The title gets you, right? Well, on this week’s podcast we report on a new study that examines epigenetic profiles of sperm and how they related to child outcomes. Do some of the marks on bio-dad’s sperm match to those found in kids with ASD? what about genes related to autism? Also, can parents be good proxies of their child’s intellectual ability? For the most part yes, but sometimes they tend to overestimate this ability. This means they are good, but not perfect reporters. How could they be if the child has a severe intellectual disability?
Podcast: Sperm
Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Cav1.2. Here, we find that acute pharmacological modulation of Cav1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced γ-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by interneuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.
Keywords: GABA; Timothy syndrome; assembloids; calcium; interneurons; organoids.
Background: Fragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and is commonly associated with autism. Previous studies have linked the structural and functional alterations in FXS with impaired sensory processing and sensory hypersensitivity, which may hinder the early development of cognitive functions such as language comprehension. In this study, we compared the P1 response of the auditory evoked potential and its habituation to repeated auditory stimuli in male children (2-7 years old) with and without FXS, and examined their association with clinical measures in these two groups.
Methods: We collected high-density electroencephalography (EEG) data in an auditory oddball paradigm from 12 male children with FXS and 11 age- and sex-matched typically developing (TD) children. After standardized EEG pre-processing, we conducted a spatial principal component (PC) analysis and identified two major PCs-a frontal PC and a temporal PC. Within each PC, we compared the P1 amplitude and inter-trial phase coherence (ITPC) between the two groups, and performed a series of linear regression analysis to study the association between these EEG measures and several clinical measures, including assessment scores for language abilities, non-verbal skills, and sensory hypersensitivity.
Results: At the temporal PC, both early and late standard stimuli evoked a larger P1 response in FXS compared to TD participants. For temporal ITPC, the TD group showed greater habituation than the FXS group. However, neither group showed significant habituation of the frontal or temporal P1 response. Despite lack of habituation, exploratory analysis of brain-behavior associations observed that within the FXS group, reduced frontal P1 response to late standard stimuli, and increased frontal P1 habituation were both associated with better language scores.
Conclusion: We identified P1 amplitude and ITPC in the temporal region as a contrasting EEG phenotype between the FXS and the TD groups. However, only frontal P1 response and habituation were associated with language measures. Larger longitudinal studies are required to determine whether these EEG measures could be used as biomarkers for language development in patients with FXS.
Keywords: EEG; ERP; Fragile X syndrome; autism; language; neural habituation; phase coherence.
What do anxiety, prevalence, ketamine, other neurodevelopmental disorders, siblings, genetics, brain imaging and the autistic researcher committee at INSAR all have in common? They were all topics at the last Day of Learning. You can hear a 20 minute summary of the talks on this week’s ASFpodcast.
Just like no two people are the same, no two strains of mice are the same. Using dozens of different strains of mice with and without a genetic mutation associated with autism called CHD8, researchers at University of Southern California showed great variability in the effect of this mutation on behaviors associated with neurodevelopmental disorders. This can reflect the great differences across people with autism and even people with a rare genetic syndrome associated with autism. It isn’t just one gene, it’s the other hundreds of genes that can contribute to susceptibility or resilience to different features of NDDs. One thing this study did not do was overlay environmental factors, which will also significantly influence the variability seen across the different background genetics in these mice. Listen to the podcast here.
The media has just called another biological marker a “diagnostic test”, when in this case, it was always intended to be an aid, not a test itself. It involves using baby hair strands to look a variation in metabolism of certain chemical elements across time. Remarkably, it showed similar results in autistic children in Japan, the US and Sweden. It’s not ready to be used as a diagnostic test, so what is it supposed to do? Listen to an interview with the inventor and researcher, Dr. Manish Arora from The Icahn School of Medicine at Mt. Sinai School here.
The full article (open access) can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740182/
It’s that time! The ASF Year of End Science Wrap-up was published in December, so it’s time to share it on the podcast. We cover everything from parent mediated interventions to genetics and racial and ethnic disparities. You can listen here or read it on the ASF website here: https://autismsciencefoundation.org/autism-research-in-2022/
Is there a specific “signature’ that make the autism brain unique? Can there be a common set of findings that certain gene expression goes up and another go down and where? And is it linked to behavior? This week, Dr. Michael Gandal at University of Pennsylvania (formerly UCLA) explains his recent findings that looks at the largest number of brain tissue samples so far from multiple brain regions to show a common up regulation of immune genes in the brain and a common down regulation of genes which control synapse formation and neuronal communication. It is most pronounced in areas involved in sensory processing of the brain. You can listen to the podcast today and read the whole paper here:
Background: Canonical babbling-producing syllables with a mature consonant, full vowel, and smooth transition-is an important developmental milestone that typically occurs in the first year of life. Some studies indicate delayed or reduced canonical babbling in infants at high familial likelihood for autism spectrum disorder (ASD) or who later receive an ASD diagnosis, but evidence is mixed. More refined characterization of babbling in the first year of life in infants with high likelihood for ASD is needed.
Methods: Vocalizations produced at 6 and 12 months by infants (n = 267) taking part in a longitudinal study were coded for canonical and non-canonical syllables. Infants were categorized as low familial likelihood (LL), high familial likelihood diagnosed with ASD at 24 months (HL-ASD) or not diagnosed (HL-Neg). Language delay was assessed based on 24-month expressive and receptive language scores. Canonical babble ratio (CBR) was calculated by dividing the number of canonical syllables by the number of total syllables. Generalized linear (mixed) models were used to assess the relationship between group membership and CBR, controlling for site, sex, and maternal education. Logistic regression was used to assess whether canonical babbling ratios at 6 and 12 months predict 24-month diagnostic outcome.
Results: No diagnostic group differences in CBR were detected at 6 months, but HL-ASD infants produced significantly lower CBR than both the HL-Neg and LL groups at 12 months. HL-Neg infants with language delay also showed reduced CBR at 12 months. Neither 6- nor 12-month CBR was significant predictors of 24-month diagnostic outcome (ASD versus no ASD) in logistic regression.
Limitations: Small numbers of vocalizations produced by infants at 6 months may limit the reliability of CBR estimates. It is not known if results generalize to infants who are not at high familial likelihood, or infants from more diverse racial and socioeconomic backgrounds.
Conclusions: Lower canonical babbling ratios are apparent by the end of the first year of life in ASD regardless of later language delay, but are also observed for infants with later language delay without ASD. Canonical babbling may lack specificity as an early marker when used on its own.
Competitive interactions have a vital role in the ecology of most animal species1-3 and powerfully influence the behaviour of groups4,5. To succeed, individuals must exert effort based on not only the resources available but also the social rank and behaviour of other group members2,6,7. The single-cellular mechanisms that precisely drive competitive interactions or the behaviour of social groups, however, remain poorly understood. Here we developed a naturalistic group paradigm in which large cohorts of mice competitively foraged for food as we wirelessly tracked neuronal activities across thousands of unique interactions. By following the collective behaviour of the groups, we found neurons in the anterior cingulate that adaptively represented the social rank of the animals in relation to others. Although social rank was closely behaviourally linked to success, these cells disambiguated the relative rank of the mice from their competitive behaviour, and incorporated information about the resources available, the environment, and past success of the mice to influence their decisions. Using multiclass models, we show how these neurons tracked other individuals within the group and accurately predicted upcoming success. Using neuromodulation techniques, we also show how the neurons conditionally influenced competitive effort-increasing the effort of the animals only when they were more dominant to their groupmates and decreasing it when they were subordinate-effects that were not observed in other frontal lobe areas. Together, these findings reveal cingulate neurons that serve to adaptively drive competitive interactions and a putative process that could intermediate the social and economic behaviour of groups.
Abstract
Importance: Presence of developmental delays in autism is well established, yet few studies have characterized variability in developmental milestone attainment in this population.
Objective: To characterize variability in the age at which autistic individuals attain key developmental milestones based on co-occurring intellectual disability (ID), presence of a rare disruptive genetic variant associated with neurodevelopmental disorders (NDD), age at autism diagnosis, and research cohort membership.
Design: The study team harmonized data from 4 cross-sectional autism cohorts: the Autism Genetics Research Exchange (n = 3284; 1997-2015), The Autism Simplex Collection (n = 694; 2008-2011), the Simons Simplex Collection (n = 2753; 2008-2011), and the Simons Foundation Powering Autism Research for Knowledge (n = 10 367; 2016-present). The last sample further included 4145 siblings without an autism diagnosis or ID.
Participants: Convenience sample of 21 243 autistic individuals or their siblings without an autism diagnosis aged 4 to 17 years.
Main outcomes and measures: Parents reported ages at which participants attained key milestones including smiling, sitting upright, crawling, walking, spoon-feeding self, speaking words, speaking phrases, and acquiring bladder and bowel control. A total of 5295 autistic individuals, and their biological parents, were genetically characterized to identify de novo variants in NDD-associated genes. The study team conducted time-to-event analyses to estimate and compare percentiles in time with milestone attainment across autistic individuals, subgroups of autistic individuals, and the sibling sample.
Results: Seventeen thousand ninety-eight autistic individuals (mean age, 9.15 years; 80.8% male) compared with 4145 siblings without autism or ID (mean age, 10.2 years; 50.2% female) showed delays in milestone attainment, with median (IQR) delays ranging from 0.7 (0.3-1.6) to 19.7 (11.4-32.2) months. More severe and more variable delays in autism were associated with the presence of co-occurring ID, carrying an NDD-associated rare genetic variant, and being diagnosed with autism by age 5 years. More severe and more variable delays were also associated with membership in earlier study cohorts, consistent with autism’s diagnostic and ascertainment expansion over the last 30 years.
Conclusions and relevance: As the largest summary to date of developmental milestone attainment in autism, to our knowledge, this study demonstrates substantial developmental variability across different conditions and provides important context for understanding the phenotypic and etiological heterogeneity of autism.
Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection.
Methods
Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning–based predictive tests examined cerebellar–frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar–default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections.
Results
Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections.
Conclusions
We failed to identify cerebellar functional connectivity–based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.