Near-death experiences after cardiac arrest: a scoping review.

BACKGROUND: This scoping review aimed to characterise near-death experiences in the setting of cardiac arrest, a phenomenon that is poorly understood and may have clinical consequences. METHOD: PubMed/MEDLINE was searched to 23 July 2023 for prospective studies describing near-death experiences in cardiac arrest. PRISMA-ScR guidelines were adhered to. Qualitative and quantitative data were synthesised. Meta-analysis was precluded due to data heterogeneity. RESULTS: 60 records were identified, of which 11 studies involving interviews were included from various countries. Sample size ranged from 28-344, and proportion of female patients (when reported) was 0-50%, with mean age (when reported) ranging 54-64 years. Comorbidities and reasons for cardiac arrest were heterogeneously reported. Incidence of near-death experiences in the included studies varied from 6.3% to 39.3%; with variation between in-hospital (6.3-39.3%) versus out-of-hospital (18.9-21.2%) cardiac arrest. Individual variables regarding patient characteristics demonstrated statistically significant association with propensity for near-death experiences. Reported content of near-death experiences tended to reflect the language of the questionnaires used, rather than the true language used by individual study participants. Three studies conducted follow-up, and all suggested a positive life attitude change, however one found significantly higher 30-day all-cause mortality in patients with near-death experiences versus those without, in non-controlled analysis. CONCLUSIONS: From prospective studies that have investigated the phenomenon, near-death experiences may occur in as frequent as over one-third of patients with cardiac arrest. Lasting effects may follow these events, however these could also be confounded by clinical characteristics.

Digital footprints as a new translational approach for mental health care: a commentary.

There is a crisis in mental health care, with more people suffering from psychiatric disorders than resources that are available for treatment, even though spending is substantial. Millions who suffer from addiction, psychosis, depression and suicidality are either untreated or inadequately treated and organized psychiatry is unable to reach them. Possibly as reflection of under-treatment of psychiatric disorders, the rates of suicide have risen: from 1999 through 2014, the age-adjusted suicide rate in the US increased 24%, from 10.5 to 13.0 per 100,000. Assessment of psychiatric symptoms in ongoing outpatient settings is costly, inadequate and unable to detect clinical changes over time. One's digital phenotype is assessed through footprints left over as result of our interface with technology, including automated assessments of quantity and quality of social media activity, patterns and speed of device usage, and physiological data that is automatically collected, such as location, quantity and type of movement, heart rate, and sleep patterns. The use of digital footprints has been advocated for large-scale data collection that can facilitate psychiatric research in naturalistic settings. We highlight recent papers in Discover Mental Health addressing digital approaches to mental health and we also advance here the concept that digital footprints are ready for clinical use. However, before that happens there needs to be discussion on the appropriate boundaries between care that is driven by signals from digital footprints and the rights to privacy and self-determination.

Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors.

Major depressive disorder represents a serious public health challenge worldwide; however, the underlying cellular and molecular mechanisms are mostly unknown. Here, we profile the dorsolateral prefrontal cortex of female cynomolgus macaques with social stress-associated depressive-like behaviors using single-nucleus RNA-sequencing and spatial transcriptomics. We find gene expression changes associated with depressive-like behaviors mostly in microglia, and we report a pro-inflammatory microglia subpopulation enriched in the depressive-like condition. Single-nucleus RNA-sequencing data result in the identification of six enriched gene modules associated with depressive-like behaviors, and these modules are further resolved by spatial transcriptomics. Gene modules associated with huddle and sit alone behaviors are expressed in neurons and oligodendrocytes of the superficial cortical layer, while gene modules associated with locomotion and amicable behaviors are enriched in microglia and astrocytes in mid-to-deep cortical layers. The depressive-like behavior associated microglia subpopulation is enriched in deep cortical layers. In summary, our findings show cell-type and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behaviors in female non-human primates.

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis.

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Depression after stoma surgery: a systematic review and meta-analysis.

BACKGROUND: Depression is the leading cause of global disability and can develop following the change in body image and functional capacity associated with stoma surgery. However, reported prevalence across the literature is unknown. Accordingly, we performed a systematic review and meta-analysis aiming to characterise depressive symptoms after stoma surgery and potential predictive factors. METHODS: PubMed/MEDLINE, Embase, CINAHL and Cochrane Library were searched from respective database inception to 6 March 2023 for studies reporting rates of depressive symptoms after stoma surgery. Risk of bias was assessed using the Downs and Black checklist for non-randomised studies of interventions (NRSIs), and Cochrane RoB2 tool for randomised controlled trials (RCTs). Meta-analysis incorporated meta-regressions and a random-effects model. REGISTRATION: PROSPERO, CRD42021262345. RESULTS: From 5,742 records, 68 studies were included. According to Downs and Black checklist, the 65 NRSIs were of low to moderate methodological quality. According to Cochrane RoB2, the three RCTs ranged from low risk of bias to some concerns of bias. Thirty-eight studies reported rates of depressive symptoms after stoma surgery as a proportion of the respective study populations, and from these, the median rate across all timepoints was 42.9% 42.9% (IQR: 24.2-58.9%). Pooled scores for respective validated depression measures (Hospital Anxiety and Depression Score (HADS), Beck Depression Inventory (BDI), and Patient Health Questionnaire-9 (PHQ-9)) across studies reporting those scores were below clinical thresholds for major depressive disorder according to severity criteria of the respective scores. In the three studies that used the HADS to compare non-stoma versus stoma surgical populations, depressive symptoms were 58% less frequent in non-stoma populations. Region (Asia-Pacific; Europe; Middle East/Africa; North America) was significantly associated with postoperative depressive symptoms (p = 0.002), whereas age (p = 0.592) and sex (p = 0.069) were not. CONCLUSIONS: Depressive symptoms occur in almost half of stoma surgery patients, which is higher than the general population, and many inflammatory bowel disease and colorectal cancer populations outlined in the literature. However, validated measures suggest this is mostly at a level of clinical severity below major depressive disorder. Stoma patient outcomes and postoperative psychosocial adjustment may be enhanced by increased psychological evaluation and care in the perioperative period.

Changes in cytokine and cytokine receptor levels during postnatal development of the human dorsolateral prefrontal cortex.

In addition to their traditional roles in immune cell communication, cytokines regulate brain development. Cytokines are known to influence neural cell generation, differentiation, maturation, and survival. However, most work on the role of cytokines in brain development investigates rodents or focuses on prenatal events. Here, we investigate how mRNA and protein levels of key cytokines and cytokine receptors change during postnatal development of the human prefrontal cortex. We find that most cytokine transcripts investigated (IL1B, IL18, IL6, TNF, IL13) are lowest at birth and increase between 1.5 and 5 years old. After 5 years old, transcriptional patterns proceeded in one of two directions: decreased expression in teens and young adults (IL1B, p = 0.002; and IL18, p = 0.004) or increased mean expression with maturation, particularly in teenagers (IL6, p = 0.004; TNF, p = 0.002; IL13, p < 0.001). In contrast, cytokine proteins tended to remain elevated after peaking significantly around 3 years of age (IL1B, p = 0.012; IL18, p = 0.026; IL6, p = 0.039; TNF, p < 0.001), with TNF protein being highest in teenagers. An mRNA-only analysis of cytokine receptor transcripts found that early developmental increases in cytokines were paralleled by increases in their ligand-binding receptor subunits, such as IL1R1 (p = 0.033) and IL6R (p < 0.001) transcripts. In contrast, cytokine receptor-associated signaling subunits, IL1RAP and IL6ST, did not change significantly between age groups. Of the two TNF receptors, the 'pro-death' TNFRSF1A and 'pro-survival' TNFRSF1B, only TNFRSF1B was significantly changed (p = 0.028), increasing first in toddlers and again in young adults. Finally, the cytokine inhibitor, IL13, was elevated first in toddlers (p = 0.006) and again in young adults (p = 0.053). While the mean expression of interleukin-1 receptor antagonist (IL1RN) was highest in toddlers, this increase was not statistically significant. The fluctuations in cytokine expression reported here support a role for increases in specific cytokines at two different stages of human cortical development. The first is during the toddler/preschool period (IL1B, IL18, and IL13), and the other occurs at adolescence/young adult maturation (IL6, TNF and IL13).

The gut microbiome modulates the transformation of microglial subtypes.

Clinical and animal studies have shown that gut microbiome disturbances can affect neural function and behaviors via the microbiota-gut-brain axis, and may be implicated in the pathogenesis of several brain diseases. However, exactly how the gut microbiome modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize the cell type-specific transcriptomic changes in the prefrontal cortex and hippocampus derived from germ-free (GF), specific pathogen free, and colonized-GF mice. We found that the absence of gut microbiota resulted in cell-specific transcriptomic changes. Furthermore, microglia transcriptomes were preferentially influenced, which could be effectively reversed by microbial colonization. Significantly, the gut microbiome modulated the mutual transformation of microglial subpopulations in the two regions. Cross-species analysis showed that the transcriptome changes of these microglial subpopulations were mainly associated with Alzheimer's disease (AD) and major depressive disorder (MDD), which were further supported by animal behavioral tests. Our findings demonstrate that gut microbiota mainly modulate the mutual transformation of microglial subtypes, which may lead to new insights into the pathogenesis of AD and MDD.

Perturbed gut microbiota is gender-segregated in unipolar and bipolar depression.

OBJECTIVE: This study aimed to explore the gender specificity of gut microbiome in patients with unipolar and bipolar depression disorder by analyzing the data of gut microbiome in this two mental disorders and healthy people. METHODS: A case-control study using 16S ribosomal RNA gene sequencing from fecal samples of MDD (male set, n = 43; female set, n = 77) and BD (male set, n = 82; female set, n = 83) compared with HCs (male set, n = 71; female set, n = 100) was conducted. Linear discriminant analysis was used to identify microbial characteristics. Through cooccurrence analysis, the potential correlations of the differential gut microbiota in different genders was explored. Finally, the gender-specific distinguishing microorganisms were identified as biomaker, and the diagnostic performance was verified by five-fold cross validation. RESULTS: A specific cluster was found enriched only in female MDD set, including 4 Bacteroideae OTUs. Similarly, 3 Lachnospiraceae OTUs was found significantly increased in female BD compared with other groups. In addition, the consistent enrichment of Pseudomonadacea in male and female may be the characteristic disease-related gut microbiota of BD. Besides, the diagnostic potential of gender specific biomarker panel in male (male validation AUC: 0.758-0.874, accurancy: 0.693-0.792; female validation AUC: 0.727-0.883, accurancy: 0.678-0.781) and female (male validation AUC: 0.787-0.883, accurancy: 0.719-0.784; female validation AUC: 0.795-0.898, accurancy: 0.689-0.838) has also been identified and confirmed. CONCLUSIONS: The microbiological changes in both MDD and BD are sex specific, and gender specific biomarker panel has better diagnostic performance, which provide a certain reference in sex difference for future clinical differentiation and microbial intervention.

The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes.

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.

Achieving health equity in US suicides: a narrative review and commentary.

Suicide rates in the United States (US) reached a peak in 2018 and declined in 2019 and 2020, with substantial and often growing disparities by age, sex, race/ethnicity, geography, veteran status, sexual minority status, socioeconomic status, and method employed (means disparity). In this narrative review and commentary, we highlight these many disparities in US suicide deaths, then examine the possible causes and potential solutions, with the overarching goal of reducing suicide death disparities to achieve health equity.The data implicate untreated, undertreated, or unidentified depression or other mental illness, and access to firearms, as two modifiable risk factors for suicide across all groups. The data also reveal firearm suicides increasing sharply and linearly with increasing county rurality, while suicide rates by falls (e.g., from tall structures) decrease linearly by increasing rurality, and suicide rates by other means remain fairly constant regardless of relative county urbanization. In addition, for all geographies, gun suicides are significantly higher in males than females, and highest in ages 51-85 + years old for both sexes. Of all US suicides from 1999-2019, 55% of male suicides and 29% of female suicides were by gun in metropolitan (metro) areas, versus 65% (Male) and 42% (Female) suicides by gun in non-metro areas. Guns accounted for 89% of suicides in non-metro males aged 71-85 + years old. Guns (i.e., employment of more lethal means) are also thought to be a major reason why males have, on average, 2-4 times higher suicide rates than women, despite having only 1/4-1/2 as many suicide attempts as women. Overall the literature and data strongly implicate firearm access as a risk factor for suicide across all populations, and even more so for male, rural, and older populations.To achieve the most significant results in suicide prevention across all groups, we need 1) more emphasis on policies and universal programs to reduce suicidal behaviors, and 2) enhanced population-based strategies for ameliorating the two most prominent modifiable targets for suicide prevention: depression and firearms.

The gut microbiome and mental health: advances in research and emerging priorities.

The gut microbiome exerts a considerable influence on human neurophysiology and mental health. Interactions between intestinal microbiology and host regulatory systems have now been implicated both in the development of psychiatric conditions and in the efficacy of many common therapies. With the growing acceptance of the role played by the gut microbiome in mental health outcomes, the focus of research is now beginning to shift from identifying relationships between intestinal microbiology and pathophysiology, and towards using this newfound insight to improve clinical outcomes. Here, we review recent advances in our understanding of gut microbiome-brain interactions, the mechanistic underpinnings of these relationships, and the ongoing challenge of distinguishing association and causation. We set out an overarching model of the evolution of microbiome-CNS interaction and examine how a growing knowledge of these complex systems can be used to determine disease susceptibility and reduce risk in a targeted manner.

Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors.

The neuropeptide oxytocin (OXT) is well recognized for eliciting anxiolytic effects and promoting social reward. However, emerging evidence shows that OXT increases aversive events. These seemingly inconsistent results may be attributable to the broad OXT receptor (OXTr) expression in the central nervous system. This study selectively activated septal neurons expressing OXTr using chemogenetics. We found that chemogenetic activation of septal OXTr neurons induced anxiety- but not depressive-like behavior. In addition, septal OXTr neurons projected dense fibers to the horizontal diagonal band of Broca (HDB), and selective stimulation of those HDB projections also elicited anxiety-like behaviors. We also found that septal OXTr neurons express the vesicular GABA transporter (vGAT) protein and optogenetic stimulation of septal OXTr projections to the HDB inactivated HDB neurons. Our data collectively reveal that septal OXTr neurons increase anxiety by projecting inhibitory GABAergic inputs to the HDB.

Reduced motor cortex GABABR function following chronic alcohol exposure.

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that POU3F2 regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2-binding efficiency at the promoter region of TRIM8. We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.

The gut microbiome modulates gut-brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression.

Emerging research demonstrates that microbiota-gut-brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut-brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axis' role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism.

Climate change and mental health: a commentary.

Climate change represents a major global challenge. Some hallmarks of climate change that have been connected to human activity include an increase of 0.8-1.2 °C in global temperatures as well as the warming of upper ocean water. Importantly, approximately 500 million people worldwide face the consequences of desertification. Simultaneously, the world population has grown from 1.6 billion in 1900 to 7.7 billion today, greatly exacerbating the human toll of devastating environmental disasters, which result in increasingly larger and more common mass migrations that also fuel human trafficking and modern-day slavery. The mental health outcomes are staggering and include, in the context of chronic stress, addiction, anxiety disorders, post-traumatic stress disorder (PTSD), bipolar disorder, major depression, and suicidality. Mental health practitioners, healthcare systems, and governments across the world need to be prepared to address the mental health sequelae of climate change.