Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.
Methods
We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.
Findings
Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.
Interpretation
This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.
{"title":"Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study","authors":"Kiran Thapaliya, Sonya Marshall-Gradisnik, Maira Inderyas, Leighton Barnden","doi":"10.1016/j.bbih.2025.101142","DOIUrl":"10.1016/j.bbih.2025.101142","url":null,"abstract":"<div><h3>Background</h3><div>Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.</div></div><div><h3>Methods</h3><div>We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.</div></div><div><h3>Findings</h3><div>Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.</div></div><div><h3>Interpretation</h3><div>This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101142"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101152
May A. Beydoun , Jordan Weiss , Michael F. Gerogescu , Jason Ashe , Christian A. Maino Vieytes , Tianyi Huang , Hind A. Beydoun , Nicole Noren Hooten , Indira C. Turney , Michele K. Evans , Alan B. Zonderman
Socio-environmental and health-related variables were examined in relation to longitudinal change in select neuroimaging markers through metabolomics. Data from 2255 dementia-free UK Biobank participants were utilized. Statistical analyses involved descriptives, Principal Components Analysis (PCA) for metabolomic data reduction, mixed-effects linear regression models to assess longitudinal change (i.e. empirical Bayes estimators of slope), and Additive Bayesian Networks (ABN). Age was the primary consistent contributor to brain health decline over time, with specific metabolomic markers, mainly “free cholesterol in very large high-density lipoproteins (HDL)”, potentially offering protective effects against declines in microstructural integrity, through reduction of or slower pace of increase in mean Orientation Dispersion (ODmean). Air pollution, individual and household-level SES, sex and racial minority status correlated indirectly with brain health through intracranial volumes and time interval between assessments. These insights emphasize using a multifactorial approach to understanding brain aging for predictive models of neurodegeneration.
{"title":"Socio-environmental and health-related factors and their association with longitudinal change in brain neuroimaging markers through the plasma metabolome among UK adults: An additive Bayesian network analysis","authors":"May A. Beydoun , Jordan Weiss , Michael F. Gerogescu , Jason Ashe , Christian A. Maino Vieytes , Tianyi Huang , Hind A. Beydoun , Nicole Noren Hooten , Indira C. Turney , Michele K. Evans , Alan B. Zonderman","doi":"10.1016/j.bbih.2025.101152","DOIUrl":"10.1016/j.bbih.2025.101152","url":null,"abstract":"<div><div>Socio-environmental and health-related variables were examined in relation to longitudinal change in select neuroimaging markers through metabolomics. Data from 2255 dementia-free UK Biobank participants were utilized. Statistical analyses involved descriptives, Principal Components Analysis (PCA) for metabolomic data reduction, mixed-effects linear regression models to assess longitudinal change (i.e. empirical Bayes estimators of slope), and Additive Bayesian Networks (ABN). Age was the primary consistent contributor to brain health decline over time, with specific metabolomic markers, mainly “free cholesterol in very large high-density lipoproteins (HDL)”, potentially offering protective effects against declines in microstructural integrity, through reduction of or slower pace of increase in mean Orientation Dispersion (OD<sub>mean</sub>). Air pollution, individual and household-level SES, sex and racial minority status correlated indirectly with brain health through intracranial volumes and time interval between assessments. These insights emphasize using a multifactorial approach to understanding brain aging for predictive models of neurodegeneration.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101152"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101156
Wilson Vincent , Annesa Flentje , Benjamin S. Dominguez , Robert H. Paul , Savita Pahwa , Suresh Pallikkuth , Margaret Roach , Dietmar Fuchs , Samantha E. Dilworth , Torsten B. Neilands , Peter W. Hunt , Gowri Sunder , Cody Lentz , Sydney Telaak , Adam W. Carrico
Background
Microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors are interacting pathophysiologic processes linked to neuropsychiatric comorbidities and faster HIV disease progression. We examined correlates of distinct phenotypes of gut-immune dysregulation in people living with HIV (PWH) who use methamphetamine.
Methods
Participants were 122 PWH who had biochemically confirmed recent methamphetamine use, including non-injection use. Peripheral plasma markers reflected: intestinal permeability, microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors. Using latent profile analysis (i.e., clustering) of these markers, we identified gut-immune phenotypes and their clinical, demographic, and stigma-related correlates.
Results
Three immune profiles emerged: (1) low gut-immune dysregulation with lower microbial translocation, macrophage activation, inflammation, and tryptophan catabolism; (2) moderate gut-immune dysregulation with all markers within average range; and (3) high gut-immune dysregulation with higher microbial translocation, immune activation, inflammation, and tryptophan catabolism. In adjusted analyses, higher viral load (one log10 copy/ml; AOR = 1.97, 95 % CI = 1.02–3.82), injection of methamphetamine (AOR = 3.60, 95 % CI = 1.23–10.50), and internalized stigma (AOR = 1.78, 95 % CI = 1.01–3.15) were associated with having a moderate gut-immune dysregulation profile. Additionally, higher viral load (AOR = 2.98, 95 % CI = 1.53–5.24) and injecting methamphetamine (AOR = 5.45, 95 % CI = 1.34–17.78) were associated with having a high gut-immune dysregulation profile.
Conclusions
Distinct patterns of microbial translocation, immune activation, inflammation, and metabolism of amino acid precursors distinguished gut-immune phenotypes of PWH reporting injection methamphetamine use and greater internalized stigma. Interventions tailored to PWH who inject methamphetamine or struggle with internalized stigma could optimize HIV-related health outcomes.
微生物易位、免疫激活、炎症和神经递质前体代谢失调是与神经精神合并症和更快的HIV疾病进展相关的相互作用的病理生理过程。我们研究了使用甲基苯丙胺的HIV感染者（PWH）肠道免疫失调的不同表型的相关性。方法研究对象为122名生物化学证实近期使用甲基苯丙胺（包括非注射使用）的PWH。外周血浆标志物反映：肠道通透性、微生物易位、免疫激活、炎症和神经递质前体代谢失调。利用这些标记物的潜在特征分析（即聚类），我们确定了肠道免疫表型及其临床、人口统计学和耻感相关因素。结果出现了三种免疫特征：(1)低肠道免疫失调，微生物易位、巨噬细胞激活、炎症和色氨酸分解代谢降低；(2)中度肠道免疫失调，各项指标均在平均范围内；(3)肠道免疫高度失调，微生物易位、免疫激活、炎症和色氨酸分解代谢增加。在校正分析中，较高的病毒载量（1 log10拷贝/ml； AOR = 1.97, 95% CI = 1.02-3.82）、注射甲基苯丙胺（AOR = 3.60, 95% CI = 1.23-10.50）和内化病耻感（AOR = 1.78, 95% CI = 1.01-3.15）与中度肠道免疫失调相关。此外，较高的病毒载量（AOR = 2.98, 95% CI = 1.53-5.24）和注射甲基苯丙胺（AOR = 5.45, 95% CI = 1.34-17.78）与较高的肠道免疫失调相关。结论不同的微生物易位、免疫激活、炎症和氨基酸前体代谢模式区分了PWH报告注射甲基苯丙胺的肠道免疫表型和更大的内化耻感。针对注射甲基苯丙胺或与内在耻辱作斗争的PWH量身定制的干预措施可以优化与艾滋病毒相关的健康结果。
{"title":"Body talk: Correlates of gut-immune dysregulation phenotypes in people living with HIV who use methamphetamine","authors":"Wilson Vincent , Annesa Flentje , Benjamin S. Dominguez , Robert H. Paul , Savita Pahwa , Suresh Pallikkuth , Margaret Roach , Dietmar Fuchs , Samantha E. Dilworth , Torsten B. Neilands , Peter W. Hunt , Gowri Sunder , Cody Lentz , Sydney Telaak , Adam W. Carrico","doi":"10.1016/j.bbih.2025.101156","DOIUrl":"10.1016/j.bbih.2025.101156","url":null,"abstract":"<div><h3>Background</h3><div>Microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors are interacting pathophysiologic processes linked to neuropsychiatric comorbidities and faster HIV disease progression. We examined correlates of distinct phenotypes of gut-immune dysregulation in people living with HIV (PWH) who use methamphetamine.</div></div><div><h3>Methods</h3><div>Participants were 122 PWH who had biochemically confirmed recent methamphetamine use, including non-injection use. Peripheral plasma markers reflected: intestinal permeability, microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors. Using latent profile analysis (i.e., clustering) of these markers, we identified gut-immune phenotypes and their clinical, demographic, and stigma-related correlates.</div></div><div><h3>Results</h3><div>Three immune profiles emerged: (1) <em>low gut-immune dysregulation</em> with lower microbial translocation, macrophage activation, inflammation, and tryptophan catabolism; (2) <em>moderate gut-immune dysregulation</em> with all markers within average range; and (3) <em>high gut-immune dysregulation</em> with higher microbial translocation, immune activation, inflammation, and tryptophan catabolism. In adjusted analyses, higher viral load (one log10 copy/ml; <em>AOR</em> = 1.97, 95 % CI = 1.02–3.82), injection of methamphetamine (<em>AOR</em> = 3.60, 95 % CI = 1.23–10.50), and internalized stigma (<em>AOR</em> = 1.78, 95 % CI = 1.01–3.15) were associated with having a moderate gut-immune dysregulation profile. Additionally, higher viral load (<em>AOR</em> = 2.98, 95 % CI = 1.53–5.24) and injecting methamphetamine (<em>AOR</em> = 5.45, 95 % CI = 1.34–17.78) were associated with having a high gut-immune dysregulation profile.</div></div><div><h3>Conclusions</h3><div>Distinct patterns of microbial translocation, immune activation, inflammation, and metabolism of amino acid precursors distinguished gut-immune phenotypes of PWH reporting injection methamphetamine use and greater internalized stigma. Interventions tailored to PWH who inject methamphetamine or struggle with internalized stigma could optimize HIV-related health outcomes.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"51 ","pages":"Article 101156"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101148
Silvia Flaj Prados , Esperanza Herradón Pliego , Carlos Goicoechea Garcia , Eva Ma Sánchez-Robles , Lars Arendt-Nielsen , Cesar Fernández-de-las-Peñas , Visitación López-Miranda
Introduction
Many COVID-19 survivors suffer long-term multi-organ damage leading to some symptoms such as brain fog. Around 25 % of patients report persistent memory loss, concentration difficulties, or other cognitive impairments after a SARS-COV-2 infection. Animal models are crucial for studying the pathophysiology of post-acute COVID-19 sequelae (PASC).
Objective
To assess the presence of neuro-inflammatory and glial activation biomarkers in brain tissue after a SARS-CoV-2 infection in an animal model to better understand the pathophysiology of neurocognitive symptoms.
Methods
Twelve C57BL/6 female hACE2 mice infected with SARS-CoV-2 Omicron variant (BA.1.17 lineage) and eleven non-infected female mice were included. Different proteins evaluating the innate immune activation in neuro-inflammation (TLR4, MyD88, NF-κB signalling pathway), inflammatory state (interleukins IL-6, IL-18 and IL-1β), and glial neuro-inflammatory response (CD11d, Iba1, GFAP expression) were evaluated from cerebral tissue 28 days after infection.
Results
As compared to non-infected mice, significant higher (p = 0.014) post-COVID expression of IL-18 (suggesting an inflammatory state) and significant higher (p = 0.0473) post-COVID GFAP expression (indicating enhanced astrocytic glia activation in response to the infection) was observed in brain tissue. No significant differences in TLR4 (p = 0.512), MyD88 (p = 0.151), NF-κB p65 (p = 0.712), IL-6 (p = 0.962), IL-1β (p = 0.343), CD11d (p = 0.750), and Iba1 (p = 0.935) expressions were observed.
Conclusions
This study provides evidence on brain neuro-inflammation, highlighting glial activation and IL-18 overexpression after an acute SARS-CoV-2 infection. These findings improve current understanding of post-COVID neuroinflammation and could aid in the design of treatment strategies for persistent neurological sequelae, such as cognitive impairment and mental confusion.
{"title":"Glial activation and increase in cerebral pro-inflammatory cytokine expression in a female animal post-COVID model","authors":"Silvia Flaj Prados , Esperanza Herradón Pliego , Carlos Goicoechea Garcia , Eva Ma Sánchez-Robles , Lars Arendt-Nielsen , Cesar Fernández-de-las-Peñas , Visitación López-Miranda","doi":"10.1016/j.bbih.2025.101148","DOIUrl":"10.1016/j.bbih.2025.101148","url":null,"abstract":"<div><h3>Introduction</h3><div>Many COVID-19 survivors suffer long-term multi-organ damage leading to some symptoms such as brain fog. Around 25 % of patients report persistent memory loss, concentration difficulties, or other cognitive impairments after a SARS-COV-2 infection. Animal models are crucial for studying the pathophysiology of post-acute COVID-19 sequelae (PASC).</div></div><div><h3>Objective</h3><div>To assess the presence of neuro-inflammatory and glial activation biomarkers in brain tissue after a SARS-CoV-2 infection in an animal model to better understand the pathophysiology of neurocognitive symptoms.</div></div><div><h3>Methods</h3><div>Twelve C57BL/6 female hACE2 mice infected with SARS-CoV-2 Omicron variant (BA.1.17 lineage) and eleven non-infected female mice were included. Different proteins evaluating the innate immune activation in neuro-inflammation (TLR4, MyD88, NF-κB signalling pathway), inflammatory state (interleukins IL-6, IL-18 and IL-1β), and glial neuro-inflammatory response (CD11d, Iba1, GFAP expression) were evaluated from cerebral tissue 28 days after infection.</div></div><div><h3>Results</h3><div>As compared to non-infected mice, significant higher (p = 0.014) post-COVID expression of IL-18 (suggesting an inflammatory state) and significant higher (p = 0.0473) post-COVID GFAP expression (indicating enhanced astrocytic glia activation in response to the infection) was observed in brain tissue. No significant differences in TLR4 (p = 0.512), MyD88 (p = 0.151), NF-κB p65 (p = 0.712), IL-6 (p = 0.962), IL-1β (p = 0.343), CD11d (p = 0.750), and Iba1 (p = 0.935) expressions were observed.</div></div><div><h3>Conclusions</h3><div>This study provides evidence on brain neuro-inflammation, highlighting glial activation and IL-18 overexpression after an acute SARS-CoV-2 infection. These findings improve current understanding of post-COVID neuroinflammation and could aid in the design of treatment strategies for persistent neurological sequelae, such as cognitive impairment and mental confusion.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101148"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.bbih.2025.101135
Kao Yamaoka , Yuri Ishii , Yuri Terasawa
Systemic inflammation affects psychological processes. Although the association between inflammation and psychophysiological state has been extensively investigated in patients with depression or inflammatory disease, how this relationship manifests in healthy individuals is not clearly known. Not all individuals exhibit distress in response to elevated inflammatory markers, suggesting the presence of psychological moderators. Elucidating the effect of elevated inflammatory markers on healthy adults would broaden the understanding of the relationship between inflammation and psychophysiological state. We investigated the moderating effect of individual factors, including emotion regulation, sleep quality, and interoceptive awareness, on the relationship between inflammatory markers and psychophysiological states in healthy adults. A total of 155 participants aged 30–59 years were assessed for inflammatory markers, individual factors, and subjective psychological and physical symptoms. Hierarchical regression and interaction models revealed that individuals with poor emotion regulation or low-quality sleep showed stronger associations between inflammatory markers and symptoms such as fatigue, somatic complaints, depression, and anxiety. Conversely, individuals with effective emotion regulation or high-quality sleep exhibited attenuated or even reversed associations, suggesting protective effects. Interoceptive awareness showed weaker and more context-dependent moderating effects. These results highlight the importance of psychological traits in modulating the effects of inflammation on mental and physical well-being in clinically healthy adults. Targeted interventions for enhancing emotion regulation and sleep quality may mitigate the psycho-physiological burden of inflammation and reduce the risk of future disease onset. The findings underscore the need for individualized psychoneuroimmunological models that incorporate trait-level moderators to explain variability in stress-related health outcomes.
{"title":"Moderating effects of individual factors on the relationship between inflammation and psychophysiological states in healthy adults","authors":"Kao Yamaoka , Yuri Ishii , Yuri Terasawa","doi":"10.1016/j.bbih.2025.101135","DOIUrl":"10.1016/j.bbih.2025.101135","url":null,"abstract":"<div><div>Systemic inflammation affects psychological processes. Although the association between inflammation and psychophysiological state has been extensively investigated in patients with depression or inflammatory disease, how this relationship manifests in healthy individuals is not clearly known. Not all individuals exhibit distress in response to elevated inflammatory markers, suggesting the presence of psychological moderators. Elucidating the effect of elevated inflammatory markers on healthy adults would broaden the understanding of the relationship between inflammation and psychophysiological state. We investigated the moderating effect of individual factors, including emotion regulation, sleep quality, and interoceptive awareness, on the relationship between inflammatory markers and psychophysiological states in healthy adults. A total of 155 participants aged 30–59 years were assessed for inflammatory markers, individual factors, and subjective psychological and physical symptoms. Hierarchical regression and interaction models revealed that individuals with poor emotion regulation or low-quality sleep showed stronger associations between inflammatory markers and symptoms such as fatigue, somatic complaints, depression, and anxiety. Conversely, individuals with effective emotion regulation or high-quality sleep exhibited attenuated or even reversed associations, suggesting protective effects. Interoceptive awareness showed weaker and more context-dependent moderating effects. These results highlight the importance of psychological traits in modulating the effects of inflammation on mental and physical well-being in clinically healthy adults. Targeted interventions for enhancing emotion regulation and sleep quality may mitigate the psycho-physiological burden of inflammation and reduce the risk of future disease onset. The findings underscore the need for individualized psychoneuroimmunological models that incorporate trait-level moderators to explain variability in stress-related health outcomes.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101135"},"PeriodicalIF":3.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sleep is a fundamental physiological state essential for immune function, metabolic regulation, and recovery from illness. During infection, sleep patterns are altered in a stereotyped fashion-characterized by increased non-rapid eye movement (NREM) sleep and reduced rapid eye movement (REM) sleep. These sleep changes are not incidental consequences of illness but reflect an evolutionarily conserved neuroimmune adaptation driven by proinflammatory cytokines. In particular, interleukin 1b (IL-1b) and tumor necrosis factor-a (TNFa) modulate sleep by acting directly on central nervous system circuits, including the serotonergic system and homeostatic sleep regulation. In this review, we synthesize current knowledge on how IL-1b and TNFa interact with sleep-regulating networks to alter behavioral state transitions during immune challenge. We also explore the broader clinical relevance of cytokine-driven sleep changes across infectious, psychiatric, and neurodegenerative disorders, and highlight emerging therapeutic opportunities targeting neuroimmune pathways to restore sleep homeostasis. Understanding these interactions is essential for advancing mechanistic insight into sleep regulation and for improving clinical management of inflammation-related sleep disturbances.
{"title":"IL-1b and TNF-a-driven sleep alterations: Neuroimmune mechanisms and behavioral implications","authors":"Nathan Zhang , Kyungsoo Park , Shinjae Chung , Yeong Shin Yim","doi":"10.1016/j.bbih.2025.101139","DOIUrl":"10.1016/j.bbih.2025.101139","url":null,"abstract":"<div><div>Sleep is a fundamental physiological state essential for immune function, metabolic regulation, and recovery from illness. During infection, sleep patterns are altered in a stereotyped fashion-characterized by increased non-rapid eye movement (NREM) sleep and reduced rapid eye movement (REM) sleep. These sleep changes are not incidental consequences of illness but reflect an evolutionarily conserved neuroimmune adaptation driven by proinflammatory cytokines. In particular, interleukin 1b (IL-1b) and tumor necrosis factor-a (TNFa) modulate sleep by acting directly on central nervous system circuits, including the serotonergic system and homeostatic sleep regulation. In this review, we synthesize current knowledge on how IL-1b and TNFa interact with sleep-regulating networks to alter behavioral state transitions during immune challenge. We also explore the broader clinical relevance of cytokine-driven sleep changes across infectious, psychiatric, and neurodegenerative disorders, and highlight emerging therapeutic opportunities targeting neuroimmune pathways to restore sleep homeostasis. Understanding these interactions is essential for advancing mechanistic insight into sleep regulation and for improving clinical management of inflammation-related sleep disturbances.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101139"},"PeriodicalIF":3.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145521108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.bbih.2025.101138
Isabel Garcia , Fatmanur Kilic , Chris-Ann Bryan , Jose Castro-Vildosola , Sai Anusha Jonnalagadda , Akhila Kasturi , Jacqueline Tilly , Jordyn Smith , Sofia Valentin , Sergio Moncayo , Tamara Hala , Eric Klein , Brian F. Corbett
Psychological stress causes gut dysbiosis, which is associated with adverse effects on physical and mental health in humans and mice. Identifying taxa of gut bacteria changed by stress, and whether stress differentially alters their relative abundance in males and females, has important implications for stress-related disorders. We modeled individual differences in resilience or susceptibility using the chronic social defeat stress (CSDS) paradigm. Here, C57BL/6 mice are exposed to a novel retired breeder CD-1 aggressor for 10 min per day for 10 days. In this paradigm, resilient and susceptible subpopulations can be identified using the social interaction paradigm following CSDS. Fecal samples were collected immediately following Day 1 and Day 10 of CSDS. 16S ribosomal RNA sequencing was used to identify the relative abundance of 200 bacteria species. We analyzed group differences in phyla, genera, and species in resilient, susceptible, and non-stressed control male and female C57/BL/6 intruders along with CD-1 aggressors. Stress reduced microbiome diversity and caused gut dysbiosis in all groups, including aggressors. These changes were not observed in non-stressed mice. CSDS altered the relative abundance of every gut bacteria phylum. CSDS reduced genera in the Firmicutes phylum whereas sex altered fewer genera. The relative abundance of an uncultured Ruminococcus species on Day 1 predicted social avoidance following CSDS, with a stronger correlation in stressed females compared to males. Together, our findings demonstrate that CSDS changes gut microbiome composition in male and female mice.
{"title":"Social stress changes gut microbiome composition in male, female, and aggressor mice","authors":"Isabel Garcia , Fatmanur Kilic , Chris-Ann Bryan , Jose Castro-Vildosola , Sai Anusha Jonnalagadda , Akhila Kasturi , Jacqueline Tilly , Jordyn Smith , Sofia Valentin , Sergio Moncayo , Tamara Hala , Eric Klein , Brian F. Corbett","doi":"10.1016/j.bbih.2025.101138","DOIUrl":"10.1016/j.bbih.2025.101138","url":null,"abstract":"<div><div>Psychological stress causes gut dysbiosis, which is associated with adverse effects on physical and mental health in humans and mice. Identifying taxa of gut bacteria changed by stress, and whether stress differentially alters their relative abundance in males and females, has important implications for stress-related disorders. We modeled individual differences in resilience or susceptibility using the chronic social defeat stress (CSDS) paradigm. Here, C57BL/6 mice are exposed to a novel retired breeder CD-1 aggressor for 10 min per day for 10 days. In this paradigm, resilient and susceptible subpopulations can be identified using the social interaction paradigm following CSDS. Fecal samples were collected immediately following Day 1 and Day 10 of CSDS. 16S ribosomal RNA sequencing was used to identify the relative abundance of 200 bacteria species. We analyzed group differences in phyla, genera, and species in resilient, susceptible, and non-stressed control male and female C57/BL/6 intruders along with CD-1 aggressors. Stress reduced microbiome diversity and caused gut dysbiosis in all groups, including aggressors. These changes were not observed in non-stressed mice. CSDS altered the relative abundance of every gut bacteria phylum. CSDS reduced genera in the Firmicutes phylum whereas sex altered fewer genera. The relative abundance of an uncultured <em>Ruminococcus</em> species on Day 1 predicted social avoidance following CSDS, with a stronger correlation in stressed females compared to males. Together, our findings demonstrate that CSDS changes gut microbiome composition in male and female mice.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101138"},"PeriodicalIF":3.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.bbih.2025.101137
Luise Victoria Claaß , Franziska Schick , Tonia Rocktäschel , Alejandra P. Garza , Christian Gaser , Philipp A. Reuken , Andreas Stallmach , Kathrin Finke , Sharmili Edwin Thanarajah , Martin Walter , Ildiko Rita Dunay , Bianca Besteher , Nils Opel
Background
Obesity, a condition associated with low-grade peripheral inflammation, is an independent risk factor for severe COVID-19 and has been linked to structural brain alterations. Given that post-COVID condition (PCC) is also associated with structural brain abnormalities and lingering immunological alterations, this study aimed to assess whether obesity contributes to these neural and immunological differences in PCC patients.
Methods
We investigated a previously established cohort of PCC patients (n = 61), recruited between April 2021 and June 2022. Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry (VBM). Obesity, as measured by body mass index (BMI), as well as age, sex, and total intracranial volume (TIV), were included as regressors in a linear model. Signature immunological markers were quantified in 50 participants using a LEGENDplex™ multiplex bead-based assay.
Results
A significant negative association was found between BMI and GMV in the right thalamus (p(FWE) = 0.039, k = 209, TFCE = 1037.97, x = 18, y = −21, z = 8). Moreover, BMI and thalamic GMV were significantly associated with immunological markers in PCC. Specifically, BMI was positively associated with Interleukin-6 (p = 0.021) and negatively with Interleukin-7 (p = 0.021), while GMV showed positive associations with Interleukin-8 (p = 0.05).
Conclusion
The results suggest that BMI contributes to GMV alterations in PCC patients, with both BMI and GMV demonstrating correlations with peripheral immunological markers. These findings indicate that converging mechanisms involving inflammation and structural brain alterations may contribute to obesity and PCC.
背景：肥胖是一种与低度外周炎症相关的疾病，是严重COVID-19的独立危险因素，与大脑结构改变有关。鉴于新冠肺炎后状态（PCC）也与结构性脑异常和持续的免疫改变有关，本研究旨在评估肥胖是否与PCC患者的这些神经和免疫差异有关。方法：我们调查了先前建立的PCC患者队列（n = 61），于2021年4月至2022年6月招募。全脑灰质体积（GMV）比较采用基于体素的形态测量法（VBM）。通过体重指数（BMI）以及年龄、性别和总颅内容积（TIV）测量的肥胖作为回归因子纳入线性模型。使用基于LEGENDplex™的多重头部检测对50名参与者的特征免疫标记物进行量化。结果BMI与右丘脑GMV呈显著负相关（p(FWE) = 0.039, k = 209, TFCE = 1037.97, x = 18, y = - 21, z = 8）。此外，BMI和丘脑GMV与PCC的免疫标志物显著相关。其中，BMI与白细胞介素-6呈正相关（p = 0.021），与白细胞介素-7呈负相关（p = 0.021）， GMV与白细胞介素-8呈正相关（p = 0.05）。结论BMI与PCC患者GMV的改变有关，BMI和GMV均与外周血免疫标志物相关。这些发现表明，涉及炎症和脑结构改变的趋同机制可能导致肥胖和PCC。
{"title":"Relationship between body mass index, gray matter volume and peripheral inflammation in patients with post-COVID condition","authors":"Luise Victoria Claaß , Franziska Schick , Tonia Rocktäschel , Alejandra P. Garza , Christian Gaser , Philipp A. Reuken , Andreas Stallmach , Kathrin Finke , Sharmili Edwin Thanarajah , Martin Walter , Ildiko Rita Dunay , Bianca Besteher , Nils Opel","doi":"10.1016/j.bbih.2025.101137","DOIUrl":"10.1016/j.bbih.2025.101137","url":null,"abstract":"<div><h3>Background</h3><div>Obesity, a condition associated with low-grade peripheral inflammation, is an independent risk factor for severe COVID-19 and has been linked to structural brain alterations. Given that post-COVID condition (PCC) is also associated with structural brain abnormalities and lingering immunological alterations, this study aimed to assess whether obesity contributes to these neural and immunological differences in PCC patients.</div></div><div><h3>Methods</h3><div>We investigated a previously established cohort of PCC patients (n = 61), recruited between April 2021 and June 2022. Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry (VBM). Obesity, as measured by body mass index (BMI), as well as age, sex, and total intracranial volume (TIV), were included as regressors in a linear model. Signature immunological markers were quantified in 50 participants using a LEGENDplex™ multiplex bead-based assay.</div></div><div><h3>Results</h3><div>A significant negative association was found between BMI and GMV in the right thalamus (p(FWE) = 0.039, k = 209, TFCE = 1037.97, x = 18, y = −21, z = 8). Moreover, BMI and thalamic GMV were significantly associated with immunological markers in PCC. Specifically, BMI was positively associated with Interleukin-6 (p = 0.021) and negatively with Interleukin-7 (p = 0.021), while GMV showed positive associations with Interleukin-8 (p = 0.05).</div></div><div><h3>Conclusion</h3><div>The results suggest that BMI contributes to GMV alterations in PCC patients, with both BMI and GMV demonstrating correlations with peripheral immunological markers. These findings indicate that converging mechanisms involving inflammation and structural brain alterations may contribute to obesity and PCC.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101137"},"PeriodicalIF":3.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145521107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.bbih.2025.101136
Shao-Cheng Wang , Chih-Hui Wang , Tung-Hsia Liu , Hsian-Wei Kuo , Yu-Li Liu
Alcohol dependence significantly impacts both physiological and psychological health and is strongly linked to increased suicide attempt. However, the neurobiological mechanisms connecting alcohol use disorder (AUD) to suicidality remain inadequately understood. This study evaluated the severity of alcohol dependence in 24 patients diagnosed with AUD using the Alcohol Use Disorders Identification Test (AUDIT). In parallel, peripheral blood levels of neurofilament light chain (NfL), a bioindicator of neuronal injury, and serotonin, a neurotransmitter implicated in mood regulation and suicidality, were quantified. One patient with a prior history of suicide attempts exhibited markedly elevated plasma NfL levels (1350 pg/ml), greatly exceeding the mean observed in non-suicidal AUD patients (33.06 pg/ml). Despite the absence of detectable brain abnormalities on imaging, the patient presented with a lumbar vertebral burst fracture, suggesting spinal cord trauma as the source of neuronal injury. Moreover, serotonin levels in this individual were substantially reduced (89.41 ng/ml) relative to the group average (340.5 ng/ml). These findings suggest that elevated NfL levels may reflect neural injury originating from spinal, rather than cerebral, sources in AUD patients with suicide attempts. Additionally, reduced serotonin levels may serve as a clinically useful bioindicator to stratify suicide attempt in this population.
{"title":"Serotonin and neurofilament light chain in alcohol-related suicide: Preliminary case observations","authors":"Shao-Cheng Wang , Chih-Hui Wang , Tung-Hsia Liu , Hsian-Wei Kuo , Yu-Li Liu","doi":"10.1016/j.bbih.2025.101136","DOIUrl":"10.1016/j.bbih.2025.101136","url":null,"abstract":"<div><div>Alcohol dependence significantly impacts both physiological and psychological health and is strongly linked to increased suicide attempt. However, the neurobiological mechanisms connecting alcohol use disorder (AUD) to suicidality remain inadequately understood. This study evaluated the severity of alcohol dependence in 24 patients diagnosed with AUD using the Alcohol Use Disorders Identification Test (AUDIT). In parallel, peripheral blood levels of neurofilament light chain (NfL), a bioindicator of neuronal injury, and serotonin, a neurotransmitter implicated in mood regulation and suicidality, were quantified. One patient with a prior history of suicide attempts exhibited markedly elevated plasma NfL levels (1350 pg/ml), greatly exceeding the mean observed in non-suicidal AUD patients (33.06 pg/ml). Despite the absence of detectable brain abnormalities on imaging, the patient presented with a lumbar vertebral burst fracture, suggesting spinal cord trauma as the source of neuronal injury. Moreover, serotonin levels in this individual were substantially reduced (89.41 ng/ml) relative to the group average (340.5 ng/ml). These findings suggest that elevated NfL levels may reflect neural injury originating from spinal, rather than cerebral, sources in AUD patients with suicide attempts. Additionally, reduced serotonin levels may serve as a clinically useful bioindicator to stratify suicide attempt in this population.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101136"},"PeriodicalIF":3.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.bbih.2025.101134
Martí Llaurador-Coll , Itziar Montalvo , Francesc Estrada , Vanessa Sánchez-Gistau , Henrik Zetterberg , Javier Labad , Andrea L. Benedet , Elisabet Vilella
Background
Early diagnosis of psychosis is crucial, and biomarker detection may provide insights into the pathophysiology of psychosis and the potential for the development of early diagnostic tools. In particular, blood-based proteomic profiling has yielded promising results for psychiatric disorders because of the use of novel high-throughput techniques and the feasibility of performing blood extractions in routine clinical practice.
Study design and methodology
Here, we studied 182 participants (33.3 % females, age = 24.66 ± 5.05), comprising 50 healthy controls (HCs), 37 patients with an at-risk mental state (ARMS) and 95 patients with a first episode of psychosis (FEP). We used a panel of 92 neurology-related proteins in a multiplex immunoassay to identify the plasma protein profiles of each group, their coexpression patterns and biological relevance, and their associations with psychotic symptoms and cognitive performance.
Results
CPA2 was overexpressed in both ARMS participants (β = 0.876, adj. p = 0.009) and FEP participants (β = 0.568, adj. p = 0.011) compared with HCs. In FEP participants, in addition to CPA2, 31 other proteins were overexpressed, with GFRA1 being the most differentially expressed protein (β = 1.159, adj. p < 0.001). Coexpression clusters in FEP patients were involved in several biological processes, such as the regulation of myelination, cell adhesion, multicellular organismal processes and axon guidance. In ARMS patients, THY1 expression was inversely correlated with symptom severity (ρ = −0.640, adj. p = 0.039), and IL12 expression was correlated with cognitive performance (ρ = 0.707, adj. p = 0.007); however, no further correlations were found after the false discovery rate adjustment.
Conclusions
Our findings suggest the involvement of CPA2, GFRA1 and IL12, among other neurology-related proteins, in the early phases of psychosis, which, if confirmed, could become promising biomarkers for diagnosis, psychotic symptom development and psychosis-associated cognitive impairment. However, future studies with larger samples, a longitudinal design, and more extensive proteomic panels are needed to validate these biomarkers and refine their clinical applicability.
背景精神病的诊断是至关重要的，生物标志物检测可以提供对精神病病理生理学的见解和早期诊断工具的发展潜力。特别是，基于血液的蛋白质组学分析在精神疾病方面产生了有希望的结果，因为使用了新的高通量技术和在常规临床实践中进行血液提取的可行性。研究设计和方法在这里，我们研究了182名参与者（33.3%为女性，X - age = 24.66±5.05），其中包括50名健康对照（hc）， 37名有危险精神状态（ARMS）的患者和95名有首发精神病（FEP）的患者。我们在多重免疫分析中使用了一组92种神经学相关蛋白，以确定每组的血浆蛋白谱、它们的共表达模式和生物学相关性，以及它们与精神病症状和认知表现的关联。结果scpa2在ARMS组（β = 0.876, adj. p = 0.009）和FEP组（β = 0.568, adj. p = 0.011）与hc组相比均过表达。在FEP参与者中，除了CPA2外，还有31种其他蛋白过表达，其中GFRA1是差异表达最多的蛋白（β = 1.159, adj. p < 0.001）。FEP患者的共表达簇参与多个生物学过程，如髓鞘形成、细胞粘附、多细胞有机体过程和轴突引导的调节。在ARMS患者中，THY1表达与症状严重程度呈负相关（ρ = - 0.640, adj. p = 0.039）， IL12表达与认知能力相关（ρ = 0.707, adj. p = 0.007）；然而，调整错误发现率后，没有发现进一步的相关性。结论研究结果提示CPA2、GFRA1和IL12等神经相关蛋白参与了精神病的早期阶段，如果得到证实，这些蛋白可能成为诊断、精神病症状发展和精神病相关认知障碍的有希望的生物标志物。然而，未来的研究需要更大的样本，纵向设计和更广泛的蛋白质组学面板来验证这些生物标志物并完善其临床适用性。
{"title":"Plasma profiles of neurology-related proteins in at-risk mental state and first-episode psychosis: Associations with psychotic symptoms and cognitive performance","authors":"Martí Llaurador-Coll , Itziar Montalvo , Francesc Estrada , Vanessa Sánchez-Gistau , Henrik Zetterberg , Javier Labad , Andrea L. Benedet , Elisabet Vilella","doi":"10.1016/j.bbih.2025.101134","DOIUrl":"10.1016/j.bbih.2025.101134","url":null,"abstract":"<div><h3>Background</h3><div>Early diagnosis of psychosis is crucial, and biomarker detection may provide insights into the pathophysiology of psychosis and the potential for the development of early diagnostic tools. In particular, blood-based proteomic profiling has yielded promising results for psychiatric disorders because of the use of novel high-throughput techniques and the feasibility of performing blood extractions in routine clinical practice.</div></div><div><h3>Study design and methodology</h3><div>Here, we studied 182 participants (33.3 % females, <span><math><mrow><mover><mi>X</mi><mo>‾</mo></mover></mrow></math></span><sub>age</sub> = 24.66 ± 5.05), comprising 50 healthy controls (HCs), 37 patients with an at-risk mental state (ARMS) and 95 patients with a first episode of psychosis (FEP). We used a panel of 92 neurology-related proteins in a multiplex immunoassay to identify the plasma protein profiles of each group, their coexpression patterns and biological relevance, and their associations with psychotic symptoms and cognitive performance.</div></div><div><h3>Results</h3><div>CPA2 was overexpressed in both ARMS participants (β = 0.876, adj. p = 0.009) and FEP participants (β = 0.568, adj. p = 0.011) compared with HCs. In FEP participants, in addition to CPA2, 31 other proteins were overexpressed, with GFRA1 being the most differentially expressed protein (β = 1.159, adj. p < 0.001). Coexpression clusters in FEP patients were involved in several biological processes, such as the regulation of myelination, cell adhesion, multicellular organismal processes and axon guidance. In ARMS patients, THY1 expression was inversely correlated with symptom severity (ρ = −0.640, adj. p = 0.039), and IL12 expression was correlated with cognitive performance (ρ = 0.707, adj. p = 0.007); however, no further correlations were found after the false discovery rate adjustment.</div></div><div><h3>Conclusions</h3><div>Our findings suggest the involvement of CPA2, GFRA1 and IL12, among other neurology-related proteins, in the early phases of psychosis, which, if confirmed, could become promising biomarkers for diagnosis, psychotic symptom development and psychosis-associated cognitive impairment. However, future studies with larger samples, a longitudinal design, and more extensive proteomic panels are needed to validate these biomarkers and refine their clinical applicability.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101134"},"PeriodicalIF":3.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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