Katarina Dedovic

Deactivation of the Limbic System During Acute Psychosocial Stress: Evidence from Positron Emission Tomography and Functional Magnetic Resonance Imaging Studies

BACKGROUND Stress-induced metabolic changes can have detrimental health effects. Newly developed paradigms to investigate stress in neuroimaging environments allow the assessment of brain activation changes in association with the perception of and the metabolic response to stress. METHODS We exposed human subjects to a psychosocial stressor in one positron emission tomography (n = 10) and one functional magnetic resonance imaging (fMRI; n = 40) experiment. RESULTS We observed a profound deactivation of limbic system components including hippocampus, hypothalamus, medio-orbitofrontal cortex and anterior cingulate cortex in subjects who reacted to the stressor with a significant increase of the endocrine stress marker cortisol. Further, in the fMRI study, the degree of deactivation in the hippocampus was correlated with the release of cortisol in response to the stress task. CONCLUSIONS The observed deactivation of limbic system structures suggests elevated activation at rest and during nonstressful situations. A model is proposed where the observed reduction in limbic system activity is essential for the initiation of the stress response.

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.

Self-esteem, locus of control, hippocampal volume, and cortisol regulation in young and old adulthood

Self-esteem, the value we place on ourselves, has been associated with effects on health, life expectancy, and life satisfaction. Correlated with self-esteem is internal locus of control, the individuals perception of being in control of his or her outcomes. Recently, variations in self-esteem and internal locus of control have been shown to predict the neuroendocrine cortisol response to stress. Cumulative exposure to high levels of cortisol over the lifetime is known to be related to hippocampal atrophy. We therefore examined hippocampal volume and cortisol regulation, to investigate potential biological mechanisms related to self-esteem. We investigated 16 healthy young (age range 20-26 years of age) and 23 healthy elderly subjects (age range 60-84 years). The young subjects were exposed to a psychosocial stress task, while the elderly subjects were assessed for their basal cortisol regulation. Structural Magnetic Resonance Images were acquired from all subjects, and volumetric analyses were performed on medial temporal lobe structures, and whole brain gray matter. Standardized neuropsychological assessments in the elderly were performed to assess levels of cognitive performance, and to exclude the possibility of neurodegenerative disease. Self-esteem and internal locus of control were significantly correlated with hippocampal volume in both young and elderly subjects. In the young, the cortisol response to the psychosocial stress task was significantly correlated with both hippocampal volume and levels of self-esteem and locus of control, while in the elderly, these personality traits moderated age-related patterns of cognitive decline, cortisol regulation, and global brain volume decline.

Stress regulation in the central nervous system: evidence from structural and functional neuroimaging studies in human populations - 2008 Curt Richter Award Winner

The metabolic effects of stress are known to have significant health effects in both humans and animals. Most of these effects are mediated by the major stress hormonal axis in the body, the hypothalamic-pituitary-adrenal (HPA) axis. Within the central nervous system (CNS), the hippocampus, the amygdala and the prefrontal cortex as part of the limbic system are believed to play important roles in the regulation of the HPA axis. With the advent of structural and functional neuroimaging techniques, the role of different CNS structures in the regulation of the HPA axis can be investigated more directly. In the current paper, we summarize the findings obtained in our laboratory in the context of stress and HPA axis regulation. Our laboratory has developed and contributed to the development of manual and automated segmentation protocols from structural magnetic resonance imaging (MRI) scans for assessment of hippocampus, amygdala, medial temporal lobe and frontal lobe structures. Employing these protocols, we could show significant age-related changes in HC volumes, which were different between men and women, with pre-menopausal women showing smaller age-related volume decline compared to men. We could recently extent these findings by showing how estrogen therapy after menopause leads to higher volumes in the HC. Investigating possible neurotoxicity effects of steroids, we showed effects of long-term steroid exposure on HC volumes, and investigated variability of HC volumes in relation to HPA axis regulation in young and elderly populations. Here, we were able to follow-up from non-imaging studies showing that subjects low in self-esteem have higher cortisol stress responses, and the HC emerged as the critical link between these variables. Recently, we have made two more important discoveries with regard to HC volume: we could show that HC volume is as variable in young as it is in older adults, in subjects ranging in age from 18 to 80 years. Also, we have linked birth weight and maternal care to HC volumes in young adults, demonstrating the effects of variations in maternal care on the integrity of the CNS. Besides structural assessments, there is increasing interest in functional techniques to investigate possible links between CNS activity and HPA axis regulation. These two approaches complement each other; some aspects of HPA axis regulation might be linked to the integrity of a specific CNS structure, while other aspects might be linked to the function of a specific structure with no involvement of CNS morphology. Thus, we have developed a mental arithmetic stress task that can be employed in functional neuroimaging studies, and have used it in a number of functional neuroimaging studies. Employing positron emission tomography (PET), we were able to demonstrate that stress causes dopamine release if subjects reported low maternal care early in life. Finally, employing the task in functional magnetic resonance imaging (fMRI), we could show how exposure to stress and activation of the HPA axis are associated with decreased activity in major portions of the limbic system, a result that allows to speculate on the effects of stress on cognitive and emotional regulation in the brain. Taken together, the use of neuroimaging techniques in Psychoneuroendocrinology opens exciting new possibilities for the investigation of stress effects in the central nervous system.

What Stress Does to Your Brain: A Review of Neuroimaging Studies

Objective: Recent neuroimaging studies aimed at investigating effects of psychological stress on the neural activity have used a range of experimental paradigms to elicit an acute stress response. The goal of this review is to, first, summarize results from these studies from a perspective of task design and, second, assess the appropriateness of the different stress tasks used. Method: We completed a PubMed search on recent articles that have examined the effects of psychological stress on neural processes in a neuroimaging environment. Selected articles were arranged according to the stress task used in the following categories: script-driven stress stimuli, Stroop colour-word interference task, speech in front of an audience, serial subtraction, and Montreal Imaging Stress Task (MIST). Results: Only studies using serial subtraction or the MIST were able to induce a significant cortisol stress response in their participants. Most consistent findings include decreased activity in orbitofrontal regions in response to stress. Additional findings of note are increases in activity in the frontal lobes, particularly the anterior cingulate cortex, as well as deactivation of the limbic system, particularly the hippocampus. Conclusion: Research to date is beginning to outline the involvement of prefrontal and limbic regions in perception and modulation of psychological stress. However, additional research is needed in designing a neuroimaging stress task that will yield a significant cortisol stress response consistently, across populations and laboratories.

Neural correlates of processing stressful information: An event-related fMRI study

Recent neuroimaging studies investigating neural correlates of psychological stress employ cognitive paradigms that induce a significant hormonal stress response in the scanner. The Montreal Imaging Stress Task (MIST) is one such task that combines challenging mental arithmetic with negative social evaluative feedback. Due to the block design nature of the MIST, it has not been possible thus far to investigate which brain areas respond specifically to the key components of the MIST (mental arithmetic, failure, negative social evaluation). In the current study, we developed an event-related MIST (eventMIST) in order to investigate which neural activation patterns are associated with performing mental arithmetic vs. processing of social evaluative threat. Data was available from twenty healthy university students. The eventMIST induced a significant stress response in a subsample of subjects, called the responders (n=7). Direct comparison between brain activity changes in responders vs. non-responders, in response to challenging math, revealed increased activity bilaterally in dorsomedial prefrontal cortex (PFC), left temporal pole, and right dorsolateral PFC. In response to negative social evaluation, responders showed reduction of brain activity in limbic system regions (medial orbitofrontal cortex and hippocampus), which was largely lacking in non-responders. Direct comparison between the groups for this contrast did not reveal any significant difference, probably due to small number of events available. This is the first study to use an event-related paradigm to investigate brain activity patterns in relation to challenging math and social evaluative threat separately.

The Role of Sex and Gender Socialization in Stress Reactivity

Individual health is determined by a myriad of factors. Interestingly, simply being male or female is one such factor that carries profound implications for ones well-being. Intriguing differences between men and women have been observed with respect to vulnerability to and prevalence of particular illnesses. The activity of the major stress hormone axis in humans, the hypothalamus-pituitary-adrenal axis, is directly and indirectly associated with the onset and propagation of these conditions. Previous studies have shown differences between men and women at the level of stress hormone regulation, suggesting that the metabolic effects of stress may be related to susceptibility for stress-related disease. While the majority of studies have suggested that biological differences are responsible, few have also considered the role of gender socialization. In this selective review, the authors summarize evidence on sex differences and highlight some recent results from endocrinological, developmental, and neuroimaging studies that suggest an important role of gender socialization on the metabolic effects of stress. Finally, a model is proposed that integrates these specific findings, highlighting gender socialization and stress responsivity.

Perceived early-life maternal care and the cortisol response to repeated psychosocial stress

BACKGROUND In the past decade, a body of animal and human research has revealed a profound influence of early-life experiences, ranging from variations in parenting behaviour to severe adversity, on hypothalamic-pituitary-adrenal axis regulation in adulthood. In our own previous studies, we have shown how variations in early-life parental care influence the development of the hippocampus and modify the cortisol awakening response. METHODS In the present study, we investigated the influence of early-life maternal care on cortisol, heart rate and subjective psychological responses to the repeated administration of a psychosocial laboratory stressor in a population of 63 healthy young adults. Low, medium and high early-life maternal care groups were identified using the Parental Bonding Instrument. RESULTS Controlling for the effect of sex, we found an inverted u-shaped relation between increasing levels of maternal care and cortisol stress responsivity. Specifically, overall and stress-induced cortisol levels went from below normal in the low maternal care, to normal in the medium care, back to below normal in the high maternal care groups. We found no group differences with respect to heart rate and subjective psychological stress measures. Whereas low and high maternal care groups exhibited similarly low endocrine stress responses, their psychological profiles were opposed with increased levels of depression and anxiety and decreased self-esteem in the low care group. LIMITATIONS Sex was unequally distributed among maternal care groups, whereby the number of men with low maternal care was too small to allow introducing sex as a second between-group variable. CONCLUSION We discuss the potential significance of this dissociation between endocrine and psychological parameters with respect to stress vulnerability and resistance for each maternal care group.

Greater amygdala activity and dorsomedial prefrontal–amygdala coupling are associated with enhanced inflammatory responses to stress

Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n=31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression.

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.