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Developmental prediction modeling based on diffusion tensor imaging uncovering age-dependent heterogeneity in early childhood autistic brain. 基于扩散张量成像的发展预测模型揭示了儿童早期自闭症大脑中年龄依赖性的异质性。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-10-30 DOI: 10.1186/s13229-023-00573-2
Xinyue Huang, Yating Ming, Weixing Zhao, Rui Feng, Yuanyue Zhou, Lijie Wu, Jia Wang, Jinming Xiao, Lei Li, Xiaolong Shan, Jing Cao, Xiaodong Kang, Huafu Chen, Xujun Duan

Objective: There has been increasing evidence for atypical white matter (WM) microstructure in autistic people, but findings have been divergent. The development of autistic people in early childhood is clouded by the concurrently rapid brain growth, which might lead to the inconsistent findings of atypical WM microstructure in autism. Here, we aimed to reveal the developmental nature of autistic children and delineate atypical WM microstructure throughout early childhood while taking developmental considerations into account.

Method: In this study, diffusion tensor imaging was acquired from two independent cohorts, containing 91 autistic children and 100 typically developing children (TDC), aged 4-7 years. Developmental prediction modeling using support vector regression based on TDC participants was conducted to estimate the WM atypical development index of autistic children. Then, subgroups of autistic children were identified by using the k-means clustering method and were compared to each other on the basis of demographic information, WM atypical development index, and autistic trait by using two-sample t-test. Relationship of the WM atypical development index with age was estimated by using partial correlation. Furthermore, we performed threshold-free cluster enhancement-based two-sample t-test for the group comparison in WM microstructures of each subgroup of autistic children with the rematched subsets of TDC.

Results: We clustered autistic children into two subgroups according to WM atypical development index. The two subgroups exhibited distinct developmental stages and age-dependent diversity. WM atypical development index was found negatively associated with age. Moreover, an inverse pattern of atypical WM microstructures and different clinical manifestations in the two stages, with subgroup 1 showing overgrowth with low level of autistic traits and subgroup 2 exhibiting delayed maturation with high level of autistic traits, were revealed.

Conclusion: This study illustrated age-dependent heterogeneity in early childhood autistic children and delineated developmental stage-specific difference that ranged from an overgrowth pattern to a delayed pattern. Trial registration This study has been registered at ClinicalTrials.gov (Identifier: NCT02807766) on June 21, 2016 ( https://clinicaltrials.gov/ct2/show/NCT02807766 ).

目的:越来越多的证据表明自闭症患者存在非典型白质(WM)微观结构,但研究结果存在分歧。自闭症患者在儿童早期的发展受到同时快速大脑生长的影响,这可能导致自闭症中非典型WM微观结构的不一致发现。在这里,我们旨在揭示自闭症儿童的发展本质,并在考虑发展因素的同时,描绘整个幼儿期非典型WM微观结构。方法:在本研究中,从两个独立的队列中获得扩散张量成像,包括91名自闭症儿童和100名4-7岁的典型发育中儿童(TDC)。基于TDC参与者,使用支持向量回归进行发展预测建模,以估计自闭症儿童的WM非典型发展指数。然后,使用k-means聚类方法确定自闭症儿童的亚组,并使用双样本t检验在人口统计学信息、WM非典型发展指数和自闭症特征的基础上相互比较。WM非典型发展指数和年龄的关系用偏相关估计。此外,我们对自闭症儿童各亚组与TDC亚组的WM微观结构进行了基于无阈值聚类增强的双样本t检验。结果:我们根据WM非典型发育指数将自闭症儿童分为两个亚组。这两个亚组表现出不同的发育阶段和年龄依赖性的多样性。WM非典型发育指数与年龄呈负相关。此外,在这两个阶段中,非典型WM微观结构和不同临床表现的相反模式被揭示,亚组1表现出过度生长,具有低水平的自闭症特征,而亚组2表现出延迟成熟,具有高水平的自闭主义特征。结论:本研究阐明了儿童早期自闭症儿童的年龄依赖性异质性,并描绘了从过度生长模式到延迟模式的发育阶段特异性差异。试验注册本研究已于2016年6月21日在ClinicalTrials.gov(标识符:NCT02807766)上注册(https://clinicaltrials.gov/ct2/show/NCT02807766)。
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引用次数: 0
Effect of presentation rate on auditory processing in Rett syndrome: event-related potential study. Rett综合征呈现率对听觉处理的影响:事件相关电位研究。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-10-26 DOI: 10.1186/s13229-023-00566-1
Daria Kostanian, Anna Rebreikina, Victoria Voinova, Olga Sysoeva

Background: Rett syndrome (RS) is a rare neurodevelopmental disorder characterized by mutations in the MECP2 gene. Patients with RS have severe motor abnormalities and are often unable to walk, use hands and speak. The preservation of perceptual and cognitive functions is hard to assess, while clinicians and care-givers point out that these patients need more time to process information than typically developing peers. Neurophysiological correlates of auditory processing have been also found to be distorted in RS, but sound presentation rates were relatively quick in these studies (stimulus onset asynchrony, SOA < 1000 ms). As auditory event-related potential (ERP) is typically increased with prolongation of SOA we aim to study if SOA prolongation might compensate for observed abnormalities.

Methods: We presented a repetitive stimulus (1000 Hz) at three different SOAs of 900 ms, 1800 ms, and 3600 ms in children with RS (N = 24, Mean age = 9.0 ± 3.1) and their typical development (TD) peers (N = 27, Mean age = 9.7 ± 3.4) while recording 28-channels electroencephalogram, EEG. Some RS participants (n = 10) did not show clear ERP and were excluded from the analysis.

Results: Major ERP components (here assessed as N1P1 and P2N1 peak-to-peak values) were smaller at SOA 900 than at longer SOAs in both groups, pointing out that the basic mechanism of adaptation in the auditory system is preserved in at least in RS patients with evident ERPs. At the same time the latencies of these components were significantly delayed in the RS than in TD. Moreover, late components (P2N1 and N2P2) were drastically reduced in Rett syndrome irrespective of the SOA, suggesting a largely affected mechanism of integration of upcoming sensory input with memory. Moreover, developmental stagnation of auditory ERP characterized patients with RS: absence of typical P2N1 enlargement and P1 and N1 shortening with age at least for shortest SOA.

Limitations: We could not figure out the cause for the high percentage of no-evident ERP RS participants and our final sample of the RS group was rather small. Also, our study did not include a control clinical group.

Conclusions: Thus, auditory ERPs inform us about abnormalities within auditory processing that cannot be fully overcomed by slowing presentation rate.

背景:雷特综合征是一种罕见的以MECP2基因突变为特征的神经发育障碍。RS患者有严重的运动异常,通常无法行走、用手和说话。感知和认知功能的保存很难评估,而临床医生和护理人员指出,这些患者比通常发育中的同龄人需要更多的时间来处理信息。在RS中,听觉处理的神经生理学相关性也被发现是扭曲的,但在这些研究中,声音呈现率相对较快(刺激发作不同步,SOA 方法:我们在患有RS(N = 24,平均年龄 = 9 ± 3.1)及其典型发展(TD)同行(N = 27,平均年龄 = 9.7 ± 3.4)同时记录28个通道的脑电图。一些RS参与者(n = 10) 没有显示出明确的ERP,因此被排除在分析之外。结果:在SOA 900时,两组的主要ERP成分(此处评估为N1P1和P2N1峰间值)均小于较长SOA时,这表明至少在具有明显ERP的RS患者中,听觉系统的基本适应机制得以保留。同时,与TD相比,RS中这些成分的潜伏期显著延迟。此外,无论SOA如何,Rett综合征中的晚期成分(P2N1和N2P2)都显著减少,这表明即将到来的感觉输入与记忆的整合机制受到了很大影响。此外,听觉ERP的发育停滞是RS患者的特征:至少在最短的SOA中,没有典型的P2N1增大和P1和N1随年龄缩短。局限性:我们无法找出没有明显ERP RS参与者的高百分比的原因,我们对RS组的最终样本相当小。此外,我们的研究不包括对照临床组。结论:因此,听觉ERPs告知我们听觉处理中的异常,这些异常不能通过减慢呈现率来完全克服。
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引用次数: 1
Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations. 结节性硬化综合征1患者来源的神经祖细胞的Translatomy分析显示雷帕霉素依赖性和独立性改变。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-10-25 DOI: 10.1186/s13229-023-00572-3
Inci S Aksoylu, Pauline Martin, Francis Robert, Krzysztof J Szkop, Nicholas E Redmond, Srirupa Bhattacharyya, Jennifer Wang, Shan Chen, Roberta L Beauchamp, Irene Nobeli, Jerry Pelletier, Ola Larsson, Vijaya Ramesh

Background: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin.

Methods: Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272.

Results: Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin.

Conclusions: Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.

背景:结节性硬化综合征(TSC)是一种由TSC1或TSC2基因突变引起的遗传性神经皮肤疾病,患者经常表现出神经发育(ND)表现,称为TSC相关神经精神障碍(TAND),包括自闭症谱系障碍(ASD)和智力残疾。Hamartin(TSC1)和tuberin(TSC2)蛋白形成雷帕霉素复合物1(mTORC1)信号传导的复合物抑制机制靶标。TSC1或TSC2的缺失激活mTORC1,在几个靶标中,mTORC1通过抑制翻译阻遏物eIF4E结合蛋白来控制蛋白质合成。使用TSC1患者来源的神经祖细胞(NPC),我们最近报道了早期ND表型变化,包括TSC1缺失的NPC中细胞增殖增加和轴突生长改变,这些细胞不受mTORC1抑制剂雷帕霉素的影响。方法:在这里,我们使用多组分析,在转录组水平上量化mRNA丰度和翻译效率的变化,来比较CRISPR编辑的TSC1-null和由一个TSC供体(一个克隆/基因型)产生的CRISPR校正的TSC1-WT NPC。为了评估已确定的基因表达改变的相关性,我们对ASD供体和年龄匹配的对照组的死后大脑进行了多聚体分析。我们进一步比较了在使用变构抑制剂雷帕霉素抑制mTORC1后对NPCs中转录物子集的翻译和早期ND表型的拯救的影响与第三代双空间,mTORC1选择性抑制剂RMC-6272结果:NPC的多聚体图谱显示了许多与TSC1相关的mRNA翻译变化,这些变化在人类ASD大脑中大量重现。此外,尽管雷帕霉素治疗部分逆转了TSC1相关的mRNA翻译改变,但大多数与神经活动/突触调节或ASD相关的基因对雷帕霉素不敏感。相反,RMC-6272治疗抑制了雷帕霉素不敏感的翻译,并逆转了TSC1相关的早期ND表型,包括不受雷帕霉素影响的增殖和轴突生长。结论:我们的工作揭示了TSC1患者来源的NPC中大量的mRNA翻译改变,这些改变概括了ASD脑样本中的mRNA翻译。此外,RMC-6272对TSC1相关但雷帕霉素不敏感的翻译和ND表型的抑制揭示了更有效地靶向mTORC1作为TAND的优越治疗策略的潜在意义。
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引用次数: 0
Age-related changes in neural responses to sensory stimulation in autism: a cross-sectional study. 自闭症患者对感觉刺激的神经反应的年龄相关变化:一项横断面研究。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-10-11 DOI: 10.1186/s13229-023-00571-4
Melis E Cakar, Kaitlin K Cummings, Susan Y Bookheimer, Mirella Dapretto, Shulamite A Green

Background: Sensory over-responsivity (SOR) is an impairing sensory processing challenge in autism spectrum disorder (ASD) which shows heterogenous developmental trajectories and appears to improve into adulthood in some but not all autistic individuals. However, the neural mechanisms underlying interindividual differences in these trajectories are currently unknown.

Methods: Here, we used functional magnetic resonance imaging (fMRI) to investigate the association between age and neural activity linearly and nonlinearly in response to mildly aversive sensory stimulation as well as how SOR severity moderates this association. Participants included 52 ASD (14F) and 41 (13F) typically developing (TD) youth, aged 8.6-18.0 years.

Results: We found that in pre-teens, ASD children showed widespread activation differences in sensorimotor, frontal and cerebellar regions compared to TD children, while there were fewer differences between ASD and TD teens. In TD youth, older age was associated with less activation in the prefrontal cortex. In contrast, in ASD youth, older age was associated with more engagement of sensory integration and emotion regulation regions. In particular, orbitofrontal and medial prefrontal cortices showed a nonlinear relationship with age in ASD, with an especially steep increase in sensory-evoked neural activity during the mid-to-late teen years. There was also an interaction between age and SOR severity in ASD youth such that these age-related trends were more apparent in youth with higher SOR.

Limitations: The cross-sectional design limits causal interpretations of the data. Future longitudinal studies will be instrumental in determining how prefrontal engagement and SOR co-develop across adolescence.

Conclusions: Our results suggest that enhanced recruitment of prefrontal regions may underlie age-related decreases in SOR for a subgroup of ASD youth.

背景:在自闭症谱系障碍(ASD)中,感觉过度反应(SOR)是一种削弱感觉处理的挑战,表现出异质性的发展轨迹,在一些但并非所有自闭症个体中,似乎在成年后有所改善。然而,这些轨迹中个体间差异的神经机制目前尚不清楚。方法:在这里,我们使用功能性磁共振成像(fMRI)来研究年龄与对轻度厌恶性感觉刺激反应的神经活动之间的线性和非线性关系,以及SOR严重程度如何调节这种关系。参与者包括52名ASD(14F)和41名(13F)典型发育(TD)青年,年龄为8.6-18.0岁。结果:我们发现,与TD儿童相比,在青少年前期,ASD儿童在感觉运动、额叶和小脑区域表现出广泛的激活差异,而ASD和TD青少年之间的差异较小。在TD青年中,年龄越大,前额叶皮层的激活越少。相反,在ASD青年中,年龄越大,感觉统合和情绪调节区域的参与程度越高。特别是,ASD患者的眶额皮质和内侧前额叶皮质与年龄呈非线性关系,在青少年中后期,感觉诱发神经活动急剧增加。ASD青年的年龄和SOR严重程度之间也存在相互作用,因此这些与年龄相关的趋势在SOR较高的青年中更为明显。局限性:横断面设计限制了对数据的因果解释。未来的纵向研究将有助于确定前额叶参与和SOR如何在整个青春期共同发展。结论:我们的研究结果表明,前额叶区域的募集增强可能是ASD青年亚组SOR与年龄相关降低的原因。
{"title":"Age-related changes in neural responses to sensory stimulation in autism: a cross-sectional study.","authors":"Melis E Cakar, Kaitlin K Cummings, Susan Y Bookheimer, Mirella Dapretto, Shulamite A Green","doi":"10.1186/s13229-023-00571-4","DOIUrl":"10.1186/s13229-023-00571-4","url":null,"abstract":"<p><strong>Background: </strong>Sensory over-responsivity (SOR) is an impairing sensory processing challenge in autism spectrum disorder (ASD) which shows heterogenous developmental trajectories and appears to improve into adulthood in some but not all autistic individuals. However, the neural mechanisms underlying interindividual differences in these trajectories are currently unknown.</p><p><strong>Methods: </strong>Here, we used functional magnetic resonance imaging (fMRI) to investigate the association between age and neural activity linearly and nonlinearly in response to mildly aversive sensory stimulation as well as how SOR severity moderates this association. Participants included 52 ASD (14F) and 41 (13F) typically developing (TD) youth, aged 8.6-18.0 years.</p><p><strong>Results: </strong>We found that in pre-teens, ASD children showed widespread activation differences in sensorimotor, frontal and cerebellar regions compared to TD children, while there were fewer differences between ASD and TD teens. In TD youth, older age was associated with less activation in the prefrontal cortex. In contrast, in ASD youth, older age was associated with more engagement of sensory integration and emotion regulation regions. In particular, orbitofrontal and medial prefrontal cortices showed a nonlinear relationship with age in ASD, with an especially steep increase in sensory-evoked neural activity during the mid-to-late teen years. There was also an interaction between age and SOR severity in ASD youth such that these age-related trends were more apparent in youth with higher SOR.</p><p><strong>Limitations: </strong>The cross-sectional design limits causal interpretations of the data. Future longitudinal studies will be instrumental in determining how prefrontal engagement and SOR co-develop across adolescence.</p><p><strong>Conclusions: </strong>Our results suggest that enhanced recruitment of prefrontal regions may underlie age-related decreases in SOR for a subgroup of ASD youth.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"38"},"PeriodicalIF":6.2,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10566124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41205296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
EEG functional connectivity in infants at elevated familial likelihood for autism spectrum disorder. 自闭症谱系障碍家族性可能性增高的婴儿脑电图功能连接。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-10-07 DOI: 10.1186/s13229-023-00570-5
Christian O'Reilly, Scott Huberty, Stefon van Noordt, James Desjardins, Nicky Wright, Julie Scorah, Sara Jane Webb, Mayada Elsabbagh

Background: Many studies have reported that autism spectrum disorder (ASD) is associated with atypical structural and functional connectivity. However, we know relatively little about the development of these differences in infancy.

Methods: We used a high-density electroencephalogram (EEG) dataset pooled from two independent infant sibling cohorts, to characterize such neurodevelopmental deviations during the first years of life. EEG was recorded at 6 and 12 months of age in infants at typical (N = 92) or elevated likelihood for ASD (N = 90), determined by the presence of an older sibling with ASD. We computed the functional connectivity between cortical sources of EEG during video watching using the corrected imaginary part of phase-locking values.

Results: Our main analysis found no significant association between functional connectivity and ASD, showing only significant effects for age, sex, age-sex interaction, and site. Given these null results, we performed an exploratory analysis and observed, at 12 months, a negative correlation between functional connectivity and ADOS calibrated severity scores for restrictive and repetitive behaviors (RRB).

Limitations: The small sample of ASD participants inherent to sibling studies limits diagnostic group comparisons. Also, results from our secondary exploratory analysis should be considered only as potential relationships to further explore, given their increased vulnerability to false positives.

Conclusions: These results are inconclusive concerning an association between EEG functional connectivity and ASD in infancy. Exploratory analyses provided preliminary support for a relationship between RRB and functional connectivity specifically, but these preliminary observations need corroboration on larger samples.

背景:许多研究报道,自闭症谱系障碍(ASD)与非典型的结构和功能连接有关。然而,我们对婴儿期这些差异的发展了解相对较少。方法:我们使用来自两个独立的婴儿兄弟姐妹队列的高密度脑电图(EEG)数据集来表征生命最初几年的神经发育偏差。在6个月和12个月大时,在典型(N = 92)或ASD可能性升高(N = 90),由患有ASD的年长兄弟姐妹的存在来确定。我们使用相位锁定值的校正虚部计算了视频观看过程中EEG皮层源之间的功能连接。结果:我们的主要分析发现,功能连接与ASD之间没有显著关联,仅对年龄、性别、年龄-性别互动和部位有显著影响。鉴于这些无效结果,我们进行了探索性分析,并在12个月时观察到,功能连接与ADOS校准的限制性和重复性行为严重程度评分(RRB)之间存在负相关。局限性:兄弟姐妹研究固有的ASD参与者的小样本限制了诊断组的比较。此外,鉴于二次探索性分析的结果更容易出现假阳性,因此只能将其视为需要进一步探索的潜在关系。结论:关于婴儿期脑电图功能连接与ASD之间的关系,这些结果是不确定的。探索性分析为RRB和功能连接之间的关系提供了初步支持,但这些初步观察结果需要在更大的样本上得到证实。
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引用次数: 0
The neuroanatomical substrates of autism and ADHD and their link to putative genomic underpinnings. 自闭症和多动症的神经解剖学基础及其与假定的基因组基础的联系。
IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-10-04 DOI: 10.1186/s13229-023-00568-z
Lisa M Berg, Caroline Gurr, Johanna Leyhausen, Hanna Seelemeyer, Anke Bletsch, Tim Schaefer, Charlotte M Pretzsch, Bethany Oakley, Eva Loth, Dorothea L Floris, Jan K Buitelaar, Christian F Beckmann, Tobias Banaschewski, Tony Charman, Emily J H Jones, Julian Tillmann, Chris H Chatham, Thomas Bourgeron, Declan G Murphy, Christine Ecker

Background: Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings.

Methods: We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings.

Results: In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes.

Limitations: Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting.

Conclusion: Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.

背景:自闭症谱系障碍(ASD)是伴随大脑发育差异的神经发育状况。自闭症的神经解剖学差异因个体而异,可能是不同临床表型的基础。为了分析异质性,有必要确定ASD的神经生物学是如何被与共同发生的条件相关的差异所调节的,例如注意力缺陷/多动障碍(ADHD)。本研究旨在(1)调查患有和不患有合并多动症的自闭症患者的组间差异,并(2)将这些差异与假定的基因组基础联系起来。方法:我们在来自欧洲自闭症纵向项目的533名个体样本中检测了皮层厚度(CT)和表面积(SA)的差异及其基因组关联。使用包括自闭症和多动症的主要影响以及由多动症相互作用引起的ASD的一般线性模型,我们研究了多动症在多大程度上调节自闭症相关的神经解剖学。此外,利用艾伦人脑图谱的空间基因表达数据,我们确定了空间表达模式与我们的神经影像学发现相似的基因。结果:除了对额颞区、边缘区和枕区的ASD和ADHD有显著的主要影响外,我们还分别在左中央前回和右额回观察到ASD与ADHD的显著相互作用。此外,ASD患者 + ADHD的CT表现与无CT者不同。ASD的主要作用和相互作用都很丰富,但ADHD相关基因却没有。局限性:尽管我们采用了多中心设计来克服单点招募的局限性,但我们的样本量N = 与其他亚组相比,仅患有多动症的组中的25人相对较小,这限制了结果的可推广性。此外,我们根据DSM-5评定量表将受试者分为多动症阳性组。虽然这足以获得多动症的研究诊断,但我们的方法没有考虑症状出现的时间,这通常是在临床环境中评估多动症时考虑的。结论:因此,我们的研究结果表明,自闭症谱系障碍的神经解剖学受到多动症的显著调节,同时患有多动症的自闭症患者可能具有特定的神经解剖学基础,可能由非典型基因表达介导。
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引用次数: 0
Increased rates of chronic physical health conditions across all organ systems in autistic adolescents and adults. 自闭症青少年和成年人所有器官系统的慢性身体健康状况发生率增加。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-09-20 DOI: 10.1186/s13229-023-00565-2
John H Ward, Elizabeth Weir, Carrie Allison, Simon Baron-Cohen
<p><strong>Background: </strong>The poorer physical health of autistic adults compared to non-autistic adults has been highlighted by several epidemiological studies. However, research has so far been limited to specific geographical areas and has primarily focused on young autistic individuals (aged 35 years and younger). Recent studies indicate a higher rate of mortality in autistic people, as well as poorer quality of self-reported healthcare interactions. This study aims to determine, first, whether autistic people experience greater levels of non-communicable health conditions and second, whether these are explained by differences in demographics (i.e. sex, country of residence, ethnicity, education level), alcohol use, smoking, body mass index (BMI), or family history of medical conditions.</p><p><strong>Method: </strong>We employed a cross-sectional, convenience-sampling study via an anonymous, online survey of autistic and non-autistic adults (n = 2305, mean age = 41.6, 65.9% female, 49% autistic). The survey asked participants to self-report information about their demographics, autism diagnosis, diet, exercise, sleep, sexual health, substance use, personal medical history, and family medical history (for all first-degree, biological relatives). Binomial logistic regression across four iterative models of increasing complexity was applied to assess rates of physical health conditions. The Benjamini-Hochberg correction was used to account for multiple testing, and only physical health conditions that achieved at least 1% endorsement within the overall sample (n > 22) were included in the analysis to reduce risk of Type I errors. We also used novel network analysis methods to test whether there are increased levels of multimorbidity between autistic and non-autistic people.</p><p><strong>Results: </strong>There were significantly elevated rates of non-communicable conditions across all organ systems in autistic people, including gastrointestinal, neurological, endocrine, visual, ear/nose/throat, skin, liver and kidney, and haematological conditions. We confirmed previous findings by showing highly significant differences in rates of neurological and gastrointestinal symptoms (p < 0.0001). In addition, we established in the largest sample to date that Ehler-Danlos Syndrome (EDS) was more likely to occur among autistic females compared to non-autistic females. Finally, we found a higher prevalence of Coeliac's disease among autistic individuals compared to non-autistic individuals after controlling for sex, ethnicity, country of residence, alcohol use, smoking, and BMI, but these results became non-significant after accounting for family history.</p><p><strong>Limitations: </strong>Our study is biased towards females, white individuals, highly educated people, and UK residents, likely due to sampling biases. Our self-report study design may also exclude those who lack access to computers, or those with intellectual disability. Our network an
背景:几项流行病学研究强调,与非自闭症成年人相比,自闭症成年人的身体健康状况较差。然而,到目前为止,研究仅限于特定的地理区域,主要集中在年轻的自闭症患者(35岁及以下)身上。最近的研究表明,自闭症患者的死亡率较高,自我报告的医疗保健互动质量较差。这项研究旨在确定,首先,自闭症患者是否经历了更严重的非传染性健康状况,其次,这些状况是否可以通过人口统计学(即性别、居住国、种族、教育水平)、饮酒、吸烟、体重指数(BMI)或家族病史的差异来解释。方法:我们通过对自闭症和非自闭症成年人(n = 2305,平均年龄 = 41.6,65.9%为女性,49%为自闭症患者)。该调查要求参与者自我报告他们的人口统计信息、自闭症诊断、饮食、锻炼、睡眠、性健康、药物使用、个人病史和家族病史(针对所有一级生物学亲属)。应用四个复杂度不断增加的迭代模型的二项式逻辑回归来评估身体健康状况的发生率。Benjamini Hochberg校正用于解释多次测试,并且只有在总体样本中达到至少1%认可的身体健康状况(n > 22),以降低I型错误的风险。我们还使用了新的网络分析方法来测试自闭症患者和非自闭症患者之间的多发病率是否增加。结果:自闭症患者所有器官系统的非传染性疾病发生率显著升高,包括胃肠道、神经系统、内分泌、视觉、耳鼻喉、皮肤、肝脏和肾脏以及血液系统疾病。我们通过显示神经和胃肠道症状发生率的高度显著差异(p 局限性:我们的研究偏向于女性、白人、受过高等教育的人和英国居民,这可能是由于抽样偏见。我们的自我报告研究设计也可能将那些无法使用电脑的人或智力残疾的人排除在外。我们的网络分析在规模上也是有限的。结论:本研究使用二元逻辑回归和网络模型,为自闭症成年人与非自闭症成年人相比,几乎所有主要器官系统都存在广泛的身体健康共病提供了证据。医疗保健专业人员必须意识到在自闭症患者中可能更常见的一系列共同发生的身体健康状况。然而,我们的发现也指出了需要进一步探索的潜在途径,例如自闭症与乳糜泻和EDS的关系。
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引用次数: 1
Cortex-restricted deletion of Foxp1 impairs barrel formation and induces aberrant tactile responses in a mouse model of autism. 在自闭症小鼠模型中,Foxp1的皮质限制性缺失损害了桶的形成并诱导异常的触觉反应。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-09-11 DOI: 10.1186/s13229-023-00567-0
Xue Li, Shishuai Hao, Shimin Zou, Xiaomeng Tu, Weixi Kong, Tian Jiang, Jie-Guang Chen

Background: Many children and young people with autism spectrum disorder (ASD) display touch defensiveness or avoidance (hypersensitivity), or engage in sensory seeking by touching people or objects (hyposensitivity). Abnormal sensory responses have also been noticed in mice lacking ASD-associated genes. Tactile sensory information is normally processed by the somatosensory system that travels along the thalamus to the primary somatosensory cortex. The neurobiology behind tactile sensory abnormalities, however, is not fully understood.

Methods: We employed cortex-specific Foxp1 knockout (Foxp1-cKO) mice as a model of autism in this study. Tactile sensory deficits were measured by the adhesive removal test. The mice's behavior and neural activity were further evaluated by the whisker nuisance test and c-Fos immunofluorescence, respectively. We also studied the dendritic spines and barrel formation in the primary somatosensory cortex by Golgi staining and immunofluorescence.

Results: Foxp1-cKO mice had a deferred response to the tactile environment. However, the mice exhibited avoidance behavior and hyper-reaction following repeated whisker stimulation, similar to a fight-or-flight response. In contrast to the wild-type, c-Fos was activated in the basolateral amygdala but not in layer IV of the primary somatosensory cortex of the cKO mice. Moreover, Foxp1 deficiency in cortical neurons altered the dendrite development, reduced the number of dendritic spines, and disrupted barrel formation in the somatosensory cortex, suggesting impaired somatosensory processing may underlie the aberrant tactile responses.

Limitations: It is still unclear how the defective thalamocortical connection gives rise to the hyper-reactive response. Future experiments with electrophysiological recording are needed to analyze the role of thalamo-cortical-amygdala circuits in the disinhibiting amygdala and enhanced fearful responses in the mouse model of autism.

Conclusions: Foxp1-cKO mice have tactile sensory deficits while exhibit hyper-reactivity, which may represent fearful and emotional responses controlled by the amygdala. This study presents anatomical evidence for reduced thalamocortical connectivity in a genetic mouse model of ASD and demonstrates that the cerebral cortex can be the origin of atypical sensory behaviors.

背景:许多患有自闭症谱系障碍(ASD)的儿童和年轻人表现出触摸防御或回避(超敏反应),或通过触摸人或物体进行感官寻求(低敏反应)。在缺乏ASD相关基因的小鼠中也发现了异常的感觉反应。触觉信息通常由体感系统处理,体感系统沿着丘脑到达初级体感皮层。然而,触觉感觉异常背后的神经生物学尚不完全清楚。方法:本研究采用皮质特异性Foxp1基因敲除(Foxp1-cKO)小鼠作为自闭症模型。触觉感觉缺陷通过粘合剂去除测试来测量。分别通过胡须滋扰试验和c-Fos免疫荧光法进一步评估小鼠的行为和神经活动。我们还通过高尔基染色和免疫荧光研究了初级体感皮层的树突棘和桶状物的形成。结果:Foxp1 cKO小鼠对触觉环境有延迟反应。然而,小鼠在反复刺激胡须后表现出回避行为和过度反应,类似于“要么战斗,要么逃跑”的反应。与野生型相比,c-Fos在cKO小鼠的基底外侧杏仁核中被激活,但在初级体感皮层的IV层中没有被激活。此外,皮层神经元中Foxp1的缺乏改变了树突的发育,减少了树突棘的数量,并破坏了体感皮层中桶的形成,这表明体感处理受损可能是异常触觉反应的基础。局限性:目前尚不清楚丘脑-皮质连接缺陷是如何引起高反应的。未来需要进行电生理记录实验,以分析丘脑皮层杏仁核回路在自闭症小鼠模型中抑制杏仁核和增强恐惧反应中的作用。结论:Foxp1 cKO小鼠具有触觉感觉缺陷,同时表现出高反应性,这可能代表由杏仁核控制的恐惧和情绪反应。这项研究提供了ASD遗传小鼠模型中丘脑-皮质连接减少的解剖学证据,并证明大脑皮层可能是非典型感觉行为的起源。
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引用次数: 1
Autistic adults benefit from and enjoy learning via social interaction as much as neurotypical adults do. 自闭症成年人和神经正常的成年人一样,从社交互动中受益并享受学习。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-09-06 DOI: 10.1186/s13229-023-00561-6
S De Felice, A Hatilova, F Trojan, I Tsui, Antonia F de C Hamilton

Background: Autistic people show poor processing of social signals (i.e. about the social world). But how do they learn via social interaction?

Methods: 68 neurotypical adults and 60 autistic adults learned about obscure items (e.g. exotic animals) over Zoom (i) in a live video-call with the teacher, (ii) from a recorded learner-teacher interaction video and (iii) from a recorded teacher-alone video. Data were analysed via analysis of variance and multi-level regression models.

Results: Live teaching provided the most optimal learning condition, with no difference between groups. Enjoyment was the strongest predictor of learning: both groups enjoyed the live interaction significantly more than other condition and reported similar anxiety levels across conditions.

Limitations: Some of the autistic participants were self-diagnosed-however, further analysis where these participants were excluded showed the same results. Recruiting participants over online platforms may have introduced bias in our sample. Future work should investigate learning in social contexts via diverse sources (e.g. schools).

Conclusions: These findings advocate for a distinction between learning about the social versus learning via the social: cognitive models of autism should be revisited to consider social interaction not just as a puzzle to decode but rather a medium through which people, including neuro-diverse groups, learn about the world around them. Trial registration Part of this work has been pre-registered before data collection https://doi.org/10.17605/OSF.IO/5PGA3.

背景:自闭症患者对社会信号(即关于社会世界)的处理能力较差。但是他们是如何通过社交来学习的呢?方法:68名神经正常成年人和60名自闭症成年人通过Zoom(i)在与老师的实时视频通话中,(ii)从录制的学习者-教师互动视频中,以及(iii)从单独录制的教师视频中学习模糊项目(如外来动物)。通过方差分析和多层次回归模型对数据进行分析。结果:现场教学提供了最佳的学习条件,各组之间没有差异。快乐是学习的最强预测因素:两组人都比其他条件下更喜欢现场互动,并且在不同条件下的焦虑水平相似。局限性:一些自闭症参与者是自我诊断的,然而,将这些参与者排除在外的进一步分析显示了相同的结果。通过在线平台招募参与者可能在我们的样本中引入了偏见。未来的工作应通过各种来源(如学校)调查社会背景下的学习情况。结论:这些发现主张区分社交学习和通过社交学习:自闭症的认知模型应该重新审视,将社交互动不仅视为一个需要解码的谜题,而且是人们(包括神经多样性群体)了解周围世界的媒介。试验注册本工作的一部分已在数据收集前预先注册https://doi.org/10.17605/OSF.IO/5PGA3.
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引用次数: 0
Linking functional and structural brain organisation with behaviour in autism: a multimodal EU-AIMS Longitudinal European Autism Project (LEAP) study. 将自闭症患者的功能和结构大脑组织与行为联系起来:一项多模式EU-AIMS欧洲自闭症纵向项目(LEAP)研究。
IF 6.2 1区 医学 Q1 GENETICS & HEREDITY Pub Date : 2023-08-31 DOI: 10.1186/s13229-023-00564-3
Lennart M Oblong, Alberto Llera, Ting Mei, Koen Haak, Christina Isakoglou, Dorothea L Floris, Sarah Durston, Carolin Moessnang, Tobias Banaschewski, Simon Baron-Cohen, Eva Loth, Flavio Dell'Acqua, Tony Charman, Declan G M Murphy, Christine Ecker, Jan K Buitelaar, Christian F Beckmann, Natalie J Forde

Neuroimaging analyses of brain structure and function in autism have typically been conducted in isolation, missing the sensitivity gains of linking data across modalities. Here we focus on the integration of structural and functional organisational properties of brain regions. We aim to identify novel brain-organisation phenotypes of autism. We utilised multimodal MRI (T1-, diffusion-weighted and resting state functional), behavioural and clinical data from the EU AIMS Longitudinal European Autism Project (LEAP) from autistic (n = 206) and non-autistic (n = 196) participants. Of these, 97 had data from 2 timepoints resulting in a total scan number of 466. Grey matter density maps, probabilistic tractography connectivity matrices and connectopic maps were extracted from respective MRI modalities and were then integrated with Linked Independent Component Analysis. Linear mixed-effects models were used to evaluate the relationship between components and group while accounting for covariates and non-independence of participants with longitudinal data. Additional models were run to investigate associations with dimensional measures of behaviour. We identified one component that differed significantly between groups (coefficient = 0.33, padj = 0.02). This was driven (99%) by variance of the right fusiform gyrus connectopic map 2. While there were multiple nominal (uncorrected p < 0.05) associations with behavioural measures, none were significant following multiple comparison correction. Our analysis considered the relative contributions of both structural and functional brain phenotypes simultaneously, finding that functional phenotypes drive associations with autism. These findings expanded on previous unimodal studies by revealing the topographic organisation of functional connectivity patterns specific to autism and warrant further investigation.

自闭症患者大脑结构和功能的神经影像学分析通常是孤立进行的,缺少跨模式连接数据的敏感性。在这里,我们关注大脑区域的结构和功能组织特性的整合。我们的目的是鉴定自闭症的新型大脑组织表型。我们使用了来自欧盟AIMS欧洲自闭症纵向项目(LEAP)的多模式MRI(T1-,扩散加权和静息状态功能)、行为和临床数据 = 206)和非自闭症(n = 196)参与者。其中,97个具有来自2个时间点的数据,导致总扫描次数为466。从各自的MRI模态中提取灰质密度图、概率束描记连接矩阵和连接图,然后与关联独立分量分析相结合。线性混合效应模型用于评估成分和组之间的关系,同时用纵向数据说明参与者的协变量和非独立性。运行了额外的模型来调查与行为维度测量的关联。我们确定了一个组间差异显著的成分(系数 = 0.33,padj = 0.02)。这是由右侧梭状回连接图2的方差驱动的(99%)。而存在多个标称(未校正的p
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Molecular Autism
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