Neurobiological Mechanisms Research Articles

Neural basis of collective social behavior during environmental challenge.

Humans and animals have a remarkable capacity to collectively coordinate their behavior to respond to environmental challenges. However, the underlying neurobiology remains poorly understood. Here, we found that groups of mice self-organize into huddles at cold ambient temperature during the thermal challenge assay. We found that mice make active (self-initiated) and passive (partner-initiated) decisions to enter or exit a huddle. Using microendoscopic calcium imaging, we found that active and passive decisions are encoded distinctly within the dorsomedial prefrontal cortex (dmPFC). Silencing dmPFC activity in some mice reduced their active decision-making, but also induced a compensatory increase in active decisions by non-manipulated partners, conserving the group's overall huddle time. These findings reveal how collective behavior is implemented in neurobiological mechanisms to meet homeostatic needs during environmental challenges.

Predictive Neuromarker Patterns for Calcification Metaplasia in Early Tendon Healing.

Unsuccessful tendon healing leads to fibrosis and occasionally calcification. In these metaplastic drifts, the mouse AT preclinical injury model represents a robust experimental setting for studying tendon calcifications. Previously, calcium deposits were found in about 30% of tendons after 28 days post-injury. Although a neuromediated healing process has previously been documented, the expression patterns of NF200, NGF, NPY, GAL, and CGRP in mouse AT and their roles in metaplastic calcific repair remain to be explored. This study included a spatiotemporal analysis of these neuromarkers during the inflammatory phase (7 days p.i.) and the proliferative/early-remodelling phase (28 days p.i.). While the inflammatory phase is characterised by NF200 and CGRP upregulation, in the 28 days p.i., the non-calcified tendons (n = 16/24) showed overall NGF, NPY, GAL, and CGRP upregulation (compared to 7 days post-injury) and a return of NF200 expression to values similar to pre-injury. Presenting a different picture, in calcified tendons (n = 8), NF200 persisted at high levels, while NGF and NPY significantly increased, resulting in a higher NPY/CGRP ratio. Therefore, high levels of NF200 and imbalance between vasoconstrictive (NPY) and vasodilatory (CGRP) neuromarkers may be indicative of calcification. Tendon cells contributed to the synthesis of neuromarkers, suggesting that their neuro-autocrine/paracrine role is exerted by coordinating growth factors, cytokines, and neuropeptides. These findings offer insights into the neurobiological mechanisms of early tendon healing and identify new neuromarker profiles predictive of tendon healing outcomes.

Expanded gray matter atrophy with severity stages of adult comorbid insomnia and sleep apnea

ObjectiveTo investigate gray matter volume (GMV) changes in patients with comorbid insomnia and sleep apnea (COMISA) of differing severity and relationships between GMV alterations and clinical measures. MethodsThirty-four COMISA patients and 24 healthy controls (HC) were recruited. All patients underwent structural MRI and completed measures related to respiration, sleep, mood, and cognition. COMISA patients were further divided into a mild and moderate COMISA (MC) and a severe COMISA (SC) group. Changes in GMV of COMISA patients were investigated via VBM. The voxel-wise differences in GMV were compared between HC group and COMISA group. Analysis of covariance (ANCOVA) was performed on individual GMV maps in MC, SC, and HC groups to further investigate effects of different stages of COMISA severity on GMV. Partial correlation analysis was then performed to analyze relationships between altered GMV and clinical measures. ResultsGMV atrophy was mainly located in the temporal lobes and fusiform gyrus in COMISA group. The post-hoc analysis of the ANCOVA revealed temporal lobes and fusiform gyrus atrophy in MC and SC groups compared to HC and the temporal lobe atrophy was expanded in SC group based on cluster size. Moreover, the SC group showed GMV atrophy of the right amygdala compared to both MC and HC groups. Partial correlation analysis revealed positive relationships between the GMV and mood-and cognitive-related measures and negative correlation between GMV and respiration measure. ConclusionsOur findings showed GMV atrophy expansion from temporal lobe to limbic system (right amygdala) as severity stages increase in COMISA patients. These findings contribute to our understanding of neurobiological mechanisms underlying different stages of severity in COMISA patients.

Testing a Conceptual Model of Early Adversity, Neural Function, and Psychopathology: Protocol for a Retrospective Observational Cohort Study.

Early adversity, broadly defined as a set of negative exposures during childhood, is extremely common and increases risk for psychopathology across the life span. Previous research suggests that separate dimensions of adversity increase risk through developmental plasticity mechanisms shaping unique neurobiological pathways. Specifically, research suggests that deprivation is associated with deficits in higher order cognition, while threat is associated with atypicality in fear learning and emotion dysregulation. However, most of this research has been conducted in adolescent and adult samples, long after exposure to adversity occurs and far from periods of peak developmental plasticity. The Wellness Health and Life Experiences (WHALE) study examines the neurobiological and behavioral mechanisms by which deprivation, threat, and unpredictability increase risk for psychopathology in early childhood (age 4-7 years) directly following periods of peak developmental plasticity. The objective of this study is to describe the study rationale and aims, the research design and procedures, and the analytical plan to test the study hypotheses. This is a retrospective cohort study that examines associations between exposure to deprivation and threat and their hypothesized neurobiological mechanisms, how these neurobiological mechanisms link early adversity and psychopathology, and associations between unpredictability, reward learning, and psychopathology. The sample was a convenience sample of children (aged 4-7 years) and their families, identified through flyers, email blasts to listserves, school-based advertising, and involvement in community events. Data were collected during a home visit, a subsequent laboratory visit, and a final neuroimaging visit. Planned analyses include linear regression, path analyses, and functional magnetic resonance imaging analyses to explore the role of neural function in the association between early adversity and psychopathology. Participants (N=301) have been recruited into the study, and data collection has commenced. The expected results will be available in 2024. The findings of this study will help elucidate the neurobiological mechanisms by which early adversity increases risk for psychopathology in early childhood. This study represents the earliest test of an influential theory of biological embedding of early adversity. DERR1-10.2196/59636.

Effects of Neuroticism–Anxiety and Sociability Personality Traits on the Relationship Between Testosterone and Risk Propensity in Finance

Risky financial decisions, defined as rational calculations between expected risk and reward, are subject to various psychological and neurobiological mechanisms. In this context, the relationship between testosterone levels and risk propensity has been investigated, but the results are inconsistent. Here, the effects of some personality traits, neuroticism–anxiety and sociability, on the relationship between testosterone levels and risk propensity were examined in decisions under risk (GDT) and under uncertainty (BART). In a mixed-sex sample of 100 graduate students and experienced decision makers, we found that basal testosterone levels were positively correlated with risk propensity for decisions under risk in males with low neuroticism–anxiety scores, whereas they were negatively correlated with risk propensity for decisions under risk in males with high neuroticism–anxiety scores. However, they were not correlated in i) decisions under uncertainty in males, independent of neuroticism–anxiety, ii) decisions under risk or under uncertainty in males, independent of sociability, and iii) decisions under risk or under uncertainty in females, independent of sociability and neuroticism–anxiety. These results indicate that neuroticism–anxiety, but not sociability, may affect the relationship between testosterone levels and risk propensity only in decisions under risk and only in males, and provide evidence for the complexity of this relationship in males.

The relationship between Parkinson's disease and sexual hyperactivity secondary to drug treatment: A systematic review.

This review addresses the prevalence of hypersexual behavior in Parkinson's patients and the underlying neurobiological mechanisms, identifying risk and protective factors, comparing incidence among different treatments, and proposing recommendations for management and prevention. To conduct a review on the relationship between Parkinson's disease and hypersexual behavior as a result of pharmacological treatment. The search strategy, guided by PRISMA and PICOS criteria, focuses on the correlation between Parkinson's disease and hypersexual behavior due to pharmacological treatment. Utilizing databases like PubMed and Proquest, studies from the last 10 years in English or Spanish were selected, emphasizing clinical trials with Parkinson's patients under treatment. Inaccessible, irrelevant, or mixed-sample studies were excluded. The Cochrane Scale assessed the risk of bias. Out of 122 records, 103 remained after eliminating duplicates; 48 were reviewed, and ultimately, 6 studies met the inclusion criteria for analysis. Synthesizing the risk and protective factors linked to hypersexual behavior in Parkinson's patients receiving pharmacological treatment underscores the critical need for early detection and incorporation of these factors into clinical care. The suggested guidelines for managing and preventing hypersexual behavior in these patients carry substantial practical implications.

Conspiracy theories, social polarization and crises

Social media facilitate the distribution of conspiracy theories. It is uncertain whether indeed the number of myths and also the number of those who appropriate myths has increased. Conspiracy theories have so far essentially been the subject of sociological and psychosociological research showing ageneral disposition to become infected irrespective of the topic of amyth. Are there specific psychopathological risk factors for becoming infected by conspiracy myths? Are there effective therapeutic or preventive measures? Asystematic search was carried out in PubMed using the query "conspir*[title] AND review" followed by manual selection and appraisal only of publications addressing conspiracy theories in general, i.e. not limited to specific myths, with afocus on systematic reviews and meta-analyses. Moreover, the publications identified were manually screened for further meta-analyses. The search resulted in 166 hits. The available evidence is essentially based on studies using questionnaires, which can clarify only associations but not causalities. The evidence suggests that the strongest correlates of conspiratorial ideation pertain to low cognitive abilities, nonanalytic style of thought resulting in reduced balancing of probabilities before deciding, feelings of loss of control, paranoia, schizotypy and the dark triad (narcissism, Machiavellianism, authoritarianism). Specific psychological characteristics are risk factors for conspiratorial ideation. Current research approaches are unsuitable to clarify whether psychiatric disorders are overrepresented. Sociodemographic risk factors include male gender, low level of education, low income, social isolation and are non-specific. Group processes promote, again presumably nonspecifically, conspiracy theories thus contributing to social polarization. The genetic basis and neurobiological mechanisms are unknown. Conspiracy theories were and are used as an instrument of political contention. The enlightened democratic social contract requires free, unbiased thinking. Consequently, the risk factors identified so far facilitate conspiratorial ideation and question the very fundaments of the social contract by impairing unbiased evaluation and decision making. Therefore, prevention is warranted. .

Amygdala Reactivity, Antidepressant Discontinuation, and Relapse

Antidepressant discontinuation substantially increases the risk of a depression relapse, but the neurobiological mechanisms through which this happens are not known. Amygdala reactivity to negative information is a marker of negative affective processes in depression that is reduced by antidepressant medication, but it is unknown whether amygdala reactivity is sensitive to antidepressant discontinuation or whether any change is related to the risk of relapse after antidepressant discontinuation. To investigate whether amygdala reactivity to negative facial emotions changes with antidepressant discontinuation and is associated with subsequent relapse. The Antidepressiva Absetzstudie (AIDA) study was a longitudinal, observational study in which adult patients with remitted major depressive disorder (MDD) and currently taking antidepressants underwent 2 task-based functional magnetic resonance imaging (fMRI) measurements of amygdala reactivity. Patients were randomized to discontinuing antidepressants either before or after the second fMRI measurement. Relapse was monitored over a 6-month follow-up period. Study recruitment took place from June 2015 to January 2018. Data were collected between July 1, 2015, and January 31, 2019, and statistical analyses were conducted between June 2021 and December 2023. The study took place in a university setting in Zurich, Switzerland, and Berlin, Germany. Of 123 recruited patients, 83 were included in analyses. Of 66 recruited healthy control individuals matched for age, sex, and education, 53 were included in analyses. Discontinuation of antidepressant medication. Task-based fMRI measurement of amygdala reactivity and MDD relapse within 6 months after discontinuation. Among patients with MDD, the mean (SD) age was 35.42 (11.41) years, and 62 (75%) were women. Among control individuals, the mean (SD) age was 33.57 (10.70) years, and 37 (70%) were women. Amygdala reactivity of patients with remitted MDD and taking medication did not initially differ from that of control individuals (t125.136 = 0.33; P = .74). An increase in amygdala reactivity after antidepressant discontinuation was associated with depression relapse (3-way interaction between group [12W (waited) vs 1W2 (discontinued)], time point [MA1 (first scan) vs MA2 (second scan)], and relapse: β, 18.9; 95% CI, 0.8-37.1; P = .04). Amygdala reactivity change was associated with shorter times to relapse (hazard ratio, 1.05; 95% CI, 1.01-1.09; P = .01) and predictive of relapse (leave-one-out cross-validation balanced accuracy, 67%; 95% posterior predictive interval, 53-80; P = .02). An increase in amygdala reactivity was associated with risk of relapse after antidepressant discontinuation and may represent a functional neuroimaging marker that could inform clinical decisions around antidepressant discontinuation.

Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3,4-methylenedioxyamphetamine.

Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential.

Rice Protein Peptides Ameliorate DSS-Induced Cognitive Impairment and Depressive Behavior in Mice by Modulating Phenylalanine Metabolism and the BDNF/TRKB/CREB Pathway.

Rice protein peptide (RPP) has been reported to alleviate the symptoms of dextran sulfate sodium (DSS)-induced colitis, but its potential protective effect and fundamental neurobiological mechanisms against DSS-induced inflammatory bowel disease (IBD), coupled with depression and cognitive impairment, remain unclear. In this study, RPP treatment in DSS-induced mice inhibited decreases in body weight and colon length and improved intestinal barrier function and behavioral performance. RPP treatment enhanced phenylalanine and tyrosine metabolism in the brains of mice, and it upregulated metabolites such as l-dopa, phenylethylamine, and 3,4-dihydroxyphenylacetate. Additionally, RPP treatment enhanced the brain-derived neurotrophic factor (BDNF) by upregulating the BDNF/TrkB/CREB signaling pathway. Spearman's correlation analysis revealed that the phenylalanine and tyrosine contents in the brain were significantly negatively correlated with the BDNF/TrkB/CREB signaling pathway and behavioral performance. In conclusion, this study suggested that RPP may serve as a unique nutritional strategy for preventing IBD and its associated cognitive impairment and depression symptoms.

Lifestyle, biological, and genetic factors related to brain iron accumulation across adulthood

Iron is necessary for many neurobiological mechanisms, but its overaccumulation can be harmful. Factors triggering age-related brain iron accumulation remain largely unknown and longitudinal data are insufficient. We examined associations between brain iron load and accumulation and, blood markers of iron metabolism, cardiovascular health, lifestyle factors (smoking, alcohol use, physical activity, diet), and ApoE status using longitudinal data from the IronAge study (n = 208, age = 20–79, mean follow-up time = 2.75 years). Iron in cortex and basal ganglia was estimated with magnetic resonance imaging using quantitative susceptibility mapping (QSM). Our results showed that (1) higher peripheral iron levels (i.e., composite score of blood iron markers) were related to greater iron load in the basal ganglia; (2) healthier diet was related to higher iron levels in the cortex and basal ganglia, although for the latter the association was significant only in younger adults (age = 20–39); (3) worsening cardiovascular health was related to increased iron accumulation; (4) younger ApoE ε4 carriers accumulated more iron in basal ganglia than younger non-carriers. Our results demonstrate that modifiable factors, including lifestyle, cardiovascular, and physiological ones, are linked to age-related brain iron content and accumulation, contributing novel information on potential targets for interventions in preventing brain iron-overload.

Neurobiological mechanisms in the kynurenine pathway and major depressive disorder.

Major depressive disorder (MDD) is a prevalent psychiatric disorder that has damage to people's quality of life. Tryptophan is the precursor to serotonin, a critical neurotransmitter in mood modulation. In mammals, most free tryptophan is degraded by the kynurenine pathway (KP), resulting in a range of metabolites involved in inflammation, immune response, and neurotransmission. The imbalance between quinolinic acid (QA), a toxic metabolite, and kynurenic acid (KynA), a protective metabolite, is a relevant phenomenon involved in the pathophysiology of MDD. Proinflammatory cytokines increase the activity of the enzyme indoleamine 2,3-dioxygenase (IDO), leading to the degradation of tryptophan in the KP and an increase in the release of QA. IDO activates proinflammatory genes, potentiating neuroinflammation and deregulating other physiological mechanisms related to chronic stress and MDD. This review highlights the physiological mechanisms involved with stress and MDD, which are underlying an imbalance of the KP and discuss potential therapeutic targets.

Understanding the Bidirectional Relationship between Alzheimer's and Depression

Abstract: With an ageing global population, understanding the potential links between mental health and neurodegenerative disorders has become increasingly crucial for comprehensive patient care. A comprehensive search of electronic databases yielded a selection of studies encompassing clinical trials, longitudinal cohorts, and cross-sectional analyses, published between 2000 and 2023. Key inclusion criteria focused on investigations involving both Alzheimer's disease and depression, encompassing a range of methodologies, including neuroimaging, epidemiological surveys, and clinical assessments. The analysis reveals compelling evidence of a bidirectional relationship, where depression serves as a potential precursor to Alzheimer's disease, and vice versa. Neurobiological mechanisms, including neuroinflammation, neurotransmitter imbalances, and genetic predispositions, emerge as significant contributors to this complex association. Furthermore, psychosocial factors, such as chronic stress and social isolation, are identified as potential accelerators of cognitive decline in individuals with co-occurring depression and Alzheimer's. Additionally, therapeutic interventions targeting both conditions concurrently exhibit promising outcomes in mitigating cognitive decline and ameliorating depressive symptoms. Approaches encompassing cognitive behavioural therapy, pharmacological interventions, and lifestyle modifications demonstrate potential avenues for integrated treatment strategies. This review underscores the imperative for a multidisciplinary approach to patient care, emphasizing the importance of early detection and intervention for individuals presenting with symptoms of depression and cognitive impairment. Future research avenues should prioritize longitudinal studies with larger cohorts to delineate the causal pathways and further elucidate effective treatment modalities for this intricate comorbidity. By unravelling the complexities of the Alzheimer's-depression nexus, we pave the way for more targeted and comprehensive interventions to improve the lives of those affected by these debilitating conditions.

Resting-state brain networks alterations in adolescents with Internet Gaming Disorder associate with cognitive control impairments.

Research indicates that cognitive control is compromised in individuals with internet gaming disorder (IGD). However, the neural mechanisms behind it are still unclear. This study aims to investigate alterations in resting-state brain networks in adolescents with IGD and the potential neurobiological mechanisms underlying cognitive dysfunction. A total of 44 adolescent IGD subjects (male/female: 38/6) and 50 healthy controls (male/female: 40/10) were enrolled. Participants underwent demographic assessments, Young's Internet Addiction Scale, Barratt Impulsiveness Scale 11 Chinese Revised Version, the Chinese Adolescents' Maladaptive Cognitions Scale, exploratory eye movement tests, and functional magnetic resonance imaging (fMRI). FMRI data were analyzed using the GIFT software for independent component analysis, focusing on functional connectivity within and between resting-state brain networks. In comparison to the control group, impulsivity in adolescent IGD subjects showed a positive correlation with the severity of IGD (r=0.6350, p < 0.001), linked to impairments in the Executive Control Network (ECN) and a decrease in functional connectivity between the Salience Network (SN) and ECN (r=0.4307, p=0.0021; r=-0.5147, p=0.0034). Decreased resting state activity of the dorsal attention network (DAN) was associated with attentional dysregulation of IGD in adolescents (r=0.4071, p=0.0017), and ECN increased functional connectivity with DAN. The degree of IGD was positively correlated with enhanced functional connectivity between the ECN and DAN (r=0.4283, p=0.0037). This research demonstrates that changes in the ECN and DAN correlate with heightened impulsivity and attentional deficits in adolescents with IGD. The interaction between cognitive control disorders and resting-state brain networks in adolescent IGD is related.

Leveraging ultra-high field (7T) MRI in psychiatric research.

Non-invasive brain imaging has played a critical role in establishing our understanding of the neural properties that contribute to the emergence of psychiatric disorders. However, characterizing core neurobiological mechanisms of psychiatric symptomatology requires greater structural, functional, and neurochemical specificity than is typically obtainable with standard field strength MRI acquisitions (e.g., 3T). Ultra-high field (UHF) imaging at 7 Tesla (7T) provides the opportunity to identify neurobiological systems that confer risk, determine etiology, and characterize disease progression and treatment outcomes of major mental illnesses. Increases in scanner availability, regulatory approval, and sequence availability have made the application of UHF to clinical cohorts more feasible than ever before, yet the application of UHF approaches to the study of mental health remains nascent. In this technical review, we describe core neuroimaging methodologies which benefit from UHF acquisition, including high resolution structural and functional imaging, single (1H) and multi-nuclear (e.g., 31P) MR spectroscopy, and quantitative MR techniques for assessing brain tissue iron and myelin. We discuss advantages provided by 7T MRI, including higher signal- and contrast-to-noise ratio, enhanced spatial resolution, increased test-retest reliability, and molecular and neurochemical specificity, and how these have begun to uncover mechanisms of psychiatric disorders. Finally, we consider current limitations of UHF in its application to clinical cohorts, and point to ongoing work that aims to overcome technical hurdles through the continued development of UHF hardware, software, and protocols.

Divergent neural nodes are species- and hormone-dependent in the brood parasitic brain.

Avian brood parasitism is an evolutionarily derived behavior for which the neurobiological mechanisms are mostly unexplored. We aimed to identify brain regions that have diverged in the brood-parasitic brain using relative transcript abundance of social neuropeptides and receptors. We compared behavioral responses and transcript abundance in three brain regions in the brown-headed cowbird (BHCO), a brood parasite, and a closely related parental species, the red-winged blackbird (RWBL). Females of both species were treated with mesotocin (MT; avian homolog of oxytocin) or saline prior to exposure to nest stimuli. Results reveal that MT promotes approach toward nests with eggs rather than nests with begging nestlings in both species. We also examined relative transcript abundance of the five social neuropeptides and receptors in the brain regions examined: preoptic area (POA), paraventricular nucleus (PVN) and bed nucleus of the stria terminalis (BST). We found that MT-treated cowbirds but not blackbirds exhibited lower transcript abundance for two receptors, corticotropin-releasing factor 2 (CRFR2) and prolactin receptor (PRLR) in BST. Additionally, MT-treated cowbirds had higher PRLR in POA, comparable to those found in blackbirds, regardless of treatment. No other transcripts of interest exhibited significant differences as a result of MT treatment, but we found a significant effect of species in the three regions. Together, these results indicate that POA, PVN, and BST represent neural nodes that have diverged in avian brood parasites and may serve as neural substrates of brood-parasitic behavior.

Sex-specific and Developmental Effects of Early Life Adversity on Stress Reactivity are Rescued by Postnatal Knockdown of 5-HT 1A Autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT 1A ) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT 1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT 1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT 1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT 1A autoreceptors as potential targets to prevent these enduring effects of ELA.

Impairments of neurovascular coupling after stroke lower glymphatic system function and lead to depressive symptom: A longitudinal cohort study

BackgroundRespective changes in neurovascular coupling (NVC) and glymphatic function have been reported in post-stroke depression (PSD). Recent studies have found a link between NVC and waste clearance by the glymphatic system, which has not been illustrated in PSD. MethodWe prospectively recruited ninety-six stroke patients and forty-four healthy controls (HC), with fifty-nine patients undergoing a second MRI scan. NVC metrics were investigated by exploring Pearson correlation coefficients and ratios between cerebral blood flow (CBF) and BOLD-derived quantitative maps (ALFF, fALFF, REHO maps). Diffusion tensor imaging along the perivascular (DTI-ALPS) index was used to reflect glymphatic function. We first analyzed the altered NVC metrics in stroke patients relative to the HC group. Then, we explored the relationship between NVC metrics, ALPS index and depressive symptoms at baseline and during the follow-up period through correlation and mediation analyses. ResultsStroke patients exhibited significantly lower global CBF-fALFF coupling and ALPS index. At the regional level, abnormal NVC alterations in brain regions involved in cognition, emotion, and sensorimotor function in PSD. Baseline analyses showed that ALPS index exhibited positive associations with both global and local NVC and abnormal regional NVC may contribute to generation of PSD by reducing glymphatic function (β = −0.075, p < 0.05, CI = [−0.169 to −0.012]). Longitudinal analyses similarly showed that ALPS index changes were positively associated with changes in NVC and mediated improvements in depressive symptoms. ConclusionOur findings suggest that NVC abnormalities leading to impaired glymphatic system function may be a potential neurobiological mechanism of PSD.

Open-Label Placebo Injection for Chronic Back Pain With Functional Neuroimaging

Chronic back pain (CBP) is a leading cause of disability. Placebo treatments often provide as much pain relief as bona fide treatments, such as steroid injections. Open-label (honestly prescribed) placebos (OLPs) may relieve CBP without deception, but OLP mechanisms remain poorly understood. To investigate the long-term efficacy and neurobiological mechanisms of OLP for CBP. A randomized clinical trial of CBP with longitudinal functional magnetic resonance imaging (MRI) comparing OLP with usual care, with 1-year follow-up, was conducted in a university research setting and a community orthopedic clinic. Participants were individuals aged 21 to 70 years with CBP. The trial was conducted from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Data analysis was performed from April 2020 to May 2024. The primary analysis was conducted on an intention-to-treat sample. Participants randomized to OLP received a 1-time subcutaneous lumbar saline injection presented as placebo accompanied by information about the power of placebo to relieve pain, alongside their ongoing care. Usual care participants continued their ongoing care. The primary outcome was pain intensity (0-10, with 0 indicating no pain and 10 the most intense) at 1 month posttreatment. Secondary outcomes included pain interference, depression, anxiety, anger, and sleep quality. Functional MRI was performed before and after treatment during evoked and spontaneous back pain. A total of 101 adults (52 [51.4%] females; mean [SD] age, 40.4 [15.4] years) with moderate severity CBP (mean [SD], 4.10 [1.25] intensity; duration, 9.7 [8.5] years) were enrolled. Compared with usual care, OLP reduced CBP intensity posttreatment (relative reduction, 0.61; Hedges g = 0.45; 95% CI, -0.89 to 0.04; P = .02). Through 1-year follow-up, pain relief did not persist, although significant benefits were observed for depression, anger, anxiety, and sleep disruption (Hedges g = 0.3-0.5; all P < .03). Brain responses to evoked back pain for OLP vs usual care increased in rostral anterior cingulate and ventromedial prefrontal cortex and decreased in somatomotor cortices and thalamus. During spontaneous pain, functional connectivity analyses identified OLP vs usual care increases in ventromedial prefrontal cortex connectivity to the rostral ventral medulla, a pain-modulatory brainstem nucleus. No adverse effects of treatment were reported by participants. In this randomized clinical trial of OLP vs usual care, a single nondeceptive placebo injection reduced CBP intensity for 1 month posttreatment and provided benefits lasting for at least 1 year posttreatment. Brain mechanisms of OLP in a clinical population overlap with those of deceptive placebos in healthy volunteers, including engagement of prefrontal-brainstem pain modulatory pathways. ClinicalTrials.gov Identifier: NCT03294148.

Postoperative Delirium and Neurocognitive Disorders: A Comprehensive Review of Pathophysiology, Risk Factors, and Management Strategies.

Postoperative delirium (POD) and neurocognitive disorders (NCDs) are common and serious complications that can occur after surgery, particularly in older adults and those with preexisting cognitive impairments. These conditions are associated with significant morbidity, increased healthcare costs, and reduced quality of life. Understanding the underlying mechanisms, risk factors, and effective management strategies for POD and NCDs is critical for improving patient outcomes and reducing the burden on healthcare systems. This comprehensive review aims to synthesize current knowledge on the pathophysiology, risk factors, and management strategies for POD and NCDs. It explores the neurobiological and molecular mechanisms contributing to these conditions, identifies the patient-related, surgical, and environmental factors that increase risk, and evaluates pharmacological and non-pharmacological approaches to prevention and treatment. A thorough literature review was conducted using recent studies, clinical guidelines, and expert consensus to provide a detailed overview of the pathophysiology, risk factors, clinical presentation, prevention, and management of POD and NCDs. The pathophysiology of POD and NCDs involves complex interactions between neuroinflammatory processes, neurotransmitter imbalances, and brain network disruptions. Risk factors include advanced age, preexisting cognitive impairment, type and duration of surgery, and perioperative complications. Management strategies emphasize a multidisciplinary approach, incorporating preoperative optimization, careful intraoperative management, and postoperative interventions. Pharmacological treatments, such as antipsychotics, and non-pharmacological approaches, including environmental modifications and cognitive rehabilitation, play crucial roles in management. Postoperative delirium and NCDs are multifactorial conditions with significant impacts on surgical outcomes. Effective management requires a comprehensive understanding of their pathophysiology and risk factors and the implementation of targeted prevention and treatment strategies. Future research should focus on personalized approaches to prevention and treatment, further elucidation of mechanisms, and developing predictive models to enhance care for patients at risk of these neurocognitive complications.