1. Green J, Aldred C, Charman T, Le Couteur A, Emsley RA, Grahame V, Howlin P, Humphrey N, Leadbitter K, McConachie H, Parr JR, Pickles A, Slonims V, Taylor C. {{Paediatric Autism Communication Therapy-Generalised (PACT-G) against treatment as usual for reducing symptom severity in young children with autism spectrum disorder: study protocol for a randomised controlled trial}}. {Trials}. 2018; 19(1): 514.
BACKGROUND: Prior evidence shows that behaviours closely related to the intervention delivered for autism are amenable to change, but it is more difficult to generalise treatment effects beyond the intervention context. We test an early autism intervention designed to promote generalisation of therapy-acquired skills into home and school contexts to improve adaptive function and reduce symptoms. A detailed mechanism study will address the process of such generalisation. Objective 1 will be to test if the PACT-G intervention improves autism symptom outcome in the home and school context of the intervention as well as in the primary outcome research setting. Objective 2 will use the mechanism analysis to test for evidence of acquired skills from intervention generalizing across contexts and producing additive effects on primary outcome. METHODS/DESIGN: This is a three-site, two-parallel-group, randomised controlled trial of the experimental treatment plus treatment as usual (TAU) versus TAU alone. Children aged 2-11 years (n = 244 (122 intervention/122 TAU; ~ 82/site) meeting criteria for core autism will be eligible. The experimental intervention builds on a clinic-based Pre-school Autism Communication Treatment model (PACT), delivered with the primary caregiver, combined with additional theory- and evidence-based strategies designed to enhance the generalisation of effects into naturalistic home and education contexts. The control intervention will be TAU. PRIMARY OUTCOME: autism symptom outcome, researcher-assessed using a standardised protocol. SECONDARY OUTCOMES: autism symptoms, child interaction with parent or teacher, language and reported functional outcomes in home and school settings. Outcomes measured at baseline and 12-month endpoint in all settings with interim interaction measurements (7 months) to test treatment effect mechanisms. Primary analysis will estimate between-group difference in primary outcome using analysis of covariance with test of homogeneity of effect across age group. Mechanism analysis will use regression models to test for mediation on primary outcome by parent-child and teaching staff-child social interaction. DISCUSSION: This is an efficacy and mechanism trial of generalising evidence-based autism treatment into home and school settings. It will provide data on whether extending treatment across naturalistic contexts enhances overall effect and data on the mechanism in autism development of the generalisation of acquired developmental skills across contexts. TRIAL REGISTRATION: ISRCTN, ID: 25378536 . Prospectively registered on 9 March 2016.
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2. O’Keefe JA, Robertson EE, Ouyang B, Carns D, McAsey A, Liu Y, Swanson M, Bernard B, Berry-Kravis E, Hall DA. {{Cognitive function impacts gait, functional mobility and falls in fragile X-associated tremor/ataxia syndrome}}. {Gait & posture}. 2018; 66: 288-93.
BACKGROUND: Executive function and information processing speed deficits occur in fragile X premutation carriers (PMC) with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Gait is negatively impacted by cognitive deficits in many patient populations resulting in increased morbidity and falls but these relationships have not been studied in FXTAS. RESEARCH QUESTION: We sought to investigate the associations between executive function and information processing speed and gait, turning and falls in PMC with and without FXTAS compared to healthy controls. METHODS: Global cognition and the cognitive domains of information processing speed, attention, response inhibition, working memory and verbal fluency were tested with a neuropsychological test battery in 18 PMC with FXTAS, 15 PMC without FXTAS, and 27 controls. An inertial sensor based instrumented Timed Up and Go was employed to test gait, turns and functional mobility. RESULTS: Lower information processing speed was significantly associated with shorter stride length, reflecting slower gait speed, in PMC with FXTAS (p = 0.0006) but not PMC without FXTAS or controls. Lower response inhibition was also significantly associated with slower turn-to-sit times in PMC with FXTAS (p = 0.034) but not in those without FXTAS or controls. Lower information processing speed (p = 0.012) and working memory (p = 0.004), were significantly correlated with a greater number of self-reported falls in the past year in FXTAS participants. SIGNIFICANCE: This is the first study demonstrating that worse executive function and slower information processing speed is associated with reduced gait speed and functional mobility, as well as with a higher retrospective fall history in participants with FXTAS. This information may be important in the design of cognitive and motor interventions for this neurodegenerative disorder.
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3. Olusanya BO, de Vries PJ. {{Nurturing care for children with developmental disabilities: a moral imperative for sub-Saharan Africa}}. {The Lancet Child & adolescent health}. 2018.
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4. Pujol CN, Pellissier LP, Clement C, Becker JAJ, Le Merrer J. {{Back-translating behavioral intervention for autism spectrum disorders to mice with blunted reward restores social abilities}}. {Translational psychiatry}. 2018; 8(1): 197.
The mu opioid receptor (MOR) plays a critical role in modulating social behavior in humans and animals. Accordingly, MOR null mice display severe alterations in their social repertoire as well as multiple other behavioral deficits, recapitulating core and secondary symptoms of autism spectrum disorder (ASD). Such behavioral profile suggests that MOR dysfunction, and beyond this, altered reward processes may contribute to ASD etiopathology. Interestingly, the only treatments that proved efficacy in relieving core symptoms of ASD, early behavioral intervention programs, rely principally on positive reinforcement to ameliorate behavior. The neurobiological underpinnings of their beneficial effects, however, remain poorly understood. Here we back-translated applied behavior analysis (ABA)-based behavioral interventions to mice lacking the MOR (Oprm1(-/-)), as a model of autism with blunted reward processing. By associating a positive reinforcement, palatable food reward, to daily encounter with a wild-type congener, we were able to rescue durably social interaction and preference in Oprm1(-/-) mice. Along with behavioral improvements, the expression of marker genes of neuronal activity and plasticity as well as genes of the oxytocin/vasopressin system were remarkably normalized in the reward/social circuitry. Our study provides further evidence for a critical involvement of reward processes in driving social behavior and opens new perspectives regarding therapeutic intervention in ASD.
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5. Vahabzadeh A, Keshav NU, Abdus-Sabur R, Huey K, Liu R, Sahin NT. {{Improved Socio-Emotional and Behavioral Functioning in Students with Autism Following School-Based Smartglasses Intervention: Multi-Stage Feasibility and Controlled Efficacy Study}}. {Behavioral sciences (Basel, Switzerland)}. 2018; 8(10).
Background: Students with Autism Spectrum Disorder (ASD) commonly demonstrate prominent social communication deficits, symptoms of attention-deficit/hyperactivity disorder, and chronic irritability. These challenges hinder academic progress and frequently persist despite educational, behavioral, and medical interventions. An assistive smartglasses technology may aid these individuals, especially if the technology is efficacious in ecologically-valid school settings. This study explored the feasibility and efficacy of Empowered Brain, a computerized smartglasses intervention designed as a socio-emotional behavioral aid for students with ASD. Methods: This two-part six-week study involved four school children with ASD from a public elementary school. The study incorporated an initial three-week feasibility stage followed by a three-week controlled longitudinal efficacy stage. Both stages involved the use of a twice-daily socio-emotional intervention with the smartglasses. Educators completed pre-intervention and post-intervention Aberrant Behavioral Checklist (ABC) ratings at the start of the feasibility stage, and weekly during the efficacy stage. Primary outcome measures were improvements in the ABC subscales of irritability, hyperactivity, and social withdrawal. Results: Students in both feasibility and efficacy stages demonstrated improvements (decreases) in irritability, hyperactivity, and social withdrawal compared to a baseline period and control periods, respectively. Participants in the controlled efficacy stage demonstrated decreased ABC subscale scores of 90% for irritability, 41.6% for hyperactivity, and 45.6% for social withdrawal. An intervention exposure-response improvement in irritability and hyperactivity was found during the efficacy stage. Educators rated the technology as superior or vastly superior compared to other assistive technologies. Conclusion: A substantial number of school children with ASD demonstrate chronic and impairing cognitive and behavioral challenges. This study provides evidence that Empowered Brain, a smartglasses-based socio-emotional aid for autism, is both feasible and efficacious in improving symptoms of social withdrawal, irritability, and hyperactivity in students with autism. The improvement is demonstrated as part of a longitudinal school-based intervention. Further studies involving larger samples and incorporation of randomized controlled trial methodology are underway to further elucidate the impact of this technology.
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6. Yan J, Porch MW, Court-Vazquez B, Bennett MVL, Zukin RS. {{Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice}}. {Proceedings of the National Academy of Sciences of the United States of America}. 2018.
Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (Fmr1-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway. However, a role for autophagy in the pathophysiology of FXS is, as yet, unclear. Here we show that autophagic flux, a functional readout of autophagy, and biochemical markers of autophagy are down-regulated in hippocampal neurons of fragile X mice. We further show that enhanced activity of mammalian target of rapamycin complex 1 (mTORC1) and translocation of Raptor, a defining component of mTORC1, to the lysosome are causally related to reduced autophagy. Activation of autophagy by delivery of shRNA to Raptor directly into the CA1 of living mice via the lentivirus expression system largely corrects aberrant spine structure, synaptic plasticity, and cognition in fragile X mice. Postsynaptic density protein (PSD-95) and activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), proteins implicated in spine structure and synaptic plasticity, respectively, are elevated in neurons lacking fragile X mental retardation protein. Activation of autophagy corrects PSD-95 and Arc abundance, identifying a potential mechanism by which impaired autophagy is causally related to the fragile X phenotype and revealing a previously unappreciated role for autophagy in the synaptic and cognitive deficits associated with fragile X syndrome.
