Publications by authors named "Latha Soorya"

48 Publications

Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome.

Mol Autism 2021 04 28;12(1):29. Epub 2021 Apr 28.

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Background: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS.

Methods: Here, we analyze EEG data collected across multiple sites in individuals with PMS (n = 26) and typically developing individuals (n = 15). We quantify oscillatory power, alpha-gamma phase-amplitude coupling strength, and phase bias, a measure of the phase of cross frequency coupling thought to reflect the balance of feedforward (bottom-up) and feedback (top-down) activity.

Results: We find individuals with PMS display increased alpha-gamma phase bias (U = 3.841, p < 0.0005), predominantly over posterior electrodes. Most individuals with PMS demonstrate positive overall phase bias while most typically developing individuals demonstrate negative overall phase bias. Among individuals with PMS, strength of alpha-gamma phase-amplitude coupling was associated with Sameness, Ritualistic, and Compulsive behaviors as measured by the Repetitive Behavior Scales-Revised (Beta = 0.545, p = 0.011).

Conclusions: Increased phase bias suggests potential circuit-level mechanisms underlying phenotype in PMS, offering opportunities for back-translation of findings into animal models and targeting in clinical trials.
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http://dx.doi.org/10.1186/s13229-020-00411-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082621PMC
April 2021

Prerequisite Skills in Cognitive Testing: Innovations in theory and recommendations for practice.

Cogn Dev 2021 Apr-Jun;58. Epub 2021 Mar 25.

Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD.

Testing cognitive skill development is important for diagnostic, prognostic, and monitoring purposes, especially for young children and individuals with neurodevelopmental disorders. Developmental tests have been created for infants and toddlers, while traditional IQ tests are often employed beginning in the later preschool period. However, IQ tests rely on developmental skills that are rapidly changing during early childhood. Here, we introduce the idea of in developmental domains, which are discrete skills required for, but not explicitly tested by, traditional IQ tests. Focusing on general cognition, particularly among children with a chronological or mental age under 4 years, may fail to capture important nuances in skill development. New skill-based assessments are needed in general, and in particular for categorization, which is foundational to higher-order cognitive skills. Novel measures quantifying categorization skills would provide a more sensitive measure of development for young children and older individuals with low developmental levels.
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http://dx.doi.org/10.1016/j.cogdev.2021.101038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023649PMC
March 2021

The Autism Palette: Combinations of Impairments Explain the Heterogeneity in ASD.

Front Psychiatry 2020 2;11:503462. Epub 2020 Dec 2.

Department of Artificial Intelligence, Faculty of Informatics, Eötvös Loránd University, Budapest, Hungary.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition traditionally defined by core symptoms in social behavior, speech/communication, repetitive behavior, and restricted interests. Beyond the core symptoms, autism has strong association with other disorders such as intellectual disability (ID), epilepsy, schizophrenia among many others. This paper outlines a theory of ASD with capacity to connect heterogeneous "core" symptoms, medical and psychiatric comorbidities as well as other etiological theories of autism in a unifying cognitive framework rooted in neuroscience and genetics. Cognition is embedded into an ever-developing structure modified by experiences, including the outcomes of environment influencing behaviors. The key constraint of cognition is that the brain can handle only 7±2 relevant variables at a time, whereas sensory variables, i.e., the number of sensory neurons is orders of magnitude larger. As a result, (a) the extraction, (b) the encoding, and (c) the capability for the efficient cognitive manipulation of the relevant variables, and (d) the compensatory mechanisms that counteract computational delays of the distributed components are critical. We outline our theoretical model to describe a Cartesian Factor (CF) forming, autoencoder-like cognitive mechanism which breaks combinatorial explosion and is accelerated by internal reinforcing machineries and discuss the neural processes that support CF formation. Impairments in any of these aspects may disrupt learning, cognitive manipulation, decisions on interactions, and execution of decisions. We suggest that social interactions are the most susceptible to combinations of diverse small impairments and can be spoiled in many ways that pile up. Comorbidity is experienced, if any of the many potential impairments is relatively strong. We consider component spoiling impairments as the basic colors of autism, whereas the combinations of individual impairments make the palette of autism. We put forth arguments on the possibility of dissociating the different main elements of the impairments that can appear together. For example, impairments of generalization (domain general learning) and impairments of dealing with many variable problems, such as social situations may appear independently and may mutually enhance their impacts. We also consider mechanisms that may lead to protection.
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http://dx.doi.org/10.3389/fpsyt.2020.503462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738611PMC
December 2020

Psychometric Study of the Social Responsiveness Scale in Phelan-McDermid Syndrome.

Autism Res 2020 08 14;13(8):1383-1396. Epub 2020 May 14.

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

The Social Responsiveness Scale-2 (SRS-2) is a quantitative measure used to characterize symptoms of autism spectrum disorder (ASD). However, research suggests that SRS-2 scores are significantly influenced by language ability and intellectual disability (ID). Efforts to refine the SRS-2 by Sturm, Kuhfeld, Kasari, and Mccracken [Journal of Child Psychology and Psychiatry, 58(9), 1053-1061] yielded a shortened form, yet its psychometric properties in populations with severe ID remain unknown. This study aims to examine the psychometric properties of the SRS-2 in Phelan-McDermid syndrome (PMS), a genetic condition associated with ASD and ID, thereby guiding score interpretation in this population and future development of targeted scales. Analyses, including Item Response Theory (IRT), were conducted on a sample of individuals with PMS (n = 91) recruited at six sites nationally. Psychometric properties evaluated include measures of reliability (internal consistency, test-retest reliability) and validity (structural, construct, content). While both SRS-2 forms are reliable, the shortened SRS-2 shows superior validity to the full SRS-2 for measuring ASD symptoms in PMS. On IRT analysis, the shortened SRS-2 shows excellent discrimination and precisely evaluates respondents across a wide range of ASD symptomatology but interpretation is limited by uncertain content validity and small sample size. The shortened SRS-2 shows some promise for use in PMS, but future refinements and additions are needed to develop items that are tailored to identify ASD in children with severe ID and specifically PMS. LAY SUMMARY: This study determined that a shortened form of the Social Responsiveness Scale, Second Edition (SRS-2) shows both promise and limitations for the characterization of autism symptomatology in individuals with Phelan-McDermid syndrome (PMS), a population characterized by intellectual disability (ID). Caution should be used when interpreting SRS-2 scores in individuals with ID and future research should modify existing items and develop new items to improve the SRS-2's ability to accurately characterize autism symptomatology in PMS. Autism Res 2020, 13: 1383-1396. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.2299DOI Listing
August 2020

Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome.

Pediatr Neurol 2020 05 31;106:24-31. Epub 2020 Jan 31.

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: This cohort study utilized diffusion tensor imaging tractography to compare the uncinate fasciculus and inferior longitudinal fasciculus in children with Phelan-McDermid syndrome with age-matched controls and investigated trends between autism spectrum diagnosis and the integrity of the uncinate fasciculus and inferior longitudinal fasciculus white matter tracts.

Methods: This research was conducted under a longitudinal study that aims to map the genotype, phenotype, and natural history of Phelan-McDermid syndrome and identify biomarkers using neuroimaging (ClinicalTrial NCT02461420). Patients were aged three to 21 years and underwent longitudinal neuropsychologic assessment over 24 months. MRI processing and analyses were completed using previously validated image analysis software distributed as the Computational Radiology Kit (http://crl.med.harvard.edu/). Whole-brain connectivity was generated for each subject using a stochastic streamline tractography algorithm, and automatically defined regions of interest were used to map the uncinate fasciculus and inferior longitudinal fasciculus.

Results: There were 10 participants (50% male; mean age 11.17 years) with Phelan-McDermid syndrome (n = 8 with autism). Age-matched controls, enrolled in a separate longitudinal study (NIH R01 NS079788), underwent the same neuroimaging protocol. There was a statistically significant decrease in the uncinate fasciculus fractional anisotropy measure and a statistically significant increase in uncinate fasciculus mean diffusivity measure, in the patient group versus controls in both right and left tracts (P ≤ 0.024).

Conclusion: Because the uncinate fasciculus plays a critical role in social and emotional interaction, this tract may underlie some deficits seen in the Phelan-McDermid syndrome population. These findings need to be replicated in a larger cohort.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190002PMC
May 2020

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome.

Pediatr Neurol 2019 01 21;90:37-43. Epub 2018 Sep 21.

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Objective: Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan-McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients.

Methods: We performed volumetric analysis of baseline brain MRIs of Phelan-McDermid syndrome patients (ages three to 21 years) enrolled in a prospective natural history study (ClinicalTrials.gov NCT02461420). Using MRI segmentations carried out with PSTAPLE algorithm, we measured relative volumes (volume of the structure divided by the volume of the brain parenchyma) of basal ganglia and cerebellar structures. We compared these measurements to those of age- and sex-matched healthy controls part of another study. Among the patients, we performed linear regression of each relative volume using Repetitive Behavior Scale-Revised total score and Aberrant Behavior Checklist stereotypy score. Eleven patients with Phelan-McDermid syndrome (six females, five males) and 11 healthy controls were in this analysis.

Results: At time of MRI, the mean age of the patients and controls was 9.24 (5.29) years and 9.00 (4.49) years, respectively (P = 0.66). Compared to controls, patients had decreased caudate (P ≤ 0.013), putamen (P ≤ 0.026), and left pallidum (P = 0.033) relative volumes. Relative volume of cerebellar vermal lobules I to V (beta coefficient = -17119, P = 0.017) decreased with increasing Repetitive Behavior Scale-Revised total score.

Conclusions: The volumes of the striatum and left pallidum are decreased in individuals with Phelan-McDermid syndrome. Cerebellar vermis volume may predict repetitive behavior severity in Phelan-McDermid syndrome. These findings warrant further investigation in larger samples.
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http://dx.doi.org/10.1016/j.pediatrneurol.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309632PMC
January 2019

A Multisite, Multidisciplinary Delphi Consensus Study Describing "Usual Care" Intervention Strategies for School-Age to Transition-Age Youth With Autism.

J Clin Child Adolesc Psychol 2019 31;48(sup1):S247-S268. Epub 2018 Jan 31.

c Department of Psychology , Stony Brook University.

Understanding usual care is important to reduce health disparities and improve the dissemination of evidence-based practices for youth (ages 7-22 years) with autism spectrum disorder (ASD). A barrier to describing "usual ASD care" is the lack of a common vocabulary and inventory of the practices used by a diverse provider field. To address this barrier, we gathered input from expert providers to develop an inventory of usual care practices and assess expert familiarity and perceptions of these practices as interventions for anxiety, externalizing, and social difficulties in ASD. Purposeful sampling recruited 66 expert ASD providers representing multiple disciplines from 5 sites. Via a 2-round Delphi poll, experts reviewed, suggested revisions to and rated 49 literature-derived practices on several dimensions (familiarity, usefulness, common use, research support). A revised list of 55 practices and anonymous summary of group characteristics and ratings was then returned for further review. Results yielded 55 intervention practices, 48 of which were identified as "familiar" approaches by consensus (≥ 75% endorsement). Greater variation was observed in practices identified by consensus as most often used, useful, and research supported, depending upon the target problem. Findings provide an inventory of practices, reflective of the multidisciplinary language and approaches of expert ASD providers. This inventory may be used to better assess what constitutes usual care for youth with ASD in the United States. Moreover, findings offer insights from clinical experts regarding the range and acceptability of practices that may inform and ground treatment research, dissemination, and implementation efforts.
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http://dx.doi.org/10.1080/15374416.2017.1410826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067994PMC
May 2020

Framework for assessing individuals with rare genetic disorders associated with profound intellectual and multiple disabilities (PIMD): the example of Phelan McDermid Syndrome.

Clin Neuropsychol 2018 Aug - Oct;32(7):1226-1255. Epub 2017 Dec 21.

b Intramural Research Program , National Institute of Mental Health , Bethesda , MD , USA.

Background: Specialized strategies are needed to understand the complex neuropsychological impairments reported in individuals with profound intellectual and multiple disabilities (PIMD) associated with rare genetic disorders.

Methods: This narrative review focuses on assessment of individuals with Phelan-McDermid Syndrome (PMS) as a condition commonly associated with PIMD. Published case series and prospective studies were reviewed to evaluate approaches to cognitive, language, motor/sensory, and behavioral domains. This review is framed using general principles for neuropsychological evaluation in PIMD.

Results: Neuropsychological assessment domains and tools varied across published reports. Adaptive behavior measures, out-of-range developmental assessments, and social-communication measures were commonly used. Available findings were used to shape a recommended framework with potential to improve measurement of clinical outcomes and advance scientific discovery.

Conclusions: The recommended framework outlines an inter-disciplinary and multimodal neuropsychological assessment process relying on modified standardized assessments, functional assessments, and caregiver/informant reports when evaluating individuals with PIMD. Arrested development and skill variability/regression are also discussed as additional, important considerations in neuropsychological evaluation of individuals with PIMD and rare genetic disorders.
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http://dx.doi.org/10.1080/13854046.2017.1413211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417924PMC
August 2019

Heightened brain response to pain anticipation in high-functioning adults with autism spectrum disorder.

Eur J Neurosci 2018 03 25;47(6):592-601. Epub 2017 May 25.

Department of Psychology, Queens College, The City University of New York, Flushing, NY, 11367, USA.

Autism spectrum disorder (ASD) is marked by both socio-communicative difficulties and abnormalities in sensory processing. Much of the work on sensory deficits in ASD has focused on tactile sensations and the perceptual aspects of somatosensation, such as encoding of stimulus intensity and location. Although aberrant pain processing has often been noted in clinical observations of patients with ASD, it remains largely uninvestigated. Importantly, the neural mechanism underlying higher order cognitive aspects of pain processing such as pain anticipation also remains unknown. Here we examined both pain perception and anticipation in high-functioning adults with ASD and matched healthy controls (HC) using an anticipatory pain paradigm in combination with functional magnetic resonance imaging (fMRI) and concurrent skin conductance response (SCR) recording. Participants were asked to choose a level of electrical stimulation that would feel moderately painful to them. Compared to HC group, ASD group chose a lower level of stimulation prior to fMRI. However, ASD participants showed greater activation in both rostral and dorsal anterior cingulate cortex during the anticipation of stimulation, but not during stimulation delivery. There was no significant group difference in insular activation during either pain anticipation or perception. However, activity in the left anterior insula correlated with SCR during pain anticipation. Taken together, these results suggest that ASD is marked with aberrantly higher level of sensitivity to upcoming aversive stimuli, which may reflect abnormal attentional orientation to nociceptive signals and a failure in interoceptive inference.
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http://dx.doi.org/10.1111/ejn.13598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659957PMC
March 2018

Erratum to: Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome.

J Neurodev Disord 2016 15;8. Epub 2016 Mar 15.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, NY 10029 USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY USA.

[This corrects the article DOI: 10.1186/s11689-016-9138-9.].
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http://dx.doi.org/10.1186/s11689-016-9143-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791933PMC
March 2016

Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome.

J Neurodev Disord 2016 23;8. Epub 2016 Feb 23.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, NY 10029 USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY USA.

Background: Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by deletion or mutation in the SHANK3 gene, is one of the more common single-locus causes of autism spectrum disorder (ASD). PMS is characterized by global developmental delay, hypotonia, delayed or absent speech, increased risk of seizures, and minor dysmorphic features. Impairments in language and communication are one of the most consistent characteristics of PMS. Although there is considerable overlap in the social communicative deficits associated with PMS and ASD, there is a dearth of data on underlying abnormalities at the level of neural systems in PMS. No controlled neuroimaging studies of PMS have been reported to date. The goal of this study was to examine the neural circuitry supporting the perception of auditory communicative signals in children with PMS as compared to idiopathic ASD (iASD).

Methods: Eleven children with PMS and nine comparison children with iASD were scanned using functional magnetic resonance imaging (fMRI) under light sedation. The fMRI paradigm was a previously validated passive auditory task, which presented communicative (e.g., speech, sounds of agreement, disgust) and non-communicative vocalizations (e.g., sneezing, coughing, yawning).

Results: Previous research has shown that the superior temporal gyrus (STG) responds selectively to communicative vocal signals in typically developing children and adults. Here, selective activity for communicative relative to non-communicative vocalizations was detected in the right STG in the PMS group, but not in the iASD group. The PMS group also showed preferential activity for communicative vocalizations in a range of other brain regions associated with social cognition, such as the medial prefrontal cortex (MPFC), insula, and inferior frontal gyrus. Interestingly, better orienting toward social sounds was positively correlated with selective activity in the STG and other "social brain" regions, including the MPFC, in the PMS group. Finally, selective MPFC activity for communicative sounds was associated with receptive language level in the PMS group and expressive language in the iASD group.

Conclusions: Despite shared behavioral features, children with PMS differed from children with iASD in their neural response to communicative vocal sounds and showed relative strengths in this area. Furthermore, the relationship between clinical characteristics and neural selectivity also differed between the two groups, suggesting that shared ASD features may partially reflect different neurofunctional abnormalities due to differing etiologies.
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http://dx.doi.org/10.1186/s11689-016-9138-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763436PMC
February 2016

Erratum: A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

Mol Autism 2015 2;6:31. Epub 2015 Jun 2.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1230, New York, NY 10029 USA ; Icahn School of Medicine at Mount Sinai, New York, NY USA ; Friedman Brain Institute, New York, NY USA ; Mindich Child Health Institute, New York, NY USA ; Departments of Psychiatry, New York, NY USA ; Departments of Neuroscience, New York, NY USA ; Departments of Genetics and Genomic Sciences, New York, NY USA.

[This corrects the article DOI: 10.1186/2040-2392-5-54.].
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http://dx.doi.org/10.1186/s13229-015-0025-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450831PMC
June 2015

Autonomic and brain responses associated with empathy deficits in autism spectrum disorder.

Hum Brain Mapp 2015 Sep 21;36(9):3323-38. Epub 2015 May 21.

Department of Psychology, Queens College, The City University of New York, Flushing, New York.

Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high-functioning adults with ASD and seventeen matched controls while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD.
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http://dx.doi.org/10.1002/hbm.22840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545680PMC
September 2015

Randomized comparative trial of a social cognitive skills group for children with autism spectrum disorder.

J Am Acad Child Adolesc Psychiatry 2015 Mar 20;54(3):208-216.e1. Epub 2014 Dec 20.

Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai, New York.

Objective: This study evaluated the efficacy of a targeted social skills training group in school-aged children with autism spectrum disorder (ASD). The intervention, Seaver-NETT (Nonverbal communication, Emotion recognition, and Theory of mind Training), is a 12-session cognitive-behavioral intervention (CBI) for verbal, school-aged children targeting ASD-specific social behavioral impairments.

Method: Sixty-nine children with ASD, 8 to 11 years of age, with verbal IQs greater than 70, participated in a randomized comparative trial to examine the efficacy of NETT relative to a facilitated play group. Treatment outcomes included caregiver reports of social behavior and neuropsychological assessments of social cognition conducted by blinded raters. Outcomes were collected at baseline, endpoint, and 3 months posttreatment.

Results: Significant improvements were found on social behavior outcomes such as nonverbal communication, empathic responding, and social relations in the NETT condition relative to the active control at endpoint. Verbal IQ moderated the interaction effect on social behavior, with higher verbal IQ associated with improvements in the CBI condition. No significant improvements were found on social cognitive outcomes. No significant group differences were found at 3-month follow-up conducted with approximately half the sample (n = 34).

Conclusion: These data indicate that targeted CBI social skills groups such as NETT improve social communication deficits in verbal, school-aged children with ASD. The moderating effects of high verbal IQ suggest a need to consider participant and treatment characteristics associated with outcomes in future studies. Clinical trial registration information-Neural and Behavioral Outcomes of Social Skills Groups in Children With Autism Spectrum Disorder; https://clinicaltrials.gov; NCT01190917.
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http://dx.doi.org/10.1016/j.jaac.2014.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346205PMC
March 2015

A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

Mol Autism 2014 12;5(1):54. Epub 2014 Dec 12.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1230, New York, NY 10029 USA ; Friedman Brain Institute, New York, NY USA ; Mindich Child Health Institute, New York, NY USA ; Departments of Psychiatry, New York, NY USA ; Departments of Neuroscience, New York, NY USA ; Departments of Genetics and Genomic Sciences, New York, NY USA ; Icahn School of Medicine at Mount Sinai, New York, NY USA.

Background: Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.

Methods: Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.

Results: Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.

Conclusions: This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.
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http://dx.doi.org/10.1186/2040-2392-5-54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326443PMC
February 2015

Altered cingulum bundle microstructure in autism spectrum disorder.

Acta Neuropsychiatr 2013 Oct;25(5):275-82

3 Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.

Objective: Here, we examined the cingulum bundle, a long-range white matter tract mediating dorsal limbic connectivity, using diffusion tensor imaging (DTI) tractography, in children and adolescents with autism spectrum disorder (ASD) versus controls. We hypothesised that cingulum bundle microstructure would be altered in ASD, based on evidence implicating abnormal white matter connectivity in this disorder.

Methods: DTI data were acquired for 19 ASD participants (IQ ⩾ 70; 7-18 years; mean = 12.4 ± 3.1) and 16 age-matched controls (7-18 years; mean = 12.3 ± 3.6) on a 3 T magnetic resonance imaging system. Deterministic tractography was used to isolate the cingulum bundle. Left and right cingulum bundles were examined for differences in several DTI metrics in ASD children/adolescents versus controls, including: fractional anisotropy (FA), mean, axial, and radial diffusivity.

Results: Significant age × group interaction effects were found for all DTI metrics (mean diffusivity: F 1,28 = 9.5, p = 0.005, radial diffusivity: F 1,28 = 7.8, p = 0.009, axial diffusivity: F 1,28 = 5.2, p = 0.03, FA: F 1,28 = 4.4, p = 0.04). Interaction effects were driven by increases in cingulum bundle diffusivity (mean, radial, and axial diffusivity), and decreased FA, in younger ASD participants within our sample versus controls.

Conclusion: Our results point to immature microstructural organisation of the cingulum bundle in ASD, particularly during the early years of life, with implications for limbic network synchronisation and complex socio-emotional performance.
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http://dx.doi.org/10.1017/neu.2013.2DOI Listing
October 2013

Low-contrast response deficits and increased neural noise in children with autism spectrum disorder.

Neuropsychologia 2014 Oct 5;63:10-8. Epub 2014 Aug 5.

Hunter College, New York, United States.

A battery of short-duration neurophysiological tests were designed and implemented using visual evoked potentials (VEPs) to examine specific neural mechanisms in children with and without autism spectrum disorder (ASD). Contrast-sweep conditions (bright or dark isolated-checks) were used to elicit steady-state VEPs to examine the integrity of ON/OFF pathways. Children with ASD displayed deficits in low-contrast responses at the stimulus frequency of 12.5 Hz, notably under conditions that emphasized activity in the magnocellular pathway. Signal-to-noise ratios were weaker in the ASD group, particularly for the OFF pathway. There were no group differences in the amplitude of responses. In addition, the ASD group displayed significantly higher levels of neural noise than controls. For the response at the stimulus frequency, the ASD group produced a relatively constant level of noise across the contrast range tested, with higher levels than controls at low contrasts and approximately equal levels of noise at moderate to high contrasts.
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http://dx.doi.org/10.1016/j.neuropsychologia.2014.07.031DOI Listing
October 2014

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Am J Hum Genet 2014 May 24;94(5):677-94. Epub 2014 Apr 24.

Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland; Children's University Hospital Temple Street, Dublin 1, Ireland.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067558PMC
May 2014

Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth.

Brain Res 2014 Sep 5;1580:188-98. Epub 2014 Feb 5.

University of Minnesota, Department of Psychiatry & Pediatrics, 2101 6th Street SE, Minneapolis, MN 55455, USA.

Background: There is a paucity of treatments targeting core symptom domains in Autism Spectrum Disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD.

Methods: Fifteen children and adolescents with verbal IQs≥70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex.

Results: Among 4 doses tested, the highest dose evaluated, 0.4 IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin.

Conclusions: This pilot study suggests that daily administration of intranasal oxytocin at 0.4 IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted. This article is part of a Special Issue entitled Oxytocin and Social Behav.
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http://dx.doi.org/10.1016/j.brainres.2014.01.049DOI Listing
September 2014

Metabolic mapping of deep brain structures and associations with symptomatology in autism spectrum disorders.

Res Autism Spectr Disord 2014 Jan;8(1):44-51

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, 150 Kilgour Road, Toronto, Ontario, Canada M4G 1R8.

Structural neuroimaging studies in autism report atypical volume in deep brain structures which are related to symptomatology. Little is known about metabolic changes in these regions, and how they vary with age and sex, and/or relate to clinical behaviors. Using magnetic resonance spectroscopy we measured N-acetylaspartate, choline, creatine, myoinositol and glutamate in the caudate, putamen, and thalamus of 20 children with autism and 16 typically developing controls (7-18 years). Relative to controls, individuals with autism had elevated glutamate/creatine in the putamen. In addition, both groups showed age-related increases in glutamate in this region. Boys, relative to girls had increased choline/creatine in the thalamus. Lastly, there were correlations between glutamate, choline, and myoinositol in all three regions, and behavioral scores in the ASD group. These findings suggest changes in deep gray matter neurochemistry, which are sensitive to diagnosis, age and sex, and are associated with behavioral differences.
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http://dx.doi.org/10.1016/j.rasd.2013.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897261PMC
January 2014

Abnormal autonomic and associated brain activities during rest in autism spectrum disorder.

Brain 2014 Jan;137(Pt 1):153-71

1 Department of Psychology, Queens College, City University of New York, Flushing, NY 11367, USA.

Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.
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http://dx.doi.org/10.1093/brain/awt294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891443PMC
January 2014

Neural correlates of inhibition of socially relevant stimuli in adults with autism spectrum disorder.

Brain Res 2013 Oct 17;1533:80-90. Epub 2013 Aug 17.

Department of Diagnostic Imaging, The Hospital for Sick Children, Canada. Electronic address:

Adults with autism spectrum disorder (ASD) can demonstrate difficulties with inhibiting inappropriate social responses. Presently, little research has utilized socially relevant stimuli to explore the modulatory effects of emotion on cognitive control in this population. To assess neural mechanisms of inhibiting social stimuli, we presented images of happy or sad facial expressions in a Go/NoGo task to unmedicated adults with ASD and to controls during functional magnetic resonance imaging (fMRI). Groups did not differ on behavioral measures. Brain activation in response to NoGo vs. Go trials revealed differing regional patterns of activation within groups. Controls recruited brain regions involved in inhibition (dorsal- [DLPFC] and ventro-lateral prefrontal cortices [VLPFC], anterior cingulate cortex [ACC]), response suppression (parietal lobe), interoceptive awareness (insula), and also the fusiform and middle temporal gyri. Adults with ASD only recruited the VLPFC and right fusiform gyrus, and weakly activated the ACC and insula. Between-group comparisons indicated that controls activated the DLPFC, while adults with ASD relied on the VLPFC and the fusiform gyrus to inhibit responses. Adults with ASD may have relied more on visual association cortex, possibly as a means of recruiting additional neural processes that could act as a compensatory mechanism.
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http://dx.doi.org/10.1016/j.brainres.2013.08.021DOI Listing
October 2013

Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.

Mol Autism 2013 Jun 11;4(1):18. Epub 2013 Jun 11.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.

Methods: A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.

Results: Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.

Conclusions: This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.
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http://dx.doi.org/10.1186/2040-2392-4-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707861PMC
June 2013

Effects of age and symptomatology on cortical thickness in autism spectrum disorders.

Res Autism Spectr Disord 2013 Jan;7(1):141-150

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Road, Toronto, Ontario, M4G 1R8, Canada.

Several brain regions show structural and functional abnormalities in individuals with autism spectrum disorders (ASD), but the developmental trajectory of abnormalities in these structures and how they may relate to social and communicative impairments are still unclear. We assessed the effects of age on cortical thickness in individuals with ASD, between the ages of 7 and 39 years in comparison to typically developing controls. Additionally, we examined differences in cortical thickness in relation to symptomatology in the ASD group, and their association with age. Analyses were conducted using a general linear model, controlling for sex. Social and communication scores from the Autism Diagnostic Interview-Revised (ADI-R) were correlated with the thickness of regions implicated in those functions. Controls showed widespread cortical thinning relative to the ASD group. Within regions-of-interest, increased thickness in the rostral anterior cingulate cortex was associated with poorer social scores. Additionally, a significant interaction between age and social impairment was found in the orbitofrontal cortex, with more impaired younger children having decreased thickness in this region. These results suggest that differential neurodevelopmental trajectories are present in individuals with ASD and some differences are associated with diagnostic behaviours.
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http://dx.doi.org/10.1016/j.rasd.2012.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652338PMC
January 2013

Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial.

Mol Autism 2012 Dec 5;3(1):16. Epub 2012 Dec 5.

Mount Sinai School of Medicine, One Gustave L, Levy Place, New York, NY 10029-6574, USA.

Unlabelled:

Background: There are no effective medications for the treatment of social cognition/function deficits in autism spectrum disorder (ASD), and adult intervention literature in this area is sparse. Emerging data from animal models and genetic association studies as well as early, single-dose intervention studies suggest that the oxytocin system may be a potential therapeutic target for social cognition/function deficits in ASD. The primary aim of this study was to examine the safety/therapeutic effects of intranasal oxytocin versus placebo in adults with ASD, with respect to the two core symptom domains of social cognition/functioning and repetitive behaviors.

Methods: This was a pilot, randomized, double-blind, placebo-controlled, parallel design trial of intranasal oxytocin versus placebo in 19 adults with ASD (16 males; 33.20 ± 13.29 years). Subjects were randomized to 24 IU intranasal oxytocin or placebo in the morning and afternoon for 6 weeks. Measures of social function/cognition (the Diagnostic Analysis of Nonverbal Accuracy) and repetitive behaviors (Repetitive Behavior Scale Revised) were administered. Secondary measures included the Social Responsiveness Scale, Reading-the-Mind-in-the-Eyes Test and the Yale Brown Obsessive Compulsive Scale - compulsion subscale and quality of life (World Health Organization Quality of Life Questionnaire - emotional/social subscales). Full-information maximum-likelihood parameter estimates were obtained and tested using mixed-effects regression analyses.

Results: Although no significant changes were detected in the primary outcome measures after correcting for baseline differences, results suggested improvements after 6 weeks in measures of social cognition (Reading-the-Mind-in-the-Eyes Test, p = 0.002, d = 1.2), and quality of life (World Health Organization Quality of Life Questionnaire - emotion, p = 0.031, d = 0.84), both secondary measures. Oxytocin was well tolerated and no serious adverse effects were reported.

Conclusions: This pilot study suggests that there is therapeutic potential to daily administration of intranasal oxytocin in adults with ASD and that larger and longer studies are warranted.

Trial Registration: NCT00490802.
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http://dx.doi.org/10.1186/2040-2392-3-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539865PMC
December 2012

Functional deficits of the attentional networks in autism.

Brain Behav 2012 Sep 27;2(5):647-60. Epub 2012 Aug 27.

Department of Psychology, Queens College, City University of New York New York ; Department of Psychiatry, Mount Sinai School of Medicine New York ; Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine New York ; Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine New York.

Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.
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http://dx.doi.org/10.1002/brb3.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489817PMC
September 2012

Individual common variants exert weak effects on the risk for autism spectrum disorders.

Hum Mol Genet 2012 Nov 26;21(21):4781-92. Epub 2012 Jul 26.

Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
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http://dx.doi.org/10.1093/hmg/dds301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471395PMC
November 2012

The effect of diagnosis, age, and symptom severity on cortical surface area in the cingulate cortex and insula in autism spectrum disorders.

J Child Neurol 2013 Jun 25;28(6):732-9. Epub 2012 Jul 25.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.

Functional activity in the anterior cingulate cortex and insula has been reported to be abnormal during social tasks in autism spectrum disorders. However, few studies have examined surface morphometry in these regions and how this may be related to autism spectrum disorder symptomatology. In this study, 27 individuals with autism spectrum disorders and 25 controls between the ages of 7 to 39 years underwent structural magnetic resonance imaging. Our primary analysis examined differences in surface area in the cingulate and insula, between individuals with and without autism spectrum disorders, as well as age-related changes and associations with social impairments. Surface area in the right cingulate was significantly different between groups and decreased more rapidly with age in autism spectrum disorder participants. In addition, greater surface area in the insula and isthmus was associated with poorer social behaviors. Results suggest atypical surface morphometry in brain regions involved in social function, which appeared to be related to poorer social ability scores.
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http://dx.doi.org/10.1177/0883073812451496DOI Listing
June 2013

Complex autism spectrum disorder in a patient with a 17q12 microduplication.

Am J Med Genet A 2012 May 4;158A(5):1170-7. Epub 2012 Apr 4.

Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York 100029, USA.

Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.
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http://dx.doi.org/10.1002/ajmg.a.35267DOI Listing
May 2012

A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders.

Am J Psychiatry 2012 Mar;169(3):292-9

Autism and Obsessive-Compulsive Spectrum Program, Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, USA.

Objective: The effects of fluoxetine and placebo on repetitive behaviors and global severity were compared in adults with autism spectrum disorders (ASDs).

Method: Adults with ASDs were enrolled in a 12-week double-blind placebo-controlled fluoxetine trial. Thirty-seven were randomly assigned to fluoxetine (N=22) or placebo (N=15). Dosage followed a fixed schedule, starting at 10 mg/day and increasing as tolerated up to 80 mg/day. Repetitive behaviors were measured with the compulsion subscale of the Yale-Brown Obsessive Compulsive Scale; the Clinical Global Impression (CGI) improvement scale was used to rate improvement in obsessive-compulsive symptoms and overall severity.

Results: There was a significant treatment-by-time interaction indicating a significantly greater reduction in repetitive behaviors across time for fluoxetine than for placebo. With overall response defined as a CGI global improvement score of 2 or less, there were significantly more responders at week 12 in the fluoxetine group than in the placebo group. The risk ratio was 1.5 for CGI global improvement (responders: fluoxetine, 35%; placebo, 0%) and 1.8 for CGI-rated improvement in obsessive-compulsive symptoms (responders: fluoxetine, 50%; placebo, 8%). Only mild and moderate side effects were observed.

Conclusions: Fluoxetine treatment, compared to placebo, resulted in significantly greater improvement in repetitive behaviors, according to both the Yale-Brown compulsion subscale and CGI rating of obsessive-compulsive symptoms, as well as on the CGI overall improvement rating. Fluoxetine appeared to be well tolerated. These findings stand in contrast to findings in a trial of citalopram for childhood autism.
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http://dx.doi.org/10.1176/appi.ajp.2011.10050764DOI Listing
March 2012