Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis.

Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD.

Mother-infant interaction and infant development in women at risk of postpartum psychosis with and without a postpartum relapse.

BACKGROUND: This study aimed to investigate mother-infant interaction and infant development in women at-risk of postpartum psychosis (PP), with and without a postpartum relapse. METHODS: 103 women (and their offspring) were included, 43 at-risk-of-PP because of a diagnosis of bipolar disorder, schizoaffective disorder or previous PP, and 60 with no current/previous mental illness or family history of PP. Of the at-risk women, 18 developed a psychiatric relapse within 4 weeks after delivery (AR-unwell), while 25 remained symptom-free (AR-well). Mother-infant interaction was assessed using the CARE-Index at 8 weeks' and 12 months' postpartum and infant development using the Bayley-III at 12 months' postpartum. RESULTS: Women at-risk-of-PP as a group, regardless of whether they developed a psychiatric relapse within 4 weeks after delivery, had less synchronous mother-infant interactions and had infants with less optimal cognitive, language, motor and socio-emotional development than healthy controls. In particular, boys of at-risk women had the lowest scores in cognitive, language and motor development and in mother-infant interaction, while girls of the at-risk women had the lowest scores in socio-emotional development. The synchrony in the dyad predicted infant cognitive and language development. There was no evidence for a difference in mother-infant interaction nor in infant development between the AR-unwell and AR-well groups. CONCLUSIONS: These results suggest that, while there is a lack of evidence that an early postpartum relapse in women at-risk-of-PP could represent a risk for the infant per se, maternal risk for PP may be associated with less optimal mother-infant interaction and infant development.

Cognitive function in early-phase schizophrenia-spectrum disorder: IQ subtypes, brain volume and immune markers.

BACKGROUND: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation. METHOD: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF-α. RESULTS: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ (F(2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ (F(2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls. CONCLUSIONS: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Comparative efficacy of psychological interventions on immune biomarkers: A systematic review and network meta-analysis (NMA).

Psychological interventions are viable, cost-effective strategies for improving clinical and psychological impact of inflammation-related conditions. However, their efficacy on immune system function remains controversial. We performed a systematic review and frequentist random-effects network meta-analysis of randomised controlled trials (RCTs) assessing the effects of psychological interventions, against a control condition, on biomarkers of innate and adaptive immunity in adults. PubMed, Scopus, PsycInfo, and Web of Science were searched from inception up to Oct 17, 2022. Cohen's d at 95% confidence interval (CI) was calculated to assess the effect sizes of each class of intervention against active control conditions at post-treatment. The study was registered in PROSPERO (CRD42022325508). Of the 5024 articles retrieved, we included 104 RCTs reporting on 7820 participants. Analyses were based on 13 types of clinical interventions. Compared with the control conditions, cognitive therapy (d =  - 0.95, 95% CI: -1.64 to - 0.27), lifestyle (d =  - 0.51, 95% CI: -0.99 to - 0.02), and mindfulness-based (d =  - 0.38, 95% CI: -0.66 to - 0.09) interventions were associated with post-treatment reduction of proinflammatory cytokines and markers. Mindfulness-based interventions were also significantly associated with post-treatment increase in anti-inflammatory cytokines (d = 0.69, 95% CI: 0.09 to 1.30), while cognitive therapy was associated also with post-treatment increase in white blood cell count (d = 1.89, 95% CI: 0.05 to 3.74). Results on natural killer cells activity were non-significant. Grade of evidence was moderate for mindfulness and low-to-moderate for cognitive therapy and lifestyle interventions; however, substantial overall heterogeneity was detected in most of the analyses.

Sickness behaviour and depression: An updated model of peripheral-central immunity interactions.

Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice requires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target intervention. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery-brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.

Mapping acute neuroinflammation in vivo with diffusion-MRI in rats given a systemic lipopolysaccharide challenge.

It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostly ex vivo and/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammation in vivo in a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n = 20) vs. vehicle-treated controls (n = 12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.

Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity.

OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.

Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms.

Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19.

OBJECTIVE AND DESIGN: Fatigue is a prominent symptom in the general population and may follow viral infection, including SARS-CoV2 infection which causes COVID-19. Chronic fatigue lasting more than three months is the major symptom of the post-COVID syndrome (known colloquially as long-COVID). The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of long-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual prior to COVID-19. SUBJECTS AND METHODS: We analyzed pre-pandemic plasma levels of IL-6, which plays a key role in persistent fatigue, in N = 1274 community dwelling adults from TwinsUK. Subsequent COVID-19-positive and -negative participants were categorized based on SARS-CoV-2 antigen and antibody testing. Chronic fatigue was assessed using the Chalder Fatigue Scale. RESULTS: COVID-19-positive participants exhibited mild disease. Chronic fatigue was a prevalent symptom among this population and significantly higher in positive vs. negative participants (17% vs 11%, respectively; p = 0.001). The qualitative nature of chronic fatigue as determined by individual questionnaire responses was similar in positive and negative participants. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in negative, but not positive individuals. Raised BMI was associated with chronic fatigue in positive participants. CONCLUSIONS: Pre-existing increased IL-6 levels may contribute to chronic fatigue symptoms, but there was no increased risk in individuals with mild COVID-19 compared with uninfected individuals. Elevated BMI also increased the risk of chronic fatigue in mild COVID-19, consistent with previous reports.

Women with depression in pregnancy or a history of depression have decreased quality of mentalization in the speech to their infants.

BACKGROUND: Our study aims to understand whether depression, either in pregnancy or lifetime, affects cognitive biases (comprising the attentional focus and affective state) and mentalizing features (ability to understand children's internal mental states, thereby detecting and comprehending their behavior and intention), in maternal speech during mother-infant interaction in the first postnatal year. METHODS: We recruited 115 pregnant women (44 healthy, 46 with major depressive disorder [MDD] in pregnancy, and 25 with a history of MDD but healthy pregnancy) at 25 weeks' gestation. Three-minute videos were recorded at 8 weeks and 12 months postnatally for each dyad. Maternal speech was transcribed verbatim and coded for cognitive biases and mentalizing comments using the Parental Cognitive Attributions and Mentalization Scale (PCAMs). RESULTS: Women suffering from antenatal depression showed a decreased proportion of mentalizing comments compared with healthy women, at both 8 weeks (0.03 ± 0.01 vs. 0.07 ± 0.01, P = 0.002) and 12 months (0.02 ± 0.01 vs. 0.04 ± 0.01, P = 0.043). Moreover, compared with healthy women, both those with antenatal depression and those with a history of depression showed decreased positive affection in speech (0.13 ± 0.01 vs. 0.07 ± 0.01 and 0.08 ± 0.02, respectively P = 0.003 and P = 0.043), and made significantly fewer comments focused on their infants' experience at 8 weeks (0.67 ± 0.03 vs. 0.53 ± 0.04 and 0.49 ± 0.05, respectively P = 0.015 and P = 0.005). In linear regression models women's socioeconomic difficulties and anxiety in pregnancy contribute to these associations, while postnatal depression did not. CONCLUSIONS: Both antenatal depression and a lifetime history of depression are associated with a decreased quality of women's speech to their infants, as shown by less focus on their infant's experience, decreased positive affection, and less able to mentalize. Examining maternal speech to their infants in the early postnatal months may be particularly relevant to identify women who could benefit from strategies addressing these aspects of the interactive behavior and thus improve infant outcome in the context of depression.

Electronic health records (EHRs) in clinical research and platform trials: Application of the innovative EHR-based methods developed by EU-PEARL.

OBJECTIVE: Electronic Health Record (EHR) systems are digital platforms in clinical practice used to collect patients' clinical information related to their health status and represents a useful storage of real-world data. EHRs have a potential role in research studies, in particular, in platform trials. Platform trials are innovative trial designs including multiple trial arms (conducted simultaneously and/or sequentially) on different treatments under a single master protocol. However, the use of EHRs in research comes with important challenges such as incompleteness of records and the need to translate trial eligibility criteria into interoperable queries. In this paper, we aim to review and to describe our proposed innovative methods to tackle some of the most important challenges identified. This work is part of the Innovative Medicines Initiative (IMI) EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project's work package 3 (WP3), whose objective is to deliver tools and guidance for EHR-based protocol feasibility assessment, clinical site selection, and patient pre-screening in platform trials, investing in the building of a data-driven clinical network framework that can execute these complex innovative designs for which feasibility assessments are critically important. METHODS: ISO standards and relevant references informed a readiness survey, producing 354 criteria with corresponding questions selected and harmonised through a 7-round scoring process (0-1) in stakeholder meetings, with 85% of consensus being the threshold of acceptance for a criterium/question. ATLAS cohort definition and Cohort Diagnostics were mainly used to create the trial feasibility eligibility (I/E) criteria as executable interoperable queries. RESULTS: The WP3/EU-PEARL group developed a readiness survey (eSurvey) for an efficient selection of clinical sites with suitable EHRs, consisting of yes-or-no questions, and a set-up of interoperable proxy queries using physicians' defined trial criteria. Both actions facilitate recruiting trial participants and alignment between study costs/timelines and data-driven recruitment potential. CONCLUSION: The eSurvey will help create an archive of clinical sites with mature EHR systems suitable to participate in clinical trials/platform trials, and the interoperable proxy queries of trial eligibility criteria will help identify the number of potential participants. Ultimately, these tools will contribute to the production of EHR-based protocol design.

Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation.

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn's cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

Do different types of stress differentially alter behavioural and neurobiological outcomes associated with depression in rodent models? A systematic review.

Cataloguing the effects of different types of stress on behaviour and physiology in rodent models has not been comprehensively attempted. Here, we systematically review whether chronic exposure to physical stress, psychosocial stress, or both types of stress can induce different behavioural and neurobiological outcomes in male and female rodents. We found that physical stress consistently increased depressive-like behaviour, impaired social interaction and decreased body weight, while psychosocial stress consistently increased both anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity, peripheral inflammation and microglial activation, and decreased hippocampal neurogenesis in male rodents. Moreover, we found that the combined effect of both stress types resulted in a more severe pathological state defined by increased anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity and central inflammation, and reduced hippocampal neurogenesis and neural plasticity in male rodents. Phenotypes for females were less consistent, irrespective of the type of stress exposure, on account of the limited number of studies using females. This review highlights that the type of stress may indeed matter and will help animal researchers to more appropriately choose a stress/depression model that fits their research purposes.

Gut-derived systemic inflammation as a driver of depression in chronic liver disease.

Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.

Birth of the blues: emotional sound processing in infants exposed to prenatal maternal depression.

BACKGROUND: Offspring exposed to prenatal maternal depression (PMD) are vulnerable to depression across their lifespan. The underlying cause(s) for this elevated intergenerational risk is most likely complex. However, depression is underpinned by a dysfunctional frontal-limbic network, associated with core information processing biases (e.g. attending more to sad stimuli). Aberrations in this network might mediate transmission of this vulnerability in infants exposed to PMD. In this study, we aimed to explore the association between foetal exposure to PMD and frontal-limbic network function in infancy, hypothesising that, in response to emotional sounds, infants exposed to PMD would exhibit atypical activity in these regions, relative to those not exposed to PMD. METHOD: We employed a novel functional magnetic resonance imaging sequence to compare brain function, whilst listening to emotional sounds, in 78 full-term infants (3-6 months of age) born to mothers with and without a diagnosis of PMD. RESULTS: After exclusion of 19 datasets due to infants waking up, or moving excessively, we report between-group brain activity differences, between 29 infants exposed to PMD and 29 infants not exposed to PMD, occurring in temporal, striatal, amygdala/parahippocampal and frontal regions (p < 0.005). The offspring exposed to PMD exhibited a relative increase in activation to sad sounds and reduced (or unchanged) activation to happy sounds in frontal-limbic clusters. CONCLUSIONS: Findings of a differential response to positive and negative valanced sounds by 3-6 months of age may have significant implications for our understanding of neural mechanisms that underpin the increased risk for later-life depression in this population.

Mediators and moderators in the relationship between maternal childhood adversity and children's emotional and behavioural development: a systematic review and meta-analysis.

Maternal experiences of childhood adversity can increase the risk of emotional and behavioural problems in their children. This systematic review and meta-analysis provide the first narrative and quantitative synthesis of the mediators and moderators involved in the link between maternal childhood adversity and children's emotional and behavioural development. We searched EMBASE, PsycINFO, Medline, Cochrane Library, grey literature and reference lists. Studies published up to February 2021 were included if they explored mediators or moderators between maternal childhood adversity and their children's emotional and behavioural development. Data were synthesised narratively and quantitatively by meta-analytic approaches. The search yielded 781 articles, with 74 full-text articles reviewed, and 41 studies meeting inclusion criteria. Maternal mental health was a significant individual-level mediator, while child traumatic experiences and insecure maternal-child attachment were consistent family-level mediators. However, the evidence for community-level mediators was limited. A meta-analysis of nine single-mediating analyses from five studies indicated three mediating pathways: maternal depression, negative parenting practices and maternal insecure attachment, with pooled indirect standardised effects of 0.10 [95% CI (0.03-0.17)), 0.01 (95% CI (-0.02 to 0.04)] and 0.07 [95% CI (0.01-0.12)], respectively. Research studies on moderators were few and identified some individual-level factors, such as child sex (e.g. the mediating role of parenting practices being only significant in girls), biological factors (e.g. maternal cortisol level) and genetic factors (e.g. child's serotonin-transporter genotype). In conclusion, maternal depression and maternal insecure attachment are two established mediating pathways that can explain the link between maternal childhood adversity and their children's emotional and behavioural development and offer opportunities for intervention.

The influence of comorbid depression and overweight status on peripheral inflammation and cortisol levels.

BACKGROUND: Depression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels. METHODS: Participants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels. RESULTS: Overweight patients with depression had significantly higher hsCRP compared with overweight controls (p = 0.042), normal-weight depressed patients (p < 0.001) and normal-weight controls (p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28-3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7-2.41), while depression also contributed a significant risk (OR 1.09, 0.27-2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels. CONCLUSION: Comorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.

From dried bear bile to molecular investigation: A systematic review of the effect of bile acids on cell apoptosis, oxidative stress and inflammation in the brain, across pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorders.

Bile acids, mainly ursodeoxycholic acid (UDCA) and its conjugated species glycoursodeoxycholic acid (GUDCA) and tauroursodeoxycholic acid (TUDCA) have long been known to have anti-apoptotic, anti-oxidant and anti-inflammatory properties. Due to their beneficial actions, recent studies have started to investigate the effect of UDCA, GUDCA, TUDCA on the same mechanisms in pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorders, where increased cell apoptosis, oxidative stress and inflammation in the brain are often observed. A total of thirty-five pre-clinical studies were identified through PubMed/Medline, Web of Science, Embase, PsychInfo, and CINAHL databases, investigating the role of the UDCA, GUDCA and TUDCA in the regulation of brain apoptosis, oxidative stress and inflammation, in pre-clinical models of neurological, neurodegenerative and neuropsychiatric disorders. Findings show that UDCA reduces apoptosis, reactive oxygen species (ROS) and tumour necrosis factor (TNF)-α production in neurodegenerative models, and reduces nitric oxide (NO) and interleukin (IL)-1ß production in neuropsychiatric models; GUDCA decreases lactate dehydrogenase, TNF-α and IL-1ß production in neurological models, and also reduces cytochrome c peroxidase production in neurodegenerative models; TUDCA decreases apoptosis in neurological models, reduces ROS and IL-1ß production in neurodegenerative models, and decreases apoptosis and TNF-α production, and increases glutathione production in neuropsychiatric models. In addition, findings suggest that all the three bile acids would be equally beneficial in models of Huntington's disease, whereas UDCA and TUDCA would be more beneficial in models of Parkinson's disease and Alzheimer's disease, while GUDCA in models of bilirubin encephalopathy and TUDCA in models of depression. Overall, this review confirms the therapeutic potential of UDCA, GUDCA and TUDCA in neurological, neurodegenerative and neuropsychiatric disorders, proposing bile acids as potential alternative therapeutic approaches for patients suffering from these disorders.

Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the "long COVID." The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus-pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.

Antenatal maternal depression, early life inflammation and neurodevelopment in a South African birth cohort.

BACKGROUND: Antenatal exposure to maternal psychological adversity, including depression, increases the risk of impaired neurodevelopment in children. The underlying biological mechanisms remain unclear, especially in early life during critical windows of development and maturation. This study investigated the association of antenatal maternal depression, maternal and early life inflammatory markers and neurodevelopmental outcomes in children at 2 years of age. METHODS: A subgroup of mothers and their children (n = 255) that were enrolled in a South African birth cohort study, the Drakenstein Child Health Study, were followed from the antenatal period through to 2 years of child age. Maternal depressive symptoms were measured by the Beck Depression Inventory (BDI-II) at 26 weeks gestation. Serum inflammatory markers [granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumour necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were measured in mothers at enrolment and in their children at 6-10 weeks and at 2 years. Neurodevelopment was assessed at 2 years using the Bayley Scales of Infant and Toddler Development III. RESULTS: Antenatal depressive symptoms (present in 25% of the mothers) were significantly associated with higher levels of IL-7 (p = 0.008), IL-8 (p = 0.019) and TNF-α (p = 0.031) in the mothers after correcting for sociodemographic and lifestyle factors. Serum IL-1ß and NGAL levels were significantly elevated over time in children born to mothers with depressive symptoms compared to those without depression, after controlling for maternal and child health and sociodemographic factors. Elevated infant IL-1ß at 6-10 weeks of age partially mediated the association of maternal depressive symptoms with poorer language scores at 2 years. CONCLUSION: Alterations in early life immunity, as reflected by elevated IL-1ß, is a potential pathway through which antenatal maternal depressive symptoms may impact language development in young children.