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.

Early menarche predicts increased depressive symptoms and cortisol levels in Quebec girls ages 11 to 13.

Earlier age of menarche is believed to confer greater vulnerability to depressive symptoms via increased reactivity to stressors associated with adolescence. In this longitudinal study, we measured depressive symptoms and salivary cortisol levels in 198 boys and 142 girls between the ages of 11 and 13 tested four times during Grade 7 as they transitioned from elementary school to secondary school as per Quebec's education system. Results showed that girls who had already reached menarche before starting secondary school had significantly higher depressive symptoms and salivary cortisol levels across the school year in comparison to girls who had not reached menarche, who in turn presented higher depressive scores than boys. When we divided menarcheal girls as a function of menarcheal timing in subanalyses, we found that girls with early menarche presented consistently elevated depressive symptoms across the school year while girls with on-time menarche presented transient depressive symptoms but no differences in salivary cortisol levels. Collectively, these results show that early menarche is associated with high depressive symptoms and cortisol levels in adolescent girls. This developmental milestone may render girls more vulnerable to environmental stressors and therefore represents a critical period to intervene to promote mental health.

Hippocampal activation during a cognitive task is associated with subsequent neuroendocrine and cognitive responses to psychological stress.

Increased activation of the hypothalamus pituitary adrenal (HPA) axis, marked by increased secretion of cortisol, is a biological marker of psychological stress. It is well established that the hippocampus plays an important role in the regulation of HPA axis activity. The relationship between cortisol (stress-related elevation or exogenous administration) and the hippocampal-related cognitive function is often examined. However, few human studies to date have examined the effect of stress on hippocampal activity and the interactions between stress-induced activation of the HPA axis and hippocampal function during different phases of cognitive function. On the basis of our previous work, we hypothesized that group differences in stress-sensitivity relate to differences in hippocampal-related stress-integration. To test this hypothesis, we conducted a functional MRI study using tasks known to involve the hippocampal formation: novel-picture encoding, psychological stress, and paired-picture recognition. On the basis of their cortisol responses to stress, we divided subjects into stress-responders (increase in cortisol, n = 9) and nonresponders (decrease in cortisol, n = 10). Responders showed higher hippocampal deactivation during the stress task and lower recognition scores due to a larger number of misses. Intriguingly, stress-responders showed significant differences in hippocampal activation already prior to stress, with higher levels of hippocampal activity during the picture encoding. Although effects of both cortisol and hippocampal activation on recognition were present in responders, similar effects were absent in the nonresponder group. Our results indicate that hippocampus plays an important role in adaptive behavioral responses. We hypothesize that states of hippocampal activation prior to stress might reflect states of vigilance or anxiety, which might be important for determining interindividual differences in subsequent stress response and cognitive performance.

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.

Self-esteem and risky decision-making: an ERP study.

Self-esteem, a value one places on oneself, influences one's cognitive, emotional and behavioral responses across various situations. In the case of risky decision-making, high self-esteem (SE) individuals rely on their positive self-views and tend to be less defensive in response to a risky task; low SE individuals, on the contrary, tend to have fewer accessible positive resources and thus, are more prone to risk-aversion. While past studies have provided evidence for a link between self-esteem and a behaviorally-risky response, no study has explored the relation between self-esteem and the electrophysiological correlates of risky response. Therefore, the current study investigated the correlates of risky decision-making in high SE compared to low SE participants using event-related potentials (ERP) technology in 28 undergraduate students playing a blackjack game. The results showed that there was no difference between the high SE participants and the low SE participants with respect to the behavioral assessments of the risk-taking decision-making. However, for the electrophysiological data, we observed that the amplitude of P2 (150-300 ms) was more positive in the high SE participants compared to the low SE participants over the central-posterior scalp region. Dipole source analysis indicated that this positive component was generated in posterior cingulate cortex (PCC). These findings suggest that the high SE participants experienced more emotional signals than the low SE participants during decision-making.

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.

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 one's 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.

Brain regions in response to character feedback associated with the state self-esteem.

Research on the Sociometer theory of self-esteem have demonstrated that manipulations of interpersonal appraisal reliably influence an individual's state self-esteem and that state levels of self-esteem correlate very highly with perceived acceptance and rejection. However, how social feedback from different sources (e.g., appearance vs. character) affect the state self-esteem and its neural underpinnings have not been explored. To address this, participants underwent functional magnetic resonance imaging (fMRI) while viewing either appearance-related feedback words or character-related feedback words, and for each feedback word, they were asked to rate their state self-esteem. Results showed that participants reported a higher state self-esteem following character feedback, irrespective of valence, than that following appearance feedback. Moreover, fMRI results demonstrated that the left caudate tail was more activated in response to positive character feedback and the lateral prefrontal cortex (LPFC), dorsal anterior cingulate, posterior cingulate, and precuneus were more activated in response to negative character feedback than in response to appearance feedback. Moreover, activation of the left caudate tail was significantly correlated with the difference in participant's reported state self-esteem scores after receiving positive character feedback versus that after receiving positive appearance feedback. Further, activation of the LPFC was significantly correlated with a difference in participant's reported state self-esteem scores after receiving negative character feedback versus that after receiving negative appearance feedback. These findings suggest a reward-related mechanism when processing positive social feedback and a self-critical processing when processing the negative social feedback on an important aspect of self-concept (e.g., character-related).

Blunted cortisol reactivity and risky driving in young offenders - a pilot study.

Adolescent risky driving is a significant burden on public health. Young offenders (i.e. under custody and supervision of the criminal justice system) may be particularly vulnerable, but research is scant. Previous work indicated that blunted cortisol reactivity to stress is a marker of risk-taking predisposition, including risky driving. In this study, we hypothesized that young offenders display higher levels of risky driving than a non-offender comparison group, and that cortisol reactivity contributes to the variance in risky driving independent of other associated characteristics (i.e. impulsivity, risk taking, alcohol and drug use). We found that young offenders (n = 20) showed riskier driving in simulation than comparison group (n = 9), and blunted cortisol reactivity was significantly associated with risky driving. The results suggest young offenders are prone to risky driving, and that individual differences in the cortisol stress response may be an explanatory factor.

Dorsal Anterior Cingulate Cortex Responses to Repeated Social Evaluative Feedback in Young Women with and without a History of Depression.

The dorsal anterior cingulate cortex (dACC) is recruited when a person is socially rejected or negatively evaluated. However, it remains to be fully understood how this region responds to repeated exposure to personally-relevant social evaluation, in both healthy populations and those vulnerable to Major Depressive Disorder (MDD), as well as how responding in these regions is associated with subsequent clinical functioning. To address this gap in the literature, we recruited 17 young women with past history of MDD (previously depressed) and 31 healthy controls and exposed them to a social evaluative session in a neuroimaging environment. In two bouts, participants received an equal amount of positive, negative, and neutral feedback from a confederate. All participants reported increases in feelings of social evaluation in response to the evaluative task. However, compared to healthy controls, previously depressed participants tended to show greater increases in depressed mood following the task. At the neural level, in response to negative (vs. positive) feedback, no main effect of group or evaluation periods was observed. However, a significant interaction between group and evaluation periods was found. Specifically, over the two bouts of evaluation, activity in the dACC decreased among healthy participants while it increased among previously depressed individuals. Interestingly and unexpectedly, in the previously depressed group specifically, this increased activity in dACC over time was associated with lower levels of depressive symptoms at baseline and at 6-months following the evaluation session (controlling for baseline levels). Thus, the subset of previously depressed participants who showed increases in the recruitment of the dACC over time in response to the negative evaluation seemed to fair better emotionally. These findings suggest that examining how the dACC responds to repeated bouts of negative evaluation reveals a new dimension to the role of the dACC in processing exclusion and contributing to mental health outcomes in a population vulnerable to MDD. Further, investigation of the dynamics of the dACC response to negative social evaluation is warranted.

Examining cortical thickness in male and female DWI offenders.

Some sex differences have been detected in driving while impaired by alcohol (DWI) offenders. However, understanding of the key factors contributing to DWI among male and female drivers remains elusive, limiting development of targeted interventions. Sex-based neurocognitive analyses could provide the much-needed insight. We examined whether male DWI offenders show cortical thickness anomalies that differ from those in female DWI offenders, when compared to their respective controls. Moderating role of sex and alcohol use on DWI status was also investigated. Sixty-one DWI offenders (29 male; 32 female) and 58 controls (29 male; 29 female) completed an anatomical brain scan and assessments on other relevant characteristics. Only male DWI offenders had reduced cortical thickness in the right dorsal posterior cingulate cortex (PCC), a region involved in cognitive control. Lower cortical thickness was associated with increased odds of DWI status only among males who have not engaged in very hazardous pattern of alcohol misuse in the previous 12 months. Thus, for these male DWI drivers, interventions that could impact PCC could be most advantageous. Continued multidimensional sex analysis of the neural characteristics of male and female DWI offenders is warranted.

Neural mechanisms linking social status and inflammatory responses to social stress.

Social stratification has important implications for health and well-being, with individuals lower in standing in a hierarchy experiencing worse outcomes than those higher up the social ladder. Separate lines of past research suggest that alterations in inflammatory processes and neural responses to threat may link lower social status with poorer outcomes. This study was designed to bridge these literatures to investigate the neurocognitive mechanisms linking subjective social status and inflammation. Thirty-one participants reported their subjective social status, and underwent a functional magnetic resonance imaging scan while they were socially evaluated. Participants also provided blood samples before and after the stressor, which were analysed for changes in inflammation. Results showed that lower subjective social status was associated with greater increases in inflammation. Neuroimaging data revealed lower subjective social status was associated with greater neural activity in the dorsomedial prefrontal cortex (DMPFC) in response to negative feedback. Finally, results indicated that activation in the DMPFC in response to negative feedback mediated the relation between social status and increases in inflammatory activity. This study provides the first evidence of a neurocognitive pathway linking subjective social status and inflammation, thus furthering our understanding of how social hierarchies shape neural and physiological responses to social interactions.

Psychological, endocrine, and neural correlates of attentional bias in subclinical depression.

BACKGROUND: Our knowledge with respect to psychological, endocrine, and neural correlates of attentional bias in individuals with high vulnerability to developing depression - the subclinically depressed, still remains limited. DESIGN: The study used a 2 × 2 mixed design. METHODS: Attentional bias toward happy and sad faces in healthy (N = 26) and subclinically depressed individuals (N = 22) was assessed via a neuroimaging dot-probe attention task. Participants also completed trait and state psychological measures and provided saliva samples for cortisol analysis. RESULTS: The subclinical group showed attentional bias toward happy faces; past use of problem-focused coping strategies when dealing with a personally relevant stressor as well as state levels of anxiety, together, contributed to this bias. In the control group, the happy attentional bias was positively correlated with activity in the right caudate. In the subclinical group, the bias was negatively associated with the left fusiform gyrus and positively with the left inferior parietal lobule and bilateral putamen. We observed group differences in association between cortisol levels during the task and neural activity during happy attentional bias processing within the key regions involved in attention. CONCLUSIONS: The attentional bias toward happy faces may reflect an active coping attempt by the subclinical participants.

The cortisol awakening response and major depression: examining the evidence.

A vast body of literature has revealed that dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress axis is associated with etiology of major depressive disorder (MDD). There are many ways that the dysregulation of the HPA axis can be assessed: by sampling diurnal basal secretion and/or in response to a stress task, pharmacological challenge, and awakening. Here, we focus on the association between cortisol awakening response (CAR), as one index of HPA axis function, and MDD, given that the nature of this association is particularly unclear. Indeed, in the following selective review, we attempt to reconcile sometimes-divergent evidence of the role of CAR in the pathway to depression. We first examine association of CAR with psychological factors that have been linked with increased vulnerability to develop depression. Then, we summarize the findings regarding the CAR profile in those with current depression, and evaluate evidence for the role of CAR following depression resolution and continued vulnerability. Finally, we showcase longitudinal studies showing the role of CAR in predicting depression onset and recurrence. Overall, the studies reveal an important, but complex, association between CAR and vulnerability to depression.

Lower Cortisol Activity is Associated with First-Time Driving while Impaired.

Driving while impaired (DWI) is a grave and persistent high-risk behavior. Previous work demonstrated that DWI recidivists had attenuated cortisol reactivity compared to non-DWI drivers. This suggests that cortisol is a neurobiological marker of high-risk driving. The present study tested the hypothesis that this initial finding would extend to first-time DWI (fDWI) offenders compared to non-DWI drivers. Male fDWI offenders (n = 139) and non-DWI drivers (n = 31) were exposed to a stress task, and their salivary cortisol activity (total output and reactivity) was measured. Participants also completed questionnaires on sensation seeking, impulsivity, substance use, and engagement in risky and criminal behaviors. As hypothesized, fDWI offenders, compared to non-DWI drivers, had lower cortisol reactivity; fDWI offenders also showed lower total output. In addition, cortisol activity was the most important predictor of group membership, after accounting for alcohol misuse patterns and consequences and other personality and problem behavior characteristics. The findings indicate that attenuated cortisol activity is an independent factor associated with DWI offending risk at an earlier stage in the DWI trajectory than previously detected.

Self-esteem modulates dorsal medial prefrontal cortical response to self-positivity bias in implicit self-relevant processing.

Processing self-related material recruits similar neural networks regardless of whether the self-relevance is made explicit or not. However, when considering the neural mechanisms that distinctly underlie cognitive and affective components of self-reflection, it is still unclear whether the same mechanisms are involved when self-reflection is explicit or implicit, and how these mechanisms may be modulated by individual personality traits, such as self-esteem. In the present functional MRI study, 25 participants were exposed to positive and negative words that varied with respect to the degree of self-relevance for each participant; however, the participants were asked to make a judgment about the color of the words. Regions-of-interest analysis showed that medial prefrontal cortex (mPFC) and posterior cingulate cortex were associated with gauging the self-relevance of information. However, no main effect of valence or an interaction effect between self-relevance and valence was observed. Further, positive correlations were observed between levels of self-esteem and response within dorsal mPFC (dmPFC) both in the contrast positive-high in self-relevance trials vs positive-low in self-relevance trials and in the contrast negative-low in self-relevance trials vs positive-low in self-relevance trials. These results suggested that the activation of dmPFC may be particularly associated with the processes of self-positivity bias.

Psychological, endocrine and neural responses to social evaluation in subclinical depression.

This study aimed to identify vulnerability patterns in psychological, physiological and neural responses to mild psychosocial challenge in a population that is at a direct risk of developing depression, but who has not as yet succumbed to the full clinical syndrome. A group of healthy and a group of subclinically depressed participants underwent a modified Montreal Imaging Stress task (MIST), a mild neuroimaging psychosocial task and completed state self-esteem and mood measures. Cortisol levels were assessed throughout the session. All participants showed a decrease in performance self-esteem levels following the MIST. Yet, the decline in performance self-esteem levels was associated with increased levels of anxiety and confusion in the healthy group, but increased levels of depression in the subclinical group, following the MIST. The subclinical group showed overall lower cortisol levels compared with the healthy group. The degree of change in activity in the subgenual anterior cingulate cortex in response to negative evaluation was associated with increased levels of depression in the whole sample. Findings suggest that even in response to a mild psychosocial challenge, those individuals vulnerable to depression already show important maladaptive response patterns at psychological and neural levels. The findings point to important targets for future interventions.

Self-esteem modulates dorsal anterior cingulate cortical response in self-referential processing.

Self-esteem can be defined as evaluations that individuals make about their worth as human beings. These evaluations are in part based on how we evaluate ourselves on our abilities, values, opinions, etc. compared with others or our past or ideal self; and they are also influenced by a thought that what others may think about us. Studies to date investigating the neural mechanisms underlying individual differences in self-esteem have focused mostly on the latter process (i.e. on how self-esteem is associated with neural correlates of processing feedback from others). However, given that people spend a lot of time thinking about themselves and evaluating their worth, we aimed to investigate neural mechanism underlying the association between levels of self-esteem and processing of self-relevant information. Seventeen participants completed a functional magnetic resonance imaging (fMRI) scan during which they were asked to evaluate whether a given statement is true about them (Self), an acquaintance of theirs (Other), or about general knowledge (Semantic). A whole brain correlational analysis revealed a significant negative correlation between levels of self-esteem and changes in activation of dorsal anterior cingulate gyrus (dACC, BA32) in response to evaluating self-relevant information (Self versus Other contrast). This result extends previous findings implicating this region in the association between processing evaluative feedback and levels of self-esteem and suggests that activity in this region is affected by self-esteem levels also when individuals are engaged in self-referencing and self-evaluation. Future studies should investigate whether these associations are affected differently based on valence of self-evaluations.

The neural correlates of implicit self-relevant processing in low self-esteem: an ERP study.

Previous neuroimaging studies have shown that implicit and explicit processing of self-relevant (schematic) material elicit activity in many of the same brain regions. Electrophysiological studies on the neural processing of explicit self-relevant cues have generally supported the view that P300 is an index of attention to self-relevant stimuli; however, there has been no study to date investigating the temporal course of implicit self-relevant processing. The current study seeks to investigate the time course involved in implicit self-processing by comparing processing of self-relevant with non-self-relevant words while subjects are making a judgment about color of the words in an implicit attention task. Sixteen low self-esteem participants were examined using event-related potentials technology (ERP). We hypothesized that this implicit attention task would involve P2 component rather than the P300 component. Indeed, P2 component has been associated with perceptual analysis and attentional allocation and may be more likely to occur in unconscious conditions such as this task. Results showed that latency of P2 component, which indexes the time required for perceptual analysis, was more prolonged in processing self-relevant words compared to processing non-self-relevant words. Our results suggested that the judgment of the color of the word interfered with automatic processing of self-relevant information and resulted in less efficient processing of self-relevant word. Together with previous ERP studies examining processing of explicit self-relevant cues, these findings suggest that the explicit and the implicit processing of self-relevant information would not elicit the same ERP components.

Increased cortisol awakening response and afternoon/evening cortisol output in healthy young adults with low early life parental care.

RATIONALE: Growing evidence from animal and human studies suggests a profound and long-lasting influence of early life experiences--ranging from variations in parenting behavior to severe adversity--on hypothalamic-pituitary-adrenal axis function. OBJECTIVES: The aim of the current investigation was to examine the association between naturally occurring variations in early life parental care and the cortisol awakening response (CAR), afternoon/evening cortisol output and key psychological variables in a sample of healthy young adults. METHODS: Fifty-eight (19 male and 39 female) participants between 18 and 30 years of age completed psychological questionnaires and collected saliva at awakening, 30 min thereafter and at 3 p.m., 6 p.m., and 9 p.m. on three non-consecutive weekdays. RESULTS: Participants with low (compared to high) parental care experiences exhibited an increased CAR, increased afternoon/evening cortisol output, decreased self-esteem, and increased depressive symptomatology and anxiety. CONCLUSIONS: We suggest that the elevated CAR and afternoon/evening cortisol levels might reflect a biological correlate of adversity-induced vulnerability for psychopathology. This study is first to show an association between the retrospective perception of early life parental care and cortisol circadian rhythms in healthy young adults.