Biological psychiatry global open science最新文献_第9页

Decreased Mitochondrial DNA Integrity and Elevated Inflammatory Markers in Late-Life Depression: A Longitudinal Study 晚年抑郁症中线粒体DNA完整性降低和炎症标志物升高：一项纵向研究

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-20 DOI: 10.1016/j.bpsgos.2025.100598

Ana Paula Mendes-Silva , Perla El-Ahmad , Ana Paula Costa , Lloyd Cenon Balbuena , Yuliya Stoycheva Nikolova , Tarek Rajji , James Lowery Kennedy , Erica Leandro Vieira , Vanessa Faria Gonçalves , Breno Satler Diniz

Background

Late-life depression (LLD) is a prevalent and severe mental disorder. The biological mechanisms underlying LLD are not fully understood, but increasing evidence suggests that mitochondria play a significant role. Impaired mitochondrial function leads to excessive production of reactive oxygen species and the release of circulating cell-free mitochondrial DNA (ccf-mtDNA). The ccf-mtDNA activates the toll-like receptor system, which triggers a systemic proinflammatory response. However, there is limited understanding of the impact of ccf-mtDNA integrity, such as deletions, on LLD pathological conditions.

Methods

We included 90 older individuals (50 LLDs, 40 nondepressed healthy control participants [HCs]), with a subset of individuals followed up at 30 months (13 LLDs, 13 HCs). Plasma was separated from blood, and DNA was extracted. Mitochondrial genes MT-ND2 and MT-ND4 were targeted to evaluate ccf-mtDNA levels and deletion using real-time quantitative polymerase chain reaction. Plasma interleukins (ILs) 1β, 5, and 6 were quantified via multiplex immunoassay.

Results

LLD was linked to increased ccf-mtDNA instability at baseline (deletion: F_88,1 = 7.105, p = .009; levels: F_88,1 = 6.885, p = .01), which was associated with more severe depressive symptoms and greater medical comorbidity burden. Longitudinal analysis revealed significant effects of diagnosis and time on ccf-mtDNA levels and the deletion rate. Additionally, higher deletion rates at baseline predicted IL-5 and IL-6 levels at 30 months (p_adjusted = .13, p_adjusted = .12, respectively).

Conclusions

Increased ccf-mtDNA instability may heighten vulnerability to emotional dysregulation and medical burden in individuals with LLD. Further research is needed to validate our findings and elucidate the mechanisms that connect mitochondrial instability and inflammation in LLD.

背景晚年抑郁症（LLD）是一种普遍而严重的精神障碍。LLD的生物学机制尚不完全清楚，但越来越多的证据表明线粒体起着重要作用。线粒体功能受损导致活性氧的过量产生和循环无细胞线粒体DNA （ccf-mtDNA）的释放。ccf-mtDNA激活toll样受体系统，从而引发全身促炎反应。然而，对ccf-mtDNA完整性（如缺失）对LLD病理状况的影响了解有限。方法我们纳入了90名老年人（50名LLDs， 40名非抑郁健康对照者[hc]），并在30个月后随访了一部分个体（13名LLDs， 13名hc）。从血液中分离血浆，提取DNA。以线粒体基因MT-ND2和MT-ND4为目标，利用实时定量聚合酶链反应评估ccf-mtDNA水平和缺失情况。血浆白细胞介素（il） 1β、5和6通过多重免疫分析法定量。结果slld与基线ccf-mtDNA不稳定性增加有关（缺失：F88,1 = 7.105, p = 0.009；缺失水平：F88,1 = 6.885, p = 0.01），这与更严重的抑郁症状和更大的医疗共病负担相关。纵向分析显示诊断和时间对ccf-mtDNA水平和缺失率有显著影响。此外，基线较高的缺失率预测了30个月时IL-5和IL-6水平（p调整后分别为0.13和0.12）。结论ccf-mtDNA不稳定性的增加可能增加LLD患者情绪失调的易感性和医疗负担。需要进一步的研究来验证我们的发现，并阐明LLD中线粒体不稳定和炎症之间的联系机制。

{"title":"Decreased Mitochondrial DNA Integrity and Elevated Inflammatory Markers in Late-Life Depression: A Longitudinal Study","authors":"Ana Paula Mendes-Silva , Perla El-Ahmad , Ana Paula Costa , Lloyd Cenon Balbuena , Yuliya Stoycheva Nikolova , Tarek Rajji , James Lowery Kennedy , Erica Leandro Vieira , Vanessa Faria Gonçalves , Breno Satler Diniz","doi":"10.1016/j.bpsgos.2025.100598","DOIUrl":"10.1016/j.bpsgos.2025.100598","url":null,"abstract":"<div><h3>Background</h3><div>Late-life depression (LLD) is a prevalent and severe mental disorder. The biological mechanisms underlying LLD are not fully understood, but increasing evidence suggests that mitochondria play a significant role. Impaired mitochondrial function leads to excessive production of reactive oxygen species and the release of circulating cell-free mitochondrial DNA (ccf-mtDNA). The ccf-mtDNA activates the toll-like receptor system, which triggers a systemic proinflammatory response. However, there is limited understanding of the impact of ccf-mtDNA integrity, such as deletions, on LLD pathological conditions.</div></div><div><h3>Methods</h3><div>We included 90 older individuals (50 LLDs, 40 nondepressed healthy control participants [HCs]), with a subset of individuals followed up at 30 months (13 LLDs, 13 HCs). Plasma was separated from blood, and DNA was extracted. Mitochondrial genes MT-ND2 and MT-ND4 were targeted to evaluate ccf-mtDNA levels and deletion using real-time quantitative polymerase chain reaction. Plasma interleukins (ILs) 1β, 5, and 6 were quantified via multiplex immunoassay.</div></div><div><h3>Results</h3><div>LLD was linked to increased ccf-mtDNA instability at baseline (deletion: <em>F</em><sub>88,1</sub> = 7.105, <em>p</em> = .009; levels: <em>F</em><sub>88,1</sub> = 6.885, <em>p</em> = .01), which was associated with more severe depressive symptoms and greater medical comorbidity burden. Longitudinal analysis revealed significant effects of diagnosis and time on ccf-mtDNA levels and the deletion rate. Additionally, higher deletion rates at baseline predicted IL-5 and IL-6 levels at 30 months (<em>p</em><sub>adjusted</sub> = .13, <em>p</em><sub>adjusted</sub> = .12, respectively).</div></div><div><h3>Conclusions</h3><div>Increased ccf-mtDNA instability may heighten vulnerability to emotional dysregulation and medical burden in individuals with LLD. Further research is needed to validate our findings and elucidate the mechanisms that connect mitochondrial instability and inflammation in LLD.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100598"},"PeriodicalIF":3.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158125","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}

引用次数: 0

Functional Connectivity in the Social Perception Pathway at Birth Is Linked to Attention to Faces at Four Months 出生时社会知觉通路的功能连通性与4个月时对面孔的注意有关

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-19 DOI: 10.1016/j.bpsgos.2025.100597

Katarzyna Chawarska , Angelina Vernetti , Huili Sun , Michelle Hampson , Chenhao Li , Suzanne Macari , Kelly Powell , R. Todd Constable , Joseph Chang , Laura R. Ment , Dustin Scheinost

Background

The right-lateralized social perception pathway, including the superior temporal sulcus, supports processing of dynamic, multimodal facial cues, while the right-lateralized ventral pathway, including the fusiform gyrus, is involved in processing static facial features. However, little is known about the early development of these pathways or their links to later social outcomes. In this study, we examined intrinsic functional connectivity (iFC) in these pathways in neonates with and without familial history of autism. We also investigated whether neonatal iFC was associated with reduced attention to faces at 4 months, an early autism biomarker.

Methods

iFC was measured in 310 full-term, typically developing neonates from the dHCP (Developing Human Connectome Project) at 41 weeks postmenstrual age (PMA) (SD = 1.7) and in 73 full-term Yale neonates with and without a family history of autism at 44 weeks PMA (SD = 1.3). Attention to faces was assessed at 4.1 months (SD = 0.3) via eye tracking in 37 Yale participants.

Results

All 4 pathways showed significant iFC (p < .001), with no sex differences (p > .159). Connectivity in the social pathway increased with age (p < .001). In Yale neonates, only iFC in the right social pathway was positively associated with attention to faces at 4 months (r₃₇ = 0.456, p = .006). Greater attention to faces predicted fewer social concerns at 18 months (r₃₃ = −0.358, p = .010).

Conclusions

The right-lateralized social perception pathway represents an area of interest for identifying early neural markers of social vulnerabilities associated with autism.

包括颞上沟在内的右侧社会知觉通路支持对动态、多模态面部线索的处理，而包括梭状回在内的右侧腹侧通路则参与对静态面部特征的处理。然而，人们对这些途径的早期发展以及它们与后来的社会结果的联系知之甚少。在这项研究中，我们在有和没有自闭症家族史的新生儿中检测了这些通路的内在功能连接（iFC）。我们还研究了新生儿iFC是否与4个月时对面孔的注意力减少有关，这是早期自闭症的生物标志物。方法对310名来自dHCP（发育中的人类连接组项目）的正常发育的足月新生儿在经后41周龄（PMA）（SD = 1.7）和73名有或无自闭症家族史的耶鲁足月新生儿在经后44周龄（SD = 1.3）进行sifc测量。在4.1个月时，通过眼动追踪对37名耶鲁大学参与者的面部注意力进行了评估（SD = 0.3）。结果4条通路均显示iFC (p < .001)，性别差异无统计学意义（p < .159）。社会通路的连通性随着年龄的增长而增加（p < .001）。在耶鲁出生的新生儿中，只有右侧社交通路的iFC与4个月时对面孔的注意力呈正相关（r37 = 0.456, p = 0.006）。对面孔的更多关注预示着18个月时较少的社会关注（r33 = - 0.358, p = 0.010）。结论：右偏侧社会知觉通路是识别自闭症相关社会脆弱性早期神经标记的重要领域。

{"title":"Functional Connectivity in the Social Perception Pathway at Birth Is Linked to Attention to Faces at Four Months","authors":"Katarzyna Chawarska , Angelina Vernetti , Huili Sun , Michelle Hampson , Chenhao Li , Suzanne Macari , Kelly Powell , R. Todd Constable , Joseph Chang , Laura R. Ment , Dustin Scheinost","doi":"10.1016/j.bpsgos.2025.100597","DOIUrl":"10.1016/j.bpsgos.2025.100597","url":null,"abstract":"<div><h3>Background</h3><div>The right-lateralized social perception pathway, including the superior temporal sulcus, supports processing of dynamic, multimodal facial cues, while the right-lateralized ventral pathway, including the fusiform gyrus, is involved in processing static facial features. However, little is known about the early development of these pathways or their links to later social outcomes. In this study, we examined intrinsic functional connectivity (iFC) in these pathways in neonates with and without familial history of autism. We also investigated whether neonatal iFC was associated with reduced attention to faces at 4 months, an early autism biomarker.</div></div><div><h3>Methods</h3><div>iFC was measured in 310 full-term, typically developing neonates from the dHCP (Developing Human Connectome Project) at 41 weeks postmenstrual age (PMA) (SD = 1.7) and in 73 full-term Yale neonates with and without a family history of autism at 44 weeks PMA (SD = 1.3). Attention to faces was assessed at 4.1 months (SD = 0.3) via eye tracking in 37 Yale participants.</div></div><div><h3>Results</h3><div>All 4 pathways showed significant iFC (<em>p</em> < .001), with no sex differences (<em>p</em> > .159). Connectivity in the social pathway increased with age (<em>p</em> < .001). In Yale neonates, only iFC in the right social pathway was positively associated with attention to faces at 4 months (<em>r</em><sub>37</sub> = 0.456, <em>p</em> = .006). Greater attention to faces predicted fewer social concerns at 18 months (<em>r</em><sub>33</sub> = −0.358, <em>p</em> = .010).</div></div><div><h3>Conclusions</h3><div>The right-lateralized social perception pathway represents an area of interest for identifying early neural markers of social vulnerabilities associated with autism.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100597"},"PeriodicalIF":3.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267144","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}

引用次数: 0

Role of the Locus Coeruleus in Response to Threat in Anxiety Disorders and Posttraumatic Stress Disorder: An Ultra-High-Field 7T Functional Magnetic Resonance Imaging Study 蓝斑在焦虑障碍和创伤后应激障碍患者威胁反应中的作用：超高场7T功能磁共振成像研究

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-16 DOI: 10.1016/j.bpsgos.2025.100596

Sarah C. Boukezzi , Philipp T. Neukam , Nicholas Balderston , Yael Jacob , Derek A. Smith , Yolanda Whitaker , Sarah B. Rutter , Vicki Soogrim , Adriana Feder , Dennis S. Charney , Christian Grillon , Prantik Kundu , Priti Balchandani , Laurel S. Morris , James W. Murrough

Background

By harnessing the enhanced spatial resolution and signal power of high-field 7T magnetic resonance imaging (MRI), we assessed the functional involvement of the locus coeruleus (LC), together with the broader threat circuitry, in anxious arousal among individuals with anxiety disorders and posttraumatic stress disorder (PTSD).

Methods

Sixty-nine individuals with and without anxiety disorders or PTSD completed a modified no (N), predictable (P), and unpredictable (U) (NPU) threat task during a 7T functional MRI scan. Anxious arousal was measured using the Mood and Anxiety Symptom Questionnaire anxious arousal subscale. Individual data-driven LC segmentations were derived from ultra-high-resolution magnetization transfer contrast scans. We conducted LC functional activation and whole-brain data analyses during the NPU task using both transdiagnostic (Research Domain Criteria–based) and categorical (DSM-5–based) approaches.

Results

Greater LC activation during unpredictable threat was positively correlated with anxious arousal across all participants. In whole-brain analyses, the posterior cingulate cortex/precuneus and the subgenual anterior cingulate cortex were significantly activated during unpredictable threat, whereas the posterior insula was significantly activated during predictable threat. Greater activation within key structures of the threat circuitry, including the brainstem, the left hippocampus/amygdala, and the insula was positively correlated with anxious arousal across conditions and participants.

Conclusions

This translational and dimensional work advances our understanding of the role of the LC system and threat circuitry in pathological anxiety. Using 7T MRI, this study highlights the functional role of the LC in processing unpredictable threat in association with anxious arousal in individuals with anxiety disorders and PTSD.

利用高场7T磁共振成像（MRI）增强的空间分辨率和信号功率，我们评估了焦虑障碍和创伤后应激障碍（PTSD）患者焦虑唤醒过程中蓝斑核（LC）和更广泛的威胁回路的功能参与。方法69例有或无焦虑障碍或创伤后应激障碍的患者在7T功能MRI扫描期间完成了修改的no (N)、predictable (P)和predictable (U) （NPU）威胁任务。焦虑唤醒采用情绪与焦虑症状问卷焦虑唤醒分量表进行测量。单个数据驱动的LC分割来自超高分辨率磁化转移对比扫描。在NPU任务期间，我们使用跨诊断（基于研究领域标准）和分类（基于dsm -5）方法进行了LC功能激活和全脑数据分析。结果所有参与者在面对不可预测的威胁时，大脑皮层的激活程度越高，焦虑唤醒越高。在全脑分析中，在不可预测的威胁下，后扣带皮层/楔前叶和亚属前扣带皮层被显著激活，而后岛在可预测的威胁下被显著激活。在威胁回路的关键结构中，包括脑干、左海马体/杏仁核和脑岛，更大的激活与各种条件和参与者的焦虑唤醒呈正相关。结论这一翻译和维度的工作促进了我们对LC系统和威胁回路在病理性焦虑中的作用的理解。本研究利用7T磁共振成像技术，在焦虑障碍和创伤后应激障碍的个体中，强调了LC在处理与焦虑唤醒相关的不可预测威胁中的功能作用。

{"title":"Role of the Locus Coeruleus in Response to Threat in Anxiety Disorders and Posttraumatic Stress Disorder: An Ultra-High-Field 7T Functional Magnetic Resonance Imaging Study","authors":"Sarah C. Boukezzi , Philipp T. Neukam , Nicholas Balderston , Yael Jacob , Derek A. Smith , Yolanda Whitaker , Sarah B. Rutter , Vicki Soogrim , Adriana Feder , Dennis S. Charney , Christian Grillon , Prantik Kundu , Priti Balchandani , Laurel S. Morris , James W. Murrough","doi":"10.1016/j.bpsgos.2025.100596","DOIUrl":"10.1016/j.bpsgos.2025.100596","url":null,"abstract":"<div><h3>Background</h3><div>By harnessing the enhanced spatial resolution and signal power of high-field 7T magnetic resonance imaging (MRI), we assessed the functional involvement of the locus coeruleus (LC), together with the broader threat circuitry, in anxious arousal among individuals with anxiety disorders and posttraumatic stress disorder (PTSD).</div></div><div><h3>Methods</h3><div>Sixty-nine individuals with and without anxiety disorders or PTSD completed a modified no (N), predictable (P), and unpredictable (U) (NPU) threat task during a 7T functional MRI scan. Anxious arousal was measured using the Mood and Anxiety Symptom Questionnaire anxious arousal subscale. Individual data-driven LC segmentations were derived from ultra-high-resolution magnetization transfer contrast scans. We conducted LC functional activation and whole-brain data analyses during the NPU task using both transdiagnostic (Research Domain Criteria–based) and categorical (DSM-5–based) approaches.</div></div><div><h3>Results</h3><div>Greater LC activation during unpredictable threat was positively correlated with anxious arousal across all participants. In whole-brain analyses, the posterior cingulate cortex/precuneus and the subgenual anterior cingulate cortex were significantly activated during unpredictable threat, whereas the posterior insula was significantly activated during predictable threat. Greater activation within key structures of the threat circuitry, including the brainstem, the left hippocampus/amygdala, and the insula was positively correlated with anxious arousal across conditions and participants.</div></div><div><h3>Conclusions</h3><div>This translational and dimensional work advances our understanding of the role of the LC system and threat circuitry in pathological anxiety. Using 7T MRI, this study highlights the functional role of the LC in processing unpredictable threat in association with anxious arousal in individuals with anxiety disorders and PTSD.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100596"},"PeriodicalIF":3.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267145","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}

引用次数: 0

Glutamate, Contextual Insensitivity, and Disorganized Speech in First-Episode Schizophrenia: A 7T Magnetic Resonance Spectroscopy Study 首发精神分裂症中的谷氨酸、语境不敏感和言语紊乱：一项7T磁共振波谱研究

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-13 DOI: 10.1016/j.bpsgos.2025.100593

Yingqi Laetitia Wang , Victoria Sharpe , Michael Mackinley , Gina R. Kuperberg , Kaustubh Supekar , Jean Theberge , Lena Palaniyappan

Background

In people with schizophrenia, formal thought disorder is a core symptom that emerges early and persists into chronic stages despite treatments. It manifests as disorganized speech and is often associated with poor long-term outcomes. A key feature of this disorganization is an impairment in the buildup and use of context provided by preceding words when choosing upcoming words. Recent work has shown that spoken words are less predictable based on global linguistic context in schizophrenia, but the neural basis of this remains unknown. Glutamate dysfunction in the anterior cingulate cortex has long been implicated in schizophrenia, but its connection to behavioral impairments remains unclear.

Methods

In this study, we investigated the relationship between linguistic contextual sensitivity and glutamate level in the dorsal anterior cingulate cortex in 39 patients with first-episode psychosis (33 men) and 33 sociodemographically matched healthy control participants (22 men). Contextual sensitivity was measured using a large language model (GPT-3), and glutamate levels were measured using 7T magnetic resonance spectroscopy.

Results

We found a significant interaction between diagnosis and glutamate level in predicting contextual sensitivity: Patients with lower glutamate levels had poor contextual sensitivity, a relationship not seen in healthy control participants. Glutamate variation was specifically explained by contextual sensitivity after controlling for other clinical and language variables, underscoring the robustness and specificity of this association.

Conclusions

These results highlight a potential glutamatergic basis for disorganized speech in schizophrenia and suggest that contextual sensitivity in speech could reflect anterior cingulate glutamate variations in early psychosis.

在精神分裂症患者中，形式思维障碍是早期出现的核心症状，尽管接受了治疗，但仍会持续到慢性阶段。它表现为言语混乱，通常与不良的长期预后有关。这种混乱的一个关键特征是，在选择接下来的单词时，会损害前一个单词提供的上下文的构建和使用。最近的研究表明，精神分裂症患者在全球语言背景下的言语预测能力较差，但这一现象的神经基础尚不清楚。长期以来，人们一直认为前扣带皮层的谷氨酸功能障碍与精神分裂症有关，但其与行为障碍的关系尚不清楚。方法研究39例首发精神病患者（33名男性）和33名社会人口统计学匹配的健康对照（22名男性）的语言语境敏感性与前扣带皮层背侧谷氨酸水平之间的关系。使用大型语言模型（GPT-3）测量上下文敏感性，使用7T磁共振波谱测量谷氨酸水平。结果我们发现诊断和谷氨酸水平在预测环境敏感性方面存在显著的相互作用：谷氨酸水平较低的患者环境敏感性较差，这一关系在健康对照组中未见。在控制了其他临床和语言变量后，谷氨酸变异可以通过上下文敏感性来解释，强调了这种关联的稳健性和特异性。结论这些结果强调了精神分裂症患者言语紊乱的潜在谷氨酸能基础，并提示言语的语境敏感性可能反映了早期精神病患者前扣带谷氨酸的变化。

{"title":"Glutamate, Contextual Insensitivity, and Disorganized Speech in First-Episode Schizophrenia: A 7T Magnetic Resonance Spectroscopy Study","authors":"Yingqi Laetitia Wang , Victoria Sharpe , Michael Mackinley , Gina R. Kuperberg , Kaustubh Supekar , Jean Theberge , Lena Palaniyappan","doi":"10.1016/j.bpsgos.2025.100593","DOIUrl":"10.1016/j.bpsgos.2025.100593","url":null,"abstract":"<div><h3>Background</h3><div>In people with schizophrenia, formal thought disorder is a core symptom that emerges early and persists into chronic stages despite treatments. It manifests as disorganized speech and is often associated with poor long-term outcomes. A key feature of this disorganization is an impairment in the buildup and use of context provided by preceding words when choosing upcoming words. Recent work has shown that spoken words are less predictable based on global linguistic context in schizophrenia, but the neural basis of this remains unknown. Glutamate dysfunction in the anterior cingulate cortex has long been implicated in schizophrenia, but its connection to behavioral impairments remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we investigated the relationship between linguistic contextual sensitivity and glutamate level in the dorsal anterior cingulate cortex in 39 patients with first-episode psychosis (33 men) and 33 sociodemographically matched healthy control participants (22 men). Contextual sensitivity was measured using a large language model (GPT-3), and glutamate levels were measured using 7T magnetic resonance spectroscopy.</div></div><div><h3>Results</h3><div>We found a significant interaction between diagnosis and glutamate level in predicting contextual sensitivity: Patients with lower glutamate levels had poor contextual sensitivity, a relationship not seen in healthy control participants. Glutamate variation was specifically explained by contextual sensitivity after controlling for other clinical and language variables, underscoring the robustness and specificity of this association.</div></div><div><h3>Conclusions</h3><div>These results highlight a potential glutamatergic basis for disorganized speech in schizophrenia and suggest that contextual sensitivity in speech could reflect anterior cingulate glutamate variations in early psychosis.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100593"},"PeriodicalIF":3.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145121205","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}

引用次数: 0

Increasing SOX10 Expression Overcomes Schizophrenia-Associated Early Oligodendrocyte Growth Deficits In Vitro 体外提高SOX10表达克服精神分裂症相关早期少突胶质细胞生长缺陷

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-13 DOI: 10.1016/j.bpsgos.2025.100592

Donna L. McPhie , Juan Antonio García-León , Catherine M. Verfaillie , Suzann M. Babb , Bruce M. Cohen

Background

Individuals with schizophrenia (SZ) tend to have lower than average brain myelin content. Gene-set analyses suggest that aberrant oligodendrocyte (OL) development is an underlying cause of this abnormality. Previously, we observed that cells from patients with SZ, reprogrammed to neural lines, had substantially reduced OL production. Furthermore, OLs produced in culture correlated strongly with myelin content observed in the brains of the donors of the lines. In the current study, we tested whether increasing expression of SOX10, crucial in determining commitment to oligodendrocyte fate, can overcome the SZ-associated deficit in OL production.

Methods

Fibroblasts from 6 participants with SZ and 6 healthy control participants were reprogrammed to neural lines. Quantitative reverse transcription polymerase chain reactions were run to determine the expression of SOX10. In addition, expression was measured for several other genes (OLIG2, SOX9, QKI, and FEZ1) that are associated with risk for SZ and also interact with SOX10 in determining OL development. Finally, using an inducible lentiviral system, SOX10 was expressed in neural precursor cells and the effect of increased SOX10 expression on the production of OLs was quantified.

Results

SOX10 expression was significantly reduced in cells from patients with SZ. Reductions in expression of SOX9 and QKI were also seen. Increasing SOX10 gene and resulting protein expression overcame the SZ-associated deficit in OL production.

Conclusions

Evidence from these studies, together with previous results, suggests that reduced SOX10 is a critical determinant of deficient OL production and, thereby, a contributing determinant of abnormal brain myelination in SZ. This abnormality could be a target for therapeutic interventions.

精神分裂症患者的脑髓磷脂含量往往低于平均水平。基因集分析表明，异常少突胶质细胞（OL）发育是这种异常的潜在原因。先前，我们观察到来自SZ患者的细胞，重新编程为神经细胞系，大大减少了OL的产生。此外，培养中产生的OLs与供体大脑中观察到的髓磷脂含量密切相关。在当前的研究中，我们测试了增加SOX10的表达是否可以克服sz相关的OL产生缺陷，SOX10是决定少突胶质细胞命运的关键。方法将6例SZ患者和6例健康对照者的成纤维细胞重编程为神经细胞系。定量逆转录聚合酶链反应测定SOX10的表达。此外，还测量了与SZ风险相关的其他几个基因（OLIG2、SOX9、QKI和FEZ1）的表达，这些基因也与SOX10相互作用，决定OL的发展。最后，利用诱导慢病毒系统，在神经前体细胞中表达SOX10，并量化SOX10表达增加对OLs产生的影响。结果SZ患者细胞中sox10表达明显降低。SOX9和QKI的表达也有所减少。增加SOX10基因和由此产生的蛋白表达克服了sz相关的OL生产缺陷。这些研究的证据以及先前的结果表明，SOX10的减少是OL产生不足的关键决定因素，因此是SZ异常脑髓鞘形成的决定因素。这种异常可能是治疗干预的目标。

{"title":"Increasing SOX10 Expression Overcomes Schizophrenia-Associated Early Oligodendrocyte Growth Deficits In Vitro","authors":"Donna L. McPhie , Juan Antonio García-León , Catherine M. Verfaillie , Suzann M. Babb , Bruce M. Cohen","doi":"10.1016/j.bpsgos.2025.100592","DOIUrl":"10.1016/j.bpsgos.2025.100592","url":null,"abstract":"<div><h3>Background</h3><div>Individuals with schizophrenia (SZ) tend to have lower than average brain myelin content. Gene-set analyses suggest that aberrant oligodendrocyte (OL) development is an underlying cause of this abnormality. Previously, we observed that cells from patients with SZ, reprogrammed to neural lines, had substantially reduced OL production. Furthermore, OLs produced in culture correlated strongly with myelin content observed in the brains of the donors of the lines. In the current study, we tested whether increasing expression of <em>SOX10</em>, crucial in determining commitment to oligodendrocyte fate, can overcome the SZ-associated deficit in OL production.</div></div><div><h3>Methods</h3><div>Fibroblasts from 6 participants with SZ and 6 healthy control participants were reprogrammed to neural lines. Quantitative reverse transcription polymerase chain reactions were run to determine the expression of <em>SOX10</em>. In addition, expression was measured for several other genes (<em>OLIG2</em>, <em>SOX9</em>, <em>QK</em><em>I</em>, and <em>FEZ1</em>) that are associated with risk for SZ and also interact with SOX10 in determining OL development. Finally, using an inducible lentiviral system, <em>SOX10</em> was expressed in neural precursor cells and the effect of increased SOX10 expression on the production of OLs was quantified.</div></div><div><h3>Results</h3><div><em>SOX10</em> expression was significantly reduced in cells from patients with SZ. Reductions in expression of <em>SOX9</em> and <em>QK</em><em>I</em> were also seen. Increasing <em>SOX10</em> gene and resulting protein expression overcame the SZ-associated deficit in OL production.</div></div><div><h3>Conclusions</h3><div>Evidence from these studies, together with previous results, suggests that reduced SOX10 is a critical determinant of deficient OL production and, thereby, a contributing determinant of abnormal brain myelination in SZ. This abnormality could be a target for therapeutic interventions.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100592"},"PeriodicalIF":3.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220167","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}

引用次数: 0

Transcriptomic Architecture of Weak Versus Strong Contextual Fear Extinction Learning Uncovers Extinction-Suppressive Role of TIA1 弱与强情境恐惧消退学习的转录组结构揭示了TIA1的消退抑制作用

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-13 DOI: 10.1016/j.bpsgos.2025.100591

Maria I. Bonilla , Hae-Lim Lee , Stephen Foster , In-Jung Kim , Andrii Rudenko

Background

Extinction, the capacity for an individual to inhibit or diminish fear memories, is a critical aspect of fear processing. In humans, weak extinction learning is often observed in anxiety and fear-related disorders such as posttraumatic stress disorder. However, the mechanisms behind regulating extinction and determining individual variability in extinction learning remain poorly understood.

Methods

To investigate the molecular basis of interindividual and sex-related differences in the ability to extinguish fear, extinction learning was analyzed in inbred wild-type male and female mice. Contextual fear conditioning and extinction were combined with profiling of the hippocampal transcriptomes associated with weak and strong extinction learning and genetic manipulations to extend our transcriptomic findings.

Results

We identified significant sex-dependent and -independent differences in hippocampal gene expression between weak and strong extinction learner animals. Very high transcriptomic overlap between weak learner males and females was especially surprising, showing upregulation of multiple genes associated with neurotoxic insult and cellular stress, including a gene encoding a major stress regulator, a prion-like TIA1. Overexpression of Tia1 in the dorsal hippocampus caused sex-independent dysregulation of microglia and diminished fear extinction learning in animals of both sexes.

Conclusions

We demonstrated the brain-based transcriptomic architecture associated with weak versus strong fear extinction learning in male and female mammalian subjects and identified the sex-independent extinction-suppressive role of hippocampal TIA1 upregulation. Our results should help to develop a better understanding of the mechanisms that underlie individual and sex-dependent differences in extinction and could inform novel therapeutic targets for pharmacological extinction augmentation strategies in fear-related disorders.

消隐是个体抑制或减少恐惧记忆的能力，是恐惧处理的一个关键方面。在人类中，弱灭绝学习经常在焦虑和恐惧相关的疾病中观察到，如创伤后应激障碍。然而，调控灭绝和决定个体在灭绝学习中的可变性背后的机制仍然知之甚少。方法对野生型雄性和雌性小鼠进行灭绝学习，研究其个体间和性别间恐惧消退能力差异的分子基础。情境恐惧条件反射和消退结合了与弱和强消退学习和遗传操作相关的海马转录组分析，以扩展我们的转录组研究结果。结果我们发现弱和强灭绝学习动物海马基因表达存在显著的性别依赖和独立差异。在学习能力弱的雄性和雌性之间非常高的转录组重叠尤其令人惊讶，显示出与神经毒性损伤和细胞应激相关的多个基因上调，包括编码主要应激调节因子的基因，朊病毒样的TIA1。海马背侧Tia1的过度表达导致雌雄动物小胶质细胞的性别无关性失调和恐惧消退学习能力下降。结论在雄性和雌性哺乳动物实验对象中，我们发现了与弱和强恐惧消退学习相关的基于大脑的转录组结构，并确定了海马TIA1上调的性别无关的消退抑制作用。我们的研究结果应该有助于更好地理解个体和性别依赖性消失差异的机制，并为恐惧相关疾病的药物消失增强策略提供新的治疗靶点。

{"title":"Transcriptomic Architecture of Weak Versus Strong Contextual Fear Extinction Learning Uncovers Extinction-Suppressive Role of TIA1","authors":"Maria I. Bonilla , Hae-Lim Lee , Stephen Foster , In-Jung Kim , Andrii Rudenko","doi":"10.1016/j.bpsgos.2025.100591","DOIUrl":"10.1016/j.bpsgos.2025.100591","url":null,"abstract":"<div><h3>Background</h3><div>Extinction, the capacity for an individual to inhibit or diminish fear memories, is a critical aspect of fear processing. In humans, weak extinction learning is often observed in anxiety and fear-related disorders such as posttraumatic stress disorder. However, the mechanisms behind regulating extinction and determining individual variability in extinction learning remain poorly understood.</div></div><div><h3>Methods</h3><div>To investigate the molecular basis of interindividual and sex-related differences in the ability to extinguish fear, extinction learning was analyzed in inbred wild-type male and female mice. Contextual fear conditioning and extinction were combined with profiling of the hippocampal transcriptomes associated with weak and strong extinction learning and genetic manipulations to extend our transcriptomic findings.</div></div><div><h3>Results</h3><div>We identified significant sex-dependent and -independent differences in hippocampal gene expression between weak and strong extinction learner animals. Very high transcriptomic overlap between weak learner males and females was especially surprising, showing upregulation of multiple genes associated with neurotoxic insult and cellular stress, including a gene encoding a major stress regulator, a prion-like TIA1. Overexpression of <em>Tia1</em> in the dorsal hippocampus caused sex-independent dysregulation of microglia and diminished fear extinction learning in animals of both sexes.</div></div><div><h3>Conclusions</h3><div>We demonstrated the brain-based transcriptomic architecture associated with weak versus strong fear extinction learning in male and female mammalian subjects and identified the sex-independent extinction-suppressive role of hippocampal TIA1 upregulation. Our results should help to develop a better understanding of the mechanisms that underlie individual and sex-dependent differences in extinction and could inform novel therapeutic targets for pharmacological extinction augmentation strategies in fear-related disorders.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100591"},"PeriodicalIF":3.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158123","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}

引用次数: 0

Functional Coupling and Longitudinal Outcome Prediction in First-Episode Psychosis 首发精神病的功能耦合和纵向预后预测

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-11 DOI: 10.1016/j.bpsgos.2025.100589

Isaac Z. Pope , Sidhant Chopra , Alexander Holmes , Shona M. Francey , Brian O’Donoghue , Vanessa L. Cropley , Barnaby Nelson , Hok Pan Yuen , Kelly Allott , Mario Alvarez-Jimenez , Susy Harrigan , Christos Pantelis , Andrew Thompson , Stephen J. Wood , Patrick D. McGorry , Alex Fornito

Background

Clinical outcomes following the first episode of psychosis (FEP) are highly heterogeneous across patients. The identification of prognostic biomarkers would greatly facilitate personalized treatments. Patients with psychosis often display brainwide disruptions of interregional functional coupling (FC), with some being linked to symptom severity and remission. Thus, FC may have prognostic potential for people experiencing psychosis.

Methods

Fifty-five antipsychotic-naïve patients with FEP (51% female, ages 15–25 years) were randomized to receive either antipsychotic or placebo tablets for 6 months alongside psychosocial interventions. Functional magnetic resonance imaging was conducted at baseline and after 3 months to evaluate whether baseline FC or 3-month change in FC could predict 6- and 12-month changes in symptoms and functioning, quantified using the Brief Psychiatric Rating Scale and the Social and Occupational Functioning Assessment Scale, respectively. We considered 3 different cross-validated prediction algorithms: 1) connectome-based predictive modeling, 2) kernel ridge regression, and 3) multilayer meta-matching. Each prediction model comprised 35 to 49 individuals.

Results

All models showed poor performance in predicting patients’ 6- and 12-month changes in symptoms and functioning (all r_mean < 0.3), and no model achieved significance via permutation testing (all p > .05).

Conclusions

Our findings suggest that brainwide measures of FC may not be suitable for predicting extended clinical outcomes over a 6- to 12-month period in patients with FEP.

背景：首次精神病发作（FEP）后的临床结果在不同患者之间存在高度异质性。预后生物标志物的识别将极大地促进个性化治疗。精神病患者经常表现出全脑区域间功能耦合（FC）的中断，其中一些与症状的严重程度和缓解有关。因此，FC可能对患有精神病的人具有预后潜力。方法55例antipsychotic-naïve FEP患者（51%为女性，年龄15-25岁）随机接受抗精神病药或安慰剂片6个月，并进行心理社会干预。在基线和3个月后进行功能磁共振成像，以评估基线FC或3个月FC变化是否可以预测6个月和12个月的症状和功能变化，分别使用简短精神病学评定量表和社会与职业功能评估量表进行量化。我们考虑了3种不同的交叉验证预测算法：1)基于连接体的预测建模，2)核脊回归和3)多层元匹配。每个预测模型由35到49个人组成。结果所有模型在预测患者6个月和12个月的症状和功能变化方面均表现不佳（均均值<； 0.3），经排列检验均无模型达到显著性（均p >； 0.05）。研究结果表明，全脑FC测量可能不适合预测FEP患者6至12个月的长期临床结果。

{"title":"Functional Coupling and Longitudinal Outcome Prediction in First-Episode Psychosis","authors":"Isaac Z. Pope , Sidhant Chopra , Alexander Holmes , Shona M. Francey , Brian O’Donoghue , Vanessa L. Cropley , Barnaby Nelson , Hok Pan Yuen , Kelly Allott , Mario Alvarez-Jimenez , Susy Harrigan , Christos Pantelis , Andrew Thompson , Stephen J. Wood , Patrick D. McGorry , Alex Fornito","doi":"10.1016/j.bpsgos.2025.100589","DOIUrl":"10.1016/j.bpsgos.2025.100589","url":null,"abstract":"<div><h3>Background</h3><div>Clinical outcomes following the first episode of psychosis (FEP) are highly heterogeneous across patients. The identification of prognostic biomarkers would greatly facilitate personalized treatments. Patients with psychosis often display brainwide disruptions of interregional functional coupling (FC), with some being linked to symptom severity and remission. Thus, FC may have prognostic potential for people experiencing psychosis.</div></div><div><h3>Methods</h3><div>Fifty-five antipsychotic-naïve patients with FEP (51% female, ages 15–25 years) were randomized to receive either antipsychotic or placebo tablets for 6 months alongside psychosocial interventions. Functional magnetic resonance imaging was conducted at baseline and after 3 months to evaluate whether baseline FC or 3-month change in FC could predict 6- and 12-month changes in symptoms and functioning, quantified using the Brief Psychiatric Rating Scale and the Social and Occupational Functioning Assessment Scale, respectively. We considered 3 different cross-validated prediction algorithms: 1) connectome-based predictive modeling, 2) kernel ridge regression, and 3) multilayer meta-matching. Each prediction model comprised 35 to 49 individuals.</div></div><div><h3>Results</h3><div>All models showed poor performance in predicting patients’ 6- and 12-month changes in symptoms and functioning (all <em>r</em><em><sub>mean</sub></em> < 0.3), and no model achieved significance via permutation testing (all <em>p</em> > .05).</div></div><div><h3>Conclusions</h3><div>Our findings suggest that brainwide measures of FC may not be suitable for predicting extended clinical outcomes over a 6- to 12-month period in patients with FEP.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100589"},"PeriodicalIF":3.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145121126","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}

引用次数: 0

Understanding the Comorbidities Among Psychiatric Disorders, Chronic Low Back Pain, and Spinal Degenerative Disease Using Observational and Genetically Informed Analyses 利用观察性和遗传学分析了解精神疾病、慢性腰痛和脊柱退行性疾病的合并症

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-11 DOI: 10.1016/j.bpsgos.2025.100588

Dan Qiu , Eleni Friligkou , Jun He , Brenda Cabrera-Mendoza , Mihaela Aslan , Mihir Gupta , Renato Polimanti

Background

Psychiatric disorders and symptoms are associated with differences in pain perception and sensitivity. These differences can have important implications in treating spinal degenerative disease (SDD) and chronic low back pain (CLBP).

Methods

Leveraging UK Biobank (UKB) (n = 402,072) and All of Us Research Program (AoU) (n = 157,415) data, we investigated the effects linking psychiatric disorders to SDD and CLBP. We applied multinominal regression models, polygenic risk scoring, and one-sample Mendelian randomization (MR) to triangulate the effects underlying the observed associations. We also performed gene ontology and drug-repurposing analyses to dissect the biology shared among mental illnesses, SDD, and CLBP.

Results

When we compared individuals affected only by SDD, those affected only by CLBP, and those affected by both conditions with control participants, observational and genetically informed analyses highlighted that the strongest effects across the 3 case groups were observed for alcohol use disorder, anxiety, depression, and posttraumatic stress disorder. Additionally, schizophrenia and its polygenic risk score appeared to have an inverse relationship with CLBP, SDD, and their comorbidity. One-sample MR highlighted a potential direct effect of internalizing disorders on the outcomes investigated that was particularly strong on SDD. Our drug repurposing analyses identified histone deacetylase inhibitors as targeting molecular pathways shared by psychiatric disorders, SDD, and CLBP.

Conclusions

These findings support that the comorbidity among psychiatric disorders, SDD, and CLBP is due to the contribution of direct effects and shared biology linking these health outcomes. These pleiotropic mechanisms, together with sociocultural factors, play a key role in shaping the SDD-CLBP comorbidity patterns that have been observed across the psychopathology spectrum.

精神疾病和症状与疼痛感知和敏感性的差异有关。这些差异对治疗脊柱退行性疾病（SDD）和慢性腰痛（CLBP）具有重要意义。方法利用UK Biobank （n = 402,072）和All of Us Research Program （n = 157,415）的数据，研究精神障碍与SDD和CLBP之间的关系。我们应用多项回归模型、多基因风险评分和单样本孟德尔随机化（MR）来三角测量观察到的关联的影响。我们还进行了基因本体论和药物再利用分析，以剖析精神疾病、SDD和CLBP之间共有的生物学特征。结果：当我们将仅受SDD影响的个体、仅受CLBP影响的个体以及同时受两种情况影响的个体与对照组进行比较时，观察性和遗传学分析强调，在3个病例组中，酒精使用障碍、焦虑、抑郁和创伤后应激障碍的影响最大。此外，精神分裂症及其多基因风险评分似乎与CLBP、SDD及其合并症呈反比关系。单样本MR强调了内化障碍对所调查结果的潜在直接影响，尤其是对SDD的影响。我们的药物再利用分析确定了组蛋白去乙酰化酶抑制剂靶向精神疾病、SDD和CLBP共有的分子途径。结论：这些发现支持精神疾病、SDD和CLBP之间的共病是由于直接影响和共同的生物学关系导致的。这些多效性机制，连同社会文化因素，在形成在精神病理谱中观察到的SDD-CLBP共病模式中起着关键作用。

{"title":"Understanding the Comorbidities Among Psychiatric Disorders, Chronic Low Back Pain, and Spinal Degenerative Disease Using Observational and Genetically Informed Analyses","authors":"Dan Qiu , Eleni Friligkou , Jun He , Brenda Cabrera-Mendoza , Mihaela Aslan , Mihir Gupta , Renato Polimanti","doi":"10.1016/j.bpsgos.2025.100588","DOIUrl":"10.1016/j.bpsgos.2025.100588","url":null,"abstract":"<div><h3>Background</h3><div>Psychiatric disorders and symptoms are associated with differences in pain perception and sensitivity. These differences can have important implications in treating spinal degenerative disease (SDD) and chronic low back pain (CLBP).</div></div><div><h3>Methods</h3><div>Leveraging UK Biobank (UKB) (<em>n</em> = 402,072) and All of Us Research Program (AoU) (<em>n</em> = 157,415) data, we investigated the effects linking psychiatric disorders to SDD and CLBP. We applied multinominal regression models, polygenic risk scoring, and one-sample Mendelian randomization (MR) to triangulate the effects underlying the observed associations. We also performed gene ontology and drug-repurposing analyses to dissect the biology shared among mental illnesses, SDD, and CLBP.</div></div><div><h3>Results</h3><div>When we compared individuals affected only by SDD, those affected only by CLBP, and those affected by both conditions with control participants, observational and genetically informed analyses highlighted that the strongest effects across the 3 case groups were observed for alcohol use disorder, anxiety, depression, and posttraumatic stress disorder. Additionally, schizophrenia and its polygenic risk score appeared to have an inverse relationship with CLBP, SDD, and their comorbidity. One-sample MR highlighted a potential direct effect of internalizing disorders on the outcomes investigated that was particularly strong on SDD. Our drug repurposing analyses identified histone deacetylase inhibitors as targeting molecular pathways shared by psychiatric disorders, SDD, and CLBP.</div></div><div><h3>Conclusions</h3><div>These findings support that the comorbidity among psychiatric disorders, SDD, and CLBP is due to the contribution of direct effects and shared biology linking these health outcomes. These pleiotropic mechanisms, together with sociocultural factors, play a key role in shaping the SDD-CLBP comorbidity patterns that have been observed across the psychopathology spectrum.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100588"},"PeriodicalIF":3.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095555","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}

引用次数: 0

Epigenetic and Structural Brain Aging and Their Associations With Major Depressive Disorder 表观遗传和结构脑老化及其与重度抑郁症的关系

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-05 DOI: 10.1016/j.bpsgos.2025.100577

Eileen Y. Xu , Claire Green , Daniel L. McCartney , Laura K.M. Han , Kathryn L. Evans , Rosie M. Walker , Danni A. Gadd , Douglas Steele , Gordon Waiter , Archie Campbell , Stephen M. Lawrie , James H. Cole , Andrew M. McIntosh , Xueyi Shen , Heather C. Whalley

Background

A growing body of evidence suggests that major depressive disorder (MDD) may be associated with premature biological aging. However, most studies reported to date have examined brain-based (BrainAge) and DNA methylation (DNAm)–based measures (DNAmAge) of biological age (BioAge) in isolation.

Methods

We investigated 2 well-studied BioAge measures in lifetime and current MDD: BrainAge and DNAmAge (4 separate DNAmAge measures based on Horvath, Hannum, GrimAge, and PhenoAge clocks). We used cross-sectional cohort data from GS:STRADL (Generation Scotland: STratifying Resilience and Depression Longitudinally) (BrainAge n = 833; DNAmAge n = 587; age range 26–76 years) and used UK Biobank (UKB) data to test for replication of BrainAge associations with MDD (BrainAge n = 12,018, age range 45–80 years). Premature brain and DNAm aging were operationalized as predicted age difference (PAD), and analyses controlled for age, sex, smoking, and alcohol intake. We also tested individual and additive associations of brain- and DNAm-based PADs to lifetime/current MDD using logistic regression.

Results

Individuals with lifetime MDD showed significantly higher BrainAge and DNAmAge in GS, ranging from 1.60 to 2.45 years, than individuals without MDD for all measures except for Horvath age. No differences were found for BrainAge in the UKB. In terms of PAD, lifetime MDD was significantly associated with GrimAge-PAD, PhenoAge-PAD, and Brain-PAD, ranging from odds ratio (OR) = 1.21−1.30 (and in UKB, Brain-PAD OR = 1.05). DNAm-PAD and Brain-PAD demonstrated shared and distinctive associations with lifetime MDD, where PhenoAge-PAD plus Brain-PAD explained maximum variance (area under the curve = 0.69, R² = 9%). No significant associations were found for current MDD.

Conclusions

Our findings highlight shared and distinct associations of premature brain and DNAm aging in lifetime MDD.

越来越多的证据表明，重度抑郁症（MDD）可能与过早的生物衰老有关。然而，迄今为止报道的大多数研究都是单独检查了基于大脑（BrainAge）和基于DNA甲基化（DNAm）的生物年龄（BioAge）测量（DNAmAge）。方法研究了两种生物年龄测量方法：BrainAge和DNAmAge（基于Horvath、Hannum、GrimAge和PhenoAge时钟的4种不同的DNAmAge测量方法）。我们使用来自GS:STRADL的横断面队列数据（苏格兰一代：纵向分层恢复力和抑郁）（BrainAge n = 833; DNAmAge n = 587；年龄范围26-76岁），并使用UK Biobank （UKB）数据来测试大脑年龄与MDD （BrainAge n = 12,018，年龄范围45-80岁）之间关联的复制。脑过早老化和dna老化作为预测年龄差异（PAD）进行操作，分析控制了年龄、性别、吸烟和饮酒。我们还使用逻辑回归测试了基于大脑和dnam的pad与终生/当前MDD的个体和附加关联。结果除Horvath年龄外，终生MDD患者的脑龄和DNAmAge均显著高于无MDD患者，在1.60 ~ 2.45岁之间。在英国没有发现大脑时代的差异。就PAD而言，终生MDD与GrimAge-PAD、PhenoAge-PAD和Brain-PAD显著相关，比值比(OR) = 1.21 - 1.30 （UKB中，Brain-PAD OR = 1.05）。DNAm-PAD和Brain-PAD显示了与终生MDD的共同和独特的关联，其中表型- pad加Brain-PAD解释了最大的方差（曲线下面积= 0.69,R2 = 9%）。未发现与当前MDD有显著关联。结论我们的研究结果强调了终身MDD患者脑过早和dna老化之间的共同和独特的关联。

{"title":"Epigenetic and Structural Brain Aging and Their Associations With Major Depressive Disorder","authors":"Eileen Y. Xu , Claire Green , Daniel L. McCartney , Laura K.M. Han , Kathryn L. Evans , Rosie M. Walker , Danni A. Gadd , Douglas Steele , Gordon Waiter , Archie Campbell , Stephen M. Lawrie , James H. Cole , Andrew M. McIntosh , Xueyi Shen , Heather C. Whalley","doi":"10.1016/j.bpsgos.2025.100577","DOIUrl":"10.1016/j.bpsgos.2025.100577","url":null,"abstract":"<div><h3>Background</h3><div>A growing body of evidence suggests that major depressive disorder (MDD) may be associated with premature biological aging. However, most studies reported to date have examined brain-based (BrainAge) and DNA methylation (DNAm)–based measures (DNAmAge) of biological age (BioAge) in isolation.</div></div><div><h3>Methods</h3><div>We investigated 2 well-studied BioAge measures in lifetime and current MDD: BrainAge and DNAmAge (4 separate DNAmAge measures based on Horvath, Hannum, GrimAge, and PhenoAge clocks). We used cross-sectional cohort data from GS:STRADL (Generation Scotland: STratifying Resilience and Depression Longitudinally) (BrainAge <em>n</em> = 833; DNAmAge <em>n</em> = 587; age range 26–76 years) and used UK Biobank (UKB) data to test for replication of BrainAge associations with MDD (BrainAge <em>n</em> = 12,018, age range 45–80 years). Premature brain and DNAm aging were operationalized as predicted age difference (PAD), and analyses controlled for age, sex, smoking, and alcohol intake. We also tested individual and additive associations of brain- and DNAm-based PADs to lifetime/current MDD using logistic regression.</div></div><div><h3>Results</h3><div>Individuals with lifetime MDD showed significantly higher BrainAge and DNAmAge in GS, ranging from 1.60 to 2.45 years, than individuals without MDD for all measures except for Horvath age. No differences were found for BrainAge in the UKB. In terms of PAD, lifetime MDD was significantly associated with GrimAge-PAD, PhenoAge-PAD, and Brain-PAD, ranging from odds ratio (OR) = 1.21−1.30 (and in UKB, Brain-PAD OR = 1.05). DNAm-PAD and Brain-PAD demonstrated shared and distinctive associations with lifetime MDD, where PhenoAge-PAD plus Brain-PAD explained maximum variance (area under the curve = 0.69, <em>R</em><sup>2</sup> = 9%). No significant associations were found for current MDD.</div></div><div><h3>Conclusions</h3><div>Our findings highlight shared and distinct associations of premature brain and DNAm aging in lifetime MDD.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100577"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019370","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}

引用次数: 0

Recruitment of Neuronal Populations in the Paraventricular Thalamus of Alcohol-Seeking Rats With Withdrawal-Related Learning Experience 具有戒断相关学习经历的嗜酒大鼠室旁丘脑神经元群的募集

IF 3.7 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2025-08-05 DOI: 10.1016/j.bpsgos.2025.100578

Hermina Nedelescu , Elias Meamari , Nami Rajaei , Alexus Grey , Ryan Bullard , Nathan O’Connor , Nobuyoshi Suto , Friedbert Weiss

Background

Stimulus-reactive neuronal populations are groups of neurons that become activated by environmental stimuli. These sparsely activated neuronal assemblies are implicated in encoding associations between environmental contexts and subjectively rewarding or aversive experiences that regulate behavior. How positive or negative hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate versus maladaptive behavior. It is well known that animals avoid noxious stimuli and experiences. However, little is known about how the conditioning of environmental stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations that lead to compulsive maladaptive behavior.

Methods

Here, we sought to identify stimulus-reactive neurons that may mediate the conditioned effects of environmental stimuli associated with the reversal of dysphoric alcohol withdrawal states using a dependent withdrawal-related learning (WDL) experimental condition (DEP-WDL) (N = 13) and 3 controls: nondependent WDL (NDEP-WDL) (N = 12), dependent no-WDL (DEP-NWDL) (N = 9), NDEP-NWDL (N = 9).

Results

The results document a role for clusters of neurons in the paraventricular nucleus of the thalamus (N = 8), the central nucleus of the amygdala (N = 8), and the dorsal striatum (N = 9) in this conditioned negative reinforcement process.

Conclusions

These findings suggest that associations between reversal of negative hedonic states and environmental contexts are encoded in distinct neuronal populations that may serve as a neural substrate of compulsive alcohol seeking and vulnerability to relapse associated with reward dysregulation and hedonic allostasis.

刺激反应性神经元群是一组被环境刺激激活的神经元。这些稀疏激活的神经元集合与环境背景和调节行为的主观奖励或厌恶体验之间的编码关联有关。积极或消极的享乐状态是如何在大脑神经回路中表现出来的，这是一个基本的问题，它与理解驱动适当与不适应行为的情感有意义刺激的处理有关。众所周知，动物会避免有害的刺激和经历。然而，对于环境刺激对行为的调节如何导致烦躁不安状态的改善，如何建立导致强迫性适应不良行为的强大关联，我们知之甚少。本研究通过依赖性戒断相关学习（WDL）实验条件（DEP-WDL）（N = 13）和3个对照：非依赖性WDL (NDEP-WDL) （N = 12）、依赖性无WDL (DEP-NWDL) （N = 9）、NDEP-NWDL (N = 9)，试图确定可能介导环境刺激条件效应的刺激反应神经元，这些神经元与烦躁性酒精戒断状态的逆转有关。结果表明，丘脑室旁核（N = 8）、杏仁核中央核（N = 8）和背纹状体（N = 9）中的神经元簇在这一条件负强化过程中发挥了作用。这些发现表明，消极享乐状态的逆转与环境背景之间的关联存在于不同的神经元群中，这些神经元群可能是强迫性酒精寻求和与奖励失调和享乐不平衡相关的复发易感性的神经基质。

{"title":"Recruitment of Neuronal Populations in the Paraventricular Thalamus of Alcohol-Seeking Rats With Withdrawal-Related Learning Experience","authors":"Hermina Nedelescu , Elias Meamari , Nami Rajaei , Alexus Grey , Ryan Bullard , Nathan O’Connor , Nobuyoshi Suto , Friedbert Weiss","doi":"10.1016/j.bpsgos.2025.100578","DOIUrl":"10.1016/j.bpsgos.2025.100578","url":null,"abstract":"<div><h3>Background</h3><div>Stimulus-reactive neuronal populations are groups of neurons that become activated by environmental stimuli. These sparsely activated neuronal assemblies are implicated in encoding associations between environmental contexts and subjectively rewarding or aversive experiences that regulate behavior. How positive or negative hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate versus maladaptive behavior. It is well known that animals avoid noxious stimuli and experiences. However, little is known about how the conditioning of environmental stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations that lead to compulsive maladaptive behavior.</div></div><div><h3>Methods</h3><div>Here, we sought to identify stimulus-reactive neurons that may mediate the conditioned effects of environmental stimuli associated with the reversal of dysphoric alcohol withdrawal states using a dependent withdrawal-related learning (WDL) experimental condition (DEP-WDL) (<em>N</em> = 13) and 3 controls: nondependent WDL (NDEP-WDL) (<em>N</em> = 12), dependent no-WDL (DEP-NWDL) (<em>N</em> = 9), NDEP-NWDL (<em>N</em> = 9).</div></div><div><h3>Results</h3><div>The results document a role for clusters of neurons in the paraventricular nucleus of the thalamus (<em>N</em> = 8), the central nucleus of the amygdala (<em>N</em> = 8), and the dorsal striatum (<em>N</em> = 9) in this conditioned negative reinforcement process.</div></div><div><h3>Conclusions</h3><div>These findings suggest that associations between reversal of negative hedonic states and environmental contexts are encoded in distinct neuronal populations that may serve as a neural substrate of compulsive alcohol seeking and vulnerability to relapse associated with reward dysregulation and hedonic allostasis.</div></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"5 6","pages":"Article 100578"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095554","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}

引用次数: 0