Neural response to stress and perceived stress differ in patients with left temporal lobe epilepsy

Patients with epilepsy are often able to predict seizure occurrence subsequent to an acute stress experience. However, neuroimaging investigations into the neural basis of this relationship or the potential influence of perceived life stress are limited. The current study assessed the relationship between perceived stress and the neurobehavioral response to stress in patients with left temporal lobe epilepsy (LTLE) and healthy controls (HCs) using heart rate, salivary cortisol level, and functional magnetic resonance imaging and compared these effects between HCs and LTLE. Matched on perceived stress levels, groups of 36 patients with LTLE and 36 HCs completed the Montreal Imaging Stress Task, with control and stress math task conditions. Among LTLEs, 27 reported that prior (acute) stress affected their seizures (LTLES+), while nine did not (LTLES?). The results revealed that increased perceived stress was associated with seizure frequency in LTLE. Further, cortisol secretion was greater in LTLE, but did not vary with perceived stress as observed in HCs. A linear mixed‐effects analysis revealed that as perceived stress increased, activation in the hippocampal complex (parahippocampal gyrus and hippocampus) decreased during stressful math in the LTLES+, increased in HCs, but did not vary in the LTLES?. Task‐based functional connectivity analyses revealed LTLE differences in hippocampal functional connectivity with sensory cortex specific to stressor modalities. We argue that the current study demonstrates an inhibitory hippocampal mechanism underlying differences in resilience to stress between HCs and LTLE, as well as LTLE patients who report stress as a precipitant of seizures.     

Amygdala Reward Reactivity Mediates the Association Between Preschool Stress Response and Depression Severity

Background

Research in adolescents and adults has suggested that altered neural processing of reward following early life adversity is a highly promising depressive intermediate phenotype. However, very little is known about how stress response, neural processing of reward, and depression are related in very young children. The present study examined the concurrent associations between cortisol response following a stressor, functional brain activity to reward, and depression severity in children 4 to 6 years old.

Cortisol levels and hippocampus volumes in healthy preadolescent children.

BACKGROUND: Research in animal models has demonstrated that elevated levels of glucocorticoids can inflict damage within the hippocampus. In adult humans, elevated cortisol levels have been associated with reduced hippocampal volumes; however, normative data in children are not available. The objective of this study was to examine possible associations of serum cortisol levels with hippocampal volumes and morphology in healthy children. METHODS: Morning serum cortisol levels and hippocampus magnetic resonance imaging were measured in 17 healthy children (8 girls, 9 boys) between 7 and 12 years of age. RESULTS: Cortisol levels were not associated with total hippocampal volumes; however, with an analysis of surface morphology, significant associations were found for regionally specific portions of the hippocampus. Positive associations were detected for the anterior segment of the hippocampus and inverse associations along the lateral aspects of the hippocampus. CONCLUSIONS: Associations of cortisol levels with regionally specific variations in hippocampal morphology were detected during early development in healthy preadolescent children.     

Maternal stimulation in infancy predicts hypothalamic–pituitary–adrenal axis reactivity in young men

Evidence from animal research has demonstrated the effect of early maternal care on the offspring’s endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother–child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19 years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3 months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic–pituitary–adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring’s hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.     

Early life stress and inherited variation in monkey hippocampal volumes.

BACKGROUND: Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes. METHODS: Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging. RESULTS: Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size. CONCLUSIONS: In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.     

Multiparity reveals the blunting effect of breastfeeding on physiological reactivity to psychological stress

Rat studies show that hypothalamic-pituitary-adrenal (HPA) responsiveness to physical and emotional stressors is attenuated during lactation, although situations evoking pup endangerment can supersede this phenomenon. In the human population, blunted cortisol responses are seen in primiparous breastfeeding compared to bottlefeeding mothers following physical stress, but not after psychosocial stress. It is currently unknown whether stressor salience (child-related versus nonrelated stressor) has a differential effect on cortisol reactivity as a function of infant feeding choice and whether HPA responses to stress could be modified by parity. We investigated the impact of infant feeding type and maternal parity on salivary cortisol and alpha-amylase response to stress in 5-20-week postpartum mothers using exposure to the Trier Social Stress Test (TSST) and to an emotional film evoking threats to a child. Analyses show that alpha-amylase responses were similar in all groups and for both types of stress, suggesting that sympathetic reactivity was independent of infant feeding type and parity. By contrast, cortisol response was affected by these variables. In primiparous mothers, cortisol reactivity to psychological stressors did not vary as a function of infant feeding type while, among multiparous mothers, breastfeeding was associated with reduced responsiveness to the TSST and child-related stressor. We speculate that changes in neural mechanisms occurring as a result of pregnancy and lactation and that modulate the HPA axis in women might be exacerbated with multiple repeats of the pregnancy/lactation period. This would serve to 'desensitise' stress circuits and reduce the overall stress-induced cortisol secretion after multiple births.     

Early-life stress and recurrent psychological distress over the lifecourse predict divergent cortisol reactivity patterns in adulthood

Early-life stress (ELS) is associated with substantially increased lifetime risk for recurrent psychological problems, with evidence indicating that dysregulation of the physiological stress reactivity system may be partly responsible. However, some ELS-exposed people remain psychologically resilient. Although two distinct patterns of hypothalamic-pituitary-adrenal axis (HPA) stress reactivity have been observed in ELS-exposed samples (hyper- and hypo-reactive), the hypothesis that these patterns may be associated with long-term history of psychological problems has not been explored. We used healthy Whitehall II study subjects (n=543) who participated in the 2008 Heart Scan Study (HSS) to assess salivary cortisol responses to a cognitive stressor, ELS exposure, and other psychosocial factors. Mean age of the sample at the HSS was 63 years. HSS data were linked to nearly 20 years of participants' Whitehall data, including repeated measures of psychological distress (GHQ-28). Piecewise growth curve analyses revealed that ELS-exposed persons with a history of recurrent psychological distress in adulthood had significantly blunted cortisol reactivity compared to non-ELS-exposed participants, while ELS-exposed persons with little or no history of distress had significantly elevated baseline cortisol, prolonged responses, and greater total cortisol production. Our findings indicate that for ELS-exposed individuals, different trajectories in psychological health over their adult lifetimes predict different cortisol reactivity patterns. These findings have important implications for our understanding of ELS-related mental health risk and treatment of these disorders.     

Acute exposure to predator odor elicits a robust increase in corticosterone and a decrease in activity without altering proliferation in the adult rat hippocampus

Stress has long been implicated as a major cause of depression in humans and more recently has been suggested to decrease neurogenesis, which may be a contributing factor to depression development. Animal models of stress may be a relevant tool for investigating links between neurogenesis and depression. This has largely been investigated using chronic stress models in rodents. However, stress may be chronic or experienced in discrete episodes. Acute stress may be particularly relevant to humans experiencing unexpected societal pressures and obligations. Our study examined the effect of acute stress on the proliferative phase of adult hippocampal neurogenesis. Young adult rats were exposed for 20 min to the predator odor TMT, a natural stressor for rodents with significant ethological relevance. BrdU IP injections were concurrent with TMT exposure to assess proliferation effects with animal sacrifice 2 h after BrdU injection. Robust stress responses were evident following TMT exposure as detected by elevated corticosterone (CORT) levels and a significant reduction in exploratory behavior. Exposure to TMT did not alter the number of BrdU-positive cells in the hippocampus despite physiological and behavioral evidence of stress. CORT level elevation has long been accepted as a marker of stress; however, this study indicates that increases in CORT level may not always correlate with diminished neurogenic proliferation. This study further suggests that various stressors may not operate through the same biological substrates resulting in a differential ability to modulate neurogenesis.     

Depression and cortisol responses to psychological stress: a meta-analysis

The purpose of this meta-analysis is to examine the association between depression and cortisol responses to psychological stressors. A total of seven studies comparing plasma or cortisol responses to psychological stressors in clinically depressed (MDD) and non-depressed (ND) individuals (N = 196: 98 MDD, 98 ND; 83 men, 113 women; mean age = 40 years) were included. Sample size-adjusted effect sizes (Cohen's d statistic) were calculated and averaged across baseline (before stressor onset), stress (stressor onset up to 25 min after stressor offset), and recovery (more than 25 min after stressor offset) periods. Overall, MDD and ND individuals exhibited similar baseline and stress cortisol levels, but MDD patients had much higher cortisol levels during the recovery period than their ND counterparts. There was also a significant time of day effect in which afternoon studies were more likely to reveal higher baseline cortisol levels, blunted stress reactivity, and impaired recovery in MDD patients. This blunted reactivity-impaired recovery pattern observed among the afternoon studies was most pronounced in studies with older and more severely depressed patients.     

Relationships among socioeconomic status, stress induced changes in cortisol, and blood pressure in african american males

The inverse relation between socioeconomic status (SES) and cardiovascular disease (CVD) risk has been posited to be partially due to exaggerated cardiovascular reactivity (CVR) to stress. Stress elicits hypothalamic-pituitary-adrenal axis activation (e.g., increased cortisol secretion), which may contribute to subsequent blood pressure (BP) elevation. Univariate associations among SES, cortisol secretion, and aggregated change scores to stressors (i.e., video game and forehead cold) for systolic BP (SBP) and diastolic BP (DBP) were assessed in a sample of 24 African American males (M age = 18.8, ± 2.7 years). Circadian variability of cortisol level was taken into account by partialling out collection time. Family SES was inversely related to initial cortisol level (partial r = -.46, p < .03). Neighborhood SES was inversely related to DBP reactivity (r = -.41, p < .05). The change in cortisol level during the stressor protocol was related to SBP reactivity (partial r = .44, p < .05). These results suggest that SES may be linked to CVD via BP and cortisol reactivity to stress, but prospective studies are needed to clarify whether such is the case. Preparation of this article was supported in part by Grants HL 69999 and HL 41781 from the National Institutes of Health.     

The relation between emotion regulation strategies and physiological stress responses in middle childhood

The current study sought to examine whether children's spontaneous use of the emotion regulation strategies suppression and reappraisal during a psychosocial stress task was related to their cortisol and alpha-amylase responses to that task. Salivary cortisol and alpha-amylase responses to a psychosocial stress task were assessed in 158 10-year-old children (83 girls). The children completed a self-report questionnaire measuring use of reappraisal and suppression during the task. Results showed overall increases in cortisol and alpha-amylase in response to the stressor, with higher cortisol reactivity in girls than in boys. With regard to emotion regulation, more use of suppression was related to lower cortisol reactivity in girls, and lower alpha-amylase reactivity and quicker alpha-amylase recovery in all children. The use of reappraisal was not related to the children's cortisol or alpha-amylase responses. The current study is the first to investigate the relation between the spontaneous use of reappraisal and suppression, and physiological stress responses to a psychosocial stressor in children. Our results indicate that reappraisal and suppression are used and can be measured even in 10-year-olds. At this age reappraisal appears ineffective at down-regulating physiological responses, while suppression was related to lower physiological responses. For cortisol reactivity there was a sex difference in the relation with suppression, indicating the importance of including sex as a moderator variable in research studying stress reactivity and its correlates in this age group.     

Stronger endocrine responses after brief psychological stress in women at familial risk of breast cancer

Recent research has linked exposure to chronic stress to altered acute stress responses and suggests a sensitizing effect of chronic stress leading to a stronger endocrine and cardiovascular response to acute stressors. Substantial evidence indicates that familial breast cancer risk is a chronic life stressor with higher levels of self reported distress. In this study, we investigated whether the endocrine response to a brief psychological stressor was stronger for women at familial risk for breast cancer. Thirty-six women at normal risk of breast cancer (FR- Stress Group) and 17 women at familial risk (FR+ Stress Group) underwent a brief psychological laboratory stress test (speech task and mental arithmetic) over a 15 min period. Thirty women at normal risk not subjected to the stressful task served as controls (FR- Control Group). Plasma epinephrine, norepinephrine and cortisol were measured at baseline, directly after the stress test (15 min) and at 30 min and 45 min post baseline. Heart rate data confirmed the effectiveness of the stress regimen. While there were no significant baseline group differences in the endocrine parameters, the response curves for the familial risk group revealed stronger epinephrine and cortisol reactivity to the stress test, as confirmed by significant group by time interactions. Norepinephrine levels showed a similar pattern, but results did not reach significance. These findings are in line with previous research documenting the facilitating effects of chronic stressors on acute stress response in animals and humans and provide the first evidence in the literature of a heightened endocrine reactivity to acute psychological stress in women at familial risk of breast cancer. The heightened endocrine reactivity to the experimental tasks seen here suggests that these women may experience stronger responses to stressors in their daily lives. According to the recently proposed concept of allostatic load, repeated overly strong stress responses may cumulatively have negative health implications.     

Early Life Stress and Childhood Aggression: Mediating and Moderating Effects of Child Callousness and Stress Reactivity

Early life stress (ELS) has been implicated in the development of aggression, though the exact mechanisms remain unknown. This study tested associations between ELS, callousness, and stress reactivity in the prediction of school-age and persistent early childhood aggression. A longitudinal sample of 185 mother–child dyads completed a lab visit and mothers completed an online follow-up when children were preschool-aged and school-aged, respectively. Physiological and behavioral measures of stress reactivity were collected during the preschool period. Ratings of child aggressive behavior, ELS, and callousness were collected as well. The results suggested that ELS was related to measures of both school-age and persistent early childhood aggression, and that callousness had a mediating role in this process. Cortisol reactivity also moderated the association between ELS and persistent childhood aggression, such that the ELS–aggression relationship was stronger among children who had higher levels of cortisol reactivity during the preschool period. Clinical implications are discussed.     

Associations among parenting experiences during childhood and adolescence, hypothalamus-pituitary-adrenal axis hypoactivity, and hippocampal gray matter volume reduction in young adults

Recent human studies have indicated that adverse parenting experiences during childhood and adolescence are associated with adulthood hypothalamus-pituitary-adrenal (HPA) axis hypoactivity. Chronic HPA axis hypoactivity inhibits hippocampal gray matter (GM) development, as shown by animal studies. However, associations among adverse parenting experiences during childhood and adolescence, HPA axis activity, and brain development, particularly hippocampal development, are insufficiently investigated in humans. In this voxel-based structural magnetic resonance imaging study, using a cross-sectional design, we examined the associations among the scores of parental bonding instrument (PBI; a self-report scale to rate the attitudes of parents during the first 16 years), cortisol response determined by the dexamethasone/corticotropin-releasing hormone test, and regional or total hippocampal GM volume in forty healthy young adults with the following features: aged between 18 and 35 years, no cortisol hypersecretion in response to the dexamethasone test, no history of traumatic events, or no past or current conditions of significant medical illness or neuropsychiatric disorders. As a result, parental overprotection scores significantly negatively correlated with cortisol response. Additionally, a significant positive association was found between cortisol response and total or regional hippocampal GM volume. No significant association was observed between PBI scores and total or regional hippocampal GM volume. In conclusion, statistical associations were found between parental overprotection during childhood and adolescence and adulthood HPA axis hypoactivity, and between HPA axis hypoactivity and hippocampal GM volume reduction in healthy young adults, but no significant relationship was observed between any PBI scores and adulthood hippocampal GM volume.     

Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging

Adult neurogenesis exists in most mammalian species, including humans, in two main areas: the subventricular zone (new cells migrate to the olfactory bulbs) and the dentate gyrus of the hippocampus. Many factors affect neurogenesis in the hippocampus and the subventricular zone, however the focus of this review will be on factors that affect hippocampal neurogenesis, particularly in females. Sex differences are often seen in levels of hippocampal neurogenesis, and these effects are due in part to differences in circulating levels of steroid hormones such as estradiol, progesterone, and corticosterone during the estrous cycle, in response to stress, with reproduction (including pregnancy and lactation), and aging. Depletion and administration of these same steroid hormones also has marked effects on hippocampal neurogenesis in the adult female, and these effects are dependent upon reproductive status and age. The present review will focus on current research investigating how hippocampal neurogenesis is altered in the adult female rodent across the lifespan.     

Sex-specific effects of mindfulness on romantic partners’ cortisol responses to conflict and relations with psychological adjustment

Mindfulness is known to improve individuals’ and couples’ subjective stress regulation, but little is known about how it impacts hypothalamic–pituitary–adrenal (HPA) axis responses to acute psychosocial stress. The current study tested effects of dispositional mindfulness facets on young adult couples’ cortisol responses to a conflict discussion stressor, as well as associations with psychological adjustment. One hundred heterosexual couples completed the five facet mindfulness questionnaire one week before engaging in a conflict discussion task. Each partner provided five saliva samples from pre- to post-conflict, which were assayed for cortisol. Measures of adjustment – depression and anxiety symptoms and global well-being – were also completed at this session. Hierarchical linear modeling of cortisol trajectories revealed sex-specific effects; whereas women's mindfulness (nonreactivity facet) predicted higher conflict stress cortisol levels, men's mindfulness (describing facet) predicted less pronounced cortisol reactivity/recovery curves. These patterns were related to better adjustment—lower depression symptoms for women and greater well-being for men. Implications for sex differences in mindfulness benefits are discussed.     

Differences in hypothalamic–pituitary–adrenal axis functioning among children with ADHD predominantly inattentive and combined types

Some evidence suggests that the HPA axis may be dysfunctional in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children. A total of 100 prepubertal subjects [52 children with ADHD combined type (ADHD-C), 23 children with ADHD predominantly inattentive type (ADHD-I), and 25 healthy control subjects] were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor. When a distinction was made between responders and non-responders (a subject was classified as a responder when there was an increase in cortisol reactivity), hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I. Directions for future research and clinical implications are discussed.     

Longitudinal changes in amygdala,hippocampus and cortisol development following early caregiving adversity

Although decades of research have shown associations between early caregiving adversity, stress physiology and limbic brain volume (e.g., amygdala, hippocampus), the developmental trajectories of these phenotypes are not well characterized. In the current study, we used an accelerated longitudinal design to assess the development of stress physiology, amygdala, and hippocampal volume following early institutional care. Previously Institutionalized (PI; N = 93) and comparison (COMP; N = 161) youth (ages 4–20 years old) completed 1–3 waves of data collection, each spaced approximately 2 years apart, for diurnal cortisol (N = 239) and structural MRI (N = 156). We observed a developmental shift in morning cortisol in the PI group, with blunted levels in childhood and heightened levels in late adolescence. PI history was associated with reduced hippocampal volume and reduced growth rate of the amygdala, resulting in smaller volumes by adolescence. Amygdala and hippocampal volumes were also prospectively associated with future morning cortisol in both groups. These results indicate that adversity-related physiological and neural phenotypes are not stationary during development but instead exhibit dynamic and interdependent changes from early childhood to early adulthood.     

DNA methylation profiles within the serotonin transporter gene moderate the association of 5-HTTLPR and cortisol stress reactivity

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been implicated in moderating vulnerability to stress-related psychopathology upon exposure to environmental adversity. A recent meta-analysis suggests a potential biological pathway conveying genotype-dependent stress sensitivity by demonstrating a small, but significant association of 5-HTTLPR and cortisol stress reactivity. An arguably more potent approach to detect larger effects when investigating the 5-HTTLPR stress sensitivity hypothesis is to account for both genetic and epigenetic variation in the serotonin transporter gene (SLC6A4). Here, we applied this approach in an experimental setting. Two hundred healthy adults were exposed to a laboratory stressor (Trier Social Stress Test) and cortisol response patterns were assessed as a function of 5-HTTLPR and DNA methylation profiles in SLC6A4. Specifically, we analyzed 83 CpG sites within a 799-bp promoter-associated CpG island of SLC6A4 using a highly sensitive bisulfite pyrosequencing method. Our results suggest that SLC6A4 methylation levels significantly moderate the association of 5-HTTLPR and cortisol stress reactivity. For individuals displaying low levels of SLC6A4 methylation, the S allele relates to increased cortisol stress reactivity in a dose-dependent fashion accounting for 7–9% of the variance in the endocrine stress response. By contrast, no such effect occurred under conditions of high SLC6A4 methylation, indicating that epigenetic changes may compensate for genotype-dependent differences in stress sensitivity. Studying epigenetic markers may advance gene–environment interaction research on 5-HTTLPR as they possibly capture the net effects of environmental influences relevant for stress-related phenotypes under serotonergic control.     

A review of the effects of acute and chronic cannabinoid exposure on the stress response

While cannabis has been used for centuries for its stress-alleviating properties, the effects of acute and chronic cannabinoid exposure on responses to stress remain poorly understood. This review provides an overview of studies that measured stress-related endpoints following acute or chronic cannabinoid exposure in humans and animals. Acute cannabinoid exposure increases basal concentrations of stress hormones in rodents and humans and has dose-dependent effects on stress reactivity in humans and anxiety-like behavior in rodents. Chronic cannabis exposure is associated with dampened stress reactivity, a blunted cortisol awakening response (CAR), and flattened diurnal cortisol slope in humans. Sex differences in these effects remain underexamined, with limited evidence for sex differences in effects of cannabinoids on stress reactivity in rodents. Future research is needed to better understand sex differences in the effects of cannabis on the stress response, as well as downstream impacts on mental health and stress-related disorders.