1. Balakrishnan S, Mironov SL. {{Regenerative glutamate release in the hippocampus of Rett syndrome model mice}}. {PloS one}. 2018; 13(9): e0202802.
Excess glutamate during intense neuronal activity is not instantly cleared and may accumulate in the extracellular space. This has various long-term consequences such as ectopic signaling, modulation of synaptic efficacy and excitotoxicity; the latter implicated in various neurodevelopmental and neurodegenerative diseases. In this study, the quantitative imaging of glutamate homeostasis of hippocampal slices from methyl-CpG binding protein 2 knock-out (Mecp2-/y) mice, a model of Rett syndrome (RTT), revealed unusual repetitive glutamate transients. They appeared in phase with bursts of action potentials in the CA1 neurons. Both glutamate transients and bursting activity were suppressed by the blockade of sodium, AMPA and voltage-gated calcium channels (T- and R-type), and enhanced after the inhibition of HCN channels. HCN and calcium channels in RTT and wild-type (WT) CA1 neurons displayed different voltage-dependencies and kinetics. Both channels modulated postsynaptic integration and modified the pattern of glutamate spikes in the RTT hippocampus. Spontaneous glutamate transients were much less abundant in the WT preparations, and, when observed, had smaller amplitude and frequency. The basal ambient glutamate levels in RTT were higher and transient glutamate increases (spontaneous and evoked by stimulation of Schaffer collaterals) decayed slower. Both features indicate less efficient glutamate uptake in RTT. To explain the generation of repetitive glutamate spikes, we designed a novel model of glutamate-induced glutamate release. The simulations correctly predicted the patterns of spontaneous glutamate spikes observed under different experimental conditions. We propose that pervasive spontaneous glutamate release is a hallmark of Mecp2-/y hippocampus, stemming from and modulating the hyperexcitability of neurons.
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2. Chen H, Uddin LQ, Guo X, Wang J, Wang R, Wang X, Duan X, Chen H. {{Parsing brain structural heterogeneity in males with autism spectrum disorder reveals distinct clinical subtypes}}. {Human brain mapping}. 2018.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable neuroanatomical heterogeneity. Thus, how and to what extent the brains of individuals with ASD differ from each other is still unclear. In this study, brain structural MRI data from 356 right-handed, male subjects with ASD and 403 right-handed male healthy controls were selected from the Autism Brain Image Data Exchange database (age range 5-35 years old). Voxel-based morphometry preprocessing steps were conducted to compute the gray matter volume maps for each subject. Individual neuroanatomical difference patterns for each ASD individual were calculated. A data-driven clustering method was next utilized to stratify individuals with ASD into several subtypes. Whole-brain functional connectivity and clinical severity were compared among individuals within the ASD subtypes identified. A searchlight analysis was applied to determine whether subtyping ASD could improve the classification accuracy between ASD and healthy controls. Three ASD subtypes with distinct neuroanatomical difference patterns were revealed. Different degrees of clinical severity and atypical brain functional connectivity patterns were observed among these three subtypes. By dividing ASD into three subtypes, the classification accuracy between subjects of two out of the three subtypes and healthy controls was improved. The current study confirms that ASD is not a disorder with a uniform neuroanatomical signature. Understanding neuroanatomical heterogeneity in ASD could help to explain divergent patterns of clinical severity and outcomes.
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3. Collette D, Brix A, Brennan P, DeRoma N, Muir BC. {{Proloquo2Go Enhances Classroom Performance in Children With Autism Spectrum Disorder}}. {OTJR : occupation, participation and health}. 2018: 1539449218799451.
Independent participation in academic settings is decreased for children who have limited speech and are diagnosed with autism spectrum disorder (ASD). The use of technology with children with ASD changes behavior, assists with making choices, and increases communication; however, no studies evaluated its impact on performance or required support in classroom activities. The objective of this study was to determine whether an iPad with Proloquo2Go would increase independent activity/task performance and reduce required support for children with ASD, during classroom activities compared with no and other forms of technology (i.e., picture exchange communication system [PECS], SMARTBoard). The study compared the use of Proloquo2Go on the iPad to alternative technologies for performance in classroom activities in four children diagnosed with ASD. Using Proloquo2Go to respond to academic opportunities, children required less support than when using no technology, and equal support to when using a PECS or SMARTBoard. Proloquo2Go on the iPad can enhance academic occupational performance in adding voice output and a variety of response choices.
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4. Demetriou EA, Song CY, Park SH, Pepper KL, Naismith SL, Hermens DF, Hickie IB, Thomas EE, Norton A, White D, Guastella AJ. {{Autism, Early Psychosis, and Social Anxiety Disorder: a transdiagnostic examination of executive function cognitive circuitry and contribution to disability}}. {Translational psychiatry}. 2018; 8(1): 200.
The disability burden in clinical cohorts with social impairment is significant, leading to poor functional outcomes. Some of this impairment has been linked to executive dysfunction. In this study, a transdiagnostic approach was taken to identify executive function (EF) processes in young adults that may underpin social impairment and to evaluate their contribution to disability. Comparisons were made between three prominent disorders that are characterized by social impairments, Autism Spectrum Disorder (ASD), Early Psychosis (EP) and Social Anxiety Disorder (SAD), as well as a neurotypically developing group (TYP). We examined whether overall disability could be predicted by neuropsychological and self-report assessments of EF. Our study showed that ASD participants demonstrated impaired performance on most domains of EF compared to the TYP group (mental flexibility, sustained attention and fluency) while the EP group showed impairment on sustained attention and attentional shifting. The SAD participants showed EF impairment on self-report ratings, even though their objective performance was intact. Self-reports of EF explained a significant percentage (17%) of disability in addition to the variance explained by other predictors, and this was particularly important for ASD. This is the first study to compare EF measures across clinical groups of social impairment and suggests unique cognitive-circuitry that underpins disability within groups. Impairments in EF were broad in ASD and predicted disability, EP impairments were specific to attentional processes and SAD impairments likely relate to negative self-monitoring. Self-report, as opposed to performance-based EF, provided best capacity to predict disability. These findings contribute to transdiagnostic circuitry models and intervention strategies.
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5. Garcia-Villamisar D, Moore D, Garcia-Martinez M. {{Internalizing Symptoms Mediate the Relation Between Acute Pain and Autism in Adults}}. {Journal of autism and developmental disorders}. 2018.
Research on pain in autism spectrum disorder (ASD) is in its infancy, with almost nothing known about how individual differences may predicting pain response in ASD. In the present study, 45 adults (28 male, age 22-48 years) with diagnoses of autism and intellectual delay were observed during vaccination or dental cleaning and their pain behaviours coded and measures of autism symptom severity, anxiety, depression and obsessivity taken. Our findings showed that greater autism severity predicted greater pain response which was partially mediated by anxiety and depression. These data suggest that mental health symptoms are important when considering pain response in autism. Mood must therefore be considered in future research on pain in ASD as well as clinical pain management.
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6. Goel A, Cantu DA, Guilfoyle J, Chaudhari GR, Newadkar A, Todisco B, de Alba D, Kourdougli N, Schmitt LM, Pedapati E, Erickson CA, Portera-Cailliau C. {{Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible}}. {Nature neuroscience}. 2018; 21(10): 1404-11.
To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1(-/-)) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1(-/-) mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1(-/-) mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1(-/-) mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome.
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7. Grossard C, Palestra G, Xavier J, Chetouani M, Grynszpan O, Cohen D. {{ICT and autism care: state of the art}}. {Current opinion in psychiatry}. 2018; 31(6): 474-83.
PURPOSE OF REVIEW: Over the past 10 years, the use of information and communication technologies (ICTs) has increased in regard to the treatment of individuals with autism spectrum disorders (ASDs). ICT support mechanisms (e.g. computers, laptops, robots) are particularly attractive and are adapted to children with ASD. In addition, ICT algorithms can offer new perspectives for clinicians, outside direct apps or gaming proposals. Here, we will focus on the use of serious games and robots because of their attractiveness and their value in working on social skills. RECENT FINDINGS: The latest knowledge regarding the use of ICT in the forms of serious games and robotics applied to individuals with ASD shows that the field of serious games has already achieved interesting and promising results, although the clinical validations are not always complete. In the field of robotics, there are still many limitations on the use of ICT (e.g. most interaction are similar to the wizard of Oz), and questions remain concerning their eventual effectiveness. SUMMARY: To describe the implications of the findings for clinical practice or research, we describe two large projects, namely, JEMImE and Michelangelo, as examples of current studies that are aimed at enhancing social skills in children with ASD by including novel algorithms with clinical insights in robots or serious games.
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8. Hughes HK, Rose D, Ashwood P. {{The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders}}. {Current neurology and neuroscience reports}. 2018; 18(11): 81.
PURPOSE OF REVIEW: There is a growing body of evidence indicating the gut microbiota influence neurodevelopment and behavior. The purposes of this review are to provide an overview of studies analyzing the microbiota and their metabolites in autism spectrum disorders (ASD) and to discuss the possible mechanisms of action involved in microbial influence on the brain and behavior. RECENT FINDINGS: The microbiota-gut-brain (MGB) axis has been extensively studied in animal models, and it is clear that alterations in the composition of microbiota alter neurological and behavioral outcomes. However, findings in human studies are less abundant. Although there are several studies so far showing altered microbiota (dysbiosis) in ASD, the results are heterogeneous and often contradictory. Intervention studies such as fecal microbiota transplant therapies show promise and lend credence to the involvement of the microbiota in ASD. A role for the microbiota in ASD is likely; however, further studies elucidating microbial or metabolomic signatures and mechanisms of action are needed. Future research should focus on intervention studies that can identify specific metabolites and immune mediators that improve with treatment to help identify etiologies and pathological mechanisms of ASD.
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9. Kamen CL, Zevy DL, Ward JM, Bishnoi IR, Kavaliers M, Ossenkopp KP. {{Systemic Treatment with the Enteric Bacterial Fermentation Product, Propionic Acid, Reduces Acoustic Startle Response Magnitude in Rats in a Dose-Dependent Fashion: Contribution to a Rodent Model of ASD}}. {Neurotoxicity research}. 2018.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by cognitive and sensorimotor deficits, among others. Hypo-sensitivity and hyper-sensitivity to different stimuli within the same sensory modality, a prominent symptom of ASD, can be assessed by acoustic startle response (ASR) and prepulse inhibition (PPI). Propionic acid (PPA) is a short-chain fatty acid and a by-product of the human gut microbiome. Rodents treated with PPA has been found to produce ASD-related behavioral abnormalities, gastrointestinal discomfort, and conditioned aversions. The present study examined ASR and PPI in adult male rats treated systemically (intraperitoneal injections) with two different doses of PPA. A single injection of PPA produced significant dose-dependent reductions in startle response magnitude relative to control rats. However, PPA-treated rats did not show significant sensorimotor gating abnormalities relative to controls, based on the PPI measures. These findings add to the growing body of evidence supporting the validity of the PPA rodent model of ASD.
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10. Morello N, Schina R, Pilotto F, Phillips M, Melani R, Plicato O, Pizzorusso T, Pozzo-Miller L, Giustetto M. {{Loss of Mecp2 Causes Atypical Synaptic and Molecular Plasticity of Parvalbumin-Expressing Interneurons Reflecting Rett Syndrome-Like Sensorimotor Defects}}. {eNeuro}. 2018; 5(5).
Rett syndrome (RTT) is caused in most cases by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2). Understanding the pathological processes impacting sensory-motor control represents a major challenge for clinical management of individuals affected by RTT, but the underlying molecular and neuronal modifications remain unclear. We find that symptomatic male Mecp2 knockout (KO) mice show atypically elevated parvalbumin (PV) expression in both somatosensory (S1) and motor (M1) cortices together with excessive excitatory inputs converging onto PV-expressing interneurons (INs). In accordance, high-speed voltage-sensitive dye imaging shows reduced amplitude and spatial spread of synaptically induced neuronal depolarizations in S1 of Mecp2 KO mice. Moreover, motor learning-dependent changes of PV expression and structural synaptic plasticity typically occurring on PV(+) INs in M1 are impaired in symptomatic Mecp2 KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female Mecp2 heterozygous mice. These results indicate that in Mecp2 mutant mice the configuration of PV(+) INs network is shifted toward an atypical plasticity state in relevant cortical areas compatible with the sensory-motor dysfunctions characteristics of RTT.
