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A computational signature of self-other mergence in Borderline Personality Disorder. 边缘型人格障碍中自我与他人融合的计算特征。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-19 DOI: 10.1038/s41398-024-03170-w
Giles W Story, Sam Ereira, Stephanie Valle, Samuel R Chamberlain, Jon E Grant, Raymond J Dolan

A tendency to merge mental representations of self and other is thought to underpin the intense and unstable relationships that feature in Borderline Personality Disorder (BPD). However, clinical theories of BPD do not specify, in computational terms, how the perspectives of self and other might become confused. To address this question, we used a probabilistic false belief task (p-FBT) to examine how individuals with BPD (N = 38) and matched controls from the general population (N = 74) selectively assigned beliefs to self or other. The p-FBT requires participants to track a gradually changing quantity, whilst also predicting another person's belief about that quantity. We found that BPD participants showed less selectivity in belief assignment compared with controls (Cohen's d = 0.64). Behaviourally, participants with BPD tended to predict that others' beliefs resembled their own. Modelling analysis revealed that BPD participants were prone to generalise their own learning signals to others. Furthermore, this generalising tendency correlated with BPD symptomatology across participants, even when controlling for demographic factors and affective psychopathology. Our results support a computational account of self-other mergence, based on a generalisation of learning across agents. Self-other generalisation in learning purports to explain key clinical features of BPD, and suggests a potential transdiagnostic marker of mentalising capability.

边缘型人格障碍(Borderline Personality Disorder,BPD)的特点是人际关系紧张且不稳定,而这种倾向被认为是自我和他人心理表征合并的基础。然而,边缘型人格障碍的临床理论并没有从计算的角度说明自我和他人的视角是如何混淆的。为了解决这个问题,我们使用概率错误信念任务(p-FBT)来研究 BPD 患者(38 人)和普通人群中的匹配对照组(74 人)如何选择性地将信念分配给自我或他人。p-FBT 要求参与者追踪一个逐渐变化的数量,同时预测他人对该数量的信念。我们发现,与对照组相比,BPD 参与者在信念分配方面表现出较低的选择性(Cohen's d = 0.64)。从行为上看,BPD 参与者倾向于预测他人的信念与自己的信念相似。建模分析表明,BPD 参与者容易将自己的学习信号泛化到他人身上。此外,即使在控制了人口统计学因素和情感心理病理学的情况下,这种泛化倾向也与参与者的 BPD 症状相关。我们的研究结果支持一种基于跨代理学习泛化的自他融合计算方法。学习中的自我-他者泛化旨在解释 BPD 的关键临床特征,并提出了心智化能力的潜在跨诊断标记。
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引用次数: 0
Association of polygenic liabilities for schizophrenia and bipolar disorder with educational attainment and cognitive aging. 精神分裂症和双相情感障碍的多基因责任与教育程度和认知老化的关系。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-16 DOI: 10.1038/s41398-024-03182-6
Chi-Shin Wu, Chia-Lin Hsu, Mei-Chen Lin, Mei-Hsin Su, Yen-Feng Lin, Chia-Yen Chen, Po-Chang Hsiao, Yi-Jiun Pan, Pei-Chun Chen, Yen-Tsung Huang, Shi-Heng Wang

To elucidate the specific and shared genetic background of schizophrenia (SCZ) and bipolar disorder (BPD), this study explored the association of polygenic liabilities for SCZ and BPD with educational attainment and cognitive aging. Among 106,806 unrelated community participants from the Taiwan Biobank, we calculated the polygenic risk score (PRS) for SCZ (PRSSCZ) and BPD (PRSBPD), shared PRS between SCZ and BPD (PRSSCZ+BPD), and SCZ-specific PRS (PRSSCZvsBPD). Based on the sign-concordance of the susceptibility variants with SCZ/BPD, PRSSCZ was split into PRSSCZ_concordant/PRSSCZ_discordant, and PRSBPD was split into PRSBPD_concordant/PRSBPD_discordant. Ordinal logistic regression models were used to estimate the association with educational attainment. Linear regression models were used to estimate the associations with cognitive aging (n = 27,005), measured by the Mini-Mental State Examination (MMSE), and with MMSE change (n = 6194 with mean follow-up duration of 3.9 y) in individuals aged≥ 60 years. PRSSCZ, PRSBPD, and PRSSCZ+BPD were positively associated with educational attainment, whereas PRSSCZvsBPD was negatively associated with educational attainment. PRSSCZ was negatively associated with MMSE, while PRSBPD was positively associated with MMSE. The concordant and discordant parts of polygenic liabilities have contrasting association, PRSSCZ_concordant and PRSBPD_concordant mainly determined these effects mentioned above. PRSSCZvsBPD predicted decreases in the MMSE scores. Using a large collection of community samples, this study provided evidence for the contrasting effects of polygenic architecture in SCZ and BPD on educational attainment and cognitive aging and suggested that SCZ and BPD were not genetically homogeneous.

为了阐明精神分裂症(SCZ)和躁郁症(BPD)的特定和共有遗传背景,本研究探讨了SCZ和BPD的多基因责任与教育程度和认知老化的关联。在来自台湾生物库的 106,806 位无亲属关系的社区参与者中,我们计算了 SCZ(PRSSCZ)和 BPD(PRSBPD)的多基因风险评分(PRS)、SCZ 和 BPD 的共享风险评分(PRSSCZ+BPD)以及 SCZ 的特异性风险评分(PRSSCZvsBPD)。根据易感性变异与 SCZ/BPD 的符号一致性,PRSSCZ 被分为 PRSSCZ_concordant/PRSSCZ_discordant 两类,PRSBPD 被分为 PRSBPD_concordant/PRSBPD_discordant 两类。采用顺序逻辑回归模型来估计与教育程度的关系。线性回归模型用于估计与认知老化(n = 27 005)(通过小型精神状态检查(MMSE)测量)以及与 MMSE 变化(n = 6194,平均随访时间为 3.9 年)(年龄≥ 60 岁)的相关性。PRSSCZ、PRSBPD和PRSSCZ+BPD与受教育程度呈正相关,而PRSSCZvsBPD与受教育程度呈负相关。PRSSCZ 与 MMSE 呈负相关,而 PRSBPD 与 MMSE 呈正相关。多基因负债的一致和不一致部分具有相反的关联,PRSSCZ_一致和 PRSBPD_一致主要决定了上述效应。PRSSCZvsBPD 预测了 MMSE 分数的下降。本研究通过收集大量社区样本,为 SCZ 和 BPD 的多基因结构对教育程度和认知老化的不同影响提供了证据,并表明 SCZ 和 BPD 在基因上并不一致。
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引用次数: 0
Psychotropic-induced weight gain and telomere length: results from a one-year longitudinal study and a large population-based cohort. 精神药物引起的体重增加和端粒长度:一项为期一年的纵向研究和一个大型人群队列的结果。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-15 DOI: 10.1038/s41398-024-03177-3
Marianna Piras, Jue Lin, Marie Catherine Sadler, Setareh Ranjbar, Claire Grosu, Nermine Laaboub, Martin Preisig, Franziska Gamma, Kerstin Jessica Plessen, Armin von Gunten, Philippe Conus, Zoltan Kutalik, Chin B Eap

Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general population's yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m2, respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p < 0.001, p < 0.001, respectively). Ultimately, telomere trajectories were associated with 1 year weight gain and increases in CRP levels, with telomere shortening strongly enhanced by BMI increments among patients receiving weight-inducing psychotropic treatments.

导致体重增加的精神药物治疗是心血管疾病等老年相关疾病的风险因素,而这些疾病与炎症和端粒长度缩短有关。本研究采用纵向设计,在考虑体重变化和炎症生物标志物高敏C反应蛋白(CRP)的情况下,评估了服用体重诱导精神药物一年后端粒长度的变化轨迹。在200名患者中,观察到端粒缩短的总体中位数为-41.2 bp(p = 0.014),与普通人群每年端粒损耗的情况相当。线性回归结果显示,在体重指数<或≥30 kg/m2的人群中,体重指数每增加5个单位,端粒平均缩短-93.1和-58.9 bp(分别为p = 0.003和p = 0.009)。重要的是,在基线体重较低(即 50 千克)和治疗 1 年后临床相关体重增加(≥ 7%)的患者中,端粒总体缩短率预计会增加 4 倍(相关体重增加与基线体重之间的交互项:+6.3 bp,p = 0.009):+6.3 bp,p = 0.016)。体重增加的患者CRP水平更高(+ 49%; p = 0.016),每当CRP水平增加一倍,端粒就会缩短-36.2 bp(p = 0.010)。利用英国生物银行数据进行的孟德尔随机分析表明,体重指数对端粒缩短具有因果效应,与未服用此类药物的精神病患者(n = 16228)和非精神病对照组(n = 252932)相比,接受体重诱导性精神药物治疗的患者(n = 9798)的因果效应明显更强(beta:分别为-0.37、-0.12、-0.06;P = 0.004,P = 0.005。
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引用次数: 0
The contribution of attention-deficit/hyperactivity disorder polygenic load to metabolic and cardiovascular health outcomes: a large-scale population and sibling study. 注意缺陷/多动障碍多基因负荷对代谢和心血管健康结果的影响:大规模人群和同胞研究。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-13 DOI: 10.1038/s41398-024-03178-2
Ebba Du Rietz, Tian Xie, Rujia Wang, Rosa Cheesman, Miguel Garcia-Argibay, Zihan Dong, Jia Zhang, Jacobien Niebuur, Melissa Vos, Harold Snieder, Henrik Larsson, Catharina A Hartman

Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and biomarkers. Furthermore, we investigated to what extent the PGS effect was influenced by direct and indirect genetic effects (i.e., shared familial effects). We derived ADHD-PGS in 50,768 individuals aged 18-90 years from the Dutch Lifelines Cohort study. Using generalised estimating equations, we estimated the association of PGS with cardiometabolic diseases, derived from self-report and several biomarkers measured during a physical examination. We additionally ran within-sibling PGS analyses, using fixed effects models, to disentangle direct effects of individuals' own ADHD genetic risk from confounding due to indirect genetic effects of relatives, as well as population stratification. We found that higher ADHD-PGS were statistically significantly associated with several cardiometabolic diseases (R-squared [R2] range = 0.03-0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R2 range = 0.01-0.16%) (P < 0.05). Adjustment for shared familial factors attenuated the associations between ADHD-PGS and cardiometabolic outcomes (on average 56% effect size reduction), and significant associations only remained for metabolic disease. Overall our findings suggest that increased genetic liability for ADHD confers a small but significant risk increase for cardiometabolic health outcomes in adulthood. These associations were observable in the general population, even in individuals without ADHD diagnosis, and were partly explained by familial factors shared among siblings.

新的证据表明,多动症与代谢和心血管(心血管代谢)疾病风险的增加有关。然而,人们对这些关联的机制了解仍然有限。在这项研究中,我们估算了多动症的多基因评分(PGS)与几种心血管代谢疾病和生物标志物的关联。此外,我们还研究了 PGS 效应在多大程度上受到直接和间接遗传效应(即共同的家族效应)的影响。我们从荷兰生命线队列研究(Dutch Lifelines Cohort study)中 50,768 名 18-90 岁的个体中得出了 ADHD-PGS。通过使用广义估计方程,我们估计了 PGS 与心脏代谢疾病的关系,该关系来自自我报告和体检中测量的几种生物标志物。此外,我们还使用固定效应模型进行了同胞内部的 PGS 分析,以将个体自身多动症遗传风险的直接影响与亲属的间接遗传效应以及人群分层造成的混淆区分开来。我们发现,在统计学上,较高的 ADHD-PGS 与多种心脏代谢疾病(R 平方 [R2] 范围 = 0.03-0.50%)和生物标志物(与炎症、血压、脂代谢等有关)(R2 范围 = 0.01-0.16%)显著相关(P<0.05)。
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引用次数: 0
Circulating metabolome in relation to cognitive impairment: a community-based cohort of older adults. 循环代谢组与认知障碍的关系:基于社区的老年人队列。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-11 DOI: 10.1038/s41398-024-03147-9
Yuhui Huang, Xuehui Sun, Qingxia Huang, Qiumin Huang, Xiao Chen, Xiaofeng Zhou, Hui Chen, Jie Shen, Mengyan Gao, Yiying Gong, Hui Zhang, Huiru Tang, Xiaofeng Wang, Xiaoyan Jiang, Yan Zheng, Changzheng Yuan

The role of circulating metabolome in cognitive impairment is inconclusive, and whether the associations are in the severity-dependent manner remains unclear. We aimed to identify plasma metabolites associated with cognitive impairment and evaluate the added predictive capacity of metabolite biomarkers on incident cognitive impairment beyond traditional risk factors. In the Rugao Longevity and Ageing Study (RuLAS), plasma metabolome was profiled by nuclear magnetic resonance spectroscopy. Participants were classified into the cognitively normal, moderately impaired, and severely impaired groups according to their performance in two objective cognitive tests. A two-step strategy of cross-sectional discovery followed by prospective validation was applied. In the discovery stage, we included 1643 participants (age: 78.9 ± 4.5 years) and conducted multinomial logistic regression. In the validation stage, we matched 68 incident cases of cognitive impairment (moderately-to-severely impaired) during the 2-year follow-up with 204 cognitively normal controls by age and sex at a 1:3 ratio, and conducted conditional logistic regression. We identified 28 out of 78 metabolites cross-sectionally related to severely impaired cognition, among which IDL particle number, ApoB in IDL, leucine, and valine were prospectively associated with 28%, 28%, 29%, and 33% lower risk of developing cognitive impairment, respectively. Incorporating 13 metabolite biomarkers selected through Lasso regression into the traditional risk factors-based prediction model substantially improved the ability to predict incident cognitive impairment (AUROC: 0.839 vs. 0.703, P < 0.001; AUPRC: 0.705 vs. 0.405, P < 0.001). This study identified specific plasma metabolites related to cognitive impairment. Incorporation of specific metabolites substantially improved the prediction performance for cognitive impairment.

循环代谢组在认知障碍中的作用尚无定论,其关联是否与严重程度有关仍不清楚。我们的目的是确定与认知障碍相关的血浆代谢物,并评估代谢物生物标志物在传统风险因素之外对认知障碍事件的额外预测能力。在如皋长寿与老龄化研究(RuLAS)中,我们通过核磁共振波谱分析了血浆代谢组。根据参与者在两项客观认知测试中的表现,将他们分为认知正常组、中度受损组和严重受损组。我们采用了先横断面发现后前瞻性验证的两步策略。在发现阶段,我们纳入了 1643 名参与者(年龄:78.9 ± 4.5 岁),并进行了多项式逻辑回归。在验证阶段,我们按年龄和性别以 1:3 的比例将 68 例在 2 年随访期间出现认知障碍(中度至重度)的病例与 204 例认知正常的对照组进行了配对,并进行了条件逻辑回归。我们在 78 个代谢物中发现了 28 个与认知功能严重受损有关的横断面代谢物,其中 IDL 颗粒数、IDL 中的载脂蛋白 B、亮氨酸和缬氨酸分别与 28%、28%、29% 和 33% 的认知功能受损发生风险呈前瞻性相关。将通过 Lasso 回归筛选出的 13 个代谢物生物标志物纳入传统的基于风险因素的预测模型,大大提高了预测认知障碍事件的能力(AUROC:0.839 vs. 0.703,P
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引用次数: 0
Ketamine attenuates kidney damage and depression-like behaviors in mice with cisplatin-induced acute kidney injury. 氯胺酮可减轻顺铂诱导的急性肾损伤小鼠的肾损伤和抑郁样行为。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-09 DOI: 10.1038/s41398-024-03176-4
Tianwen Huang, Yangyang He, Ruijuan Cheng, Qiuping Zhang, Xiang Zhong, Kenji Hashimoto, Yi Liu, Yaoyu Pu

Acute kidney injury (AKI) is a serious condition characterized by decreased urine output, often accompanied by psychiatric symptoms like depression. However, there are limited pharmacological treatments available for AKI and its associated depressive symptoms. In this study, we investigated whether cisplatin-induced AKI in mice leads to depression-like behaviors and whether ketamine could alleviate both the kidney injury and these behaviors. Mice with cisplatin-induced AKI exhibited elevated levels of creatinine and urea, kidney damage, increased kidney injury molecule-1 protein, and pathological changes in the liver, colon, and spleen. They also showed depression-like behaviors and reduced expression of synaptic proteins in the prefrontal cortex. Remarkably, a single dose of ketamine significantly reduced these symptoms and pathological changes. Interestingly, the beneficial effects of ketamine on the kidneys, other organs, and depression-like behaviors, were reversed by the tropomyosin receptor kinase B (TrkB) inhibitor ANA-12. Western blot analysis revealed the involvement of the TrkB and ERK (extracellular signal-regulated kinase)-CREB (cAMP response element binding protein) signaling pathway. Additionally, metabolomics analysis indicated that blood metabolites, such as C16-ceramide, may contribute to the effects of ketamine in this model. These findings suggest that cisplatin-induced nephrotoxicity in AKI mice contributes to depression-like behaviors, and ketamine can alleviate both kidney damage and depression-like symptoms by modulating the TrkB and ERK-CREB signaling pathways, as well as altering blood metabolites. However, the role of the kidney-brain axis in these depression-like behaviors remains unclear. Furthermore, ketamine may have therapeutic potential for treating kidney diseases such as AKI, along with associated depressive symptoms.

急性肾损伤(AKI)是一种以尿量减少为特征的严重疾病,通常伴有抑郁症等精神症状。然而,目前针对 AKI 及其相关抑郁症状的药物治疗非常有限。在这项研究中,我们调查了顺铂诱导的小鼠 AKI 是否会导致抑郁样行为,以及氯胺酮是否能减轻肾损伤和这些行为。顺铂诱导的 AKI 小鼠表现出肌酐和尿素水平升高、肾脏损伤、肾损伤分子-1 蛋白增加以及肝脏、结肠和脾脏的病理变化。他们还表现出类似抑郁的行为,前额叶皮层的突触蛋白表达减少。值得注意的是,单剂量氯胺酮能明显减轻这些症状和病理变化。有趣的是,氯胺酮对肾脏、其他器官和抑郁样行为的有益影响被肌球蛋白受体激酶B(TrkB)抑制剂ANA-12逆转。Western印迹分析显示,TrkB和ERK(细胞外信号调节激酶)-CREB(cAMP反应元件结合蛋白)信号通路参与其中。此外,代谢组学分析表明,血液代谢物(如 C16-神经酰胺)可能有助于氯胺酮在该模型中的作用。这些研究结果表明,顺铂诱导的AKI小鼠肾毒性会导致抑郁样行为,而氯胺酮可以通过调节TrkB和ERK-CREB信号通路以及改变血液代谢物来减轻肾损伤和抑郁样症状。然而,肾-脑轴在这些抑郁样行为中的作用仍不清楚。此外,氯胺酮可能具有治疗肾脏疾病(如 AKI)以及相关抑郁症状的潜力。
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引用次数: 0
Re-evaluating our focus in addiction: emotional dysregulation is a critical driver of relapse to drug use. 重新评估我们的戒毒重点:情绪失调是导致复吸的关键因素。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-09 DOI: 10.1038/s41398-024-03159-5
Lexi J Hand, Louise M Paterson, Anne R Lingford-Hughes

Most addiction research has focused on reward- and impulsivity-related neurocircuitry. However, the impact of the withdrawal/negative affect stage in the addiction cycle has been somewhat overlooked, despite it being commonly evident in the clinic. This stage crucially drives negative reinforcement of repeated drug use and relapse, yet less is known about its neural underpinnings. How negative emotional processing is dysregulated in substance dependence is incompletely understood and may manifest differentially across the types of substances. In turn, the regions involved in negative emotional processing may show different patterns of dysregulation. Understanding how neurocircuitry involved in negative states differs across various substances may help inform new targets for treatments. Following a comprehensive literature search of studies examining negative emotional processing in substance dependence, a quantitative approach was deemed inappropriate. Instead, we employed a narrative approach to exploring neural responses to tasks involving emotional processing in alcohol, cocaine, opioid and cannabis dependence. Regions that were found to be dysregulated included the amygdala, insula, anterior cingulate, and medial prefrontal cortex. However, patterns of reactivity differed across alcohol, cocaine, opioid and cannabis dependence. Brain activation in alcohol dependence broadly appeared blunted in response to negative affective stimuli and emotional faces, whilst conversely appeared heightened in cocaine dependence. In opioid dependence, the amygdala was consistently implicated, whilst the insula, anterior cingulate, and medial prefrontal cortex were implicated in cannabis dependence. However, there was wide variability amongst the studies, with very few studies investigating opioid and cannabis dependence. These findings suggest emotional dysregulation varies according to the type of substance dependence. However, the variability in findings and lack of studies highlights the need for more research in this area. Further characterisation of emotional dysregulation in substance dependence will enable identification of treatment targets. More targeted treatments that modulate negative emotional processing could substantially improve outcomes by aiding relapse prevention.

大多数成瘾研究都侧重于与奖赏和冲动相关的神经回路。然而,成瘾周期中的戒断/负面影响阶段的影响却在某种程度上被忽视了,尽管它在临床上很常见。这一阶段对重复吸毒和复吸的负强化起着至关重要的作用,但人们对其神经基础却知之甚少。人们对药物依赖中的负性情绪处理是如何失调的尚不完全清楚,不同类型的药物可能表现出不同的负性情绪处理。反过来,消极情绪处理所涉及的区域也可能表现出不同的失调模式。了解不同物质导致的消极状态所涉及的神经回路有何不同,可能有助于找到新的治疗目标。在对有关药物依赖中负面情绪处理的研究进行了全面的文献检索后,我们认为定量的方法并不合适。相反,我们采用了一种叙事方法来探索神经对涉及酒精、可卡因、阿片类药物和大麻依赖的情绪处理任务的反应。结果发现,杏仁核、脑岛、前扣带回和内侧前额叶皮层等区域出现了失调。然而,酒精、可卡因、阿片类药物和大麻依赖的反应模式各不相同。酒精依赖症患者的大脑激活对负面情绪刺激和情绪面孔的反应普遍减弱,而可卡因依赖症患者的大脑激活则相反地增强。在阿片类药物依赖中,杏仁核一直受到牵连,而在大麻依赖中,岛叶、前扣带回和内侧前额叶皮层受到牵连。然而,这些研究之间存在很大差异,只有极少数研究对阿片类药物和大麻依赖进行了调查。这些发现表明,情绪失调因药物依赖类型而异。然而,研究结果的差异和研究的缺乏凸显了在这一领域开展更多研究的必要性。进一步描述药物依赖中情绪失调的特征将有助于确定治疗目标。更有针对性的治疗方法可以调节消极情绪处理,从而有助于预防复发,从而大大改善治疗效果。
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引用次数: 0
Identification of a DNA methylation signature in whole blood of newborn guinea pigs and human neonates following antenatal betamethasone exposure. 产前接触倍他米松后新生豚鼠和人类新生儿全血中 DNA 甲基化特征的鉴定。
IF 8.3 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-07 DOI: 10.1038/s41398-024-03175-5
Bona Kim, Alisa Kostaki, Sarah McClymont, Stephen G Matthews

Antenatal corticosteroids (ACS) are administered where there is risk of preterm birth to promote fetal lung development and improve perinatal survival. However, treatment may be associated with increased risk of developing neurobehavioural disorders. We have recently identified that ACS results in significant changes to DNA methylation patterns in the newborn and juvenile prefrontal cortex (PFC) of exposed guinea pig offspring. Methylation changes at transcription factor binding sites (TFBS) for PLAGL1, TFAP2C, ZNF263, and SP1 were consistently noted at both post-natal stages, suggesting a long-lasting signature of ACS exposure. In this study, we determined if comparable methylation changes are also present in the newborn blood of ACS-exposed guinea pig offspring, as this would determine whether blood methylation patterns may be used as a peripheral biomarker of changes in the brain. Pregnant guinea pigs were treated with saline or betamethasone (1 mg/kg) on gestational days 50/51. gDNA from whole blood of term-born offspring on post-natal day (PND) 1 was used for reduced representation bisulfite sequencing. Overall, 1677 differentially methylated CpG sites (DMCs) were identified in response to ACS. While no specific DMCs identified in the blood overlapped with those previously reported in the PFC of PND1 offspring, significant differential methylation at TFBSs for PLAGL1, TFAP2C, EGR1, ZNF263, and SP1 was persistently observed. Furthermore, re-examination of our previously reported data of DMCs in human neonatal blood following ACS identified the presence of this same TFBS signature in human infants, suggesting the potential for clinical translation of our epigenomic data.

产前使用皮质类固醇(ACS)可促进胎儿肺部发育,提高围产期存活率。然而,治疗可能会增加患神经行为障碍的风险。我们最近发现,ACS 会导致暴露的豚鼠后代的新生儿和幼年前额叶皮层(PFC)的 DNA 甲基化模式发生显著变化。PLAGL1、TFAP2C、ZNF263 和 SP1 的转录因子结合位点(TFBS)的甲基化变化在出生后的两个阶段都持续存在,这表明暴露于 ACS 会产生持久的特征。在这项研究中,我们确定了暴露于 ACS 的豚鼠后代的新生儿血液中是否也存在类似的甲基化变化,因为这将确定血液甲基化模式是否可用作大脑变化的外周生物标记。在妊娠第 50/51 天,用生理盐水或倍他米松(1 毫克/千克)对怀孕豚鼠进行处理,并用出生后第 1 天足月儿全血中的 gDNA 进行还原表征亚硫酸氢盐测序。总体而言,共鉴定出 1677 个不同甲基化 CpG 位点(DMCs)对 ACS 的反应。虽然在血液中发现的特定 DMCs 与之前报道的在 PND1 后代 PFC 中发现的 DMCs 没有重叠,但在 PLAGL1、TFAP2C、EGR1、ZNF263 和 SP1 的 TFBSs 上持续观察到显著的甲基化差异。此外,我们对之前报告的 ACS 后人类新生儿血液中 DMCs 的数据进行了重新检查,发现人类婴儿中也存在这种相同的 TFBS 特征,这表明我们的表观基因组学数据有可能被应用于临床。
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引用次数: 0
An exploratory study of metabolomics in endogenous and cannabis-use-associated psychotic-like experiences in adolescence. 对青春期内源性和大麻使用相关精神病样经历中代谢组学的探索性研究。
IF 8.3 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-07 DOI: 10.1038/s41398-024-03163-9
Karoliina Kurkinen, Olli Kärkkäinen, Soili M Lehto, Ilona Luoma, Siiri-Liisi Kraav, Petri Kivimäki, Sebastian Therman, Tommi Tolmunen

In adolescence, psychotic-like experiences (PLE) may indicate potential prodromal symptoms preceding the onset of psychosis. Metabolomic studies have shown promise in providing valuable insights into predicting psychosis with enhanced precision compared to conventional clinical features. This study investigated metabolomic alterations associated with PLE in 76 depressed adolescents aged 14-20 years. Serum concentrations of 92 metabolites were analyzed with liquid chromatography-mass spectrometry. PLE were assessed using the Youth Experiences and Health (YEAH) questionnaire. The associations between PLE symptom dimensions (delusions, paranoia, hallucinations, negative symptoms, thought disorder, and dissociation) and metabolite concentrations were analyzed in linear regression models adjusted for different covariates. The symptom dimensions consistently correlated with the metabolome in different models, except those adjusted for cannabis use. Specifically, the hallucination dimension was associated with 13 metabolites (acetoacetic acid, allantoin, asparagine, decanoylcarnitine, D-glucuronic acid, guanidinoacetic acid, hexanoylcarnitine, homogentisic acid, leucine, NAD+, octanoylcarnitine, trimethylamine-N-oxide, and valine) in the various linear models. However, when adjusting for cannabis use, eight metabolites were associated with hallucinations (adenine, AMP, cAMP, chenodeoxycholic acid, cholic acid, L-kynurenine, neopterin, and D-ribose-5-phosphate). The results suggest diverse mechanisms underlying PLE in adolescence; hallucinatory experiences may be linked to inflammatory functions, while cannabis use may engage an alternative metabolic pathway related to increased energy demand and ketogenesis in inducing PLE. The limited sample of individuals with depression restricts the generalizability of these findings. Future research should explore whether various experiences and related metabolomic changes jointly predict the onset of psychoses and related disorders.

在青春期,类似精神病的经历(PLE)可能预示着精神病发病前的潜在前驱症状。与传统的临床特征相比,代谢组学研究有望为更精确地预测精神病提供有价值的见解。本研究调查了 76 名 14-20 岁抑郁青少年与 PLE 相关的代谢组学变化。采用液相色谱-质谱法分析了血清中 92 种代谢物的浓度。采用青少年经历与健康(YEAH)调查问卷评估了抑郁症。通过线性回归模型分析了精神分裂症症状维度(妄想、偏执、幻觉、消极症状、思维紊乱和分离)与代谢物浓度之间的关联,并对不同的协变量进行了调整。在不同的模型中,症状维度始终与代谢组相关,但根据大麻使用情况进行调整的模型除外。具体而言,在不同的线性模型中,幻觉维度与 13 种代谢物(乙酰乙酸、尿囊素、天冬酰胺、癸酰肉碱、D-葡萄糖醛酸、胍基乙酸、己酰肉碱、高戊二酸、亮氨酸、NAD+、辛酰肉碱、三甲胺-N-氧化物和缬氨酸)相关。然而,在对大麻使用情况进行调整后,有八种代谢物与幻觉有关(腺嘌呤、AMP、cAMP、去氧胆酸、胆酸、L-犬尿氨酸、新蝶呤和 D-核糖-5-磷酸)。研究结果表明,青春期抑郁症的发病机制多种多样;幻觉体验可能与炎症功能有关,而吸食大麻可能与能量需求增加和酮体生成有关,是诱发抑郁症的另一种代谢途径。抑郁症患者样本有限,限制了这些研究结果的普遍性。未来的研究应探讨各种经历和相关代谢组变化是否会共同预测精神病和相关疾病的发病。
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引用次数: 0
Effect of the social environment on olfaction and social skills in wild-type and a mouse model of autism. 社会环境对野生型和自闭症小鼠模型嗅觉和社交能力的影响
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-11-07 DOI: 10.1038/s41398-024-03174-6
Caroline Gora, Ana Dudas, Lucas Court, Anil Annamneedi, Gaëlle Lefort, Thiago S Nakahara, Nicolas Azzopardi, Adrien Acquistapace, Anne-Lyse Laine, Anne-Charlotte Trouillet, Lucile Drobecq, Emmanuel Pecnard, Benoît Piégu, Pascale Crépieux, Pablo Chamero, Lucie P Pellissier

Autism spectrum disorders (ASD) are complex, polygenic and heterogenous neurodevelopmental conditions. The severity of autism-associated variants is influenced by environmental factors, particularly social experiences during the critical neurodevelopmental period. While early behavioral interventions have shown efficacy in some children with autism, pharmacological support for core features - impairments in social interaction and communication, and stereotyped or restricted behaviors - is currently lacking. In this study, we examined how the social environment influences both wild-type (WT) and Shank3 knockout (KO) mice, a model reflecting core autism-like traits. Our findings revealed that chronic social isolation enhanced social interaction and olfactory neuron responses in WT animals. Furthermore, it restored impairments in social novelty preference and olfactory function, as well as self-grooming in Shank3 KO mice. Conversely, an enriched social environment heightened social interest toward novel conspecifics in WT mice, but elicited the opposite effect in Shank3 KO mice. Notably, Shank3 KO mice displayed distinct social responses when exposed to WT or Shank3 KO mice. These results offer novel insights that could favor the implementation of behavioral interventions and inclusive classroom programs for children with ASD.

自闭症谱系障碍(ASD)是一种复杂、多基因和异质性的神经发育疾病。自闭症相关变异的严重程度受环境因素的影响,尤其是神经发育关键时期的社会经历。虽然早期行为干预对一些自闭症儿童有疗效,但目前还缺乏针对核心特征(社会交往和沟通障碍以及刻板或限制性行为)的药物支持。在这项研究中,我们考察了社会环境如何影响野生型(WT)小鼠和 Shank3 基因敲除(KO)小鼠(一种反映类似自闭症核心特征的模型)。我们的研究结果表明,慢性社会隔离增强了 WT 动物的社会互动和嗅觉神经元反应。此外,它还能恢复 Shank3 KO 小鼠在社会新奇偏好和嗅觉功能以及自我梳理方面的损伤。相反,在丰富的社会环境中,WT 小鼠对新的同种动物的社会兴趣增强了,但在 Shank3 KO 小鼠中却产生了相反的效果。值得注意的是,Shank3 KO小鼠在与WT或Shank3 KO小鼠接触时会表现出不同的社会反应。这些结果提供了新的见解,有助于对患有自闭症的儿童实施行为干预和包容性课堂计划。
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引用次数: 0
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Translational Psychiatry
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