Processing speed as a marker to stimulant effect in clinical sample of children with high functioning autism spectrum disorder.
- 作者列表："Peled J","Cassuto H","Berger I
:Background: Patients with co-occurring Attention-Deficit/Hyperactivity Disorder (ADHD) and ASD might benefit from stimulants. There is a progressive increase in prescribing ADHD aimed medications for children diagnosed with Autism Spectrum Disorder (ASD), despite scarce knowledge and no distinct clinical guidelines for that matter.Aim: This study aims to analyze the effect of stimulant on processing speed performance and attention indices in children with ASD and ADHD.Methods: Forty children aged 6-18 years diagnosed with ASD who also met the criteria for ADHD were recruited. All children performed a computerized performance test for the assessment of cognitive attention performance three times: twice while they are drug naïve and once an hour after taking a single dose of 10 mg. methylphenidate (MPH). This performance was compared to a group of children diagnosed with 'ADHD only' without ASD.Results: A significant difference (p < 0.001) was found only in the parameter of measuring cognitive processing speed. This effect is significantly different from the response of the 'ADHD only' group.Conclusions: The reaction to MPH among ASD children is different than among ADHD children. In ASD, MPH significantly improved cognitive processing speed without changing other measured attention parameters. Improving processing speed, might improve every day functioning in children with ASD who also met the criteria for ADHD, in other means than expected. This unique response suggests new research targets for treatment with stimulants in ASD and ADHD children and its influence on cognitive parameters.
背景: 同时发生注意缺陷/多动障碍 (ADHD) 和 ASD 的患者可能从兴奋剂中获益。尽管知识匮乏，没有针对该问题的独特临床指南，但为诊断为自闭症谱系障碍 (ASD) 的儿童开具针对 ADHD 的药物的处方逐渐增加。目的: 本研究旨在分析兴奋剂对 ASD 和 ADHD 儿童加工速度、表现和注意指数的影响。方法:招募 40 名 6-18 岁诊断为 ASD 且符合 ADHD 标准的儿童。所有儿童进行了三次计算机性能测试以评估认知注意性能: 两次，当他们是药物初治时，一次，服用单次剂量 10 mg 后一小时。哌醋甲酯 (MPH)。将该表现与一组诊断为 “仅 adhd” 而无 ASD 的儿童进行比较。结果: 仅在测量认知加工速度的参数中发现显著差异 (p <0.001)。这种效应与 “仅 ADHD” 组的反应显著不同。结论: ASD 儿童对 MPH 的反应不同于 ADHD 儿童。在 ASD 中，MPH 显著提高了认知处理速度，而不改变其他测量的注意参数。提高处理速度，可能会以其他方式改善符合 ADHD 标准的 ASD 儿童的日常功能。这种独特的反应提出了 ASD 和 ADHD 儿童兴奋剂治疗的新研究靶点及其对认知参数的影响。
METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.