PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (87)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Autism Spectrum and Obsessive–Compulsive Disorders: OC Behaviors, Phenotypes and Genetics 
Autism spectrum disorders (ASDs) are a phenotypically and etiologically heterogeneous set of disorders that include obsessive–compulsive behaviors (OCB) that partially overlap with symptoms associated with obsessive–compulsive disorder (OCD). The OCB seen in ASD vary depending on the individual’s mental and chronological age as well as the etiology of their ASD. Although progress has been made in the measurement of the OCB associated with ASD, more work is needed including the potential identification of heritable endophenotypes. Likewise, important progress toward the understanding of genetic influences in ASD has been made by greater refinement of relevant phenotypes using a broad range of study designs, including twin and family-genetic studies, parametric and nonparametric linkage analyses, as well as candidate gene studies and the study of rare genetic variants. These genetic analyses could lead to the refinement of the OCB phenotypes as larger samples are studied and specific associations are replicated. Like ASD, OCB are likely to prove to be multidimensional and polygenic. Some of the vulnerability genes may prove to be generalist genes influencing the phenotypic expression of both ASD and OCD while others will be specific to subcomponents of the ASD phenotype. In order to discover molecular and genetic mechanisms, collaborative approaches need to generate shared samples, resources, novel genomic technologies, as well as more refined phenotypes and innovative statistical approaches. There is a growing need to identify the range of molecular pathways involved in OCB related to ASD in order to develop novel treatment interventions.
doi:10.1002/aur.108
PMCID: PMC3974607  PMID: 20029829
2.  Oxytocin and vasopressin in children and adolescents with autism spectrum disorders: Sex differences and associations with symptoms 
There has been intensified interest in the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) in autism spectrum disorders (ASD) given their role in affiliative and social behavior in animals, positive results of treatment studies using OT, and findings that genetic polymorphisms in the AVP-OT pathway are present in individuals with ASD. Nearly all such studies in humans have focused only on males. With this preliminary study, we provide basic and novel information on the involvement of OT and AVP in autism with an investigation of blood plasma levels of these neuropeptides in 75 preadolescent and adolescent girls and boys ages 8–18: 40 with high-functioning ASD (19 girls, 21 boys) and 35 typically developing children (16 girls, 19 boys). We related neuropeptide levels to social, language, repetitive behavior, and internalizing symptom measures in these individuals. There were significant gender effects: Girls showed higher levels of OT while boys had significantly higher levels of AVP. There were no significant effects of diagnosis on OT or AVP. Higher OT values were associated with greater anxiety in all girls and with better pragmatic language in all boys and girls. AVP levels were positively associated with restricted and repetitive behaviors in girls with ASD but negatively (non-significantly) associated with these behaviors in boys with ASD. Our results challenge the prevailing view that plasma OT levels are lower in individuals with ASD and suggest there are distinct and sexually dimorphic mechanisms of action for OT and AVP underlying anxiety and repetitive behaviors.
Lay Abstract
Oxytocin (OT) and arginine vasopressin (AVP) are neuropeptides that are involved in affiliative and social behavior. Previous studies have shown that boys with autism spectrum disorders (ASD) have lower levels of OT than boys without ASD, and treatment studies have found that intranasal infusions of OT increase social behaviors in mostly males with ASD. With this study, we provide basic and novel information on the involvement of OT and AVP in ASD with an investigation of blood plasma levels of these neuropeptides in 75 preadolescent and adolescent girls and boys ages 8–18: 40 with high-functioning ASD and 35 typically developing children. We related OT and AVP levels to social, language, repetitive behavior, and internalizing symptom measures in these individuals. Girls had higher levels of OT while boys had higher levels of AVP. There were no differences in OT or AVP levels between the ASD and typically developing groups. Higher OT values were associated with greater anxiety in all girls and with less impaired social language in all boys and girls. Higher levels of AVP were associated with greater restricted and repetitive behaviors in girls with ASD whereas lower levels of AVP levels were associated with lower levels of these behaviors in boys with ASD. Results challenge the prevailing view that OT levels are lower in individuals with ASD, and suggest there are distinct mechanisms of action for OT and AVP underlying anxiety and repetitive behavior symptoms for boys versus girls.
doi:10.1002/aur.1270
PMCID: PMC3657571  PMID: 23413037
Neuropeptides; oxytocin; vasopressin; autism; sex differences; repetitive behaviors; anxiety
3.  The Broad Autism Phenotype Questionnaire: Prevalence and Diagnostic Classification 
The Broad Autism Phenotype Questionnaire (BAPQ; Hurley et al, 2007) was administered to a large community-based sample of biological parents of children with autism (PCAs) and comparison parents (CPs) (n = 1692). Exploratory factor analysis and internal consistency parameters confirmed a robust three factor structure of the BAPQ, corresponding to the proposed aloof, pragmatic language and rigidity subscales. Based upon the distribution of BAP features in the general population, new normative cutoff values for BAPQ subscales were established that provide increased specificity relative to those previously reported (Hurley et al, 2007), and thus enhance the utility of the BAPQ for diagnostically classifying the BAP. These cutoffs were also used to estimate prevalence of the BAP and its three components, with rates ranging between 14 – 23% for PCAs and between 5 – 9% for CPs. Analysis of patterns of BAP characteristics within family members revealed that BAP features were more likely to co-occur in PCAs relative to CPs. Collectively, these findings extend the utility of the BAPQ and provide additional evidence that it is an efficient and reliable tool for disaggregating the heterogeneity of autism through the identification of meaningful subgroups of parents.
doi:10.1002/aur.1272
PMCID: PMC3661685  PMID: 23427091
Autism; Broad Autism Phenotype; Assessment; Prevalence; Genetics
4.  Endogenous spatial attention: evidence for intact functioning in adults with autism 
Lay Abstract
Attention allows us to selectively process the vast amount of information with which we are confronted. Focusing on a certain location of the visual scene (visual spatial attention) enables the prioritization of some aspects of information while ignoring others. Rapid manipulation of the attention field (i.e., the location and spread of visual spatial attention) is a critical aspect of human cognition, and previous research on spatial attention in individuals with autism spectrum disorders (ASD) has produced inconsistent results. In a series of three experiments, we evaluated claims in the literature that individuals with ASD exhibit a deficit in voluntarily controlling the deployment and size of the spatial attention field. We measured how well participants perform a visual discrimination task (accuracy) and how quickly they do so (reaction time), with and without spatial uncertainty (i.e., the lack of predictability concerning the spatial position of the upcoming stimulus). We found that high–functioning adults with autism exhibited slower reactions times overall with spatial uncertainty, but the effects of attention on performance accuracies and reaction times were indistinguishable between individuals with autism and typically developing individuals, in all three experiments. These results provide evidence of intact endogenous spatial attention function in high–functioning adults with ASD, suggesting that atypical endogenous spatial attention cannot be a latent characteristic of autism in general.
Scientific Abstract
Rapid manipulation of the attention field (i.e., the location and spread of visual spatial attention) is a critical aspect of human cognition, and previous research on spatial attention in individuals with autism spectrum disorders (ASD) has produced inconsistent results. In a series of three psychophysical experiments, we evaluated claims in the literature that individuals with ASD exhibit a deficit in voluntarily controlling the deployment and size of the spatial attention field. We measured the spatial distribution of performance accuracies and reaction times to quantify the sizes and locations of the attention field, with and without spatial uncertainty (i.e., the lack of predictability concerning the spatial position of the upcoming stimulus). We found that high–functioning adults with autism exhibited slower reactions times overall with spatial uncertainty, but the effects of attention on performance accuracies and reaction times were indistinguishable between individuals with autism and typically developing individuals, in all three experiments. These results provide evidence of intact endogenous spatial attention function in high–functioning adults with ASD, suggesting that atypical endogenous attention cannot be a latent characteristic of autism in general.
doi:10.1002/aur.1269
PMCID: PMC3661738  PMID: 23427075
Attention; spatial attention; endogenous attention; psychophysics; adults; autism; autism spectrum disorders; ASD
5.  Stability and Validity of an Automated Measure of Vocal Development From Day-Long Samples in Children With and Without Autism Spectrum Disorder 
Lay Abstract
Measuring the degree to which young children’s vocalizations, many of which are non-words, have acoustic characteristics similar to speech may eventually help us match expectations and treatment methods to individual needs and abilities. To accomplish this goal, we need vocal measures that have scientific utility. The current study indicates that a single all-day recording and subsequent computer-analysis of its acoustic characteristics produces a measure of vocal development that is highly related to expressive language in children with ASD and in children who are typically developing. These findings provide the needed basis for future use of this measure for clinical and scientific purposes.
Scientific Abstract
Individual difference measures of vocal development may eventually aid our understanding of the variability in spoken language acquisition in children with autism spectrum disorder (ASD). Large samples of child vocalizations may be needed to maximize the stability of vocal development estimates. Day-long vocal samples can now be automatically analyzed based on acoustic characteristics of speech-likeness identified in theoretically-driven and empirically cross-validated quantitative models of typical vocal development. This report indicates that a single day-long recording can produce a stable estimate for a measure of vocal development that is highly related to expressive spoken language in a group of young children with ASD and in a group that is typically developing.
doi:10.1002/aur.1271
PMCID: PMC3664259  PMID: 23436778
6.  Longitudinal Heschl’s gyrus growth during childhood and adolescence in typical development and autism 
Heightened auditory sensitivity and atypical processing of sounds by the brain are common in autism. Functional studies that measure brain activity suggest abnormal neural response to sounds, yet the development underlying atypical sound processing in autism is unknown. We examined the growth of the first cortical area of the brain to process sound, the primary auditory cortex, also known as Heschl’s gyrus. Volume of Heschl’s gyrus gray and white matter was measured using structural MRI in 40 children and adolescents with autism and 17 typically developing participants. Up to three time points of volumetric brain data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at their first scan. Our study is the first to examine volumetric changes during childhood and adolescence in Heschl’s gyrus longitudinally, or in the same individuals over time. Consistent with previous studies using only one time point of data, no differences between the participant groups were found in Heschl’s gyrus gray matter volume. However, reduced longitudinal growth of Heschl’s gyrus gray matter volume was found in the right hemisphere in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical growth of Heschl’s gyrus white matter volume was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened reported sensitivity to sounds, obtained from the Sensory Profile, was associated with reduced gray matter volume growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl’s gyrus throughout childhood and adolescence in both typical development and autism.
doi:10.1002/aur.1265
PMCID: PMC3669648  PMID: 23436773
autism; Heschl’s gyrus; longitudinal development; MRI
7.  Neonatal Brainstem Function and Four-Month Arousal Modulated Attention are Jointly Associated with Autism 
Lay Abstract
A stronger preference for high rates of stimulation when tested after feeding at four months of age has been reported in Neonatal Intensive Care Unit (NICU) graduates who later were diagnosed with autism relative to those who were not. This visual preference is typical of newborns, is likely mediated by arousal systems in the brainstem, and should no longer be present by four months. The fact that it was so persistent in babies who later developed autism suggested they may have had atypical brainstem development or functioning. There exists a group of newborns who initially fail Auditory Brainstem Response screens (ABRs; a measure of the integrity of their brainstem auditory pathways) but eventually recover by hospital discharge suggesting they have atypical brainstem development. We therefore examined the extent to which this problem with ABR functioning along with four-month-olds’ preference for high rates of stimulation predicts the later occurrence of autism in toddlers and preschoolers. We found that preference for higher rates of stimulation at four months was highly associated with later measures of autism severity and with language development problems but only in those who had initially abnormal ABRs. It was concluded that the joint occurrence of initially abnormal neonatal ABRs and preference for more stimulation at four months, both indices of early brainstem dysfunction, may be a marker for the development of autism.
Scientific Abstract
The authors evaluated the contribution of initially abnormal neonatal Auditory Brainstem Responses (ABRs) and four month Arousal Modulated Attention visual preference to later Autism Spectrum Disorder (ASD) behaviors in Neonatal Intensive Care Unit (NICU) graduates. A longitudinal study design was used to compare NICU graduates with normal ABRs (n=28) to those with initially abnormal ABRs (n=46) that later resolved. At four months post-term-age, visual preference (measured after feeding) for random check patterns flashing at 1, 3, or 8 Hz, and gestational age (GA) served as additional predictors. Outcome measures were PDD Behavior Inventory (PDDBI) scores at 3.4 (SD=1.2) years, and DQs obtained around the same age with the Griffiths Mental Development Scales (GMDS). Preferences for higher rates of stimulation at four months were highly correlated with PDDBI scores (all p values <.01), and the GMDS Hearing and Speech DQ but only in those with initially abnormal ABRs. Effects were strongest for a PDDBI social competence measure most associated with a diagnosis of autism. For those with abnormal ABRs, increases in preference for higher rates of stimulation as infants were linked to non-linear increases in severity of ASD at three years and to an ASD diagnosis. Abnormal ABRs were associated with later reports of repetitive and ritualistic behaviors irrespective of four month preference for stimulation. The joint occurrence of initially abnormal neonatal ABRs and preference for more stimulation at four months, both indices of early brainstem dysfunction, may be a marker for the development of autism in this cohort.
doi:10.1002/aur.1259
PMCID: PMC3578986  PMID: 23165989
Auditory Brainstem Response; Infancy; Attention; Arousal; Repetitive and Ritualistic Behaviors; Autism Spectrum Disorder
8.  The behavioral phenotype in MECP2 duplication syndrome: A comparison to idiopathic autism 
Alterations in the X-linked gene MECP2 encoding the methyl-CpG-binding protein 2 (MeCP2) have been linked to autism spectrum disorders (ASD). Most recently, data suggest that overexpression of MECP2 may be related to ASD. To better characterize the relevance of MECP2 overexpression to ASD-related behaviors, we compared the core symptoms of ASD in MECP2 duplication syndrome to nonverbal-mental-age-matched boys with idiopathic ASD. Within the MECP2 duplication group we further delineated aspects of the behavioral phenotype, and also examined how duplication size and gene content corresponded to clinical severity. We compared 10 males with MECP2 duplication syndrome (ages 3–10) to a chronological and mental age-matched sample of 9 nonverbal males with idiopathic ASD. Our results indicate that boys with MECP2 duplication syndrome share the core behavioral features of ASD (e.g. social affect, restricted/repetitive behaviors). Direct comparisons of ASD profiles revealed that a majority of boys with MECP2 duplication syndrome are similar to idiopathic ASD; they have impairments in social affect (albeit to a lesser degree than idiopathic ASD) and similar severity in restricted/repetitive behaviors. Nonverbal mental age did not correlate with severity of social impairment or repetitive behaviors. Within the MECP2 duplication group, breakpoint size does not predict differences in clinical severity. In addition to social withdrawal and stereotyped behaviors, we also found that hyposensitivity to pain/temperature are part of the behavioral phenotype of MECP2 duplication syndrome. Our results illustrate that overexpression/increased dosage of MECP2 is related to core features of ASD.
doi:10.1002/aur.1262
PMCID: PMC3578988  PMID: 23169761
Autism; MECP2; genetics; phenotype; social affect; overexpression
9.  Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: A 1H-MRS study 
Lay Abstract
We investigated brain chemistry of the primary region of the brain involved in auditory processing in adults with autism spectrum disorder (ASD). Due to the highly heritable nature of ASD and the lack of prior brain chemistry data on unaffected first-degree relatives, we also enrolled parents of children with ASD (pASD), comparing both groups to a healthy adult control group. The technique used to quantify chemical signals was magnetic resonance spectroscopy (MRS), which we used to assess the concentration of auditory glutamate, the primary excitatory brain neurotransmitter, as well as other metabolites that assess neuronal integrity and metabolism. We found significantly higher levels of auditory glutamate in persons with ASD. In addition, increases in two other metabolites, n-acetyl-aspartate (NAA), and creatine (Cr), were observed in the ASD group. No differences were observed in the pASD group in any MRS measurement. We interpret the glutamate finding as suggestive of an increase in brain excitability, and the NAA and Cr findings as indicative of a change in brain energy metabolism in ASD.
Scientific Abstract
Increased glutamate levels have been reported in the hippocampal and frontal regions of persons with autism using proton magnetic resonance spectroscopy (1H-MRS). Although autism spectrum disorders (ASD) are highly heritable, MRS studies have not included relatives of persons with ASD. We therefore conducted a study to determine if glutamate levels are elevated in people with autism and parents of children with autism.
Single-voxel, point resolved spectroscopy (PRESS) data were acquired at 3T for left and right hemisphere auditory cortical voxels in 13 adults with autism, 15 parents of children with autism, and 15 adult control subjects. The primary measure was Glx. Additional measures included n-acetyl-aspartate (NAA), choline (Cho), myoinositol (mI) and creatine (Cr).
The autism group had significantly higher Glx, NAA and Cr concentrations than the control subjects. Parents did not differ from control subjects on any measures. No significant differences in Cho or mI levels were seen among groups. No reliable correlations between autism symptom measures and MRS variables were seen after Bonferroni correction for multiple comparisons.
The elevation in Glx in autism is consistent with prior MRS data in the hippocampus and frontal lobe and may suggest increased cortical excitability. Increased NAA and Cr may indicate brain metabolism disturbances in autism. In the current study, we found no reliable evidence of a familial effect for any spectroscopy measure. This may indicate that these metabolites have no heritable component in autism, the presence of a compensatory factor in parents, or sample specific limitations such the participation of singleton families.
doi:10.1002/aur.1260
PMCID: PMC3580156  PMID: 23166003
glutamate; n-acetyl-aspartate; creatine; spectroscopy; auditory cortex
10.  Macrocephaly as a Clinical Indicator of Genetic Subtypes in Autism 
An association between autism and large head size has been previously described. Historically a subset of these cases have been correlated with mutations in the gene phosphatase and tensin homolog (PTEN). However, for the majority of cases the etiology is not known. We have studied 33 patients with autism and large head size. Within this group, we confirm the association of PTEN mutations and extreme head size and identify mutations in 22% of cases, including three novel PTEN mutations. In addition we define three novel phenotypic subgroups: (1) cases associated with somatic overgrowth (2) those with disproportionate macrocephaly and (3) those with relative macrocephaly. Members of these subgroups lack changes in the PTEN gene and furthermore we report two novel copy number changes in these patients.
An association between autism and macrocephaly has been previously described. A subset of cases with extreme macrocephaly (>3SD, 99.7th %ile) have been correlated to mutations in the gene phosphatase and tensin homolog (PTEN). However, the phenotypic and genetic characterization of the remaining cases remains unclear. We report the phenotypic classification and genetic testing evaluation of a cohort of 33 patients with autism and macrocephaly. Within our cohort, we confirm the association of PTEN mutations and extreme macrocephaly (> 3SD, 99.7th %ile) and identify mutations in 22% of cases, including three novel PTEN mutations. In addition we define three phenotypic subgroups: (1) those cases associated with somatic overgrowth, (2) those with disproportionate macrocephaly, and (3) those will relative macrocephaly. We have devised a novel way to segregate patients into these subgroups that will aide in the stratification of autism macrocephaly cases. Within these subgroups, we further expand the genetic etiologies for autism cases with macrocephaly by describing two novel suspected pathogenic Copy Number Variants (CNVs) located at 6q23.2 and 10q24.32. These findings demonstrate the phenotypic heterogeneity of autism cases associated with macrocephaly and their genetic etiologies. The clinical yield from PTEN mutation analysis is 22% and 9% from Chromosomal Microarray (CMA) testing within this cohort. The identification of three distinct phenotypic subgroups within macrocephaly autism patients may allow for the identification of their respective distinct genetic etiologies which to date have remained elusive.
doi:10.1002/aur.1266
PMCID: PMC3581311  PMID: 23361946
Autism; Macrocephaly; PTEN; Overgrowth; Hypotonia
11.  Quantifying Repetitive Speech in Autism Spectrum Disorders and Language Impairment 
We report on an automatic technique for quantifying two types of repetitive speech: repetitions of what the child says him/herself (self-repeats) and of what is uttered by an interlocutor (echolalia). We apply this technique to a sample of 111 children between the ages of four and eight: 42 typically developing children (TD), 19 children with specific language impairment (SLI), 25 children with autism spectrum disorders (ASD) plus language impairment (ALI), and 25 children with ASD with normal, non-impaired language (ALN). The results indicate robust differences in echolalia between the TD and ASD groups as a whole (ALN + ALI), and between TD and ALN children. There were no significant differences between ALI and SLI children for echolalia or self-repetitions. The results confirm previous findings that children with ASD repeat the language of others more than other populations of children. On the other hand, self-repetition does not appear to be significantly more frequent in ASD, nor does it matter whether the child’s echolalia occurred within one (immediate) or two turns (near-immediate) of the adult’s original utterance. Furthermore, non-significant differences between ALN and SLI, between TD and SLI, and between ALI and TD are suggestive that echolalia may not be specific to ALN or to ASD in general. One important innovation of this work is an objective fully automatic technique for assessing the amount of repetition in a transcript of a child’s utterances.
doi:10.1002/aur.1301
PMCID: PMC3808497  PMID: 23661504
autism spectrum disorder; specific language impairment; echolalia; repetitive behavior
12.  Deficits in Mental State Attributions in Individuals with 22q11.2 Deletion Syndrome (Velo-Cardio-Facial Syndrome) 
Velo-cardio-facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically-developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video-based task to assess mentalizing at two sites (UCLA and SUNY Upstate Medical University). The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e., mentalizing) and Appropriateness. Using Repeated Measures ANOVA, we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM, but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real-life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions.
doi:10.1002/aur.1252
PMCID: PMC3528795  PMID: 22962003
22q11.2 deletion syndrome; Velo-cardio-facial syndrome; Theory of Mind; Autism Spectrum Disorders; reciprocal social behavior; social cognition
13.  The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1 
The methyl-CpG-binding domain (MBD) gene family was first linked to autism over a decade ago when Rett syndrome, which falls under the umbrella of autism spectrum disorders (ASDs), was revealed to be predominantly caused by MECP2 mutations. Since that time, MECP2 alterations have been recognized in idiopathic ASD patients by us and others. Individuals with deletions across the MBD5 gene also present with ASDs, impaired speech, intellectual difficulties, repetitive behaviors, and epilepsy. These findings suggest that further investigations of the MBD gene family may reveal additional associations related to autism. We now describe the first study evaluating individuals with ASD for rare variants in four autosomal MBD family members, MBD5, MBD6, SETDB1, and SETDB2, and expand our initial screening in the MECP2 gene. Each gene was sequenced over all coding exons and evaluated for copy number variations in 287 patients with ASD and an equal number of ethnically matched control individuals. We identified 186 alterations through sequencing, approximately half of which were novel (96 variants, 51.6%). We identified seventeen ASD specific, nonsynonymous variants, four of which were concordant in multiplex families: MBD5 Tyr1269Cys, MBD6 Arg883Trp, MECP2 Thr240Ser, and SETDB1 Pro1067del. Furthermore, a complex duplication spanning the MECP2 gene was identified in two brothers who presented with developmental delay and intellectual disability. From our studies, we provide the first examples of autistic patients carrying potentially detrimental alterations in MBD6 and SETDB1, thereby demonstrating that the MBD gene family potentially plays a significant role in rare and private genetic causes of autism.
doi:10.1002/aur.1251
PMCID: PMC3528798  PMID: 23055267
autism spectrum disorders (ASDs); copy number variation (CNV); methyl-CpG-binding domain (MBD); Rett syndrome; single nucleotide polymorphism (SNP)
14.  Autism Risk Gene MET Variation and Cortical Thickness in Typically Developing Children and Adolescents 
MET receptor tyrosine kinase (MET) has been proposed as a candidate risk gene for autism spectrum disorder (ASD) based on associations between MET polymorphisms and ASD diagnosis, as well as evidence from animal studies that MET protein may regulate early development of cortical regions implicated in the neurobiology of ASD. The relevance of differences in MET signaling for human cortical development remains unexamined, however. We sought to address this issue by relating genotype at a functional single nucleotide polymorphism within the MET promoter (rs1858830, G→C), to in vivo measures of cortical thickness development derived from 222 healthy children and adolescents with 514 longitudinally acquired structural MRI brain scans between ages 9 and 22 years. We identified a statistically significant, developmentally fixed, and stepwise CT reduction with increasing C allele dose in superior and middle temporal gyri, ventral pre- and post-central gyri, and anterior cingulate bilaterally, and in the right fronto-polar cortex. We were also able to demonstrate that mean CT within these cortical regions showed a statistically significant reduction with increasing scores on a continuous measure of autistic traits (the Social Responsiveness Scale). The cortical regions highlighted by our analyses are not only established areas of MET expression during prenatal life, but are also key components of the “social brain” which have frequently shown structural and functional abnormalities in autism. Our results suggest that genetic differences in the MET gene may influence the development of cortical systems implicated in the neurobiology of ASD
doi:10.1002/aur.1256
PMCID: PMC3528800  PMID: 23097380
MET receptor tyrosine kinase; cortex; autism; development; MRI
15.  Atypical Cry Acoustics in 6-Month-Old Infants at Risk for Autism Spectrum Disorder 
This study examined differences in acoustic characteristics of infant cries in a sample of babies at risk for autism and a low-risk comparison group. Cry samples derived from vocal recordings of 6-month-old infants at risk for autism spectrum disorder (ASD; n = 21) and low-risk infants (n = 18) were subjected to acoustic analyses using analysis software designed for this purpose. Cries were categorized as either pain-related or non-pain-related based on videotape coding. At-risk infants produced pain-related cries with higher and more variable fundamental frequency (F0) than low-risk infants. At-risk infants later classified with ASD at 36 months had among the highest F0 values for both types of cries and produced cries that were more poorly phonated than those of nonautistic infants, reflecting cries that were less likely to be produced in a voiced mode. These results provide preliminary evidence that disruptions in cry acoustics may be part of an atypical vocal signature of autism in early life.
doi:10.1002/aur.1244
PMCID: PMC3517274  PMID: 22890558
autism; infancy; cry; vocalizations; acoustic analysis
16.  Children with Autism Show Reduced Somatosensory Response: An MEG Study 
Lay Abstract
Autism spectrum disorders are reported to affect nearly one out of every one hundred children, with over 90% of these children showing behavioral disturbances related to the processing of basic sensory information. Behavioral sensitivity to light touch, such as profound discomfort with clothing tags and physical contact, is a ubiquitous finding in children on the autism spectrum. In this study, we investigate the strength and timing of brain activity in response to simple, light taps to the fingertip. Our results suggest that children with autism show a diminished early response in the primary somatosensory cortex (S1). This finding is most evident in the left hemisphere. In exploratory analysis, we also show that tactile sensory behavior, as measured by the Sensory Profile, may be a better predictor of the intensity and timing of brain activity related to touch than a clinical autism diagnosis. We report that children with atypical tactile behavior have significantly lower amplitude somatosensory cortical responses in both hemispheres. Thus sensory behavioral phenotype appears to be a more powerful strategy for investigating neural activity in this cohort. This study provides evidence for atypical brain activity during sensory processing in autistic children and suggests that our sensory behavior based methodology may be an important approach to investigating brain activity in people with autism and neurodevelopmental disorders.
Scientific Abstract
The neural underpinnings of sensory processing differences in autism remain poorly understood. This prospective magnetoencephalography (MEG) study investigates whether children with autism show atypical cortical activity in the primary somatosensory cortex (S1) in comparison to matched controls. Tactile stimuli were clearly detectable, painless taps applied to the distal phalanx of the second (D2) and third (D3) fingers of the right and left hands. Three tactile paradigms were administered: an oddball paradigm (standard taps to D3 at an inter-stimulus interval (ISI) of 0.33 and deviant taps to D2 with ISI ranging from 1.32–1.64s); a slow-rate paradigm (D2) with an ISI matching the deviant taps in the oddball paradigm; and a fast-rate paradigm (D2) with an ISI matching the standard taps in the oddball. Study subjects were boys (age 7–11 years) with and without autism disorder. Sensory behavior was quantified using the Sensory Profile questionnaire. Boys with autism exhibited smaller amplitude left hemisphere S1 response to slow and deviant stimuli during the right hand paradigms. In post-hoc analysis, tactile behavior directly correlated with the amplitude of cortical response. Consequently, the children were re-categorized by degree of parent-report tactile sensitivity. This regrouping created a more robust distinction between the groups with amplitude diminution in the left and right hemispheres and latency prolongation in the right hemisphere in the deviant and slow-rate paradigms for the affected children. This study suggests that children with autism have early differences in somatosensory processing, which likely influence later stages of cortical activity from integration to motor response.
doi:10.1002/aur.1247
PMCID: PMC3474892  PMID: 22933354
Cognitive Neuroscience; Event Related Potential; School age; Low-level perception; Magnetoencephalography
17.  Diffusion Tensor Imaging in Autism Spectrum Disorder: A Review 
Lay Abstract
White matter tracts are like the “highways” of the brain, allowing for fast and efficient communication among diverse brain regions. The purpose of this paper is to review the results of autism studies that have used Diffusion Tensor Imaging (DTI), which is a neuroimaging method that allows us to examine the structure and integrity of these white matter tracts. From the 48 studies we reviewed, persons with ASD tended to have decreased white matter integrity spanning across many regions of the brain but most consistently in regions such as the corpus callosum (connecting the left and right hemispheres and associated with motor skill and complex information processing), the cingulum bundles (connecting regions along the middle-line of the brain with important frontal projections and associated with executive function), and white matter tracts that pass through the temporal lobe (connecting temporal lobe regions with other brain regions and associated with social functioning). The pattern of results in these studies suggests that the white matter tracts may be atypical in persons with ASD. Additionally, the review suggests that people with ASD may not exhibit the typical left-greater-than-right-brain asymmetry in white matter integrity compared to people with typical development. White matter alterations in persons with ASD are a target of emerging interventions and may help identify the brain basis of individual differences in this population.
Scientific Abstract
White matter tracts of the brain allow neurons and neuronal networks to communicate and function with high efficiency. The aim of this review is to briefly introduce Diffusion Tensor Imaging (DTI) methods that examine white matter tracts and then to give an overview of the studies that have investigated white matter integrity in the brains of individuals with Autism Spectrum Disorder (ASD). From the 48 studies we reviewed, persons with ASD tended to have decreased fractional anisotropy and increased mean diffusivity in white matter tracts spanning many regions of the brain but most consistently in regions such as the corpus callosum, cingulum, and aspects of the temporal lobe. This decrease in fractional anisotropy was often accompanied by increased radial diffusivity. Additionally, the review suggests possible atypical lateralization in some white matter tracts of the brain and a possible atypical developmental trajectory of white matter microstructure in persons with ASD. Clinical implications and future research directions are discussed.
doi:10.1002/aur.1243
PMCID: PMC3474893  PMID: 22786754
Diffusion Tensor Imaging; Neuroimaging; Autism; White Matter
18.  Same but different: Nine-month-old infants at average and high risk for autism look at the same facial features but process them using different brain mechanisms 
Lay Abstract
Reduced attention to the eyes and/or increased focus on the mouth have been described as features of atypical face processing in individuals with autism spectrum disorders (ASD). In this study, we examined whether 9-month-old infants at average vs. high risk for ASD differ in their detection of changes in individual facial features (eyes vs. mouth) and whether this ability is related to infants’ social and communicative skills. Eye tracking data and electrical brain activity were recorded while infants viewed repeated presentations of a smiling unfamiliar female face. Occasionally, the eyes or the mouth of that face were replaced with corresponding parts from a different face. There were no group differences in the number or duration of fixations on the eye or mouth regions for any of the face stimuli. Brain activity data revealed that all infants detected both eye and mouth changes, and that these changes were associated with changes in activity of the face-specific perception mechanisms for average-risk infants only. For all infants, the size and speed of brain responses correlated with parental reports of communication use and understanding, suggesting that differences in brain processing of faces and their features in infants are associated with individual differences in early communication skills.
Scientific Abstract
The study examined whether 9-month-old infants at average vs. high risk for autism spectrum disorder (ASD) process facial features (eyes, mouth) differently, and whether such differences are related to infants’ social and communicative skills. Eye tracking and visual event-related potentials (ERPs) were recorded in 35 infants (20 average-risk typical infants, 15 high-risk siblings of children with ASD) while they viewed photographs of a smiling unfamiliar female face. On 30% of the trials, the eyes or the mouth of that face were replaced with corresponding features from a different female. There were no group differences in the number, duration, or distribution of fixations, and all infants looked at the eyes and mouth regions equally. However, increased attention to the mouth was associated with weaker receptive communication skills and increased attention to the eyes correlated with better interpersonal skills. ERP results revealed that all infants detected eye and mouth changes but did so using different brain mechanisms. Changes in facial features were associated with changes in activity of the face perception mechanisms (N290) for the average-risk group, but not for the high-risk infants. For all infants, correlations between ERP and eye tracking measures indicated that larger and faster ERPs to feature changes were associated with fewer fixations on the irrelevant regions of stimuli. The size and latency of the ERP responses also correlated with parental reports of receptive and expressive communication skills, suggesting that differences in brain processing of human faces are associated with individual differences in social-communicative behaviors.
doi:10.1002/aur.1231
PMCID: PMC3422441  PMID: 22674669
Face processing; ERP; eye tracking; infants; ASD; Vineland
19.  The ADOS Calibrated Severity Score: Relationship to Phenotypic Variables and Stability over Time 
LAY ABSTRACT
Measuring the severity of autism is a challenge for researchers and clinicians. Recently, Gotham et al., (2009) addressed this issue by creating calibrated severity scores (CSS) based on raw total scores of the Autism Diagnostic Observation Schedule (ADOS), a standardized measure commonly used in autism diagnosis. We tested the utility of the CSS by comparing its scores to raw scores from the ADOS in a sample of 368 children aged 2–12 years with autism, PDD-NOS, non-spectrum delay, or typical development. As expected, we found that the CSS were more uniformly distributed within diagnostic categories and across ADOS modules than were raw scores. In particular, CSS were useful in controlling for differences in verbal development. Follow-up evaluations showed good temporal stability of the CSS over 12–24 months in children with autism. The results of this study support the use of the CSS to measure the severity of the core symptoms of autism. Further research is needed to determine if the CSS can also be used to measure changes in symptom severity and serve as a tool for clinical research.
SCIENTIFIC ABSTRACT
Measurement of the severity of autism at a single time point, and over time, is a widespread challenge for researchers. Recently, Gotham et al., (2009) published a severity metric (calibrated severity scores; CSS) that takes into account age and language level and is based on raw total scores of the Autism Diagnostic Observation Schedule (ADOS), a standardized measure commonly used in autism diagnosis. The present study examined psychometric characteristics of the CSS compared to raw scores in an independent sample of 368 children aged 2–12 years with autism, PDD-NOS, non-spectrum delay, or typical development. Reflecting the intended calibration, the CSS were more uniformly distributed within clinical diagnostic category and across ADOS modules than were raw scores. Cross sectional analyses examining raw and severity scores and their relationships to participant characteristics revealed that verbal developmental level was a significant predictor of raw score, but accounted for significantly less variance in the CSS. Longitudinal analyses indicated overall stability of the CSS over 12–24 months in children with autism. Findings from this study support the use of the CSS as a more valid indicator of autism severity than the ADOS raw total score, and extend the literature by examining the stability over 12–24 months of the CSS in children with ASD.
doi:10.1002/aur.1238
PMCID: PMC3422401  PMID: 22628087
Autism Diagnostic Observation Schedule (ADOS); Autism Spectrum Disorders; Severity; Diagnosis
20.  Children With Autism Demonstrate Circumscribed Attention During Passive Viewing of Complex Social and Nonsocial Picture Arrays 
Although circumscribed interests are a hallmark characteristic of autism spectrum disorders, providing a means for quantifying their functional impairment has proven difficult. We developed a passive viewing task to measure aspects of visual attention in children with autism spectrum disorders and typically developing controls. Task stimuli included picture arrays that were matched for social and nonsocial content. Nonsocial content was balanced to include items related to circumscribed interests (e.g., trains) as well as more commonplace items (e.g., furniture). Discrete aspects of gaze behavior were quantified using eye-tracking technology. Results indicate that visual attention in the autism group was more circumscribed (as indicated by the exploration of fewer images), more perseverative (as indicated by longer fixation times per image explored), and more detail oriented (as indicated by a greater number of discrete fixations on explored images). This pattern of results was similar for both social and object arrays. Within the autism group, overall severity of repetitive behavior symptoms correlated positively with exploration of object pictures and negatively with perseveration on social pictures. Results suggest that children with autism have a domain-general pattern of atypical visual attention that may represent an exaggeration of a typical attentional process and is related to a tendency to perseverate on images of interest and explore them in a more detail-oriented manner. Discrete measures of visual attention may therefore provide a reasonable means of quantifying aspects of the repetitive behavior phenotype in autism.
doi:10.1002/aur.4
PMCID: PMC3709846  PMID: 19360648
autism; repetitive behavior; circumscribed interests; visual exploration; attention
21.  The Autism Diagnosis in Translation: Shared Affect in Children and Mouse Models of ASD 
In recent years, there have been significant improvements in assessment and diagnostic procedures for autism spectrum disorders (ASD). Standardized diagnostic instruments have been developed, promoting consistent diagnostic practices among clinicians. For clinical researchers, these instruments have facilitated collaborations across different sites by providing standardized metrics with which to evaluate ASD symptoms. Nevertheless, because ASD remains a diagnosis that is defined on the basis of behavior, there are significant challenges associated with modeling ASD social behaviors in laboratory animals. In order to more effectively study the causes of ASD symptoms and behaviors, there is a need to develop new ways of measuring social behaviors that can be applied to non-human species. Critically, while verbal dialogue between the clinician and patient is integral to clinical diagnoses, it cannot be employed for studies of animal models. However, observations of autistic-like social interactions can be modeled in animals. In this regard, communication between professionals in the clinical and basic sciences is necessary to break down the complex diagnosis into units of social impairment that can be more feasibly measured in different species. This paper presents a discussion between an animal researcher and a clinical psychologist. Using shared affect as an example, we explore potential avenues for increasing the utility of animal models to move us toward a better understanding of the mechanisms underlying social impairments in ASD.
In the absence of molecular biomarkers that can be used to diagnose ASD, current diagnostic tools depend upon clinical assessments of behavior. Research efforts with human subjects have successfully utilized standardized diagnostic instruments, which include clinician interviews with parents and direct observation of the children themselves (Risi et al., 2006). However, because clinical instruments are semi-structured and rely heavily on dynamic social processes and clinical skill, scores from these measures do not necessarily lend themselves directly to experimental investigations into the causes of ASD. Studies of the neurobiology of autism require experimental animal models. Mice are particularly useful, in this regard, for elucidating genetic and toxicologjcal contributions to impairments in social function (Halladay et al., 2009). Behavioral tests have been developed that are relevant to autism (Crawley, 2004, 2007), including measures of repetitive behaviors (Lewis, Tanimura, Lee, & Bodfish, 2007; Moy et al., 2008), social behavior (Brodkin, 2007; Lijam et al., 1997; Moretti, Bouwknecht, Teague, Paylor, & Zoghbi, 2005), and vocal communication (Panksepp et al., 2007). Advances also include development of high-throughput measures of mouse sociability that can be used to reliably compare inbred mouse strains (Moy, et al., 2008; Nadler et al., 2004), as well as measures of social reward (Panksepp & Lahvis, 2007) and empathy (Chen, Panksepp, & Lahvis, 2009; Langford et al., 2006). With continued generation of mouse gene-targeted mice that are directly relevant to genetic linkages in ASD, there remains an urgent need to utilize a full suite of mouse behavioral tests that allows for a comprehensive assessment of the spectrum of social difficulties relevant to ASD. Using impairments in shared affect as an example, this paper explores potential avenues for collaboration between clinical and basic scientists, within an amply considered translational framework.
doi:10.1002/aur.216
PMCID: PMC3684385  PMID: 21882361
22.  “Communities” in Community Engagement: Lessons Learned from Autism Research in South Africa and South Korea 
Scientific Abstract
Little research has been conducted on behavioral characteristics of children with ASD from diverse cultures within the US or from countries outside of the US or Europe, with little reliable information yet reported from developing countries. We describe the process used to engage diverse communities in ASD research in two community-based research projects—an epidemiological investigation of 7–12 year olds in South Korea and the Early Autism Project, an ASD detection program for 18–36 month old Zulu-speaking children in South Africa. Despite the differences in wealth between these communities, ASD is under-diagnosed in both settings, generally not reported in clinical or educational records. Moreover, in both countries there is low availability of services. In both cases, local knowledge helped researchers to address both ethnographic as well as practical problems. Researchers identified the ways in which these communities generate and negotiate the cultural meanings of developmental disorders. Researchers incorporated that knowledge as they engaged communities in a research protocol, adapted and translated screening and diagnostic tools, and developed methods for screening, evaluating, and diagnosing children with ASD.
doi:10.1002/aur.1229
PMCID: PMC3552431  PMID: 22566396
23.  [No title available] 
PMCID: PMC3644181  PMID: 21328570
24.  Allelic Variation within the Putative Autism Spectrum Disorder Risk Gene Homeobox-A-1 (HOXA1) and Cerebellar Maturation in Typically Developing Children and Adolescents 
Autism Research  2012;5(2):93-100.
LAY ABSTRACT
Autism is known to be highly heritable, and has been associated with abnormalities in the development of several brain structures, including the cerebellum. Previous research has hinted that a gene controlling the development of posterior brain regions such as the cerebellum, may influence risk for autism. This gene is called Homeobox Domain A1 (HOXA1), and the variant within HOXA1 that has been most studied in relation to autism (A218G) falls within a gene region that is important for HOXA1 protein functioning. Although we know that autism appear to influence the dynamics of brain development, and that cerebellar anatomy continues to change over the lifespan – we do not know if A218G genotype influences cerebellar development over time. We studied this issue in typically developing controls who had a total of 296 repeat structural brain scans taken between ages 5 and 23 years of age. The volume of multiple cerebellar components was measures by hand in each scan, and we related developmental changes in these volumes to A218G genotype. We found that, in a part of the cerebellum implicated in autism, A218G genotype modified the rate of cerebellar growth. This suggests for the first time that the putative ASD risk gene HOXA1 has the capacity to modify the longitudinal development of cerebellar systems implicated in ASD neurobiology.
SCIENTIFIC ABSTRACT
Homeobox-A-1 (HOXA1) has been proposed as a candidate gene for autism spectrum disorder (ASD) as it regulates embryological patterning of hind-brain structures implicated in autism neurobiology. In line with this notion, a non-synonymous single nucleotide polymorphism within a highly conserved domain of HOXA1 - A218G (rs10951154) - has been linked to both ASD risk, and cross-sectional differences in superior posterior lobar cerebellar anatomy in late adulthood. Despite evidence for early onset and developmentally dynamic cerebellar involvement in ASD, little is known of the relationship between A218G genotype and maturation of the cerebellum over early development. We addressed this issue using 296 longitudinally acquired structural magnetic resonance imaging brain scans from 116 healthy individuals between 5 and 23 years of age. Mixed models were used to compare the relationship between age and semi-automated measures of cerebellar volume in A-homozygotes (AA) and carriers of the G allele (Gcar). Total cerebellar volume increased between ages 5 and 23 years in both groups. However, this was accelerated in the Gcar relative to the AA group (Genotype-by-age interaction term, p=0.03), and driven by genotype-dependent differences in the rate of bilateral superior posterior lobar volume change with age (p=0.002). Resultantly, although superior posterior lobar volume did not differ significantly between genotype groups at age 5 (p=0.9), by age 23 it was 12% greater in Gcar than AA (p=0.002). Our results suggest that common genetic variation within this putative ASD risk gene has the capacity to modify the development of cerebellar systems implicated in ASD neurobiology.
doi:10.1002/aur.238
PMCID: PMC3329569  PMID: 22359339
Autism; HOXA1; Cerebellum; Gene; Brain; MRI
25.  DISORDERED PORPHYRIN METABOLISM: A POTENTIAL BIOLOGICAL MARKER FOR AUTISM RISK ASSESSMENT 
Autism Research  2012;5(2):84-92.
Autism (AUT) is a complex neurodevelopmental disorder that, together with Asperger Syndrome and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), comprises the expanded classification of autistic spectrum disorder (ASD). The heterogeneity of ASD underlies the need to identify biomarkers or clinical features that can be employed to identify meaningful subtypes of ASD, define specific etiologies, and inform intervention and treatment options. Previous studies have shown that disordered porphyrin metabolism, manifested principally as significantly elevated urinary concentrations of pentacarboxyl- (penta) and copro- porphyrins, is commonly observed among some children with ASD. Here, we extend these observations by specifically evaluating penta and copro porphyrins as biological indicators of ASD among 76 male children comprising 30 with validated AUT, 14 with PDD-NOS and 32 neurotypical (NT) controls. ASD children (AUT and PDD-NOS) had higher mean urinary penta (p < 0.006) and copro (p < 0.006) concentrations compared to same-aged NT children, each characterized by a number of extreme values. Using Receiver Operating Characteristic (ROC) curve analysis, we evaluated the sensitivity and specificity of penta, copro and their combined Z-scores in ASD detection. The penta sensitivity was 30% for AUT and 36% for PDD-NOS, with 94% specificity. The copro sensitivity was 33% and 14%, respectively, with 94% specificity. The combined Z-score measure had 33% and 21% sensitivity for AUT and PDD-NOS, respectively, with 100% specificity. These findings demonstrate that porphyrin measures are strong predictors of both AUT and PDD-NOS and support the potential clinical utility of urinary porphyrin measures for identifying a subgroup of ASD subjects in whom disordered porphyrin metabolism may be a salient characteristic.
doi:10.1002/aur.236
PMCID: PMC3329579  PMID: 22298513
autistic spectrum disorder; porphyrins; heme; biomarker; children

Results 1-25 (87)