Fig. 11.1
Neurocardiac Model of Early Stress, Mental Disorders, and Cardiovascular Function
The Effects of Early Stress on Neurohormonal and Neurochemical Systems
Stress is associated with activation of the hypothalamic–pituitary–adrenal (HPA) axis. Corticotropin-releasing factor (CRF) is released from the hypothalamus, with stimulation of adrenocorticotropin hormone (ACTH) release from the pituitary, resulting in cortisol release from the adrenal. This process, in turn, has a negative feedback effect on the HPA axis at the level of the pituitary as well as central brain sites including hypothalamus and hippocampus. In addition to its role in activating the HPA axis, CRF acts centrally to mediate fear-related behaviors (Arborelius et al. 1999) and triggers other neurochemical responses to stress such as the noradrenergic neurotransmitter system via the brainstem’s locus coeruleus (Melia and Duman 1991).
Early life stress leads to long-term sensitization of the HPA axis and increases in CRF (Levine et al. 1993; Stanton et al. 1988). Early life stress such as disruption of the maternal bond in animals leads to a decrease in glucocorticoid receptors, and an increase in stress-induced CRF and glucocorticoid release (Coplan et al. 1996; Makino et al. 1995; Plotsky and Meaney 1993). Stress also results in chronic over-activation of the norepinephrine system, which plays a critical role in the fight or flight response (Bremner et al. 1996a, b).
Effects of Early Life Stress on the Brain
The model for the neural circuits of early abuse in women involves a network of brain areas involved in memory and fear, including the hippocampus, medial prefrontal cortex, and amygdala (Bremner 2005; Rauch et al. 2006). The hippocampus plays a critical role in memory and is also sensitive to stress. Studies in animals showed that stress resulted in damage to neurons in the CA3 region of the hippocampus (Gould et al. 1998; Magarinos et al. 1996; McEwen et al. 1992; Nibuya et al. 1995; Sapolsky 1996; Sapolsky et al. 1990). High levels of glucocorticoids seen with stress were also associated with deficits in new learning (Diamond et al. 1996; Luine et al. 1994).
Brain-derived neurotrophic factor (BDNF) is a neuropeptide found in the hippocampus and other brain regions that has a trophic effect on neurons. Stress resulted in a reduction in BDNF mRNA; CRF also had a direct effect on the hippocampus in early development (Brunson et al. 2001). Antidepressant drugs, some anticonvulsants, and electroconvulsive therapy had the opposite effect on BDNF levels in the hippocampus (Malberg et al. 2000; Nibuya et al. 1995; Watanabe et al. 1992).
Changes in the environment can also have an effect on the hippocampus, a finding which has implications for early stress in women. Social enrichment was found to increase hippocampal neurogenesis (Kempermann et al. 1998). Early maternal behavior also affected glucocorticoid receptors in the hippocampus, an effect that can have consequences later in development (Liu et al. 2000; Meaney et al. 1988). Based on these findings studies were conducted to examine the effects of antidepressants on the brain and cognition in patients with PTSD (reviewed in detail below).
Another brain area that plays an important role in the early stress response is the medial prefrontal cortex, which includes anterior cingulate, orbitofrontal cortex, and adjacent areas. Dopaminergic function in this area is highly sensitive to stress (Arnsten 2000; Deutch and Roth 1990). The mesofrontal dopaminergic system also plays a role in emotional responses, as well as selective information processing, and coping with the external world (Devinsky et al. 1995; Pani et al. 2000). Inputs from the medial prefrontal cortex inhibit function of the amygdala, a brain area involved in fear learning responses. These circuits mediate the extinction (or forgetting) of fear responses (Milad and Quirk 2002; Quirk et al. 2006). Animal studies show that early stress is associated with a decrease in branching of neurons in the medial prefrontal cortex (Radley et al. 2004). Outputs from this area regulate neurohormonal responses to stress in the periphery, which has implications for the increase in heart disease seen in women with early life stress (Diorio et al. 1993; Feldman et al. 1995; Frysztak and Neafsey 1994). The insula also plays a critical role in integrating the physiological stress response. Together with the hippocampus, these brain areas work in concert to orchestrate the stress response.
Neurobiology of Early Life Stress in Women with PTSD
Research in traumatized girls is complicated by factors related to difficulties in making psychiatric diagnoses in children, problems with reliability in assessment of trauma, reliability of symptom reporting, and the issues around obtaining consent (Cicchetti and Walker 2001). Some studies classify children according to psychiatric diagnoses such as PTSD, and others do not. In one study, sexually abused girls (in which effects of specific psychiatric diagnosis were not examined) had normal baseline cortisol and blunted ACTH response to CRF (De Bellis et al. 1994a). Another study of traumatized children in which the diagnosis of PTSD was established showed increased levels of cortisol measured in 24-h urines (De Bellis et al. 1999a, b). Emotionally neglected children from a Romanian orphanage had elevated cortisol levels over a diurnal period compared to controls (Gunnar et al. 2001). Maltreated school-aged children with clinical-level internalizing problems had elevated cortisol compared to controls (Cicchetti and Rogosch 2001). Depressed preschool children showed increased cortisol response to separation stress (Luby et al. 2003). In a study of ACTH response to CRF challenge in children with depression with and without a history of childhood abuse, children with depression and abuse had an increased ACTH response to CRF challenge compared to children with depression without abuse. These children were in a chaotic environment at the time of the study, indicating that the ongoing stressor may have played a role in the potentiation of the ACTH response to CRF (Kaufman et al. 1997).
Early life trauma results in lasting effects on neurobiology that extend into adulthood in women with PTSD (Cicchetti and Rogosch 2001; Shea et al. 2004). We have studied the long-term effects of early childhood sexual abuse on neurobiology in adult women with a history of childhood sexual abuse-related PTSD. These studies compared abused women with PTSD to abused women without PTSD, and women without a history of abuse or PTSD (Bremner 2005; Bremner et al. 2008). Women were assessed with the Early Trauma Inventory (ETI), a reliable and valid measure of early abuse (Bremner et al. 2000b, 2007a). Women with abuse-related PTSD had decreased baseline cortisol based on 24-h diurnal assessments of plasma with 10-min sampling periods, a flattening of the normal diurnal cortisol curve, and increased pulsatility of cortisol reflecting dysregulation of CRF release, compared to women with abuse without PTSD, and women without abuse or PTSD (Bremner et al. 2007b). Lower cortisol at baseline correlated with increased symptoms of PTSD in the PTSD group (Bremner et al. 2007b). Women with PTSD compared to abused controls also had an exaggerated cortisol response to stressors (traumatic stressors involving the reading of a personalized script of the childhood abuse) (Elzinga et al. 2003). Another study of men and women with childhood abuse showed increased cortisol response to cognitive stressors (mental stress challenge involving mental arithmetic and problem solving with negative feedback), although the magnitude of response was not as great in women with PTSD following traumatic reminder stress (Bremner et al. 2003a, b). One study of 24-h urine collection showed increased cortisol in women with childhood abuse-related PTSD (Lemieux and Coe 1995). Twenty-four-hour urine collection, however, might not be as reliable as 24-h plasma sampling with 10-min sampling periods. Another study showed that adult women with depression and a history of early childhood abuse had an increased cortisol response to a stressful cognitive challenge relative to controls (Heim et al. 2000) and a blunted ACTH response to CRF challenge (Heim et al. 2001).
The effect of early life stress in women on glucocorticoid receptors in the hippocampus has also been studied. Women with early childhood sexual abuse and PTSD had an increased suppression of cortisol with low dose (0.5 mg) dexamethasone, suggesting increased sensitivity of glucocorticoid receptors (Stein et al. 1997b). Men and women with PTSD from a range of causes including childhood abuse had a blunted effect of glucocorticoids (dexamethasone) on declarative memory function, suggesting decreased sensitivity of glucocorticoid receptors in the hippocampus (Bremner et al. 2004c). These studies suggest that early abuse in women, especially those suffering from chronic PTSD, is associated with long-term changes in the HPA axis.
Few studies have examined noradrenergic function related to childhood abuse in women. Studies have found increased noradrenergic function in adults with PTSD (Bremner et al. 1996b). Studies in children with abuse in which diagnosis of PTSD was not established found increased catecholamines in 24-h urine (including norepinephrine, epinephrine, and dopamine) (De Bellis et al. 1994b). Studies in children with the diagnosis of PTSD also showed elevations in catecholamine levels in urine at baseline (De Bellis et al. 1999a). A study of adult women with childhood sexual abuse-related PTSD found increased concentrations of norepinephrine and epinephrine in 24-h urine (Lemieux and Coe 1995). Heart rate and skin conductance are mediated in part by the noradrenergic system. Women with childhood sexual abuse-related PTSD had increased heart rate, skin conductance, and facial electromyographic responses following exposure to personalized scripts of childhood sexual abuse compared to controls (Orr et al. 1998). These findings are consistent with animal studies showing increased noradrenergic activity following early stress.
Women with PTSD related to childhood abuse have smaller volume of the hippocampus as measured with magnetic resonance imaging (MRI), and deficits in declarative memory function, consistent with animal studies (Bremner 2005). Studies in children with PTSD from a variety of traumas have shown deficits in verbal memory and verbal IQ (Moradi et al. 1999; Saigh et al. 2006; Saltzman et al. 2006). These deficits are felt to be mediated at least in part by the hippocampus (Elzinga and Bremner 2002). Women with childhood sexual abuse-related PTSD showed deficits in verbal declarative memory compared to both women with abuse without PTSD and non-abused non-PTSD women (Bremner et al. 2004a). Another study in women with early childhood sexual abuse in which some, but not all, of the patients had PTSD showed no difference in declarative memory between abused and non-abused women (Stein et al. 1999). Women with childhood abuse-related PTSD also show cognitive impairments as evidenced by an increase in false recall of critical lures on a memory test involving recall from a list of highly semantically related words (Bremner et al. 2000a; Clancy et al. 2000).
Studies have also consistently shown smaller hippocampal volume in both male and female adults with PTSD related to a range of traumas, including childhood abuse (Bremner 2006; Karl et al. 2006; Kitayama et al. 2005; Smith 2005). A study of women with early sexual abuse, most of whom met criteria for PTSD, showed smaller hippocampal volume compared to non-abused women (Stein et al. 1997a). Women with early childhood sexual abuse and PTSD had smaller hippocampal volume compared to both abused women without PTSD and non-abused non-PTSD women (Bremner et al. 2003c). Another study showed smaller hippocampal volume in adult women with PTSD only in those who were abused at specific periods in early childhood (Andersen et al. 2008). One study of adult women with child abuse-related PTSD did not show smaller hippocampal volume or memory deficits in comparison to controls (Pederson et al. 2004). Studies of children with abuse-related PTSD have not shown smaller hippocampal volume (Carrion et al. 2001; De Bellis et al. 1999b, 2001), although one study showed a correlation between cortisol and reduction in hippocampal volume over time (Carrion et al. 2007). Meta-analyses show that smaller hippocampal volume is seen to an equal degree in both men and women with PTSD, related to both childhood abuse and adult traumas like combat, and in both left and right hippocampi (Kitayama et al. 2005; Smith 2005). Findings of smaller hippocampal volume in women with early childhood abuse-related PTSD, but not in abused girls, suggest a delayed effect of abuse on the brain, which is consistent with findings from animal studies (Brunson et al. 2005).
Women with early childhood sexual abuse-related PTSD also have deficits in hippocampal function. Women with childhood sexual abuse-related PTSD had deficits in hippocampal activation while performing a verbal declarative memory task as measured with brain imaging compared to non-PTSD women (Bremner et al. 2003b). Both hippocampal atrophy and hippocampal-based memory deficits reversed with treatment with the SSRI, paroxetine, in men and women with PTSD related to a range of traumas (Vermetten et al. 2003). Stress-induced hippocampal dysfunction may mediate many of the symptoms of PTSD which are related to memory dysregulation, including both explicit memory deficits and fragmentation of memory in abuse survivors (Bremner 2005).
The medial prefrontal cortex (including anterior cingulate) is also affected by childhood sexual abuse-related PTSD in women. One study showed that women with childhood abuse-related PTSD had smaller anterior cingulate volume as measured with MRI compared to controls (Kitayama et al. 2005), while others showed smaller frontal lobe volumes (Andersen et al. 2008). Reduced NAA (indicating loss of neuronal integrity) was found in medial prefrontal cortex in boys and girls with childhood PTSD (De Bellis et al. 2000). Other findings related to volumetrics include smaller volume of the corpus callosum in women with childhood abuse-related PTSD (Andersen et al. 2008; Kitayama et al. 2007). In children with PTSD, boys showed greater reduction in corpus callosum and greater ventricular volumes than girls (De Bellis and Keshavan 2003).
Neural Circuits in Women with Early Life Stress and PTSD
Studies of brain function in women with early life trauma-related PTSD showed consistent abnormalities in a network of brain regions including medial prefrontal cortex, amygdala, and hippocampus (Bremner 2010). Girls with a history of poor emotional response to maltreatment had a relative decrease in left versus right frontal lobe activity as measured by electroencephalogram (EEG) (Curtis and Cicchetti 2007). Other studies showed alterations in EEG measures of brain activity in the frontal cortex and left hemisphere in boys and girls with a variety of traumas, about half of whom had a psychiatric diagnosis (Ito et al. 1993; Schiffer et al. 1995). A study in adolescent girls maltreated in childhood showed a similar pattern of EEG abnormalities (Miskovic et al. 2010).
Brain imaging studies are also consistent with abnormalities in these areas in women with childhood abuse-related PTSD. Exposure to memories of childhood sexual abuse with personalized traumatic scripts in women with childhood sexual abuse-related PTSD resulted in decreased blood flow in the medial prefrontal cortex/anterior cingulate, including Brodmann’s area 25, or subcallosal gyrus, and area 32, as well as decreased blood flow in parietal cortex and inferior frontal gyrus (Bremner et al. 1999; Shin et al. 1999), hippocampus, and visual association cortex (Bremner et al. 1999). Retrieval of emotionally valenced words (Bremner et al. 2001) (e.g., “rape-mutilate”) in women with PTSD from early abuse resulted in decreases in blood flow in an extensive area which included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (Brodmann’s areas 25, 32, 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex (Bremner et al. 2003c). Another study found a failure of medial prefrontal cortical/anterior cingulate activation, and decreased visual association and parietal cortex function, in women with abuse and PTSD relative to women with abuse without PTSD, during performance of the emotional Stroop task (i.e., naming the color of a word such as “rape”) (Bremner et al. 2004b). Women with childhood sexual abuse-related PTSD had increased amygdala activation with classical fear conditioning (pairing a shock and a visual stimulus), and decreased medial prefrontal cortex function with extinction, compared to healthy non-abused women (Bremner et al. 2005). An increase in activation in parietal cortex, precentral gyrus, and posterior cingulate was seen in women with a history of childhood maltreatment during exposure to neutral smells (Croy et al. 2010). The findings described above point to a network of related regions mediating symptoms of PTSD, including medial prefrontal cortex/anterior cingulate, hippocampus, and amygdala (Bremner 2002b).
Neurobiology of Trauma-Spectrum Psychiatric Disorders in Women with a History of Childhood Abuse
Bremner has argued for a trauma-spectrum range of psychiatric disorders related to early childhood abuse, which include PTSD, depression, dissociative identity disorder (DID), and borderline personality disorder (BPD) (Bremner 2002a). BPD is characterized by intense feelings of emptiness and fears of abandonment with associated disruptive relationships and self-destruction. DID is characterized by alterations and distortions in personal identity, and is associated with symptoms of depersonalization (feeling out of body), derealization (feeling like you are in a dream), and amnesia (gaps in memory). Both are closely linked with early trauma and are more common in women, as is depression, which in about half of patients is linked to early trauma (Zanarini 1997).
According to the trauma-spectrum disorders model, early trauma results in specific changes in brain and neurobiology that underlie the symptoms of PTSD, BPD, DID, and depression in women with early childhood abuse. Additionally, PTSD is considered to be more appropriately grouped with these disorders related to trauma, rather than with the other anxiety disorders, as it currently is. This model would predict similar biological correlates in these disorders, e.g., deficits in hippocampus and medial prefrontal cortex, not seen in the other anxiety disorders.
Early Life Stress and Cardiovascular Disease
The epidemiological evidence supporting a link between early life trauma and cardiovascular disease in women has been explored at length in chap. 6. Early stress may cause heart disease indirectly via risky habits or directly through activation of the neurohormonal with subsequent effects on cardiovascular function. Another possibility is genetic profile that could increase the risk for both stress-related psychopathology and cardiovascular disease. If there is a link between these conditions and heart disease, it must act through the brain (Vythilingam et al. 2000, 2002), since the first response to trauma is that the information is taken in through the senses of sight, hearing, touch, and smell, and this information is transmitted to primary sensory areas of the brain, and from them on to other networked regions that activate both the fear response and the peripheral neurohormonal response to stress. Stress acts through mental disorders, risky behaviors, and/or directly on the stress response system to increase the risk for heart disease. A combination of these pathways likely accounts for the association. Different pathways may play varying roles in different individuals. The stress response is mediated by a collection of brain areas that are interconnected, including the amygdala, medial prefrontal cortex, hippocampus, posterior cingulate and anterior cingulated (Milad et al., 2002; Radley et al., 2004). These regions play a critical role in the stress response (J. L. LeDoux, 1993). Women with early trauma may become sensitized to stress and have alterations in this circuit’s response to daily stressors. These brain circuits have direct or indirect outputs through the hypothalamus, amygdala, and medial prefrontal cortex to neurohormonal systems like cortisol and norepinephrine, as outlined above. These systems influence myocardial function (Hitchcock et al., 1991). The medial prefrontal cortex and anterior cingulate directly mediate cortisol and sympathetic responses through direct connections to the brainstem (Diorio et al., 1993). The hippocampus has direct inputs to the amygdale (J. E. LeDoux, 1996; MacLean, 1949). Early stress is also associated with changes in immune function which could contribute via increased risk for atherosclerosis and other mechanisms (Danese et al., 2012, see Chap.6). This neurohormonal activation is critical for survival. However with chronic stress and chronic activation these neurohormonal systems lead to changes in the endothelium, acceleration of atherosclerosis, alterations in heart rate variability, increased risk for arrhythmias, increased platelet aggregation, and other factors that increase the risk for cardiovascular mortality in patients with depression (Vaccarino et al., 2011, see Chap.6).
There are other areas of overlap in neurobiology in women with a history of childhood abuse and different trauma-spectrum disorders. Like abuse-related PTSD, BPD patients with a history of early abuse show HPA axis dysfunction, and a functional dysregulation of the prefrontal–limbic axis (Donegan et al. 2003; Driessen et al. 2004; Juengling et al. 2003; Lange et al. 2005; Schmahl and Bremner 2006; Schmahl et al. 2002, 2003a, 2004a, b). However, BPD and PTSD patients, even in groups where all subjects were exposed to childhood sexual abuse, have important differences in the types of stimuli that provoke physiological reactivity, with BPD subjects responding to reminders (scripts) of abandonment but not trauma, and PTSD subjects having the opposite response (Schmahl et al. 2004a). These findings are consistent with a common neurobiology and neurocircuitry underlying the trauma-spectrum disorders, including PTSD, DID, BPD, and depression related to early abuse, in women with childhood abuse, although some differences may mediate differences in symptoms. It should be emphasized, however, that many of the symptoms of these disorders overlap with each other, and there is very high comorbidity.
Conclusions and Future Directions
Studies show that early childhood abuse has long-term effects on brain areas involved in memory and emotion, including the hippocampus, amygdala, and medial prefrontal cortex. Brain circuits mediating the stress response including norepinephrine and the HPA axis also play a role. There are important public health implications of biological changes with childhood abuse. Stress-related changes in neurobiology also affect work and social function in adulthood, since brain areas such as the medial portion of the prefrontal cortex that are affected by stress play an important role in the regulation of social behavior. The increase in risk for cardiovascular disease in women with early trauma has important public health implications, as it appears that these types of behavioral factors may play as important a role in morbidity and mortality as traditional risk factors for heart disease. Future efforts should further outline the mechanisms by which stress acts on the brain and neurobiology to increase the risk of cardiovascular disease as an effort to improve public health for women.
The work presented in this review was supported by grants from the United States National Institutes of Health (MH56120), R01 MH056120, R01 HL088726, K24 MH076955, K24HL077506, and P01 HL101398, and the Department of Veterans Affairs.
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