substrates using the framework of developmental traumatology. The chapter starts with a brief discussion of the field of developmental traumatology to be followed by a discussion of the relevant biological stress response systems. The focus then shifts to comparing biological stress systems and brain development in healthy and maltreated children with PTSD symptoms. The final sections of the chapter examines strength of the evidence, resilience among maltreated children, and treatment implications.
Developmental Traumatology
Developmental traumatology is the systematic investigation of the neurobiological impact of chronic interpersonal violence on the developing child. It is a new field of study that synthesizes knowledge from developmental psychopathology, developmental neuroscience, and stress and trauma research. In this area of research, measureable aspects of traumatic experiences (e.g., type, age of onset, and duration of child maltreatment) and other biopsychosocial factors (e.g., child temperament, social support for the child and family) are regarded as independent variables, whereas behavioral, cognitive, emotional, and neurobiological measures are considered dependent variables.
Abuse and neglect are extreme forms of dysfunctional family and interpersonal functioning, which often occur in the context of multiple adversities. It is therefore difficult to disentangle the effects of socioeconomic disadvantage, parental mental illness, parental alcohol and substance use disorders, and lack of social support from the effects of chronic maltreatment-related stress on brain maturation and the development of biological stress systems. An important mission for the field of developmental traumatology is to unravel the complex developmental transactions among an individual’s genetic constitution, neurophysiology, and unique psychosocial environment taking into consideration experience-dependent critical periods of neurobiological and psychological development. In addition, research should be directed at discovering those processes that contribute to resilience as well as risk given that there is great variability in outcome following child maltreatment. Ultimately, it is hoped that research in the field of developmental traumatology will contribute to an improved understanding of risk and resiliency in maltreated children, and thus lead to improved interventions for this population.
The Biological Stress Response Systems
Traumatic experiences within the context of child maltreatment include chronic neglect or maternal deprivation, physical and sexual abuse, emotional abuse, medical abuse, and exposure to domestic violence. (Domestic violence creates an environment of terror within the family.) Traumatic experiences affect an individual’s development through activation of the body’s biological stress systems. Stress responses are activated when external stimuli perceived via the senses are processed through the brain’s thalamus, activating the amygdala fear detection circuit; projections from the amygdale then transmit signals to intermediary connections in the basal forebrain, paraventricular nucleus (PVN) of the hypothalamus, and brainstem. , In contrast to the mainly activating role of the amygdala, the hippocampus and medial prefrontal cortex (mPFC) both exert largely inhibitory control over activation of the stress response. The biological stress response itself is primarily mediated by four interacting systems: the hypothalamic-pituitary-adrenal (HPA) axis, the locus coeruleus noradrenergic neurotransmitter (LC/NA) system, the autonomic nervous system (ANS), and the immune system. The purpose of the stress response is twofold: (1) to direct attention to threats in the environment, and (2) to direct metabolic resources away from homeostatic functions such as thinking and digestion to prepare for responding to environmental contingency (i.e., “fight, flight, or freezing”).
The HPA axis plays a critical role in adjusting physiological functioning in response to stressors. Activation of the stress response causes the hypothalamus to secrete corticotrophin-releasing hormone (CRH) or factor (CRF). CRH functions as both a neurotransmitter and a neuroendocrine factor. In addition to producing anxiogenic effects by binding to receptors throughout the brain, CRH binds specifically to receptors in the anterior pituitary to stimulate the release of adrenocorticotropic hormone (ACTH). ACTH, in turn, binds to receptors in the adrenal cortex, resulting in cortisol secretion.
Cortisol is a glucocorticoid hormone that binds to receptors throughout the body, notably in the central nervous system (CNS). The main effects of increased cortisol secretion are suppression of the immune system, gluconeogenesis, and regulation of the stress response system. In the mPFC, cortisol acts primarily to attenuate the stress response, whereas in the amygdala it has the opposite effect, promoting the stress response. Cortisol exerts negative feedback control over its own secretion by inhibiting the release of both CRH by the hypothalamus and ACTH by the pituitary.
Activation of the stress response and release of CRH by the hypothalamus also activates the LC/NA system. The LC innervates a wide range of regions in the brain and is responsible for the increased release of norepinephrine. This results in elevated arousal, vigilance, and anxiety. The LC/NA system and HPA axis are mutually excitatory and act together in a positive feedback loop to sustain and enhance the stress response. The LC noradrenergic system also activates the sympathetic nervous system (SNS), the branch of the ANS that is classically associated with the “fight or flight” response. In addition, the SNS innervates the adrenal medulla and causes it to secrete epinephrine and norepinephrine. Increased SNS activity along with increased plasma epinephrine and norepinephrine act together to increase heart rate, blood pressure, sweating, and muscle tone; decrease renal sodium excretion; and generally prepare an individual for action by redistributing blood away from the skin, intestines, and kidney and to the brain, heart, and skeletal muscle. In addition, LC/NA system activity also acts to promote hypervigilance and to focus attention on threat-related cues in the environment. For a complete review, refer to De Bellis.
The Biological Stress Response Systems in Maltreated Children
The HPA Axis in Maltreated Children
Preclinical studies in animals have shown that early life stress results in elevated HPA reactivity in adulthood, and elevated levels of CRH have been consistently reported in traumatized adults. The findings regarding HPA axis regulation in maltreated children suggest a complex pattern of alterations. Most studies have found that baseline or resting levels of cortisol are higher in maltreated children with symptoms of anxiety and depression than nonmaltreated children. Increased 24-hour urinary-free cortisol levels were found in maltreated boys and girls with PTSD and in sexually abused girls, and elevated mean, morning, and afternoon salivary cortisol were found in maltreated children with significant internalizing symptoms. In addition, elevated mean salivary cortisol levels were found in maltreated children with impairing threshold and subthreshold PTSD symptoms. Similarly, elevated salivary cortisol levels were seen in 6- to 12-year-old children raised in Romanian orphanages for more than the first 8 months of their lives, as compared with early adopted children.
Studies that challenge the HPA axis show that a chronic compensatory adaptation of the HPA axis is seen in children with past abuse. Attenuated plasma ACTH responses to ovine CRH in sexually abused girls were found several years after abuse disclosure. When compared with controls, the abused girls exhibited reduced evening basal, ovine CRH-stimulated, and time-integrated total plasma ACTH concentrations. Plasma total and free cortisol responses to ovine CRH stimulation did not differ between the two groups. Thus, sexually abused girls manifested a dysregulatory disorder of the LHPA axis associated with hyporesponsiveness of the pituitary to exogenous CRH, but normal overall cortisol secretion to CRH challenge. CRH hypersecretion might have led to an adaptive down-regulation of CRH receptors in the anterior pituitary, which is similar to the mechanism suggested in adults with combat-related PTSD.
Priming can occur as a reflection of chronic compensatory adaptation of the HPA axis after trauma exposure. HPA axis regulation is affected by other stress biochemicals, such as arginine vasopressin and the catecholamines, both of which act synergistically with CRH. A so-called primed system “hyperresponds” during acute stress. Thus, when a new emotional stressor is experienced, HPA axis functioning is enhanced (i.e., higher ACTH and higher 24-hour cortisol concentrations in response to stress). This “hyperresponse” was seen in depressed abused children, currently experiencing psychosocial adversity, during CFH challenge and was seen as well in women who experienced sexual abuse and suffered from current adverse events and major depression. Episodes of neglect affect the HPA axis in similar ways as child abuse. Brief maternal separations or brief neglect during infancy affect the functioning of the HPA axis and glucocorticoid receptor gene expression in the hippocampus and frontal cortex in rats. Thus, the data show that in children developing some forms of internalizing psychopathology following maltreatment, cortisol levels are elevated at rest and during stress challenges. It remains to be investigated whether the dysregulation of the HPA axis contributes to the brain and cognition changes observed in maltreated children.
The Locus Coeruleus Noradrenergic Neurotransmitter System and the Autonomic Nervous System in Maltreated Children
A limited number of studies in maltreated children have found evidence of increased LC/NA tone in maltreated children including elevated heart rate and decreased platelet α 2 -adrenergic receptors, as well as elevated 24-hour excretion of catecholamine metabolites in sexually abused girls and 24-hour catecholamine excretion in children with maltreatment-related PTSD. In the latter study, levels of catecholamine positively correlated with PTSD symptoms. These findings are consistent with studies of combat-related PTSD in adults.
The Immune System in Maltreated Children
Prolonged activation of HPA axis and the LC/NA systems can have deleterious effects on homeostatic functioning, including hypertension, accelerated atherosclerosis, metabolic syndrome, impaired growth, and immune system suppression. , Adverse childhood experiences are associated with multiple and serious health problems in adulthood. For example, a significantly higher incidence of plasma antinuclear antibody titers was seen in sexually abused girls when compared with the frequency of positive antinuclear antibody titers in a sample of healthy adult women. One may hypothesize that the severe stress of sexual abuse may lead to suppression of the mechanisms (T suppressor cells) that actively suppress the autoantibody-producing lymphocytes (B lymphocytes) and thus increase the incidence of positive antinuclear antibody titers in the sexually abused girls studied. The influences of abuse and neglect on physical health warrant further study in maltreated children.
A Review of Healthy Brain Development
Birth to adulthood is marked by progressive physical, behavioral, cognitive, and emotional development. Paralleling these stages are changes in brain maturation. Intracranial volume increases steadily until age 10, with near completion of adult intracranial volume by age 5. Brain development takes place by an overproduction of neurons in utero, increases in synaptic neuropil (neuron size and synapses) during childhood, and then selective elimination of many of these neurons (apoptosis) with corresponding increases in myelination during adolescence and young adulthood.
There are regionally specific nonlinear preadolescent increases followed by postadolescent decreases in cortical grey matter. Neurons enlarge with age and axons become thicker as they myelinate and form neural networks, which are presumably involved in learning mechanisms. From ages 5 to 18 years, myelination by oligodendrocytes is most influential in determining brain size and function. The most dramatic increase in myelination, reflected by the corpus callosum, which connects major subdivisions of the cerebral cortex, occurs from the ages of 6 months to 3 years and continues into the third decade. Subcortical grey matter and limbic system structures (e.g., hippocampus and amygdala), which are involved in the regulation of emotions and memory, increase in volume nonlinearly and peak at age 16.6 years. The prefrontal cortex, which subserves executive cognitive functions and regulates the stress responses, continues its development into the third decade.
Interestingly, sex steroids influence neurodevelopment throughout the life span (for a review, see McEwen. ) However, in humans, brain maturational sex differences are an understudied area. In one pediatric neuroimaging study of healthy children and adolescents, boys showed significantly greater loss of grey matter volume and an increase in both white matter volume and corpus callosum area as compared with girls, over a similar age range, suggesting sex differences in both cerebral grey and white matter maturational processes in childhood. In summary, many factors influence brain development, including early life experiences, genetics, hormones, growth factors, nutrients, and degree of environmental stimulation.
Brain Development in Maltreated Children
The Brain and the Corpus Callosum in Maltreated Children
In the developing brain, elevated levels of catecholamines and cortisol can lead to adverse brain development through the mechanisms of “premature aging” or accelerated loss (or metabolism) of neurons, delays in myelination, abnormalities in developmentally appropriate pruning, and/or the inhibition of neurogenesis. Furthermore, stress decreases brain-derived neurotrophic factor expression. Thus, the stress of child maltreatment can have adverse influences on children’s brain maturation.
Myelinated areas of the brain appear particularly susceptible to the effects of early exposure to significantly elevated levels of stress biochemicals. Magnetic resonance imaging (MRI) methods are noninvasive, safe methods of observing and measuring grey and white matter brain structure, brain development, and brain function in children. MRI procedures have allowed comparison of the brain structures of healthy children to those exposed to maltreatment. This field of study is new and is limited to the study of maltreated children with PTSD symptoms. A handful of published studies indicate that adverse brain development might be a consequence of maltreatment resulting in PTSD or subthreshold symptoms of PTSD (i.e., nonspecific symptoms of anxiety and depression).
Teicher et al provided the initial data that suggested early childhood trauma had a deleterious effect on the development of the corpus callosum, a brain structure that anatomically and functionally connects the cerebral hemispheres. The size of the corpus callosum was affected by early adverse experience, and this effect appeared to be gender dependent. These researchers found a reduction in the middle portion of the corpus callosum in children who were hospitalized at psychiatric facilities with documented histories of abuse or neglect, as compared with psychiatric controls. These findings were more significant in males. Sanchez and colleagues used structural brain MRI to study global brain differences in maternally deprived rhesus monkeys. These monkeys had a reduction in the midsagittal size of the corpus callosum, in parallel to a decrease in white (but not grey) matter volume, in the prefrontal and parietal cortices. These decreases occurred in parallel with cognitive impairments.
Imaging methods were used to examine structural differences in 44 maltreated children and adolescents with PTSD as compared with 61 age- and sex-matched controls. Many of the maltreated subjects in this study suffered from sexual abuse, and witnessing domestic violence was a common secondary form of abuse. Decreased total midsagittal area of the corpus callosum and enlarged right, left, and total lateral ventricles were seen in PTSD-diagnosed subjects compared with controls. Male children with PTSD had smaller measurements of the corpus callosum, and a trend for smaller total brain volume than female children with PTSD. These findings suggested that males may be more vulnerable to the effects of severe stress on brain structures than females, although adverse effects were found in both genders. In addition, it was noted that the intracranial volume was decreased by 7%, and total brain volume by 8%, in PTSD subjects compared with controls. Earlier onset of abuse and longer duration of abuse correlated with smaller intracranial volume. Furthermore, smaller intracranial volumes and smaller total corpus callosum area were associated with elevated PTSD symptoms of reexperiencing, avoidance, and hyperarousal, as well as with elevated dissociative symptoms. These findings not only suggested adverse brain development in patients with maltreatment-related PTSD, but also indicated that adverse effects might be greater with abuse exposure in early childhood. The correlation of lower intracranial volume with longer duration of abuse also suggested that recurrent and chronic abuse might have a cumulative, harmful effect on brain development.
Another study reported that children with PTSD or subthreshold PTSD showed smaller total brain and cerebral volumes when compared with healthy age- and gender-matched archival controls. In addition, attenuation of frontal lobe asymmetry in maltreated children with PTSD symptoms was observed. These findings were consistent with the earlier work.
De Bellis replicated this work in another study of 28 psychotropic-naïve children and adolescents with maltreatment-related PTSD. The PTSD subjects showed smaller intracranial, cerebral cortex, prefrontal cortex, prefrontal cortical white matter, and right temporal lobe volumes in comparison with 66 sociodemographically matched healthy controls. Compared with these carefully matched controls, subjects with PTSD had decreased areas of the corpus callosum and in subregions 2, 4, 5, 6, and 7, and larger frontal lobe cerebrospinal fluid volumes than controls, even after adjustment for total cerebral volume. Midsagittal divisions of the corpus callosum for quantitative MRI measurements include: Region 1 (rostrum), which reflects the orbital prefrontal and inferior premotor cortical brain structures; Region 2 (genu), which reflects the prefrontal cortical brain structures; Region 3 (rostral body), which reflects the premotor and supplementary motor cortical regions; Region 4 (anterior midbody), which reflects the cortical motor regions; Region 5 (posterior midbody), which reflects the somatesthetic and association posterior parietal regions; Region 5 (isthmus), which reflects the superior temporal and association posterior parietal regions; and Region 6 (splenium), which reflects the occipital, inferior temporal cortical regions and subcorticol limbic system. Total brain volume positively correlated with age of onset of the trauma that caused PTSD (i.e., smaller volumes with earlier onset of trauma) and negatively correlated with duration of abuse (i.e., longer duration of abuse with smaller volumes). A significant gender-by-group interaction was found, with maltreated males with PTSD having larger ventricular volumes than maltreated females with PTSD ( Figure 53-1 ).
