Leveraging interindividual variability in threat conditioning of inbred mice to model trait anxiety.

Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the interindividual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalised trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype behavioral marker in both sexes, females were consistently associated with an increased freezing response. RNA-sequencing of CeA, BLA, ACC, and BNST revealed massive differences in phasic and sustained responders' transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.

The causal effect of mental health on labor market outcomes: The case of stress-related mental disorders following a human-made disaster.

As disasters increase due to climate change, population density, epidemics, and technology, information is needed about postdisaster consequences for people's mental health and how stress-related mental disorders affect multiple spheres of life, including labor-market attachment. We tested the causal hypothesis that individuals who developed stress-related mental disorders as a consequence of their disaster exposure experienced subsequent weak labor-market attachment and poor work-related outcomes. We leveraged a natural experiment in an instrumental variables model, studying a 2004 fireworks factory explosion disaster that precipitated the onset of stress-related disorders (posttraumatic stress disorder, anxiety, and depression) among individuals in the local community (N = 86,726). We measured labor-market outcomes using longitudinal population-level administrative data: sick leave, unemployment benefits, early retirement pension, and income from wages from 2007 to 2010. We found that individuals who developed a stress-related disorder after the disaster were likely to go on sickness benefit, both in the short- and long-term, were likely to use unemployment benefits and to lose wage income in the long term. Stress-related disorders did not increase the likelihood of early retirement. The natural experiment design minimized the possibility that omitted confounders biased these effects of mental health on work outcomes. Addressing the mental health and employment needs of survivors after a traumatic experience may improve their labor-market outcomes and their nations' economic outputs.

The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Neural circuits underlying a psychotherapeutic regimen for fear disorders.

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.

Eye movement intervention facilitates concurrent perception and memory processing.

A widely used psychotherapeutic treatment for post-traumatic stress disorder (PTSD) involves performing bilateral eye movement (EM) during trauma memory retrieval. However, how this treatment-described as eye movement desensitization and reprocessing (EMDR)-alleviates trauma-related symptoms is unclear. While conventional theories suggest that bilateral EM interferes with concurrently retrieved trauma memories by taxing the limited working memory resources, here, we propose that bilateral EM actually facilitates information processing. In two EEG experiments, we replicated the bilateral EM procedure of EMDR, having participants engaging in continuous bilateral EM or receiving bilateral sensory stimulation (BS) as a control while retrieving short- or long-term memory. During EM or BS, we presented bystander images or memory cues to probe neural representations of perceptual and memory information. Multivariate pattern analysis of the EEG signals revealed that bilateral EM enhanced neural representations of simultaneously processed perceptual and memory information. This enhancement was accompanied by heightened visual responses and increased neural excitability in the occipital region. Furthermore, bilateral EM increased information transmission from the occipital to the frontoparietal region, indicating facilitated information transition from low-level perceptual representation to high-level memory representation. These findings argue for theories that emphasize information facilitation rather than disruption in the EMDR treatment.

The multiscale topological organization of the functional brain network in adolescent PTSD.

The experience of an extremely aversive event can produce enduring deleterious behavioral, and neural consequences, among which posttraumatic stress disorder (PTSD) is a representative example. Although adolescence is a period of great exposure to potentially traumatic events, the effects of trauma during adolescence remain understudied in clinical neuroscience. In this exploratory work, we aim to study the whole-cortex functional organization of 14 adolescents with PTSD using a data-driven method tailored to our population of interest. To do so, we built on the network neuroscience framework and specifically on multilayer (multisubject) community analysis to study the functional connectivity of the brain. We show, across different topological scales (the number of communities composing the cortex), a hyper-colocalization between regions belonging to occipital and pericentral regions and hypo-colocalization in middle temporal, posterior-anterior medial, and frontal cortices in the adolescent PTSD group compared to a nontrauma exposed group of adolescents. These preliminary results raise the question of an altered large-scale cortical organization in adolescent PTSD, opening an interesting line of research for future investigations.

Neural and psychological correlates of post-traumatic stress symptoms in a community adult sample.

A multitude of factors are associated with the symptoms of post-traumatic stress disorder. However, establishing which predictors are most strongly associated with post-traumatic stress disorder symptoms is complicated because few studies are able to consider multiple factors simultaneously across the biopsychosocial domains that are implicated by existing theoretical models. Further, post-traumatic stress disorder is heterogeneous, and studies using case-control designs may obscure which factors relate uniquely to symptom dimensions. Here we used Bayesian variable selection to identify the most important predictors for overall post-traumatic stress disorder symptoms and individual symptom dimensions in a community sample of 569 adults (18 to 85 yr of age). Candidate predictors were selected from previously established risk factors relevant for post-traumatic stress disorder and included psychological measures, behavioral measures, and resting state functional connectivity among brain regions. In a follow-up analysis, we compared results controlling for current depression symptoms in order to examine specificity. Poor sleep quality and dimensions of temperament and impulsivity were consistently associated with greater post-traumatic stress disorder symptom severity. In addition to self-report measures, brain functional connectivity among regions commonly ascribed to the default mode network, central executive network, and salience network explained the unique variability of post-traumatic stress disorder symptoms. This study demonstrates the unique contributions of psychological measures and neural substrates to post-traumatic stress disorder symptoms.

Multilayer analysis of dynamic network reconfiguration in pediatric posttraumatic stress disorder.

Neuroimage studies have reported functional connectome abnormalities in posttraumatic stress disorder (PTSD), especially in adults. However, these studies often treated the brain as a static network, and time-variance of connectome topology in pediatric posttraumatic stress disorder remain unclear. To explore case-control differences in dynamic connectome topology, resting-state functional magnetic resonance imaging data were acquired from 24 treatment-naïve non-comorbid pediatric posttraumatic stress disorder patients and 24 demographically matched trauma-exposed non-posttraumatic stress disorder controls. A graph-theoretic analysis was applied to construct time-varying modular structure of whole-brain networks by maximizing the multilayer modularity. Network switching rate at the global, subnetwork, and nodal levels were calculated and compared between posttraumatic stress disorder and trauma-exposed non-posttraumatic stress disorder groups, and their associations with posttraumatic stress disorder symptom severity and sex interactions were explored. At the global level, individuals with posttraumatic stress disorder exhibited significantly lower network switching rates compared to trauma-exposed non-posttraumatic stress disorder controls. This difference was mainly involved in default-mode and dorsal attention subnetworks, as well as in inferior temporal and parietal brain nodes. Posttraumatic stress disorder symptom severity was negatively correlated with switching rate in the global network and default mode network. No significant differences were observed in the interaction between diagnosis and sex/age. Pediatric posttraumatic stress disorder is associated with dynamic reconfiguration of brain networks, which may provide insights into the biological basis of this disorder.

Can you remember silence? Epigenetic memory and reversibility as a site of intervention.

Just over 20 years ago, molecular biologists Leonie Ringrose and Renato Paro published an article with a provocative title, "Remembering Silence", in BioEssays. The article focused on how epigenetic elements could return to their silent state, operationally defined as their epigenetic status before their modulation by experimental or environmental factors. Though Ringrose and Paro's article was on fruit flies and factors affecting embryological growth, the article asked a question of considerable importance to rapidly expanding research in neuroepigenetics on the correlation between trauma and neuropsychiatric risk: If you experience a traumatic event and, as a result, acquire an epigenetic trait that is considered pathological, can you free yourself of that trait? Ultimately, we are interested in how a return to silence is envisioned in neuroepigenetics research, how interventions purported to bring about that silence might function, and what this might mean for people who live in the aftermath of trauma.

NETfacts: An integrated intervention at the individual and collective level to treat communities affected by organized violence.

War and crises affect mental health, social attitudes, and cultural norms, which can exacerbate the state of long-term insecurity. With decades of armed conflict, the Democratic Republic of Congo is one example, and violence has become normalized in civilian settings. In this study, we tested the effectiveness of the NETfacts health system, an integrated model of evidence-based individual trauma treatment (Narrative Exposure Therapy [NET]) and a trauma-informed community-based intervention (NETfacts). Alongside changes in mental health outcomes (posttraumatic stress disorder, depression, social disapproval, and shame) we also investigated change in attitudes, including rape myth acceptance, stigmatization of survivors of sexual violence, and skepticism about the reintegration of former combatants. To test whether the additional community intervention is superior to individual NET alone, we implemented a randomized controlled design with six villages and interviewed a sample of 1,066 community members. Our results demonstrate that the NETfacts health system in comparison with NET alone more effectively reduced rape myth acceptance and with it ongoing victimization and perpetration. Community members of the NETfacts group also presented with less stigmatizing attitudes against survivors of sexual violence. Skepticism about the reintegration of former combatants declined in both groups. NETfacts appears to have increased motivation to engage in individual treatment. Synergizing the healing effects of individual and collective trauma exposure, the NETfacts health system appears to be an effective and scalable approach to correct degrading or ignominious norms and restore functioning and mental health in postconflict communities.

The Management of Posttraumatic Stress Disorder and Acute Stress Disorder: Synopsis of the 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

DESCRIPTION: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article summarizes the 2023 clinical practice guideline (CPG) and its development process, focusing on assessments and treatments for which evidence was sufficient to support a recommendation for or against. METHODS: Subject experts from both departments developed 12 key questions and reviewed the published literature after a systematic search using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) method. The evidence was then evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Recommendations were made after consensus was reached; they were based on quality and strength of evidence and informed by other factors, including feasibility and patient perspectives. Once the draft was peer reviewed by an external group of experts and their inputs were incorporated, the final document was completed. RECOMMENDATIONS: The revised CPG includes 34 recommendations in the following 5 topic areas: assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of posttraumatic stress disorder (PTSD) with co-occurring conditions. Six recommendations on PTSD treatment were rated as strong. The CPG recommends use of specific manualized psychotherapies over pharmacotherapy; prolonged exposure, cognitive processing therapy, or eye movement desensitization and reprocessing psychotherapy; paroxetine, sertraline, or venlafaxine; and secure video teleconferencing to deliver recommended psychotherapy when that therapy has been validated for use with video teleconferencing or when other options are unavailable. The CPG also recommends against use of benzodiazepines, cannabis, or cannabis-derived products. Providers are encouraged to use this guideline to support evidence-based, patient-centered care and shared decision making to optimize individuals' health outcomes and quality of life.

Trends in U.S. Medical Cannabis Registrations, Authorizing Clinicians, and Reasons for Use From 2020 to 2022.

BACKGROUND: As medical cannabis availability increases, up-to-date trends in medical cannabis licensure can inform clinical policy and care. OBJECTIVE: To describe current trends in medical cannabis licensure in the United States. DESIGN: Ecological study with repeated measures. SETTING: Publicly available state registry data from 2020 to 2022. PARTICIPANTS: People with medical cannabis licenses and clinicians authorizing cannabis licenses in the United States. MEASUREMENTS: Total patient volume and prevalence per 10 000 persons in the total population, symptoms or conditions qualifying patients for licensure (that is, patient-reported qualifying conditions), and number of authorizing clinicians. RESULTS: In 2022, of 39 jurisdictions allowing medical cannabis use, 34 reported patient numbers, 19 reported patient-reported qualifying conditions, and 29 reported authorizing clinician numbers. Enrolled patients increased 33.3% from 2020 (3 099 096) to 2022 (4 132 098), with a corresponding 23.0% increase in the population prevalence of patients (175.0 per 10 000 in 2020 to 215.2 per 10 000 in 2022). However, 13 of 15 jurisdictions with nonmedical adult-use laws had decreased enrollment from 2020 to 2022. The proportion of patient-reported qualifying conditions with substantial or conclusive evidence of therapeutic value decreased from 70.4% (2020) to 53.8% (2022). Chronic pain was the most common patient-reported qualifying condition in 2022 (48.4%), followed by anxiety (14.2%) and posttraumatic stress disorder (13.0%). In 2022, the United States had 29 500 authorizing clinicians (7.7 per 1000 patients), 53.5% of whom were physicians. The most common specialties reported were internal or family medicine (63.4%), physical medicine and rehabilitation (9.1%), and anesthesia or pain (7.9%). LIMITATION: Missing data (for example, from California), descriptive analysis, lack of information on individual use patterns, and changing evidence base. CONCLUSION: Enrollment in medical cannabis programs increased overall but generally decreased in jurisdictions with nonmedical adult-use laws. Use for conditions or symptoms without a strong evidence basis continues to increase. Given these trends, more research is needed to better understand the risks and benefits of medical cannabis. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse of the National Institutes of Health.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Emotional Memory Processing during REM Sleep with Implications for Post-Traumatic Stress Disorder.

REM sleep is important for the processing of emotional memories, including fear memories. Rhythmic interactions, especially in the theta band, between the medial prefrontal cortex (mPFC) and limbic structures are thought to play an important role, but the ways in which memory processing occurs at a mechanistic and circuits level are largely unknown. To investigate how rhythmic interactions lead to fear extinction during REM sleep, we used a biophysically based model that included the infralimbic cortex (IL), a part of the mPFC with a critical role in suppressing fear memories. Theta frequency (4-12 Hz) inputs to a given cell assembly in IL, representing an emotional memory, resulted in the strengthening of connections from the IL to the amygdala and the weakening of connections from the amygdala to the IL, resulting in the suppression of the activity of fear expression cells for the associated memory. Lower frequency (4 Hz) theta inputs effected these changes over a wider range of input strengths. In contrast, inputs at other frequencies were ineffective at causing these synaptic changes and did not suppress fear memories. Under post-traumatic stress disorder (PTSD) REM sleep conditions, rhythmic activity dissipated, and 4 Hz theta inputs to IL were ineffective, but higher-frequency (10 Hz) theta inputs to IL induced changes similar to those seen with 4 Hz inputs under normal REM sleep conditions, resulting in the suppression of fear expression cells. These results suggest why PTSD patients may repeatedly experience the same emotionally charged dreams and suggest potential neuromodulatory therapies for the amelioration of PTSD symptoms.SIGNIFICANCE STATEMENT Rhythmic interactions in the theta band between the mPFC and limbic structures are thought to play an important role in processing emotional memories, including fear memories, during REM sleep. The infralimbic cortex (IL) in the mPFC is thought to play a critical role in suppressing fear memories. We show that theta inputs to the IL, unlike other frequency inputs, are effective in producing synaptic changes that suppress the activity of fear expression cells associated with a given memory. Under PTSD REM sleep conditions, lower-frequency (4 Hz) theta inputs to the IL do not suppress the activity of fear expression cells associated with the given memory but, surprisingly, 10 Hz inputs do. These results suggest potential neuromodulatory therapies for PTSD.

Association of Posttraumatic Stress Disorder and Race on Readmissions After Stroke.

BACKGROUND: There is limited research on outcomes of patients with posttraumatic stress disorder (PTSD) who also develop stroke, particularly regarding racial disparities. Our goal was to determine whether PTSD is associated with the risk of hospital readmission after stroke and whether racial disparities existed. METHODS: The analytical sample consisted of all veterans receiving care in the Veterans Health Administration who were identified as having a new stroke requiring inpatient admission based on the International Classification of Diseases codes. PTSD and comorbidities were identified using the International Classification of Diseases codes and given the date of first occurrence. The retrospective cohort data were obtained from the Veterans Affairs Corporate Data Warehouse. The main outcome was any readmission to Veterans Health Administration with a stroke diagnosis. The hypothesis that PTSD is associated with readmission after stroke was tested using Cox regression adjusted for patient characteristics including age, sex, race, PTSD, smoking status, alcohol use, and comorbidities treated as time-varying covariates. RESULTS: Our final cohort consisted of 93 651 patients with inpatient stroke diagnosis and no prior Veterans Health Administration codes for stroke starting from 1999 with follow-up through August 6, 2022. Of these patients, 12 916 (13.8%) had comorbid PTSD. Of the final cohort, 16 896 patients (18.0%) with stroke were readmitted. Our fully adjusted model for readmission found an interaction between African American veterans and PTSD with a hazard ratio of 1.09 ([95% CI, 1.00-1.20] P=0.047). In stratified models, PTSD has a significant hazard ratio of 1.10 ([95% CI, 1.02-1.18] P=0.01) for African American but not White veterans (1.05 [95% CI, 0.99-1.11]; P=0.10). CONCLUSIONS: Among African American veterans who experienced stroke, preexisting PTSD was associated with increased risk of readmission, which was not significant among White veterans. This study highlights the need to focus on high-risk groups to reduce readmissions after stroke.

Spaced conditioned stimulus presentation facilitates the extinction of strong fear memory in mice.

Inducing fear memory extinction by re-presenting a conditioned stimulus (CS) is the foundation of exposure therapy for post-traumatic stress disorder (PTSD). Investigating differences in the ability of different CS presentation patterns to induce extinction learning is crucial for improving this type of therapy. Using a trace fear conditioning paradigm in mice, we demonstrate that spaced presentation of the CS facilitated the extinction of a strong fear memory to a greater extent than continuous CS presentation. These results lay the groundwork for developing more effective exposure therapy techniques for PTSD.

Daily routine disruptions and psychiatric symptoms amid COVID-19: a systematic review and meta-analysis of data from 0.9 million individuals in 32 countries.

BACKGROUND: There is currently a deficit of knowledge about how to define, quantify, and measure different aspects of daily routine disruptions amid large-scale disasters like COVID-19, and which psychiatric symptoms were more related to the disruptions. This study aims to conduct a systematic review and meta-analysis on the probable positive associations between daily routine disruptions and mental disorders amid the COVID-19 pandemic and factors that moderated the associations. METHODS: PsycINFO, Web of Science, PubMed, and MEDLINE were systematically searched up to April 2023 (PROSPERO: CRD42023356846). Independent variables included regularity, change in frequency, and change in capability of different daily routines (i.e., physical activity, diet, sleep, social activities, leisure activities, work and studies, home activities, smoking, alcohol, combined multiple routines, unspecified generic routines). Dependent variables included symptoms and/or diagnoses of mental disorders (i.e., depression, anxiety, post-traumatic stress disorder, and general psychological distress). RESULTS: Fifty-three eligible studies (51 independent samples, 910,503 respondents) were conducted in five continents. Daily routine disruptions were positively associated with depressive symptoms (r = 0.13, 95% CI = [0.06; 0.20], p < 0.001), anxiety symptoms (r = 0.12, 95% CI = [0.06; 0.17], p < 0.001), and general psychological distress (r = 0.09, 95% CI = [0.02; 0.16], p = 0.02). The routine-symptom associations were significant for physical activity, eating, sleep, and smoking (i.e., type), routines that were defined and assessed on regularity and change in capability (i.e., definition and assessment), and routines that were not internet-based. While the positive associations remained consistent across different sociodemographics, they were stronger in geo-temporal contexts with greater pandemic severity, lower governmental economic support, and when the routine-symptom link was examined prospectively. CONCLUSIONS: This is one of the first meta-analytic evidence to show the positive association between daily routine disruptions and symptoms of mental disorders among large populations as COVID-19 dynamically unfolded across different geo-temporal contexts. Our findings highlight the priority of behavioral adjustment for enhancing population mental health in future large-scale disasters like COVID-19.

Effect of a Standardized Family Participation Program in the ICU: A Multicenter Stepped-Wedge Cluster Randomized Controlled Trial.

OBJECTIVES: To determine the effect of a standardized program for family participation in essential care activities in the ICU on symptoms of anxiety, depression, posttraumatic stress and satisfaction among relatives, and perceptions and experiences of ICU healthcare providers (HCPs). DESIGN: Multicenter stepped-wedge cluster randomized controlled trial. SETTING: Seven adult ICUs, one university, and six general teaching hospitals. PARTICIPANTS: Three hundred six relatives and 235 ICU HCPs. INTERVENTIONS: A standardized program to facilitate family participation inpatient communication, amusement/distraction, comfort, personal care, breathing, mobilization, and nutrition. MEASUREMENTS AND MAIN RESULTS: Data were collected through surveys among relatives and ICU HCPs. There were no significant differences in symptoms of anxiety in relatives in the intervention period compared with the control period (median Hospital Anxiety and Depression Scale [HADS] 5 [interquartile range (IQR) 2-10] vs 6 [IQR 3-9]; median ratio [MR] 0.72; 95% CI, 0.46-1.13; p = 0.15), depression (median HADS 4 [IQR 2-6] vs 3 [IQR 1-6]; MR 0.85; 95% CI, 0.55-1.32; p = 0.47) or posttraumatic stress (median Impact of Event Scale-Revised score 0.45 [IQR 0.27-0.82] vs 0.41 [IQR 0.14-1]; MR 0.94; 95% CI, 0.78-1.14; p = 0.54). Reported satisfaction was slightly lower in the intervention period (mean 8.90 [ sd 1.10] vs mean 9.06 [ sd 1.10], difference -0.60; 95% CI, -1.07 to -0.12; p = 0.01). ICU HCPs perceived that more relatives knew how to participate: 47% in the intervention period versus 22% in the control period (odds ratio [OR] 3.15; 95% CI, 1.64-6.05; p < 0.01). They also reported relatives having sufficient knowledge (41% vs 16%; OR 3.56; 95% CI, 1.75-7.25; p < 0.01) and skills (44% vs 25%; OR 2.38; 95% CI, 1.22-4.63; p = 0.01) to apply family participation. CONCLUSIONS: Application of a standardized program to facilitate family participation did not change mental health symptoms in relatives of ICU patients 3 months after discharge. ICU HCPs reported increased clarity, knowledge, and skills among relatives and ICU HCPs.