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1.  [No title available] 
PMCID: PMC3943749  PMID: 24150989
2.  Reduced Serotonin Receptor Subtypes in a Limbic and a Neocortical Region in Autism 
Autism is a behaviorally defined, neurological disorder with symptom onset before the age of three. Abnormalities in social-emotional behaviors are a core deficit in autism and are characterized by impaired reciprocal social interaction, lack of facial expressions, and the inability to recognize familiar faces. The posterior cingulate cortex (PCC) and fusiform gyrus (FG) are two regions within an extensive limbic-cortical network that contribute to social-emotional behaviors. Evidence indicates that changes in brains of individuals with autism begin prenatally. Serotonin (5HT) is one of the earliest expressed neurotransmitters, and plays an important role in synaptogenesis, neurite outgrowth, and neuronal migration. Abnormalities in 5HT systems have been implicated in several psychiatric disorders including autism, as evidenced by immunology, imaging, genetics, pharmacotherapy, and neuropathology. Although information is known regarding peripheral 5HT in autism, there is emerging evidence that 5HT systems in the CNS, including various 5HT receptor subtypes and transporters, are affected in autism. The present study demonstrated significant reductions in 5HT1A receptor binding density in superficial and deep layers of the PCC and FG, and in the density of 5HT2A receptors in superficial layers of the PCC and FG. Significant reduction in the density of serotonin transporters (5-HTT) was also found in the deep layers of the FG, but normal levels were demonstrated in both layers of the PCC and superficial layers of the FG. These studies provide potential substrates for decreased 5-HT modulation/innervation in the autism brain, and implicate two 5-HT receptor subtypes as potential neuromarkers for novel or existing pharmacotherapies.
doi:10.1002/aur.1317
PMCID: PMC3859849  PMID: 23894004
Autism; Serotonin; 5-HT1A receptors; 5-HT2A receptors; 5-HT transporters; pharmacotherapy; Selective Serotonin Re-uptake Inhibitors (SSRIs)
3.  Minimally Verbal School-Aged Children with Autism Spectrum Disorder: The Neglected End of the Spectrum 
It is currently estimated that about 30% of children with autism spectrum disorder remain minimally verbal, even after receiving years of interventions and a range of educational opportunities. Very little is known about the individuals at this end of the autism spectrum; in part because this is a highly variable population with no single set of defining characteristics or patterns of skills or deficits, and in part because it is extremely challenging to provide reliable or valid assessments of their developmental functioning. In this paper we summarize current knowledge based on research including minimally verbal children. We review promising new novel methods for assessing the verbal and nonverbal abilities of minimally verbal school-aged children, including eye-tracking and brain imaging methods that do not require overt responses. We then review what is known about interventions that may be effective in improving language and communication skills, including discussion of both non-augmentative and augmentative methods. In the final section of the paper we discuss the gaps in the literature and needs for future research.
doi:10.1002/aur.1329
PMCID: PMC3869868  PMID: 24124067
4.  Parental broader autism subphenotypes in ASD affected families: Relationship to gender, child's symptoms, SSRI treatment and platelet serotonin 
Relationships between parental broader autism phenotype (BAP) scores, gender, selective serotonin reuptake inhibitor (SSRI) treatment, serotonin (5HT) levels and the child's symptoms were investigated in a family study of autism spectrum disorder (ASD). The Broader Autism Phenotype Questionnaire (BAPQ) was used to measure the BAP of 275 parents. Fathers not taking SSRIs (F-SSRI; N = 115) scored significantly higher on BAP Total and Aloof subscales compared to mothers not receiving treatment (M-SSRI; N = 136.) However, mothers taking SSRIs (M+SSRI; N = 19) scored higher than those not taking medication on BAP Total and Rigid subscales, and they were more likely to be BAPQ Total, Aloof and Rigid positive. Significant correlations were noted between proband autism symptoms and parental BAPQ scores such that Total, Aloof and Rigid subscale scores of F-SSRI correlated with proband restricted repetitive behavior (RRB) measures on the ADOS, CRI and RBS-R. However, only the Aloof subscale score of M+SSRI correlated with proband RRB on the ADOS. The correlation between the BAPQ scores of mothers taking SSRIs and child scores, as well as the increase in BAPQ scores of this group of mothers requires careful interpretation and further study because correlations would not withstand multiple corrections. As expected by previous research, significant parent-child correlations were observed for 5HT levels. However 5HT levels were not correlated with behavioral measures. Study results suggest that the expression of the BAP varies not only across parental gender, but also across individuals using psychotropic medication and those who do not.
doi:10.1002/aur.1322
PMCID: PMC3869872  PMID: 23956104
broader autism phenotype; serotonin; autism; SSRI
5.  More is less: Pitch discrimination and language delays in children with optimal outcomes from autism 
Lay Abstract
Parents, clinicians, teachers, and researchers seem to agree that individuals with autism spectrum disorders often have sharper hearing, including abilities like perfect pitch, better memory for specific sounds, better abilities to tell one sound apart from even a very similar sound, and so on. We asked whether this sharper hearing ability is related to some of the difficulties in autism, including later development of language: Is better hearing part of having ASD? One important part of this study is that it includes a group of people from all over the U.S. and Canada who had ASD when they were younger (diagnosed before age five years), but who do not have any symptoms now that they are teenagers. We call this an “optimal outcome”. They do not have any symptoms, they do not need any special education services, and their IQ scores are in the normal or high-normal range. We measured the ability to hear the difference between two tones, or pitches, in 26 teenagers with optimal outcomes, 29 teenagers with high-functioning autism, and 20 teenagers with typical development. The teenagers who have ASD were better at hearing pitch differences, suggesting that this special ability is part of ASD; the teenagers with optimal outcomes did not differ from the typically-developing group. Also, the teenagers with the best pitch abilities tended to be the latest to start talking when they were toddlers. The paper discusses what these results mean for communication in ASD, and for the process of learning language more generally.
Scientific Abstract
The autism spectrum disorders (ASD) are neurodevelopmental disorders, diagnosed behaviorally but associated with differences in brain development. Individuals with ASD exhibit superior auditory perceptual skills, which may correlate with ASD symptomatology, particularly language skills. We describe findings from individuals diagnosed with ASD before age five, who now have no symptoms (e.g., having optimal outcomes). Unlike an ASD group, which shows heightened pitch discrimination, the Optimal Outcome group’s abilities do not differ from those of typically developing controls. Furthermore, pitch discrimination is associated with both current autism symptomatology and early language milestones. Findings illuminate processes associated with resolution of autism. We also discuss a specific mechanism by which heightened auditory discrimination leads to language delays in ASD.
doi:10.1002/aur.1324
PMCID: PMC3869875  PMID: 23929787
Language; Language Delays; Auditory perception; Autism; Long-Term Outcomes
6.  Repetitive Behavior and Restricted Interests in Young Children with Autism: Comparisons with Controls and Stability Over Two Years 
Restricted, repetitive and stereotyped patterns of behavior, interests and activities (RRBs) are among the core symptoms of autism spectrum disorders (ASD). Previous studies have indicated that RRBs differentiate ASD from other developmental disorders and from typical development. This study examined the presentation of RRBs as reported on the Repetitive Behavior Scale-Revised (Bodfish, Symons, Parker & Lewis, 2000), a caregiver report, in children with ASD (separated into autism and Pervasive Developmental Disorder-Not Otherwise Specified groups) compared to children with non-spectrum developmental delays or typical development. We examined the role of age, cognitive functioning, sex and social communication impairment as they relate to RRBs. The stability of RRBs in children with autism was also examined over the course of two years. Results of the study confirmed that the amount and type of RRBs differs by diagnosis. Age, cognitive functioning, sex and social-communication impairment were not significant correlates. Among children with autism, RRBs remained stable over time.
doi:10.1002/aur.1316
PMCID: PMC3869876  PMID: 23868881
Autism spectrum disorders; repetitive behaviors
7.  Interaction of Finger Representations in the Cortex of Individuals with Autism: A Functional Window into Cortical Inhibition 
An established neural biomarker of autism spectrum disorder (ASD) has the potential to provide novel biological and pharmacological targets for treatment. Lower level of inhibition in brain circuits is a leading biomarker candidate. A physiological investigation of the functional levels of inhibition in the cortex of individuals with autism can provide a strong test of the hypothesis. The amplitude of cortical response to the stimulation of adjacent fingers is controlled by the level of cortical inhibition and provides just such a test. Using magnetoencephalography, we recorded the response of the somatosensory cortex to the passive tactile stimulation of the thumb (D1), and index finger (D2), and to the simultaneous stimulation of both fingers combined (D1, D2) of the dominant (right) hand of young subjects with and without autism. For each participant, we measured the response to the stimulation of both fingers combined (D1, D2) relative to the post hoc sum of the responses to the stimulation of each finger alone (D1+D2) in multiple different ways and linearly regressed the ASD and neurotypical (NT) groups’ responses. The resulting slopes were then compared: Smaller slope values imply attenuated response to paired finger stimulation, and enhanced levels of inhibition. The short-latency M40 and mid-latency M80 response slopes of the group with autism obtained in different ways were either significantly smaller, or statistically indistinguishable from NT. The result does not support reduced inhibition in the somatosensory cortex of individuals with autism, contrary to the seminal hypothesis of reduced inhibition. Implications are discussed including refinements of current theory.
doi:10.1002/aur.1314
PMCID: PMC4059006  PMID: 23983203
evoked potentials; homeostasis; somatosensory cortex; cortical interaction; finger representation; source modeling; tactile
8.  Reward-based Decision Making and Electrodermal Responding by Young Children with Autism Spectrum Disorders During a Gambling Task 
In this study, we explore reward-based decision making and electrodermal responding (EDR) among children with autism spectrum disorder (ASD) during a children’s gambling task. In addition, we examine whether individual behavioral and EDR responses predict social communication, repetitive symptoms, parent reports of executive function, and behavioral challenges. The ability to form advantageous strategies for long-term gain is of interest for children with ASDs, who exhibit both difficulty with executive function and atypical responses to reward. Twenty-one children ages 6–7 years with ASD and no intellectual disability and 21 age- and IQ-matched typically developing children participated. Both groups exhibited a similar pattern of gambling selections, but children with ASD showed less knowledge of the reward contingencies of the decks after playing. In addition, although EDR was similar between groups in anticipation of selections, children with ASD exhibited greater EDR during feedback about rewards as the task progressed. Children with ASD who exhibited the greatest increases in EDR were more likely to exhibit repetitive symptoms, particularly rituals and the need for sameness, as well as internalizing behaviors and reduced executive function in other settings.
doi:10.1002/aur.1307
PMCID: PMC4104611  PMID: 23893954
autism; reward; executive function; decision-making; repetitive behavior; internalizing; electrodermal response
9.  Assessing the Minimally Verbal School-Aged Child with Autism Spectrum Disorder 
This paper addresses the issue of assessing communication, language, and associated cognitive and behavioral abilities of minimally verbal children with Autism Spectrum Disorder (ASD), presenting a summary of a year-long series of meetings held by a group of experts in the field of ASD and NIH staff. In this paper, our goals were to first define the population and then present general guidelines for optimizing assessment sessions for this challenging population. We then summarize the available measures that can be used across a variety of behavioral domains that are most directly relevant to developing language skills, including: oral motor skills, vocal repertoire, receptive and expressive language, imitation, intentional communication, play, social behavior, repetitive and sensory behaviors, special interests, atypical behavior and nonverbal cognition. We conclude with a discussion of some of the limitations in the available measures and highlight recommendations for future research in this area.
doi:10.1002/aur.1334
PMCID: PMC4139180  PMID: 24353165
10.  Social Attention in a Virtual Public Speaking Task in Higher Functioning Children with Autism 
Background
Impairments in social attention play a major role in autism, but little is known about their role in development after preschool. In this study a public speaking task was used to study social attention, its moderators, and its association with classroom learning in elementary and secondary students with higher functioning Autism Spectrum Disorder (HFASD).
Method
Thirty-seven students with HFASD and 54 age and IQ-matched peers without symptoms of ASD were assessed in a virtual classroom public speaking paradigm. This paradigm assessed the ability to attend to 9 avatar peers seated at a table, while simultaneously answering self-referenced questions.
Results
Students with HFASD looked less frequently to avatar peers in the classroom while talking. However, social attention was moderated in the HFASD sample such that students with lower IQ, and/or more symptoms of social anxiety, and/or more ADHD Inattentive symptoms, displayed more atypical social attention. Group differences were more pronounced when the classroom contained social avatars versus non-social targets. Moreover, measures of social attention rather than non-social attention were significantly associated with parent report and objective measures of learning in the classroom.
Conclusions
The data in this study supports the hypothesis of the Social Attention Model of ASD that social attention disturbance remains part of the school-aged phenotype of autism that is related to syndrome specific problems in social learning. More research of this kind would likely contribute to advances in the understanding of the development of autism and educational intervention approaches for affected school-aged children.
doi:10.1002/aur.1302
PMCID: PMC3778085  PMID: 23696132
11.  Fear-Potentiated Startle Response Is Unrelated to Social or Emotional Functioning in Adolescents With Autism Spectrum Disorders 
It has been suggested that atypical amygdala function contributes to the social impairments characteristic of autism spectrum disorders (ASDs). Previous research has demonstrated that adolescents and adults with ASD generate normal response during a fear-potentiated startle paradigm, suggesting this aspect of amygdala function is intact and may not account for the social dysfunction associated with the condition. The amygdala also plays a crucial role in the expression of anxiety and may contribute to high rates of reported anxiety in individuals with ASD. The present study partially replicates prior work by examining the fear-potentiated startle response in adolescents with ASD, and extends this to investigate the relationship between startle response and anxiety. Eyeblink magnitude and latency (electromyographic activity; EMG) were collected from 20 adolescents with ASD and 19 typically developing (TD) age-matched adolescents during a fear-potentiated startle paradigm. Parent report and self-report of anxiety and additional psychiatric symptoms were collected. Parental reports indicated higher rates of associated psychopathology in adolescents with ASD compared with TD adolescents. Consistent with previous results, both groups showed normal potentiated startle response, and no group differences in EMG were found. Symptoms of anxiety and level of social impairment were unrelated to startle response. These findings held for all levels of anxiety, suggesting that within the context of the fear-potentiated startle paradigm, amygdala response is not associated with degree of atypical social or emotional functioning in ASD.
doi:10.1002/aur.1289
PMCID: PMC4141562  PMID: 23495221
autism spectrum disorders; anxiety; startle response; amygdala
12.  Individual Differences in the Real-Time Comprehension of Children with ASD 
Lay Abstract
Spoken language processing is related to language and cognitive skills in typically developing children, but very little is known about how children with autism spectrum disorders (ASD) comprehend words in real time. Studying this area is important because it may help us understand why many children with autism have delayed language comprehension. Thirty-four children with ASD (3–6 years old) participated in this study. They took part in a language comprehension task that involved looking at pictures on a screen and listening to questions about familiar nouns (e.g., Where’s the shoe?). Children as a group understood the familiar words, but accuracy and processing speed varied considerably across children. The children who were more accurate were also faster to process the familiar words. Children’s language processing accuracy was related to processing speed and language comprehension on a standardized test; nonverbal cognition did not explain additional information after accounting for these factors. Additionally, lexical processing accuracy at age 5½ was related to children’s vocabulary comprehension three years earlier, at age 2½. Autism severity and years of maternal education were unrelated to language processing. Words typically acquired earlier in life were processed more quickly than words acquired later. These findings point to similarities in patterns of language development in typically developing children and children with ASD. Studying real-time comprehension in children with ASD may help us better understand mechanisms of language comprehension in this population. Future work may help explain why some children with ASD develop age-appropriate language skills, whereas others experience lasting deficits.
Scientific Abstract
Many children with autism spectrum disorders (ASD) demonstrate deficits in language comprehension, but little is known about how they process spoken language as it unfolds. Real-time lexical comprehension is associated with language and cognition in children without ASD, suggesting that this may also be the case for children with ASD. This study adopted an individual differences approach to characterizing real-time comprehension of familiar words in a group of 34 three- to six-year-olds with ASD. The looking-while-listening paradigm was employed; it measures online accuracy and latency through language-mediated eye movements and has limited task demands. On average, children demonstrated comprehension of the familiar words, but considerable variability emerged. Children with better accuracy were faster to process the familiar words. In combination, processing speed and comprehension on a standardized language assessment explained 63% of the variance in online accuracy. Online accuracy was not correlated with autism severity or maternal education, and nonverbal cognition did not explain unique variance. Notably, online accuracy at age 5½ was related to vocabulary comprehension three years earlier. The words typically learned earliest in life were processed most quickly. Consistent with a dimensional view of language abilities, these findings point to similarities in patterns of language acquisition in typically developing children and those with ASD. Overall, our results emphasize the value of examining individual differences in real-time language comprehension in this population. We propose that the looking-while-listening paradigm is a sensitive and valuable methodological tool that can be applied across many areas of autism research.
doi:10.1002/aur.1304
PMCID: PMC3808474  PMID: 23696214
autism; comprehension; language processing; receptive vocabulary; eye-gaze methodology; individual differences
13.  Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism 
Animal models that express autism-related behavioral characteristics have been used to promote our understanding of factors that can influence specific behavioral aspects of the disorder. The BTBR T+tf/J (BTBR) mouse has been described as a mouse model of autism because it displays three core features of the disorder, including repetitive behavior patterns. The purpose of this study was to examine the effects of environmental enrichment on the quantity and quality of repetitive behaviors in the BTBR mouse model. Two types of repetitive behavior were examined: 1) repetitive grooming behaviors were investigated as a lower-order repetitive motor behavior and 2) repetitive object exploration was measured as a higher-order repetitive cognitive behavior. Baseline scores taken from mice at seven weeks of age confirmed that BTBR mice spend significantly more time grooming than control C57BL/6J mice and use a more rigid grooming sequence. After thirty days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming compared to BTBR mice placed in standard housing; no differences were found with regard to grooming sequence between enriched and standard housed BTBR mice. At baseline no differences were found between BTBR mice and control mice for the object exploration task. In addition, no differences were found in relation to sequential object exploration between BTBR mice housed in enriched vs. standard cages. The results suggest that environmental enrichment may be beneficial for reducing time spent engaging in lower-order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest.
Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at seven weeks of age followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice on the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower-order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest.
doi:10.1002/aur.1298
PMCID: PMC4158697  PMID: 23813950
14.  Emotion Regulation Patterns in Adolescents With High-Functioning Autism Spectrum Disorder: Comparison to Typically Developing Adolescents and Association With Psychiatric Symptoms 
Autism spectrum disorder (ASD) is often associated with poor emotional control and psychopathology, such as anxiety and depression; however, little is known about the underlying mechanisms. Emotion regulation (ER) is a potential contributing factor, but there has been limited research on ER and its role in comorbid psychopathology in ASD. In this study, we compared self-reported ER with self- and parent reports of psychopathology in 25 high-functioning adolescents with ASD and 23 age- and Intelligence Quotient (IQ)-matched typically developing controls. Contrary to expectations, both groups reported similar levels of adaptive, voluntary forms of ER (problem solving, acceptance, etc.). However, the ASD group reported significantly greater use of involuntary forms of ER that are typically maladaptive, including remaining focused on the stressor (e.g. rumination and emotional arousal) and shutting down (e.g. emotional numbing and being unable to think or act). Associations between ER and psychopathology were generally more robust using self-report rather than parent report. For both groups, greater endorsement of involuntary ER strategies was associated with higher ratings of psychopathology, whereas voluntary ER strategies focused on changing or adapting to the situation were significantly associated with lower levels of psychopathology. The magnitude and direction of association between ER types and psychopathology were similar for measures of depression and anxiety. These findings can help guide the development of psychosocial treatments targeting dysfunctional ER in adolescents with ASD. Interventions focused on ER as a transdiagnostic process may be a more robust method to improve emotional control and decrease emotional distress in ASD than disorder-specific interventions.
doi:10.1002/aur.1366
PMCID: PMC4136477  PMID: 24610869
emotion regulation; psychiatric comorbidity; depression; anxiety; coping
15.  Geographic Distribution of Autism in California: A Retrospective Birth Cohort 
Prenatal environmental exposures are among the risk factors being explored for associations with autism. We applied a new procedure combining multiple scan cluster detection tests to identify geographically defined areas of increased autism incidence. This procedure can serve as a first hypothesis-generating step aimed at localized environmental exposures, but would not be useful for assessing widely distributed exposures, such as household products, nor for exposures from non-point sources, such as traffic.
Geocoded mothers' residences on 2,453,717 California birth records, 1996–2000, were analyzed including 9,900 autism cases recorded in the California Department of Developmental Services (DDS) database through February 2006 which were matched to their corresponding birth records. We analyzed each of the 21 DDS Regional Center (RC) catchment areas separately because of wide variation in diagnostic practices. Ten clusters of increased autism risk were identified in eight RC regions, and one potential cluster in each of two other RC regions.
After determination of clusters, multiple mixed Poisson regression models were fit to assess differences in known demographic autism risk factors between births within and outside areas of elevated autism incidence, independent of case status.
Adjusted for other covariates, the majority of areas of autism clustering were characterized by high parental education, e.g., relative risks >4 for collegegraduate versus non-high school graduate parents. This geographic association possibly occurs because RCs do not actively conduct case finding and parents with lower education are, for various reasons, less likely to successfully seek services.
doi:10.1002/aur.110
PMCID: PMC4071143  PMID: 20049980
autism; cluster; environmental; epidemiology; scan tests; spatial; geographic; sociodemographic
16.  Independent and Dependent Contributions of Advanced Maternal and Paternal Ages to Autism Risk 
LAY ABSTRACT
Previous reports on autism among children born to older parents have yielded conflicting results as to which parent, or whether neither, or both, contributes to the risk. We analyzed ten years of births in California, comprising approximately 5 million children. Autism cases were identified from the California Department of Developmental Services database and linked to birth files from 1990–1999. Due to the size of this population, we were able to observe the trend in autism risk for each parent’s age, restricted to a narrow age range of the other parent. Analysis was confined to singleton births with complete data on ages and educational levels of both parents (n=4,947,935, cases=12,159). We observed consistent stepwise increased risk for autism with advancing maternal age regardless of the father’s age, whereas increased risk with advancing paternal age was primarily observed among younger mothers, namely those <30 years of age. The different effects of father’s age depending on the mother’s age may indicate that the risk for autism from advancing maternal age past 30 years overwhelms the risk contributed by the father’s age. Additionally, we showed that if the distribution of mothers’ age had been the only factor to change between 1990 and 1999, then we would have expected the cumulative incidence to have risen only 4.6% during the decade from 1990 to 1999.
SCIENTIFIC ABSTRACT
Reports on autism and parental age have yielded conflicting results on whether mothers, fathers, or both, contribute to increased risk. We analyzed restricted strata of parental age in a ten-year California birth cohort to determine the independent or dependent effect from each parent. Autism cases from California Department of Developmental Services records were linked to State birth files (1990–1999). Only singleton births with complete data on parental age and education were included (n=4,947,935, cases=12,159). In multivariate logistic regression models, advancing maternal age increased risk for autism monotonically regardless of the paternal age. Compared with mothers 25–29 years of age, the adjusted odds ratio (aOR) for mothers 40+ years was 1.51 (95% CI: 1.35–1.70), or compared with mothers <25 years of age, aOR=1.77 (95% CI, 1.56–2.00). In contrast, autism risk was associated with advancing paternal age primarily among mothers <30: aOR =1.59 (95% CI, 1.37–1.85) comparing fathers 40+ vs. 25–29 years of age. However, among mothers > 30, the aOR was 1.13 (95% CI, 1.01–1.27) for fathers 40+ vs. 25–29 years of age, almost identical to the aOR for fathers <25 years. Based on the first examination of heterogeneity in parental age effects, it appears that women’s risk for delivering a child who develops autism increases throughout their reproductive years whereas father’s age confers increased risk for autism when mothers are <30, but has little effect when mothers are past age 30. We also calculated that the recent trend towards delayed childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.
doi:10.1002/aur.116
PMCID: PMC4068119  PMID: 20143326
autism; maternal age; paternal age; effect measure modification; attributable risk; advanced maternal age; advanced paternal age; interaction
17.  Knockout of NMDA Receptors in Parvalbumin Interneurons Recreates Autism-Like Phenotypes 
Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism.
doi:10.1002/aur.1264
PMCID: PMC4064157  PMID: 23441094
autism; electrophysiology; endophenotype; animal models; NMDA receptor 1 knockout
18.  Functional assays of local connectivity in the somatosensory cortex of individuals with autism 
Emerging evidence for differences between individuals with autism spectrum disorder (ASD) and neurotypical (NT) individuals in somatic processing and brain response to touch suggests somatosensory cortex as a promising substrate for elucidating differences in functional brain connectivity between individuals with and without autism. Signals from adjacent digits project to neighboring locations or representations in somatosensory cortex. When a digit is stimulated, i.e. touched, its representation in cortex is directly activated; local intracortical connections indirectly activate non-primary cortical representations corresponding to adjacent digits. The response of the non-primary cortical representations is thus a proxy for connection strength. Local overconnectivity in autism implies that the nonprimary/primary response ratios of the ASD group will be higher than those of the NT group. D1 and D2 of the dominant hand of the participant were individually stimulated while we recorded neural responses using magnetoencephalography (MEG). The cortical representations of D1 and D2 (somatosensory evoked fields) were computed from the ensemble averaged data using (i) dipole model fits, and (ii) singular value decomposition (SVD). Individual adjacent/primary response ratios were measured, and group response ratio data were fitted with straight lines. Local overconnectivity in autism implies steeper ASD versus NT group slopes. Our findings did not support local overconnectivity. Slopes were found to be significantly shallower for the ASD group than the NT group. Our findings support the idea of local underconnectivity in the somatosensory cortex of the brains of individuals with ASD.
doi:10.1002/aur.1276
PMCID: PMC3661715  PMID: 23427110
Connectivity; Somatotopy; Cortical inhibition; Local excitation; Tactile; Homeostasis; Touch; MEG
19.  Letting a typical mouse judge whether mouse social interactions are atypical 
LAY ABSTRACT
Diagnosis of an autism spectrum disorder (ASD) requires a qualitative assessment of social aptitude: one person judging whether another person interacts in a ‘typical’ way. Quantitative or computerized assessment of social aptitude cannot substitute for this subjective judgment. We hypothesized that mice could be used to make a similar judgment if they prefer ‘typical’ over ‘atypical’ social interactions with mouse models relevant to ASD. We used typical C57BL/6 (B6) mice as ‘judges’ and evaluated their preference for a chamber containing a ‘typical’ or an ‘atypical’ mouse. For our atypical mice, we chose two strains with well-documented social phenotypes, as well a mutant line with abnormal social behavior and seizures. Overall, we observed a characteristic pattern of behavior over the course of 30 minutes, with the judges preferring the typical mouse chamber to the atypical mouse chamber during the last 10 minutes of the test. When we evaluated the individual stimulus pairings, two of the three showed a similar pattern as the overall results, and the other stimulus comparison showed a trend for a preference for the typical mouse chamber across the entire test. We repeated the experiments using the 129S6 strain of typical mice as judges and found a much less strong preference pattern across time. These data suggest that a characteristic pattern of exploration in B6 mice can distinguish some socially atypical animals from controls.
SCIENTIFIC ABSTRACT
Diagnosis of an autism spectrum disorder (ASD) requires a qualitative assessment of social aptitude: one person judging whether another person interacts in a ‘typical’ way. We hypothesized that mice could be used to make a similar judgment if they prefer ‘typical’ over ‘atypical’ social interactions with mouse models relevant to ASD. We used wildtype C57BL/6 (B6) mice as ‘judges’ and evaluated their preference for a chamber containing a ‘typical’ (B6 or 129S6) or an ‘atypical’ mouse. For our atypical mouse stimuli, we chose two inbred strains with well-documented social phenotypes (BTBR and BALB/c), as well a mutant line with abnormal social behavior and seizures (Gabrb3 +/−). Overall, we observed a stimulus by time interaction (P < 0.0001), with B6 mice preferring the typical mouse chamber during the last 10 minutes of the 30-minute test. For two of the individual stimulus pairings, we observed a similar chamber by time interaction (BALB/c vs. 129S6, P = 0.0007; Gabrb3 +/− vs. 129S6, P = 0.033). For the third stimulus pairing, we found a trend for preference of the typical mouse across time (BTBR vs. B6, P = 0.051). We repeated the experiments using 129S6 mice as judges and found a significant overall interaction (P = 0.034), but only one stimulus pairing reached significance on its own (BALB/c vs. 129S6, P = 0.0021). These data suggest that a characteristic pattern of exploration in B6 mice can distinguish some socially atypical animals from controls.
doi:10.1002/aur.1280
PMCID: PMC3664268  PMID: 23436806
20.  Behavior and Sleep Problems in Children with a Family History of Autism 
The present study explores behavioral and sleep outcomes in preschool age siblings of children with autism spectrum disorders (ASD). This study focuses on behavior problems that are common in children with ASD, such as emotional reactivity, anxiety, inattention, aggression, and sleep problems. Infant siblings were recruited from families with at least one older child with ASD (high-risk group, n = 104) or families with no history of ASD (low-risk group, n = 76). As part of a longitudinal prospective study, children completed the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, and parents completed the Child Behavior Checklist (CBCL) and the Social Communication Questionnaire at 36 months of age. This study focuses on developmental concerns outside of ASD; therefore, only siblings who did not develop an ASD were included in analyses. Negative binomial regression analyses revealed that children in the high-risk group were more likely to have elevated behavior problems on the CBCL Anxious/Depressed and Aggression subscales. To explore sleep problems as a correlate of these behavior problems, a second series of models was specified. For both groups of children, sleep problems were associated with elevated behavior problems in each of the areas assessed (reactivity, anxiety, somatic complaints, withdrawal, attention, and aggression). These findings support close monitoring of children with a family history of ASD for both behavioral and sleep issues.
doi:10.1002/aur.1278
PMCID: PMC3947924  PMID: 23436793
autism; siblings; behavior problems; sleep
21.  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
22.  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
23.  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
24.  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
25.  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

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