The neural circuitry of social homeostasis: Consequences of acute versus chronic social isolation.

Social homeostasis is the ability of individuals to detect the quantity and quality of social contact, compare it to an established set-point in a command center, and adjust the effort expended to seek the optimal social contact expressed via an effector system. Social contact becomes a positive or negative valence stimulus when it is deficient or in excess, respectively. Chronic deficits lead to set-point adaptations such that reintroduction to the previous optimum is experienced as a surplus. Here, we build upon previous models for social homeostasis to include adaptations to lasting changes in environmental conditions, such as with chronic isolation.

Adapting the proteostasis capacity to sustain brain healthspan.

Sustaining neuronal proteostasis during the course of our life is a central aspect required for brain function. The dynamic nature of synaptic composition and abundance is a requisite to drive cognitive and motor processes involving a tight control of many aspects of protein biosynthesis and degradation. Through the concerted action of specialized stress sensors, the proteostasis network monitors and limits the accumulation of damaged, misfolded, or aggregated proteins. These stress pathways signal to the cytosol and nucleus to reprogram gene expression, enabling adaptive programs to recover cell function. During aging, the activity of the proteostasis network declines, which may increase the risk of accumulating abnormal protein aggregates, a hallmark of most neurodegenerative diseases. Here, I discuss emerging concepts illustrating the functional significance of adaptive signaling pathways to normal brain physiology and their contribution to age-related disorders. Pharmacological and gene therapy strategies to intervene and boost proteostasis are expected to extend brain healthspan and ameliorate disease states.

Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders.

Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics. A decade ago, there were few reproducible findings, and now there are hundreds. In this review, we focus on the findings that have illuminated the genetic architecture of psychiatric disorders and the challenges of using these findings to inform our understanding of pathophysiology. The evidence is now overwhelming that psychiatric disorders are "polygenic"-that many genetic loci contribute to risk. With the exception of a subset of those with ASD, few individuals with a psychiatric disorder have a single, deterministic genetic cause; rather, developing a psychiatric disorder is influenced by hundreds of different genetic variants, consistent with a polygenic model. As progressively larger studies have uncovered more about their genetic architecture, the need to elucidate additional architectures has become clear. Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture-the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes. Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative? Given that the genetic architectures of different psychiatric disorders often strongly overlap, we are challenged to re-evaluate and refine the diagnostic architectures of psychiatric disorders using fundamental genetic and neurobiological data.

Making cities mental health friendly for adolescents and young adults.

Urban life shapes the mental health of city dwellers, and although cities provide access to health, education and economic gain, urban environments are often detrimental to mental health1,2. Increasing urbanization over the next three decades will be accompanied by a growing population of children and adolescents living in cities3. Shaping the aspects of urban life that influence youth mental health could have an enormous impact on adolescent well-being and adult trajectories4. We invited a multidisciplinary, global group of researchers, practitioners, advocates and young people to complete sequential surveys to identify and prioritize the characteristics of a mental health-friendly city for young people. Here we show a set of ranked characteristic statements, grouped by personal, interpersonal, community, organizational, policy and environmental domains of intervention. Life skills for personal development, valuing and accepting young people's ideas and choices, providing safe public space for social connection, employment and job security, centring youth input in urban planning and design, and addressing adverse social determinants were priorities by domain. We report the adversities that COVID-19 generated and link relevant actions to these data. Our findings highlight the need for intersectoral, multilevel intervention and for inclusive, equitable, participatory design of cities that support youth mental health.

Smartphones and the Neuroscience of Mental Health.

Improvements in understanding the neurobiological basis of mental illness have unfortunately not translated into major advances in treatment. At this point, it is clear that psychiatric disorders are exceedingly complex and that, in order to account for and leverage this complexity, we need to collect longitudinal data sets from much larger and more diverse samples than is practical using traditional methods. We discuss how smartphone-based research methods have the potential to dramatically advance our understanding of the neuroscience of mental health. This, we expect, will take the form of complementing lab-based hard neuroscience research with dense sampling of cognitive tests, clinical questionnaires, passive data from smartphone sensors, and experience-sampling data as people go about their daily lives. Theory- and data-driven approaches can help make sense of these rich data sets, and the combination of computational tools and the big data that smartphones make possible has great potential value for researchers wishing to understand how aspects of brain function give rise to, or emerge from, states of mental health and illness.

A synergistic mindsets intervention protects adolescents from stress.

Social-evaluative stressors-experiences in which people feel they could be judged negatively-pose a major threat to adolescent mental health1-3 and can cause young people to disengage from stressful pursuits, resulting in missed opportunities to acquire valuable skills. Here we show that replicable benefits for the stress responses of adolescents can be achieved with a short (around 30-min), scalable 'synergistic mindsets' intervention. This intervention, which is a self-administered online training module, synergistically targets both growth mindsets4 (the idea that intelligence can be developed) and stress-can-be-enhancing mindsets5 (the idea that one's physiological stress response can fuel optimal performance). In six double-blind, randomized, controlled experiments that were conducted with secondary and post-secondary students in the United States, the synergistic mindsets intervention improved stress-related cognitions (study 1, n = 2,717; study 2, n = 755), cardiovascular reactivity (study 3, n = 160; study 4, n = 200), daily cortisol levels (study 5, n = 118 students, n = 1,213 observations), psychological well-being (studies 4 and 5), academic success (study 5) and anxiety symptoms during the 2020 COVID-19 lockdowns (study 6, n = 341). Heterogeneity analyses (studies 3, 5 and 6) and a four-cell experiment (study 4) showed that the benefits of the intervention depended on addressing both mindsets-growth and stress-synergistically. Confidence in these conclusions comes from a conservative, Bayesian machine-learning statistical method for detecting heterogeneous effects6. Thus, our research has identified a treatment for adolescent stress that could, in principle, be scaled nationally at low cost.

Mental health concerns during the COVID-19 pandemic as revealed by helpline calls.

Mental health is an important component of public health, especially in times of crisis. However, monitoring public mental health is difficult because data are often patchy and low-frequency1-3. Here we complement established approaches by using data from helplines, which offer a real-time measure of 'revealed' distress and mental health concerns across a range of topics4-9. We collected data on 8 million calls from 19 countries, focusing on the COVID-19 crisis. Call volumes peaked six weeks after the initial outbreak, at 35% above pre-pandemic levels. The increase was driven mainly by fear (including fear of infection), loneliness and, later in the pandemic, concerns about physical health. Relationship issues, economic problems, violence and suicidal ideation, however, were less prevalent than before the pandemic. This pattern was apparent both during the first wave and during subsequent COVID-19 waves. Issues linked directly to the pandemic therefore seem to have replaced rather than exacerbated underlying anxieties. Conditional on infection rates, suicide-related calls increased when containment policies became more stringent and decreased when income support was extended. This implies that financial relief can allay the distress triggered by lockdown measures and illustrates the insights that can be gleaned from the statistical analysis of helpline data.

The sleep-circadian interface: A window into mental disorders.

Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep-circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.

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.

Sex and mental health are related to subcortical brain microstructure.

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.

Translational bioinformatics and data science for biomarker discovery in mental health: an analytical review.

Translational bioinformatics and data science play a crucial role in biomarker discovery as it enables translational research and helps to bridge the gap between the bench research and the bedside clinical applications. Thanks to newer and faster molecular profiling technologies and reducing costs, there are many opportunities for researchers to explore the molecular and physiological mechanisms of diseases. Biomarker discovery enables researchers to better characterize patients, enables early detection and intervention/prevention and predicts treatment responses. Due to increasing prevalence and rising treatment costs, mental health (MH) disorders have become an important venue for biomarker discovery with the goal of improved patient diagnostics, treatment and care. Exploration of underlying biological mechanisms is the key to the understanding of pathogenesis and pathophysiology of MH disorders. In an effort to better understand the underlying mechanisms of MH disorders, we reviewed the major accomplishments in the MH space from a bioinformatics and data science perspective, summarized existing knowledge derived from molecular and cellular data and described challenges and areas of opportunities in this space.

The self in context: brain systems linking mental and physical health.

Increasing evidence suggests that mental health and physical health are linked by neural systems that jointly regulate somatic physiology and high-level cognition. Key systems include the ventromedial prefrontal cortex and the related default-mode network. These systems help to construct models of the 'self-in-context', compressing information across time and sensory modalities into conceptions of the underlying causes of experience. Self-in-context models endow events with personal meaning and allow predictive control over behaviour and peripheral physiology, including autonomic, neuroendocrine and immune function. They guide learning from experience and the formation of narratives about the self and one's world. Disorders of mental and physical health, especially those with high co-occurrence and convergent alterations in the functionality of the ventromedial prefrontal cortex and the default-mode network, could benefit from interventions focused on understanding and shaping mindsets and beliefs about the self, illness and treatment.

Greenspaces And Cardiovascular Health.

Accumulating evidence suggests that living in areas of high surrounding greenness or even brief exposures to areas of high greenery is conducive to cardiovascular health, which may be related to the environmental, social, psychological, and physiological benefits of greenspaces. Recent data from multiple cross-sectional, longitudinal, and cohort studies suggest that living in areas of high surrounding greenness is associated with a lower risk of all-cause and cardiovascular mortality. High levels of neighborhood greenery have been linked also to a decrease in the burden of cardiovascular disease risk factors as reflected by lower rates of hypertension, dyslipidemia, and diabetes. Those who live in greener environments report better mental health and more frequent social interactions, which can benefit cardiovascular health as well. In this narrative review, we discuss evidence linking greenspaces to cardiovascular health as well as the potential mechanisms underlying the beneficial effects of greenspaces, including the impact of vegetation on air, noise and light pollution, ambient temperature, physical activity, mental health, and biodiversity. We review literature on the beneficial effects of acute and chronic exposure to nature on cardiovascular disease risk factors, inflammation and immune function, and we highlight the potential cardiovascular effects of biogenic volatile organic compounds that are emitted by trees and shrubs. We identify current knowledge gaps in this area and underscore the need for additional population studies to understand more clearly and precisely the link between greenness and health. Such understanding is urgently needed to fully redeem the promise of greenspaces in preventing adverse environmental exposures, mitigating the effects of climate change, and creating healthier living environments.

Illuminating the dark spaces of healthcare with ambient intelligence.

Advances in machine learning and contactless sensors have given rise to ambient intelligence-physical spaces that are sensitive and responsive to the presence of humans. Here we review how this technology could improve our understanding of the metaphorically dark, unobserved spaces of healthcare. In hospital spaces, early applications could soon enable more efficient clinical workflows and improved patient safety in intensive care units and operating rooms. In daily living spaces, ambient intelligence could prolong the independence of older individuals and improve the management of individuals with a chronic disease by understanding everyday behaviour. Similar to other technologies, transformation into clinical applications at scale must overcome challenges such as rigorous clinical validation, appropriate data privacy and model transparency. Thoughtful use of this technology would enable us to understand the complex interplay between the physical environment and health-critical human behaviours.

The benefits of nature exposure: The need for research that better informs implementation.

Concern about humanity's detachment from nature has spawned a global push to increase the availability of green spaces within cities. One impetus for this movement is a growing collection of studies documenting an association between improved human well-being and exposure to nature. The challenge lies in translating this research into pragmatic recommendations for cities. The usefulness of the existing research portfolio is diminished by the limitations of prevailing research designs. For example, most nature exposure studies (>80%) are observational. The rare randomized manipulative experiments tend to be indoors or virtual and rely on nature exposures on the order of ten to fifteen minutes. "Nature" and "biodiversity" are commonly invoked together as benefiting human well-being despite little evidence that biodiversity has particular importance for human psychological and emotional health. The most glaring gap in nature exposure research is the neglect of differences among cultures and ethnic groups with respect to the nature they prefer. In the few cases where researchers looked for differences among groups, they often found heterogeneous responses. Finally, few studies have compared greening interventions to other possible efforts to improve urban life. Thus, the utopian city of the future might be resplendent with urban parks on every block, but it is not clear whether those parks should offer basketball and pickleball courts, or small woodlands with a cornucopia of birds. We advocate for the next generation of nature exposure research that better informs the envisioning of our future sustainable cities with enhanced and equitable access to nature.

Emotional (in)stability: Neuroticism is associated with increased variability in negative emotion after all.

The personality trait neuroticism is tightly linked to mental health, and neurotic people experience stronger negative emotions in everyday life. But, do their negative emotions also show greater fluctuation? This commonsensical notion was recently questioned by [Kalokerinos et al. Proc Natl Acad Sci USA 112, 15838-15843 (2020)], who suggested that the associations found in previous studies were spurious. Less neurotic people often report very low levels of negative emotion, which is usually measured with bounded rating scales. Therefore, they often pick the lowest possible response option, which severely constrains the amount of emotional variability that can be observed in principle. Applying a multistep statistical procedure that is supposed to correct for this dependency, [Kalokerinos et al. Proc Natl Acad Sci USA 112, 15838-15843 (2020)] no longer found an association between neuroticism and emotional variability. However, like other common approaches for controlling for undesirable effects due to bounded scales, this method is opaque with respect to the assumed mechanism of data generation and might not result in a successful correction. We thus suggest an alternative approach that a) takes into account that emotional states outside of the scale bounds can occur and b) models associations between neuroticism and both the mean and variability of emotion in a single step with the help of Bayesian censored location-scale models. Simulations supported this model over alternative approaches. We analyzed 13 longitudinal datasets (2,518 individuals and 11,170 measurements in total) and found clear evidence that more neurotic people experience greater variability in negative emotion.

Differential spatial-social accessibility to mental health care and suicide.

In recent years, the United States has been experiencing historically high suicide rates. In the face of mental health care provider shortages that leave millions needing to travel longer to find providers with schedule openings, if any are available at all, the inaccessibility of mental health care has become increasingly central in explaining suicidality. To examine the relationship between access to care and suicide, we leverage a dataset mapping all licensed US psychiatrists and psychotherapists (N= 711,214), as of early 2020, and employ real-world transportation data to model patients' mobility barriers. We find a strong association between reduced mental health care provider spatial-social accessibility and heightened suicide risk. Using a machine learning approach to condition on a host of 22 contextual factors known to be implicated in suicide (e.g., race, education, divorce, gun shop prevalence), we find that in locales where individuals seeking care can access fewer mental health care providers, already more likely to be saturated by demand, suicide risk is increased (3.2% for each reduced SD of psychiatrist accessibility; 2.3% for psychotherapists). Additionally, we observe that local spatial-social accessibility inequalities are associated with further heightened risk of suicide, underscoring the need for research to account for the highly localized barriers preventing many Americans from accessing needed mental health services.

Multigenerational adversity impacts on human gut microbiome composition and socioemotional functioning in early childhood.

Adversity exposures in the prenatal and postnatal period are associated with an increased risk for psychopathology, which can be perpetuated across generations. Nonhuman animal research highlights the gut microbiome as a putative biological mechanism underlying such generational risks. In a sample of 450 mother-child dyads living in Singapore, we examined associations between three distinct adversity exposures experienced across two generations-maternal childhood maltreatment, maternal prenatal anxiety, and second-generation children's exposure to stressful life events-and the gut microbiome composition of second-generation children at 2 y of age. We found distinct differences in gut microbiome profiles linked to each adversity exposure, as well as some nonaffected microbiome features (e.g., beta diversity). Remarkably, some of the microbial taxa associated with concurrent and prospective child socioemotional functioning shared overlapping putative functions with those affected by adversity, suggesting that the intergenerational transmission of adversity may have a lasting impact on children's mental health via alterations to gut microbiome functions. Our findings open up a new avenue of research into the underlying mechanisms of intergenerational transmission of mental health risks and the potential of the gut microbiome as a target for intervention.

Generational differences in mental health trends in the twenty-first century.

Given the observed deterioration in mental health among Australians over the past decade, this study investigates to what extent this differs in people born in different decades-i.e., possible birth cohort differences in the mental health of Australians. Using 20 y of data from a large, nationally representative panel survey (N = 27,572), we find strong evidence that cohort effects are driving the increase in population-level mental ill-health. Deteriorating mental health is particularly pronounced among people born in the 1990s and seen to a lesser extent among the 1980s cohort. There is little evidence that mental health is worsening with age for people born prior to the 1980s. The findings from this study highlight that it is the poorer mental health of Millennials that is driving the apparent deterioration in population-level mental health. Understanding the context and changes in society that have differentially affected younger people may inform efforts to ameliorate this trend and prevent it continuing for emerging cohorts.

Fostering Psychological Safety and Supporting Mental Health Among Cardiovascular Health Care Workers: A Science Advisory From the American Heart Association.

The psychological safety of health care workers is an important but often overlooked aspect of the rising rates of burnout and workforce shortages. In addition, mental health conditions are prevalent among health care workers, but the associated stigma is a significant barrier to accessing adequate care. More efforts are therefore needed to foster health care work environments that are safe and supportive of self-care. The purpose of this brief document is to promote a culture of psychological safety in health care organizations. We review ways in which organizations can create a psychologically safe workplace, the benefits of a psychologically safe workplace, and strategies to promote mental health and reduce suicide risk.