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BACKGROUND: Asymmetric patterns of frontal brain activity and brain corticotropin-releasing hormone (CRH) systems have both been separately implicated in the processing of normal and abnormal emotional responses. Previous studies in rhesus monkeys demonstrated that individuals with extreme right frontal asymmetric brain electrical activity have high levels of trait-like fearful behavior and increased plasma cortisol concentrations. METHODS: In this study we assessed cerebrospinal fluid (CSF) CRH concentrations in monkeys with extreme left and extreme right frontal brain electrical activity. CSF was repeatedly collected at 4, 8, 14, 40, and 52 months of age. RESULTS: Monkeys with extreme right frontal brain activity had increased CSF CRH concentrations at all ages measured. In addition, individual differences in CSF CRH concentrations were stable from 4 to 52 months of age. CONCLUSIONS: These findings suggest that, in primates, the fearful endophenotype is characterized by increased fearful behavior, a specific pattern of frontal electrical activity, increased pituitary-adrenal activity, and increased activity of brain CRH systems. Data from other preclinical studies suggests that the increased brain CRH activity may underlie the behavioral and physiological characteristics of fearful endophenotype.
Summary Stress disorders are among the most commonly occurring of all mental disorders. In this context, the question arises whether the stress inevitably unfolding around us has the potential to “contaminate” and compromise us. In the current multi-center study, we investigate the existence of such empathic stress (defined as a full-blown physiological stress response that arises solely by observing a target undergo a stressful situation), and whether empathic stress permeates to the core of the stress system, the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, we investigate whether empathic stress responses may be modulated by the familiarity between observer and target (partners vs. strangers), the modality of observation (real-life vs. virtual) and observer sex (female vs. male). Participants were tested in dyads, paired with a loved one or a stranger of the opposite sex. While the target of the dyad (n = 151) was exposed to a psychosocial stressor, the observer (n = 211) watched through a one-way mirror or via live video transmission. Overall, 26% of the observers displayed physiologically significant cortisol increases. This empathic stress was more pronounced in intimate observer-target dyads (40%) and during the real-life representation of the stressor (30%). Empathic stress was further modulated by interindividual differences in empathy measures. Despite the higher prevalence of empathic stress in the partner and real-life observation conditions, significant cortisol responses also emerged in strangers (10%) and the virtual observation modality (24%). The occurrence of empathic stress down to the level of HPA-axis activation, in some cases even in total strangers and when only virtually witnessing another's distress, may have important implications for the development of stress-related diseases.
The prefrontal cortex (PFC) has been well known for its role in higher order cognition, affect regulation and social reasoning. Although the precise underpinnings have not been sufficiently described, increasing evidence also supports a prefrontal involvement in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. Here we investigate the PFC's role in HPA axis regulation during a psychosocial stress exposure in 14 healthy humans. Regional brain metabolism was assessed using positron emission tomography (PET) and injection of fluoro-18-deoxyglucose (FDG). Depending on the exact location within the PFC, increased glucose metabolic rate was associated with lower or higher salivary cortisol concentration in response to a psychosocial stress condition. Metabolic glucose rate in the rostral medial PFC (mPFC) (Brodman area (BA) 9 and BA 10) was negatively associated with stress-induced salivary cortisol increases. Furthermore, metabolic glucose rate in these regions was inversely coupled with changes in glucose metabolic rate in other areas, known to be involved in HPA axis regulation such as the amygdala/hippocampal region. In contrast, metabolic glucose rate in areas more lateral to the mPFC was positively associated with saliva cortisol. Subjective ratings on task stressfulness, task controllability and self-reported dispositional mood states also showed positive and negative associations with the glucose metabolic rate in prefrontal regions. These findings suggest that in humans, the PFC is activated in response to psychosocial stress and distinct prefrontal metabolic glucose patterns are linked to endocrine stress measures as well as subjective ratings on task stressfulness, controllability as well as dispositional mood states.
Numerous studies demonstrate that the rhesus monkey is an excellent species with which to investigate mechanisms underlying human emotion and psychopathology. To examine the role of the central nucleus of the amygdala (CeA) in mediating the behavioral and physiological responses associated with fear and anxiety, we used rhesus monkeys to assess the effects of excitotoxic lesions of the CeA. Behavioral and physiological responses of nine monkeys with bilateral CeA destruction (ranging from 46 to 98%) were compared with five animals with asymmetric lesions (42-86.5% destruction on the most affected side) and with 16 unoperated controls. Results suggest that similar to rodent species, the primate CeA plays a role in mediating fear- and anxiety-related behavioral and endocrine responses. Compared with controls and the asymmetric-lesion group, bilaterally lesioned monkeys displayed significantly less fear-related behavior when exposed to a snake and less freezing behavior when confronted by a human intruder. In addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin-releasing factor (CRF), and both lesioned groups had decreased plasma ACTH concentrations. In contrast to these findings, patterns of asymmetric frontal brain electrical activity, as assessed by regional scalp EEG, did not significantly differ between control and lesioned monkeys. These findings suggest that in primates, the CeA is involved in mediating fear- and anxiety-related behavioral and pituitary-adrenal responses as well as in modulating brain CRF activity.
This study, based on a sample of 172 children, examined the relation between average afternoon salivary cortisol levels measured at home at age 4.5 years and socioemotional adjustment a year and a half later, as reported by mothers, fathers, and teachers. Cortisol levels were hypothesized to be positively associated with withdrawal-type behaviors (e.g., internalizing, social wariness) and inversely related to approach-type behaviors, both negative and positive (e.g., externalizing, school engagement). Higher cortisol levels at age 4.5 predicted more internalizing behavior and social wariness as reported by teachers and mothers, although child gender moderated the relation between cortisol and mother report measures. An inverse relation was found between boys' cortisol levels and father report of externalizing behavior. A marginal inverse relation was found between child cortisol levels and teacher report of school engagement. Behavior assessed concurrently with cortisol collection did not account for the prospective relations observed,suggesting that cortisol adds uniquely to an understanding of behavioral development.
BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) system activation is adaptive in response to stress, and HPA dysregulation occurs in stress-related psychopathology. It is important to understand the mechanisms that modulate HPA output, yet few studies have addressed the neural circuitry associated with HPA regulation in primates and humans. Using high-resolution F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we assessed the relation between individual differences in brain activity and HPA function across multiple contexts that varied in stressfulness. METHODS: Using a logical AND conjunctions analysis, we assessed cortisol and brain metabolic activity with FDG-PET in 35 adolescent rhesus monkeys exposed to two threat and two home-cage conditions. To test the robustness of our findings, we used similar methods in an archival data set. In this data set, brain metabolic activity and cortisol were assessed in 17 adolescent male rhesus monkeys that were exposed to three stress-related contexts. RESULTS: Results from the two studies revealed that subgenual prefrontal cortex (PFC) metabolism (Brodmann's area 25/24) consistently predicted individual differences in plasma cortisol concentrations regardless of the context in which brain activity and cortisol were assessed. CONCLUSIONS: These findings suggest that activation in subgenual PFC may be related to HPA output across a variety of contexts (including familiar settings and novel or threatening situations). Individuals prone to elevated subgenual PFC activity across multiple contexts may be individuals who consistently show heightened cortisol and may be at risk for stress-related HPA dysregulation.