The Lack of TRPA1 Ion Channel Does Not Affect the Chronic Stress-Induced Activation of the Locus Ceruleus.

We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger-Westphal nucleus. The noradrenergic locus ceruleus (LC) is also an important player in mood control. We aimed at investigating whether the TRPA1 is expressed in the LC, and to test if the response to chronic variable mild stress (CVMS) is affected by a lack of TRPA1. The TRPA1 expression was examined via RNAscope in situ hybridization. We investigated TRPA1 knockout and wildtype mice using the CVMS model of depression. Tyrosine hydroxylase (TH) and FOSB double immunofluorescence were used to test the functional neuromorphological changes in the LC. No TRPA1 expression was detected in the LC. The TH content was not affected by CVMS exposure. The CVMS-induced FOSB immunosignal did not co-localize with the TH neurons. TRPA1 is not expressed in the LC. A lack of functional TRPA1 receptor neither directly nor indirectly affects the TH content of LC neurons under CVMS.

The mind-skin connection: A narrative review exploring the link between inflammatory skin diseases and psychological stress.

Inflammatory skin diseases are known to negatively impact patient psychology, with individuals experiencing higher rates of stress and subsequent diminished quality of life, as well as mental health issues including anxiety and depression. Moreover, increased psychological stress has been found to exacerbate existing inflammatory skin diseases. The association between inflammatory skin diseases and psychological stress is a timely topic, and a framework to better understand the relationship between the two that integrates available literature is needed. In this narrative review article, we discuss potential neurobiological mechanisms behind psychological stress due to inflammatory skin diseases, focusing mainly on proinflammatory cytokines in the circulating system (the brain-gut-skin communications) and the default mode network in the brain. We also discuss potential descending pathways from the brain that lead to aggravation of inflammatory skin diseases due to psychological stress, including the central and peripheral hypothalamic-pituitary-adrenal axes, peripheral nerves and the skin barrier function.

Modulation of learning safety signals by acute stress: paraventricular thalamus and prefrontal inhibition.

Distinguishing between cues predicting safety and danger is crucial for survival. Impaired learning of safety cues is a central characteristic of anxiety-related disorders. Despite recent advances in dissecting the neural circuitry underlying the formation and extinction of conditioned fear, the neuronal basis mediating safety learning remains elusive. Here, we showed that safety learning reduces the responses of paraventricular thalamus (PVT) neurons to safety cues, while activation of these neurons controls both the formation and expression of safety memory. Additionally, the PVT preferentially activates prefrontal cortex somatostatin interneurons (SOM-INs), which subsequently inhibit parvalbumin interneurons (PV-INs) to modulate safety memory. Importantly, we demonstrate that acute stress impairs the expression of safety learning, and this impairment can be mitigated when the PVT is inhibited, indicating PVT mediates the stress effect. Altogether, our findings provide insights into the mechanism by which acute stress modulates safety learning.

Dorsal peduncular cortex activity modulates affective behavior and fear extinction in mice.

The medial prefrontal cortex (mPFC) is critical to cognitive and emotional function and underlies many neuropsychiatric disorders, including mood, fear and anxiety disorders. In rodents, disruption of mPFC activity affects anxiety- and depression-like behavior, with specialized contributions from its subdivisions. The rodent mPFC is divided into the dorsomedial prefrontal cortex (dmPFC), spanning the anterior cingulate cortex (ACC) and dorsal prelimbic cortex (PL), and the ventromedial prefrontal cortex (vmPFC), which includes the ventral PL, infralimbic cortex (IL), and in some studies the dorsal peduncular cortex (DP) and dorsal tenia tecta (DTT). The DP/DTT have recently been implicated in the regulation of stress-induced sympathetic responses via projections to the hypothalamus. While many studies implicate the PL and IL in anxiety-, depression-like and fear behavior, the contribution of the DP/DTT to affective and emotional behavior remains unknown. Here, we used chemogenetics and optogenetics to bidirectionally modulate DP/DTT activity and examine its effects on affective behaviors, fear and stress responses in C57BL/6J mice. Acute chemogenetic activation of DP/DTT significantly increased anxiety-like behavior in the open field and elevated plus maze tests, as well as passive coping in the tail suspension test. DP/DTT activation also led to an increase in serum corticosterone levels and facilitated auditory fear extinction learning and retrieval. Activation of DP/DTT projections to the dorsomedial hypothalamus (DMH) acutely decreased freezing at baseline and during extinction learning, but did not alter affective behavior. These findings point to the DP/DTT as a new regulator of affective behavior and fear extinction in mice.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Combined effects of cumulative stress and daily stressors on daily health.

OBJECTIVE: It has been proposed that cumulative stress, one's experience of chronic stressors across multiple domains, worsens health by altering the extent to which daily stressors impact daily affect and physical symptoms. Recent work confirms that high cumulative stress exacerbates the association between daily stressor exposure and increased daily negative affect, though it remains untested the extent to which cumulative stress and daily stressor exposure interact to predict daily symptoms. METHOD: We employed data from the second wave of the midlife in the U.S. Survey (N = 2,022; Mage = 56.2; 57.2% female) to examine whether levels of cumulative stress compound daily symptoms on days with (vs. without) stressful events. Experiences of life stressors across eight domains, occurrence of daily stressors, and occurrence, number, and severity of daily physical symptoms were analyzed using multilevel modeling. RESULTS: Greater cumulative stress and experiencing (vs. not experiencing) a daily stressor independently increased the odds of occurrence, number, and severity of daily symptoms (ps ≤ .016). Moreover, after adjusting for covariates (e.g., sociodemographic characteristics, chronic health conditions, percent of days with reported stressors, and health behaviors), the associations between daily stressor exposure and odds of occurrence, number, and severity of daily symptoms were potentiated as levels of cumulative stress increased (ps ≤ .009). CONCLUSIONS: The negative implications of daily stressor exposure for daily health may be most pronounced in those who report higher levels of cumulative stress across multiple life domains and across time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of Acute Stress on Rigid Learning, Flexible Learning, and Value-Based Decision-Making in Spatial Navigation.

The current study investigated how stress affects value-based decision-making during spatial navigation and different types of learning underlying decisions. Eighty-two adult participants (42 females) first learned to find object locations in a virtual environment from a fixed starting location (rigid learning) and then to find the same objects from unpredictable starting locations (flexible learning). Participants then decided whether to reach goal objects from the fixed or unpredictable starting location. We found that stress impairs rigid learning in females, and it does not impair, and even improves, flexible learning when performance with rigid learning is controlled for. Critically, examining how earlier learning influences subsequent decision-making using computational models, we found that stress reduces memory integration, making participants more likely to focus on recent memory and less likely to integrate information from other sources. Collectively, our results show how stress impacts different memory systems and the communication between memory and decision-making.

Amygdala and nucleus accumbens activation during reward anticipation moderates the association between life stressor frequency and depressive symptoms.

BACKGROUND: Life stressors confer risk for depressive symptoms, but individuals vary in the extent of their sensitivity to life stressors. One protective factor may be an individual's level of reward sensitivity, e.g., a stronger neurobiological response to environmental rewards may mitigate emotional responses to stressors. However, the nature of neurobiological reward sensitivity that corresponds with stress resilience is unknown. Further, this model is untested in adolescence, when life stressor frequency and depression increase. METHODS: We tested the hypothesis that stronger reward-related activation in the left and right nucleus accumbens (NAc), amygdala, and medial prefrontal cortex (mPFC) attenuates the strength of the stress-depression relation. We measured BOLD activation throughout Win and Lose blocks of a monetary reward task, as well as during anticipation and outcome phases of the task. Participants (N = 151, ages 13-19) were recruited to be stratified on risk for mood disorders to enhance variance in depressive symptoms. RESULTS: Activation during anticipation of rewards in the bilateral amygdala and NAc, but not mPFC, buffered the association between life stressors and depressive symptoms. This buffering effect was not found for reward outcome activation or activation across Win blocks. CONCLUSIONS: Results highlight the importance of reward anticipation activation of subcortical structures in attenuating the stress-depression link, suggesting that reward motivation may be a cognitive mechanism through which this stress buffering occurs.

A non-invasive wearable stress patch for real-time cortisol monitoring using a pseudoknot-assisted aptamer.

Stress is part of everyone's life and is exacerbated by traumatic events such as pandemics, disasters, violence, lifestyle changes, and health disorders. Chronic stress has many detrimental health effects and can even be life-threatening. Long-term stress monitoring outside of a hospital is often accomplished by measuring heart rate variability. While easy to measure, this digital biomarker has low specificity, greatly limiting its utility. To address this shortcoming, we report a non-invasive, wearable biomolecular sensor to monitor cortisol levels in sweat. Cortisol is a neuroendocrine hormone that regulates homeostasis as part of the stress pathway. Cortisol is detected using an electrochemical sensor functionalized with a pseudoknot-assisted aptamer and a flexible microfluidic sweat sampling system. The skin-worn microfluidic sampler provides rapid sweat collection while separating old and new sweat. The conformation-switching aptamer provides high specificity towards cortisol while being regenerable, allowing it to monitor temporal changes continuously. The aptamer was engineered to add a pseudoknot, restricting it to only two states, thus minimizing the background signal and enabling high sensitivity. An electrochemical pH sensor allows pH-corrected amperometric measurements. Device operation was demonstrated invitro with a broad linear dynamic range (1 pM - 1 µM) covering the physiological range and a sub-picomolar (0.2 pM) limit of detection in sweat. Real-time, on-body measurements were collected from human subjects using an induced stress protocol, demonstrating in-situ signal regeneration and the ability to detect dynamic cortisol fluctuations continuously for up to 90 min. The reported device has the potential to improve prognosis and enable personalized treatments.

Cognitive and Emotional Symptoms Induced by Chronic Stress Are Regulated by EGR1 in a Subpopulation of Hippocampal Pyramidal Neurons.

Chronic stress is a core risk factor for developing a myriad of neurological disorders, including major depression. The chronicity of such stress can lead to adaptive responses or, on the contrary, to psychological maladaptation. The hippocampus is one of the most affected brain regions displaying functional changes in chronic stress. Egr1, a transcription factor involved in synaptic plasticity, is a key molecule regulating hippocampal function, but its role in stress-induced sequels has been poorly addressed. Emotional and cognitive symptoms were induced in mice by using the chronic unpredictable mild stress (CUMS) protocol. We used inducible double-mutant Egr1-CreERT2 x R26RCE mice to map the formation of Egr1-dependent activated cells. Results show that short- (2 days) or long-term (28 days) stress protocols in mice induce activation or deactivation, respectively, of hippocampal CA1 neural ensembles in an Egr1-activity-dependent fashion, together with an associated dendritic spine pathology. In-depth characterization of these neural ensembles revealed a deep-to-superficial switch in terms of Egr1-dependent activation of CA1 pyramidal neurons. To specifically manipulate deep and superficial pyramidal neurons of the hippocampus, we then used Chrna7-Cre (to express Cre in deep neurons) and Calb1-Cre mice (to express Cre in superficial neurons). We found that specific manipulation of superficial but not deep pyramidal neurons of the CA1 resulted in the amelioration of depressive-like behaviors and the restoration of cognitive impairments induced by chronic stress. In summary, Egr1 might be a core molecule driving the activation/deactivation of hippocampal neuronal subpopulations underlying stress-induced alterations involving emotional and cognitive sequels.

Mediators of inflammation at the maternal-fetal interface are altered by SARS-CoV-2 infection and pandemic stress.

PROBLEM: It is now recognized that SARS-CoV-2 infection and pandemic-related stress impacts maternal health. However, their effects at the maternal-fetal interface are still debated. METHOD OF STUDY: We recruited 199 women between March 2020 and July 2021, 79 SARS-CoV-2+ and 120 negative (the latter exposed to pandemic stress only). We also included 40 historic controls (i.e. pre-pandemic uncomplicated pregnancies recruited before March 2020). Placental samples were collected for protein and histological analysis. RESULTS: The majority of SARS-CoV-2+ women were multiethnic, had higher pre-pregnancy BMI and elevated preterm birth rate (17%) vs SARS-CoV-2- or historic control. Placental inflammatory profile revealed increased IL-1Ra and CRP, independently of SARS-CoV-2 status, whilst MCP-1, IL-6 and IFNγ were elevated in the negative, but pandemic stress-exposed, group. These changes were predominant in placentas with inflammatory lesions on histopathological analysis. Furthermore, we observed elevated immune cells (CD45+) in placentas from SARS-CoV-2+ and negative pregnancies vs historic controls, even when individuals with pregnancy complications were excluded. CONCLUSIONS: Placental inflammatory profiles differed between SARS-CoV-2 statuses, namely exposed to pandemic stress +/- SARS-CoV-2 infection. This highlights the need to understand the differences between the effects of pandemic-related stress and the added burden of SARS-CoV-2 infection on placental health.

High Perceived Stress is Associated With Increased Risk of Ulcerative Colitis Clinical Flares.

BACKGROUND & AIMS: Although perceived stress (PS) has been associated with symptomatic flares in inflammatory bowel disease, clinical and physiological measures associated with perceived stress and flare are not known. The aim of this study was to identify physiological factors associated with perceived stress in ulcerative colitis (UC) subjects, and their relationship with flare. METHODS: Patients with UC in clinical remission (Simple Colitis Clinical Activity Index [SCCAI] score <5) underwent clinical and behavioral assessments, morning salivary cortisol measurements, autonomic nervous system activity testing (heart rate variability, electrodermal activity) at baseline with patient-reported SCCAI every 2 weeks over 1 to 2 years and fecal calprotectin at time of flare. Clinical flares (SCCAI ≥5) and biochemical flares (SCCAI ≥5 with fecal calprotectin ≥250 µg/g) were evaluated. RESULTS: One hundred ten patients with UC were enrolled, with mean follow-up of 65.6 weeks. Patients with UC with higher and lower PS were determined. Although the high PS group had 3.6 times higher odds of a clinical flare than the low PS group, no significant differences in biochemical flares were observed between the low and high PS groups. The high vs low PS group differed in tonic sympathetic arousal as indexed by significantly greater baseline electrodermal activity (4.3 vs 3.4 microsiemens; P = .026) in the high PS group, but not in terms of heart rate variability and morning cortisol levels. Increased fecal calprotectin was associated with cardioautonomic measures, suggesting lower parasympathetic activity. CONCLUSIONS: Increased PS assessed at baseline is associated with tonic sympathetic arousal and greater odds of clinical flares in patients with UC.

Blunted cardiovascular reactivity to psychological stress and prospective health: a systematic review.

Novel research demonstrates that lower or 'blunted' cardiovascular reactions to stress are associated with a range of adverse outcomes. The aim of the current review was (1) to examine the prospective outcomes predicted by blunted cardiovascular reactivity and (2) to identify a range of blunted cardiovascular reaction levels that predict these outcomes. Electronic databases were systematically searched (Medline, PsycArticles, PsycInfo, CINAHL, PubMed, Web of Science). Studies were included if they examined the prospective influence of blunted cardiovascular reactivity to psychological stress (SBP, DBP or HR) on a negative health, behavioural or psychological outcome. A total of 23 studies were included in the review. Blunted reactivity predicted (1) adverse cardiovascular health, primarily in cardiac samples (e.g., myocardial infarction, carotid atherosclerosis) and (2) outcomes associated with motivational and behavioural dysregulation in healthy samples (e.g., obesity, smoking addiction, depression). The cardiovascular reactivity threshold levels that were predictive of adverse health outcomes ranged between -3.00-12.59 bpm (14.41% to 136.59% lower than the sample mean) and -2.4-5.00 mmhg (65.99% to 133.80% lower than sample mean), for HR and DBP respectively. We posit that blunted reactions lower than, or equal to, the ranges reported here may be utilised by clinicians and researchers to identify individuals who are at increased risk of adverse cardiovascular health outcomes, as well as outcomes associated with motivational and behavioural dysregulation.

Genetic Variation, Stress, and Physiological Stress Response in Adults With Food Allergy or Celiac Disease.

BACKGROUND: Persistently high chronic stress can lead to maladaptive psychological, behavioral, and physiological stress responses and poor mental and physical health, highlighting the importance of identifying individuals at increased risk. Chronic health condition diagnosis and genetics are 2 characteristics that can influence stress, stress response, and health outcomes. PURPOSE: Food allergy (FA) and celiac disease (CD) require constant vigilance in daily life and can lead to increased stress. The purpose of this exploratory analysis was to examine the association of variants in selected stress-related genes with stress exposures, stress, clinical measures of physiological stress response, and mental health symptoms in adults with and without FA or CD. METHODS: We compared stress exposures, symptoms of PTSD, depression, anxiety, and stress, BMI, and waist-hip ratio between cases and controls. We analyzed the association of SNPs in genes with known or hypothesized associations with stress-related measures in 124 cases and 124 matched controls: CRHBP (rs7718461, rs10474485), CRHR1 (rs242940) and OXTR (rs2268490). For this exploratory study, p-values ≤ 0.10 were considered suggestive. RESULTS: For cases and controls, rs7718461 was associated with stress symptoms, rs2268490 with symptoms of stress and PTSD, and rs242940 with symptoms of stress, PTSD, anxiety, and depression. Further analyses found that stress-related outcomes in individuals with FA or CD may be influenced by SNP genotype. CONCLUSIONS: Given these suggestive findings, larger prospective studies should examine similar relationships in individuals with other chronic health conditions, incorporating factors such as environmental exposures, individual experiences, and epigenetic modifications.

Identification of a Stress-Sensitive Anorexigenic Neurocircuit From Medial Prefrontal Cortex to Lateral Hypothalamus.

BACKGROUND: A greater understanding of how the brain controls appetite is fundamental to developing new approaches for treating diseases characterized by dysfunctional feeding behavior, such as obesity and anorexia nervosa. METHODS: By modeling neural network dynamics related to homeostatic state and body mass index, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans (n = 53). We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice. RESULTS: In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under nonstressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose seeking in mice. CONCLUSIONS: These studies identify a glutamatergic mPFC-LH circuit as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake.

Social trauma engages lateral septum circuitry to occlude social reward.

In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.

Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits.

Chronic stress exposure induces maladaptive behavioral responses and increases susceptibility to neuropsychiatric conditions. However, specific neuronal populations and circuits that are highly sensitive to stress and trigger maladaptive behavioral responses remain to be identified. Here we investigate the patterns of spontaneous activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus following exposure to chronic unpredictable stress (CUS) for 10 days, a stress paradigm used to induce behavioral deficits such as anhedonia and behavioral despair [1, 2]. CUS exposure increased spontaneous firing of POMC neurons in both male and female mice, attributable to reduced GABA-mediated synaptic inhibition and increased intrinsic neuronal excitability. While acute activation of POMC neurons failed to induce behavioral changes in non-stressed mice of both sexes, subacute (3 days) and chronic (10 days) repeated activation of POMC neurons was sufficient to induce anhedonia and behavioral despair in males but not females under non-stress conditions. Acute activation of POMC neurons promoted susceptibility to subthreshold unpredictable stress in both male and female mice. Conversely, acute inhibition of POMC neurons was sufficient to reverse CUS-induced anhedonia and behavioral despair in both sexes. Collectively, these results indicate that chronic stress induces both synaptic and intrinsic plasticity of POMC neurons, leading to neuronal hyperactivity. Our findings suggest that POMC neuron dysfunction drives chronic stress-related behavioral deficits.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial.

Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.

Stress, mental disorder and ketamine as a novel, rapid acting treatment.

The experience of stress is often utilised in models of emerging mental illness and neurobiological systems are implicated as the intermediary link between the experience of psychological stress and the development of a mental disorder. Chronic stress and prolonged glucocorticoid exposure have potent effects on neuronal architecture particularly in regions that modulate the hypothalamic-pituitary-adrenal (HPA) axis and are commonly associated with psychiatric disorders. This review provides an overview of stress modulating neurobiological and neurochemical systems which underpin stress-related structural and functional brain changes. These changes are thought to contribute not only to the development of disorders, but also to the treatment resistance and chronicity seen in some of our most challenging mental disorders. Reports to date suggest that stress-related psychopathology is the aetiological mechanism of these disorders and thus we review the rapid acting antidepressant ketamine as an effective emerging treatment. Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, is shown to induce a robust treatment effect in mental disorders via enhanced synaptic strength and connectivity in key brain regions. Whilst ketamine's glutamatergic effect has been previously examined, we further consider ketamine's capacity to modulate the HPA axis and associated pathways.