The DSM5/RDoC debate on the future of mental health research: implication for studies on human stress and presentation of the signature bank.

In 2008, the National Institute of Mental Health (NIMH) announced that in the next few decades, it will be essential to study the various biological, psychological and social "signatures" of mental disorders. Along with this new "signature" approach to mental health disorders, modifications of DSM were introduced. One major modification consisted of incorporating a dimensional approach to mental disorders, which involved analyzing, using a transnosological approach, various factors that are commonly observed across different types of mental disorders. Although this new methodology led to interesting discussions of the DSM5 working groups, it has not been incorporated in the last version of the DSM5. Consequently, the NIMH launched the "Research Domain Criteria" (RDoC) framework in order to provide new ways of classifying mental illnesses based on dimensions of observable behavioral and neurobiological measures. The NIMH emphasizes that it is important to consider the benefits of dimensional measures from the perspective of psychopathology and environmental influences, and it is also important to build these dimensions on neurobiological data. The goal of this paper is to present the perspectives of DSM5 and RDoC to the science of mental health disorders and the impact of this debate on the future of human stress research. The second goal is to present the "Signature Bank" developed by the Institut Universitaire en Santé Mentale de Montréal (IUSMM) that has been developed in line with a dimensional and transnosological approach to mental illness.

Environmental influence of problematic social relationships on adolescents' daily cortisol secretion: a monozygotic twin-difference study.

BACKGROUND: This study investigated the potential environmental effects of peer victimization and the quality of relationships with parents and friends on diurnal cortisol secretion in mid-adolescence. METHOD: This study used the monozygotic (MZ) twin-difference design to control for genetic effects and thus estimate the unique environmental influences on diurnal cortisol. Participants were 136 MZ twin pairs (74 female pairs) for whom cortisol was assessed four times per day over four collection days grouped in a 2-week period in grade 8 (mean age = 14.07 years). Participants also provided self-reports of peer victimization from grade 4 to grade 8 and of the relationship quality with the mother, father and best friend in grade 8. RESULTS: The expected pattern of diurnal cortisol secretion was observed, with high levels at awakening followed by an increase 30 min later and a progressive decrease subsequently. Controlling for a host of confounders, only within-twin pair differences in peer victimization and a problematic relationship with the mother were significantly linked to twin differences in diurnal cortisol secretion. Specifically, whereas a more problematic mother-child relationship was associated with morning cortisol secretion, peer victimization was linked to cortisol secretion later in the day (diurnal slope). CONCLUSIONS: Controlling for genetic influences and other confounders, stressful relationships with peers and the mother exert unique and time-specific environmental influences on the pattern of diurnal cortisol secretion in mid-adolescence.

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

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

A multivariate twin study of hippocampal volume, self-esteem and well-being in middle-aged men.

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.

Depressive symptoms, cortisol, and cognition during human aging: the role of negative aging perceptions.

Depressive symptoms and memory impairments are associated with heightened stress hormone levels during aging. A factor that is related to memory deficits during aging is internalized negative aging stereotypes; the idea people have about the process of aging. In this study, we assessed the associations between internalized negative aging stereotypes, depressive symptoms, subjective and objective memory assessments, and cortisol concentration among older adults. Forty older adults aged between 58 and 85 years (18 females and 22 males; mean age ± SD: 71.25 ± 8.80 years) were assessed in this study. Measures of internalized negative aging stereotypes, depressive symptoms, and both subjective and objective memory performance were assessed. Salivary samples were obtained for measurement of cortisol concentration. Stepwise linear regressions were executed in our main analyses. Internalized negative aging stereotypes were associated with increased depressive symptoms and subjective memory complaints. No significant differences were observed for objective memory performance, or cortisol concentration. Internalized negative aging stereotypes are associated with increased depressive symptomatology and subjective complaints of memory; however, they do not predict increased cortisol concentration nor objective memory performance during aging. These results indicate that the mechanism underlying the association between internalized negative aging stereotypes and cognitive impairments may not be related to dysregulations of cortisol secretion among older adults.

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.

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.

Influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on stress markers in older adults: a 3-year study.

The present study examined the influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on GC secretion, cognition and personality in 66 healthy older adults. These particular variables were chosen given that they have been shown to be associated with human stress (i.e.stress markers). Measures included basal serum GC levels and cognitive scores on declarative memory obtained annually over 3 years. Also, self-esteem, neuroticism and depression were evaluated. Results showed that participants with the APOE E4-BCHE K variant (E4-K group) present increased basal levels of GCs and poorer cognitive performance when compared to non-carriers of these variants. In addition, the E4-K group reported lower self-esteem and higher levels of depression. These findings may indicate a genotype effect on markers of stress and cognitive integrity years before symptoms of dementia are apparent.

The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition.

In this review, we report on studies that have assessed the effects of exogenous and endogenous increases in stress hormones on human cognitive performance. We first describe the history of the studies on the effects of using exogenous stress hormones such as glucocorticoids as anti-inflammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis of glucocorticoid-induced 'steroid psychosis' in human populations and which demonstrated that these stress hormones could thus cross the blood-brain barrier and access the brain where they could influence cognition and mental health. We then summarize studies that assessed the effects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the frontal lobes and amygdala. In the second section of the paper, we summarize the effects of the endogenous release of glucocorticoids induced by exposure to a stressful situation on human cognition and we further dissociate the effects of emotion from those of stress on human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance. In order to make our point, we discuss the field of memory and aging and we suggest that some of the 'age-related memory impairments' observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that these inverse correlations could be partly due to the effects of contextual stress in young and older adults, as a function of age-related differences in hippocampal volume.

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.

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.

Do corticosteroids damage the brain?

Corticosteroids are an essential component of the body's homeostatic system. In common with other such systems, this implies that corticosteroid levels in blood and, more importantly, in the tissues remain within an optimal range. It also implies that this range may vary according to circumstance. Lack of corticosteroids, such as untreated Addison's disease, can be fatal in humans. In this review, we are principally concerned with excess or disturbed patterns of circulating corticosteroids in the longer or shorter term, and the effects they have on the brain.

Successful ageing: from cell to self.

Many people see ageing as a time of cognitive and physical decline. For the past three decades, most scientists and the general public have accepted this negative age-stereotype as the norm, but fortunately this view is now challenged. New findings show that well-being and a positive view of ageing are major protective factors against the effects of age on the organism. These results challenge the scientific studies that place emphasis on the negative side of ageing. This ageism view has been observed in each sphere of science, from genetics to social sciences. Perspectives from each domain are described, and new integrative views of successful ageing are summarized.

Acute modulation of aged human memory by pharmacological manipulation of glucocorticoids.

In a previous longitudinal study of basal cortisol levels and cognitive function in humans, we showed that elderly humans with 4- to 7-yr cumulative exposure to high levels of cortisol present memory impairments, compared with elderly humans with moderate cortisol levels over years. Here, we measured whether memory performance in two groups of elderly humans separated on the basis of their cortisol history over a 5-yr period could be modulated by a hormone-replacement protocol in which we inhibited cortisol secretion by the administration of metyrapone and then restored baseline cortisol levels by infusion of hydrocortisone. We showed that in elderly subjects with a 5-yr history of moderate cortisol levels (n = 8), metyrapone treatment significantly impaired memory performance, a deficit that was reversed following hydrocortisone replacement. In the elderly subjects with a 5-yr history of high cortisol levels and current memory deficits (n = 9), metyrapone treatment did not have any significant effect on memory performance, but hydrocortisone treatment significantly decreased delayed memory. These results suggest that memory function in elderly humans can be intensely modulated by pharmacological manipulation of glucocorticoids, although the direction of these effects depends on the cortisol history of each individual.

Stress, memory, and the hippocampus: can't live with it, can't live without it.

Since the 1968s discovery of receptors for stress hormones (corticosteroids) in the rodent hippocampus, a tremendous amount of data has been gathered on the specific and somewhat isolated role of the hippocampus in stress reactivity. The hippocampal sensitivity to stress has also been extended in order to explain the negative impact of stress and related stress hormones on animal and human cognitive function. As a consequence, a majority of studies now uses the stress-hippocampus link as a working hypothesis in setting up experimental protocols. However, in the last decade, new data were gathered showing that stress impacts on many cortical and subcortical brain structures other than the hippocampus. The goal of this paper is to summarize the four major arguments previously used in order to confirm the stress-hippocampus link, and to describe new data showing the implication of other brain regions for each of these previously used arguments. The conclusion of this analysis will be that scientists should gain from extending the impact of stress hormones to other brain regions, since hormonal functions on the brain are best explained by their modulatory role on various brain structures, rather than by their unique impact on one particular brain region.

Can poverty get under your skin? basal cortisol levels and cognitive function in children from low and high socioeconomic status.

It is well known that individuals from more advantaged social classes enjoy better mental and physical health than do individuals within lower classes. Various mechanisms have been evoked to explain the association between socioeconomic status (SES) and health. One mechanism that has received particular attention in recent years is stress. It has been shown that individuals lower in SES report greater exposure to stressful life events and a greater impact of these events on their life than individuals higher in SES. In order to measure whether the development of the relationship between SES and mental health is sustained by exposure to high levels of glucocorticoids, we measured morning salivary cortisol levels as well as cognitive function (memory, attention, and language) in 307 children (from 6 to 16 years of age) from low versus high SES in the Montreal area in Canada. The results revealed that low SES children from 6 to 10 years old present significantly higher salivary cortisol levels when compared to children from high SES. This difference disappears at the time of school transition, and no SES differences are observed in salivary cortisol levels during high school. However, children from low and high SES do not differ with regard to memory or to attentional and linguistic functions. Also, mothers of low SES children reported higher feelings of depression and more unhealthy behaviors, while mothers of high SES children reported higher stress related to work or family transitions. Altogether, these results show that low SES in young children is related to increased cortisol secretion, although the impact of SES on cortisol secretion is absent after transition to high school. These data are interpreted within the context of the equalization process of class patterning. Four social explanatory factors are suggested to explain the disappearance of SES differences in basal cortisol levels after school transition, taking into account the influence of family environment on the child's secretion of stress hormones.

Circulating human corticotropin-releasing factor-binding protein levels following cortisol infusions.

Corticotropin-releasing factor-binding protein (CRF-BP) is a 37 kDa protein present in the brain and plasma and is known to regulate the actions of CRF. It has been demonstrated that CRF-BP in the brain and the pituitary appears to be positively regulated by glucocorticoids. In this study, the effect of various doses of hydrocortisone infusions on plasma CRF-BP levels was assessed. Four groups of 10 age-matched males received a 100 min infusion of either placebo (saline), 40 microg/kg/h, 300 microg/kg/h or 600 microg/kg/h hydrocortisone. CRF-BP levels were measured via a LIRMA. In addition, levels of plasma ACTH and cortisol were measured by standard radioimmunoassay. As expected, plasma cortisol levels increased and plasma ACTH levels were suppressed following the infusion. When expressed as proportion of pre-infusion baseine, no significant changes in plasma CRF-BP levels were observed following the infusion for all hydrocortisone groups relative to the control group. However, a significant time-averaged positive correlation was found between CRF-BP and cortisol levels at low to moderate, but not high, cortisol levels. The data obtained in this study indicate that CRF binding protein levels within the time course examined may slightly appear to be affected in the peripheral circulation in response to pronounced, sustained hypercortisolemia.

Child's stress hormone levels correlate with mother's socioeconomic status and depressive state.

BACKGROUND: Individuals with lower socioeconomic status report greater exposure to stressful life events and a greater impact of these events on their lives than individuals with higher socioeconomic status, and this relationship between socioeconomic status and health begins at the earliest stages of life. To extend on these results, we performed a psychoneuroendocrine study of 217 children and 139 mothers. METHODS: Salivary cortisol levels and cognitive function were assessed in children, and a semistructured phone interview measuring symptoms of stress and depression was conducted with their mothers. RESULTS: Children with low socioeconomic status present significantly higher salivary cortisol levels than children with high socioeconomic status, and this socioeconomic status effect emerges as early as age 6. We also report that a child's cortisol level is significantly correlated with his or her mother's extent of depressive symptomatology. CONCLUSIONS: These results offer a neurobiological determinant to the well-known association between socioeconomic status and health that begins early in life.

Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans.

The effects of various doses (40 microg/kg/hr, 300 microg/kg/hr, 600 microg/kg/hr or placebo) of hydrocortisone on tasks assessing working and declarative memory function were measured in 4 groups of 10 young men. During the infusion, participants were given an item-recognition working memory task, a paired-associate declarative memory task, and a continuous performance task used to control possible concomitant effects of corticosteroids on vigilance. The results revealed significant acute effects of the highest dose of hydrocortisone on working memory function, without any significant effect on declarative memory function or arousal-vigilance performance. These results suggest that working memory is more sensitive than declarative memory to the acute elevations of corticosteroids, which could explain the detrimental effects of corticosteroids on acquisition and consolidation of information, as reported in the literature.