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1. Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task

   https://doi.org/10.1002/aur.2154  

   Nygaard, Kayla R. ; Maloney, Susan E. ; Dougherty, Joseph D. ( June 2019 , Autism Research)

   The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon existing assays to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD‐relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within‐group comparisons only, and then interpret a difference insignificancelevels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs: Erroneous Within‐group Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach could produce misleading inferences. Our review of Social Approach studies of high‐confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often does not correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models.Autism Res2019, 12: 1171–1183. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.

   The Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret these data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies.

    

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2. Dysregulation of temporal dynamics of synchronous neural activity in adolescents on autism spectrum

   https://doi.org/10.1002/aur.2219  

   Malaia, Evie A. ; Ahn, Sungwoo ; Rubchinsky, Leonid L. ( November 2019 , Autism Research)

   Autism spectrum disorder is increasingly understood to be based on atypical signal transfer among multiple interconnected networks in the brain. Relative temporal patterns of neural activity have been shown to underlie both the altered neurophysiology and the altered behaviors in a variety of neurogenic disorders. We assessed brain network dynamics variability in autism spectrum disorders (ASD) using measures of synchronization (phase‐locking) strength, and timing of synchronization and desynchronization of neural activity (desynchronization ratio) across frequency bands of resting‐state electroencephalography (EEG). Our analysis indicated that frontoparietal synchronization is higher in ASD but with more short periods of desynchronization. It also indicates that the relationship between the properties of neural synchronization and behavior is different in ASD and typically developing populations. Recent theoretical studies suggest that neural networks with a high desynchronization ratio have increased sensitivity to inputs. Our results point to the potential significance of this phenomenon to the autistic brain. This sensitivity may disrupt the production of an appropriate neural and behavioral responses to external stimuli. Cognitive processes dependent on the integration of activity from multiple networks maybe, as a result, particularly vulnerable to disruption.Autism Res2020, 13: 24–31. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.

   Parts of the brain can work together by synchronizing the activity of the neurons. We recorded the electrical activity of the brain in adolescents with autism spectrum disorder and then compared the recording to that of their peers without the diagnosis. We found that in participants with autism, there were a lot of very short time periods of non‐synchronized activity between frontal and parietal parts of the brain. Mathematical models show that the brain system with this kind of activity is very sensitive to external events.

    

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3. Digital Behavioral Phenotyping Detects Atypical Pattern of Facial Expression in Toddlers with Autism

   https://doi.org/10.1002/aur.2391  

   Carpenter, Kimberly L. H. ; Hahemi, Jordan ; Campbell, Kathleen ; Lippmann, Steven J. ; Baker, Jeffrey P. ; Egger, Helen L. ; Espinosa, Steven ; Vermeer, Saritha ; Sapiro, Guillermo ; Dawson, Geraldine ( September 2020 , Autism Research)

   Commonly used screening tools for autism spectrum disorder (ASD) generally rely on subjective caregiver questionnaires. While behavioral observation is more objective, it is also expensive, time‐consuming, and requires significant expertise to perform. As such, there remains a critical need to develop feasible, scalable, and reliable tools that can characterize ASD risk behaviors. This study assessed the utility of a tablet‐based behavioral assessment for eliciting and detecting one type of risk behavior, namely, patterns of facial expression, in 104 toddlers (ASDN= 22) and evaluated whether such patterns differentiated toddlers with and without ASD. The assessment consisted of the child sitting on his/her caregiver's lap and watching brief movies shown on a smart tablet while the embedded camera recorded the child's facial expressions. Computer vision analysis (CVA) automatically detected and tracked facial landmarks, which were used to estimate head position and facial expressions (Positive, Neutral, All Other). Using CVA, specific points throughout the movies were identified that reliably differentiate between children with and without ASD based on their patterns of facial movement and expressions (area under the curves for individual movies ranging from 0.62 to 0.73). During these instances, children with ASD more frequently displayed Neutral expressions compared to children without ASD, who had more All Other expressions. The frequency of All Other expressions was driven by non‐ASD children more often displaying raised eyebrows and an open mouth, characteristic of engagement/interest. Preliminary results suggest computational coding of facial movements and expressions via a tablet‐based assessment can detect differences in affective expression, one of the early, core features of ASD.

   This study tested the use of a tablet in the behavioral assessment of young children with autism. Children watched a series of developmentally appropriate movies and their facial expressions were recorded using the camera embedded in the tablet. Results suggest that computational assessments of facial expressions may be useful in early detection of symptoms of autism.

    

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4. Differential effect of NMDA receptor GluN2C and GluN2D subunit ablation on behavior and channel blocker-induced schizophrenia phenotypes

   https://doi.org/10.1038/s41598-019-43957-2  

   Shelkar, Gajanan P. ; Pavuluri, Ratnamala ; Gandhi, Pauravi J. ; Ravikrishnan, Aparna ; Gawande, Dinesh Y. ; Liu, Jinxu ; Stairs, Dustin J. ; Ugale, Rajesh R. ; Dravid, Shashank M. ( May 2019 , Scientific Reports)

   The GluN2C- and GluN2D-containing NMDA receptors are distinct from GluN2A- and GluN2B-containing receptors in many aspects including lower sensitivity to Mg²⁺block and lack of desensitization. Recent studies have highlighted the unique contribution of GluN2C and GluN2D subunits in various aspects of neuronal and circuit function and behavior, however a direct comparison of the effect of ablation of these subunits in mice on pure background strain has not been conducted. Using knockout-first strains for theGRIN2CandGRIN2Dproduced on pure C57BL/6N strain, we compared the effect of partial or complete ablation of GluN2C and GluN2D subunit on various behaviors relevant to mental disorders. A large number of behaviors described previously in GluN2C and GluN2D knockout mice were reproduced in these mice, however, some specific differences were also observed possibly representing strain effects. We also examined the response to NMDA receptor channel blockers in these mouse strains and surprisingly found that unlike previous reports GluN2D knockout mice were not resistant to phencyclidine-induced hyperlocomotion. Interestingly, the GluN2C knockout mice showed reduced sensitivity to phencyclidine-induced hyperlocomotion. We also found that NMDA receptor channel blocker produced a deficit in prepulse inhibition which was prevented by a GluN2C/2D potentiator in wildtype and GluN2C heterozygous mice but not in GluN2C knockout mice. Together these results demonstrate a unique role of GluN2C subunit in schizophrenia-like behaviors.

    

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5. Extensive characterization of a Williams syndrome murine model shows Gtf2ird1 ‐mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior

   https://doi.org/10.1111/gbb.12853  

   Nygaard, Kayla R. ; Maloney, Susan E. ; Swift, Raylynn G. ; McCullough, Katherine B. ; Wagner, Rachael E. ; Fass, Stuart B. ; Garbett, Krassimira ; Mirnics, Karoly ; Veenstra‐VanderWeele, Jeremy ; Dougherty, Joseph D. ( June 2023 , Genes, Brain and Behavior)

   Williams syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams syndrome is caused by a microdeletion of 26–28 genes on chromosome 7, includingGTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias and language delay. Thus, genes in the region appear to regulate social motivation in a dose‐sensitive manner. A “complete deletion” mouse, heterozygously eliminating the syntenic Williams syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role ofGtf2ird1in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressingGtf2ird1, which can be used both to model duplication of this gene alone and to rescueGtf2ird1expression in the complete deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams syndrome critical region regulates social motivation along with motor and anxiety phenotypes, but thatGtf2ird1complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However,Gtf2ird1complementation does rescue light‐aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

    

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