Stress System Activation in Children and Adolescents With Autism Spectrum Disorder

The mission of the human stress system is the maintenance of homeostasis in the presence of real or perceived, acute or chronic stressors. The hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS) are the stress system-related neuroendocrine pathways. There is abundant evidence that children and adolescents with autism spectrum disorder (ASD) may exhibit atypical function within the HPA axis and the ANS both at the resting state and during the presence of social and/or non-social stressors. The aim of this review is to provide an up-to-date summary of the findings regarding stress system alterations in children and adolescents with ASD. We focus on the variations of stress hormones circadian rhythms, specifically cortisol and alpha-amylase (i.e., a surrogate index of epinephrine/norepinephrine secretion), and on the alterations of stress system responsivity to different stressors. Also, we present imaging and immunological findings that have been associated with stress system dysregulation in children and adolescents with ASD. Finally, we review the pivotal role of HPA axis-ANS coordination, the developmental trajectory of the stress system in ASD, and the possible role of early life stress in the dysregulation of the stress system demonstrated in children and adolescents with ASD. This synthesis will hopefully provide researchers with a foundation for an integrated approach to future research into stress system variations in children and adolescents with ASD.

Silencing MR-1 Protects against Myocardial Injury Induced by Chronic Intermittent Hypoxia by Targeting Nrf2 through Antioxidant Stress and Anti-Inflammation Pathways

Background. Patients with obstructive sleep apnea hypopnea syndrome (OSAHS) often have cardiac insufficiency mainly due to hypoxia/reperfusion injury caused by chronic intermittent hypoxia (CIH). Inflammation and oxidative stress are involved in the cardiovascular events of OSAHS patients. Studies have found that myofibrillation regulator-1 (MR-1) participates in the pathological process of OSAHS-induced myocardial injury, but the specific mechanism is still unclear. Methods. We used a CIH-induced rat model to simulate the process of OSAHS disease. Indices of myocardial injury, inflammation, and oxidative stress were detected using quantitative PCR and enzyme-linked immunosorbent assay (ELISA). After administration of adenoassociated viral vector (AAV) encoding silencing RNA against MR-1, we examined expression of the classic antioxidant stress pathway protein NF-E2-related factor 2 (Nrf2) using western blotting. Results. We found that levels of serum inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 were increased, and we further observed disturbance of the oxidative stress system, in which the content of reactive oxygen species (ROS), superoxide dismutase (SOD), reduced glutathione (GSH), and malondialdehyde (MDA) was enhanced in CIH-induced rats. Subsequently, we detected that expression of Nrf2 and heme oxygenase-1 (HO-1) was slightly increased, while the expression of Kelch-like ECH-associated protein 1 (Keap-1) was significantly increased in the CIH model. Interestingly, after administration of silencing MR-1 AAV, the elevated levels of inflammatory factors were reduced, and the disordered oxidative stress system was corrected. Additionally, the expression of Nrf2 and HO-1 was distinctly increased, but the high expression of Keap-1 was decreased. Conclusions. Our research results demonstrate that silencing MR-1 rescued the myocardium the injury from inflammatory and oxidative stress in CIH-induced rats by administration of the Nrf2 signaling pathway.

No Stress System Requires Recursive Feet

A recursive foot is one in which a foot is embedded inside another foot of the same type: e.g., iambic (iaσ(iaσσ́)) or trochaic (tr(trσ́σ)σ). Recent work has used such feet to model stress systems with full or partial ternary rhythm, in which stress falls on every third syllable or mora. I show here that no stress system requires recursive feet, that phonological processes in such languages likely don’t either, and that the notion of recursive foot is theoretically suspect.

Stress system dysfunction revealed by integrating reactivity of stress pathways to psychological stress in lean and overweight/obese men

While the patterns of response within the sympatho-adrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis are interesting and important in their own accord, the overall response to acute psychological stress involves reactivity of both pathways We tested the hypothesis that consideration of the integrated response of these pathways may reveal dysregulation of the stress systems that is not evident when considering either system alone. Age matched lean and overweight/obese men were subjected to a Trier Social Stress Test and reactivity of the SAM system (salivary alpha amylase, systolic blood pressure, diastolic blood pressure and heart rate) and the HPA axis (salivary cortisol) were measured. Relative reactivity of SAM system and HPA axis was calculated as the ratio between the measures from each pathway. While analysis of reactivity of individual stress pathways showed no evidence of dysfunction in overweight/obese compared with lean men, analysis of HPA/SAM reactivity revealed significantly lower cortisol over systolic blood pressure (CoSBP) and cortisol over diastolic blood pressure (CoDBP) reactivity in overweight/obese compared with lean men. Other measures of HPA/SAM reactivity and all measures of SAM/HPA reactivity were unaltered in overweight/obese compared with lean men. These findings suggest that the cortisol response per unit of blood pressure response is blunted in men with elevated adiposity. Further, these findings support a notion of a coordinated overall approach to activation of the stress pathways with the degree of activation in one pathway being related to the degree of activation of the other.

In Favour of Layered Feet

In this response we argue that the factorial typology predicted in Martínez-Paricio & Kager (2015), which representationally relies on the existence of internally layered ternary feet, is complete and accurate. We demonstrate it does not suffer from the problematic cases of overgeneration pointed out by Golston (this issue). Additionally, we corroborate the idea that the internally layered ternary foot is a metrical representation that is typologically warranted for stress phenomena as well as for segmental and tonal metrically conditioned distributions. We suggest that Golston’s claim that “no stress system requires internally layered ternary feet” appears to be too strong and is not empirically substantiated.

Glucocorticoid-Mediated Developmental Programming of Vertebrate Stress Responsivity

Glucocorticoids, vertebrate steroid hormones produced by cells of the adrenal cortex or interrenal tissue, function dynamically to maintain homeostasis under constantly changing and occasionally stressful environmental conditions. They do so by binding and thereby activating nuclear receptor transcription factors, the Glucocorticoid and Mineralocorticoid Receptors (MR and GR, respectively). The GR, by virtue of its lower affinity for endogenous glucocorticoids (cortisol or corticosterone), is primarily responsible for transducing the dynamic signals conveyed by circadian and ultradian glucocorticoid oscillations as well as transient pulses produced in response to acute stress. These dynamics are important determinants of stress responsivity, and at the systemic level are produced by feedforward and feedback signaling along the hypothalamus-pituitary–adrenal/interrenal axis. Within receiving cells, GR signaling dynamics are controlled by the GR target gene and negative feedback regulator fkpb5. Chronic stress can alter signaling dynamics via imperfect physiological adaptation that changes systemic and/or cellular set points, resulting in chronically elevated cortisol levels and increased allostatic load, which undermines health and promotes development of disease. When this occurs during early development it can “program” the responsivity of the stress system, with persistent effects on allostatic load and disease susceptibility. An important question concerns the glucocorticoid-responsive gene regulatory network that contributes to such programming. Recent studies show that klf9, a ubiquitously expressed GR target gene that encodes a Krüppel-like transcription factor important for metabolic plasticity and neuronal differentiation, is a feedforward regulator of GR signaling impacting cellular glucocorticoid responsivity, suggesting that it may be a critical node in that regulatory network.

Tilapia Head Protein Hydrolysate Attenuates Scopolamine-Induced Cognitive Impairment through the Gut-Brain Axis in Mice

The destruction of the homeostasis in the gut-brain axis can lead to cognitive impairment and memory decline. Dietary intervention with bioactive peptides from aquatic products is an innovative strategy to prevent cognitive deficits. The present study aimed to determine the neuroprotective effect of tilapia head protein hydrolysate (THPH) on scopolamine-induced cognitive impairment in mice, and to further explore its mechanism through the microbiota–gut-brain axis. The results showed that THPH administration significantly improved the cognitive behavior of mice, and normalized the cholinergic system and oxidative stress system of the mice brain. The histopathological observation showed that THPH administration significantly reduced the pathological damage of hippocampal neurons, increased the number of mature neurons marked by NeuN and delayed the activation of astrocytes in the hippocampus of mice. In addition, THPH administration maintained the stability of cholinergic system, alleviated oxidative stress and further improved the cognitive impairment by reshaping the gut microbiota structure of scopolamine-induced mice and alleviating the disorder of lipid metabolism and amino acid metabolism in serum. In conclusion, our research shows that THPH supplementation is a nutritional strategy to alleviate cognitive impairment through the gut-brain axis.

Emerging Phonology Under Language Contact: The Case of Sino-Russian Idiolects

The main aim of this study is to examine what kind of phonological system emerges because of language contact wherein adult speakers of L1 (Chinese) attempt to speak L2 (Russian) without any previous instruction in L2. The main findings of this study are as follows: a) The speakers of L1 largely adopt the phonetic inventory and phonotactics of L2 and b) the only underlying (distinctive) features in the emerging phonological system are those of place of articulation while voicing plays no distinctive role in the emerging phonological system of Chinese speakers. Moreover, the speakers of L1 faithfully replicate the stress system of L2, even though L1 (Chinese) is a tonal language and L2, Russian, is a stress language. The most important finding of this study is that speakers of L1 discern the entity ‘word’ in L2. The emerging phonological system is geared towards assuring the identifiability of words in L2 rather than towards consistency of phonological rules.

Sleep markers in psychiatry: do insomnia and disturbed sleep play as markers of disrupted neuroplasticity in mood disorders? A proposed model

Introduction: Since insomnia and disturbed sleep may affect neuroplasticity, we aimed at reviewing their potential role as markers of disrupted neuroplasticity involved in mood disorders. Method: We performed a systematic review, according to PRIMA, on PubMed, PsycINFO and Embase electronic databases for literature regarding mood disorders, insomnia, sleep loss/deprivation in relation to different pathways involved in the impairment of neuroplasticity in mood disorders such as 1] alterations in neurodevelopment 2] activation of the stress system 3] neuroinflammation 4] neurodegeneration/neuroprogression, 4] deficit in neuroprotection. Results: Sixty-five articles were analyzed and a narrative/ theoretical review was conducted. Studies showed that insomnia, sleep loss and sleep deprivation might impair brain plasticity of those areas involved in mood regulation throughout different pathways. Insomnia and disrupted sleep may act as neurobiological stressors that by over-activating the stress and inflammatory systems may affect neural plasticity causing neuronal damage. In addition, disturbed sleep may favor a deficit in neuroprotection hence contributing to impaired neuroplasticity. Conclusions: Insomnia and disturbed sleep may play a role as markers of alteration in brain plasticity in mood disorders. Assessing and targeting insomnia in the clinical practice may potentially play a neuroprotective role, contributing to “repairing” alterations in neuroplasticity or to the functional recovery of those areas involved in mood and emotion regulation.

Impact of antenatal glucocorticoid exposure on the activity of the stress system, cognition and behavior in 8 to 9-year-old children: a clinical cohort study

Objective: To determine stress-sensitivity and neurodevelopmental outcome in 8- to 9-year-old children following antenatal exposure to glucocorticoid (GC) prophylaxis for neonatal respiratory distress syndrome. Design: Clinical cohort study. Setting: University-based obstetric clinic in Central Germany. Population: 31 term or near-term born children whose mothers received single or multiple courses of betamethasone (BM) to induce fetal lung maturation in threatened preterm birth compared to 39 non-exposed children. Methods: Multi-system assessment of the individual stress response together with an analysis of cognitive, behavioral and electrocortical functioning. Main Outcome Measures: Activity of the hypothalamus-pituitary-adrenal axis (HPAA, primary outcome domain) and the autonomic nervous system (ANS, secondary outcome domain) including markers of heart rate variability (HRV). Additional endpoints were the cognitive performance (IQ) and attention-deficit/hyperactivity disorder (ADHD) core symptoms. Results: HPAA activity was not affected by antenatal GC-exposure. ANS activity in GC-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of HRV (1313 vs. 762 msec2/Hz, p=0.03). BM-exposed children had lower cognitive performance (IQ 96.9 vs. 108.0, p<0.01) and a marginally higher ADHD score (FBB-ADHD scale 5.5 vs. 4.6 points, p=0.04). A monotonic dose-response relationship between GC-exposure and stress-induced activity of the ANS and IQ was estimated post-hoc. Conclusions: Antenatal exposure to supraphysiological concentrations of BM in the context of threatened preterm birth was associated with multidimensional changes in stress-sensitivity and neurodevelopment in later life. As these changes may be dose-dependent, antenatal GC prophylaxis should be used at the minimum effective dose after a careful risk-benefit assessment.