Pub Date : 2025-12-28DOI: 10.1016/j.bbi.2025.106249
Erik D. Wiström , Julian Fuhrer , Alexey Shadrin , Vera Fominykh , Kevin S. O’Connell , Piotr Jaholkowski , Nils Eiel Steen , Sara E. Stinson , Pravesh Parekh , Oleksandr Frei , Linn Rødevand , Nadine Parker , Jan Haavik , Srdjan Djurovic , Anders M. Dale , Ole A. Andreassen , Olav B. Smeland
Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune thyroiditis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes), involving a total of 667,518 cases from 10 genome-wide association studies. While MD was positively genetically correlated with five autoimmune diseases, BD and SCZ were only positively correlated with IBD, suggesting differences in the genetic signal shared with autoimmunity across these mental disorders. A considerable fraction of genetic variants influencing autoimmune diseases (range 17.1–88.4 %) was estimated to overlap with mental disorders; however, this constitutes only a minor part of genetic variants influencing the more polygenic mental disorders. Finally, we identified 172 genetic loci jointly affecting mental disorders and autoimmune diseases, implicating both lipid metabolism and TNF signaling. In conclusion, MD, BD, and SCZ have a small but distinct genetic overlap with autoimmune diseases, which may inform new possible immune targets for treatment in mental illness.
{"title":"Dissecting the genetic relationship between severe mental disorders and autoimmune diseases","authors":"Erik D. Wiström , Julian Fuhrer , Alexey Shadrin , Vera Fominykh , Kevin S. O’Connell , Piotr Jaholkowski , Nils Eiel Steen , Sara E. Stinson , Pravesh Parekh , Oleksandr Frei , Linn Rødevand , Nadine Parker , Jan Haavik , Srdjan Djurovic , Anders M. Dale , Ole A. Andreassen , Olav B. Smeland","doi":"10.1016/j.bbi.2025.106249","DOIUrl":"10.1016/j.bbi.2025.106249","url":null,"abstract":"<div><div>Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune thyroiditis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes), involving a total of 667,518 cases from 10 genome-wide association studies. While MD was positively genetically correlated with five autoimmune diseases, BD and SCZ were only positively correlated with IBD, suggesting differences in the genetic signal shared with autoimmunity across these mental disorders. A considerable fraction of genetic variants influencing autoimmune diseases (range 17.1–88.4 %) was estimated to overlap with mental disorders; however, this constitutes only a minor part of genetic variants influencing the more polygenic mental disorders. Finally, we identified 172 genetic loci jointly affecting mental disorders and autoimmune diseases, implicating both lipid metabolism and TNF signaling. In conclusion, MD, BD, and SCZ have a small but distinct genetic overlap with autoimmune diseases, which may inform new possible immune targets for treatment in mental illness.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106249"},"PeriodicalIF":7.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-25DOI: 10.1016/j.bbi.2025.106246
Madison M. Garvin , Urjoshi Kar , Cassandra L. Kooiker , Jessica L. Bolton
<div><div>Early-life adversity (ELA) is a significant risk factor for emotional disorders like depression, likely due to changes in stress-related circuit development. We have previously shown that ELA increases the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) by decreasing microglial synapse engulfment. Here, we hypothesize that ELA induces microglial dysfunction via inhibition of the microglial phagocytic receptor, MerTK, thus resulting in the observed changes in synapses and stress-related behavior. To determine whether deleting MerTK in microglia phenocopies the effects of ELA, microglia-specific conditional knockout (m)MerTK-KO (CX3CR1-Cre<sup>+</sup>::MerTK<sup>fl/fl</sup>) mice were crossed with ‘wild-type’ (CX3CR1-Cre<sup>-</sup>::MerTK<sup>fl/fl</sup>) mice, and their litters were reared in either a control or ELA (induced by limited bedding and nesting) environment, from postnatal days (P)2–10. Excitatory synapses in the PVN were assessed at P10, microglial engulfment was assessed at P8, and adult offspring were tested in a behavioral battery to measure threat-response (known to be dependent on PVN-CRH+ neurons) and anxiety-like behavior, followed by acute restraint stress to measure the neuroendocrine stress response. Following ELA at P10, we find that excitatory, but not inhibitory, synapses in the PVN are increased in males, which is mimicked by mMerTK-KO in control males, but causes no further increase in ELA males. Correspondingly, ELA and mMerTK-KO decrease microglial engulfment of excitatory presynaptic terminals at P8 in males. In contrast, females already have higher numbers of excitatory synapses at baseline, and exhibit no further increase with ELA or mMerTK-KO. Remarkably, the pattern of threat-response behavior in males closely matches the excitatory synapses, with mMerTK-KO control males escaping more from the simulated predator threat in the looming-shadow threat task, similar to ELA males. Again, females do not show any significant changes due to ELA or mMerTK-KO in the threat-response, although they do exhibit ELA-induced changes in anxiety-like behavior. ELA provokes a greater corticosterone response to acute stress in males, but not females, although females were again already higher at baseline. In sum, our results demonstrate that ELA provokes decreased microglial engulfment during development, leading to increased excitatory synapses in the PVN and an increased active response to threat in the looming-shadow test in males only. Deleting MerTK specifically from microglia recapitulates both the synaptic and behavioral effects in control males, but does not have an effect in ELA males or control females, suggesting that the MerTK pathway is already inhibited by ELA in males and less active in females at baseline. Our work is the first to elucidate the mechanisms underlying the male-biased microglial dysfunction caused by ELA, with prom
早期生活逆境（ELA）是抑郁症等情绪障碍的重要风险因素，可能会引发与压力相关的神经回路发育的变化。我们之前的研究表明，ELA通过减少小胶质突触的吞噬，增加了室旁核（PVN）中表达促肾上腺皮质激素释放激素（CRH）的神经元上的兴奋性突触的数量。在这里，我们假设ELA通过抑制小胶质吞噬受体MerTK诱导小胶质功能障碍，从而导致观察到的突触和应激相关行为的变化。为了确定在小胶质细胞中删除MerTK是否会影响ELA的作用，将小胶质细胞特异性条件敲除(m)MerTK- ko （CX3CR1-Cre+::MerTKfl/fl）小鼠与“野生型”（CX3CR1-Cre-::MerTKfl/fl）小鼠杂交，并将它们的窝仔从出生后2-10天(P)开始饲养在对照或ELA（由有限的床上和筑巢诱导）环境中。在P10时评估PVN中的兴奋性突触，在P8时评估小胶质吞噬，并在行为电池中测试成年后代以测量威胁反应（已知依赖PVN- crh + 神经元）和焦虑样行为，随后进行急性约束应激以测量神经内分泌应激反应。在P10发生ELA后，我们发现雄性PVN中的兴奋性突触增加，而不是抑制性突触增加，这在对照雄性中被mMerTK-KO模仿，但ELA雄性没有进一步增加。相应地，ELA和mMerTK-KO减少雄性P8兴奋性突触前末端的小胶质吞噬。相比之下，雌性在基线时已经有更多的兴奋性突触，并且在ELA或mMerTK-KO组中没有进一步增加。值得注意的是，雄性的威胁-反应行为模式与兴奋性突触密切匹配，mMerTK-KO控制的雄性在隐现阴影威胁任务中更多地逃避模拟捕食者的威胁，与ELA雄性相似。同样，女性在威胁反应中没有表现出ELA或mMerTK-KO的显著变化，尽管她们确实表现出ELA引起的焦虑样行为的变化。ELA在男性中对急性应激的皮质酮反应更强，而在女性中没有，尽管女性在基线时已经更高了。总之，我们的研究结果表明，ELA在发育过程中引起小胶质细胞吞噬减少，导致PVN中兴奋性突触增加，并且在阴影测试中对威胁的积极反应增加。从小胶质细胞中特异性删除MerTK在对照雄性小鼠中具有突触和行为效应，但对ELA雄性小鼠和对照组雌性小鼠均无影响，这表明MerTK通路在雄性小鼠中已被ELA抑制，而雌性小鼠在基线时活性较低。我们的研究首次阐明了由ELA引起的男性偏向性小胶质细胞功能障碍的机制，有望为高危儿童开发更好的预防和治疗策略。
{"title":"Deletion of the microglial phagocytic receptor MerTK mimics early-life adversity-induced changes in synapses and behavior in male mice","authors":"Madison M. Garvin , Urjoshi Kar , Cassandra L. Kooiker , Jessica L. Bolton","doi":"10.1016/j.bbi.2025.106246","DOIUrl":"10.1016/j.bbi.2025.106246","url":null,"abstract":"<div><div>Early-life adversity (ELA) is a significant risk factor for emotional disorders like depression, likely due to changes in stress-related circuit development. We have previously shown that ELA increases the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) by decreasing microglial synapse engulfment. Here, we hypothesize that ELA induces microglial dysfunction via inhibition of the microglial phagocytic receptor, MerTK, thus resulting in the observed changes in synapses and stress-related behavior. To determine whether deleting MerTK in microglia phenocopies the effects of ELA, microglia-specific conditional knockout (m)MerTK-KO (CX3CR1-Cre<sup>+</sup>::MerTK<sup>fl/fl</sup>) mice were crossed with ‘wild-type’ (CX3CR1-Cre<sup>-</sup>::MerTK<sup>fl/fl</sup>) mice, and their litters were reared in either a control or ELA (induced by limited bedding and nesting) environment, from postnatal days (P)2–10. Excitatory synapses in the PVN were assessed at P10, microglial engulfment was assessed at P8, and adult offspring were tested in a behavioral battery to measure threat-response (known to be dependent on PVN-CRH+ neurons) and anxiety-like behavior, followed by acute restraint stress to measure the neuroendocrine stress response. Following ELA at P10, we find that excitatory, but not inhibitory, synapses in the PVN are increased in males, which is mimicked by mMerTK-KO in control males, but causes no further increase in ELA males. Correspondingly, ELA and mMerTK-KO decrease microglial engulfment of excitatory presynaptic terminals at P8 in males. In contrast, females already have higher numbers of excitatory synapses at baseline, and exhibit no further increase with ELA or mMerTK-KO. Remarkably, the pattern of threat-response behavior in males closely matches the excitatory synapses, with mMerTK-KO control males escaping more from the simulated predator threat in the looming-shadow threat task, similar to ELA males. Again, females do not show any significant changes due to ELA or mMerTK-KO in the threat-response, although they do exhibit ELA-induced changes in anxiety-like behavior. ELA provokes a greater corticosterone response to acute stress in males, but not females, although females were again already higher at baseline. In sum, our results demonstrate that ELA provokes decreased microglial engulfment during development, leading to increased excitatory synapses in the PVN and an increased active response to threat in the looming-shadow test in males only. Deleting MerTK specifically from microglia recapitulates both the synaptic and behavioral effects in control males, but does not have an effect in ELA males or control females, suggesting that the MerTK pathway is already inhibited by ELA in males and less active in females at baseline. Our work is the first to elucidate the mechanisms underlying the male-biased microglial dysfunction caused by ELA, with prom","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106246"},"PeriodicalIF":7.6,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.bbi.2025.106236
Tony W. Wilson , Mikki Schantell , Sarah M. Dietz , Samantha H. Penhale , Kellen M. McDonald , Kyla R. De Luca , Molly E. Voller , Lan D. Volberding , Olivia R. Carusi , Lucy K. Horne , Yasra Arif , Ryan Glesinger , Jason A. John , Hannah J. Okelberry , Pamela E. May-Weeks , Adam J. Case , Matthew C. Zimmerman , Rachel K. Spooner
Introduction
Despite living a normal lifespan, people with HIV (PWH) are at a much greater risk of developing cognitive impairment. While the precise mechanisms are not fully understood, persistently high inflammation levels are thought to be a key contributor, as multiple studies have linked cognitive impairment and elevated inflammation. In contrast, evidence of a relationship between neural function and inflammatory activity is extremely limited in PWH and/or controls. Thus, in the current study, we integrate state-of-the-art dynamic functional brain mapping with measures of three inflammatory markers that have been widely reported as elevated in PWH.
Methods
A total of 142 participants (range: 20–66 years old; 64 PWH and 78 controls) completed a validated abstract reasoning task during magnetoencephalographic (MEG) imaging, underwent comprehensive neuropsychological testing, and provided a blood sample for plasma-based inflammatory marker analysis of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interferon γ-induced protein 10 (IP-10). The two groups were matched on age, sex, race/ethnicity, body-mass index (BMI), handedness, anxiety, substance use, and common medical conditions such as diabetes. Oscillatory neural responses supporting abstract reasoning were imaged by applying a beamformer to the processed MEG data, and whole-brain, voxel-wise analyses were conducted using each individual’s CRP, TNF-α and IP-10 concentrations, controlling for age and BMI, to identify the differential impact of inflammation on oscillatory neural dynamics in PWH.
Results
PWH exhibited significantly higher levels on each of the three inflammatory markers and performed more poorly on the abstract reasoning task than matched controls, with CRP levels being significantly related to performance across all participants. Critically, TNF-α levels were significantly related to the strength of theta oscillations during abstract reasoning in the left inferior frontal gyrus, with higher TNF-α scaling with weaker theta and the strength of this relationship differing by group. A similar relationship among increasing CRP levels and decreasing gamma oscillations was found in the left inferior parietal cortices, while increasing CRP was also associated with decreasing gamma in the right dorsolateral prefrontal cortex across both groups, with the latter being coupled to behavioral performance in controls.
Discussion
These findings provide the first evidence linking elevated inflammatory levels to altered brain dynamics and performance in PWH. Such data provides crucial empirical evidence supporting the long-held view that elevated inflammation may be central to the higher rates of cognitive decline in PWH. Future work should examine whether decreasing these inflammatory levels leads to improvements in cognitive function in PWH.
{"title":"Neural oscillations serving abstract reasoning are differentially associated with inflammatory markers in people with HIV","authors":"Tony W. Wilson , Mikki Schantell , Sarah M. Dietz , Samantha H. Penhale , Kellen M. McDonald , Kyla R. De Luca , Molly E. Voller , Lan D. Volberding , Olivia R. Carusi , Lucy K. Horne , Yasra Arif , Ryan Glesinger , Jason A. John , Hannah J. Okelberry , Pamela E. May-Weeks , Adam J. Case , Matthew C. Zimmerman , Rachel K. Spooner","doi":"10.1016/j.bbi.2025.106236","DOIUrl":"10.1016/j.bbi.2025.106236","url":null,"abstract":"<div><h3>Introduction</h3><div>Despite living a normal lifespan, people with HIV (PWH) are at a much greater risk of developing cognitive impairment. While the precise mechanisms are not fully understood, persistently high inflammation levels are thought to be a key contributor, as multiple studies have linked cognitive impairment and elevated inflammation. In contrast, evidence of a relationship between neural function and inflammatory activity is extremely limited in PWH and/or controls. Thus, in the current study, we integrate state-of-the-art dynamic functional brain mapping with measures of three inflammatory markers that have been widely reported as elevated in PWH.</div></div><div><h3>Methods</h3><div>A total of 142 participants (range: 20–66 years old; 64 PWH and 78 controls) completed a validated abstract reasoning task during magnetoencephalographic (MEG) imaging, underwent comprehensive neuropsychological testing, and provided a blood sample for plasma-based inflammatory marker analysis of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interferon γ-induced protein 10 (IP-10). The two groups were matched on age, sex, race/ethnicity, body-mass index (BMI), handedness, anxiety, substance use, and common medical conditions such as diabetes. Oscillatory neural responses supporting abstract reasoning were imaged by applying a beamformer to the processed MEG data, and whole-brain, voxel-wise analyses were conducted using each individual’s CRP, TNF-α and IP-10 concentrations, controlling for age and BMI, to identify the differential impact of inflammation on oscillatory neural dynamics in PWH.</div></div><div><h3>Results</h3><div>PWH exhibited significantly higher levels on each of the three inflammatory markers and performed more poorly on the abstract reasoning task than matched controls, with CRP levels being significantly related to performance across all participants. Critically, TNF-α levels were significantly related to the strength of theta oscillations during abstract reasoning in the left inferior frontal gyrus, with higher TNF-α scaling with weaker theta and the strength of this relationship differing by group. A similar relationship among increasing CRP levels and decreasing gamma oscillations was found in the left inferior parietal cortices, while increasing CRP was also associated with decreasing gamma in the right dorsolateral prefrontal cortex across both groups, with the latter being coupled to behavioral performance in controls.</div></div><div><h3>Discussion</h3><div>These findings provide the first evidence linking elevated inflammatory levels to altered brain dynamics and performance in PWH. Such data provides crucial empirical evidence supporting the long-held view that elevated inflammation may be central to the higher rates of cognitive decline in PWH. Future work should examine whether decreasing these inflammatory levels leads to improvements in cognitive function in PWH.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106236"},"PeriodicalIF":7.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.bbi.2025.106244
Mehwish Younas , Harry R. Deijnen , Ruth Stephens , Alison Harris , Thomas O. Williams , Sabrina Tamburrano , Ian E. Prise , Craig J. Smith , Stuart M. Allan , Laura McCulloch , John R. Grainger , Barry W. McColl
Distinct B cell populations are found in circulation, including those with innate-like properties, that have varied functions in pathogen protection, vaccination and immunoregulation. The effects of tissue injury on circulating B cell populations are poorly explored. Here we show that, following acute ischaemic stroke (AIS), a common cause of neurological disability associated with systemic immune dysfunction, the circulating B cell compartment has altered functionality, alongside marked reductions in marginal zone (MZ)-like B cells, an innate-like B cell subset. Of note, release of Immunoglobulin (Ig) M, a key innate-like B cell-derived factor important in anti-bacterial responses, and regulatory cytokines including IL-6 and IL-10, was impaired upon stimulation of sorted B cells from AIS patients. B cells express adrenergic receptors (ARs), in both control and AIS patients, and release of the β2-AR agonist noradrenaline (NA) is elevated acutely following stroke. In vitro exposure of B cells from healthy individuals to NA recapitulated some of the functional modulation observed in AIS patients. Moreover, increased cell death of MZ-like B cells was observed in response to NA. Secondary infection is a common post-stroke complication that could be responsible for altered B cell characteristics. However, in line with the impact of NA on B cell populations, alterations were largely driven by stroke rather than secondary infection. Taken together, these findings demonstrate that neuroimmune factors are an important signal that could rapidly modify defined B cell populations early after tissue injury and highlight altered innate-like B cell function as a previously unappreciated characteristic of the systemic immunological response to acute stroke.
{"title":"Acute ischaemic stroke alters the composition and function of circulating B cells","authors":"Mehwish Younas , Harry R. Deijnen , Ruth Stephens , Alison Harris , Thomas O. Williams , Sabrina Tamburrano , Ian E. Prise , Craig J. Smith , Stuart M. Allan , Laura McCulloch , John R. Grainger , Barry W. McColl","doi":"10.1016/j.bbi.2025.106244","DOIUrl":"10.1016/j.bbi.2025.106244","url":null,"abstract":"<div><div>Distinct B cell populations are found in circulation, including those with innate-like properties, that have varied functions in pathogen protection, vaccination and immunoregulation. The effects of tissue injury on circulating B cell populations are poorly explored. Here we show that, following acute ischaemic stroke (AIS), a common cause of neurological disability associated with systemic immune dysfunction, the circulating B cell compartment has altered functionality, alongside marked reductions in marginal zone (MZ)-like B cells, an innate-like B cell subset. Of note, release of Immunoglobulin (Ig) M, a key innate-like B cell-derived factor important in anti-bacterial responses, and regulatory cytokines including IL-6 and IL-10, was impaired upon stimulation of sorted B cells from AIS patients. B cells express adrenergic receptors (ARs), in both control and AIS patients, and release of the β2-AR agonist noradrenaline (NA) is elevated acutely following stroke. <em>In vitro</em> exposure of B cells from healthy individuals to NA recapitulated some of the functional modulation observed in AIS patients. Moreover, increased cell death of MZ-like B cells was observed in response to NA. Secondary infection is a common post-stroke complication that could be responsible for altered B cell characteristics. However, in line with the impact of NA on B cell populations, alterations were largely driven by stroke rather than secondary infection. Taken together, these findings demonstrate that neuroimmune factors are an important signal that could rapidly modify defined B cell populations early after tissue injury and highlight altered innate-like B cell function as a previously unappreciated characteristic of the systemic immunological response to acute stroke.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106244"},"PeriodicalIF":7.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.bbi.2025.106241
Yinxian Chen , Sarina Abrishamcar , Jasmine K. Aqua , Christian Dye , Linda C. Gallo , Maria M. Llabre , Frank J. Penedo , Carmen R. Isasi , Krista M. Perreira , Bharat Thyagarajan , Martha Daviglus , Amber Pirzada , Andrea Baccarelli , Karen N. Conneely , Rebecca Jones-Antwi , Shakira F. Suglia
Background
This study examined whether social factors, including social support, social networks, and familism, modify the longitudinal association between ACEs and epigenetic age acceleration (EAA).
Methods
We analyzed DNA methylation (DNAm) profile data from two visits (approximately six years apart) among 960 Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). GrimAge epigenetic age and DunedinPACE pace of aging were used. Linear mixed models examined effect modification of social support, social networks (network diversity and the number of embedded networks), and familism (family obligation, support, and as referents) on the association between high vs. low-to-moderate ACEs (i.e., ≥ 4 vs. < 4 ACEs) and repeatedly measured EAA. Models adjusted for age, sex, parental education, childhood economic hardship, nativity, and cell-type proportions. We also dichotomized the levels of social support and both subscales of social networks to low (≤ 75th percentile) and high (> 75th percentile), and assessed joint effect modification by social support and networks.
Results
The mean difference in GrimAge acceleration (AgeAccelGrim) between high and low-to-moderate ACEs was statistically significantly attenuated when social support levels were higher (β for interaction = -0.73 years; 95 % CI: −1.23, −0.24; p = 0.003). No evidence of effect modification was found for social networks or familism. Having only high social support (β for interaction = -1.40 years; 95 % CI: −2.79, −0.01; p = 0.049) or both high social support and network diversity (β for interaction = -1.57 years; 95 % CI: −2.72, −0.42; p = 0.008) significantly decreased the mean difference in AgeAccelGrim between high and low-to-moderate ACEs.
Conclusion
Social support may independently buffer the adverse impact of ACEs on biological age acceleration among Hispanic/Latino adults, and the buffering effect may be stronger when accompanied by diverse social networks.
背景：本研究探讨了社会支持、社会网络和家族主义等社会因素是否改变了ace与表观遗传年龄加速（EAA）之间的纵向关联。方法：我们分析了西班牙裔社区健康研究/拉丁裔研究（HCHS/SOL）中960名西班牙裔/拉丁裔成年人两次访问（间隔约6年）的DNA甲基化（DNAm）数据。采用GrimAge表观遗传年龄和DunedinPACE衰老速度。线性混合模型检验了社会支持、社会网络（网络多样性和嵌入网络的数量）和家庭主义（家庭义务、支持和作为参考）对高与低至中度ace（即≥4 vs 第75百分位）之间关联的效应修正，并评估了社会支持和网络的联合效应修正。结果：当社会支持水平较高时，高、低中度ace之间的平均grage加速（AgeAccelGrim）差异有统计学意义（β交互作用 = -0.73 年；95 % CI: -1.23, -0.24; p = 0.003）。没有证据表明社会网络或家庭主义的影响会改变。只有高社会支持(β互动 = -1.40 年;95年 % CI: -2.79, -0.01; p = 0.049)或高社会支持和网络多样性(β互动 = -1.57 年;95年 % CI: -2.72, -0.42; p = 0.008)显著下降的平均差AgeAccelGrim高和中度ace之间。结论：社会支持可以独立地缓冲ace对西班牙/拉丁裔成人生理年龄加速的不利影响，并且当社会网络多样化时，缓冲作用可能更强。
{"title":"Social factors as buffers for the adverse impact of adverse childhood experiences on biological age acceleration among adults in Hispanic Community Health Study / Study of Latinos","authors":"Yinxian Chen , Sarina Abrishamcar , Jasmine K. Aqua , Christian Dye , Linda C. Gallo , Maria M. Llabre , Frank J. Penedo , Carmen R. Isasi , Krista M. Perreira , Bharat Thyagarajan , Martha Daviglus , Amber Pirzada , Andrea Baccarelli , Karen N. Conneely , Rebecca Jones-Antwi , Shakira F. Suglia","doi":"10.1016/j.bbi.2025.106241","DOIUrl":"10.1016/j.bbi.2025.106241","url":null,"abstract":"<div><h3>Background</h3><div>This study examined whether social factors, including social support, social networks, and familism, modify the longitudinal association between ACEs and epigenetic age acceleration (EAA).</div></div><div><h3>Methods</h3><div>We analyzed DNA methylation (DNAm) profile data from two visits (approximately six years apart) among 960 Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). GrimAge epigenetic age and DunedinPACE pace of aging were used. Linear mixed models examined effect modification of social support, social networks (network diversity and the number of embedded networks), and familism (family obligation, support, and as referents) on the association between high vs. low-to-moderate ACEs (i.e., ≥ 4 vs. < 4 ACEs) and repeatedly measured EAA. Models adjusted for age, sex, parental education, childhood economic hardship, nativity, and cell-type proportions. We also dichotomized the levels of social support and both subscales of social networks to low (≤ 75th percentile) and high (> 75th percentile), and assessed joint effect modification by social support and networks.</div></div><div><h3>Results</h3><div>The mean difference in GrimAge acceleration (AgeAccelGrim) between high and low-to-moderate ACEs was statistically significantly attenuated when social support levels were higher (β for interaction = -0.73 years; 95 % CI: −1.23, −0.24; p = 0.003). No evidence of effect modification was found for social networks or familism. Having only high social support (β for interaction = -1.40 years; 95 % CI: −2.79, −0.01; p = 0.049) or both high social support and network diversity (β for interaction = -1.57 years; 95 % CI: −2.72, −0.42; p = 0.008) significantly decreased the mean difference in AgeAccelGrim between high and low-to-moderate ACEs.</div></div><div><h3>Conclusion</h3><div>Social support may independently buffer the adverse impact of ACEs on biological age acceleration among Hispanic/Latino adults, and the buffering effect may be stronger when accompanied by diverse social networks.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106241"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.bbi.2025.106240
J.C. Zwiep , F. Lamers , C.H. Vinkers , N.J.A. van der Wee , B.W.J.H. Penninx , L. Nawijn , Y. Milaneschi
Introduction
Depression manifests heterogenous bio-clinical profiles. Anhedonia has been previously linked to inflammation. Other research has associated inflammation and metabolic dysregulations with atypical, energy-related depressive symptoms (AES). In the present study, we examined the associations of inflammation and metabolic dysregulations with anhedonia and compared these associations with those of inflammation and metabolic dysregulations with AES, and with a negative control symptom profile, previously shown unrelated to inflammation and metabolic dysregulation.
Methods
Data was from 2,981 persons of the Netherlands Study of Depression and Anxiety (NESDA). Inflammatory markers included C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and glycoprotein acetyls. Metabolic markers were body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Anhedonia, AES and negative control symptom profiles were based on sum scores from different items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR). The results were internally replicated in NESDA’s 6-year follow-up (N = 2,256).
Results
Anhedonia was positively associated with IL-6, glycoprotein acetyls, BMI, waist circumference, triglycerides, glucose, and leptin (β ranging from 0.063 to 0.122) and negatively associated with HDL cholesterol (β = -0.063). Associations were only partially explained by major lifestyle and health-related factors and confirmed at 6-year follow-up (r = 0.939 correlation between estimates at baseline and follow-up). AES showed highly consistent associations with the markers, with relatively larger effects as compared to anhedonia, while the negative control symptoms were linked only to higher glycoprotein acetyls.
Conclusion
Our results indicate consistent associations between several markers of inflammation and metabolic dysregulation with anhedonia and AES. Full characterization of depression profiles and their complex interrelations should be leveraged in future clinical research to select specific subgroup of depressed patients and develop more targeted treatment approaches.
{"title":"Inflammation, metabolic dysregulation, and depression profiles related to anhedonia and atypical, energy-related symptoms","authors":"J.C. Zwiep , F. Lamers , C.H. Vinkers , N.J.A. van der Wee , B.W.J.H. Penninx , L. Nawijn , Y. Milaneschi","doi":"10.1016/j.bbi.2025.106240","DOIUrl":"10.1016/j.bbi.2025.106240","url":null,"abstract":"<div><h3>Introduction</h3><div>Depression manifests heterogenous bio-clinical profiles. Anhedonia has been previously linked to inflammation. Other research has associated inflammation and metabolic dysregulations with atypical, energy-related depressive symptoms (AES). In the present study, we examined the associations of inflammation and metabolic dysregulations with anhedonia and compared these associations with those of inflammation and metabolic dysregulations with AES, and with a negative control symptom profile, previously shown unrelated to inflammation and metabolic dysregulation.</div></div><div><h3>Methods</h3><div>Data was from 2,981 persons of the Netherlands Study of Depression and Anxiety (NESDA). Inflammatory markers included C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and glycoprotein acetyls. Metabolic markers were body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Anhedonia, AES and negative control symptom profiles were based on sum scores from different items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR). The results were internally replicated in NESDA’s 6-year follow-up (N = 2,256).</div></div><div><h3>Results</h3><div>Anhedonia was positively associated with IL-6, glycoprotein acetyls, BMI, waist circumference, triglycerides, glucose, and leptin (β ranging from 0.063 to 0.122) and negatively associated with HDL cholesterol (β = -0.063). Associations were only partially explained by major lifestyle and health-related factors and confirmed at 6-year follow-up (<em>r</em> = 0.939 correlation between estimates at baseline and follow-up). AES showed highly consistent associations with the markers, with relatively larger effects as compared to anhedonia, while the negative control symptoms were linked only to higher glycoprotein acetyls.</div></div><div><h3>Conclusion</h3><div>Our results indicate consistent associations between several markers of inflammation and metabolic dysregulation with anhedonia and AES. Full characterization of depression profiles and their complex interrelations should be leveraged in future clinical research to select specific subgroup of depressed patients and develop more targeted treatment approaches.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106240"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.bbi.2025.106239
Hatice Satilmis , Adrien Denis , Karin Vanderkerken , Elke De Bruyne , Eline Menu , Erica K Sloan , Kim De Veirman
The role of the sympathetic nervous system (SNS) in cancer biology has gained increasing attention, and its ability to affect immunotherapy is starting to become clearer. Extensive evidence shows that neuro-onco-immune interactions significantly influence tumor progression and the effectiveness of cancer treatments. Blocking SNS signaling, primarily through β-adrenergic receptors, enhances immune cell functions, by increasing CD8+ T-cell activation and cytokine production, while reducing immunosuppressive cell populations.
This review explores the relationship between SNS signaling and cancer immunotherapy, emphasizing how SNS activation affects the efficacy of various immunotherapies, including immune modulators, immune checkpoint inhibitors, oncolytic virus therapy, therapeutic vaccines, and CAR-T cell therapies. We summarize retrospective studies investigating the use of β-blockers during immunotherapy, suggesting potential benefits for treatment outcomes of blocking SNS signaling in the tumor microenvironment. We examine ongoing clinical trials that evaluate the use of beta-blockers with immune checkpoint inhibitors, which aim to improve patient outcomes. While translational and preclinical studies provide ample evidence for targeting SNS signaling in cancer immunotherapy, clinical studies are only beginning to emerge. Ultimately, this review underscores the need for further research to better understand how SNS signaling can be targeted to optimize immunotherapy, paving the way for more effective treatment strategies.
{"title":"Neural control of Immunotherapy: how Tumor-innervation shapes Anti-Tumor immune responses","authors":"Hatice Satilmis , Adrien Denis , Karin Vanderkerken , Elke De Bruyne , Eline Menu , Erica K Sloan , Kim De Veirman","doi":"10.1016/j.bbi.2025.106239","DOIUrl":"10.1016/j.bbi.2025.106239","url":null,"abstract":"<div><div>The role of the sympathetic nervous system (SNS) in cancer biology has gained increasing attention, and its ability to affect immunotherapy is starting to become clearer. Extensive evidence shows that neuro-onco-immune interactions significantly influence tumor progression and the effectiveness of cancer treatments. Blocking SNS signaling, primarily through β-adrenergic receptors, enhances immune cell functions, by increasing CD8<sup>+</sup> T-cell activation and cytokine production, while reducing immunosuppressive cell populations.</div><div>This review explores the relationship between SNS signaling and cancer immunotherapy, emphasizing how SNS activation affects the efficacy of various immunotherapies, including immune modulators, immune checkpoint inhibitors, oncolytic virus therapy, therapeutic vaccines, and CAR-T cell therapies. We summarize retrospective studies investigating the use of β-blockers during immunotherapy, suggesting potential benefits for treatment outcomes of blocking SNS signaling in the tumor microenvironment. We examine ongoing clinical trials that evaluate the use of beta-blockers with immune checkpoint inhibitors, which aim to improve patient outcomes. While translational and preclinical studies provide ample evidence for targeting SNS signaling in cancer immunotherapy, clinical studies are only beginning to emerge. Ultimately, this review underscores the need for further research to better understand how SNS signaling can be targeted to optimize immunotherapy, paving the way for more effective treatment strategies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106239"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.bbi.2025.106242
Natalie M. Antenucci , Mallory J. Feldman , Tatum A. Jolink , Taylor N. West , Megan N. Cardenas , Gabriella M. Alvarez , Keely A. Muscatell
While social group divisions occur naturally, inauspicious contexts like pathogen threat may exacerbate divides, driving in-group favoritism and out-group derogation. Minimal work has examined biological underpinnings of intergroup dynamics, particularly immune changes likely to accompany pathogen threat. To address this, we administered the influenza vaccine to 44 young adult participants. Before and after receiving the vaccine, participants completed a modified affect misattribution procedure, wherein they rated the trustworthiness of racial in-group and out-group faces. Participants also provided pre- and post-vaccine blood samples which were assayed for the inflammatory cytokine interleukin-6 (IL-6). Results showed a negative association between inflammatory reactivity and ratings of out-group faces: those who experienced greater increases in IL-6 rated racial out-group faces as less trustworthy than those with less IL-6 reactivity. This work begins exploring the role of inflammation in intergroup processes and findings, while preliminary, suggest a novel biological process that is associated with intergroup perception.
{"title":"Increases in inflammation are associated with decreased trust of racial out-group members","authors":"Natalie M. Antenucci , Mallory J. Feldman , Tatum A. Jolink , Taylor N. West , Megan N. Cardenas , Gabriella M. Alvarez , Keely A. Muscatell","doi":"10.1016/j.bbi.2025.106242","DOIUrl":"10.1016/j.bbi.2025.106242","url":null,"abstract":"<div><div>While social group divisions occur naturally, inauspicious contexts like pathogen threat may exacerbate divides, driving in-group favoritism and out-group derogation. Minimal work has examined biological underpinnings of intergroup dynamics, particularly immune changes likely to accompany pathogen threat. To address this, we administered the influenza vaccine to 44 young adult participants. Before and after receiving the vaccine, participants completed a modified affect misattribution procedure, wherein they rated the trustworthiness of racial in-group and out-group faces. Participants also provided pre- and post-vaccine blood samples which were assayed for the inflammatory cytokine interleukin-6 (IL-6). Results showed a negative association between inflammatory reactivity and ratings of out-group faces: those who experienced greater increases in IL-6 rated racial out-group faces as less trustworthy than those with less IL-6 reactivity. This work begins exploring the role of inflammation in intergroup processes and findings, while preliminary, suggest a novel biological process that is associated with intergroup perception.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106242"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.bbi.2025.106243
Jay O’Shields , Helisha Soni , Orion Mowbray
Objective
Major depression is often difficult to treat, particularly among individuals exposed to psychosocial risks like childhood maltreatment, loneliness, and recent stress. These experiences may lead to biological dysregulation consistent with allostatic load theory. This study explored whether distinct biological profiles among adults with depression are associated with specific psychosocial and health-related factors.
Method
Data were drawn from the Midlife in the United States study (MIDUS), including 367 participants with clinically significant depressive symptoms (CES-D ≥ 16). Latent profile analysis identified biological profiles based on 23 biomarkers across seven systems: inflammation, glucose, sympathetic and parasympathetic nervous systems, HPA-axis, cardiovascular, and lipids. Multinomial regression models examined associations between profile membership and psychosocial (childhood maltreatment, loneliness, recent stress), health (alcohol use, smoking, exercise), and demographic variables (sex, race/ethnicity, age, education).
Results
A five-profile solution best fit the data: High Inflammation & Glucose (n = 74), Low PNS (n = 83), High PNS (n = 73), Healthy Depression (n = 67), and High HPA-Axis (n = 70). Childhood maltreatment significantly predicted membership in the High Inflammation & Glucose and Low PNS profiles compared to the Healthy Depression group, even after controlling for health behaviors and demographics. Loneliness and recent stress were not significant predictors.
Conclusion
Childhood maltreatment is a predictor of biological dysregulation in depression, differentially predicting profiles characterized by inflammatory and metabolic vs parasympathetic functioning. These may represent different vulnerability pathways from social experiences to depressive illness. Incorporating measurement strategies specific to these pathways may aide in selecting treatment options for people who have depression and a history of childhood maltreatment.
目的：重度抑郁症通常很难治疗，特别是那些暴露于心理社会风险的个体，如童年虐待、孤独和最近的压力。这些经历可能导致与适应负荷理论一致的生物失调。这项研究探讨了成人抑郁症患者的不同生物学特征是否与特定的社会心理和健康相关因素有关。方法：数据来自Midlife in the United States研究（MIDUS），包括367名具有临床显著抑郁症状（CES-D ≥ 16）的参与者。潜在特征分析确定了基于七个系统的23个生物标志物的生物特征：炎症、葡萄糖、交感和副交感神经系统、hpa轴、心血管和脂质。多项回归模型检验了档案成员与社会心理（童年虐待、孤独、最近的压力）、健康（饮酒、吸烟、锻炼）和人口统计变量（性别、种族/民族、年龄、教育）之间的关联。结果:five-profile解决方案最适合的数据:高炎症和葡萄糖(n = 74),低pn (n = 83),高pn (n = 73),健康的抑郁症(n = 67),和高hpa轴(n = 70)。与健康抑郁组相比，童年虐待显著预测了高炎症、高血糖和低PNS特征的成员，即使在控制了健康行为和人口统计学之后也是如此。孤独和最近的压力并不是显著的预测因子。结论：童年虐待是抑郁症生物学失调的预测因子，预测炎症和代谢与副交感神经功能的差异。这些可能代表了从社会经历到抑郁症的不同脆弱性途径。结合特定于这些途径的测量策略可能有助于为患有抑郁症和童年虐待史的人选择治疗方案。
{"title":"Using social risk factors to predict allostatic biotypes of depression: A latent profile and multinomial regression analysis","authors":"Jay O’Shields , Helisha Soni , Orion Mowbray","doi":"10.1016/j.bbi.2025.106243","DOIUrl":"10.1016/j.bbi.2025.106243","url":null,"abstract":"<div><h3>Objective</h3><div>Major depression is often difficult to treat, particularly among individuals exposed to psychosocial risks like childhood maltreatment, loneliness, and recent stress. These experiences may lead to biological dysregulation consistent with allostatic load theory. This study explored whether distinct biological profiles among adults with depression are associated with specific psychosocial and health-related factors.</div></div><div><h3>Method</h3><div>Data were drawn from the Midlife in the United States study (MIDUS), including 367 participants with clinically significant depressive symptoms (CES-D ≥ 16). Latent profile analysis identified biological profiles based on 23 biomarkers across seven systems: inflammation, glucose, sympathetic and parasympathetic nervous systems, HPA-axis, cardiovascular, and lipids. Multinomial regression models examined associations between profile membership and psychosocial (childhood maltreatment, loneliness, recent stress), health (alcohol use, smoking, exercise), and demographic variables (sex, race/ethnicity, age, education).</div></div><div><h3>Results</h3><div>A five-profile solution best fit the data: High Inflammation & Glucose (<em>n</em> = 74), Low PNS (<em>n</em> = 83), High PNS (<em>n</em> = 73), Healthy Depression (<em>n</em> = 67), and High HPA-Axis (<em>n</em> = 70). Childhood maltreatment significantly predicted membership in the High Inflammation & Glucose and Low PNS profiles compared to the Healthy Depression group, even after controlling for health behaviors and demographics. Loneliness and recent stress were not significant predictors.</div></div><div><h3>Conclusion</h3><div>Childhood maltreatment is a predictor of biological dysregulation in depression, differentially predicting profiles characterized by inflammatory and metabolic vs parasympathetic functioning. These may represent different vulnerability pathways from social experiences to depressive illness. Incorporating measurement strategies specific to these pathways may aide in selecting treatment options for people who have depression and a history of childhood maltreatment.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106243"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.bbi.2025.106235
Yan Li , Guangfa Wang , Xinyu Fang , Yuru Ling , Chao Zhou , Jin Fang , Renliang Cai , Yunshan Hu , Chaoran Wu , Shaotong Zhang , Ayesha Zafar Iqbal , Yu Wang , Kuan-Pin Su , Xiangrong Zhang
Background
Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.
Methods
We conducted untargeted metabolomics analyses (GC–MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.
Results
Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.
Conclusions
This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT’s therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.
{"title":"Metabolomic signatures of electroconvulsive therapy in schizophrenia: Mitochondrial energy metabolism and inflammation as therapeutic targets","authors":"Yan Li , Guangfa Wang , Xinyu Fang , Yuru Ling , Chao Zhou , Jin Fang , Renliang Cai , Yunshan Hu , Chaoran Wu , Shaotong Zhang , Ayesha Zafar Iqbal , Yu Wang , Kuan-Pin Su , Xiangrong Zhang","doi":"10.1016/j.bbi.2025.106235","DOIUrl":"10.1016/j.bbi.2025.106235","url":null,"abstract":"<div><h3>Background</h3><div>Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.</div></div><div><h3>Methods</h3><div>We conducted untargeted metabolomics analyses (GC–MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.</div></div><div><h3>Results</h3><div>Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.</div></div><div><h3>Conclusions</h3><div>This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT’s therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106235"},"PeriodicalIF":7.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号