Browsing by Subject "Autism spectrum disorders"
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Item A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder(Springer Nature, 2022) McDougle, Christopher J.; Thom, Robyn P.; Ravichandran, Caitlin T.; Palumbo, Michelle L.; Politte, Laura C.; Mullett, Jennifer E.; Keary, Christopher J.; Erickson, Craig A.; Stigler, Kimberly A.; Mathieu-Frasier, Lauren; Posey, David J.; Psychiatry, School of MedicineThis study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Item Autism Spectrum Disorders: Wading through the controversies on the web(Taylor & Francis, 2009) Coates, Heather L.Autism is one of three developmental disorders in the group known as the autism spectrum disorders (ASDs). This spectrum of disorders has an estimated prevalence of one in 150 children. Increased awareness and diagnosis has led to an explosion of information available about the disorder. This explosion has made scientific research more readily available, along with inaccurate and spurious information. Autism is a disorder without a known cause or cure and few treatments with sufficient evidence to indicate effectiveness. Due to the variable presentation of autism, there is no single intervention that is effective for all individuals. The complexity of the disorder is addressed by research and practice across several disciplines, including education, psychology, psychiatry, neurology, genetics, and internal medicine. This resource guide will introduce the range of autism spectrum disorders, its various perspectives and treatments, and will point librarians and patrons to introductory resources to provide links for further learning.Item Autism: the micro-movement perspective(Frontiers Media, 2013-07-24) Torres, Elizabeth B.; Brincker, Maria; Isenhower, Robert W.; Yanovich, Polina; Stigler, Kimberly A.; Nurnberger, John I.; Metaxas, Dimitris N.; José, Jorge V.; Neurology, School of MedicineThe current assessment of behaviors in the inventories to diagnose autism spectrum disorders (ASD) focus on observation and discrete categorizations. Behaviors require movements, yet measurements of physical movements are seldom included. Their inclusion however, could provide an objective characterization of behavior to help unveil interactions between the peripheral and the central nervous systems (CNSs). Such interactions are critical for the development and maintenance of spontaneous autonomy, self-regulation, and voluntary control. At present, current approaches cannot deal with the heterogeneous, dynamic and stochastic nature of development. Accordingly, they leave no avenues for real time or longitudinal assessments of change in a coping system continuously adapting and developing compensatory mechanisms. We offer a new unifying statistical framework to reveal re-afferent kinesthetic features of the individual with ASD. The new methodology is based on the non-stationary stochastic patterns of minute fluctuations (micro-movements) inherent to our natural actions. Such patterns of behavioral variability provide re-entrant sensory feedback contributing to the autonomous regulation and coordination of the motor output. From an early age, this feedback supports centrally driven volitional control and fluid, flexible transitions between intentional and spontaneous behaviors. We show that in ASD there is a disruption in the maturation of this form of proprioception. Despite this disturbance, each individual has unique adaptive compensatory capabilities that we can unveil and exploit to evoke faster and more accurate decisions. Measuring the kinesthetic re-afference in tandem with stimuli variations we can detect changes in their micro-movements indicative of a more predictive and reliable kinesthetic percept. Our methods address the heterogeneity of ASD with a personalized approach grounded in the inherent sensory-motor abilities that the individual has already developed.Item A Biomarker Characterizing Neurodevelopment with applications in Autism(Nature Publishing Group, 2018-01-12) Wu, Di; José, Jorge V.; Nurnberger, John I., Jr.; Torres, Elizabeth B.; Medicine, School of MedicineDespite great advances in neuroscience and genetic studies, our understanding of neurodevelopmental disorders is still quite limited. An important reason is not having objective psychiatric clinical tests. Here we propose a quantitative neurodevelopment assessment by studying natural movement outputs. Movement is central to behaviors: It involves complex coordination, temporal alterations, and precise dynamic controls. We carefully analyzed the continuous movement output data, collected with high definition electromagnetic sensors at millisecond time scales. We unraveled new metrics containing striking physiological information that was unseen neither by using traditional motion assessments nor by naked eye observations. Our putative biomarker leads to precise individualized classifications. It illustrates clear differences between Autism Spectrum Disorder (ASD) subjects from mature typical developing (TD) individuals. It provides an ASD complementary quantitative classification, which closely agrees with the clinicaly assessed functioning levels in the spectrum. It also illustrates TD potential age-related neurodevelopmental trajectories. Applying our movement biomarker to the parents of the ASD individuals studied in the cohort also shows a novel potential familial signature ASD tie. This paper proposes a putative behavioral biomarker to characterize the level of neurodevelopment with high predicting power, as illustrated in ASD subjects as an example.Item Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition(Springer Nature, 2023) Palmer, Elizabeth E.; Pusch, Michael; Picollo, Alessandra; Forwood, Caitlin; Nguyen, Matthew H.; Suckow, Vanessa; Gibbons, Jessica; Hoff, Alva; Sigfrid, Lisa; Megarbane, Andre; Nizon, Mathilde; Cogné, Benjamin; Beneteau, Claire; Alkuraya, Fowzan S.; Chedrawi, Aziza; Hashem, Mais O.; Stamberger, Hannah; Weckhuysen, Sarah; Vanlander, Arnaud; Ceulemans, Berten; Rajagopalan, Sulekha; Nunn, Kenneth; Arpin, Stéphanie; Raynaud, Martine; Motter, Constance S.; Ward-Melver, Catherine; Janssens, Katrien; Meuwissen, Marije; Beysen, Diane; Dikow, Nicola; Grimmel, Mona; Haack, Tobias B.; Clement, Emma; McTague, Amy; Hunt, David; Townshend, Sharron; Ward, Michelle; Richards, Linda J.; Simons, Cas; Costain, Gregory; Dupuis, Lucie; Mendoza-Londono, Roberto; Dudding-Byth, Tracy; Boyle, Jackie; Saunders, Carol; Fleming, Emily; El Chehadeh, Salima; Spitz, Marie-Aude; Piton, Amelie; Gerard, Bénédicte; Warde, Marie-Thérèse Abi; Rea, Gillian; McKenna, Caoimhe; Douzgou, Sofia; Banka, Siddharth; Akman, Cigdem; Bain, Jennifer M.; Sands, Tristan T.; Wilson, Golder N.; Silvertooth, Erin J.; Miller, Lauren; Lederer, Damien; Sachdev, Rani; Macintosh, Rebecca; Monestier, Olivier; Karadurmus, Deniz; Collins, Felicity; Carter, Melissa; Rohena, Luis; Willemsen, Marjolein H.; Ockeloen, Charlotte W.; Pfundt, Rolph; Kroft, Sanne D.; Field, Michael; Laranjeira, Francisco E. R.; Fortuna, Ana M.; Soares, Ana R.; Michaud, Vincent; Naudion, Sophie; Golla, Sailaja; Weaver, David D.; Bird, Lynne M.; Friedman, Jennifer; Clowes, Virginia; Joss, Shelagh; Pölsler, Laura; Campeau, Philippe M.; Blazo, Maria; Bijlsma, Emilia K.; Rosenfeld, Jill A.; Beetz, Christian; Powis, Zöe; McWalter, Kirsty; Brandt, Tracy; Torti, Erin; Mathot, Mikaël; Mohammad, Shekeeb S.; Armstrong, Ruth; Kalscheuer, Vera M.; Medical and Molecular Genetics, School of MedicineMissense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.Item Multi-level analysis of the gut–brain axis shows autism spectrum disorder-associated molecular and microbial profiles(Springer Nature, 2023) Morton, James T.; Jin, Dong-Min; Mills, Robert H.; Shao, Yan; Rahman, Gibraan; McDonald, Daniel; Zhu, Qiyun; Balaban, Metin; Jiang, Yueyu; Cantrell, Kalen; Gonzalez, Antonio; Carmel, Julie; Frankiensztajn, Linoy Mia; Martin-Brevet, Sandra; Berding, Kirsten; Needham, Brittany D.; Zurita, María Fernanda; David, Maude; Averina, Olga V.; Kovtun, Alexey S.; Noto, Antonio; Mussap, Michele; Wang, Mingbang; Frank, Daniel N.; Li, Ellen; Zhou, Wenhao; Fanos, Vassilios; Danilenko, Valery N.; Wall, Dennis P.; Cárdenas, Paúl; Baldeón, Manuel E.; Jacquemont, Sébastien; Koren, Omry; Elliott, Evan; Xavier, Ramnik J.; Mazmanian, Sarkis K.; Knight, Rob; Gilbert, Jack A.; Donovan, Sharon M.; Lawley, Trevor D.; Carpenter, Bob; Bonneau, Richard; Taroncher-Oldenburg, Gaspar; Anatomy, Cell Biology and Physiology, School of MedicineAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut–brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.Item Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders(Springer Nature, 2014) McCracken, J. T.; Badashova, K. K.; Posey, D. J.; Aman, M. G.; Scahill, L; Tierney, E.; Arnold, L. E.; Vitiello, B.; Whelan, F.; Chuang, S. Z.; Davies, M.; Shah, B.; McDougle, C. J.; Nurmi, E. L.; Psychiatry, School of MedicineMethylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.Item Tele-assessment of young children referred for autism spectrum disorder evaluation during COVID-19: Associations among clinical characteristics and diagnostic outcome(Sage, 2023) McNally Keehn, Rebecca; Enneking, Brett; Ryan, Tybytha; James, Cristina; Tang, Qing; Blewitt, Audra; Tomlin, Angela; Corona, Laura; Wagner, Liliana; Pediatrics, School of MedicineThe diagnosis of autism spectrum disorder (ASD) has traditionally been made through in-person evaluation. While the COVID-19 pandemic disrupted access to ASD services, there has been remarkable growth in research focused on novel ASD diagnostic practices, including the use of telemedicine. We implemented a standard ASD tele-assessment evaluation procedure, including use of a novel remote clinician-coached, caregiver-delivered ASD assessment tool (TELE-ASD-PEDS; TAP), with the goal of continuing to provide diagnostic services to young children and their families during the pandemic. We examined the relationship between child characteristics and diagnostic outcome for 335 children, ages 14-78 months, who received ASD tele-assessment conducted by psychologists and pediatricians in an outpatient clinic of a Midwestern academic medical center. We found that clinicians could make a determination about ASD diagnosis for most children (85%) evaluated using tele-assessment. Child clinical characteristics, including TAP scores and clinician ratings of ASD symptoms, were related to diagnostic outcome (i.e. diagnosis of ASD, no ASD, and Unsure about ASD). When all clinical characteristics were examined together, the presence of specific repetitive behaviors predicted ASD diagnosis. We also found that the TAP is effective for making an ASD diagnosis when used as part of comprehensive tele-assessment evaluation in children ⩾ 36 months of age with delayed language. Our study adds to an increasing body of research supporting use of tele-assessment for diagnosis of ASD. Although further research is needed, telemedicine may help families from different backgrounds and geographic locations to access high-quality diagnostic services.Item The association between self-injurious behaviors and autism spectrum disorders(Dove Press, 2014-04-12) Minshawi, Noha F.; Hurwitz, Sarah; Fodstad, Jill C.; Biebl, Sara; Morriss, Danielle H.; McDougle, Christopher J.; Psychiatry, School of MedicineA key area of concern in children with autism spectrum disorders (ASDs) are self-injurious behaviors (SIBs). These are behaviors that an individual engages in that may cause physical harm, such as head banging, or self-biting. SIBs are more common in children with ASD than those who are typically developing or have other neurodevelopmental disabilities. Therefore, it is important that clinicians who work with children with ASD have a solid understanding of SIB. The purpose of this paper is to review the research on the epidemiology of SIB in children with ASD, factors that predict the presence of SIB in this population, and the empirically supported behavioral treatments available.