1. Armstrong JL, Canal CE. Targeting 5-HT(1A) Receptors to Correct Perineuronal Net and Social Behavioral Deficits in Fmr1 Knockout Mice, a Model of Fragile X Syndrome. FASEB J;2022 (May);36 Suppl 1

Fragile X syndrome (FXS), caused by FMR1gene silencing and subsequent loss of the RNA-binding protein FMRP, is the leading monogenic cause of intellectual disability and autism spectrum disorder, characterized by social deficits and repetitive behaviors. Currently, there are no approved medications for FXS. MMP-9 is an extracellular matrix regulating enzyme and a significant target of FMRP-the loss of FMRP in FXS leads to overexpression of MMP-9. MMP-9 degrades perineuronal nets (PNNs) that stabilize glutamatergic and GABAergic neurotransmission, and imbalance in these neurotransmitter systems is a hallmark of FXS, suggesting correcting MMP-9 overactivity may restore neuronal homeostasis in FXS by normalizing PNNs. For example, we show significantly decreased PNN density in hippocampal CA2 in juvenile Fmr1 knockout (KO) mice, a neural system critical for social memory, compared to wild-type (WT) mice (P=0.0043, N=8 and 7, respectively). In parallel with PNN deficits, we show that juvenile Fmr1KO mice have social memory impairments compared to WT mice. Juvenile Fmr1 KO mice have no preference for interacting with novel mice than familiar mice (number of interactions, P=0.54; amount of time interacting, P=0.27; N=10). In contrast, WT mice interact more frequently and spend more time with novel mice (P=0.014 and P=0.028, respectively; N=11). Modulating distinct serotonin receptors (5-HTRs) can regulate MMP-9 expression, neuroanatomical plasticity, social behaviors, and memory. Previously we showed that FPT, a novel medication candidate with potent 5-HT(1A) R agonist activity, increases social interactions in adult Fmr1KO and WT mice (Armstrong et al., 2020 https://doi.org/10.1021/acsptsci.9b00101). However, we did not investigate FPT’s effects on social behavior or social memory in juvenile mice-focusing on critical neurodevelopmental periods-nor have we explored mechanisms underlying FPT’s therapeutic-like effects. We are now testing the hypothesis that FPT corrects social memory deficits in juvenile Fmr1 KO mice and works, in part, by decreasing MMP-9 levels and restoring PNN levels in hippocampal CA2 via a 5-HT(1A) R mechanism. Results from these studies will provide critical mechanistic information regarding the preclinical neurotherapeutic effects of FPT in FXS.

Lien vers le texte intégral (Open Access ou abonnement)

2. Bahry JA, Fedder-Semmes KN, Sceniak MP, Sabo SL. Corrigendum: An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning. Front Cell Neurosci;2022;16:892217.

[This corrects the article DOI: 10.3389/fncel.2021.692232.].

Lien vers le texte intégral (Open Access ou abonnement)

3. Bouw N, Swaab H, Tartaglia N, Cordeiro L, van Rijn S. Early Social Behavior in Young Children with Sex Chromosome Trisomies (XXX, XXY, XYY): Profiles of Observed Social Interactions and Social Impairments Associated with Autism Spectrum Disorder (ASD). J Autism Dev Disord;2022 (May 12)

Individuals with Sex Chromosome Trisomies (SCT; XXX, XXY, XYY) have an increased vulnerability for developing challenges in social adaptive functioning. The present study investigates social interaction behavior in the context of varying social load, and Autism Spectrum Disorder (ASD) symptomatology in young children aged 1-7.5 years old, with SCT (N = 105) and control children (N = 101). Children with SCT show less interaction behaviors and more social withdrawal, as compared to their control peers, which were most evident in the high social load condition. Second, social impairments related to ASD are more prevalent, as compared to controls (27.1% at clinical level). These findings stress the importance of early monitoring and (preventive) support of early social development in young children with SCT.

Lien vers le texte intégral (Open Access ou abonnement)

4. Brown C, Sobrian S, Hudson T. Potential Drug Therapy For Fragile X Tremor/Ataxia Syndrome. FASEB J;2022 (May);36 Suppl 1

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurological disorder that affects carriers of the alleles for the Fragile X gene, Fragile X Mental Retardation (FMR1) due to the CGG triplet repeat expansion within the 5’UTR of FMR1. Clinical symptoms that are likely to occur are progressive ataxia, intention tremor, intranuclear inclusions, and Parkinsonian-like motor symptoms. The goal of this research is to assess the biological efficacy of Curcumin, Muscadine Grape Seed Extract (MSKE) on the neuroprotective capacity with respect to mitochondrial damage, and their ability to restore mitochondrial health in patient with FXTAS. To establish mitochondrial dysfunction, normal human cell lines and human-induced pluripotent cells were treated with multiple concentrations of glucose/ glucose oxidase (GluOx) at 2,12,and 24 hour time points to induce varying intensities of oxidative stress. The degrees of oxidative stress were measured by apoptosis and mitochondrial reactive oxygen species (ROS) production. Curcumin and MSKE, compounds effective against oxidative damage in mitochondria, were used to rescue glucose oxidase induced oxidative damage in both cell lines. To test the ability of these drugs to restore mitochondrial health, cell viability and cellular superoxide production were assessed by propidium iodide and the MitoSox fluorescence assay, respectively. We anticipated that GluOx at varying concentrations and time points would proportionally increase levels of apoptosis and mitochondrial ROS, reflective of mitochondrial damage, with the most severe dysfunction occurring at a dose of 25 nM and the longest duration of 24-hr exposure. Administration of MSKE in concentrations ranging from 10(-8) to 10(-5) M in half log increments, did not reverse the oxidative defects induced in the cell lines. However, curcumin concentrations increased cell viability at the 2, 12, and 24 hour time period. Results indicate that the research design should be modified by increasing concentration of both glucose and MSKE to provide a reliable test of the hypothesis. Although, the research design will be modified to better assessed the hypothesis, the overall research is translational in that it lends flexibility to testing therapeutics in neuronal FXTAS models and expands the discovery of mitochondrial markers for the syndrome.

Lien vers le texte intégral (Open Access ou abonnement)

5. Buch A, Fisher N, Frietas G, Vermudez S, Weiss K, Gogliotti R, Niswender C. Phenotypic profiling of mGlu(7) overexpressing mice and its implications for neurodevelopmental disorders such as Rett syndrome. FASEB J;2022 (May);36 Suppl 1

Neurodevelopmental disorders (NDDs) are characterized by deficits in communication, cognition, attention, social behavior and/or motor control. Previous studies have pointed to the involvement of genes that regulate synaptic structure and function in the pathogenesis of these disorders. One such gene, GRM7, encodes the metabotropic glutamate receptor 7 (mGlu(7) ), a G protein-coupled receptor that regulates presynaptic neurotransmitter release. Mutations and polymorphisms in GRM7 have been associated with (NDDs) in clinical populations; however, limited preclinical studies have evaluated mGlu(7) in the context of this specific disease class. Rett syndrome (RTT) is an NDD caused by mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene. The cognitive deficits seen in RTT model mice have been previously correlated with a deficit in long-term potentiation (LTP) at Schaffer collateral-CA1 (SC-CA1) synapses in the hippocampus. mGlu(7) is abundantly expressed presynaptically at SC-CA1 synapses and its role in the regulation of GABA release is imperative for the induction of LTP. Previous studies from our lab have shown that mGlu(7) expression is reduced in autopsy samples from patients diagnosed with RTT and in mouse models of RTT. Our lab has also shown that abnormal phenotypes in RTT mice can be corrected with mGlu(7) positive allosteric modulators (PAMs). Despite the beneficial effects of mGlu(7) potentiation, it is important to understand how an increase in mGlu(7) expression affects phenotypes seen in NDDs like Rett syndrome. Here, we hypothesize that an excess of either of the two mGlu(7) isoforms, mGlu(7) a and mGlu(7) b, in mice is sufficient to alter phenotypes. mGlu(7) was globally overexpressed in mice by crossing a Grm7(a/b) (Flx/+) male with a CMV-Cre(+/-) female. Starting at 6 weeks of age, behavioral assays were conducted for motor, cognitive, and stereotypic phenotypes. After the behavioral phenotyping, tissue was collected and processed for expression studies. Our data indicate abnormal phenotypes in motor, cognitive, and stereotypic assays. In particular, mGlu(7) over-expressing mice, regardless of isoform, display hyperactivity in a locomotor assay, associative memory deficits in a contextual fear conditioning assay, and increased repetitive behaviors as assessed by hindlimb clasping. In conclusion, our study indicates that overexpressing mGlu(7) in mice leads to abnormal phenotypes. We are now assessing synaptic plasticity phenotypes, including abnormal long-term potentiation in mGlu(7) overexpressing mice, and determining the effect of mGlu(7) allosteric modulators in affecting these cognitive aberrations. Overall, these studies aim to capitalize on previous studies demonstrating the role of mGlu(7) in the manifestation of phenotypes associated with NDDs.

Lien vers le texte intégral (Open Access ou abonnement)

6. Buchanan CB, Stallworth JL, Joy AE, Dixon RE, Scott AE, Beisang AA, Benke TA, Glaze DG, Haas RH, Heydemann PT, Jones MD, Lane JB, Lieberman DN, Marsh ED, Neul JL, Peters SU, Ryther RC, Skinner SA, Standridge SM, Kaufmann WE, Percy AK. Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study. J Neurodev Disord;2022 (May 14);14(1):31.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281.

Lien vers le texte intégral (Open Access ou abonnement)

7. Burkitt CC, Genik LM. Special issue on pain and intellectual and developmental disabilities. Paediatr Neonatal Pain;2022 (Mar);4(1):1-2.

Lien vers le texte intégral (Open Access ou abonnement)

8. Cazalis F, Reyes E, Leduc S, Gourion D. Evidence That Nine Autistic Women Out of Ten Have Been Victims of Sexual Violence. Front Behav Neurosci;2022;16:852203.

BACKGROUND: Research indicates that sexual violence affects about 30% of women in the general population and between two to three times as much for autistic women. MATERIALS AND METHODS: We investigated prevalence of sexual abuse, autistic traits and a range of symptoms, using an online survey addressed to the women of the French autistic community (n = 225). We assessed victimization through an open question and through a specific questionnaire, derived from the Sexual Experiences Survey-Short Form Victimization. RESULTS: Both case identification methods yielded high figures: 68.9% victimization (open question) compared to 88.4% (standardized questionnaire). Two thirds of the victims were very young when they were first assaulted: among 199 victims, 135 were aged 18 or below and 112 participants were aged 15 or below. 75% of participants included in our study reported several aggressions. Analyses indicate that primo-victimization was highly correlated to revictimization and that being young increased that risk. Young victims were also at higher risk of developing post-traumatic stress disorder. A third of the victims reported the assault. 25% of those were able to file a complaint (n = 12) and/or receive care (n = 13). For the remainder 75%, reporting did not lead to action. DISCUSSION: Those findings indicate a very large proportion of victims of sexual assault among autistic women, consistently with previous research. The World Health Organization states unambiguously that sexual violence is systemic and that vulnerable individuals are preferably targeted by offenders. We therefore postulate that it would be erroneous to consider that victimization of autistic women is mainly due to autism. On the contrary, autism seems to be just a vulnerability factor. Some authors propose that educating potential victims to better protect themselves would help preventing abuse. We reviewed this proposition in the light of our results and found it to be impossible to apply since more than half of the victims were below or at the age of consent. Literature about sexual violence is discussed. Large-scale prevention programs proposed by World Health Organization and the Center for Disease Control aim at cultural changes in order to diminish gender inequality, that they identify as the very root of sexual violence.

Lien vers le texte intégral (Open Access ou abonnement)

9. Critchfield-Jain I, Lahodny A, Gentillon R, Read CC, Banner E, Wisco JJ. Qualitative Analysis of Autism Spectrum Disorder Student Body Language and Teacher Pedagogical Techniques while Scanning for Frontal Lobe Activation Using fNIRS. FASEB J;2022 (May);36 Suppl 1

INTRODUCTION: Autism Spectrum Disorder (ASD) is a neurological and developmental disorder that often becomes evident in early childhood. The common signs of ASD are difficulty with communication, difficulty with social interactions, repetitive behaviors, and difficulty dealing with emotions. In this study, we examined how students with ASD displayed their thinking physically through their body language. We were also interested in studying the frontal lobe activation using functional Near Infrared Spectroscopy (fNIRS) during a teaching/learning experience. METHODS: Teachers and students wore fNIRS NIRSIT (Soterix Medical, Inc.) systems during a 30-minute simulated math lesson consisting of three phases: didactic instruction, facilitated practice problem solving, and supervised independent study. fNIRSs were used to indicate what teaching and learning moments resulted in the most frontal lobe activation of the students, and the results were compared between groups. In addition, we used grounded theory thematic analysis to analyze the video recordings of the learning space. RESULTS: Teaching techniques were coupled with student body language to compare activation levels within the brain. Although body language for each student was presented differently, frontal lobe activation for the following examples were high. One student stared at his paper throughout the lesson and bounced his finger while reading his paper. Another student was staring at the table; however, was able to acknowledge the teacher when she was speaking to him and answer her questions. Other students chose to sit up straight and engage with the teacher the entire lesson. In regards to teachers, they used a variety of techniques to engage with students. In each of the following examples, frontal lobe activation in teachers was high. One teacher made sure that she did not have her back to the students for a long time. Another teacher made use of deliberate pauses which allowed students the time they needed to process information. CONCLUSION: These results demonstrate that even though body language may be different for the students, it cannot be used as a measure of engagement as different presentations of body language still displayed high activation on the fNIRS. Several students who did not appear engaged were processing and retaining the information according to the high frontal lobe activation. It appears that ASD students use different signals in their body language, such as the finger bounce, as a way to show that they are thinking and concentrating. Therefore, teachers should examine the body language of the student and adjust their teaching techniques accordingly. For example, the teacher who used pauses in their lectures allowed the students to take a moment to think about whether or not they truly understood what was being said. This group of students had more verbal « aha » moments, displaying true understanding of the material and a higher activation in their frontal lobe. This also required a higher level of thinking for the students and encouraged them to engage in metacognitive processes beyond the typical memorization paradigm of learning.

Lien vers le texte intégral (Open Access ou abonnement)

10. de Korte MWP, van Dongen-Boomsma M, Oosterling IJ, Buitelaar JK, Staal WG. Pivotal Response Treatment (PRT) parent group training for young children with autism spectrum disorder: a pilot study. Sci Rep;2022 (May 11);12(1):7691.

Pivotal Response Treatment (PRT) is a promising intervention addressing core symptoms of autism spectrum disorder (ASD), with parent involvement as key component. Parent group-delivered PRT may be an effective treatment model, but currently the evidence is limited. Also, little attention has been paid to therapeutic involvement of multiple important contexts (e.g. home, school, community) of the young child. The current study explores a 14-week protocol of PRT parent group training (PRT-PG), complemented with individual parent-child sessions and involvement of teachers and other childcare providers. Children aged 2-6 years old with ASD and their parents (n = 20) were included. Preliminary results showed a significant increase in spontaneous initiations during a semi-structured therapist-child interaction together with widespread gains in clinical global functioning. No significant improvement on parent-rated general social-communication skills was observed. These findings justify further research on parent group delivered PRT models.

Lien vers le texte intégral (Open Access ou abonnement)

11. DeRuisseau LR, Mora L, Zheng A, Amin BS, Bonsu SO, Cilhoroz BT, DeRuisseau KC, Kowalchuk AM, MacDonald JL. Vitamin D Supplementation Partially Rescues Breathing Deficits in Mecp2 Hemizygous Null Mice, a Model of Rett Syndrome. FASEB J;2022 (May);36 Suppl 1

Rett syndrome (RTT) is a severe X-linked progressive neurodevelopmental disorder affecting ~1 in 10,000 females. It is the second most common genetic cause of cognitive disability in girls, after Down syndrome. Girls with this devastating disorder develop relatively normally for 6-18 months, after which they undergo a period of rapid regression. They lose many motor skills, the growth of their brain slows, and they develop repetitive, autistic behaviors and seizures. Autonomic disruptions are a leading cause of early death in RTT, and rescue of breathing deficits is considered a primary goal in the development of therapeutic interventions. We initiated a proof-of-concept study by investigating male Mecp2 hemizygous null mice as they have the strongest phenotype which occurs at an early age; male Mecp2-null (KO) mice have also been characterized thoroughly in the literature. We tested the hypothesis that Vitamin D supplementation (VitD) would ameliorate, or partially rescue breathing and cardiovascular deficits in Mecp2 KO mice. Mice were tested at 4 weeks of age (PRE), then placed on a control (1 IU Vitamin D/g) or VitD (50 IU Vitamin D/g) diet, and re-tested at 8 weeks of age (POST). To examine our hypothesis, unrestrained barometric plethysmography was used to quantify breathing frequency (breaths/min), tidal volume (VT; mL/breath), VT/inspiratory time (VT/Ti; mL/sec), minute ventilation (VE; mL/min/g) and the ventilatory equivalent for CO2 (VE/VCO2) in both wildtype (WT; n=6) and Mecp2 KO (n=5) littermates. Data Sciences International Ponemah software was used to analyze flow tracings during exposure to air (20.93% O2, balanced N2). The MouseOx Plus by STARR Life Sciences was utilized to collect heart rate (HR) and oxygen saturation in freely moving conscious mice. Data are expressed as mean ± S.D., WT vs. KO. In the PRE group, Mecp2 KO mice had dysregulated breathing and HR as previously demonstrated in the literature (data not shown). In the POST VitD diet groups, VT (0.24±0.02 vs 0.15±0.06 mL/breath; p=0.01) and VT/Ti remained lower (2.085±0.313 vs. 1.291±0.583 mL/sec; p=0.017) in Mecp2 KO. However, breathing frequency (166±21 vs. 166±19 breaths/min), VE/g (1.07±0.12 vs. 0.99±0.57 mL/min/g), ratio of VE/VCO2 (112±47 vs. 103±46) and HR (582±84 vs. 532±59 beats/min) were similar between WT and KO. The number of oxygen desaturations were not significant between WT and KO, but the values were variable across groups and included a number of desaturations (12±7 vs. 5±7 desaturations/30 minutes), similar to findings we have previously described in young control mice. These data reveal a partial rescue of breathing and HR deficits in Mecp2 KO mice following 4 weeks of VitD. The reduced VT/Ti suggests an attenuated neural drive to breath in Mecp2 KO vs. WT that persists after VitD. Current studies are examining the responses to hypoxia and hypercapnia and will identify more information about oxygen and carbon dioxide sensing in these mice following control and VitD diets.

Lien vers le texte intégral (Open Access ou abonnement)

12. Espelöer J, Proft J, Falter-Wagner CM, Vogeley K. Alarmingly large unemployment gap despite of above-average education in adults with ASD without intellectual disability in Germany: a cross-sectional study. Eur Arch Psychiatry Clin Neurosci;2022 (May 14)

For individuals with autism spectrum disorder (ASD), both getting access to as well as staying in the labor market are very challenging. However, the detailed educational, vocational, and employment characteristics of persons with ASD without intellectual disabilities are not yet studied. We conducted a retrospective study on a sample of 232 clinically late-diagnosed adults with ASD without intellectual disabilities. Data were compared to the general German population obtained from the public database of the German Federal Employment Agency. Results showed that the majority of persons with ASD graduated from high school and obtained a university entrance qualification (ASD: 50.4%; general population: 32.5%). Also, lower rates of basic secondary education were found in the ASD sample (ASD: 16.5%, general population: 29.6%). Significantly less individuals with ASD completed vocational training (40.1%) in comparison to the German population (56.3%). Despite the above-average level of education, the unemployment rate of the sample substantially exceeds that of the general population by the factor 5 (ASD: 25.2%; general population: 5.2%). Periods of unwanted unemployment of persons with ASD lasted on average 23 months with interpersonal problems being the main reason for contract termination. A higher level of educational qualification does not protect against a higher risk of unemployment for individuals with ASD presumably due to autism-specific interpersonal difficulties. Data emphasize the necessity to develop and spread both specific employment support activities for individuals with ASD as well as adequate awareness raising strategies. Funded by a public grant of the « Landschaftsverband Rheinland (LVR) ».

Lien vers le texte intégral (Open Access ou abonnement)

13. Fitzpatrick R, McGuire BE, Lydon HK. Improving pain-related communication in children with autism spectrum disorder and intellectual disability. Paediatr Neonatal Pain;2022 (Mar);4(1):23-33.

The communication of pain in individuals with co-morbid Autism Spectrum Disorder and intellectual disability (ASD-ID) is largely unexplored. The communication deficits associated with ASD-ID can result in nonverbal behavior such as self-injurious behavior, aggression, irritability, and reduced activity as a means to communicate that pain is present. The objective of this study was to determine whether a behavioral-based educational intervention could increase the pain-related communication of children with ASD-ID who experience pain frequently. Specifically, the study aimed to determine if children with ASD-ID can label the location of their pain or quantify pain severity and request pain relief. The sample included three children with ASD-ID who experienced pain frequently. The intervention utilized educational materials and behavioral reinforcements and the intervention was conducted using a series of case studies. Pain was assessed daily by caregivers using the Non-Communicating Children’s Pain Checklist-Postoperative (NCCPC-PV) and the ability of the individual to identify and express pain was recorded using the Wong Baker FACES Pain (WBFPS) Scale. Challenging behavior was recorded based on frequency count. The results indicated that all participants displayed the ability to independently respond to a question about how they were feeling by vocalizing the location of pain or indicating their level of pain on the WBFPS and requesting pain relief. The results suggest a role for behavioral-based educational interventions to promote communication of pain in people with ASD-ID.

Lien vers le texte intégral (Open Access ou abonnement)

14. Ghahremani R, Mohammadkhani R, Salehi I, Karimi SA, Zarei M. Sex Differences in Spatial Learning and Memory in Valproic Acid Rat Model of Autism: Possible Beneficial Role of Exercise Interventions. Front Behav Neurosci;2022;16:869792.

In the current study, we first tried to determine sex differences in spatial learning and memory in the valproic acid (VPA) rat model of autism. Second, the effects of interval training (IT) and continuous training (CT) exercises were examined in male and female offsprings. To induce autism-like animal model, the pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) at the embryonic day 12.5. IT and CT aerobic exercises were started at postnatal day 56. Then, on postnatal days 84-89, a Morris water maze (MWM) test was conducted on the separate groups of offsprings. Aerobic training was performed on a rodent treadmill with 0% slope for 8 weeks, 5 days/week, and 50 min/day. Unlike control animals, VPA-exposed female offspring had a better performance than VPA-exposed male offspring in MWM acquisition. In the case of MWM reference memory, we did not observe a sex difference between VPA-exposed male and VPA-exposed female offspring. Both IT and CT exercises in both control and VPA-exposed male rats significantly improved MWM acquisition. Moreover, both IT and CT exercises significantly improved MWM acquisition in control female rats. In addition, IT exercise (but not CT) significantly improved MWM acquisition in VPA-exposed female offsprings. Both IT and CT exercises in VPA-exposed that male and female offsprings improved the MWM reference memory. In conclusion, our observation demonstrated that prenatal exposure to VPA affects the spatial learning and memory in a sex dependent manner. We have shown that both IT and CT exercises are able to improve cognitive function in healthy and autistic rat offsprings.

Lien vers le texte intégral (Open Access ou abonnement)

15. Hong SJ, Mottron L, Park BY, Benkarim O, Valk SL, Paquola C, Larivière S, Vos de Wael R, Degré-Pelletier J, Soulieres I, Ramphal B, Margolis A, Milham M, Di Martino A, Bernhardt BC. A convergent structure-function substrate of cognitive imbalances in autism. Cereb Cortex;2022 (May 12)

BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental diagnosis showing substantial phenotypic heterogeneity. A leading example can be found in verbal and nonverbal cognitive skills, which vary from elevated to impaired compared with neurotypical individuals. Moreover, deficits in verbal profiles often coexist with normal or superior performance in the nonverbal domain. METHODS: To study brain substrates underlying cognitive imbalance in ASD, we capitalized categorical and dimensional IQ profiling as well as multimodal neuroimaging. RESULTS: IQ analyses revealed a marked verbal to nonverbal IQ imbalance in ASD across 2 datasets (Dataset-1: 155 ASD, 151 controls; Dataset-2: 270 ASD, 490 controls). Neuroimaging analysis in Dataset-1 revealed a structure-function substrate of cognitive imbalance, characterized by atypical cortical thickening and altered functional integration of language networks alongside sensory and higher cognitive areas. CONCLUSION: Although verbal and nonverbal intelligence have been considered as specifiers unrelated to autism diagnosis, our results indicate that intelligence disparities are accentuated in ASD and reflected by a consistent structure-function substrate affecting multiple brain networks. Our findings motivate the incorporation of cognitive imbalances in future autism research, which may help to parse the phenotypic heterogeneity and inform intervention-oriented subtyping in ASD.

Lien vers le texte intégral (Open Access ou abonnement)

16. Javadi S, Li Y, Sheng J, Zhao L, Fu Y, Wang D, Zhao X. Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of fragile X syndrome. BMC Med;2022 (May 13);20(1):163.

BACKGROUND: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic forms of autism, is caused by a loss of fragile X messenger ribonucleoprotein 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice, and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. METHODS: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying the persistent effects of Nutlin-3, we analyzed the proliferation and differentiation of neural stem/progenitor cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. RESULTS: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6 months of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to the extracellular matrix, secreted factors, and cell membrane proteins in the FMR1-deficient hippocampus. CONCLUSIONS: Our data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes likely through modulating adult neurogenic niche that impact adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.

Lien vers le texte intégral (Open Access ou abonnement)

17. Joudar SS, Albahri AS, Hamid RA. Triage and priority-based healthcare diagnosis using artificial intelligence for autism spectrum disorder and gene contribution: A systematic review. Comput Biol Med;2022 (May 9);146:105553.

The exact nature, harmful effects and aetiology of autism spectrum disorder (ASD) have caused widespread confusion. Artificial intelligence (AI) science helps solve challenging diagnostic problems in the medical field through extensive experiments. Disease severity is closely related to triage decisions and prioritisation contexts in medicine because both have been widely used to diagnose various diseases via AI, machine learning and automated decision-making techniques. Recently, taking advantage of high-performance AI algorithms has achieved accessible success in diagnosing and predicting risks from clinical and biological data. In contrast, less progress has been made with ASD because of obscure reasons. According to academic literature, ASD diagnosis works from a specific perspective, and much of the confusion arises from the fact that how AI techniques are currently integrated with the diagnosis of ASD concerning the triage and priority strategies and gene contributions. To this end, this study sought to describe a systematic review of the literature to assess the respective AI methods using the available datasets, highlight the tools and strategies used for diagnosing ASD and investigate how AI trends contribute in distinguishing triage and priority for ASD and gene contributions. Accordingly, this study checked the Science Direct, IEEE Xplore Digital Library, Web of Science (WoS), PubMed, and Scopus databases. A set of 363 articles from 2017 to 2022 is collected to reveal a clear picture and a better understanding of all the academic literature through a final set of 18 articles. The retrieved articles were filtered according to the defined inclusion and exclusion criteria and classified into three categories. The first category includes ‘Triage patients based on diagnosis methods’ which accounts for 16.66% (n = 3/18). The second category includes ‘Prioritisation for Risky Genes’ which accounts for 66.6% (n = 12/18) and is classified into two subcategories: ‘Mutations observation based’, ‘Biomarkers and toxic chemical observations’. The third category includes ‘E-triage using telehealth’ which accounts for 16.66% (n = 3/18). This multidisciplinary systematic review revealed the taxonomy, motivations, recommendations and challenges of ASD research that need synergistic attention. Thus, this systematic review performs a comprehensive science mapping analysis and discusses the open issues that help perform and improve the recommended solution of ASD research direction. In addition, this study critically reviews the literature and attempts to address the current research gaps in knowledge and highlights weaknesses that require further research. Finally, a new developed methodology has been suggested as future work for triaging and prioritising ASD patients according to their severity levels by using decision-making techniques.

Lien vers le texte intégral (Open Access ou abonnement)

18. Junnarkar VS, Tong HJ, Hanna KMB, Aishworiya R, Duggal M. Occupational and speech therapists’ perceptions of their role in dental care for children with autism spectrum disorder: A qualitative exploration. Int J Paediatr Dent;2022 (May 13)

BACKGROUND: Children with autism spectrum disorders (ASD) have challenges in home oral care, accessing a dentist and accepting dental treatment. Occupational therapists (OTs) and speech therapists (STs) are likely to be involved earlier in managing communication, behavioural and sensory processing issues. AIM: To determine the perceived barriers and potential solutions to dental care for children with ASD in Singapore from the perspective of OTs and STs. DESIGN: Semi-structured interviews and a focus group discussion involving OTs and STs who treat children with ASD were conducted. Audio-recordings were transcribed and coded into themes using NVivo 12 software. RESULTS: Emergent themes indicated that: 1) OTs and STs have important roles in recognition of issues with toothbrushing, oral pathology and harmful oral habits 2) OTs and STs were able to identify reasons for difficulties in oral home care for children with ASD and offer helpful strategies 3) OTs and STs can play a role in pre-dental visit preparations, but lack a clear dental referral pathway. CONCLUSION: OTs and STs are in a unique position to assist in early identification and dental referrals of children with ASD. Interprofessional collaboration with dentists should be further explored to aid in provision of preventive dental advice.

Lien vers le texte intégral (Open Access ou abonnement)

19. Kang LRJ, Barlott T, Turpin M, Urbanowicz A. A trial of the AASPIRE healthcare toolkit with Australian adults on the autism spectrum. Aust J Prim Health;2022 (May 13)

BACKGROUND: Autistic adults experience barriers to accessing health care, such as service provider communication not meeting their needs, healthcare facilities causing sensory discomfort and feeling fear or anxiety regarding their healthcare visit. The Academic Autism Spectrum Partnership in Research and Education (AASPIRE) developed and trialled an online healthcare toolkit to reduce such barriers and improve healthcare interactions between autistic adults and their primary care providers in the United States. This preliminary study aimed to explore experiences of autistic adults using the AASPIRE Healthcare Toolkit in Australia. METHODS: Semi-structured interviews were conducted with six autistic adults about their experiences and perceptions of utilising the toolkit in an Australian healthcare setting. RESULTS: Participants identified that the toolkit facilitated their interactions with health professionals by providing structure to appointments, supplementing new knowledge and increasing individual confidence. They also offered suggestions to tailor the toolkit for use in Australia. CONCLUSIONS: Future research should seek to explore the experiences of autistic adults using a version of the toolkit adapted for Australian use, as well as exploring the views of health professionals utilising it.

Lien vers le texte intégral (Open Access ou abonnement)

20. Lahodny A, Critchfield-Jain I, Gentillon R, Read C, Banner L, Wisco J. Qualitative analysis of the role of teacher rapport on autism spectrum disorder student engagement while scanning for frontal lobe activation using fNIRS. FASEB J;2022 (May);36 Suppl 1

INTRODUCTION: Previous research has indicated that students with Autism Spectrum Disorder (ASD) show lower levels of engagement in the classroom and often struggle to focus in most learning environments compared to neurotypical students. It has been noted that the teacher plays a crucial role in creating a safe learning environment for ASD students. Successful teachers establish rapport with their students in order to create this safe learning environment. When teachers provide encouragement to students or make an effort to engage them through personal conversations, the student is more likely to engage in the material. The purpose of this study was to determine what teacher behaviors result in the highest brain activation in the frontal lobe of ASD students. METHODS: Teachers and students wore functional Near Infrared Spectroscopy (fNIRS) NIRSIT systems (Soterix Medical, Inc.) during a 30-minute simulated math lesson consisting of three phases – didactic instruction, facilitated practice problem solving, and supervised independent study. Teachers with 3 or fewer years experience teaching ASD students, and those with more than 3 years teaching high-functioning ASD high school students ranging in grade-level math from 6th grade to 12th grade were recruited for the study. Blood Oxygenation Level Dependence (BOLD) activation of the participants were monitored to indicate what teaching and learning moments resulted in the most frontal lobe activation of the students, and the results were compared between groups. In addition, we used grounded theory thematic analysis to analyze the video recordings of the learning space. RESULTS: We observed that teacher rapport was an important factor in engaging students. Friendly remarks and encouragement allowed for students to feel comfortable to engage in learning the material, resulting in a successful lesson flow with increased participation from the students. When students were engaged with material due to teacher rapport, frontal lobe BOLD signal increased. In addition, some students were actively engaged when answering questions or providing explanations for answers, while others showed concomitant brain activation while quietly listening to the teacher or the other student. CONCLUSIONS: The creation of a friendly learning environment is an important component in engaging students and should be emphasized for teachers seeking to engage both ASD students. The results of this study illustrate that students present different behaviors in a learning environment and can be actively engaged even when their behaviors deviate from what is typically defined as engagement.

Lien vers le texte intégral (Open Access ou abonnement)

21. Lin XB, Lim CG, Lee TS. Social Deficits or Interactional Differences? Interrogating Perspectives on Social Functioning in Autism. Front Psychiatry;2022;13:823736.

Social dysfunction is a key characteristic of autism. Determining and treating autism-related social deficits have been challenging. The medical model views interpersonal difficulties in autism as a localized set of deficits to be managed, whereas the neurodiversity movement calls for the accommodation of differences by the larger community. One common assumption underlying these perspectives is a misalignment in social behaviors between autistic individuals and neurotypicals. This paper reviews and interrogates current perspectives on social functioning in autism to uncover the intricacies of such a notion. Even though extant literature has alluded to a misalignment in social behaviors between autistic and neurotypical individuals, it is uncertain where this disparity lies. Implications for future research and practice are discussed.

Lien vers le texte intégral (Open Access ou abonnement)

22. Lin YJ, Chiu YN, Wu YY, Tsai WC, Gau SS. Correction to: Developmental Changes of Autistic Symptoms, ADHD Symptoms, and Attentional Performance in Children and Adolescents with Autism Spectrum Disorder. J Autism Dev Disord;2022 (May 13)

Lien vers le texte intégral (Open Access ou abonnement)

23. Loyola A, Bhushan A, Awale PS. Anti-Epileptic Drug and Teratogen Valproic Acid Induces Microglial Cell Death in a Valproic Acid Murine Model of Autism. FASEB J;2022 (May);36 Suppl 1

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects approximately 1 in 44 children in North America, and its association with neuronal connectivity is an area of intense research. Valproic acid (VPA) is a multi-target drug widely used to treat epilepsy. It is classified as a teratogen and as a histone deacetylase inhibitor (HDACi) and fetal exposure to VPA increases the risk of ASD. The VPA model has been well characterized for behavioral and neuronal deficits, including hyperconnectivity. The cause of hyperconnectivity is poorly understood however, it is speculated that lack of pruning may be partly responsible for this anomaly. Microglia, the principal immune cells of CNS regulate dendrite and synapse formation during early brain development. The effect of VPA on microglia during early development has not been well characterized and may provide potential hints regarding the etiology of this disorder. Preliminary studies from our lab indicate that VPA reduces microglial number during peak periods of postnatal synaptogenesis in the mouse brain primary cortex. Nevertheless, the cause of this reduction is not known. Therefore, in this study, we determined the mechanism for reduced microglial numbers in the VPA model of autism. Pregnant BALBc mice were administered 600 mg/kg of VPA by subcutaneous injection on day 13.5 of gestation. We harvested the mice brains at embryonic (E) day 14, E17, and postnatal day 1 (PD1). Brain tissue was double immunolabeled for microglia (IBA1) and cell death marker (TUNEL). We found a gradual increase in TUNEL staining beginning E14 to PD1 compared to age-matched controls. The mechanism for reduced microglial number may be due to cell death. Thus, our findings possibly have pathophysiological/pathogenic implications in autism and may, ultimately, lead to the discovery of new therapeutic target(s) for autism.

Lien vers le texte intégral (Open Access ou abonnement)

24. Manyukhina VO, Prokofyev AO, Galuta IA, Goiaeva DE, Obukhova TS, Schneiderman JF, Altukhov DI, Stroganova TA, Orekhova EV. Globally elevated excitation-inhibition ratio in children with autism spectrum disorder and below-average intelligence. Mol Autism;2022 (May 12);13(1):20.

BACKGROUND: Altered neuronal excitation-inhibition (E-I) balance is strongly implicated in ASD. However, it is not known whether the direction and degree of changes in the E-I ratio in individuals with ASD correlates with intellectual disability often associated with this developmental disorder. The spectral slope of the aperiodic 1/f activity reflects the E-I balance at the scale of large neuronal populations and may uncover its putative alternations in individuals with ASD with and without intellectual disability. METHODS: Herein, we used magnetoencephalography (MEG) to test whether the 1/f slope would differentiate ASD children with average and below-average (< 85) IQ. MEG was recorded at rest with eyes open/closed in 49 boys with ASD aged 6-15 years with IQ ranging from 54 to 128, and in 49 age-matched typically developing (TD) boys. The cortical source activity was estimated using the beamformer approach and individual brain models. We then extracted the 1/f slope by fitting a linear function to the log-log-scale power spectra in the high-frequency range. RESULTS: The global 1/f slope averaged over all cortical sources demonstrated high rank-order stability between the two conditions. Consistent with previous research, it was steeper in the eyes-closed than in the eyes-open condition and flattened with age. Regardless of condition, children with ASD and below-average IQ had flatter slopes than either TD or ASD children with average or above-average IQ. These group differences could not be explained by differences in signal-to-noise ratio or periodic (alpha and beta) activity. LIMITATIONS: Further research is needed to find out whether the observed changes in E-I ratios are characteristic of children with below-average IQ of other diagnostic groups. CONCLUSIONS: The atypically flattened spectral slope of aperiodic activity in children with ASD and below-average IQ suggests a shift of the global E-I balance toward hyper-excitation. The spectral slope can provide an accessible noninvasive biomarker of the E-I ratio for making objective judgments about treatment effectiveness in people with ASD and comorbid intellectual disability.

Lien vers le texte intégral (Open Access ou abonnement)

25. Marôco JL, Angarten V, Pinto R, Santos V, Santa-Clara H, Fernhall B, Melo X. Effects of Maximal Exercise on Central and Peripheral Arterial Stiffness in Adults with and without Intellectual and Developmental Disabilities. FASEB J;2022 (May);36 Suppl 1

Adults with Down-Syndrome seem to be protected from early aging-associated increases in arterial stiffness and to present blunted responses to maximal aerobic exercise in comparison to age-matched controls, possibly underlying diminished vascular reserve. However, whether these arterial stiffness responses apply to adults with intellectual and developmental disabilities (IDD) in general remains unknown. We compared central and peripheral arterial stiffness response patterns between persons with and without IDD of different age groups following maximal aerobic exercise. We hypothesized that adults with IDD would show an attenuated arterial stiffness response to maximal aerobic exercise in comparison to young and middle-aged adults without IDD. Thirty young adults with (n=15, age= 30 ± 7 years) and without (n=15, age= 27 ± 7 years) IDD, and 15 middle-aged adults (age= 51 ± 4 years) without IDD performed a bout of maximal aerobic exercise. Central and peripheral arterial stiffness were measured at rest and following maximal aerobic exercise using applanation tonometry estimates of carotid-femoral (cfPWV), carotid-distal (cdPWV), and carotid-radial (crPWV) pulse wave velocity, respectively. cfPWV was unchanged following maximal aerobic exercise in young adults with and without IDD (figure) but increased in middle-aged adults (d= 0.85; 95% CI: 0.27 to 1.42 m.s(-1) , p= 0.005), whereas cdPWV was reduced (d= -0.77; 95% CI: -1.06 to -0.48 m.s(-1) , p< 0.001) and crPWV unchanged in all three groups, independent of changes in mean arterial pressure. Overall group differences suggest that young adults with (d= -1.78; 95% CI: -3.20 to -0.37 m.s(-1) , p= 0.009) and without(d= -1.84; 95% CI: -3.26 to -0.43 m.s(-1) , p= 0.007) IDD had lower cfPWV than middle-aged adults. We found no evidence of early vascular aging and or a diminished vascular reserve following maximal aerobic exercise in adults with IDD.

Lien vers le texte intégral (Open Access ou abonnement)

26. Nebel MB, Lidstone DE, Wang L, Benkeser D, Mostofsky SH, Risk BB. Accounting for motion in resting-state fMRI: What part of the spectrum are we characterizing in autism spectrum disorder?. Neuroimage;2022 (May 10):119296.

The exclusion of high-motion participants can reduce the impact of motion in functional Magnetic Resonance Imaging (fMRI) data. However, the exclusion of high-motion participants may change the distribution of clinically relevant variables in the study sample, and the resulting sample may not be representative of the population. Our goals are two-fold: 1) to document the biases introduced by common motion exclusion practices in functional connectivity research and 2) to introduce a framework to address these biases by treating excluded scans as a missing data problem. We use a study of autism spectrum disorder in children without an intellectual disability to illustrate the problem and the potential solution. We aggregated data from 545 children (8-13 years old) who participated in resting-state fMRI studies at Kennedy Krieger Institute (173 autistic and 372 typically developing) between 2007 and 2020. We found that autistic children were more likely to be excluded than typically developing children, with 28.5% and 16.1% of autistic and typically developing children excluded, respectively, using a lenient criterion and 81.0% and 60.1% with a stricter criterion. The resulting sample of autistic children with usable data tended to be older, have milder social deficits, better motor control, and higher intellectual ability than the original sample. These measures were also related to functional connectivity strength among children with usable data. This suggests that the generalizability of previous studies reporting naïve analyses (i.e., based only on participants with usable data) may be limited by the selection of older children with less severe clinical profiles because these children are better able to remain still during an rs-fMRI scan. We adapt doubly robust targeted minimum loss based estimation with an ensemble of machine learning algorithms to address these data losses and the resulting biases. The proposed approach selects more edges that differ in functional connectivity between autistic and typically developing children than the naïve approach, supporting this as a promising solution to improve the study of heterogeneous populations in which motion is common.

Lien vers le texte intégral (Open Access ou abonnement)

27. Ortug A, Guo Y, Feldman HA, Ou Y, Dieuveuil H, Baumer NT, Faja SK, Takahashi E. Human Fetal Brain Magnetic Resonance Imaging (MRI) Tells Future Emergence of Autism Spectrum Disorders. FASEB J;2022 (May);36 Suppl 1

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which can result from a range of observed symptoms pertaining to social, emotional, and cognitive processing difficulties especially regarding communication of their own feelings, opinions, and thoughts with others. Although a diagnosis received by 1 in 68 children in the United States, a cause for autism is still unknown. Both genetic and environmental factors during prenatal and postnatal development are believed to account for the emergence of ASD. It is known that early treatment improves language and cognitive abilities later. However, currently, the earliest diagnosis of ASD can be made only around 18 months of age. It is critical to be aware of an altered initial brain anatomy in ASD for better predicting what aspects of brain function will likely preferentially and precociously deteriorate, which would allow for potentially earlier/better prevention and treatment. We hypothesized that prospective ASD patients will show region-specific abnormalities in developmental stages. We have used retrospective clinical brain MRI of the fetuses who were diagnosed as ASD in later age to obtain earliest MRI-based regional volumetric biomarkers. Thirty-nine fetuses (mean age 24.87 ± 5.05 gestational week [GW]) were included in this study (9 prospective ASD patients, 20 neurotypical controls, 6 non-ASD controls with neurological comorbidities observed in the prospective ASD patients, and 4 non-ASD controls with non-neurological comorbidities observed in the prospective ASD patients. After preprocessing, the images were segmented automatically with an atlas-based automated anatomical labeling method. A set of three-factor ANOVA was performed for lobar and regional comparisons of the segmented brain regions. The insula/insular lobe showed statistically significantly larger volume in ASD than that in all three control groups in the lobar comparison. In the regional comparison, the ASD group had statistically significantly larger amygdala, hippocampal commissure, and insula compared to the non-ASD controls with neurological and non-neurological comorbidities. Our results suggest that an increased volume of the insula/insular lobe may be a strong prenatal MRI biomarker that could predict the emergence of ASD later in life. The larger amygdala and hippocampal commissure could be additional biomarkers for identifying such prospective ASD patients.

Lien vers le texte intégral (Open Access ou abonnement)

28. Pedapati EV, Schmitt LM, Ethridge LE, Miyakoshi M, Sweeney JA, Liu R, Smith E, Shaffer RC, Dominick KC, Gilbert DL, Wu SW, Horn PS, Binder DK, Lamy M, Axford M, Erickson CA. Neocortical localization and thalamocortical modulation of neuronal hyperexcitability contribute to Fragile X Syndrome. Commun Biol;2022 (May 11);5(1):442.

Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key disorder features. Translating these findings into patients may identify tractable treatment targets. Using source modeling of resting-state electroencephalography data, we report findings in FXS, including 1) increases in localized gamma activity, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of low and high-frequency abnormalities based on female sex, and 4) relationship of this physiology to intellectual disability and neuropsychiatric symptoms. Our observations extend findings in Fmr1(-/-) KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has implications for understanding fundamental disease mechanisms.

Lien vers le texte intégral (Open Access ou abonnement)

29. Prillinger K, Radev ST, Doganay K, Poustka L, Konicar L. Impulsivity Moderates the Effect of Neurofeedback Training on the Contingent Negative Variation in Autism Spectrum Disorder. Front Hum Neurosci;2022;16:838080.

BACKGROUND: The contingent negative variation (CNV) is a well-studied indicator of attention- and expectancy-related processes in the human brain. An abnormal CNV amplitude has been found in diverse neurodevelopmental psychiatric disorders. However, its role as a potential biomarker of successful clinical interventions in autism spectrum disorder (ASD) remains unclear. METHODS: In this randomized controlled trial, we investigated how the CNV changes following an intensive neurofeedback training. Therefore, twenty-one adolescents with ASD underwent 24 sessions of slow cortical potential (SCP) neurofeedback training. Twenty additional adolescents with ASD formed a control group and received treatment as usual. CNV waveforms were obtained from a continuous performance test (CPT), which all adolescents performed before and after the corresponding 3-month long training period. In order to utilize all available neural time series, trial-based area under the curve values for all four electroencephalogram (EEG) channels were analyzed with a hierarchical Bayesian model. In addition, the model included impulsivity, inattention, and hyperactivity as potential moderators of change in CNV. RESULTS: Our model implies that impulsivity moderates the effects of neurofeedback training on CNV depending on group. In the control group, the average CNV amplitude decreased or did not change after treatment as usual. In the experimental group, the CNV changed depending on the severity of comorbid impulsivity symptoms. The average CNV amplitude of participants with low impulsivity scores decreased markedly, whereas the average CNV amplitude of participants with high impulsivity increased. CONCLUSION: The degree of impulsivity seems to play a crucial role in the changeability of the CNV following an intensive neurofeedback training. Therefore, comorbid symptomatology should be recorded and analyzed in future EEG-based brain training interventions. CLINICAL TRIAL REGISTRATION: https://www.drks.de, identifier DRKS00012339.

Lien vers le texte intégral (Open Access ou abonnement)

30. Saha S, Chatterjee M, Dutta N, Sinha S, Mukhopadhyay K. GABA Receptor SNPs and Elevated Plasma GABA Levels Affect the Severity of the Indian ASD Probands. J Mol Neurosci;2022 (May 13)

Altered signaling of the chief inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), has been speculated in the etiology of autism spectrum disorder (ASD). We have investigated the association of six GABA(A)-receptor genetic variants and plasma GABA levels with ASD. Subjects were recruited based on the DSM, and CARS2-ST and ADI-R assessed disease severity. Peripheral blood was collected from the ASD probands (N = 251), their parents, and ethnically matched controls (N = 347). A positive correlation between the CARS2-ST and ADI-R scores was observed; domain scores of ADI-R were higher in the severe group categorized by the CARS2-ST. GABRB3 rs1432007 « A, » GABRG3 rs897173 « A, » and GABRA5 rs140682 « T » showed significant association with ASD. Trait scores were influenced by rs1432007 « AA » and rs140682 « TT. » GABA level was significantly higher in the probands than the age-matched controls. Our findings indicate an influence of GABA in the etiology of ASD in the Indian probands.

Lien vers le texte intégral (Open Access ou abonnement)

31. Schickling B, Gumusoglu S, Santillan DA, Santillan MK. Cord Blood Metabolomics and Autism Spectrum Disorder. FASEB J;2022 (May);36 Suppl 1

INTRODUCTION: Autism spectrum disorder (ASD) has increased dramatically in prevalence and incidence in recent years (1:59 in the US, CDC). With prenatal and/or genetic origins, early detection and intervention are critical to improve outcomes. Few studies have assessed perinatal biomarkers for later development of ASD. We hypothesize that cord blood plasma-based metabolomics will differentiate infants who would later be diagnosed with ASD and typically developing (TD) controls. METHODS: Banked cord blood plasma samples and clinical data from the Iowa Maternal Fetal Tissue Bank were used. Samples were analyzed via gas chromatography and mass spectrometry (GC-MS) and relative MS signal intensity of a maximum of was quantified ratiometrically. All metabolites were normalized to internal controls (succinate) to account for effects of extraction, derivatization, and/or loading. Ratiometric levels of each metabolite were compared by t-test between ASD and control groups. Results P<0.01 are reported given the pilot nature of this small study. Metabolite set enrichment analysis (MSEA) was performed against human libraries. Significantly altered metabolites were compared to a tertiary sample of cord blood from individuals later diagnosed with attention deficit hyperactivity disorder (ADHD) to determine specificity for ASD. RESULTS: 91 metabolites were detected and analyzed. Homocysteine (fold change [FC]: 1.411; p=0.017), Myristic acid (FC: 1.221; p=0.084), Pentadecanoic acid (FC: 1.256; p=0.093) were increased in ASD samples, while L-Isoleucine (FC: 0.858; p=0.047), L-Threonine (FC: 0.7131; p=0.068), O-Phosphoethanolamine (FC: 0.704; p=0.070), and 2-Hydroxybutyric acid (FC: 0.615; p=0.073) were decreased. Of these, only pentadecanoic was also significantly changed in ADHD samples (FC: 1.514; p=0.002). MSEA revealed enrichment of homocysteine degradation (p=0.017), catecholamine biosynthesis (p=0.048), threonine and 2-Oxobutanoate degradation (p=0.068), Phosphatidylcholine Biosynthesis (p=0.070), and Phosphatidylethanolamine Biosynthesis (p=0.070) in ASD cord blood samples. CONCLUSION: We found that cord blood plasma metabolomics reveals intriguing and specific differences between ASD and control samples. While some of differences are supported by evidence, these alterations have not previously been extended to the prenatal period. Future work will investigate concordance with maternal blood metabolomics to determine maternal-fetal pathways.

Lien vers le texte intégral (Open Access ou abonnement)

32. Sever IH, Ozkul B, Bozkurt MF, Erbas O. Therapeutic effect of finasteride through its antiandrogenic and antioxidant role in a propionic acid-induced autism model: Demonstrated by behavioral tests, histological findings and MR spectroscopy. Neurosci Lett;2022 (May 14);779:136622.

BACKGROUND: Autism is a clinically defined neurodevelopmental disorder with unknown origin characterized by significant social, communication and behavioral challenges. Although it can be a lifelong condition, treatments can help alleviate symptoms and enhance a patient’s quality of life. PURPOSE: We aimed to assess the therapeutic potential of finasteride in autism with biochemical markers, histopathological evaluation, behavioral tests and radiological imaging. MATERIALS AND METHODS: Propionic acid (PPA) was injected intraperitoneally into 20 out of 30 rats for 5 days to establish an autism model. Rats were randomly assigned into four groups: control group (no procedure was applied, n = 10), placebo group (intraperitoneal PPA + 1 ml/kg/day % 0.9 NaCl saline was given via oral gavage for 15 days, n = 10) and treated group (intraperitoneal PPA + 5 mg/kg/day of finasteride was given via oral gavage for 15 days, n = 10). After 4 days of behavioral tests, magnetic resonance spectroscopy (MRS) was performed for measuring creatine and lactate levels. All animals were sacrificed for histopathological examination and biochemical analysis of brain tissue. RESULTS: MDA, NFκB, TNF-α, IL-2, IL-17A and lactate levels in brain homogenates were significantly increased in the placebo group compared to the control group, while Nfr2 levels were decreased; and the levels of all biochemical markers were reversed by finasteride treatment. A significant improvement was observed in autism-like behaviors in rats treated with finasteride compared to the placebo group. Further, the creatine and lactate levels in corpus striatum in MRS, the neuronal counts and glial activity of the hippocampus and cerebellum were closer to the control group in the finasteride-treated group compared to the placebo group. CONCLUSION: Finasteride led significant improvement in autism-like symptoms with its antioxidant effect through Nrf2 modulation in addition to its anti androgen effect.

Lien vers le texte intégral (Open Access ou abonnement)

33. Shih PY, Fang YL, Shankar S, Lee SP, Hu HT, Chen H, Wang TF, Hsia KC, Hsueh YP. Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3. Nat Commun;2022 (May 13);13(1):2664.

Many synaptic proteins form biological condensates via liquid-liquid phase separation (LLPS). Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. Zinc binds the N-terminal coiled-coil region of CTTNBP2, promoting higher-order assemblies. Consequently, it leads to reduce CTTNBP2 mobility and enhance the stability and synaptic retention of CTTNBP2 condensates. Moreover, ASD-linked mutations alter condensate formation and synaptic retention of CTTNBP2 and impair mouse social behaviors, which are all ameliorated by zinc supplementation. Our study suggests the relevance of condensate formation and zinc-induced phase transition to the synaptic distribution and function of ASD-linked proteins.

Lien vers le texte intégral (Open Access ou abonnement)

34. Singha SP, Memon S, Bano U, Isaac AD, Shahani MY. Evaluation of p21 expression and related autism-like behavior in Bisphenol-A exposed offspring of Wistar albino rats. Birth Defects Res;2022 (May 12)

BACKGROUND: Bisphenol A (BPA), an endocrine disruptor, may be involved in the etiology of autism spectrum disorders (ASD); however, the mechanism of neuronal and astrocytic damage remains ambiguous. A possible role of altered expression of p21 in autistic-like behavior in rat offspring was examined with prenatal and postnatal BPA exposure. METHODS: Wistar albino dams were exposed to BPA (5 mg/kg) intraperitoneally throughout pregnancy and until the third postnatal day (PND). Pups were examined on 21st PND for behavioral test. Blood samples were collected for serum lactate levels and pups were sacrificed. Right frontal cortices were dissected out and processed for H&E, immunohistochemical analysis, and gene expression. RESULTS: Anxiety like behavior and thigmotaxis along with reduction in serum lactate concentrations were observed in pups exposed to BPA. Decline in neuronal number and decreased astrocytic population with reduced dendritic spines were revealed by H&E and immunohistochemical analysis, respectively, in right frontal cortices. Over expression of p21 was also detected in BPA-exposed offspring. CONCLUSIONS: Over expression of p21 may be associated with autistic behavior. Further studies are recommended to explore the structural alterations in other white matter pathways in frontal cortices.

Lien vers le texte intégral (Open Access ou abonnement)

35. Smith IN, Eng C. Structure-based Computational Modeling of Germline PTEN Mutations in Cancer and Autism Risk: Implications for Therapeutic Targeting. FASEB J;2022 (May);36 Suppl 1

The Phosphatase and TENsin homolog deleted on chromosome ten (PTEN) is a dual-specificity phosphatase encoded by a tumor suppressor gene frequently somatically mutated in human cancer. Individuals with germline PTEN mutations are diagnosed with PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has a variable phenotype spectrum, including distinct subsets of patients with autism spectrum disorder (ASD) and/or cancer. It remains unclear why mutations in one gene can lead to seemingly disparate phenotypes. Our pilot studies identified structural stability and functional differences in germline PTEN variants that contribute to cancer or to autismsuggesting distinct conformational disease states and a potential basis for allosteric communication via the inter-domain region of PTEN. Thus, we hypothesized that key inter-domain sites will delineate novel structurally correlated areas for potential drug targeting. Moreover, PTEN is inactivated by phosphorylation of C-tail cluster sites (Ser/Thr residues 380-385) which is known to play a critical role in the function and stability of PTEN. However, very little is known about the mechanism underlying such inactivation. We therefore sought to further understand whether C-tail phosphorylation sites represent a possible phosphodegron motif that influences distinct conformational ensembles and inter-domain interface specific to PTEN-ASD and PTEN-cancer phenotypes. By integrating in silico modeling, molecular simulations, and allosteric communication analyses we reveal the role of C-tail phosphorylation on conformational dynamics and allosteric regulation of PTEN-ASD and PTEN-cancer phenotypes that exhibited the most exaggerated disease-specific effects in our pilot studies. We show that C-tail phosphorylation in PTEN-ASD induces fluctuations in degradation-sensitive sites (K13 and K289) that render a closed conformation. Furthermore, allosteric analysis reveals inter-domain effector residues that strengthen the structural communication pathway. In contrast, a higher intrinsic flexibility and less stable conformational state emerges in PTEN-cancer. Importantly, this reveals a less dense inter-domain structural communication pathway that lacks effector degradation-sensitive residues. Our integrative approach offers new insight into structurally correlated areas for potential drug targeting and will serve as the basis for designing novel therapeutics to attenuate PHTS-associated cancer and ASD phenotypes.

Lien vers le texte intégral (Open Access ou abonnement)

36. Uono S, Egashira Y, Hayashi S, Takada M, Ukezono M, Okada T. No Influence of Emotional Faces or Autistic Traits on Gaze-Cueing in General Population. Front Psychol;2022;13:864116.

The present study addressed the controversial issue of whether autistic traits in the general population are associated with the automatic and fundamental aspects of joint attention through eye gaze. Specifically, we examined whether the degree of autistic traits is associated with the magnitude of reflexive attention orienting in the direction of another’s eye gaze embedded in neutral and emotional (angry, fearful, and happy) faces. The cue stimuli changed gaze direction and facial expressions simultaneously. Participants were asked to detect a target that appeared at the left or right of the cue stimuli. The results revealed a robust gaze-cueing effect, such that the reaction time to the target was shorter under the gazed-at-target condition than under the non-gazed-at-target condition. However, emotional expressions did not modulate the gaze-cueing effect. Furthermore, individual differences in autistic traits and emotional characteristics (social anxiety, alexithymia, and emotional disturbances) did not influence the magnitude of the gaze-cueing effect. Although the ability to orient attention in the direction of another’s gaze is a fundamental function of social development, the gaze-cueing effect measured in a controlled experiment might not be an elaborate representation of the current social cognitive function, at least in typically developing adults.

Lien vers le texte intégral (Open Access ou abonnement)

37. Vail KJ, Patrick KL, Watson R, Fischer T. The Fragile X Syndrome-Related Protein, FMRP, Modulates Innate Immune Gene Expression in Macrophages. FASEB J;2022 (May);36 Suppl 1

Fragile X mental retardation protein (FMRP) is an RNA-binding protein with a wide range of functions, including mRNA translation, mRNA transport, and mitochondrial organization. Loss of FMRP due to silencing of the FRM1 gene is associated with intellectual disability and has been implicated in viral pathogenesis and cancer risk. However, the contribution of FMRP to innate immunity in response to bacterial infection remains understudied. Given the function of FMRP in post-transcriptional regulation, we hypothesized that loss of FMRP would impair repression of inflammatory cytokines in response to infection with the bacterial pathogen Listeria monocytogenes. We used RNA-seq as an unbiased approach to identify global gene expression changes in FMRP-deficient murine macrophages, both at rest and during infection with Listeria monocytogenes. We identified 22 differentially expressed genes that were upregulated in resting FMRP KO macrophages, including aconitate decarboxylase 1 (ACOD1, IRG1), erythroid differentiation regulator 1 (Erdr1), and Cxcl10, as well as 6 downregulated genes, including microRNA 6236 and mitochondrially encoded ATP synthase 8 (MT-ATP8). Unbiased canonical pathway analysis of the upregulated genes in resting FMRP KO macrophages revealed significant enrichment of genes related to phagosome maturation and immunity. Within the downregulated genes, unbiased canonical pathway analysis revealed pathways related to EIF2 signaling and BEX2 Signaling. Analysis of L. monocytogenes infected FMRP KO macrophages revealed 31 upregulated genes, including the E3 ubiquitin ligase gene midline 1 (Mid1, Trim18) and the complement genes C1QA and C1QB, as well as 8 downregulated genes including plasminogen activator urokinase (PLAU). Canonical pathway analysis of the downregulated genes included DNA-damage signaling and role of pattern recognition receptors in recognition of bacteria and viruses. Surprisingly, when comparing differentially enriched genes in infected macrophages to uninfected macrophages, a greater number of innate immune transcripts were upregulated in resting macrophages lacking FMRP. Together, these data suggest that FMRP may also have a role in innate immunity.

Lien vers le texte intégral (Open Access ou abonnement)

38. Vanderplow AM, Kermath BA, Bernhardt CR, Gums KT, Radcliff A, Baker TL, Watters JJ, Cahill ME. Maternal sleep disordered breathing during gestation produces sexually dimorphic autism-relevant synaptic and behavioral aberrations in the offspring associated with excessive mTOR cortical signaling. FASEB J;2022 (May);36 Suppl 1

Sleep disordered breathing (SDB) is characterized by recurring breathing cessations during sleep, causing intermittent hypoxia (oxygen deprivation) often several hundred times per night. Obstructive sleep apnea is the most common form of SDB in pregnancy, and confers risk for detrimental maternal-fetal outcomes. Although many of the maternal risk factors for the onset SDB during pregnancy and the development of autism spectrum disorders (ASD) in her offspring are highly overlapping (e.g., maternal obesity, advanced maternal age), no studies to date have empirically investigated the potential link between these conditions. We subjected pregnant rat dams to intermittent hypoxia or normoxia (GIH and GNX, respectively) from gestation day 10-21 to investigate the consequences of maternal SDB on offspring neural function. We found that male GIH offspring exhibited deficits in several behaviors which were accompanied by increased pyramidal neuron dendritic spine density in the medial prefrontal cortex (PFC). These effects appear to arise from a disruption of normal developmental synaptic pruning late in childhood and persisting into early adolescence. The mTOR kinase signal transduction pathway has emerged as a critical regulator of dendritic spine formation, and dysregulation of key components of this pathway are implicated in the etiology of the increased cortical dendritic spine density of ASD. Additionally, we found that mTOR is aberrantly activated in the prefrontal cortex of male GIH offspring. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduced behavioral abnormalities within GIH offspring. These findings suggest an opportunity for clinical intervention for offspring of the SDB maternal model by targeting the mTOR signaling pathway.

Lien vers le texte intégral (Open Access ou abonnement)

39. Wawer A, Chojnicka I. Detecting autism from picture book narratives using deep neural utterance embeddings. Int J Lang Commun Disord;2022 (May 12)

BACKGROUND: Deficits in the ability to use language in social contexts, including storytelling skills, are observed across the autism spectrum. Development in machine-learning approaches may contribute to clinical psychology and psychiatry, given its potential to support decisions concerning the diagnosis and treatment of psychiatric conditions and disorders. AIMS: To evaluate the usefulness of deep neural networks for detecting autism spectrum disorder (ASD) from textual utterances, specifically from narrations produced by individuals with ASD. METHODS & PROCEDURES: We examined two text encoders: Embeddings from Language Models (ELMo) and Universal Sentence Encoder (USE), and three classification algorithms: XGBoost, support vector machines, and dense neural network layer. We aimed to classify 25 participants with ASD and 25 participants with typical development (TD) based on their narrations produced during the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) picture book task. The results of computational approaches were compared with the results of standardized testing and classifications made by two psychiatrists (raters). The raters were asked to read utterances produced by a participant (without an examiner’s statements and additional information) and assign a participant to one of the two groups: ASD or with typical development (TD). OUTCOMES & RESULTS: The computer-based models had higher sensitivity, specificity, positive predictive values and negative predictive values than the raters, and lower than the two standardized instruments: ADOS-2 and Social Communication Questionnaire (SCQ). CONCLUSIONS & IMPLICATIONS: Our findings lay the groundwork for future studies involving deep neural network-based text representation models as tools for augmenting the ASD diagnosis or screening. Both ELMo and USE text encoders provided promising specificities, sensitivities, positive predictive values and negative predictive values. Our results indicate the usefulness of page-level embeddings for utterance representation in ADOS-2 picture book task. WHAT THIS PAPER ADDS: What is already known on this subject Deficits in the use of language in social contexts, and narrative ability in particular, are observed across the autism spectrum. Most research on narrative skills has applied hand-coding methods. Hitherto, machine-learning methods were used mostly for image recognition problems and data from screening questionnaires for ASD classification. Detection of mental and developmental disorders from textual input is an emerging field for machine and deep-learning methods. What this paper adds to existing knowledge This study explored the ability of several types of deep neural network-based text representation models to detect ASD. Both ELMo and USE provided the most promising values of specificity, sensitivity, positive predictive values and negative predictive values. What are the potential or actual clinical implications of this work? Competitive accuracy, repeatability, speed and ease of operation are all advantages of computerized methods. They allow for objective and quantitative assessment of narrative ability and complex language skills. Deep neural network-based text representation models could in the future support clinicians and augment the decision-making process related to ASD diagnosis, screening and intervention planning.

Lien vers le texte intégral (Open Access ou abonnement)

40. Whitaker-Fornek JR, Levitt ES. GABAergic and Glycinergic Synaptic Transmission in Respiratory-Controlling Kolliker-Fuse Neurons in Female and Male Rett Syndrome Mice. FASEB J;2022 (May);36 Suppl 1

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by severe motor behavior disturbances including breathing problems. RTT is caused by silencing mutations in the methyl-CpG binding protein 2 (MeCP2) gene located on the X chromosome. Accordingly, girls and women account for the majority of RTT patients. The genetic nature of RTT lends itself to study in mice with loss of function mutations in the MeCP2 gene. Importantly, RTT mice display breathing irregularities similar to human patients. Insufficient inhibitory neurotransmission in the brainstem respiratory network is thought to contribute to the breathing problems in RTT. In the pontine Kölliker-Fuse (KF) area of RTT mice, there are fewer GABAergic axon terminals and injection of a GABA reuptake antagonist alleviates breathing problems in vivo. However, no one has examined the physiology of GABA or glycine synapses in the KF of RTT mice. In the present work, we tested the hypothesis that GABAergic and glycinergic synapses are deficient in the KF of RTT mice. We performed whole-cell voltage clamp recordings from KF neurons contained in brain slices of MeCP2-deficient RTT mice and wild type littermates. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the KF neurons of male RTT mice was reduced compared to wild type (WT) littermates. In contrast, female RTT mice showed no change in sIPSC frequency in the KF compared to control, despite having breathing abnormalities. The amplitude of sIPSCs in the KF of female mice were smaller compared to WT littermates, whereas male RTT mice showed no change in amplitude compared to WT littermates. These results spotlight the importance of studying respiratory controlling KF neurons in both male and female RTT mice, and suggest that reductions in IPSC frequency and amplitude are not sufficient to explain the breathing irregularities observed in RTT in females and males, respectively.

Lien vers le texte intégral (Open Access ou abonnement)

41. Wilson NJ, Lin Z, Pithouse M, Morrison B, Sumar B, George A. Qualitative Insights from A Novel Staff-Led Oral Health Champions Program Within a Residential Service For People With Intellectual and Developmental Disability. J Intellect Disabil;2022 (May 12):17446295221095654.

The oral health of people with intellectual and developmental disability is poorer than that of the general community. Any solution for people with intellectual and developmental disability living in residential services needs to include disability support workers (DSWs). Previous studies have used either didactic or train-the-trainer approaches to enhance DSW knowledge and skills. Taking a different approach, a novel program used DSWs as embedded oral health champions. This model provided educational opportunities for DSWs to learn about good oral health and then share with peers and provide benefits to people with intellectual and developmental disability that they support. Interviews with a sample of these champions were conducted and analysed using content analysis. Findings suggest that DSWs are capable of affecting change with the right type and depth of training, management and organisational support. A DSW-led champions model has merit, however requires ongoing expert support to help maintain and sustain benefits over time.

Lien vers le texte intégral (Open Access ou abonnement)

42. Wolff N, Eberlein M, Stroth S, Poustka L, Roepke S, Kamp-Becker I, Roessner V. Corrigendum: Abilities and Disabilities-Applying Machine Learning to Disentangle the Role of Intelligence in Diagnosing Autism Spectrum Disorders. Front Psychiatry;2022;13:908350.

[This corrects the article DOI: 10.3389/fpsyt.2022.826043.].

Lien vers le texte intégral (Open Access ou abonnement)

43. Yurkovic-Harding J, Lisandrelli G, Shaffer RC, Dominick KC, Pedapati EV, Erickson CA, Yu C, Kennedy DP. Children with ASD establish joint attention during free-flowing toy play without face looks. Curr Biol;2022 (May 11)

Children’s ability to share attention with another person (i.e., achieve joint attention) is critical for learning about their environments in general(1-3) and supporting language and object word learning in particular.(1)(,)(4-14) While joint attention (JA) as it pertains to autism spectrum disorder (ASD) is often more narrowly operationalized as arising from eye gaze or explicit pointing cues alone,(2)(,)(5)(,)(10)(,)(15-19) recent evidence demonstrates that JA in natural environments can be achieved more broadly through multiple other pathways beyond gaze and gestures.(2)(,)(4)(,)(20-31) Here, we use dual head-mounted eye tracking to examine pathways into and characteristics of JA episodes during free-flowing parent-child toy play, comparing children with ASD to typically developing (TD) children. Moments of JA were defined objectively as both the child’s and parent’s gaze directed to the same object at the same time. Consistent with previous work in TD children,(4)(,)(21)(,)(25)(,)(30-32) we found that both TD and ASD children rarely look at their parent’s face in this unstructured free play context. Nevertheless, both groups achieved similarly high rates of JA that far exceeded chance, suggesting the use of alternative pathways into JA. We characterize these alternate pathways, find they occur at similar levels across both groups, and achieve similar ends: namely, for both groups, targets of JA are named more frequently by parents in those moments than non-jointly attended objects. These findings broaden the conceptualization of JA abilities and impairment in ASD and raise questions regarding the mechanistic role of the face-gaze-mediated JA pathway in ASD.

Lien vers le texte intégral (Open Access ou abonnement)

44. Zhang A, Sokolova I, Domissy A, Davis J, Rao L, Hana Utami K, Wang Y, Hagerman RJ, Pouladi MA, Sanna P, Boland MJ, Loring JF. Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells. Stem Cells Transl Med;2022 (May 12)

Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by expansion of a CGG trinucleotide repeat in the 5′-UTR of the Fragile X Mental Retardation-1 (FMR1) gene. Epigenetic silencing of FMR1 results in loss of the Fragile X Mental Retardation Protein (FMRP). Although most studies to date have focused on excitatory neurons, recent evidence suggests that GABAergic inhibitory networks are also affected. To investigate human GABAergic neurogenesis, we established a method to reproducibly derive inhibitory neurons from multiple FXS and control human pluripotent stem cell (hPSC) lines. Electrophysiological analyses suggested that the developing FXS neurons had a delay in the GABA functional switch, a transition in fetal development that converts the GABAA channel’s function from depolarization to hyperpolarization, with profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14 400 single-cell transcriptomes from FXS and control cells at 2 stages of GABAergic neurogenesis. While control and FXS cells were similar at the earlier time point, the later-stage FXS cells retained expression of neuroblast proliferation-associated genes and had lower levels of genes associated with action potential regulation, synapses, and mitochondria compared with controls. Our analysis suggests that loss of FMRP prolongs the proliferative stage of progenitors, which may result in more neurons remaining immature during the later stages of neurogenesis. This could have profound implications for homeostatic excitatory-inhibitory circuit development in FXS, and suggests a novel direction for understanding disease mechanisms that may help to guide therapeutic interventions.

Lien vers le texte intégral (Open Access ou abonnement)