Inflexible neurobiological signatures precede atypical development in infants at high risk for autism
Contributors: Denisova, , Kristina, Zhao, , Guihu,
... Abstract Variability in neurobiological signatures is ubiquitous in early life but the link to adverse developmental milestones in humans is unknown. We examined how levels of signal and noise in movement signatures during the 1st year of life constrain early development in 71 healthy typically developing infants, either at High or Low familial Risk (HR or LR, respectively) for developing Autism Spectrum Disorders (ASD). Delays in early learning developmental trajectories in HR infants (validated in an analysis of 1,445 infants from representative infant-sibling studies) were predicted by worse stochastic patterns in their spontaneous head movements as early as 1–2 months after birth, relative to HR infants who showed more rapid developmental progress, as well as relative to all LR infants. While LR 1–2 mo-old infants’ movements were significantly different during a language listening task compared to during sleep, HR infants’ movements were more similar during both conditions, a striking lack of diversity that reveals context-inflexible experience of ambient information. Contrary to expectation, it is not the level of variability per se that is particularly detrimental in early life. Rather, inflexible sensorimotor systems and/or atypical transition between behavioral states may interfere with the establishment of capacity to extract structure and important cues from sensory input at birth, preceding and contributing to an atypical brain developmental trajectory in toddlerhood.
Contributors: Jernigan, , Terry, Dale, Anders, Jernigan, , Terry, , , Dale, Anders,
... Abstract The PING Data Resource is the product of a multi-site project involving developmental researchers across the United States including UC San Diego the University of Hawaii UC Los Angeles Childrens Hospital of Los Angeles of the University of Southern California UC Davis Kennedy Krieger Institute of Johns Hopkins University Sackler Institute of Cornell University University of Massachusetts Massachusetts General Hospital at Harvard University and Yale University. The Data Resource includes neurodevelopmental histories, information about developing mental and emotional functions, multimodal brain imaging data, and genotypes for well over 1000 children and adolescents between the ages of 3 and 20.
Contributors: Flora, Vaccarino, Abyzov, Alexej, Urban Alexander, , Sestan, Nenad
... Abstract Somatic mosaicism in the human brain may alter function of individual neurons. We analyzed genomes of single cells from the forebrains of three human fetuses (15 to 21 weeks post-conception) using clonal cell populations. We detected 200-400 single nucleotide variations (SNVs) per cell. SNV patterns resembled those found in cancer cell genomes, indicating a role of background mutagenesis in cancer. SNVs with a frequency of >2% in brain were shared with the spleen, revealing a pre-gastrulation origin. We reconstructed cell lineages for the first five post-zygotic cleavages and calculated a mutation rate of ~1.3 per division per cell. Later in development, during neurogenesis, the mutation spectrum shifted towards oxidative damage and the mutation rate increased. Both neurogenesis and early embryogenesis exhibit drastically more mutagenesis than adulthood.
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Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.
Contributors: Cook, Edwin H., Chen, Rui, Davis, Lea, K., Guter, Stephen, , Wie, Qiang, Jacob, Suma, Potter, Melissa H., Cox, Nancy J., Sutcliffe, James S., Li, Bingshan
... Abstract Background: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers is an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. Methods: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parents-proband trios with most (107) probands having 5-HT measurements. Results: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo gene with loss of function mutations, and provided evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We dichotomized the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels and identified novel genes related to the TGF- pathway in the High-5HT group using Network-based Gene Enrichment Analysis (NGSEA). Through analysis of rare recessively acting variants (RAVs), we found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests and observed significant association of rare variants in genes encoding the serotonin pathway with ASD. Conclusions: Our study identified novel genes harboring DNVs implicated in ASD. Leveraging 5-HT as an endophenotype, we identified genes pointing to the TGF- pathway as potentially contributing to hyperserotonemia in ASD. Our study demonstrates the value of 5-HT as an effective endophenotype for gene discovery in ASD, evincing the need for greater collection of proband 5-HT data for future ASD genetics studies.
Contributors: Fiszdon, Joanna, Choi, Kee-Hong, Bell, Morris, Choi, Jimmy, Silverstein, Steven
... Abstract The popularity of cognitive remediation (CR) interventions for individuals with psychosis is in part based on the well-established link between cognition and functioning and the assumption that by targeting cognition, function can improve. While numerous trials have reported CR's efficacy, it is still not considered an evidencebased treatment. Importantly, little is known about the mechanisms through which it may affect functioning. Method: In this study, we evaluated CR's proximal and distal effects, and examined potential mechanisms. Seventy-five individuals with psychotic disorders were randomized to a combination of strategy-based and drill and practice cognitive remediation (CR) or Wait-List Control (WLC), with assessments of training task performance, neurocognition, functional capacity, symptoms and functioning conducted at baseline, end of the 2-month intervention, and 2-month follow-up (FU). Results: Compared to TAU, CR was associated with large post-training improvements on training tasks targeting attention, visuospatial memory, and verbal learning and memory, with persisting group differences at 2-month follow-up. These generalized to mostly large improvements on neuropsychological measures targeting visuospatial memory, verbal learning and memory, delayed verbal memory, and verbal working memory. While there were no CR-associated improvements on measures of functional capacity, symptoms, or a self-report measure of independent living skills, there was an effect on an interviewer-rated measure of functioning (QLS), which appeared primarily driven by the Intrapsychic Foundations subscale. Finally, for those randomized to CR, there were significant, medium-sized correlations between training task improvement, neuropsychological improvement and functioning measures. Conclusions: this suggests a complex, multifactorial relationship between CR, cognitive and functional change.
Lack of early improvement with antipsychotics is a marker for subsequent non-response in behavioral and psychological symptoms of dementia: Analysis of CATIE-AD data
Contributors: Uchida, Hiroyuki, Yoshida, K, Roberts, R, Suzuki, T, Lebowitz, B, Reeves, S, Howard, R, Abe, T, Mimura, M
... Abstract Objective: Prediction of response/non-response to antipsychotics is especially important in patients with behavioral and psychological symptoms of dementia (BPSD) in whom antipsychotic exposure increases risks of death. We aimed to examine whether presence/absence of early improvement of BPSD with antipsychotics is associated with subsequent response/non-response. Design: Post-hoc analysis of the Clinical Antipsychotic Trials in Intervention Effectiveness with Alzheimer’s Disease (CATIE-AD) study (2001-2004) (trial registration: NCT00015548). Setting: 45 sites in the United States. Participants: 245 subjects (olanzapine, n=90; quetiapine, n=81; risperidone, n=74) with a DSM-IV diagnosis of dementia of the Alzheimer’s type who presented with a score of 1 or more in the Brief Psychiatric Rating Scale (BPRS) at baseline (Phase 1 of CATIE-AD). Intervention: Subjects were randomly assigned to treatment with olanzapine, quetiapine, risperidone, or placebo in a double-blind manner. Measurements: We examined associations between response at week 8, and demographic and clinical characteristics, including BPRS total score reduction at week 2, using logistic regression analyses. Prediction performance of binary classification (presence/absence) of improvement/no improvement at week 2 for response at week 8 was examined. Results: BPRS total score reduction at week 2 (mean percentage score reduction, 12.6%) was significantly associated with response at week 8 (odds ratio, 1.18; 95% CI, 1.11-1.26). The 5% score reduction cut-off at week 2 showed the highest accuracy (0.71) with sensitivity, specificity, PPV, and NPV of 0.76, 0.65, 0.69, and 0.72, respectively. Conclusion: Lack of even a very small early improvement with antipsychotic treatment may be a marker of subsequent non-response in BPSD.
Contributors: Yeshurun, Y, Nguyen, M, Hasson, U
... Abstract Small changes in word choice can lead to dramatically different interpretations of narratives. How does the brain accumulate and integrate such local changes to construct unique neural representations for different stories? In this study, we created two distinct narratives by changing only a few words in each sentence (e.g., "he" to "she" or "sobbing" to "laughing") while preserving the grammatical structure across stories. We then measured changes in neural responses between the two stories. We found that differences in neural responses between the two stories gradually increased along the hierarchy of processing timescales. For areas with short integration windows, such as early auditory cortex, the differences in neural responses between the two stories were relatively small. In contrast, in areas with the longest integration windows at the top of the hierarchy, such as the precuneus, temporal parietal junction, and medial frontal cortices, there were large differences in neural responses between stories. Furthermore, this gradual increase in neural differences between the stories was highly correlated with an area's ability to integrate information over time. Amplification of neural differences did not occur when changes in words did not alter the interpretation of the story (e.g., sobbing to "crying"). Our results demonstrate how subtle differences in words are gradually accumulated and amplified along the cortical hierarchy as the brain constructs a narrative over time.
Contributors: Barch, Deanna, Jirsaraiea, Robert J., Sheffield, Julia M.
... Abstract Cognitive deficits are a core feature of schizophrenia, but the neural mechanisms that contribute to these characteristics are not fully understood. This study investigated whether volume of the dorsal lateral prefrontal cortex (DLPFC), hippocampus, and white matter were associated with impairment in specific cognitive domains, including executive functioning, working memory, verbal memory, verbal fluency, processing speed, versus global functioning. The multi-site data used in this study was collected from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP), and consisted of 206 healthy controls and 247 individuals with either schizophrenia or schizoaffective disorder. The neuroimaging data was segmented based on the Destrieux atlas in FreeSurfer. Linear regression analyses revealed that DLPFC volume was positively associated with executive functioning and processing speed, but not with working memory or verbal memory. Hippocampal volume was positively associated with executive functioning, working memory, and verbal memory, but not with verbal fluency. White matter volume was positively associated with processing speed, but not verbal fluency. Volume of all three brain structures were also associated with global cognitive functioning. However, DLPFC, hippocampal, and white matter volume were significantly associated with executive functioning even when controlling for global cognition, identifying a specific relationship. These findings suggest that volume of the DLPFC, hippocampus, and white matter are associated with both the global cognitive deficit in schizophrenia and with executive functioning, but may not have specific relationships to other cognitive domains over and above the global deficit.
One thousand somatic SNVs per skin fibroblast cell set baseline of mosaic mutational load with patterns that suggest proliferative origin
Contributors: Vaccarino, Flora, Abyzov, Alexej, Tomasini, Livia, Zhou, Bo, Vasmatzis, Nikolaos, Coppola, Gianfilippo, Amenduni, Mariangela, Pattni, Reenal, Wilson, Michael, Gerstein, Mark
... Abstract Few studies have been conducted to understand post-zygotic accumulation of mutations in cells of the healthy human body. We reprogrammed 32 skin fibroblast cells from families of donors into human induced pluripotent stem cell (hiPSC) lines. The clonal nature of hiPSC lines allows a high-resolution analysis of the genomes of the founder fibroblast cells without being confounded by the artifacts of single cell whole genome amplification. We estimate that on average a fibroblast cell in children has 1,035 mostly benign mosaic SNVs. On average, 235 SNVs could be directly confirmed in the original fibroblast population by ultra-deep sequencing, down to an allele frequency (AF) of 0.1%. More sensitive droplet digital PCR experiments confirmed more SNVs as mosaic with AF as low as 0.01%, suggesting that 1,035 mosaic SNVs per fibroblast cell is the true average. Similar analyses in adults revealed no significant increase in the number of SNVs per cell, suggesting that a major fraction of mosaic SNVs in fibroblasts arises during development. Mosaic SNVs were distributed uniformly across the genome and were enriched in a mutational signature previously observed in cancers and in de novo variants and which, we hypothesize, is a hallmark of normal cell proliferation. Finally, AF distribution of mosaic SNVs had distinct narrow peaks, which could be a characteristic of clonal cell selection, clonal expansion, or both. These findings reveal a large degree of somatic mosaicism in healthy human tissues, link de novo and cancer mutations to somatic mosaicism and couple somatic mosaicism with cell proliferation.
Contributors: Eichler, EE, Dennis, MY, Dougherty, ML, Harshman, L, Nelson, BJ, Penn, O, Cantsilieris, S, Huddleston, J, Antonacci, F, Penewit, F
... Abstract Subject level data for associated publication