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Objective: Childhood trauma may contribute to poor lifelong health in part through programming of the HPA-axis response to future life stressors. To date, empirical evidence shows an association of childhood trauma with dysregulation of the HPA-axis and blunted cortisol reactivity to acute stressors. Here, we conduct an initial examination of childhood trauma as a moderator of changes over time in perceived stress levels and HPA-axis response to a major chronic stressor in adulthood., Methods: Participants were 83 maternal caregivers of children newly diagnosed with cancer who completed the Childhood Trauma Questionnaire (CTQ), and who, over the year following their child's cancer diagnosis, had hair samples collected up to 7 times for the assessment of cortisol and completed monthly measures of perceived stress., Results: CTQ scores were in the expected range for a community sample and associated with changes in perceived stress and cortisol concentration over time (γ =.003, p =.002; γ = -.0004, p =.008, respectively) independently of age, education, treatment intensity and randomization to stress management intervention. Maternal caregivers who endorsed lower childhood trauma showed a steeper decline in perceived stress and a larger increase in cortisol levels across the year than caregivers who recalled more childhood trauma., Conclusions: Findings extend animal models and studies that examine cortisol reactivity to acute stressors and suggest that childhood trauma may program a phenotype that is more psychologically reactive but shows a blunted HPA-axis response to chronic stress. While adaptive in the short-term, this early life programming may incur long-term costs for health. Further work is warranted to examine this possibility., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Activation of the HPA-axis and SNS are widely accepted to link chronic stress with elevated levels of peripheral pro-inflammatory markers in blood. Yet, empirical evidence showing that peripheral levels of glucocorticoids and/or catecholamines mediate this effect is equivocal. Recent attention has turned to the possibility that cellular sensitivity to these ligands may contribute to inflammatory mediators that accompany chronic stress. We review current evidence for the association of chronic stress with glucocorticoid receptor (GR) and β-adrenergic receptor (β-AR) signaling sensitivity. Across 15 mouse, 7 primate, and 19 human studies, we found that chronic stress reliably associates with downregulation in cellular GR sensitivity, alterations in intracellular β-AR signaling, and upregulation in pro-inflammatory biomarkers in peripheral blood. We also present evidence that alterations in GR and β-AR signaling may be specific to myeloid progenitor cells such that stress-related signaling promotes release of cells that are inherently less sensitive to glucocorticoids and differentially sensitive to catecholamines. Our findings have broad implications for understanding mechanisms by which chronic stress may contribute to pro-inflammatory phenotypes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: We have previously found that acute psychological stress may affect mitochondria and trigger an increase in serum mitochondrial DNA, known as circulating cell-free mtDNA (ccf-mtDNA). Similar to other stress reactivity measures, there are substantial unexplained inter-individual differences in the magnitude of ccf-mtDNA reactivity, as well as within-person differences across different occasions of testing. Here, we sought to identify psychological and physiological predictors of ccf-mtDNA reactivity using machine learning-based multivariate classifiers., Method: We used data from serum ccf-mtDNA concentration measured pre- and post-stress in 46 healthy midlife adults tested on two separate occasions. To identify variables predicting the magnitude of ccf-mtDNA reactivity, two multivariate classification models, partial least-squares discriminant analysis (PLS-DA) and random forest (RF), were trained to discriminate between high and low ccf-mtDNA responders. Potential predictors used in the models included state variables such as physiological measures and affective states, and trait variables such as sex and personality measures. Variables identified across both models were considered to be predictors of ccf-mtDNA reactivity and selected for downstream analyses., Results: Identified predictors were significantly enriched for state over trait measures (X 2  = 7.03; p = 0.008) and for physiological over psychological measures (X 2  = 4.36; p = 0.04). High responders were more likely to be male (X 2  = 26.95; p < 0.001) and differed from low-responders on baseline cardiovascular and autonomic measures, and on stress-induced reduction in fatigue (Cohen's d = 0.38-0.73). These group-level findings also accurately accounted for within-person differences in 90% of cases., Conclusion: These results suggest that acute cardiovascular and psychological indices, rather than stable individual traits, predict stress-induced ccf-mtDNA reactivity. This work provides a proof-of-concept that machine learning approaches can be used to explore determinants of inter-individual and within-person differences in stress psychophysiology., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Intrinsic biological mechanisms transduce psychological stress into physiological adaptation that requires energy, but the role of mitochondria and mitochondrial DNA (mtDNA) in this process has not been defined in humans. Here, we show that similar to physical injury, exposure to psychological stress increases serum circulating cell-free mtDNA (ccf-mtDNA) levels. Healthy midlife adults exposed on two separate occasions to a brief psychological challenge exhibited a 2-3-fold increase in ccf-mtDNA, with no change in ccf-nuclear DNA levels, establishing the magnitude and specificity for ccf-mtDNA reactivity. In cell-based studies, we show that glucocorticoid signaling - a consequence of psychological stress in humans - is sufficient to induce mtDNA extrusion in a time frame consistent with stress-induced ccf-mtDNA increase. Collectively, these findings provide evidence that acute psychological stress induces ccf-mtDNA and implicate neuroendocrine signaling as a potential trigger for ccf-mtDNA release. Further controlled work is needed to confirm that observed increases in ccf-mtDNA result from stress exposure and to determine the functional significance of this effect., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Communication between the brain and peripheral mediators of systemic inflammation is implicated in numerous psychological, behavioral, and physiological processes. Functional neuroimaging studies have identified brain regions that associate with peripheral inflammation in humans, yet there are open questions about the consistency, specificity, and network characteristics of these findings. The present systematic review provides a meta-analysis to address these questions. Multilevel kernel density analysis of 24 studies (37 statistical maps; 264 coordinates; 457 participants) revealed consistent effects in the amygdala, hippocampus, hypothalamus, striatum, insula, midbrain, and brainstem, as well as prefrontal and temporal cortices. Effects in some regions were specific to particular study designs and tasks. Spatial pattern analysis revealed significant overlap of reported effects with limbic, default mode, ventral attention, and corticostriatal networks, and co-activation analyses revealed functional ensembles encompassing the prefrontal cortex, insula, and midbrain/brainstem. Together, these results characterize brain regions and networks associated with peripheral inflammation in humans, and they provide a functional neuroanatomical reference point for future neuroimaging studies on brain-body interactions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Inter-individual variability in metrics of hypothalamic-pituitary-adrenocortical (HPA) activity, such as the slope of the diurnal decline in cortisol, cortisol awakening response (CAR), and total cortisol output, have been found to associate inversely with trait ratings of extraversion and positive affect (E/PA) and positively with neuroticism and negative affect (N/NA) in some, but not all, investigations. These inconsistencies may partly reflect varied intensity of cortisol sampling among studies and reliance on self-rated traits, which are subject to reporting biases and limitations of introspection. Here, we further examined dispositional correlates of HPA activity in 490 healthy, employed midlife volunteers (M age=43 years; 54% Female; 86% white). Trait ratings were requested from participants and 2 participant-elected informants using the Positive and Negative Affect Schedule (PANAS) and Extraversion and Neuroticism dimensions of NEO personality inventories. CAR was assessed as percent increase in cortisol levels from awakening to 30min after awakening; and the diurnal slope and total output of cortisol [Area Under the Curve (AUC)] were determined from cortisol measurements taken at awakening, +4 and +9h later, and bedtime, across 3 workdays. Structural equation modeling was used to estimate multi-informant E/PA and N/NA factors. We used 3days of measurement as indicators to model each of the three latent cortisol factors (slope, CAR, and AUC). With the two latent emotionality and three latent cortisol indices included there was good fit to the data (χ(2)(200)=278.38, p=0.0002; RMSEA=0.028, 90% CI=0.02-0.04; CFI/TLI=0.97/0.96; SRMR=0.04). After controlling for covariates (age, sex, race), results showed higher latent E/PA associated with a steeper diurnal slope (Standardized β=-0.19, p=0.02) and smaller CAR (Standardized β=-0.26, p=0.004), whereas N/NA did not associate with any cortisol metric (Standardized β's=-0.12 to 0.13, p's=0.10 to 0.53). These findings suggest that positive emotionality may be more closely associated with indices of diurnal cortisol release than negative emotionality., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In studies employing functional magnetic resonance imaging (fMRI), reactivity of the amygdala to threat-related sensory cues (viz., facial displays of negative emotion) has been found to correlate positively with interindividual variability in testosterone levels of women and young men and to increase on acute administration of exogenous testosterone. Many of the biological actions of testosterone are mediated by intracellular androgen receptors (ARs), which exert transcriptional control of androgen-dependent genes and are expressed in various regions of the brain, including the amygdala. Transactivation potential of the AR decreases (yielding relative androgen insensitivity) with expansion a polyglutamine stretch in the N-terminal domain of the AR protein, as encoded by a trinucleotide (CAG) repeat polymorphism in exon 1 of the X-chromosome AR gene. Here we examined whether amygdala reactivity to threat-related facial expressions (fear, anger) differs as a function of AR CAG length variation and endogenous (salivary) testosterone in a mid-life sample of 41 healthy men (mean age=45.6 years, range: 34-54 years; CAG repeats, range: 19-29). Testosterone correlated inversely with participant age (r=-0.39, p=0.012) and positively with number of CAG repeats (r=0.45, p=0.003). In partial correlations adjusted for testosterone level, reactivity in the ventral amygdala was lowest among men with largest number of CAG repeats. This inverse association was seen in both the right (r(p)=-0.34, p<0.05) and left (r(p)=-0.32, p<0.05) hemisphere. Activation of dorsal amygdala, correlated positively with individual differences in salivary testosterone, also in right (r=0.40, p<0.02) and left (r=0.32, p<0.05) hemisphere, but was not affected by number of CAG repeats. Hence, androgenic influences on threat-related reactivity in the ventral amygdala may be moderated partially by CAG length variation in the AR gene. Because individual differences in salivary testosterone also predicted dorsal amygdala reactivity and did so independently of CAG repeats, it is suggested that androgenic influences within this anatomically distinct region may be mediated, in part, by non-genomic or AR-independent mechanisms.