Interplay of hippocampal volume and hypothalamus-pituitary-adrenal axis function as markers of stress vulnerability in men at ultra-high risk for psychosis.

BACKGROUND: Altered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results. METHOD: Study participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high-resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol. RESULTS: Cortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (ρ = 0.42, p = 0.036 and ρ = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size). CONCLUSIONS: Our findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women.

Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers.

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [(11)C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg(-1), by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P < 0.04), and voxel-based analyses showed larger stress-induced decreases in [(11)C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [(11)C]raclopride binding, primarily in the sensorimotor striatum (P < 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

Effects of panel sex composition on the physiological stress responses to psychosocial stress in healthy young men and women.

Men and women differ in regard to psychosocial stress responses. Biological and contextual factors are known to mediate these differences; however, few studies investigated their interaction. In the present study, we examined contributions of both contextual and biological factors to the stress response of young healthy adults. Men and women were exposed to a modified version of Trier Social Stress Test. The participants gave a speech in front of a panel of judges, composed of either male or female panelists. Both men, and women presented a cortisol increase only when exposed to opposite sex panelists. Interestingly, this effect was only observed in women in their follicular phase. This finding showed that the induction of a psychosocial stress response does not strictly rely on direct social evaluation, but also depends on the sex composition of the panel. Implications for future studies are discussed.

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.

Cortisol response to a psychosocial stressor in schizophrenia: blunted, delayed, or normal?

BACKGROUND: Patients with schizophrenia may differ from healthy controls by having dysregulated physiological responses to stress. Our objective was to determine the extent to which cortisol reaction can discriminate between controls and schizophrenia patients while controlling for symptom severity, personality, body mass index (BMI) and smoking. METHOD: 30 chronic schizophrenia patients and 30 matched controls underwent a modified version of the Trier Social Stress Test (TSST), consisting of public speaking and mental arithmetic. Heart rate, blood pressure, and salivary cortisol were measured repeatedly throughout the TSST. In addition, participants completed the NEO Personality Inventory (NEO-FFI), and were interviewed with the Brief Psychiatric Rating Scale (BPRS). RESULTS: Both groups had a significant increase in heart rate and mean arterial pressure following the TSST. Results of a logistic regression suggests that patients can be discriminated from controls with a smaller change in cortisol between baseline and 15 min post-TSST, controlling for BMI and severity of positive symptoms. There was a trend for lower overall cortisol secretion in patients. CONCLUSIONS: Despite demonstrable effects of the stressor on cardiac measures, schizophrenia patients tend to have smaller acute cortisol reaction to psychosocial stress. The significance of this conclusion for vulnerability-stress models of schizophrenia is discussed.

Measuring indices of lifelong estrogen exposure: self-report reliability.

OBJECTIVE: The utility of clinical markers of lifelong estrogen exposure is established in the understanding of breast cancer, osteoporosis and dementia, among others. However, a good number of studies rely on self-reports to ascertain the involvement of certain estrogen exposure indices. The goal of this study is to assess the reliability of self-reported lifelong estrogen exposure indices by measuring correlation between two repeats. METHODS: A questionnaire assessing lifelong indices of estrogen exposure was developed (revised version included) and completed by 36 healthy postmenopausal women twice within a 4-year interval (age range from 50 to 79 years). Reliability was tested using Pearson's correlation coefficient. RESULTS: Strong significant correlations were observed for most estrogen exposure indices and an effect of age was revealed. Age at menopause and age at initiation of hormone therapy were the two variables leading to weaker correlations across time of measurements; no relation was found between Time 1 and Time 2 when looking at the group of older women (over 65 years of age). CONCLUSIONS: Overall, these results support the use of self-reported measures for most of the lifelong estrogen exposure indices, but they also warn us about the pitfalls of the climacteric period. However, the design of the current study did not allow us to test accuracy; thus, the validity of these self-reported variables needs to be addressed in the future.

Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans.

Previous studies in humans have shown the presence of an age-related reduction of hippocampal (HC) volume, as well as the presence of reduced HC volume in psychiatric populations suffering from schizophrenia, depression or post-traumatic stress disorder. Altogether, these data suggested that aging or psychiatric disease can have neurotoxic effects on the hippocampus, and lead to HC atrophy. However, these two sets of findings imply that HC volume in young healthy adults should present less variability than HC volume in older adults and psychiatric populations. In the present study, we assessed HC volume in 177 healthy men and women aged from 18 to 85 years of age. We show that the dispersion around the mean of HC volume is not different in young and older adults, so that 25% of young healthy adults present HC volume as small as the average participants aged 60 to 75 years. This shows that HC volume is as variable in young as in older adults and suggests that smaller HC volume attributed to the aging process in previous studies could in fact represent HC volume determined early in life. We also report that within similar age groups, the percentage of difference in HC volume between the individuals with the smallest HC volume (smallest quartile) and the group average is greater than the percentage of difference reported to exist between psychiatric populations and normal control in recent meta-analyses. Taken together, these results confront the notion of hippocampal atrophy in humans and raise the possibility that pre-determined inter-individual differences in HC volume in humans may determine the vulnerability for age-related cognitive impairments or psychopathology throughout the lifetime.

Age and gender predict volume decline in the anterior and posterior hippocampus in early adulthood.

Magnetic Resonance Imaging (MRI) provides a noninvasive method for investigating brain morphology. Within the medial temporal lobe, special attention has been paid to the hippocampus (HC) and amygdala (AG) because of their role in memory, depression, emotion, and learning. Volume changes in these areas have been observed in conjunction with certain disease states, e.g. Alzheimer's disease, post-traumatic stress disorder, and depression. Aging has also been shown to result in gray matter volume loss of the overall brain, including the HC. With regard to gender specificity, results suggest a larger shrinkage for men of brain gray matter, with controversial observations being made for the HC. With recently refined MRI acquisition and segmentation protocols, the HC and AG of 80 subjects in early adulthood (39 men and 41 women, age 18-42 years) were investigated. Whereas the volume of the AG appeared to be independent of age and gender, a significant negative correlation with age for both left and right HC was found in men (r = -0.47 and -0.44, respectively) but not in women (r = 0.01 and 0.02, respectively). The volume decline in men appeared to be linear, starting at the beginning of the third life decade and approximating 1.5% per annum. Using voxel-based regressional analysis, it was shown that changes with age occurred mostly in the head and tail of the HC. This finding underscores the need to include sociodemographic variables in functional and anatomical MRI designs.

Volumetry of hippocampus and amygdala with high-resolution MRI and three-dimensional analysis software: minimizing the discrepancies between laboratories.

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm(3)), while no interhemispheric differences for the amygdala (1154 versus 1160 mm(3)) could be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.

The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm.

Recent studies have shown that cortisol levels rapidly increase within the first 30 minutes after awakening. This response is rather robust over weeks or months and is altered by chronic stress and burnout. The present study investigated to what extent the cortisol response to awakening relates to responses following hCRH, ACTH(1-24), or psychosocial stress challenges in 22 healthy subjects. Furthermore, a 12-hour circadian cortisol profile was obtained to compare the morning response with cortisol levels obtained throughout the day. Results show that the morning cortisol response was of similar magnitude to that following injection of 1 microg/kg h-CRH or exposure to a brief psychosocial stressor (TSST). All of these were significantly smaller compared to maximal stimulation of the adrenal cortex by ACTH(1-24). Correlation analyses revealed that the morning cortisol response was closely related only to the cortisol response following 0.25 mg ACTH(1-24) (r=0.63, p=0.002). We conclude that the morning cortisol response to awakening can provide important information on the (re)activity of the HPA axis in addition to more 'traditional' methods like hCRH or Synacthen challenge tests. The sensitivity/capacity of the adrenal cortex appears to play a crucial role for the magnitude of cortisol responses observed after awakening.

Burnout, perceived stress, and cortisol responses to awakening.

OBJECTIVE: The effects of burnout and perceived stress on early morning free cortisol levels after awakening were investigated in a group of teachers. Previous studies revealed that cortisol levels show a significant increase after awakening, with high intraindividual stability. METHODS: Sixty-six teachers from local public schools (42 women and 24 men, mean age 42+/-5 years) were asked to sample saliva for cortisol analysis on 3 consecutive days. On each day, cortisol levels were measured at the time of awakening and 15, 30, and 60 minutes thereafter. On the night before the third day, subjects took 0.5 mg dexamethasone orally for testing glucocorticoid feedback inhibition. Burnout and perceived stress were measured by three different questionnaires. RESULTS: Perceived stress correlated with increases of cortisol levels during the first hour after awakening after dexamethasone pretreatment. In addition, teachers scoring high on burnout showed lower overall cortisol secretion on all sampling days, and a higher suppression of cortisol secretion after dexamethasone administration. In the subgroup of teachers with both high levels of perceived stress and high levels of burnout, a lower overall cortisol secretion was observed on the first 2 days, with stronger increases during the first hour after awakening after dexamethasone suppression. This subgroup also showed the lowest self-esteem, the highest external locus of control, and the highest number of somatic complaints. CONCLUSIONS: These results demonstrate differential effects of burnout and perceived stress on hypothalamic-pituitary-adrenal axis regulation.

Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity.

In three independent studies, free cortisol levels after morning awakening were repeatedly measured in children, adults and elderly subjects (total n=152). Cortisol was assessed by sampling saliva at 10 or 15 minute intervals for 30-60 minutes, beginning at the time of awakening for two days (Study 1 and 2) or one (Study 3) day, respectively. In all three studies, free cortisol levels increased by 50-75% within the first 30 minutes after awakening in both sexes on all days. Premenopausal women consistently showed a stronger increase with a delayed peak after awakening compared to men on all days. In Study 2, there was a tendency for lower early morning free cortisol levels for women taking oral contraceptives (p=.10). Stability of the area under the curve (AUC) of the early morning free cortisol levels over the three (Study 1 and 2) or two (Study 3) days ranged between r=.39 and r=.67 (p<.001). Neither age, weight, nor smoking showed an effect on baseline or peak cortisol levels. Sleep duration, time of awakening and alcohol consumption also appeared to be unrelated to early morning free cortisol levels. From these data we conclude that in contrast to single assessments at fixed times, early morning cortisol levels can be a reliable biological marker for the individual's adrenocortical activity when measured repeatedly with strict reference to the time of awakening.

Increasing correlations between personality traits and cortisol stress responses obtained by data aggregation.

Attempts to link personality traits and cortisol stress responses have often been inconclusive. The aim of this paper was to investigate this association by aggregating cortisol stress responses. Therefore, 20 healthy men were exposed to a task consisting of public speaking and mental arithmetics in front of an audience on five days. Six cortisol levels were measured in relation to the stressful task obtained at 10-min intervals on each day. Psychological assessment included the Questionnaire for Competence and Control (FKK) and the Giessen-Test (G-T). These questionnaires focus on assessing personality traits, i.e. locus of control and self-concept. Areas under the response curve (AUC) of the six cortisol samples were computed to obtain an index of the individual's cortisol stress response on each day. Since novelty is a random situational factor likely to mask individual differences in the stress response, the AUC cortisol stress responses of days two to five were consecutively aggregated, excluding the first day. Scales of the two questionnaires employed did not correlate with the AUC cortisol stress response of the first stress trial. The correlation pattern of the AUC cortisol measures of days two to five with the questionnaire scales was inconclusive. However, significant correlations emerged with an increasing number of cortisol stress responses aggregated. Correlations between the measure of social dominance and aggregated AUC cortisol stress responses rose from r = -.47 on day two of the experimental session to r = -.70 after aggregating days two to five. Similarly, measures of locus of control and cortisol stress responses became increasingly correlated with aggregation of several stress exposures. These data provide preliminary evidence for a relationship between questionnaire scales aiming at assessing personality traits and cortisol stress responses uncovered by repeated stress exposure and data aggregation. While novelty may mask the impact of personality on the cortisol stress response on the first exposure, differences in the ability to cope with the stressful situation may lead to different cortisol stress response patterns on subsequent stress exposures. With data aggregation, an association between the trait component of cortisol stress responses and questionnaire scales might be uncovered. For reliable investigation of correlations between personality variables and cortisol stress responses, repeated stress exposure and data aggregation is suggested.