1. Carotenuto M, Roccella M, Pisani F, Matricardi S, Verrotti A, Farello G, Operto FF, Bitetti I, Precenzano F, Messina G, Ruberto M, Ciunfrini C, Riccardi M, Merolla E, Pastorino GMG, Polito AN, Marotta R. {{Polysomnographic Findings in Fragile X Syndrome Children with EEG Abnormalities}}. {Behav Neurol};2019;2019:5202808.
Fragile X syndrome (FXS) is a genetic syndrome with intellectual disability due to the loss of expression of the FMR1 gene located on chromosome X (Xq27.3). This mutation can suppress the fragile X mental retardation protein (FMRP) with an impact on synaptic functioning and neuronal plasticity. Among associated sign and symptoms of this genetic condition, sleep disturbances have been already described, but few polysomnographic reports in pediatric age have been reported. This multicenter case-control study is aimed at assessing the sleep macrostructure and at analyzing the presence of EEG abnormalities in a cohort of FXS children. We enrolled children with FXS and, as controls, children with typical development. All subjects underwent at least 1 overnight polysomnographic recording (PSG). All recorded data obtained from patients and controls were compared. In children with FXS, all PSG-recorded parameters resulted pathological values compared to those obtained from controls, and in FXS children only, we recorded interictal epileptiform discharges (IEDs), as diffuse or focal spikes and sharp waves, usually singles or in brief runs with intermittent or occasional incidence. A possible link between IEDs and alterations in the circadian sleep-wake cycle may suggest a common dysregulation of the balance between inhibitory and excitatory pathways in these patients. The alteration in sleep pattern in children with FXS may negatively impact the neuropsychological and behavioral functioning, adding increasing burn of the disease on the overall management of these patients. In this regard, treating physicians have to early detect sleep disturbances in their patients for tailored management, in order to prevent adjunctive comorbidities.
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2. Clouse JR, Wood-Nartker J, Rice FA. {{Designing Beyond the Americans With Disabilities Act (ADA): Creating an Autism-Friendly Vocational Center}}. {Herd};2019 (Dec 30):1937586719888502.
The Americans with Disabilities Act (ADA) has been effective in establishing building standards that create accessible spaces for people with physical impairments. These guidelines have not addressed the needs of people with mental, emotional, and/or developmental disabilities. With the increase in autism diagnosis, designers/architects need to expand their planning to include more universal solutions. The purpose is to demonstrate ways of designing beyond ADA to address needs of people with autism spectrum disorder (ASD). To design effectively, designers/architects must identify sensory issues that influence these children in establishing a regulatory state enabling effective interaction with neurotypical peers. Design is also important for teachers, therapists, and parents of children with ASD to enable more successful interactions. If the environment is overstimulating for a child with ASD, then a parent/caregiver/therapist will struggle to achieve their goals. Mostafa recommended seven design criteria known as ASPECTSS: Acoustics, Spatial sequencing, Escape spaces, Compartmentalization, Transition spaces, Sensory zoning, and Safety, when designing for people with ASD. These classifications lay the groundwork for the established guidelines. As designers/architects, we have a responsibility to create inclusive environments. To help, the authors highlighted a vocational center showing one plan that meets ADA guidelines and another that illustrates additional environmental features addressing the needs of people with ASD. These criteria originated from evidence-based solutions derived from a literature review and personal interview. These recommendations demonstrate that sensitivity to the needs of people with autism creates a solution that is better for all people.
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3. Despang P, Salamon S, Breitenkamp A, Kuzmenkina E, Herzig S, Matthes J. {{Autism-associated mutations in the CaVbeta2 calcium-channel subunit increase Ba(2+)-currents and lead to differential modulation by the RGK-protein Gem}}. {Neurobiol Dis};2019 (Dec 27):104721.
Voltage-gated calcium-channels (VGCCs) are heteromers consisting of several subunits. Mutations in the genes coding for VGCC subunits have been reported to be associated with autism spectrum disorder (ASD). In a previous study, we identified electrophysiologically relevant missense mutations of CaVbeta2 subunits of VGCCs. From this, we derived the hypothesis that several CaVbeta2-mutations associated with ASD show common features sensitizing LTCCs and/or enhancing currents. Using a CaVbeta2d backbone, we performed extensive whole-cell and single-channel patch-clamp analyses of Ba(2+) currents carried by Cav1.2 pore subunits co-transfected with the previously described CaVbeta2 mutations (G167S, S197F) as well as a recently identified point mutation (V2D). Furthermore, the interaction of the mutated CaVbeta2d subunits with the RGK protein Gem was analyzed by co-immunoprecipitation assays and electrophysiological studies. Patch-clamp analyses revealed that all mutations increase Ba(2+) currents, e.g. by decreasing inactivation or increasing fraction of active sweeps. All CaVbeta2 mutations interact with Gem, but differ in the extent and characteristics of modulation by this RGK protein (e.g. decrease of fraction of active sweeps: CaVbeta2d_G167S > CaVbeta2d_V2D > CaVbeta2d_S197F). In conclusion, patch-clamp recordings of ASD-associated CaVbeta2d mutations revealed differential modulation of Ba(2+) currents carried by CaV1.2 suggesting kind of an « electrophysiological fingerprint » each. The increase in current finally observed with all CaVbeta2d mutations analyzed might contribute to the complex pathophysiology of ASD and by this indicate a possible underlying molecular mechanism.
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4. Geramita MA, Wen JA, Rannals MD, Urban NN. {{Decreased amplitude and reliability of odor-evoked responses in two mouse models of autism}}. {J Neurophysiol};2019 (Dec 31)
Sensory processing deficits are increasingly recognized as core symptoms of autism spectrum disorders (ASDs). However the molecular and circuit mechanisms that lead to sensory deficits are unknown. Here we show that two molecularly disparate mouse models of autism display similar deficits in sensory-evoked responses in the mouse olfactory system. We find that both Cntnap2 and Shank3 deficient mice of both sexes exhibit reduced response amplitude and trial to trial reliability during repeated odor presentation. Mechanistically, we show that both mouse models have weaker and fewer synapses between olfactory sensory nerve (OSN) terminals and olfactory bulb tufted cells and weaker synapses between OSN terminals and inhibitory periglomerular cells. Consequently, deficits in sensory procesing provide an excellent candidate phenotype for analysis in ASDs.
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5. Klusek J, Hong J, Sterling A, Berry-Kravis E, Mailick MR. {{Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome}}. {Brain Cogn};2019 (Dec 27);139:105511.
Individuals who carry a premutation (PM) allele on the FMR1 gene may experience executive limitations associated with their genetic status, including inhibition deficits. However, poor understanding of individualized risk factors has limited clinical management of this group, particularly in mothers who carry the PM allele who have children with fragile X syndrome (FXS). The present study examined CGG repeat length and age as factors that may account for variable expressivity of inhibition deficits. Participants were 134 carriers of the PM allele who were mothers of children with FXS. Inhibition skills were measured using both self-report and direct behavioral assessments. Increased vulnerability for inhibition deficits was observed at mid-range CGG lengths of approximately 80-100 repeats, with some evidence of a second zone of vulnerability occurring at approximately 130-140 CGG repeats. Risk associated with the genotype also became more pronounced with older age. This study identifies personalized risk factors that may be used to tailor the clinical management of executive deficits in carriers of the PM allele. Inhibition deficits may contribute to poor outcomes in carriers of the PM allele and their families, particularly in midlife and early old age, and clinical monitoring may be warranted.
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6. Mash LE, Keehn B, Linke AC, Liu T, Helm JL, Haist F, Townsend J, Muller RA. {{Atypical relationships between spontaneous EEG and fMRI activity in autism}}. {Brain Connect};2019 (Dec 30)
Autism spectrum disorders (ASDs) have been linked to atypical communication among distributed brain networks. However, despite decades of research, the exact nature of differences between typically developing (TD) individuals and those with ASDs remains unclear. ASDs have been widely studied using resting state neuroimaging methods, including both functional MRI (fMRI) and electroencephalography (EEG). However, little is known about how fMRI and EEG measures of spontaneous brain activity are related in ASDs. In the current study, two cohorts of children and adolescents underwent resting-state EEG (n = 38 per group) or fMRI (n = 66 ASD, 57 TD), with a subset of individuals in both the EEG and fMRI cohorts (n = 17 per group). In the EEG cohort, occipito-parietal EEG alpha power was found to be reduced in ASDs. In the fMRI cohort, blood oxygen level-dependent (BOLD) power was regionally increased in right temporal regions and there was widespread overconnectivity between thalamus and cortical regions in the ASD group relative to the TD group. Finally, multimodal analyses found that while TD children showed consistently positive relationships between EEG alpha power and regional BOLD power, these associations were weak or negative in ASDs. These findings suggest atypical links between alpha rhythms and regional BOLD activity in ASDs, possibly implicating neural substrates and processes that coordinate thalamocortical regulation of the alpha rhythm.
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7. Mohrle D, Fernandez M, Penagarikano O, Frick A, Allman B, Schmid S. {{What we can learn from a genetic rodent model about autism}}. {Neurosci Biobehav Rev};2019 (Dec 27)
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are caused by genetic and/or environmental impacts, often probably by the interaction of both. They are characterised by deficits in social communication and interaction and by restricted and repetitive behaviours and interests from early childhood on, causing significant impairment. While it is clear that no animal model captures the full complexity of ASD in humans, genetic models are extremely useful for studying specific symptoms associated with ASD and the underlying cellular and molecular mechanisms. In this review we summarize the behavioral paradigms used in rodents to model ASD symptoms as they are listed in the DSM-5. We then review existing genetic rodent models with disruptions in ASD candidate genes, and we map their phenotypes onto these behavioural paradigms. The goal of this review is to give a comprehensive overview on how ASD symptoms can be studied in animal models and to give guidance for which animal models are appropriate to study specific symptom clusters.
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8. Nadeem A, Ahmad SF, Al-Ayadhi LY, Attia SM, Al-Harbi NO, Alzahrani KS, Bakheet SA. {{Differential regulation of Nrf2 is linked to elevated inflammation and nitrative stress in monocytes of children with autism}}. {Psychoneuroendocrinology};2019 (Dec 23);113:104554.
Autism spectrum disorder (ASD) is a very complex neurodevelopmental disorder characterized by deficits in social and communication skills. Innate immune cells like monocytes are believed to play a cardinal role in neuroimmune inflammation and nitrative stress. On the other hand, Nrf2, a basic leucine zipper transcription factor plays a significant role in protecting the immune cells against inflammation and oxidants. However, its role in monocytes of ASD children and typically developing control (TDC) children has not been elucidated in relation with inflammation and nitrative stress. Therefore, this study was undertaken to evaluate Nrf2 expression/activity along with parameters of inflammation (NFkB, IL-6, IL-1beta) and nitrative stress (iNOS, nitrotyrosine) in monocytes of ASD/TDC children. Further, sulforaphane (SFN) was utilized as an Nrf2 activator to assess its effect on above said inflammatory and nitrative stress parameters. Our study shows that monocytes of ASD subjects have decreased Nrf2 expression/activity along with increased inflammation and nitrative stress. Further, monocytes from ASD have deficiency in induction of Nrf2 activity upon stimulation with LPS. However, activation of Nrf2 in vitro by SFN reverses LPS-induced effects on inflammation in monocytes by reduction in NFkB signaling. Further, treatment with SFN also reverses LPS-induced effects on nitrative stress (iNOS, nitrotyrosine) in monocytes of ASD subjects. This study propounds the idea that SFN protects against nitrative stress and inflammation by downregulating oxidative stress and inflammation through blockade of NFkB signaling in autistic children. This may be the reason behind reported ameliorative effects of SFN in ASD subjects.
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9. Schauder KB, Park WJ, Tsank Y, Eckstein MP, Tadin D, Bennetto L. {{Initial eye gaze to faces and its functional consequence on face identification abilities in autism spectrum disorder}}. {J Neurodev Disord};2019 (Dec 28);11(1):42.
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined and diagnosed by core deficits in social communication and the presence of restricted and repetitive behaviors. Research on face processing suggests deficits in this domain in ASD but includes many mixed findings regarding the nature and extent of these differences. The first eye movement to a face has been shown to be highly informative and sufficient to achieve high performance in face identification in neurotypical adults. The current study focused on this critical moment shown to be essential in the process of face identification. METHODS: We applied an established eye-tracking and face identification paradigm to comprehensively characterize the initial eye movement to a face and test its functional consequence on face identification performance in adolescents with and without ASD (n = 21 per group), and in neurotypical adults. Specifically, we presented a series of faces and measured the landing location of the first saccade to each face, while simultaneously measuring their face identification abilities. Then, individuals were guided to look at specific locations on the face, and we measured how face identification performance varied as a function of that location. Adolescent participants also completed a more traditional measure of face identification which allowed us to more fully characterize face identification abilities in ASD. RESULTS: Our results indicate that the location of the initial look to faces and face identification performance for briefly presented faces are intact in ASD, ruling out the possibility that deficits in face perception, at least in adolescents with ASD, begin with the initial eye movement to the face. However, individuals with ASD showed impairments on the more traditional measure of face identification. CONCLUSION: Together, the observed dissociation between initial, rapid face perception processes, and other measures of face perception offers new insights and hypotheses related to the timing and perceptual complexity of face processing and how these specific aspects of face identification may be disrupted in ASD.
