Stress and Disease: A Structural and Functional Analysis

Chronic stress, a validated health risk factor, remains an ambiguous construct in spite of years of research. We propose that chronic stress is best understood as a series of acute stress responses, and that these responses become maladaptive when they occur frequently or are of long duration. We focus on the factors that contribute to chronic stress: whether the presence of a stressor, real or imagined, is long‐lived and/or frequent (repeated activation), the degree to which the stressor is perceived as a threat even when no longer present (low or slow adaptation), and the extent to which the duration of responding is prolonged (delayed or failure to return to homeostasis). Importantly, we examine how perseverative cognitions (such as rumination and worry) contribute to chronic stress by creating and sustaining acute stress responses, largely via influencing activation, adaptation, and return to homeostasis. Finally, we discuss the implications of our stress model: that interventions can be ideographically tailored to address how an individual is experiencing chronic stress; that researchers may be better able to identify specific characteristics of chronic stress that relate most strongly to poor health; and that moderators of chronic stress may function through these contributing factors rather than via general effects on the system.     

Altered stress responses in children exposed to early adversity: a systematic review of salivary cortisol studies

Pathological stress responses are implicated in numerous disorders. Hypothalamic-pituitary-adrenal axis function is influenced by gene-environment interaction, with early-life environmental adversity having long-lasting effects. We examine the evidence that, in humans, these effects are apparent from infancy. We systematically reviewed published findings on cortisol response to a stressor, in 0-5-year-olds already exposed to adversity. Adversity was defined as a negative environmental influence present post-conception. We searched Ovid MEDLINE (1950-May 2010), EMBASE (1980-May 2010) and PsychINFO (1806-May 2010). We included peer-reviewed, English language studies that analysed salivary cortisol before and after a standardised stressor. We identified 30 studies, of which 27 reported a significant effect of adversity on the cortisol response to stress. Six of these demonstrated an effect of prenatal substance exposure. Thirteen studies found that psychosocial adversity increased cortisol reactivity. Three studies reported that cortisol reactivity could be normalised by intervention programmes. The studies were heterogeneous, both in nature of adversity studied and in stressor used, precluding meta-analysis and assessment of publication bias. Our review presents evidence that adversity disrupts the stress response from an early age. Longitudinal studies are required to determine whether effects persist, alter with time, or are reversible with intervention.     

Daily cognitive appraisals, daily affect, and long-term depressive symptoms: the role of self-esteem and self-concept clarity in the stress process

The current study investigated how self-esteem and self-concept clarity are implicated in the stress process both in the short and long term. Initial and 2-year follow-up interviews were completed by 178 participants from stepfamily unions. In twice-daily structured diaries over 7 days, participants reported their main family stressor, cognitive appraisals (perceived stressor threat and stressor controllability), and negative affect. Results of multilevel modeling indicated that high self-esteem ameliorated the effect of daily negative cognitive appraisals on daily negative affect. Self-concept clarity also buffered the effect of low self-self-esteem on depressive symptoms 2 years later. Our findings point to the vulnerability of those having low self-esteem or low self-concept clarity in terms of both short- and long-term adaptation to stress. They indicate the need for the consideration of such individual differences in designing stress management interventions.     

Persistent neuroendocrine changes in multiple hormonal axes after a single or repeated stressor exposures

Many researchers have studied acute responses to stress in animals and how they are modified by prior stressor exposure, but relatively few have examined whether responses to stressors might last for prolonged periods of time. We have previously demonstrated that trough plasma corticosterone levels in rats are elevated for three to five days after single or repeated exposures to mild restraint and inescapable tailshock. The current study measured other aspects of the adrenal axis, and activity in other neuroendocrine systems, 24 hours after one or three consecutive exposures to the same stress paradigm. The data indicated persistent activation of the adrenal axis and prolactin levels, whereas the thyroid and reproductive hormone axes were inhibited after either one or three stress sessions. These changes are remarkable in that one would have expected acute responses to even intense stressors to have ended within hours after the end of the stressor. It will be important to understand the interactions among these responding neuroendocrine systems and to know how long such persistent changes last. Finally, it will be critical to understand the relative contributions of neuroendocrine and psychological factors in maintaining these persistent neuroendocrine changes after exposure to intense stressors.     

The effects of exposure to an acute naturalistic stressor on working memory, state anxiety and salivary cortisol concentrations

Exposure to an acute naturalistic stressor induces both psychological and physiological changes in humans. The two studies reported here explored the impact of exposure to an acute naturalistic stressor on state anxiety, working memory and HPA axis activation (salivary cortisol). In both experiments, ten healthy male participants were exposed to an acute naturalistic stressor, helicopter underwater evacuation training (HUET), and their physiological and behavioural responses before (first study) and after (second study) the stressor were compared to ten non-stressed controls. The results of both experiments showed that working memory performance was preserved during anticipation of an acute stressor, but impairments were observed immediately after stress exposure. Participants reported significantly higher state anxiety levels during anticipation and following stress exposure, whereas significant elevations in cortisol levels were only observed 25 min post exposure to stress, but not before or immediately after stress exposure. The results of both experiments demonstrated a dissociation between behavioural and biochemical measures and provided evidence for a dissociation of the effects of stress on cognitive and physiological measures depending on the time of testing, with cognitive impairments most evident following stress exposure.     

Effects and aftereffects of stressor expectations

Is stressor exposure necessary to produce "stress" effects, or can these effects result from stressor anticipation alone? The present research explores whether it is possible to obtain "stress responses" during and after the period in which stressor exposure is being anticipated. In the first study, the expectation of submerging one's hand in ice water resulted in decreased frustration tolerance and increased blood pressure when compared with control groups not expecting this stressor. A second study replicated and extended these results to show that the expectation of control over the stressor ameliorates the negative impact of stressor expectation. The second study also examined the aftereffects of expectations. Particularly, it found that despite being relieved of the expectation that they would immerse their hand in ice water, subjects who had expected stressor exposure had decreased frustration tolerance when compared with either subjects who had expected a nonstressful procedure or those who had expected to have control over stressor termination. A third study, using noise as the expected stressor, replicated both the aftereffect of the anticipation period and the moderation of that effect by perceived control. The discussion (a) focuses on the implications of this work for understanding why aftereffects occur and (b) proposes that previously observed stressor exposure effects may in fact be postexpectation effects.     

A single exposure to severe stressors causes long-term desensitisation of the physiological response to the homotypic stressor

Although some laboratories have reported that a single session of stress is able to induce a long-lasting sensitisation of the hypothalamic-pituitary-adrenal (HPA) response to further exposures to stress, we have found that a single exposure to severe emotional (immobilisation, restraint or shock) or systemic (endotoxin) stressors reduces the responsiveness of the HPA to the same, but not to a novel (heterotypic), stressor, in which case a slight sensitisation was observed. Long-term desensitisation has been found to reduce not only secretion of peripheral HPA hormones (ACTH and corticosterone), but also to reduce responses of central components of the HPA axis (c-fos and CRF gene expression at the level of the paraventricular nucleus of the hypothalamus, PVN). In addition, desensitisation also applies to the impact of the stressor on food intake and, probably, to stress-induced hyperglycaemia. The development of long-term desensitisation of the HPA axis does not appear to be a universal consequence of exposure to severe stressors as it was not observed in response to insulin-induced hypoglycaemia. Whether or not the development of long-term effects of stress depend on the specific pathways activated by particular stressors remains to be tested. The observed desensitisation of the HPA axis in response to the homotypic stressor shows two special features which makes it difficult to be interpreted in terms of an habituation-like process: (a) the effect increased with time (days to weeks) elapsed between the first and second exposure to the stressor, suggesting a progressive maturational process; and (b) the stronger the stressor the greater the long-term desensitisation. Therefore, it is possible that desensitisation of the HPA axis is the sum of two different phenomena: long-term effects and habituation-like processes. The contribution of the former may be more relevant with severe stressors and longer inter-stress intervals, and that of the latter with mild stressors and repeated exposures. Long-term stress-induced changes may not take place at the level of the PVN itself, but in brain nuclei showing synaptic plasticity and putatively involved in the control of the HPA axis and other physiological responses. As for the precise areas involved, these remain to be characterized.     

Cortisol,stress, and attentional bias toward threat

Abstract

Attentional bias toward threatening stimuli is a central characteristic of anxiety and acute stress. Recent small-scale studies have provided divergent perspectives on the association between the stress hormone cortisol and attentional bias toward threat cues. In a larger sample size than previous studies, we examined this association by investigating the impact of cortisol on attentional bias in two studies using a psychological stressor (N=35) and a physical stressor (N=65), respectively. Attentional bias and salivary cortisol were measured prior to and following the administration of a stressful task designed to increase cortisol levels. Results across these studies were equivocal relative to the association between baseline cortisol and baseline attentional bias. In addition, the association between acute change in cortisol and change in attentional bias appeared to differ as a function of the presence or absence of psychological stress. There was a trend toward a stronger negative association between acute cortisol change and attentional bias change among women relative to men. These results imply that the association between cortisol and attentional bias may be moderated by additional factors, such as gender or presence of stress.     

Stress,Coping, and Mental Health Among Rural,Village, and Urban Women in Tunisia

The present study investigated stressors, coping strategies, and mental health among 45 Tunisian women living in 3 distinct environments within Tunisia: a rural Bedouin community, a mid-size village, and the capital city of Tunis. Individual interviews were conducted with each woman via a semi-structured questionnaire, which allowed for the collection of qualitative as well as quantitative information. Statistical analyses indicated no significant differences between the middle-class village and urban women on stressor levels, number of coping strategies used, or levels of psychological distress. However, the rural group of Bedouin women reported significantly greater stressor levels and numbers of depressive symptoms than the village and/or urban women. The qualitative information confirmed the greater stress of the rural environment, largely due to extreme poverty. The results suggest that rapid social changes in Tunisia since independence have improved the lives of middle-class women in the villages and cities, but have had very little impact on the situations of rural Bedouin women.     

Short- and long-term effects of juvenile stressor exposure on the expression of GABAA receptor subunits in rats

During the juvenile period rodents are particularly sensitive to stressors. Aversive events encountered during this period may have enduring effects that are not evident among animals initially stressed as adults. Interestingly, experiencing stressor during juvenile period was found to elicit a biphasic behavioral pattern over the course of development. During the juvenile period, the expression of several GABAA receptor subunits is subject to elevated plasticity, rendering the GABAergic system sensitive to stressors. In the present investigation, animals were exposed to a juvenile variable stressor regimen (JUV-S) at 27-29 postnatal days (PND): 27 PND-acute swim stress (10 min), 28 PND-elevated platform stress (3 sessions×30 min each), and 29 PND-restraint (2 h). One hour following the last exposure to stressor or in adulthood (60 PND), anxiety-related behaviors were assessed in a 5-min elevated plus maze test. The western blotting technique was used to evaluate whether the juvenile stress induced behavioral pattern will be accompanied by respective changes in GABAA α1, α2, and α3 protein expression in male rats. Our findings further established that juvenile stressor elicits hyper-reactivity when rats were tested as juveniles, whereas rats exhibited reduced activity and increased anxiety when tested as adults. Additionally, the effects of juvenile stressor on α1, α2, and α3 were more pronounced among juvenile stressed rats that were challenged as adults compared with rats that were only challenged as juveniles. Interestingly, the stress-induced modulation of the subunits was particularly evident in the amygdala, a brain region closely associated with anxiety. Thus, age- and region-specific alterations of the α subunits may contribute to the age-specific behavioral alterations observed following juvenile stress exposure.     

Timing matters: Temporal dynamics of stress effects on memory retrieval

Stress may impair memory retrieval. This retrieval impairment has been attributed to the action of the stress hormone cortisol, which is released with a delay of several minutes after a stressful encounter. Hence, most studies tested memory retrieval 20–30 min after stress, when the stress-induced cortisol increase peaks. In the present experiment, we investigated whether retrieval impairments can also be found at later intervals after stress. To this end, participants learned a list of words on day 1. Twenty-four hours later, they were first exposed to a stressor or a nonstressful control manipulation and completed a recognition test for the words either immediately thereafter, 25 min later, or 90 min later. Our findings showed that stress did not impair memory retrieval when memory was tested immediately after the stressor, before cortisol levels were elevated. However, retrieval performance was impaired 25 min after stress, when cortisol levels peaked, as well as 90 min after the stressor, when cortisol levels had already returned to baseline. The retrieval impairment 90 min after stress appeared to be even stronger than the one after 25 min. These findings suggest that the detrimental effects of stress on retrieval performance may last longer than is usually assumed.     

Water temperature determines neurochemical and behavioural responses to forced swim stress: an in vivo microdialysis and biotelemetry study in rats

Forced swimming is a behavioural stress model increasingly used to investigate the neurocircuitry of stress responses. Although forced swim stress clearly is a psychological stressor (anxiety, panic), its physical aspects are often neglected. There are indications that behavioural and neurochemical responses to swim stress depend on the water temperature. Thus, we investigated the responsiveness of hippocampal serotonergic neurotransmission (important in the coordination of stress responses), and of behaviour and core body temperature to forced swimming at different water temperatures (19, 25 and 35 degrees C). In vivo microdialysis and biotelemetry in freely-behaving rats were used. Dialysates were analysed for serotonin (5-HT) and its metabolite 5-HIAA (5-hydroxyindoleacetic acid) by HPLC with electrochemical detection. Forced swimming in water at 25 and 19 degrees C decreased core body temperature by 8 and 12 degrees C, respectively. A rapid and pronounced increase in hippocampal 5-HT and 5-HIAA was found in rats that swam at 35 degrees C, whereas biphasic responses in 5-HT and 5-HIAA were observed at 25 and 19 degrees C. Also swim stress behaviour and post-stress home cage behaviour depended on the water temperature. Comparing the serotonergic and core body temperature changes revealed that a combination of two different 5-HT and 5-HIAA responses seems to shape the neurotransmitter response. Swimming-induced increases in hippocampal extracellular concentrations of 5-HT and 5-HIAA occurred at all water temperatures, but these increases were temporarily quenched, or concentrations were transistently decreased, when core body temperature fell below 31 degrees C in water at 25 or 19 degrees C. These data demonstrate that water temperature is a key factor determining the impact of forced swim stress on behaviour and neurochemistry, and underscore that changes in these parameters should be interpreted in the light of the autonomic responses induced by this stressor.     

Testing the Ideology of Openness: The Comparative Effects of Talking,Writing, and Avoiding a Stressor on Rumination and Health

A persistent assumption across the psychological literature is that talking and writing about one's stress is inherently more beneficial than avoiding it. This study compared the effects of these stress management strategies on personal and relational health. Two hundred and fifty‐one dating individuals focused on a stressor that was a current source of rumination. Writing about one's stressor for 5 consecutive days (without talking about it) decreased anxiety the most. Talking continuously about one's stressor to a dating partner harmed the relationship more than writing about or avoiding it. The effect of talking repeatedly about one's stressor on relationship quality and brooding, however, depended upon the emotional support received from one's dating partner and the ability to reappraise (positively or neutrally) the stressor.     

The Presence of Self-Stigma,Perceived Stress,and Suicidal Ideation among Selected LGBT Filipinos

Minority group members experience what is known as “minority stress,” by which individuals suffer stress because of their membership in stigmatized social categories. In turn, minority stress may lead to self-stigmatization. This occurs when minority group members experience a sense of shame created by the view of the majority culture and then incorporate the majority opinion into their self-image. Because it is cumulative with the stress an individual is already experiencing, self-stigmatization may become a significant stressor itself, possibly contributing to the development of suicidal ideation. A total of 609 self-identified LGBT individuals were asked to answer a battery of psychological tests to assess the interrelationships between self-stigma, perceived stress, and suicidal ideation. As expected, perceived stress predicted suicidal ideation, whereas self-stigmatization predicted both perceived stress and suicidal ideation. Structural equation modeling confirms the predictive value of self-stigma together with perceived stress in determining the suicidal ideation present among LGBT Filipinos. Self-stigma exerted a direct effect upon suicidal ideation not accounted for by perceived stress.     

Psychological stress,appraisal, emotion and Cardiovascular response in a public speaking task

Forty-three undergraduates (30 males, 13 females) prepared and performed a speech task (stressor) or a reading task (no-stressor control). Preparing to speak led to greater threat appraisal, negative emotion, and cardiovascular (CV) response than preparing to read aloud, particularly in speech anxious individuals. Delivering the speech, however, did not result in an increment in CV response over and above preparation. Although threat appraisals could not explain the effect of stress on CV response during task preparation, negative emotion accounted for over half of the effect. These data support the hypothesis that CV response in these studies is at least partially accounted for by psychological processes (stressor-specific anxiety and negative emotional response) and suggests that these processes may be best studied during a period of stressor anticipation.     

The role of anxiety sensitivity in subjective and physiological responses to social and physical stressors

This study examined the specificity of the relationship between anxiety sensitivity (AS), a measure of catastrophizing about arousal-related sensations, and pain responses, by examining the effect of AS on responses to stressors of a physical and social nature. Healthy men and women (n = 129) between the ages of 18 and 25 years were recruited from the community to participate in a study examining subjective, cognitive and behavioural responses to different types of stressors. Participants were randomly assigned to one of 3 groups: (i) a neutral condition in which they sat quietly and read a popular magazine; (ii) a social stress condition in which they anticipated having to give a self-disclosing speech; and (iii) a physical stress condition in which they were presented with 3 countdown to shock trials where a mild electrical shock was administered on the non-dominant arm. Subjective ratings and physiological responses were recorded in anticipation of the stressor and immediately after stress exposure. Results indicated that AS was indirectly related to pain ratings via its effect on anticipatory anxiety ratings. AS was associated with anticipatory anxiety ratings, regardless of whether the stressor was of a physical or social nature. Furthermore, AS was not shown to be directly associated with exaggerated subjective or physiological reactions to the physical stressor. These results indicate that the role of AS in pain responses may be mediated through a global effect on anxiety, and limited to the anticipatory stage of the pain experience. If future studies yield similar findings in pain patients, then they would suggest that interventions for helping individuals high in AS should focus on catastrophic thinking in anticipation of stressors in general, rather than on pain-specific stressors.     

Effects of acute psychosocial stress exposure on endocrine and affective reactivity in college students differing in the 5-HTTLPR genotype and trait neuroticism

Enhanced stress vulnerability has been implicated in the pathogenesis of affective disorders. Although both genetic (5-HTTLPR) and cognitive (neuroticism) factors are known to increase stress vulnerability, no experimental study has investigated the interaction between these two factors on psychobiological reactivity following acute stress exposure. This study used a balanced experimental design to examine the interaction between the 5-HTTLPR genotype and trait neuroticism in neuroendocrine and affective stress responses. From a large group of 771 students, 48 carriers of the short/short (S/S) allele and 48 carriers of the long/long (L/L) allele with the lowest and the highest neuroticism scores (77 females, 19 males; mean age?±?SD: 20.6?±?2 years) were selected and exposed to an acute psychosocial stressor. Mood was assessed before and after the stressor, and salivary cortisol concentrations were measured before and at 20, 30, and 60?min after stressor onset. Acute stress increased salivary cortisol concentration regardless of either 5-HTTLPR genotype or neuroticism, but it caused a less profound negative mood change in L/L compared to S/S-allele carriers with the lowest neuroticism scores. The 5-HTTLPR genotype influences affective reactivity to acute stress conditional upon neuroticism, improving resilience to acute stress in L/L-allele carriers if they do not already possess high cognitive-affective (neuroticism) vulnerability.     

Acute stress rapidly and persistently enhances memory formation in the male rat

Previous studies, as well as the present one, report that acute exposure to intermittent tailshocks enhances classical eyeblink conditioning in male rats when trained 24 h after stressor cessation. In Experiment 1, it was determined that the facilitating effect of stress on conditioning could also be obtained in response to a stressor of acute inescapable swim stress but not inescapable noise or the unconditioned stimulus of periorbital eyelid stimulation. These selective responses arose despite comparable enhancements of the stress-related hormone corticosterone in response to tailshocks, periorbital eyelid stimulation, noise stress, and supraelevation in response to swim stress. Although corticosterone is necessary for the enhanced learning in response to stress (Beylin & Shors, 1999), these results suggest that it is not sufficient. In addition, the results suggest that the enhancement is not dependent on common characteristics between the stressor and the conditioning stimuli (stimulus generalization). In Experiment 2, it was determined that the facilitating effect of the stressor on conditioning occurs within 30 min of stressor cessation. Thus, the mechanism responsible for facilitating memory formation is rapidly induced as well as persistently expressed. In Experiment 3, it was determined that exposure to the stressor does not enhance performance of the conditioned response after the response has been acquired. Thus, exposure to the stressor enhances the formation of new associations rather than affecting retention or performance of the motor response. These studies extend the circumstances under which stress is known to enhance associative learning and implicate neural mechanisms of memory enhancement that are rapidly induced and persistently expressed.