Chronic Stress最新文献

Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention.

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.

A cardinal feature of Post-traumatic stress-related disorder (PTSD) is a paradoxical memory alteration including both intrusive emotional hypermnesia and declarative/contextual amnesia. Most preclinical, but also numerous clinical, studies focus almost exclusively on the emotional hypermnesia aiming at suppressing this recurrent and highly debilitating symptom either by reducing fear and anxiety or with the ethically questionable idea of a rather radical erasure of traumatic memory. Of very mixed efficacy, often associated with a resurgence of symptoms after a while, these approaches focus on PTSD-related symptom while neglecting the potential cause of this symptom: traumatic amnesia. Two of our preclinical studies have recently demonstrated that treating contextual amnesia durably prevents, and even treats, PTSD-related hypermnesia. Specifically, promoting the contextual memory of the trauma, either by a cognitivo-behavioral, optogenetic or pharmacological approach enhancing a hippocampus-dependent memory processing of the trauma normalizes the fear memory by inducing a long-lasting suppression of the erratic traumatic hypermnesia.

Background: Accumulating evidence implicates the endocannabinoid system, including variants in the cannabinoid-1 receptor gene (CNR1), in the pathophysiology of posttraumatic stress disorder (PTSD). The synonymous G1359A variant (rs1049353) in the CNR1 gene has been linked to PTSD in individuals exposed to childhood abuse. In this study, the effects of the rs1049353 genotype and childhood abuse on overall PTSD symptoms, as well as PTSD symptom clusters were examined in order to examine how this interaction relates to the phenotypic expression of this disorder.

Method: Data were analyzed from 1,372 Caucasian U.S. veterans who participated in the National Health and Resilience in Veterans Study. Multivariable analyses were conducted to evaluate the association between rs1049353 genotype, childhood abuse, and their interaction in relation to PTSD symptoms.

Results: A significant interaction between rs1049353 genotype and childhood abuse was observed, with A allele carriers with histories of childhood abuse reporting greater severity of PTSD symptoms, most notably anxious arousal, relative to G/G homozygotes. Significant main effects of childhood abuse on overall PTSD symptoms, and re-experiencing, emotional numbing, and dysphoric arousal symptom clusters, as well as of A allele carrier status on anxious arousal symptoms were observed.

Conclusions: Results of this study replicate prior work and suggest that the rs1049353-by-childhood abuse interaction is particularly associated with the manifestation of anxious arousal symptoms of PTSD. Taken together, these findings underscore the importance of considering the phenotypic heterogeneity of PTSD in gene-environment studies of this multifaceted disorder.

Background: Prolonged intermittent theta-burst stimulation (piTBS) and repetitive transcranial magnetic stimulation (rTMS) are effective antidepressant interventions for major depressive disorder (MDD). Cognition-modulated frontal theta (frontalθ) activity had been identified to predict the antidepressant response to 10-Hz left prefrontal rTMS. However, whether this marker also predicts that of piTBS needs further investigation.

Methods: The present double-blind randomized trial recruited 105 patients with MDD who showed no response to at least one adequate antidepressant treatment in the current episode. The recruited patients were randomly assigned to one of three groups: group A received piTBS monotherapy; group B received rTMS monotherapy; and group C received sham stimulation. Before a 2-week acute treatment period, electroencephalopgraphy (EEG) and cognition-modulated frontal theta changes (Δfrontalθ) were measured. Depression scores were evaluated at baseline, 1 week, and 2 weeks after the initiation of treatment.

Results: The Δfrontalθ at baseline was significantly correlated with depression score changes at week 1 (r = -0.383, p = 0.025) and at week 2 for rTMS group (r = -0.419, p = 0.014), but not for the piTBS and sham groups. The area under the receiver operating characteristic curve for Δfrontalθ was 0.800 for the rTMS group (p = 0.003) and was 0.549 for the piTBS group (p = 0.619).

Conclusion: The predictive value of higher baseline Δfrontalθ for antidepressant efficacy for rTMS not only replicates previous results but also implies that the antidepressant responses to rTMS could be predicted reliably at baseline and both piTBS and rTMS could be effective through different neurobiological mechanisms.

Posttraumatic stress disorder is common among military Veterans. While effective treatments exist, many Veterans either do not engage in treatment or fail to achieve full remission. Thus, there is a need to develop adjunctive complementary interventions to enhance treatment engagement and/or response. Equine-assisted activities and therapies (EAAT) are one category of animal assisted interventions that might serve this function. The aim of this article is to review the current state and challenges regarding the use of EAAT for Veterans with PTSD and provide a roadmap to move the field forward. EAAT hold promise as adjunctive complementary interventions for symptom reduction among Veterans with PTSD. Additionally, there is evidence that these approaches may enhance wellbeing in this population. At this time, many gaps in the literature exist and rigorous randomized controlled trials are needed before definitive conclusions can be drawn. The authors of this work provide recommendations as a roadmap to move the field forward. These include standardizing the EAAT nomenclature, focusing mechanism of action studies on the human-horse bond using biological metrics and using a standardized intervention model across studies.

Background: The α₁-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α₁-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined.

Methods: In a post hoc reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple comparisons.

Results: Prazosin showed the largest effect for distressing dreams, anhedonia, difficulty falling or staying asleep, difficulty concentrating, and hypervigilance. These items were also (a) of higher baseline severity in the underlying population, and (b) more related in how they fluctuated at the level of individual subjects. Covariance analysis did not support a clear cutoff between highly prazosin responsive items and those showing a smaller, not statistically significant response.

Conclusions: In this data set, twice daily prazosin substantially reduced not only nightmares and sleep disruption, but the majority of hyperarousal symptoms, with some evidence of efficacy for avoidance symptoms. The relationship of baseline symptom distribution to which symptoms showed significant response to prazosin reinforces the possibility that differences in a clinical trial's participant populations may significantly influence trial outcome. The pattern of symptom endorsement at the level of individual subjects was consistent with prazosin-responsive items sharing a common pathophysiologic mechanism.

Background: This study sought to assess the magnitude of and factors associated with mental health outcomes among frontline health care workers (FHCWs) providing care during the Spring 2020 COVID-19 pandemic surge in New York City.

Methods: A cross-sectional, survey-based study over 4 weeks during the Spring 2020 pandemic surge was used to assess symptoms of COVID-19-related posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD) in 2,579 FHCWs at the Mount Sinai Hospital. Participants were additionally asked about their occupational and personal exposures to COVID-19. Multivariable logistic regression and relative importance analyses were conducted to identify factors associated with these outcomes.

Results: A total of 3,360 of 6,026 individuals completed the survey (55.8% participation), with 2,579 (76.8%) analyzed based on endorsing frontline responsibilities and providing information related to the three outcomes. 1,005 (39.0%) met criteria for symptoms of COVID-19-related PTSD, MDD, or GAD. 599 (23.3%) screened positively for PTSD symptoms, 683 (26.6%) for MDD symptoms, and 642 (25.0%) for GAD symptoms. Multivariable analyses revealed that past-year burnout was associated with the highest risk of developing symptoms for COVID-19-related PTSD (odds ratio [OR] = 2.10), MDD (OR = 2.83), and GAD (OR = 2.68). Higher perceived support from hospital leadership was associated with a lowest risk of all outcomes [PTSD (OR = 0.75), MDD (OR = 0.72), and GAD (OR = 0.76).

Conclusion: In this large sample of FHCWs providing care during the 2020 NYC pandemic surge, 39% experienced symptoms of COVID-19-related PTSD, MDD, and/or GAD and pre-pandemic burnout as well as leadership support were identified as the most highly associated factors. These findings suggest that interventions aimed at reducing burnout and augmenting support from hospital leadership may be appropriate targets to mitigate the risk for developing further psychopathology in this population and others working in the midst of crisis.