Julie Andrews

The brain and the stress axis: the neural correlates of cortisol regulation in response to stress.

The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine stress axis of the human organism. Cortisol, the final hormone of this axis, affects metabolic, cardiovascular and central nervous systems both acutely and chronically. Recent advances in neuroimaging techniques have led to the investigation of regulatory networks and mechanisms of cortisol regulation in the central nervous system in human populations. In the following review, results from human and animal studies are being presented that investigate the specific role of hippocampus (HC), amygdala (AG), prefrontal cortex (PFC), and brainstem nuclei in cortisol regulation in response to stress. In general, the types of stressors need to be distinguished when discussing the contributions of these structures in regulating the HPA axis. We propose a basic framework on how these structures communicate as a network to regulate cortisol secretion in response to psychological stress. Furthermore, we review critical studies that have substantially contributed to the literature. Possible future research avenues in the field of neuroimaging of cortisol regulation are discussed. In combination with investigations on genetic and environmental factors that influence the development of the HPA axis, this emerging new research will eventually allow the formulation of a more comprehensive framework of functional neuroanatomy of cortisol regulation.

Chronic stress, cognitive functioning and mental health.

This review aims to discuss the evidence supporting the link between chronic stress, cognitive function and mental health. Over the years, the associations between these concepts have been investigated in different populations. This review summarizes the findings that have emerged from older populations as well as from populations suffering from pathological aging, namely Mild Cognitive Impairment and Alzheimers Disease. Although older adults are an interesting population to study in terms of chronic stress, other stress-related diseases can occur throughout the lifespan. The second section covers some of these stress-related diseases that have recently received a great deal of attention, namely burnout, depression, and post-traumatic stress disorder. Given that chronic stress contributes to the development of certain pathologies by accelerating and/or exacerbating pre-existing vulnerabilities that vary from one individual to the other, the final section summarizes data obtained on potential variables contributing to the association between chronic stress and cognition.

Cortisol awakening response and hippocampal volume: vulnerability for major depressive disorder?

BACKGROUND Major depressive disorder is associated with dysregulated basal cortisol levels and small hippocampal (HC) volume. However, it is still debated whether these phenomena are a consequence of the illness or whether they may represent a vulnerability marker existing before the illness onset. Here, we aimed to examine this notion of vulnerability by assessing whether abnormalities in basal cortisol secretion and HC volumes are already present in a sample of healthy young adults who showed varying levels of depressive tendencies, but at subclinical levels. METHODS We recruited healthy young men and women from the local university. On the basis of depression scores derived from standard questionnaires, three groups were formed: a control group (n = 27), a subclinical group (n = 23), and a high-risk subclinical group (n = 9). The participants underwent a magnetic resonance imaging scan and collected saliva samples for the assessment of diurnal cortisol levels. RESULTS Both the subclinical and the high-risk subclinical group failed to show a significant increase in cortisol levels after awakening. The high-risk subclinical group also showed a lower area-under-the-curve increase of cortisol levels after awakening compared with control subjects. In addition, this group also had smaller total HC volume compared with control subjects. CONCLUSIONS The findings from this subclinical sample suggest that dysregulated cortisol awakening response and small HC volume may constitute vulnerability factors for major depressive disorder. Further investigations are needed to discern the mechanisms that may underlie these phenomena.

Stress-induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service

Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC‐vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre‐ and post‐exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symptoms post‐exposure). We found that soldiers with decreased HC volume following military service (i.e., post‐exposure) displayed more PTSD‐related symptoms post‐exposure as well as reduced HC‐vmPFC functional and structural connectivity post‐exposure, compared to soldiers with increased HC volume following military service. In contrast, initial smaller HC volume pre‐exposure did not have an effect on any of these factors. Our results therefore suggest that reduction in HC volume and connectivity with the vmPFC together mark a maladaptive response to stressful military service. As stress‐induced HC volume reductions were previously shown to be reversible, these localized biological markers may carry valuable therapeutic potential. Hum Brain Mapp 34:2808–2816, 2013.

Effects of manipulating the amount of social-evaluative threat on the cortisol stress response in young healthy men

Perceived social-evaluative threat triggers the hypothalamic-pituitary adrenal (HPA) axis, resulting in cortisol release. The current study examined the effects of varying the levels of social-evaluative threat on the stress response. Sixty healthy men (mean age + 23.17 +/- 3.89 years) underwent a public speaking task. Four conditions were established on the basis of panel location (inside or outside the room) and number of panelists (one or two). It was hypothesized that these variations affect salivary cortisol and physiological responses in a gradient manner. The task elicited significant cortisol and blood pressure changes for all conditions, but no difference between the groups was found, suggesting that all conditions were equally stressful. Study conclusions were that, for men, the visual presence of a panel is not necessary to elicit a cortisol response. Furthermore, increasing the number of judges does not increase the intensity of the stress response in a gradual manner, but rather seems to follow a threshold pattern. Future studies should include women and try to define the possible threshold to activate the HPA axis.

Reflections on the interaction of psychogenic stress systems in humans : The stress coherence/compensation model

Although stress simultaneously affects and causes changes in central nervous system systems together with the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis, this interaction and its behavioral consequences are rarely assessed. The current paper first describes the different systems involved in the perception and processing of stressful stimuli on an anatomical and functional level, and the available measures to assess changes in these systems. It then explores, based on theoretical and empirical grounds, the interaction of the systems. This is followed by a review of previous stress models, and how these attempted to integrate the interaction of these systems. Then, it complements previous models by suggesting a complementary regulation of the stress systems, and discusses potential behavioral consequences. Finally, based on the three-system approach to assess stress it is argued that psychological measures, together with physiological and endocrine measures are indispensable. However, the lack of consensus on how to best assess the central and sympathetic nervous system components of stress make it more difficult to include measures of all systems routinely in future stress studies. Thus, the paper closes by giving some recommendations on how to include a minimum of feasible stress measures for all systems involved in stress processing and regulation.

The Combined Propranolol/TSST Paradigm : a New Method for Psychoneuroendocrinology

Upon perception of a stimulus as stressful, the human brain reacts with the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), to mobilize energy resources to better cope with the stressor. Since the perception of the stressor is the initial stimulus, a synchronicity between the subjective perception of stress and the physiological stress reactivity should be expected. However, according to a recent meta-analysis, these associations are weak and inconsistent. The goal of the current study was to investigate the interaction between the SNS, HPA and subjective stress perceptions, by introducing an experimental manipulation of this interaction. For this purpose, we combined the SNS inhibitor propranolol with the Trier Social Stress Test, and measured endocrinological and psychological responses to the stressor. Thirty healthy male participants were recruited and randomly assigned to either a propranolol (PROP; n = 15) or placebo (PLC; n = 15) group. All subjects were administered 80 mg of propranolol 60 minutes prior to exposure to psychosocial stress. Salivary cortisol and alpha amylase (sAA), heart rate, blood pressure and subjective stress responses were assessed throughout the study. We observed significantly reduced sAA levels and heart rate increases in the PROP group in response to stress, with no effects of the drug on systolic or diastolic blood pressure changes. In line with previous studies, a significant increase in cortisol was seen in response to the stress exposure. Importantly, the cortisol increase was significantly higher in the PROP group. A typical increase in subjective stress could be seen in both groups, with no significant group differences emerging. Complementing previous work, this study further demonstrates a significant interaction between the HPA and the SNS during acute stress. The HPA activity was found to be elevated in the presence of a suppressed SNS in reactivity to the TSST.

The DeStress for Success Program: effects of a stress education program on cortisol levels and depressive symptomatology in adolescents making the transition to high school.

Various studies have shown that increased activity of the hypothalamic-pituitary-adrenal (HPA) axis can predict the onset of adolescent depressive symptomatology. We have previously shown that adolescents making the transition to high school present a significant increase in cortisol levels, the main product of HPA axis activation. In the present study, we evaluated whether a school-based education program developed according to the current state of knowledge on stress in psychoneuroendocrinology decreases cortisol levels and/or depressive symptoms in adolescents making the transition to high school. Participants were 504 Year 7 high school students from two private schools in the Montreal area. Adolescents of one school were exposed to the DeStress for Success Program while adolescents from the other school served as controls. Salivary cortisol levels and depressive symptomatology were measured before, immediately after as well as 3 months after exposure to the program. Measures of negative mood were obtained at baseline in order to determine whether adolescents starting high school with specific negative moods were differentially responsive to the program. The results show that only adolescents starting high school with high levels of anger responded to the intervention with a significant decrease in cortisol levels. Moreover, we found that adolescents who took part in the intervention and showed decreasing cortisol levels following the intervention (responders) were 2.45 times less at risk to suffer from clinical and subclinical depressive states three months post-intervention in comparison to adolescents who showed increasing cortisol levels following the intervention (nonresponders). This study provides the first evidence that a school-based program on stress is effective at decreasing cortisol levels and depressive symptomatology in adolescents making the transition to high school and it helps explain which adolescents are sensitive to the program and what are some of the characteristics of these individuals.

The Combined Dexamethasone/TSST Paradigm : a New Method for Psychoneuroendocrinology

The two main physiological systems involved in the regulation of the stress response are the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). However, the interaction of these systems on the stress response remains poorly understood. To better understand the cross-regulatory effects of the different systems involved in stress regulation, we developed a new stress paradigm that keeps the activity of the HPA constant when exposing subjects to psychosocial stress. Thirty healthy male participants were recruited and randomly assigned to either a dexamethasone (DEX; n = 15) or placebo (PLC; n = 15) group. All subjects were instructed to take the Dexamethasone (2 mg) or Placebo pill the night before coming to the laboratory to undergo the Trier Social Stress Task (TSST). Salivary cortisol, salivary alpha amylase (sAA), heart rate, blood pressure and subjective stress were assessed throughout the protocol. As expected, the DEX group presented with suppressed cortisol levels. In comparison, their heart rate was elevated by approximately ten base points compared to the PLC group, with increases throughout the protocol and during the TSST. Neither sAA, nor systolic or diastolic blood pressures showed significant group differences. Subjective stress levels significantly increased from baseline, and were found to be higher before and after the TSST after DEX compared to placebo. These results demonstrate a significant interaction between the HPA and the SNS during acute stress. The SNS activity was found to be elevated in the presence of a suppressed HPA axis, with some further effects on subjective levels of stress. The method to suppress the HPA prior to inducing stress was found to completely reliable, without any adverse side effects. Therefore, we propose this paradigm as a new method to investigate the interaction of the two major stress systems in the regulation of the stress response.

Effects of manipulating the amount of social-evaluative threat on the cortisol stress response in young healthy women

Psychological stress is known to activate the hypothalamic–pituitary–adrenal axis, resulting in the release of cortisol from the adrenal cortex into the bloodstream. Cortisol is the major human stress hormone and its health correlates continue to be investigated by laboratories around the world. One line of research suggests that specific situational variables play a role in the creation of a stressful situation. The current study examined the effects of systematically varying several situational characteristics on the cortisol stress response in 80 healthy young women exposed to a public speaking task. Three main factors and its interactions were investigated by locating the expert panel either inside or outside of the room, having the subjects speak either about themselves or somebody else, and by asking half of the subjects to perform a distractor task in addition to performing the public speaking. We interpreted these manipulations as variations of social evaluative threat, ego-involvement, and divided attention. We hypothesized that the variations and their interactions would cause differences in endocrine stress responses. The results showed that only the manipulation of social-evaluative threat had a significant main effect on the cortisol stress response in women. There was a further trend (p = 0.07) for a four-way interaction effect. No other main or interaction effects could be observed. We conclude that in women, social-evaluative threat affects the endocrine stress response. This is in contrast to a previous study showing no effects of this variation in men. Thus, future studies should more closely investigate sex or gender effects that might be interacting with the situational aspects of a stressful task.