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1.  Catalysts for Change: The Role of Small Business Funders in the Creation and Dissemination of Innovation 
A gap exists between the expanding space of technological innovations to aid those affected by autism spectrum disorders, and the actual impact of those technologies on daily lives. This gap can be addressed through a very practical path of commercialization. However, the path from a technological innovation to a commercially viable product is fraught with challenges. These challenges can be mitigated through small business funding agencies, which are, more and more, catalyzing the dissemination of innovation by fostering social entrepreneurship through capital support and venture philanthropy. This letter describes the differences and nature of these agencies, and their importance in facilitating the translational and real-world impact of technological and scientific discoveries.
doi:10.1007/s10803-015-2636-x
PMCID: PMC4749456  PMID: 26481385
technology; innovation; translational science; commercialization; business; funding; venture philanthropy
2.  Behavioral phenotype in a child with Prader-Willi syndrome and comorbid 47, XYY 
Summary
We report a 12-year-old male with Prader-Willi syndrome (PWS) and 47, XYY syndrome. Genetic work up revealed 47, XYY karyotype. PWS diagnosis was made by polymerase chain reaction methylation and maternal uniparental disomy (mUPD) was determined to be the etiology. Review of distinct behavioral features, possible interplay between the two syndromes and considerations for diagnoses are presented. To our knowledge, this is the first report of behavioral features in PWS with comorbid 47, XYY.
doi:10.5582/irdr.2016.01043
PMCID: PMC4995422  PMID: 27672550
Prader-Willi syndrome; 47; XYY; autism spectrum disorder; attention deficit hyperactivity disorder
3.  Standards of care for obsessive–compulsive disorder centres 
Abstract
In recent years, many assessment and care units for obsessive–compulsive disorder (OCD) have been set up in order to detect, diagnose and to properly manage this complex disorder, but there is no consensus regarding the key functions that these units should perform. The International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) together with the Obsessive Compulsive and Related Disorders Network (OCRN) of the European College of Neuropsychopharmacology (ECNP) and the Anxiety and Obsessive Compulsive Disorders Section of the World Psychiaric Association (WPA) has developed a standards of care programme for OCD centres. The goals of this collaborative initiative are promoting basic standards, improving the quality of clinical care and enhance the validity and reliability of research results provided by different facilities and countries.
doi:10.1080/13651501.2016.1197275
PMCID: PMC4950405  PMID: 27359333
Accreditation standards; obsessive–compulsive disorder; OCD units; standards of care
4.  Baseline Factors Predicting Placebo Response to Treatment in Children and Adolescents With Autism Spectrum Disorders 
JAMA pediatrics  2013;167(11):1045-1052.
IMPORTANCE
The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population.
OBJECTIVE
To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders.
DESIGN, SETTING, AND PARTICIPANTS
Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression–Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children’s Yale-Brown Obsessive-Compulsive Scale.
INTERVENTIONS
Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d).
MAIN OUTCOMES AND MEASURES
A positive response was defined as having a score of at least much improved on the Clinical Global Impression–Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale–Revised, and the Children’s Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire.
RESULTS
Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders.
CONCLUSIONS AND RELEVANCE
This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00086645
doi:10.1001/jamapediatrics.2013.2698
PMCID: PMC4913472  PMID: 24061784
5.  Exploring the manifestations of anxiety in children with Autism Spectrum Disorders 
This study explores the manifestation and measurement of anxiety symptoms in 415 children with ASDs on a 20-item, parent-rated, DSM-IV referenced anxiety scale. In both high and low-functioning children (IQ above vs below 70), commonly endorsed items assessed restlessness, tension and sleep difficulties. Items requiring verbal expression of worry by the child were rarely endorsed. Higher anxiety was associated with functional language, IQ above 70 and higher scores on several other behavioral measures. Four underlying factors emerged: Generalized Anxiety, Separation Anxiety, Social Anxiety and Over-arousal. Our findings extend our understanding of anxiety across IQ in ASD and provide guidance for improving anxiety outcome measurement.
doi:10.1007/s10803-013-1775-1
PMCID: PMC4038127  PMID: 23400347
Autism Spectrum Disorders; anxiety; measurement; comorbidity
6.  Management of Obsessive-Compulsive Disorder 
F1000Prime Reports  2014;6:68.
Obsessive-compulsive disorder (OCD) is a common, often debilitating disorder characterized by the presence of obsessions and compulsions. Obsessions are repetitive thoughts or images which are experienced as intrusive and unwanted; they cause marked anxiety and distress. Compulsions (also known as rituals) are repetitive behaviors or mental acts that individuals with OCD perform in an attempt to decrease their anxiety. Patients tend to hide their symptoms due to shame; the amount of time between onset of symptoms and appropriate treatment is often many years. The disorder likely results from several etiological variables; functional imaging studies have consistently shown hyperactivity in the orbitofrontal cortex, anterior cingulate, thalamus, and striatum. The mainstays of treatment include cognitive-behavioral therapy in the form of exposure and response prevention (ERP) and serotonin reuptake inhibiting medications. Several pharmacological augmentation strategies exist for treatment-resistant OCD, with addition of antipsychotics being most commonly employed. Radio and neurosurgical procedures, including gamma knife radiation and deep brain stimulation, are reserved for severe, treatment-refractory disease that has not responded to multiple treatments, and some patients may benefit from transcranial magnetic stimulation.
doi:10.12703/P6-68
PMCID: PMC4126524  PMID: 25165567
7.  Lack of Efficacy of Citalopram in Children With Autism Spectrum Disorders and High Levels of Repetitive Behavior 
Archives of general psychiatry  2009;66(6):583-590.
Context
Selective serotonin reuptake inhibitors are widely prescribed for children with autism spectrum disorders.
Objectives
To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders.
Design
National Institutes of Health–sponsored randomized controlled trial.
Setting
Six academic centers, including Mount Sinai School of Medicine, North Shore–Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School.
Participants
One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders.
Interventions
Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d).
Main Outcome Measures
Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form.
Results
There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P> .99). There was no difference in score reduction on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], −2.0 [3.4] points for the citalopram-treated group and −1.9 [2.5] points for the placebo group; P=.81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus.
Conclusion
Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders.
Trial Registration
clinicaltrials.gov Identifier: NCT00086645
doi:10.1001/archgenpsychiatry.2009.30
PMCID: PMC4112556  PMID: 19487623
8.  The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome 
Current Neuropharmacology  2014;12(1):71-98.
Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.
doi:10.2174/1570159X113116660046
PMCID: PMC3915351  PMID: 24533017
AMPA receptor; Arc; autism spectrum disorder; Fragile X syndrome; GRIP1/2; kainate receptor; MAP1B; memantine; metabotropic glutamate receptor; neuroligin; NMDA receptor.
9.  Should an Obsessive-Compulsive Spectrum Grouping of Disorders Be Included in DSM-V? 
Depression and anxiety  2010;27(6):528-555.
The obsessive-compulsive (OC) spectrum has been discussed in the literature for two decades. Proponents of this concept propose that certain disorders characterized by repetitive thoughts and/or behaviors are related to obsessive-compulsive disorder (OCD), and suggest that such disorders be grouped together in the same category (i.e., grouping, or “chapter”) in DSM. This paper addresses this topic and presents options and preliminary recommendations to be considered for DSM-V. The paper builds upon and extends prior reviews of this topic that were prepared for and discussed at a DSM-V Research Planning Conference on Obsessive-Compulsive Spectrum Disorders held in 2006. Our preliminary recommendation is that an OC-spectrum grouping of disorders be included in DSM-V. Furthermore, we preliminarily recommend that consideration be given to including this group of disorders within a larger supraordinate category of “Anxiety and Obsessive-Compulsive Spectrum Disorders.” These preliminary recommendations must be evaluated in light of recommendations for, and constraints upon, the overall structure of DSM-V.
doi:10.1002/da.20705
PMCID: PMC3985410  PMID: 20533367
obsessive compulsive spectrum; obsessive compulsive disorder; classification; DSM-V
10.  OBSESSIVE–COMPULSIVE DISORDER: A REVIEW OF THE DIAGNOSTIC CRITERIA AND POSSIBLE SUBTYPES AND DIMENSIONAL SPECIFIERS FOR DSM-V 
Depression and anxiety  2010;27(6):507-527.
Background
Since the publication of the DSM-IV in 1994, research on obsessive–compulsive disorder (OCD) has continued to expand. It is timely to reconsider the nosology of this disorder, assessing whether changes to diagnostic criteria as well as subtypes and specifiers may improve diagnostic validity and clinical utility.
Methods
The existing criteria were evaluated. Key issues were identified. Electronic databases of PubMed, ScienceDirect, and PsycINFO were searched for relevant studies.
Results
This review presents a number of options and preliminary recommendations to be considered for DSM-V. These include: (1) clarifying and simplifying the definition of obsessions and compulsions(criterion A); (2) possibly deleting the requirement that people recognize that their obsessions or compulsions are excessive or unreasonable (criterion B); (3) rethinking the clinical significance criterion (criterion C) and, in the interim, possibly adjusting what is considered “time-consuming” for OCD; (4) listing additional disorders to help with the differential diagnosis (criterion D); (5) rethinking the medical exclusion criterion (criterion E) and clarifying what is meant by a “general medical condition”; (6) revising the specifiers (i.e., clarifying that OCD can involve a range of insight, in addition to “poor insight,” and adding “tic-related OCD”); and (7) highlighting in the DSM-V text important clinical features of OCD that are not currently mentioned in the criteria (e.g., the major symptom dimensions).
Conclusions
A number of changes to the existing diagnostic criteria for OCD are proposed. These proposed criteria may change as the DSM-V process progresses.
doi:10.1002/da.20669
PMCID: PMC3974619  PMID: 20217853
Obsessive compulsive disorder; DSM-V; nosology; tic disorders; early onset; symptom dimensions
11.  Predicting Response to Opiate Antagonists and Placebo in the Treatment of Pathological Gambling 
Psychopharmacology  2008;200(4):521-527.
Rationale
Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG.
Objectives
We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists.
Methods
284 subjects (137 [48.2%] women) with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] with positive response defined as ≥ 35% reduction in PG-YBOCS score for at least one month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response.
Results
The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p=.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50mg/d or 100mg/d or naltrexone 100mg/d or 150mg/d), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p=.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p=.012).
Conclusions
A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.
doi:10.1007/s00213-008-1235-3
PMCID: PMC3683409  PMID: 18581096
opiate antagonists; impulsivity; impulse control disorders; addiction; pharmacotherapy; placebo
12.  Effects of age and symptomatology on cortical thickness in autism spectrum disorders 
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.
doi:10.1016/j.rasd.2012.08.004
PMCID: PMC3652338  PMID: 23678367
Autism spectrum disorders; Structural MRI; Cortical thickness; Social impairment; Developmental changes
13.  The 5-HT2A receptor and serotonin transporter in Asperger’s Disorder: a PET study with [11C]MDL 100907 and [11C]DASB 
Psychiatry research  2011;194(3):230-234.
Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [11C]MDL 100907 and [11C]DASB to characterize the 5-HT2A receptor and serotonin transporter in Asperger’s Disorder. 17 individuals with Asperger’s Disorder (age = 34.3 ± 11.1 yr) and 17 healthy controls (age = 33.0 ± 9.6 yr) were scanned with [11C]MDL 100907. Of the 17 patients, eight (age = 29.7 ± 7.0 yr) were also scanned with [11C]DASB, as were eight healthy controls (age = 28.7 ± 7.0 yr). Patients with Asperger’s Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by 2 tissue-compartment modeling. The primary outcome measure was regional binding potential BPND. Neither regional [11C]MDL 100907 BPND nor [11C]DASB BPND were statistically different between the Asperger’s and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT2A receptors and serotonin transporters in adult subjects with Asperger’s Disorder.
doi:10.1016/j.pscychresns.2011.04.007
PMCID: PMC3225493  PMID: 22079057
autism spectrum disorders; 5-HT2A receptor; Asperger’s Disorder; positron emission tomography; serotonin transporter; serotonin
14.  Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial 
Molecular Autism  2012;3:16.
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
doi:10.1186/2040-2392-3-16
PMCID: PMC3539865  PMID: 23216716
Autism; Adults; Oxytocin; Clinical trial; Social cognition
15.  Development and Validation of the Appearance and Performance Enhancing Drug Use Schedule 
Addictive behaviors  2011;36(10):949-958.
Appearance-and-performance enhancing drug (APED) use is a form of drug use that includes use of a wide range of substances such as anabolic-androgenic steroids (AASs) and associated behaviors including intense exercise and dietary control. To date, there are no reliable or valid measures of the core features of APED use. The present study describes the development and psychometric evaluation of the Appearance and Performance Enhancing Drug Use Schedule (APEDUS) which is a semi-structured interview designed to assess the spectrum of drug use and related features of APED use. Eighty-five current APED using men and women (having used an illicit APED in the past year and planning to use an illicit APED in the future) completed the APEDUS and measures of convergent and divergent validity. Inter-rater agreement, scale reliability, one-week test-retest reliability, convergent and divergent validity, and construct validity were evaluated for each of the APEDUS scales. The APEDUS is a modular interview with 10 sections designed to assess the core drug and non-drug phenomena associated with APED use. All scales and individual items demonstrated high inter-rater agreement and reliability. Individual scales significantly correlated with convergent measures (DSM-IV diagnoses, aggression, impulsivity, eating disorder pathology) and were uncorrelated with a measure of social desirability. APEDUS subscale scores were also accurate measures of AAS dependence. The APEDUS is a reliable and valid measure of APED phenomena and an accurate measure of the core pathology associated with APED use. Issues with assessing APED use are considered and future research considered.
doi:10.1016/j.addbeh.2011.05.002
PMCID: PMC3159027  PMID: 21640487
ANABOLIC-ANDROGENIC STEROID; POLYSUBSTANCE USE; BODY IMAGE DISTURBANCE; COMPULSIVE EXERCISE; PSYCHOMETRICS; RELIABILITY; VALIDY; APPEARANCE AND PERORMANCE ENHANCING DRUG USE
16.  Oxytocin can hinder trust and cooperation in borderline personality disorder 
We investigated the effects of intranasal oxytocin (OXT) on trust and cooperation in borderline personality disorder (BPD), a disorder marked by interpersonal instability and difficulties with cooperation. Although studies in healthy adults show that intranasal OXT increases trust, individuals with BPD may show an altered response to exogenous OXT because the effects of OXT on trust and pro-social behavior may vary depending on the relationship representations and expectations people possess and/or altered OXT system functioning in BPD. BPD and control participants received intranasal OXT and played a social dilemma game with a partner. Results showed that OXT produced divergent effects in BPD participants, decreasing trust and the likelihood of cooperative responses. Additional analyses focusing on individual differences in attachment anxiety and avoidance across BPD and control participants indicate that these divergent effects were driven by the anxiously attached, rejection-sensitive participants. These data suggest that OXT does not uniformly facilitate trust and pro-social behavior in humans; indeed, OXT may impede trust and pro-social behavior depending on chronic interpersonal insecurities, and/or possible neurochemical differences in the OXT system. Although popularly dubbed the ‘hormone of love’, these data suggest a more circumspect answer to the question of who will benefit from OXT.
doi:10.1093/scan/nsq085
PMCID: PMC3190211  PMID: 21115541
oxytocin; trust; cooperation; social dilemma; borderline personality disorder; adult attachment
17.  Functional deficits of the attentional networks in autism 
Brain and Behavior  2012;2(5):647-660.
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.
doi:10.1002/brb3.90
PMCID: PMC3489817  PMID: 23139910
Alerting; anterior cingulate cortex; attentional networks; autism; executive control
18.  Mutation Screening of the PTEN Gene in Patients With Autism Spectrum Disorders and Macrocephaly 
American Journal of Medical Genetics  2007;144B(4):484-491.
Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTENmutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ≥2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.
doi:10.1002/ajmg.b.30493
PMCID: PMC3381648  PMID: 17427195
Cowden syndrome; Bannayan–Riley–Ruvalcaba syndrome; polydactyly; sequence analysis; multiplex ligation-dependent probe amplification
19.  In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism 
Brain research  2010;1380:198-205.
Attentional dysfunction is one of the most consistent findings in individuals with autism spectrum disorders (ASD). However, the significance of such findings for the pathophysiology of autism is unclear. In this study, we investigated cellular neurochemistry with proton magnetic resonance spectroscopy imaging (1H-MRS) in brain regions associated with networks subserving alerting, orienting, and executive control of attention in patients with ASD. Concentrations of cerebral N-acetyl-aspartate (NAA), creatinine + phosphocreatinine, choline-containing compounds, myo-inositol (Ins) and glutamate + glutamine (Glx) were determined by 3 T 1H-MRS examinations in 14 high-functioning medication-free adults with a diagnosis of ASD and 14 age- and IQ-matched healthy controls (HC) in the anterior cingulate cortex (ACC), thalamus, temporoparietal junction (TPJ), and areas near or along the intraparietal sulcus (IPS). Compared to HC group, the ASD group showed significantly lower Glx concentrations in right ACC and reduced Ins in left TPJ. This study provides evidence of abnormalities in neurotransmission related to networks subserving executive control and alerting of attention, functions which have been previously implicated in ASD pathogenesis.
doi:10.1016/j.brainres.2010.12.057
PMCID: PMC3073642  PMID: 21185269
autism; spectroscopy; glutamate; anterior cingulate cortex; intraparietal sulcus; myo-inositol
20.  Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study 
PLoS ONE  2011;6(11):e28044.
Background
Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.
Methods/Principal Findings
DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.
Conclusions/Significance
Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.
doi:10.1371/journal.pone.0028044
PMCID: PMC3223195  PMID: 22132206
21.  Autism and oxytocin: New developments in translational approaches to therapeutics 
Neurotherapeutics  2010;7(3):250-257.
Summary
Autism is a neurodevelopmental disorder characterized by dysfunction in three core symptom domains: speech and communication deficits, repetitive or compulsive behaviors with restricted interests, and social impairment. The neuropeptide oxytocin, along with the structurally similar peptide arginine vasopressin, may play a role in the etiology of autism, and especially in the social impairment domain. Oxytocin is a non-apeptide (i.e., it has nine amino acids). It is synthesized in magnocellular neurons in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus and is released into the bloodstream by way of axon terminals in the posterior pituitary. Oxytocin is released both peripherally, where it is involved in milk letdown and the facilitation of uterine contractions, and centrally, where it acts as a neuromodulator along with arginine vasopressin. Here, we discuss relevant translational research pertaining to the role of oxytocin in social and repetitive behaviors and consider clinical implications. We also discuss current research limitations, review recent preliminary findings from studies involving oxytocin in autism spectrum disorder patient populations, and point to possible directions for future research.
doi:10.1016/j.nurt.2010.05.006
PMCID: PMC5084228  PMID: 20643377
Autism; ASD; oxytocin; translational model; repetitive behavior; social behavior; social cognition; social functioning; therapeutics; arginine vasopressin; epigenetic
22.  A Replication of the Autism Diagnostic Observation Schedule (ADOS) Revised Algorithms 
Objective
To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282).
Method
Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment.
Results
Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified.
Conclusions
Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.
doi:10.1097/CHI.0b013e31816bffb7
PMCID: PMC3057666  PMID: 18434924
autism; pervasive developmental disorders not otherwise specified; Autism Diagnostic Observation Schedule; diagnosis
23.  Brief Report: Parental Age and the Sex Ratio in Autism 
The male-to-female (M:F) ratio for autism spectrum disorders (ASD), typically about 4:1, appears to decrease with increasing paternal age, but this relationship has not been systematically tested. With 393 ASD cases from families with two or more ASD cases, we categorized paternal age into five age groups (<30, 30–34, 35–39, 40–44, 45+) and found that the M:F ratio was significantly decreased with increasing paternal age groups and remained so after also adjusting for maternal age. No significant relationship between maternal age group and the M:F ratio was observed. This study suggests that the M:F ratio is reduced with increasing paternal age consistent with de novo genetic or genomic anomalies arising more frequently as men age and then conceive children.
doi:10.1007/s10803-009-0755-y
PMCID: PMC3056272  PMID: 19452267
Paternal age; Maternal age; Sex ratio; Genetics; Genomic anomalies; Copy number variants
24.  Divalproex Sodium vs Placebo for the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorders 
Neuropsychopharmacology  2009;35(4):990-998.
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46±2.46, mean nonverbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.
doi:10.1038/npp.2009.202
PMCID: PMC2846602  PMID: 20010551
ASD; irritability; divalproex; children; adolescents; Development/Developmental Disorders; Psychiatry & Behavioral Sciences; Psychopharmacology; Clinical Pharmacology/Trials; autism; adolescents; children; EEG; divalproex
25.  THE RELATIONSHIP BETWEEN WHOLE BLOOD SEROTONIN AND REPETITIVE BEHAVIORS IN AUTISM 
Psychiatry research  2009;175(3):274.
This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated.
doi:10.1016/j.psychres.2009.02.008
PMCID: PMC2815211  PMID: 20044143
autism; serotonin; repetitive behavior; self-injury; aggression

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