Based on a multiwave, two-year prospective design, this study is the first to examine the extent to which multilocus hypothalamic-pituitary-adrenal axis (HPA axis)-related genetic variants, childhood maltreatment, and recent stress jointly predicted prospective changes in adolescent depressive symptoms. A theory-driven multilocus genetic profile score (MGPS) was calculated to combine the effects of six common polymorphisms within HPA-axis related genes (CRHR1, NR3C1, NR3C2, FKBP5, COMT, and HTR1A) in a sample of Chinese Han adolescents (N = 827; 50.2% boys; Mage = 16.45 ± 1.36 years). The results showed that the three-way interaction of HPA-axis related MGPS, childhood maltreatment and recent interpersonal, but not noninterpersonal, stress significantly predicted prospective changes in adolescent depressive symptoms. For adolescents with high but not low HPA-axis related MGPS, exposure to severe childhood maltreatment predisposed individuals more vulnerable to recent interpersonal stress, exhibiting greater prospective changes in adolescent depressive symptoms. The findings provide preliminary evidence for the cumulative risk mechanism regarding gene-by-environment-by-environment (G × E1 × E2) interactions that underlie the longitudinal development of adolescent depressive symptoms and show effects specific to interpersonal stress.

BACKGROUND: Allostatic load (AL) is associated with a heightened predisposition to disease due to prolonged activation of biological stress-response systems. Alcohol use disorder (AUD) is known to activate these systems. The primary aim of the current study was to examine the relationship between AL and AUD.
METHODS: Participants were males (100%) with DSM-IV Alcohol Dependence (n = 48) and healthy participants with no history of substance use disorder (n = 17). Participants with AUD were 4-6 weeks abstinent. The AL index used cortisol, interleukin-6 (IL-6), fibrinogen, tumor necrosis factor-alpha (TNFα), C-reactive protein (CRP), glucose, insulin, leptin, pulse, systolic blood pressure readings, diastolic blood pressure readings, and body mass index (BMI). Physiological dysregulation for each biological measure was determined based on values within the 25th or 75th percentiles; AL was calculated as the total number of physiologically dysregulated biological measures.
RESULTS: No differences in mean AL scores between the cases and controls [t(63) = .48, p = .633] were observed. Among cases, AL was not associated with lifetime drinks per drinking day (F(2,42) = .42, p = .662), lifetime total drinks (F(2,42) = 0.48, p = .620), total drinks 6 months prior to participating in the study (F(2,43) = 0.58, p = .563), or drinks per drinking day at 3-month follow-up (F(2,35) = 1.93, p = .161). AL was negatively associated with drinks per drinking day 6 months prior to study participation (F(2,42) = 3.71, p = .033).
CONCLUSIONS: The hypotheses were not supported. Given that alcohol is likely to lead to physiological dysregulation, the apparent absence of a relationship between biomarkers of cumulative stress as indicated by AL and drinking status was both unanticipated and remarkable. Based on the results, AL in the context of drinking status or drinking among males with AUD may not be applicable.

BACKGROUND: The role of psychosocial stressors in psychiatric disorders and executive dysfunction has been reported, separately. The literature has also suggested the involvement of social support and coping strategies in these relationships. However, there is a lack of research conducted to examine the relationships among multiple stressors and neuropsychiatric comorbidities while considering the presence of social support and coping strategies. This study aims to articulate the roles of multiple psychosocial stressors, social support, and coping strategies in the subsequent occurrence of neuropsychiatric comorbidities.
METHODS: Data analyzed were from the 6th data collection of a large-scale, longitudinal population-based cohort from Southwest Montreal in Canada. The cumulative effects of multiple stressors were separately examined by a composite score and latent profile analysis. Multinomial logistic regression models were used to test the relationship between cumulative stressors and neuropsychiatric comorbidities.
RESULTS: A total of 210 participants were included in the analyses. The LPA identified a 2-class model for psychosocial stressors (low and high) and executive function (executive dysfunction and no executive dysfunction), respectively. There were 11.8% of participants with neuropsychiatric comorbidities. Both the composite stress score (RR = 1.08, 95%CI = 1.01-1.15) and latent stress groups (RR = 3.65, 95%CI = 1.15-11.57) were associated with neuropsychiatric comorbidities after adjusting for social support and coping strategies. The risk of developing neuropsychiatric comorbidities decreased when the level of social support was high (P < 0.05).
CONCLUSIONS: Exposures to multiple stressors increased the risk of subsequent neuropsychiatric comorbidities, but the risk can be modified by a higher level of social support.

Stress may impact the ability to effectively regulate emotions. To study the impact of stressful experiences in early and recent life on emotion regulation, we examined the relationship between early life stress, recent stress, and brain activation during cognitive reappraisal. We investigated two regulation goals: the decrease and increase of emotional response to both negative and positive stimuli. Furthermore, two models of stress consequences were examined: the cumulative and match/mismatch models. A total of 83 participants (Mage = 21.66) took part in the study. There was an interaction between cumulative stress and stimuli valence in the cuneus, superior lateral occipital cortex, superior parietal lobule, supramarginal gyrus extending to superior temporal gyrus, and precentral gyrus extending to supplementary motor area. Interaction between mismatched stress index and stimuli valence was found in the left hippocampus, left insula extending to the orbitofrontal cortex and amygdala, and in a cluster including the anterior cingulate cortex, superior frontal gyrus, and frontal pole. Furthermore, there were differences between the effects of cumulative and mismatched stress indices on brain activation during reappraisal of positive but not negative stimuli. Results indicate that cumulative stress and match/mismatch approaches are both useful for explaining brain activation during reappraisal. This finding is important for our understanding of the multifaceted impact of stress on emotion regulation.

The aim of this study was to characterize neural activation during the processing of negative facial expressions in a non-clinical group of individuals characterized by two factors: the levels of stress experienced in early life and in adulthood. Two models of stress consequences were investigated: the match/mismatch and cumulative stress models. The match/mismatch model assumes that early adversities may promote optimal coping with similar events in the future through fostering the development of coping strategies. The cumulative stress model assumes that effects of stress are additive, regardless of the timing of the stressors. Previous studies suggested that stress can have both cumulative and match/mismatch effects on brain structure and functioning and, consequently, we hypothesized that effects on brain circuitry would be found for both models. We anticipated effects on the neural circuitry of structures engaged in face perception and emotional processing. Hence, the amygdala, fusiform face area, occipital face area, and posterior superior temporal sulcus were selected as seeds for seed-based functional connectivity analyses. The interaction between early and recent stress was related to alterations during the processing of emotional expressions mainly in to the cerebellum, middle temporal gyrus, and supramarginal gyrus. For cumulative stress levels, such alterations were observed in functional connectivity to the middle temporal gyrus, lateral occipital cortex, precuneus, precentral and postcentral gyri, anterior and posterior cingulate gyri, and Heschl\'s gyrus. This study adds to the growing body of literature suggesting that both the cumulative and the match/mismatch hypotheses are useful in explaining the effects of stress.

Major life stress often produces a flat diurnal cortisol slope, an indicator of potential long-term health problems. Exposure to stress early in childhood or the accumulation of stress across the life span may be responsible for this pattern. However, the relative impact of life stress at different life stages on diurnal cortisol is unknown. Using a longitudinal sample of adults followed from birth, we examined three models of the effect of stress exposure on diurnal cortisol: the cumulative model, the biological-embedding model, and the sensitization model. As its name implies, the cumulative model focuses on cumulative life stress. In contrast, the biological-embedding model implicates early childhood stress, and the sensitization model posits that current life stress interacts with early life stress to produce flat diurnal cortisol slopes. Our analyses are consistent with the sensitization model, as they indicate that the combination of high stress exposure early in life and high current stress predict flat diurnal cortisol slopes. These novel findings advance understanding of diurnal cortisol patterns and point to avenues for intervention.

Mechanical stress is important in causing and healing plantar diabetic foot ulcers, but almost always studied as peak pressure only. Measuring cumulative plantar tissue stress combines plantar pressure and ambulatory activity, and better defines the load on ulcers. Our aim was to explore differences in cumulative plantar tissue stress between people with healing and non-healing plantar diabetic foot ulcers.
We analyzed a subgroup of 31 patients from a randomized clinical trial, treated with a removable offloading device for their plantar diabetic forefoot ulcer. We measured in-device dynamic plantar pressure and daily stride count to calculate cumulative plantar tissue stress at the ulcer location and associated this with ulcer healing and ulcer surface area reduction at four weeks (Student\'s t and chi-square test for significance, Cohen\'s d for effect size).
In 12 weeks, 68% (n = 21) of the ulcers healed and 32% (n = 10) did not. No statistically significant differences were found for cumulative plantar tissue stress, plantar pressure or ambulatory activity between people with healed and not-healed ulcers. Cumulative plantar tissue stress was 25% lower for people with healed ulcers (155 vs. 207 MPa·s/day; P = 0.71; Effect size: d = 0.29). Post-hoc analyses in the 27 patients who self-reported to be adherent to wearing the device showed that cumulative plantar tissue stress was 49% lower for those who reached ≥75% ulcer surface area reduction at four weeks (140 vs. 275 MPa·s/day; P = 0.09; d = 0.76); smaller differences and effect sizes were found for peak pressure (24%), peak pressure-time integral (30%) and ambulatory activity (26%); (P-value range: 0.14-0.97; Cohen\'s d range: 0.14-0.70).
Measuring cumulative plantar tissue stress may provide insight beyond that obtained from plantar pressure or ambulatory activity alone, with regard to diabetic foot ulcer healing using removable offloading devices. These explorative findings provide baseline data for further studies on this relevant topic.

Numerous studies have documented that lower socioeconomic status (SES) is associated with increased mental health problems in children. One proposed pathway for this association has been differential exposure to accumulated risk factors in children of lower SES. The aim of the current study was to investigate the socioeconomic distribution of exposure to negative life events and family stress and to examine the direct and interactive association between lower SES and exposure to life events and family stress in relation with mental health problems.
Using cross-sectional data from the second wave of the Bergen Child Study (conducted in 2006), the current study investigated the association between lower SES and exposure to negative life events, family life stressors, and mental health problems in a sample of 2043 Norwegian 11-13 years and their parents. Information about mental health was self-reported by the children using the Strengths and Difficulties Questionnaire, whereas information about SES and exposure to negative life events and family stressors were provided by their parents.
The findings showed that lower SES was associated with more symptoms of emotional-, conduct-, hyperactivity/inattention-, and peer problems and that exposure to life events and family stress explained some of this association (10-29% of the total effects).
Low SES and higher prevalence of negative life events and family stressors were associated with more symptoms of mental health problems. Overall, the effect sizes were smaller than previous investigations (f 2s = 0.015-0.031), perhaps suggesting a buffering effect of the social safety net in place in Norway.

There is increasing attention for integrating mechanistic and functional approaches to the study of (behavioural) development. As environments are mostly unstable, it is now often assumed that genetic parental information is in many cases not sufficient for offspring to become optimally adapted to the environment and that early environmental cues, either indirectly via the parents or from direct experience, are necessary to prepare them for a specific environment later in life. To study whether these early developmental processes are adaptive and through which mechanism, not only the early environmental cues but also how they impinge on the later-life environmental context has therefore to be taken into account when measuring the animal\'s performance. We first discuss at the conceptual level six ways in which interactions between influences of different time windows during development may act (consolidation, cumulative information gathering and priming, compensation, buffering, matching and mismatching, context dependent trait expression). In addition we discuss how different environmental factors during the same time window may interact in shaping the phenotype during development. Next we discuss the pros and cons of several experimental designs for testing these interaction effects, highlighting the necessity for full, reciprocal designs and the importance of adjusting the nature and time of manipulation to the animal\'s adaptive capacity. We then review support for the interaction effects from both theoretical models and animal experiments in different taxa. This demonstrates indeed the existence of interactions at multiple levels, including different environmental factors, different time windows and between generations. As a consequence, development is a life-long, environment-dependent process and therefore manipulating only the early environment without taking interaction effects with other and later environmental influences into account may lead to wrong conclusions and may also explain inconsistent results in the literature.