Cortical and subcortical alterations associated with precision visuomotor behavior in individuals with autism spectrum disorder

In addition to core deficits in social-communication abilities and repetitive behaviors and interests, many 2 patients with autism spectrum disorder (ASD) experience developmental comorbidities, including 3 sensorimotor issues. Sensorimotor issues are common in ASD and associated with more severe clinical 4 symptoms. Importantly, sensorimotor behaviors are precisely quantifiable and highly translational, 5 offering promising targets for neurophysiological studies of ASD. We used functional MRI to identify 6 brain regions associated with sensorimotor behavior using a visually-guided precision gripping task in 7 individuals with ASD (N=20) and age-, IQ-, and handedness-matched controls (N=18). During 8 visuomotor behavior, individuals with ASD showed greater force variability than controls. BOLD signal 9 for multiple cortical and subcortical regions was associated with force variability, including motor and 10 premotor cortex, posterior parietal cortex, extrastriate cortex, putamen, and cerebellum. Activation in 11 right premotor cortex scaled with sensorimotor variability in controls, but not in ASD. Individuals with 12 ASD showed greater activation than controls in left putamen and left cerebellar lobule VIIb and activation 13 in these regions was associated with more severe clinically-rated symptoms of ASD. Together, these 14 results suggest that greater sensorimotor variability in ASD is associated with altered cortical-striatal 15 processes supporting action selection and cortical-cerebellar circuits involved in feedback-guided reactive 16 adjustments of motor output. Our findings also indicate that atypical organization of visuomotor cortical 17 circuits may result in heightened reliance on subcortical circuits typically dedicated to motor skill 18 acquisition. Overall, these results provide new evidence that sensorimotor alterations in ASD involve 19 aberrant cortical and subcortical organization that may contribute to key clinical issues in patients. 20 21 New and noteworthy: This is the first known study to examine functional brain activation during 22 precision visuomotor behavior in autism spectrum disorder (ASD). We replicate previous findings of 23 elevated force variability in ASD and find these deficits are associated with atypical function of ventral 24 premotor cortex, putamen, and posterolateral cerebellum, indicating cortical-striatal processes supporting 25 action selection and cortical-cerebellar circuits involved in feedback-guided reactive adjustments of motor 26 output may be key targets for understanding the neurobiology of ASD.NICHD 055751NIMH R01 12743-01NCATS TL1 TR002368,Kansas Center for Autism Research and Training (K-CART) Research Investment Council Strategic Initiative Gran

Pre-arrest and intra-arrest prognostic factors associated with survival after in-hospital cardiac arrest : systematic review and meta-analysis

Abstract: Objective: To determine associations between important pre-arrest and intra-arrest prognostic factors and survival after in-hospital cardiac arrest. Design: Systematic review and meta-analysis. Data sources: Medline, PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews from inception to 4 February 2019. Primary, unpublished data from the United Kingdom National Cardiac Arrest Audit database. Study selection criteria: English language studies that investigated pre-arrest and intra-arrest prognostic factors and survival after in-hospital cardiac arrest. Data extraction: PROGRESS (prognosis research strategy group) recommendations and the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist were followed. Risk of bias was assessed by using the QUIPS tool (quality in prognosis studies). The primary analysis pooled associations only if they were adjusted for relevant confounders. The GRADE approach (grading of recommendations assessment, development, and evaluation) was used to rate certainty in the evidence. Results: The primary analysis included 23 cohort studies. Of the pre-arrest factors, male sex (odds ratio 0.84, 95% confidence interval 0.73 to 0.95, moderate certainty), age 60 or older (0.50, 0.40 to 0.62, low certainty), active malignancy (0.57, 0.45 to 0.71, high certainty), and history of chronic kidney disease (0.56, 0.40 to 0.78, high certainty) were associated with reduced odds of survival after in-hospital cardiac arrest. Of the intra-arrest factors, witnessed arrest (2.71, 2.17 to 3.38, high certainty), monitored arrest (2.23, 1.41 to 3.52, high certainty), arrest during daytime hours (1.41, 1.20 to 1.66, high certainty), and initial shockable rhythm (5.28, 3.78 to 7.39, high certainty) were associated with increased odds of survival. Intubation during arrest (0.54, 0.42 to 0.70, moderate certainty) and duration of resuscitation of at least 15 minutes (0.12, 0.07 to 0.19, high certainty) were associated with reduced odds of survival. Conclusion: Moderate to high certainty evidence was found for associations of pre-arrest and intra-arrest prognostic factors with survival after in-hospital cardiac arrest. Systematic review registration: PROSPERO CRD4201810479

Pre-arrest and intra-arrest prognostic factors associated with survival after in-hospital cardiac arrest : systematic review and meta-analysis

Abstract: Objective: To determine associations between important pre-arrest and intra-arrest prognostic factors and survival after in-hospital cardiac arrest. Design: Systematic review and meta-analysis. Data sources: Medline, PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews from inception to 4 February 2019. Primary, unpublished data from the United Kingdom National Cardiac Arrest Audit database. Study selection criteria: English language studies that investigated pre-arrest and intra-arrest prognostic factors and survival after in-hospital cardiac arrest. Data extraction: PROGRESS (prognosis research strategy group) recommendations and the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist were followed. Risk of bias was assessed by using the QUIPS tool (quality in prognosis studies). The primary analysis pooled associations only if they were adjusted for relevant confounders. The GRADE approach (grading of recommendations assessment, development, and evaluation) was used to rate certainty in the evidence. Results: The primary analysis included 23 cohort studies. Of the pre-arrest factors, male sex (odds ratio 0.84, 95% confidence interval 0.73 to 0.95, moderate certainty), age 60 or older (0.50, 0.40 to 0.62, low certainty), active malignancy (0.57, 0.45 to 0.71, high certainty), and history of chronic kidney disease (0.56, 0.40 to 0.78, high certainty) were associated with reduced odds of survival after in-hospital cardiac arrest. Of the intra-arrest factors, witnessed arrest (2.71, 2.17 to 3.38, high certainty), monitored arrest (2.23, 1.41 to 3.52, high certainty), arrest during daytime hours (1.41, 1.20 to 1.66, high certainty), and initial shockable rhythm (5.28, 3.78 to 7.39, high certainty) were associated with increased odds of survival. Intubation during arrest (0.54, 0.42 to 0.70, moderate certainty) and duration of resuscitation of at least 15 minutes (0.12, 0.07 to 0.19, high certainty) were associated with reduced odds of survival. Conclusion: Moderate to high certainty evidence was found for associations of pre-arrest and intra-arrest prognostic factors with survival after in-hospital cardiac arrest. Systematic review registration: PROSPERO CRD4201810479

DNA Methylation Dynamics and Cocaine in the Brain: Progress and Prospects

Cytosine modifications, including DNA methylation, are stable epigenetic marks that may translate environmental change into transcriptional regulation. Research has begun to investigate DNA methylation dynamics in relation to cocaine use disorders. Specifically, DNA methylation machinery, including methyltransferases and binding proteins, are dysregulated in brain reward pathways after chronic cocaine exposure. In addition, numerous methylome-wide and candidate promoter studies have identified differential methylation, at the nucleotide level, in rodent models of cocaine abuse and drug seeking behavior. This review highlights the current progress in the field of cocaine-related methylation, and offers considerations for future research

DNA Methylation Dynamics and Cocaine in the Brain: Progress and Prospects

Cytosine modifications, including DNA methylation, are stable epigenetic marks that may translate environmental change into transcriptional regulation. Research has begun to investigate DNA methylation dynamics in relation to cocaine use disorders. Specifically, DNA methylation machinery, including methyltransferases and binding proteins, are dysregulated in brain reward pathways after chronic cocaine exposure. In addition, numerous methylome-wide and candidate promoter studies have identified differential methylation, at the nucleotide level, in rodent models of cocaine abuse and drug seeking behavior. This review highlights the current progress in the field of cocaine-related methylation, and offers considerations for future research

BisQC: an operational pipeline for multiplexed bisulfite sequencing

BACKGROUND: Bisulfite sequencing is the most efficient single nucleotide resolution method for analysis of methylation status at whole genome scale, but improved quality control metrics are needed to better standardize experiments. RESULTS: We describe BisQC, a step-by-step method for multiplexed bisulfite-converted DNA library construction, pooling, spike-in content, and bioinformatics. We demonstrate technical improvements for library preparation and bioinformatic analyses that can be done in standard laboratories. We find that decoupling amplification of bisulfite converted (bis) DNA from the indexing reaction is an advantage, specifically in reducing total PCR cycle number and pre-selecting high quality bis-libraries. We also introduce a progressive PCR method for optimal library amplification and size-selection. At the sequencing stage, we thoroughly test the benefits of pooling non-bis DNA library with bis-libraries and find that BisSeq libraries can be pooled with a high proportion of non-bis DNA libraries with minimal impact on BisSeq output. For informatics analysis, we propose a series of optimization steps including the utilization of the mitochondrial genome as a QC standard, and we assess the validity of using duplicate reads for coverage statistics. CONCLUSION: We demonstrate several quality control checkpoints at the library preparation, pre-sequencing, post-sequencing, and post-alignment stages, which should prove useful in determining sample and processing quality. We also determine that including a significant portion of non-bisulfite converted DNA with bisulfite converted DNA has a minimal impact on usable bisulfite read output

Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster

International audienc

Medium throughput bisulfite sequencing for accurate detection of 5-methylcytosine and 5-hydroxymethylcytosine

Abstract Background Epigenetic modifications of DNA, such as 5-methylcytosine and 5-hydroxymethycytosine, play important roles in development and disease. Here, we present a cost-effective and versatile methodology for the analysis of DNA methylation in targeted genomic regions, which comprises multiplexed, PCR-based preparation of bisulfite DNA libraries followed by customized MiSeq sequencing. Results Using bisulfite and oxidative bisulfite conversion of DNA, we have performed multiplexed targeted sequencing to analyse several kilobases of genomic DNA in up to 478 samples, and achieved high coverage data of 5-methylcytosine and 5-hydroxymethycytosine at single-base resolution. Our results demonstrate the ability of this methodology to detect all levels of cytosine modifications at greater than 100\ud7 coverage in large sample sets at low cost compared to other targeted methods. Conclusions This approach can be applied to multiple settings, from candidate gene to clinical studies, and is especially useful for validation of differentially methylated or hydroxymethylated regions following whole-genome analyses