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Lower confidence and increased error sensitivity in OCD patients while learning under volatility 强迫症患者在波动性环境下学习时自信心降低,对错误的敏感性增加
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-12 DOI: 10.1038/s41398-024-03042-3
Monja Hoven, Tosca Mulder, Damiaan Denys, Ruth J. van Holst, Judy Luigjes

A decoupling between confidence and action could relate to compulsive behaviour as seen in obsessive-compulsive disorder (OCD). The link between confidence and action in OCD has been investigated in clinical case-control studies and in the general population with discrepant findings. The generalizability of findings from highly-compulsive general population samples to clinical OCD samples has been questioned. Here, we investigate action-confidence coupling for 38 OCD patients compared to 37 healthy controls (HC), using a predictive inference task. We compared those results to a comparison between matched high and low compulsive individuals from the general population. Action-updating, confidence and their coupling were compared between the groups. Moreover, computational modeling was performed to compare groups on error sensitivity and environmental parameters. OCD patients showed lower confidence and higher learning rates in reaction to (small) prediction errors than HC, signaling hyperactive error signaling and lower confidence estimation. No evidence was found for differences in action-confidence coupling between groups. In contrast high the compulsive group showed higher confidence and stronger decoupling than the low compulsive group, both of which were related to symptoms. The underlying mechanisms of obsessive-compulsive behaviour might differ between clinical and highly-compulsive general population samples, resulting in different (meta)cognitive profiles.

信心与行动之间的脱钩可能与强迫症(OCD)中的强迫行为有关。在临床病例对照研究和普通人群中对强迫症患者的信心和行动之间的联系进行了调查,但结果并不一致。高度强迫症普通人群样本的研究结果能否推广到临床强迫症样本也受到了质疑。在此,我们采用预测推理任务,对 38 名强迫症患者与 37 名健康对照者(HC)的行动-自信耦合进行了研究。我们将这些结果与普通人群中匹配的高强迫症患者和低强迫症患者进行了比较。我们比较了各组之间的行动更新、信心及其耦合。此外,我们还进行了计算建模,以比较各组的错误敏感性和环境参数。与普通人群相比,强迫症患者在对(小)预测错误做出反应时表现出较低的信心和较高的学习率,这表明他们的错误信号传递过于活跃,信心估计较低。没有证据表明各组之间在行动-信心耦合方面存在差异。相反,高强迫组比低强迫组显示出更高的自信和更强的解耦,这两者都与症状有关。在临床样本和高强迫性普通人群样本之间,强迫症行为的潜在机制可能有所不同,从而导致不同的(元)认知特征。
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引用次数: 0
Oxytocin decreases alcohol self-administration in male baboons 催产素可降低雄性狒狒的酒精自我摄取量
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-11 DOI: 10.1038/s41398-024-03076-7
Mary R. Lee, Catherine F. Moore, Elise M. Weerts

The neurohormone oxytocin (OT) has been proposed as a treatment for alcohol and nicotine use disorders. The aim of the present study was to examine whether intravenous (IV) OT decreases alcohol oral self-administration and consumption in nonhuman primates under a 6-h alcohol access procedure as well as alcohol and nicotine (IV) self-administration under 6-h concurrent access conditions. The subjects were five male baboons (Papio anubis) that self-administered oral alcohol (4% w/v) during 6-h sessions under a fixed ratio 3 (FR3) schedule per drink. Baseline levels of alcohol self-administration were established and then OT treatment was initiated. A single dose of OT (20, 40, 80, 120 IU, IV) or its vehicle (saline) was administered before and again in the middle of the 6-h drinking session for 5 consecutive days (total oxytocin dose of 40, 80, 160, 240 IU/day). After each 5-day treatment, baseline levels of alcohol self-administration were reestablished before the next 5-day OT treatment. In addition, the effect of OT on concurrent alcohol and IV nicotine self-administration was explored in 3 of the baboons where alcohol and nicotine were concurrently available during the 6-hr session each under an FR3 schedule for each drug. Establishment of baseline self-administration and 5-day OT treatments were completed as in the alcohol only study. There was a significant overall reduction in alcohol consumption with OT compared to placebo. On post-hoc analysis, after correcting for multiple comparisons, the 40 and 80 IU doses of OT significantly reduced alcohol consumption compared with vehicle, and consumption did not vary significantly within each 5-day treatment period. OT, qualitatively, also reduced the coadministration of both alcohol and nicotine in each baboon for at least one of the OT doses administered. These results underscore the therapeutic potential of oxytocin as a treatment of alcohol use disorder and possibly, co-use of nicotine.

神经激素催产素(OT)已被提议作为治疗酒精和尼古丁使用障碍的一种方法。本研究旨在探讨在 6 小时酒精摄入程序下,静脉注射催产素是否会降低非人灵长类动物的酒精口服自我给药量和消耗量,以及在 6 小时同时摄入条件下,酒精和尼古丁(静脉注射)自我给药量是否会降低。研究对象是五只雄性狒狒(Papio anubis),它们在每次饮酒的固定比例为 3(FR3)的安排下,在 6 小时的时间内自我口服酒精(4% w/v)。确定酒精自我给药的基线水平后,开始进行 OT 治疗。在连续 5 天的 6 小时饮酒过程中,分别在饮酒前和饮酒中间注射单剂量催产素(20、40、80、120 IU,静脉注射)或其载体(生理盐水)(催产素总剂量分别为 40、80、160、240 IU/天)。每个 5 天的治疗结束后,在下一个 5 天的催产素治疗前重新建立酒精自我给药的基线水平。此外,我们还对其中 3 只狒狒进行了 OT 对同时进行酒精和静脉注射尼古丁自我给药的影响研究,这 3 只狒狒在 6 小时的治疗过程中同时使用酒精和尼古丁,每种药物的治疗时间安排为 FR3。建立自我给药基线和完成为期 5 天的 OT 治疗与仅酒精研究相同。与安慰剂相比,使用 OT 后酒精消耗量明显减少。经事后分析,在校正多重比较后,40 和 80 IU 剂量的 OT 比安慰剂显著降低了酒精消耗量,而且在每个 5 天的治疗期内,酒精消耗量没有显著变化。从质量上讲,在每只狒狒中,至少有一种剂量的 OT 能减少酒精和尼古丁的同时摄入。这些结果凸显了催产素作为治疗酒精使用障碍以及可能的尼古丁联合使用的一种疗法的潜力。
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引用次数: 0
MicroRNAs: pioneering regulators in Alzheimer’s disease pathogenesis, diagnosis, and therapy 微小核糖核酸:阿尔茨海默病发病机制、诊断和治疗中的先驱调控因子
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-10 DOI: 10.1038/s41398-024-03075-8
Yao-Bo Li, Qiang Fu, Mei Guo, Yang Du, Yuewen Chen, Yong Cheng

This article delves into Alzheimer’s disease (AD), a prevalent neurodegenerative condition primarily affecting the elderly. It is characterized by progressive memory and cognitive impairments, severely disrupting daily life. Recent research highlights the potential involvement of microRNAs in the pathogenesis of AD. MicroRNAs (MiRNAs), short non-coding RNAs comprising 20–24 nucleotides, significantly influence gene regulation by hindering translation or promoting degradation of target genes. This review explores the role of specific miRNAs in AD progression, focusing on their impact on β-amyloid (Aβ) peptide accumulation, intracellular aggregation of hyperphosphorylated tau proteins, mitochondrial dysfunction, neuroinflammation, oxidative stress, and the expression of the APOE4 gene. Our insights contribute to understanding AD’s pathology, offering new avenues for identifying diagnostic markers and developing novel therapeutic targets.

阿尔茨海默病(AD)是一种主要影响老年人的神经退行性疾病。它的特征是渐进性记忆和认知障碍,严重干扰日常生活。最近的研究突出表明,microRNAs 可能参与了 AD 的发病机制。微小RNA(MiRNA)是由20-24个核苷酸组成的短小非编码RNA,通过阻碍翻译或促进目标基因的降解来显著影响基因调控。本综述探讨了特定 miRNAs 在 AD 进展中的作用,重点是它们对 β 淀粉样蛋白(Aβ)肽积累、高磷酸化 tau 蛋白细胞内聚集、线粒体功能障碍、神经炎症、氧化应激和 APOE4 基因表达的影响。我们的见解有助于理解注意力缺失症的病理,为确定诊断标志物和开发新的治疗靶点提供了新的途径。
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引用次数: 0
Testing the causal relationship of fat and sugar intake with depression and cortisol: a Mendelian Randomisation study 测试脂肪和糖的摄入与抑郁和皮质醇的因果关系:孟德尔随机研究
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-10 DOI: 10.1038/s41398-024-03089-2
Matylda Buczkowska, Eleonora Iob

Unhealthy diets high in fat and sugar content may have an impact on psychological health and increase the risk of Major Depressive Disorder (MDD) and stress levels. On the other hand, MDD and stress might be related to food choices and intake. However, it is not clear whether diet, and specifically fat and sugar intake, is causally related to stress and MDD, and whether this relationship may be bi-directional. This study utilised Mendelian Randomisation (MR) to investigate the causal nature of the relationship of fat and sugar intake with MDD and cortisol (as a proxy of stress), and to shed light on the direction of this relationship. Summary-level data for all exposure and outcome variables were obtained from large-scale, non-overlapping GWASs in individuals of European ancestry. Bidirectional analyses were performed: one with macronutrients as exposures and one with MDD/cortisol as exposures. Random-effects inverse-variance weighted regression was used as the primary analytic method for genetic instruments with at least two single nucleotide polymorphisms (SNPs) available (and individual Wald ratio was used when only one SNP was available). Higher levels of genetically predicted relative sugar intake were causally associated with lower MDD risk, for both genome-wide significant p-value threshold of p < 1 × 10−8, (OR = 0.553, 95% CI: 0.395-0.775) and relaxed p-value threshold of p < 1 × 10−6 (OR = 0.786, 95% CI: 0.630–0.981). No reverse causality was detected in the opposite direction as MDD was not associated with sugar consumption. The associations observed for all the other pairs of variables were weak and imprecise. A number of limitations was present in the study, such as low-SNP based heritability for some exposures, inability to prove whether variants were correlated with unmeasured confounders and self-reporting of MDD data. Lifestyle and/or pharmacological interventions targeting sugar-related physiological mechanisms may help to reduce depressive symptoms. However, more research is necessary on short- and long-term effects of sugar on the risk of MDD. Additionally, future studies should investigate whether the amount and type of sugar consumed may underlie the impact of sugar on mood and stress levels.

高脂肪、高糖分的不健康饮食可能会影响心理健康,增加患重度抑郁症(MDD)的风险和压力水平。另一方面,重度抑郁症和压力可能与食物的选择和摄入有关。然而,目前尚不清楚饮食,特别是脂肪和糖的摄入量,是否与压力和多发性抑郁症有因果关系,以及这种关系是否可能是双向的。本研究利用孟德尔随机法(Mendelian Randomisation,MR)调查脂肪和糖的摄入量与 MDD 和皮质醇(作为压力的替代物)之间的因果关系,并揭示这种关系的方向。所有暴露变量和结果变量的摘要级数据均来自欧洲血统个体的大规模、无重叠的全球基因组研究。研究人员进行了双向分析:一项是将宏量营养素作为暴露变量,另一项是将 MDD/皮质醇作为暴露变量。对于至少有两个单核苷酸多态性(SNPs)的遗传工具,采用随机效应逆方差加权回归作为主要分析方法(如果只有一个 SNPs,则采用个体 Wald 比率)。在全基因组显著 p 值阈值为 p < 1 × 10-8 时(OR = 0.553,95% CI:0.395-0.775)和宽松 p 值阈值为 p < 1 × 10-6 时(OR = 0.786,95% CI:0.630-0.981),较高水平的遗传预测相对糖摄入量与较低的 MDD 风险存在因果关系。由于 MDD 与糖的摄入量无关,因此没有发现反向因果关系。在所有其他变量对中观察到的相关性较弱且不精确。该研究存在一些局限性,如某些暴露的遗传率较低,无法证明变异是否与未测量的混杂因素相关,以及MDD数据的自我报告。针对糖相关生理机制的生活方式和/或药物干预可能有助于减轻抑郁症状。然而,有必要就糖对多发性抑郁症风险的短期和长期影响开展更多研究。此外,未来的研究还应该调查糖的摄入量和类型是否会对情绪和压力水平产生影响。
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引用次数: 0
Exposure to an acute stress impaired the metabolic plasticity of resilient rats by enhancing fatty acid β-oxidation in the ventral hippocampus 急性应激通过增强腹侧海马的脂肪酸β-氧化作用来损害具有恢复能力的大鼠的代谢可塑性
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-10 DOI: 10.1038/s41398-024-03080-x
Paola Brivio, Maria Teresa Gallo, Matteo Audano, Gaia Galassi, Piotr Gruca, Magdalena Lason, Ewa Litwa, Fabio Fumagalli, Mariusz Papp, Nico Mitro, Francesca Calabrese

The concept of resilience has changed over time and nowadays it refers to the positive adaptation to life adversities, rather than to the absence of a pathological response normally occurring in susceptible people. Based on our previous data showing that the exposure to the chronic mild stress (CMS) paradigm differently affected bioenergetics in the ventral hippocampus of vulnerable and resilient animals, here we investigated whether resilience is a stable trait or if the energetic strategy set in motion to sustain resilience unveils a vulnerability feature in a more dynamic situation. To this aim, vulnerable and resilient rats after 6 weeks of CMS were subjected to a further acute, unfamiliar restraint stress (ARS) and metabolomic studies were conducted in the ventral hippocampus. We observed that exposure to a single novel challenge negatively affects the fuel utilization of resilient animals. Indeed, while they increase glycolysis to sustain the non-hedonic phenotype when exposed to CMS, they shift to fatty acid β-oxidation after ARS, as vulnerable animals following CMS, suggesting that the energy strategy that guarantees resilience is fragile and can be negatively modified by a different environmental condition. These results suggest that strengthening resilience to foster individuals to bounce back from stressful life events may represent a strategy to decrease vulnerability or prevent the risk of relapsing to a pathological state.

随着时间的推移,恢复力的概念已经发生了变化,如今它指的是对生活逆境的积极适应,而不是指易感人群通常没有病理反应。根据我们之前的数据,暴露于慢性轻度应激(CMS)范例对脆弱动物和复原力动物腹侧海马的生物能产生了不同的影响,在此,我们研究了复原力是否是一种稳定的特征,或者在更动态的情况下,维持复原力的能量策略是否会显示出脆弱性特征。为此,我们对接受了6周CMS训练的脆弱大鼠和恢复力强的大鼠进一步施加了急性陌生束缚应激(ARS),并在腹侧海马进行了代谢组学研究。我们观察到,暴露于单一的新挑战会对抗逆动物的燃料利用率产生负面影响。事实上,当动物暴露于CMS时,它们会增加糖酵解以维持非血症表型,但在ARS后,它们会转向脂肪酸β-氧化,就像CMS后的脆弱动物一样。这些结果表明,加强恢复力以促进个体从生活压力事件中反弹,可能是降低脆弱性或防止复发到病理状态风险的一种策略。
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引用次数: 0
Neuroimaging markers of aberrant brain activity and treatment response in schizophrenia patients based on brain complexity 基于大脑复杂性的精神分裂症患者异常大脑活动和治疗反应的神经影像标记
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-09 DOI: 10.1038/s41398-024-03067-8
Liju Liu, Zezhi Li, Di Kong, Yanqing Huang, Diwei Wu, Huachang Zhao, Xin Gao, Xiangyang Zhang, Mi Yang

The complexity of brain activity reflects its ability to process information, adapt to environmental changes, and transition between states. However, it remains unclear how schizophrenia (SZ) affects brain activity complexity, particularly its dynamic changes. This study aimed to investigate the abnormal patterns of brain activity complexity in SZ, their relationship with cognitive deficits, and the impact of antipsychotic medication. Forty-four drug-naive first-episode (DNFE) SZ patients and thirty demographically matched healthy controls (HC) were included. Functional MRI-based sliding window analysis was utilized for the first time to calculate weighted permutation entropy to characterize complex patterns of brain activity in SZ patients before and after 12 weeks of risperidone treatment. Results revealed reduced complexity in the caudate, putamen, and pallidum at baseline in SZ patients compared to HC, with reduced complexity in the left caudate positively correlated with Continuous Performance Test (CPT) and Category Fluency Test scores. After treatment, the complexity of the left caudate increased. Regions with abnormal complexity showed decreased functional connectivity, with complexity positively correlated with connectivity strength. We observed that the dynamic complexity of the brain exhibited the characteristic of spontaneous, recurring “complexity drop”, potentially reflecting transient state transitions in the resting brain. Compared to HC, patients exhibited reduced scope, intensity, and duration of complexity drop, all of which improved after treatment. Reduced duration was negatively correlated with CPT scores and positively with clinical symptoms. The results suggest that abnormalities in brain activity complexity and its dynamic changes may underlie cognitive deficits and clinical symptoms in SZ patients. Antipsychotic treatment partially restores these abnormalities, highlighting their potential as indicators of treatment efficacy and biomarkers for personalized therapy.

大脑活动的复杂性反映了大脑处理信息、适应环境变化以及在不同状态之间转换的能力。然而,精神分裂症(SZ)如何影响大脑活动的复杂性,尤其是其动态变化,目前仍不清楚。本研究旨在探讨精神分裂症患者大脑活动复杂性的异常模式、其与认知缺陷的关系以及抗精神病药物的影响。研究纳入了44名未服药的首次发病(DNFE)SZ患者和30名人口统计学匹配的健康对照组(HC)。该研究首次利用基于功能磁共振成像的滑动窗口分析法计算加权排列熵,以描述利培酮治疗12周前后SZ患者大脑活动的复杂模式。结果表明,与HC相比,SZ患者基线时尾状核、普鲁门和苍白球的复杂性降低,左侧尾状核复杂性的降低与连续表现测试(CPT)和类别流畅性测试得分呈正相关。治疗后,左侧尾状核的复杂性增加。复杂性异常的区域显示功能连接性下降,复杂性与连接强度呈正相关。我们观察到,大脑的动态复杂性表现出自发的、反复出现的 "复杂性下降 "特征,这可能反映了静息大脑中的瞬时状态转换。与 HC 相比,患者表现出的复杂性下降的范围、强度和持续时间都有所减少,所有这些在治疗后都有所改善。持续时间的缩短与 CPT 评分呈负相关,与临床症状呈正相关。结果表明,大脑活动复杂性的异常及其动态变化可能是 SZ 患者认知缺陷和临床症状的基础。抗精神病治疗可部分恢复这些异常,从而凸显了它们作为疗效指标和个性化治疗生物标志物的潜力。
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引用次数: 0
Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study 记忆门诊队列中的神经炎症、脑血管功能障碍和昼夜皮质醇生物标志物:Co-STAR 研究的发现
IF 6.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-09 DOI: 10.1038/s41398-024-03072-x
Makrina Daniilidou, Jasper Holleman, Göran Hagman, Ingemar Kåreholt, Malin Aspö, Ann Brinkmalm, Henrik Zetterberg, Kaj Blennow, Alina Solomon, Miia Kivipelto, Shireen Sindi, Anna Matton

Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer’s disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer’s Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.

皮质醇失调、神经炎症和脑血管功能障碍是阿尔茨海默病(AD)患者分别受到影响的生物学过程。在这里,我们的目的是在 108 名患有主观认知功能减退(SCD,40 人)、轻度认知功能障碍(MCI,39 人)和阿氏痴呆症(AD,29 人)的记忆门诊患者中找出反映这些途径的生物标志物特征。研究对象来自卡罗林斯卡大学医院招募的阿尔茨海默病皮质醇和压力(Co-STAR)队列。对唾液皮质醇昼夜浓度和 41 种 CSF 蛋白质进行了分析。应用主成分分析确定了与注意力缺失症病理、突触损失和神经心理评估相关的综合生物特征,并对年龄、性别、教育程度和诊断等混杂因素进行了线性回归调整。我们发现,MCI 患者脑脊液中的 C 反应蛋白 (CRP)、干扰素 γ 诱导蛋白 (IP-10)、胸腺和活化调节趋化因子 (TARC)、细胞间粘附分子-1 (ICAM-1) 和血管细胞粘附分子-1 (VCAM-1) 水平升高。此外,皮质醇失调的标志物(唾液皮质醇唤醒反应平缓和皮质醇斜率平缓)与整个队列中胎盘生长因子(PlGF)、IP-10 和几丁质酶 3-like 1(YKL-40)水平的升高相关。由皮质醇觉醒反应、皮质醇斜率和 CSF IL-6 组成的生物特征在 AD 患者中下调。此外,反映神经炎症和血管损伤重叠病理生理过程的生物标志物特征与AD病理、突触损失和处理速度恶化有关。我们的研究结果表明,在MCI阶段,免疫和脑血管过程早期失调,并为了解AD中慢性压力和神经炎症的相互关系提供了见解。
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引用次数: 0
Orphan receptor-GPR52 inverse agonist efficacy in ameliorating chronic stress-related deficits in reward motivation and phasic accumbal dopamine activity in mice. 孤儿受体-GPR52反向激动剂在改善小鼠与慢性压力相关的奖赏动机缺陷和阶段性蓄积多巴胺活性方面的功效。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-07 DOI: 10.1038/s41398-024-03081-w
Chenfeng Zhang, Diana Kúkeľová, Hannes Sigrist, Bastian Hengerer, Ramona F Kratzer, Philipp Mracek, Azar Omrani, Moritz von Heimendahl, Christopher R Pryce

Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect-via ventral pallidium (VP)-pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.

奖赏处理功能障碍(如失乐症、冷漠症)在与压力相关的神经精神疾病(包括抑郁症和精神分裂症)中很常见,目前尚无成熟的疗法。一种潜在的治疗方法是恢复食欲行为中的奖赏预期,其缺陷与累加核(NAc)活动减弱同时存在,这可能是由于 NAc 抑制了间叶多巴胺(DA)信号传导。针对NAc调节腹侧被盖区(VTA)DA神经元对奖赏线索的反应,可能涉及直接或间接--通过腹侧苍白球(VP)--途径。其中一个候选途径是孤儿 G 蛋白偶联受体 GPR52,它由投射到 VP 的 DA 受体 2 NAc 神经元表达。在小鼠脑切片制备中,GPR52反向激动剂(GPR52-IA)可减弱NAc-VP神经元诱发的抑制性突触后电流,从而解除对VTA DA神经元的抑制。为了研究GPR52-IA的行为效应,我们应用了一种小鼠模型,在这种模型中,慢性社会应激会导致奖励学习和努力动机的降低。对照组小鼠和长期处于应激状态的小鼠接受了音调-食欲行为-蔗糖强化的辨别学习测试:应激降低了食欲反应和辨别学习能力,而这些预期行为在 GPR52-IA 的作用下得到了剂量依赖性的恢复。然后,同样的小鼠接受了操作行为-音调-蔗糖强化的努力动机测试:应激降低了努力动机,而 GPR52-IA 则剂量依赖性地恢复了努力动机。在一个新的队列中,GRABDA 传感器纤维光度计被用来测量动机测试期间的 NAc DA 活动:在应激小鼠中,动机降低与 NAc DA 活动减弱同时发生,特别是对表示强化努力行为的音调,而 GPR52-IA 改善了这两种缺陷。这些发现:(1)证明了 GPR52 反向激动剂对食欲行为中与压力相关的奖励预期缺陷的临床前疗效。(2)提出 GPR52 依赖性抑制 NAc-VP-VTA-NAc 回路,导致赚取的奖励刺激的阶段性 NAc DA 信号增加,可能是这些临床相关效应的原因。
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引用次数: 0
Next-generation precision medicine for suicidality prevention. 预防自杀的下一代精准医学。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-06 DOI: 10.1038/s41398-024-03071-y
R Bhagar, S S Gill, H Le-Niculescu, C Yin, K Roseberry, J Mullen, M Schmitz, E Paul, J Cooke, C Tracy, Z Tracy, A S Gettelfinger, D Battles, M Yard, G Sandusky, A Shekhar, S M Kurian, P Bogdan, A B Niculescu

Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.

自杀仍然是整个社会,尤其是精神疾病患者面临的一个明确而现实的危险。由于缺乏客观和/或定量信息的广泛应用,治疗和预防工作受到了阻碍。自杀倾向的严重程度不一,从认为生命不值得活下去的模糊想法,到意念、计划、尝试和完成。跟踪自杀风险的血液生物标志物为了解自杀的生物学特性提供了一个窗口,并有助于评估和治疗。我们以前的研究结果是积极的。在此,我们将介绍我们在精神病患者中进行的新研究,这些研究从全基因组入手,采用多重独立队列设计,扩大了自杀倾向血液基因表达生物标志物的识别、优先排序、验证和测试范围。通过横断面和纵向方法,我们发现了一些新的和以前已知的生物标志物,它们对高度自杀状态以及与之相关的未来精神病住院治疗具有预测作用。表达量增加最多的生物标志物是血清素转运体 SLC6A4。降幅最大的生物标志物是 TINF2,该基因突变会导致端粒极短。最大的生物通路与细胞凋亡有关。最大的上游调节因子是泼尼松龙。综上所述,我们的数据支持这样一种可能性,即从生物学角度来看,自杀是一种由极端压力驱动的主动衰老/死亡形式。与此相一致的是,我们根据临床测量结果确定的自杀亚型中,压力和焦虑程度最高。总体而言,治疗匹配度最高的药物是锂、氯氮平和氯胺酮,其中锂对女性的治疗效果更强,氯氮平对男性的治疗效果更强。药物再用途生物信息学分析发现了肾素-血管紧张素系统调节剂和环氧化酶抑制剂的潜力。此外,我们还展示了根据血液生物标志物检测结果为医生提供的病人报告,该报告按性别进行了个性化设计。我们还将血液生物标志物检测与社会决定因素和心理测量(CFI-S、自杀倾向)相结合,显示出协同效应。最后,我们将其与机器学习方法进行了比较,以优化预测能力并确定关键特征。我们认为,我们的研究结果和综合方法可以产生变革性的临床效用。
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引用次数: 0
A systematic review of deep brain stimulation for substance use disorders. 对深部脑刺激治疗药物使用障碍的系统回顾。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-06 DOI: 10.1038/s41398-024-03060-1
David Zammit Dimech, Audrey-Ann Zammit Dimech, Mark Hughes, Ludvic Zrinzo

Background: Pharmaco-psychiatric techniques remain the mainstay, first line treatments in substance use disorders (SUD), assisting in detoxification but largely ineffective at reducing dependence. The path to rehabilitation and freedom from addiction often proves uncertain and laborious for both patients and their significant others. Relapse rates for multiple substances of abuse are considerable and the number of SUD patients is on the increase worldwide.

Objective: To assess efficacy of deep brain stimulation (DBS) as a therapeutic solution for SUDs.

Methods: A systematic electronic database search of PubMed and EMBASE retrieved DBS addiction-focused studies on humans, of which a total of 26 (n = 71) from 2007 to 2023 were deemed eligible, including the first randomized controlled trial (RCT) in this field. This review was prospectively registered with PROSPERO: CRD42023411631.

Results: In addressing SUDs, DBS targeting primarily the nucleus accumbens (NAcc), with or without the anterior limb of the internal capsule, presented encouraging levels of efficacy in reducing cravings and consumption, followed by remission in some subjects, but still reporting relapses in 73.2% of patients.

Conclusions: For treatment-refractory addictions DBS use seems limited to reducing cravings with a satisfactory degree of success, yet not clinically consistent in inducing abstinence, suggesting involvement of factors unaffected by DBS intervention. Furthermore, costs and the scale of the problem are such that DBS is unlikely to have a significant societal impact. Nevertheless, DBS may provide insight into the biology of addiction and is worthy of further research using increased methodological rigor, standardized outcome measures, and pre-established surgical protocols.

背景:药物-精神治疗技术仍然是药物使用障碍(SUD)的主要一线治疗方法,有助于戒毒,但在减少依赖性方面基本无效。对于患者及其重要的人来说,康复和摆脱毒瘾的道路往往是不确定和艰难的。多种药物滥用的复发率相当高,而且全世界 SUD 患者的数量也在不断增加:评估脑深部刺激(DBS)作为治疗 SUDs 的一种解决方案的疗效:在 PubMed 和 EMBASE 电子数据库中进行了系统性检索,共检索到 2007 年至 2023 年以深部脑刺激治疗成瘾为重点的人体研究 26 项(n = 71),其中包括该领域的首个随机对照试验 (RCT)。本综述在 PROSPERO 进行了前瞻性注册:CRD42023411631.Results:结论:对于治疗难治性成瘾者,DBS主要以脑脊髓核(NAcc)为靶点,无论是否使用内囊前肢,在减少渴求和消耗方面都取得了令人鼓舞的疗效,部分受试者的病情得到缓解,但仍有73.2%的患者复发:结论:对于难治性成瘾,DBS 的使用似乎仅限于减少渴求,并取得了令人满意的效果,但在诱导戒断方面并不具有临床一致性,这表明存在一些不受 DBS 干预影响的因素。此外,从成本和问题的规模来看,DBS 不太可能对社会产生重大影响。尽管如此,DBS 仍能让人们深入了解成瘾的生物学原理,因此值得采用更严谨的方法、标准化的结果测量和预先确定的手术方案进行进一步研究。
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引用次数: 0
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Translational Psychiatry
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