Pub Date : 2024-10-05DOI: 10.1016/j.bbih.2024.100873
Liana V. Basova , Tera Riley , Donald Franklin , Violaine Delorme-Walker , Wei Ling Lim , Igor Grant , Scott L. Letendre , Jennifer E. Iudicello , Mariana Cherner , Ronald J. Ellis , Maria Cecilia Garibaldi Marcondes
The pursuit of translational biomarkers is complex due to the heterogeneous human pathophysiology, but critical for disease diagnosis, prognosis, monitoring therapeutic efficacy, and for patient stratification. In HIV-associated neurocognitive impairment (NCI), biomarkers that delineate the trajectory of neuropathogenesis and neurocognitive sequelae are critical, particularly considering confounders such as substance use, including Methamphetamine (METH). METH use is a significant health concern among persons living with HIV (PWH), aggravating cognitive deficits and neuroinflammation despite of antiretrovirals, introducing elements in the microenvironment that are fundamentally differerent in relation to non-METH users, such as high levels of dopamine (DA) affecting HIV-innate immune targets. Yet, current biomarkers do not detect these differences. We hypothesized that predefined DA-induced signatures detectable in peripheral blood leukocytes, can distinguish HIV+ METH users compared to HIV-negative or PWH that are non METH users. The elevated expression of CD8A, CREBBP, CCL5, and combinations of dopaminergic pathway transcripts clustered METH users with detectable CSF viral load and major depressive disorder (MDD), indicating neuroimmune-mechanistic links. Cathecol-o-methyltransferase (COMT) gene polymorphisms affecting DA metabolism improved the identification of PWH using METH with biomarkers. The results indicate that underlying immunedopaminergic mechanisms provide signatures and genotypes that can identify PWH that are METH users and their attributes.
{"title":"Identifying methamphetamine use predictors in HIV infection: Immune-dopaminergic signatures in peripheral leukocytes and the role of COMT genotype","authors":"Liana V. Basova , Tera Riley , Donald Franklin , Violaine Delorme-Walker , Wei Ling Lim , Igor Grant , Scott L. Letendre , Jennifer E. Iudicello , Mariana Cherner , Ronald J. Ellis , Maria Cecilia Garibaldi Marcondes","doi":"10.1016/j.bbih.2024.100873","DOIUrl":"10.1016/j.bbih.2024.100873","url":null,"abstract":"<div><div>The pursuit of translational biomarkers is complex due to the heterogeneous human pathophysiology, but critical for disease diagnosis, prognosis, monitoring therapeutic efficacy, and for patient stratification. In HIV-associated neurocognitive impairment (NCI), biomarkers that delineate the trajectory of neuropathogenesis and neurocognitive sequelae are critical, particularly considering confounders such as substance use, including Methamphetamine (METH). METH use is a significant health concern among persons living with HIV (PWH), aggravating cognitive deficits and neuroinflammation despite of antiretrovirals, introducing elements in the microenvironment that are fundamentally differerent in relation to non-METH users, such as high levels of dopamine (DA) affecting HIV-innate immune targets. Yet, current biomarkers do not detect these differences. We hypothesized that predefined DA-induced signatures detectable in peripheral blood leukocytes, can distinguish HIV+ METH users compared to HIV-negative or PWH that are non METH users. The elevated expression of CD8A, CREBBP, CCL5, and combinations of dopaminergic pathway transcripts clustered METH users with detectable CSF viral load and major depressive disorder (MDD), indicating neuroimmune-mechanistic links. Cathecol-o-methyltransferase (COMT) gene polymorphisms affecting DA metabolism improved the identification of PWH using METH with biomarkers. The results indicate that underlying immunedopaminergic mechanisms provide signatures and genotypes that can identify PWH that are METH users and their attributes.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100873"},"PeriodicalIF":3.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
About one third of patients suffering from Major Depressive Disorder (MDD) do not respond to any antidepressant medications and 75% experience relapses and general health deterioration. Importantly, inflammation can contribute to such negative outcomes, as well as to cause depression in patients who have been exposed to adverse childhood experiences and/or to viral infections, including COVID-19. Depressed patients also have an increased risk for developing comorbidities, such as cardio-metabolic dysfunctions, where inflammatory alterations, again, play a role in connecting MDD and these comorbid conditions.
Here, we present our study protocol funded by the Italian Ministry of Health in the context of the PNRR call (M6/C2_CALL 2022; Project code: PNRR-MAD-2022-12375859). The project aims to clarify the role of inflammation: i) in the onset of depression in association with environmental factors; ii) in the mechanisms associated with treatment response/resistance; iii) in depression and its comorbidity. To reach all these aims, we will perform biochemical, transcriptomic, genetic variants analyses on inflammatory/immune genes, pharmacokinetics and machine learning techniques, taking advantage of different human cohorts (adolescent depressed patients exposed to childhood trauma; adult depressed patients; treatment resistant depression patients; both prevalent and incident depression cases identified within a large population cohort). Moreover, we will use in vitro models (primary cultures of astrocytes, neurons and microglia) treated with pro-inflammatory or stressful challenges and preventive compounds to clarify the underlying mechanisms.
This 2-years project will increase the knowledge on the role of inflammation in the prevention and treatment of MDD and in comorbid disorders, and it will also provide experimental evidence for the development of novel targets and tools for innovative personalized intervention strategies.
{"title":"Inflammation and depression: A study protocol to dissect pathogenetic mechanisms in the onset, comorbidity and treatment response","authors":"Catia Scassellati , Nadia Cattane , Francesco Benedetti , Tiziana Borsello , Giuseppe Cicala , Massimo Gennarelli , Patrizia Genini , Alessandro Gialluisi , Arianna Giani , Licia Iacoviello , Alessandra Minelli , Edoardo Spina , Benedetta Vai , Erika Vitali , Annamaria Cattaneo","doi":"10.1016/j.bbih.2024.100886","DOIUrl":"10.1016/j.bbih.2024.100886","url":null,"abstract":"<div><div>About one third of patients suffering from Major Depressive Disorder (MDD) do not respond to any antidepressant medications and 75% experience relapses and general health deterioration. Importantly, inflammation can contribute to such negative outcomes, as well as to cause depression in patients who have been exposed to adverse childhood experiences and/or to viral infections, including COVID-19. Depressed patients also have an increased risk for developing comorbidities, such as cardio-metabolic dysfunctions, where inflammatory alterations, again, play a role in connecting MDD and these comorbid conditions.</div><div>Here, we present our study protocol funded by the Italian Ministry of Health in the context of the PNRR call (M6/C2_CALL 2022; Project code: PNRR-MAD-2022-12375859). The project aims to clarify the role of inflammation: i) in the onset of depression in association with environmental factors; ii) in the mechanisms associated with treatment response/resistance; iii) in depression and its comorbidity. To reach all these aims, we will perform biochemical, transcriptomic, genetic variants analyses on inflammatory/immune genes, pharmacokinetics and machine learning techniques, taking advantage of different human cohorts (adolescent depressed patients exposed to childhood trauma; adult depressed patients; treatment resistant depression patients; both prevalent and incident depression cases identified within a large population cohort). Moreover, we will use <em>in vitro</em> models (primary cultures of astrocytes, neurons and microglia) treated with pro-inflammatory or stressful challenges and preventive compounds to clarify the underlying mechanisms.</div><div>This 2-years project will increase the knowledge on the role of inflammation in the prevention and treatment of MDD and in comorbid disorders, and it will also provide experimental evidence for the development of novel targets and tools for innovative personalized intervention strategies.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100886"},"PeriodicalIF":3.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142663760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.bbih.2024.100872
Kati Wiedenbrüg , Laura Will , Lukas Reichert , Sebastian Hacker , Claudia Lenz , Karen Zentgraf , Markus Raab , Karsten Krüger
Functional cognition is relevant for athletic success and interdependent with physical exercise, yet despite repeatedly demonstrated inflammatory responses to physical training, there are no studies addressing the relationship between cognition and inflammation in athletes. The aim of this study was to investigate the relationship between cognitive performance and selected inflammatory, and further physiological biomarkers in elite athletes. Data from 350 elite athletes regarding cognitive performance (processing speed, selective attention, working memory, cognitive flexibility), systemic inflammatory markers, metabolic hormones, growth factors, tissue damage markers, and micronutrients (e.g., ferritin, 25-OH-vitamin D), as well as physiological, subjective ratings of recovery and stress were analysed by correlative and multiple regression analyses. Results show that across all athletes variance in processing speed, selective attention, and working memory, could be best explained through a combination of metabolic hormones with physiological and psychological indicators of stress, and in cognitive flexibility through vitamin D levels. Only for the subgroup of athletes from closed-skill sports, the ratio TNF-α:IL-10 significantly contributed to explanation of variance in working memory and cognitive flexibility. In general, found correlations point to the importance of inflammatory balance and sufficient long-term nutrient supply for unaffected cognitive performance.
功能认知与运动成功息息相关，并与体育锻炼相互依存，然而，尽管体育训练中的炎症反应被反复证明，却没有研究探讨运动员的认知与炎症之间的关系。本研究的目的是调查精英运动员的认知能力与选定的炎症和其他生理生物标志物之间的关系。通过相关分析和多元回归分析，对 350 名精英运动员的认知能力（处理速度、选择性注意力、工作记忆、认知灵活性）、全身炎症标志物、代谢激素、生长因子、组织损伤标志物、微量营养素（如铁蛋白、25-OH-维生素 D）以及生理、恢复和压力的主观评价进行了分析。结果显示，所有运动员在处理速度、选择性注意和工作记忆方面的差异，都可以通过代谢激素与生理和心理压力指标的结合，以及通过维生素 D 水平与认知灵活性的结合，得到最好的解释。只有在封闭技能运动的运动员亚组中，TNF-α与IL-10的比率才对工作记忆和认知灵活性的差异有显著的解释作用。总的来说，所发现的相关性表明，炎症平衡和充足的长期营养供应对于认知能力不受影响非常重要。
{"title":"Inflammation and cognitive performance in elite athletes: A cross-sectional study","authors":"Kati Wiedenbrüg , Laura Will , Lukas Reichert , Sebastian Hacker , Claudia Lenz , Karen Zentgraf , Markus Raab , Karsten Krüger","doi":"10.1016/j.bbih.2024.100872","DOIUrl":"10.1016/j.bbih.2024.100872","url":null,"abstract":"<div><div>Functional cognition is relevant for athletic success and interdependent with physical exercise, yet despite repeatedly demonstrated inflammatory responses to physical training, there are no studies addressing the relationship between cognition and inflammation in athletes. The aim of this study was to investigate the relationship between cognitive performance and selected inflammatory, and further physiological biomarkers in elite athletes. Data from 350 elite athletes regarding cognitive performance (processing speed, selective attention, working memory, cognitive flexibility), systemic inflammatory markers, metabolic hormones, growth factors, tissue damage markers, and micronutrients (e.g., ferritin, 25-OH-vitamin D), as well as physiological, subjective ratings of recovery and stress were analysed by correlative and multiple regression analyses. Results show that across all athletes variance in processing speed, selective attention, and working memory, could be best explained through a combination of metabolic hormones with physiological and psychological indicators of stress, and in cognitive flexibility through vitamin D levels. Only for the subgroup of athletes from closed-skill sports, the ratio TNF-α:IL-10 significantly contributed to explanation of variance in working memory and cognitive flexibility. In general, found correlations point to the importance of inflammatory balance and sufficient long-term nutrient supply for unaffected cognitive performance.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100872"},"PeriodicalIF":3.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1016/j.bbih.2024.100876
Phoebe H. Lam
Children and adolescents exposed to severe stressors exhibit poorer health across the lifespan. However, decades of research evaluating the Stress-Buffering model suggests that social support can attenuate stressors' negative impacts. Psychoneuroimmunology research in this area has shifted from asking whether support buffers stress to when and why support would succeed (or fail) to confer protection. This article takes a lifecourse perspective and proposes that timing of support may shape support's protective value by defining the type of protection that is provided and its operating mechanisms. Specifically, it considers three temporal scenarios: support that occurs during, after, or before stressor exposure. When support intervenes at the same developmental stage as the stressor (concurrent support), buffering effects occur wherein support prevents the development of intermediary mechanisms that reflect or increase disease risk; when support is present at a developmental stage before stressor exposure (prior support), banking effects occur such that support intervenes indirectly by fortifying the individual with resilience-promoting characteristics that in turn prevents the development of intermediary mechanisms; finally, when support arrives at a developmental stage after stressor exposure (later support), counteracting effects occur such that support offsets the impacts of intermediary mechanisms on diseases. It further posits that a match between timing of support and the linkage of interest (e.g., the stressor-mechanism path vs. the mechanism-disease path) is necessary for successful protection. The present paper discusses these postulations, reviews nascent evidence, and proposes future directions.
{"title":"An Extension to the stress-buffering model: Timing of support across the lifecourse","authors":"Phoebe H. Lam","doi":"10.1016/j.bbih.2024.100876","DOIUrl":"10.1016/j.bbih.2024.100876","url":null,"abstract":"<div><div>Children and adolescents exposed to severe stressors exhibit poorer health across the lifespan. However, decades of research evaluating the Stress-Buffering model suggests that social support can attenuate stressors' negative impacts. Psychoneuroimmunology research in this area has shifted from asking whether support buffers stress to when and why support would succeed (or fail) to confer protection. This article takes a lifecourse perspective and proposes that timing of support may shape support's protective value by defining the type of protection that is provided and its operating mechanisms. Specifically, it considers three temporal scenarios: support that occurs during, after, or before stressor exposure. When support intervenes at the same developmental stage as the stressor (concurrent support), buffering effects occur wherein support prevents the development of intermediary mechanisms that reflect or increase disease risk; when support is present at a developmental stage before stressor exposure (prior support), banking effects occur such that support intervenes indirectly by fortifying the individual with resilience-promoting characteristics that in turn prevents the development of intermediary mechanisms; finally, when support arrives at a developmental stage after stressor exposure (later support), counteracting effects occur such that support offsets the impacts of intermediary mechanisms on diseases. It further posits that a match between timing of support and the linkage of interest (e.g., the stressor-mechanism path vs. the mechanism-disease path) is necessary for successful protection. The present paper discusses these postulations, reviews nascent evidence, and proposes future directions.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100876"},"PeriodicalIF":3.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1016/j.bbih.2024.100879
Perla Ontiveros-Ángel , Julio David Vega-Torres , Timothy B. Simon , Vivianna Williams , Yaritza Inostroza-Nives , Nashareth Alvarado-Crespo , Yarimar Vega Gonzalez , Marjory Pompolius , William Katzka , John Lou , Fransua Sharafeddin , Ike De la Peña , Tien Dong , Arpana Gupta , Chi T. Viet , Marcelo Febo , Andre Obenaus , Aarti Nair , Johnny D. Figueroa
Childhood overweight/obesity is associated with stress-related psychopathology, yet the pathways connecting childhood obesity to stress susceptibility are poorly understood. We employed a systems biology approach with 62 adolescent Lewis rats fed a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a control diet (CD, 13% kcal from fat). A subset of rats underwent a 31-day model of predator exposures and social instability (PSS). Effects were assessed using behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), 16S rRNA gene sequencing for gut microbiome profiling, hippocampal microglia analysis, and targeted gene methylation. Parallel experiments on human microglia cells (HMC3) examined how palmitic acid influences cortisol-related inflammatory responses.
Rats exposed to WD and PSS exhibited deficits in sociability, increased fear/anxiety-like behaviors, food consumption, and body weight. WD/PSS altered hippocampal microstructure (subiculum, CA1, dentate gyrus), and microbiome analysis showed a reduced abundance of members of the phylum Firmicutes. WD/PSS synergistically promoted neuroinflammatory changes in hippocampal microglia, linked with microbiome shifts and altered Fkbp5 expression/methylation. In HMC3, palmitate disrupted cortisol responses, affecting morphology, phagocytic markers, and cytokine release, partially mediated by FKBP5.
This study identifies gene-environment interactions that influence microglia biology and may contribute to the connection between childhood obesity and stress-related psychopathology later in life.
{"title":"Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation","authors":"Perla Ontiveros-Ángel , Julio David Vega-Torres , Timothy B. Simon , Vivianna Williams , Yaritza Inostroza-Nives , Nashareth Alvarado-Crespo , Yarimar Vega Gonzalez , Marjory Pompolius , William Katzka , John Lou , Fransua Sharafeddin , Ike De la Peña , Tien Dong , Arpana Gupta , Chi T. Viet , Marcelo Febo , Andre Obenaus , Aarti Nair , Johnny D. Figueroa","doi":"10.1016/j.bbih.2024.100879","DOIUrl":"10.1016/j.bbih.2024.100879","url":null,"abstract":"<div><div>Childhood overweight/obesity is associated with stress-related psychopathology, yet the pathways connecting childhood obesity to stress susceptibility are poorly understood. We employed a systems biology approach with 62 adolescent Lewis rats fed a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a control diet (CD, 13% kcal from fat). A subset of rats underwent a 31-day model of predator exposures and social instability (PSS). Effects were assessed using behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), 16S rRNA gene sequencing for gut microbiome profiling, hippocampal microglia analysis, and targeted gene methylation. Parallel experiments on human microglia cells (HMC3) examined how palmitic acid influences cortisol-related inflammatory responses.</div><div>Rats exposed to WD and PSS exhibited deficits in sociability, increased fear/anxiety-like behaviors, food consumption, and body weight. WD/PSS altered hippocampal microstructure (subiculum, CA1, dentate gyrus), and microbiome analysis showed a reduced abundance of members of the phylum <em>Firmicutes</em>. WD/PSS synergistically promoted neuroinflammatory changes in hippocampal microglia, linked with microbiome shifts and altered <em>Fkbp5</em> expression/methylation. In HMC3, palmitate disrupted cortisol responses, affecting morphology, phagocytic markers, and cytokine release, partially mediated by FKBP5.</div><div>This study identifies gene-environment interactions that influence microglia biology and may contribute to the connection between childhood obesity and stress-related psychopathology later in life.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100879"},"PeriodicalIF":3.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.bbih.2024.100881
Rachel Deanna Phillips
Early experiences of stress and adversity are associated with blunted reward sensitivity and altered reward learning. Meanwhile, anhedonia is characterized by impairments in reward processing, including motivation, effort, and pleasure. Early life stress (ELS) and anhedonia share psychological, behavioral, and neurobiological correlates, and the system-level interactions that give rise to anhedonia have yet to be fully appreciated. The proposed framework uses a multilevel, multisystem approach to aid in understanding neural-immune interactions that link ELS and anhedonia. The interactions linking anhedonia and ELS presented here include reduced reward sensitivity, alterations in hypothalamic-pituitary-adrenal (HPA) axis response, elevated inflammatory cytokines or physiological markers of stress, and blunted reward circuitry functioning along the mesocorticolimbic pathway. The clinical implications and areas for future research are also discussed. Ultimately, this research may inform the development of more specific and individualized treatments for anhedonia.
早期的压力和逆境经历与奖赏敏感性减弱和奖赏学习改变有关。与此同时，失乐症的特点是奖赏处理能力受损，包括动机、努力和愉悦。早期生活压力（ELS）和失乐症有着共同的心理、行为和神经生物学相关性，而导致失乐症的系统级相互作用尚未得到充分认识。本研究提出的框架采用多层次、多系统的方法，帮助人们理解将 ELS 和失乐症联系在一起的神经-免疫相互作用。本文介绍的将失乐症和 ELS 联系起来的相互作用包括奖赏敏感性降低、下丘脑-垂体-肾上腺（HPA）轴反应改变、炎症细胞因子或应激生理标记物升高以及沿皮质中层边缘通路的奖赏回路功能减弱。此外，还讨论了临床影响和未来研究领域。最终，这项研究可能会为开发更具体、更个性化的厌食症治疗方法提供参考。
{"title":"Neural and immune interactions linking early life stress and anhedonia","authors":"Rachel Deanna Phillips","doi":"10.1016/j.bbih.2024.100881","DOIUrl":"10.1016/j.bbih.2024.100881","url":null,"abstract":"<div><div>Early experiences of stress and adversity are associated with blunted reward sensitivity and altered reward learning. Meanwhile, anhedonia is characterized by impairments in reward processing, including motivation, effort, and pleasure. Early life stress (ELS) and anhedonia share psychological, behavioral, and neurobiological correlates, and the system-level interactions that give rise to anhedonia have yet to be fully appreciated. The proposed framework uses a multilevel, multisystem approach to aid in understanding neural-immune interactions that link ELS and anhedonia. The interactions linking anhedonia and ELS presented here include reduced reward sensitivity, alterations in hypothalamic-pituitary-adrenal (HPA) axis response, elevated inflammatory cytokines or physiological markers of stress, and blunted reward circuitry functioning along the mesocorticolimbic pathway. The clinical implications and areas for future research are also discussed. Ultimately, this research may inform the development of more specific and individualized treatments for anhedonia.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100881"},"PeriodicalIF":3.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.bbih.2024.100878
Chia-Hsin Cheng , Yi Guan , Vidhi P. Chiplunkar , Farzad Mortazavi , Maria L. Medalla , Kimberly Sullivan , James P. O'Callaghan , Bang-Bon Koo , Kimberly A. Kelly , Lindsay T. Michalovicz
Gulf War Illness (GWI) is a disorder experienced by many veterans of the 1991 Gulf War, with symptoms including fatigue, chronic pain, respiratory and memory problems. Exposure to toxic chemicals during the war, such as oil well fire smoke, pesticides, physiological stress, and nerve agents, is thought to have triggered abnormal neuroinflammatory responses that contribute to GWI. Previous studies have examined the acute effects of combined physiological stress and chemical exposures using GWI rodent models and presented findings related to neuroinflammation and changes in diffusion magnetic resonance imaging (MRI) measures, suggesting a neuroimmune basis for GWI. In the current study, using ex vivo MRI, cytokine mRNA expression, and immunohistological analyses of brain tissues, we examined the brain structure and immune function of a chronic rat model of GWI. Our data showed that a combination of long-term corticosterone treatment (to mimic high physiological stress) and diisopropyl fluorophosphate exposure (to mimic sarin exposure) primed the response to subsequent systemic immune challenge with lipopolysaccharide resulting in elevations of multiple cytokine mRNAs, an increased activated glial population, and disrupted brain microstructure in the cingulate cortex and hippocampus compared to control groups. Our findings support the critical role of neuroinflammation, dysregulated glial activation, and their relationship to disrupted brain microstructural integrity in the pathophysiology of GWI and highlight the unique consequences of long-term combined exposures on brain biochemistry and structural connectivity.
{"title":"Nerve agent exposure and physiological stress alter brain microstructure and immune profiles after inflammatory challenge in a long-term rat model of Gulf War Illness","authors":"Chia-Hsin Cheng , Yi Guan , Vidhi P. Chiplunkar , Farzad Mortazavi , Maria L. Medalla , Kimberly Sullivan , James P. O'Callaghan , Bang-Bon Koo , Kimberly A. Kelly , Lindsay T. Michalovicz","doi":"10.1016/j.bbih.2024.100878","DOIUrl":"10.1016/j.bbih.2024.100878","url":null,"abstract":"<div><div>Gulf War Illness (GWI) is a disorder experienced by many veterans of the 1991 Gulf War, with symptoms including fatigue, chronic pain, respiratory and memory problems. Exposure to toxic chemicals during the war, such as oil well fire smoke, pesticides, physiological stress, and nerve agents, is thought to have triggered abnormal neuroinflammatory responses that contribute to GWI. Previous studies have examined the acute effects of combined physiological stress and chemical exposures using GWI rodent models and presented findings related to neuroinflammation and changes in diffusion magnetic resonance imaging (MRI) measures, suggesting a neuroimmune basis for GWI. In the current study, using <em>ex vivo</em> MRI, cytokine mRNA expression, and immunohistological analyses of brain tissues, we examined the brain structure and immune function of a chronic rat model of GWI. Our data showed that a combination of long-term corticosterone treatment (to mimic high physiological stress) and diisopropyl fluorophosphate exposure (to mimic sarin exposure) primed the response to subsequent systemic immune challenge with lipopolysaccharide resulting in elevations of multiple cytokine mRNAs, an increased activated glial population, and disrupted brain microstructure in the cingulate cortex and hippocampus compared to control groups. Our findings support the critical role of neuroinflammation, dysregulated glial activation, and their relationship to disrupted brain microstructural integrity in the pathophysiology of <span>GWI</span> and highlight the unique consequences of long-term combined exposures on brain biochemistry and structural connectivity.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"42 ","pages":"Article 100878"},"PeriodicalIF":3.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.bbih.2024.100877
Carola Chiarpenello, Katja Brodmann
Depression, the most prevailing mental health condition, remains untreated in over 30% of patients. This cluster presents with sub-clinical inflammation. Investigations trialling anti-inflammatory medications had mixed results. The lack of results may result from inflammation's complexity and targeting only a few of depression's abnormal pathways. Mind-body therapies' biological and neuro-imaging studies offer valuable insights into depression psychopathology. Interestingly, mind-body therapies, like yoga, reverse the aberrant pathways in depression. These aberrant pathways include decreased cognitive function, interoception, neuroplasticity, salience and default mode networks connectivity, parasympathetic tone, increased hypothalamic-pituitary-adrenal (HPA) axis activity, and metabolic hyper/hypofunction. Abundant evidence found yogic techniques improving self-reported depressive symptoms across various populations. Yoga may be more effective in treating depression in conjunction with pharmacological and cognitive therapies. Yoga's psychoneuroimmunology teaches us that reducing allostatic load is crucial in improving depressive symptoms. Mind-body therapies promote parasympathetic tone, downregulate the HPA axis, reduce inflammation and boost immunity. The reduced inflammation promotes neuroplasticity and, subsequently, neurogenesis. Improving interoception resolves the metabolic needs prediction error and restores homeostasis. Additionally, by improving functional connectivity within the salience network, they restore the dynamic switching between the default mode and central executive networks, reducing rumination and mind-wandering. Future investigations should engineer therapies targeting the mechanisms mentioned above. The creation of multi-disciplinary health teams offering a combination of pharmacological, gene, neurofeedback, behavioural, mind-body and psychological therapies may treat treatment-resistant depression.
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Pub Date : 2024-09-20DOI: 10.1016/j.bbih.2024.100863
Jeremia J. Pyuza , Marloes M.A.R. van Dorst , Koen Stam , Linda Wammes , Marion König , Vesla I. Kullaya , Yvonne Kruize , Wesley Huisman , Nikuntufya Andongolile , Anastazia Ngowi , Elichilia R. Shao , Alex Mremi , Pancras C.W. Hogendoorn , Sia E. Msuya , Simon P. Jochems , Wouter A.A. de Steenhuijsen Piters , Maria Yazdanbakhsh
Immune system and vaccine responses vary across geographical locations worldwide, not only between high and low-middle income countries (LMICs), but also between rural and urban populations within the same country. Lifestyle factors such as housing conditions, exposure to microorganisms and parasites and diet are associated with rural-and urban-living. However, the relationships between these lifestyle factors and immune profiles have not been mapped in detail. Here, we profiled the immune system of 100 healthy Tanzanians living across four rural/urban areas using mass cytometry. We developed a lifestyle score based on an individual's household assets, housing condition and recent dietary history and studied the association with cellular immune profiles. Seventeen out of 80 immune cell clusters were associated with living location or lifestyle score, with eight identifiable only using lifestyle score. Individuals with low lifestyle score, most of whom live in rural settings, showed higher frequencies of NK cells, plasmablasts, atypical memory B cells, T helper 2 cells, regulatory T cells and activated CD4+ T effector memory cells expressing CD38, HLA-DR and CTLA-4. In contrast, those with high lifestyle score, most of whom live in urban areas, showed a less activated state of the immune system illustrated by higher frequencies of naïve CD8+ T cells. Using an elastic net machine learning model, we identified cellular immune signatures most associated with lifestyle score. Assuming a link between these immune profiles and vaccine responses, these signatures may inform us on the cellular mechanisms underlying poor responses to vaccines, but also reduced autoimmunity and allergies in low- and middle-income countries.
免疫系统和疫苗反应在全球不同地理位置之间存在差异，不仅在高收入国家和中低收入国家之间存在差异，而且在同一国家的农村人口和城市人口之间也存在差异。居住条件、接触微生物和寄生虫的机会以及饮食等生活方式因素与农村和城市生活息息相关。然而，这些生活方式因素与免疫特征之间的关系还没有被详细描述。在这里，我们使用质谱细胞计数法对生活在四个城乡结合部的 100 名健康坦桑尼亚人的免疫系统进行了分析。我们根据个人的家庭资产、住房条件和最近的饮食史制定了生活方式评分，并研究了其与细胞免疫特征的关联。在 80 个免疫细胞群中，有 17 个与居住地点或生活方式评分有关，其中有 8 个只能通过生活方式评分来识别。生活方式得分低的人大多数生活在农村，他们的 NK 细胞、浆细胞、非典型记忆 B 细胞、T 辅助 2 细胞、调节性 T 细胞和表达 CD38、HLA-DR 和 CTLA-4 的活化 CD4+ T 效应记忆细胞的频率较高。与此相反，生活方式得分高的人，其中大多数生活在城市地区，其免疫系统的激活状态较差，表现为幼稚的 CD8+ T 细胞频率较高。利用弹性网机器学习模型，我们确定了与生活方式得分最相关的细胞免疫特征。假设这些免疫特征与疫苗反应之间存在联系，那么这些特征可能会让我们了解疫苗反应不佳的细胞机制，以及中低收入国家自身免疫和过敏症减少的原因。
{"title":"Lifestyle score is associated with cellular immune profiles in healthy Tanzanian adults","authors":"Jeremia J. Pyuza , Marloes M.A.R. van Dorst , Koen Stam , Linda Wammes , Marion König , Vesla I. Kullaya , Yvonne Kruize , Wesley Huisman , Nikuntufya Andongolile , Anastazia Ngowi , Elichilia R. Shao , Alex Mremi , Pancras C.W. Hogendoorn , Sia E. Msuya , Simon P. Jochems , Wouter A.A. de Steenhuijsen Piters , Maria Yazdanbakhsh","doi":"10.1016/j.bbih.2024.100863","DOIUrl":"10.1016/j.bbih.2024.100863","url":null,"abstract":"<div><div>Immune system and vaccine responses vary across geographical locations worldwide, not only between high and low-middle income countries (LMICs), but also between rural and urban populations within the same country. Lifestyle factors such as housing conditions, exposure to microorganisms and parasites and diet are associated with rural-and urban-living. However, the relationships between these lifestyle factors and immune profiles have not been mapped in detail. Here, we profiled the immune system of 100 healthy Tanzanians living across four rural/urban areas using mass cytometry. We developed a lifestyle score based on an individual's household assets, housing condition and recent dietary history and studied the association with cellular immune profiles. Seventeen out of 80 immune cell clusters were associated with living location or lifestyle score, with eight identifiable only using lifestyle score. Individuals with low lifestyle score, most of whom live in rural settings, showed higher frequencies of NK cells, plasmablasts, atypical memory B cells, T helper 2 cells, regulatory T cells and activated CD4<sup>+</sup> T effector memory cells expressing CD38, HLA-DR and CTLA-4. In contrast, those with high lifestyle score, most of whom live in urban areas, showed a less activated state of the immune system illustrated by higher frequencies of naïve CD8<sup>+</sup> T cells. Using an elastic net machine learning model, we identified cellular immune signatures most associated with lifestyle score. Assuming a link between these immune profiles and vaccine responses, these signatures may inform us on the cellular mechanisms underlying poor responses to vaccines, but also reduced autoimmunity and allergies in low- and middle-income countries.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"41 ","pages":"Article 100863"},"PeriodicalIF":3.7,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.bbih.2024.100871
C. Wessa , J. Janssens , V. Coppens , K. El Abdellati , E. Vergaelen , S. van den Ameele , C. Baeken , D. Zeeuws , Y. Milaneschi , F. Lamers , B. Penninx , S. Claes , M. Morrens , L. De Picker
<div><h3>Introduction</h3><p>Different lines of evidence confirm the involvement of the immune system in the pathophysiology of major depressive disorder. Up to 30% of depressed patients present with an immune-mediated subtype, characterized by peripheral inflammation (high-sensitive C-reactive protein (hsCRP) ≥ 3 mg/l) and an atypical symptom profile with fatigue, anhedonia, increased appetite, and hypersomnia. This immune-mediated subtype of MDD is associated with poorer response to first-line antidepressant treatment. Consequently, strategies for immune-targeted augmentation should be prioritised towards patients with this subtype. Meta-analyses have shown modest but heterogeneous treatment effects with immune-targeted augmentation in unstratified MDD cohorts, with celecoxib and minocycline as most promising first-line treatment options. However, no study has prospectively evaluated the effectiveness of <em>a priori</em> stratification by baseline inflammation levels for add-on celecoxib or minocycline in MDD.</p></div><div><h3>Methods</h3><p>The INSTA-MD trial is a multicentre, 12-week, randomised, double-blind, placebo-controlled, parallel-group stratified clinical trial of adjunctive minocycline or celecoxib to treatment-as-usual for patients with MDD. Two hundred forty adult patients with Major Depressive Disorder who failed to remit with one or two trials of antidepressant treatment will be enrolled and allocated to high-hsCRP (hsCRP ≥3 mg/L) or low-hsCRP (hsCRP <3 mg/L) strata, where disproportional stratified sampling will ensure equally sized strata. Participants in each hsCRP stratum will be randomised to augment their ongoing antidepressant treatment with either adjunctive minocycline, celecoxib or placebo for a duration of 12 weeks, resulting in six treatment arms of each 40 participants. The primary objective is to evaluate the efficacy of immune-targeted augmentation with minocycline or celecoxib versus placebo, and the use of baseline hsCRP stratification to predict treatment response. Additionally, we will perform a head-to-head analysis between the two active compounds. The primary outcome measure is change in the Hamilton Depression Rating Scale (HDRS-17) total score. Secondary outcome measures will be response and remission rates, and change in inflammation-specific symptoms, adverse events and therapy acceptability (adherence). Further exploratory analyses will be performed with an array of peripheral inflammatory biomarkers, metabolic outcomes and physiological data.</p></div><div><h3>Expected impact</h3><p>The aim of INSTA-MD is to advance the use of immune-targeted precision psychiatry, by supporting the implementation of targeted hsCRP screening and treatment of immune-mediated MDD as a cost-effective intervention in primary care settings. Based on previous studies, we expect immune-targeted augmentation with minocycline or celecoxib to yield a superior remission rate of 15–30% compared to treatment as usual for immun
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