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1.  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
2.  Frontolimbic Neural Circuitry at 6 Months Predicts Individual Differences in Joint Attention at 9 Months 
Developmental science  2012;16(2):186-197.
Elucidating the neural basis of joint attention in infancy promises to yield important insights into the development of language and social cognition, and directly informs developmental models of autism. We describe a new method for evaluating responding to joint attention performance in infancy that highlights the 9 to 10 month period as a time interval of maximal individual differences. We then demonstrate that fractional anisotropy in the right uncinate fasciculus, a white matter fiber bundle connecting the amygdala to the ventral-medial prefrontal cortex and anterior temporal pole, measured in 6 month-olds predicts individual differences in responding to joint attention at 9 months of age. The white matter microstructure of the right uncinate was not related to receptive language ability at 9 months. These findings suggest that the development of core nonverbal social communication skills in infancy is largely supported by preceding developments within right lateralized frontotemporal brain systems.
doi:10.1111/desc.12015
PMCID: PMC3582040  PMID: 23432829
joint attention; DTI; amygdala; uncinate fasciculus; infancy; development
3.  Adaptive prior probability and spatial temporal intensity change estimation for segmentation of the one-year-old human brain 
Journal of neuroscience methods  2012;212(1):43-55.
The degree of white matter (WM) myelination is rather inhomogeneous across the brain. White matter appears differently across the cortical lobes in MR images acquired during early postnatal development. Specifically at 1-year of age, the gray/white matter contrast of MR T1 and T2 weighted images in prefrontal and temporal lobes is reduced as compared to the rest of the brain, and thus, tissue segmentation results commonly show lower accuracy in these lobes. In this novel work, we propose the use of spatial intensity growth maps (IGM) for T1 and T2 weighted images to compensate for local appearance inhomogeneity. The IGM captures expected intensity changes from 1 to 2 years of age, as appearance homogeneity is greatly improved by the age of 24 months. The IGM was computed as the coefficient of a voxel-wise linear regression model between corresponding intensities at 1 and 2 years. The proposed IGM method revealed low regression values of 1–10% in GM and CSF regions, as well as in WM regions at maturation stage of myelination at 1 year. However, in the prefrontal and temporal lobes we observed regression values of 20–25%, indicating that the IGM appropriately captures the expected large intensity change in these lobes mainly due to myelination. The IGM is applied to cross-sectional MRI datasets of 1-year-old subjects via registration, correction and tissue segmentation of the IGM-corrected dataset. We validated our approach in a small leave-one-out study of images with known, manual ‘ground truth’ segmentations.
doi:10.1016/j.jneumeth.2012.09.018
PMCID: PMC3513941  PMID: 23032117
Myelination; Expectation Maximization algorithm; Tissue segmentation; Intensity growth map; and Partial volume estimation
4.  MODELING LONGITUDINAL MRI CHANGES IN POPULATIONS USING A LOCALIZED, INFORMATION-THEORETIC MEASURE OF CONTRAST 
Longitudinal MR imaging during early brain development provides important information about growth patterns and the development of neurological disorders. We propose a new framework for studying brain growth patterns within and across populations based on MRI contrast changes, measured at each time point of interest and at each voxel. Our method uses regression in the LogOdds space and an information-theoretic measure of distance between distributions to capture contrast in a manner that is robust to imaging parameters and without requiring intensity normalization. We apply our method to a clinical neuroimaging study on early brain development in autism, where we obtain a 4D spatiotemporal model of contrast changes in multimodal structural MRI.
doi:10.1109/ISBI.2013.6556794
PMCID: PMC3892761  PMID: 24443698
Contrast; longitudinal MRI; regression; Kullback-Leibler
5.  Perception of Affect in Biological Motion Cues in Anorexia Nervosa 
Objective
Nonverbal motion cues (a clenched fist) convey essential information about the intentions of the actor. Individuals with anorexia nervosa (AN) have demonstrated impairment in deciphering intention from facial affective cues but it is unknown whether such deficits extend to deciphering affect from body motion cues.
Method
We examined the capacities of adults with AN (AN; n=21) or those weight restored for >= 12 months (WR; n=20) to perceive affect in biological motion cues relative to healthy controls (HC; n=23).
Results
Overall, individuals with AN evidenced greater deficit in discriminating affect from biological motion cues than WR or HC. Follow-up analyses showed that individuals with AN differed especially across two of the five conditions—deviating most from normative data when discriminating sadness and more consistently discriminating anger relative to WR or HC.
Discussion
Implications of these findings are discussed in relation to some puzzling interpersonal features of AN.
doi:10.1002/eat.22062
PMCID: PMC3657604  PMID: 23109257
anorexia nervosa; eating disorders; social cognition; social perception; motion perception
6.  Journal of Neurodevelopmental Disorders reviewer acknowledgement 2013 
Contributing reviewers
We thank all of our reviewers who have contributed to the journal in volume 5 (2013). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal.
doi:10.1186/1866-1955-6-2
PMCID: PMC3904702  PMID: 24472142
7.  A framework for longitudinal data analysis via shape regression 
Proceedings of SPIE  2012;8314:10.1117/12.911721.
Traditional longitudinal analysis begins by extracting desired clinical measurements, such as volume or head circumference, from discrete imaging data. Typically, the continuous evolution of a scalar measurement is estimated by choosing a 1D regression model, such as kernel regression or fitting a polynomial of fixed degree. This type of analysis not only leads to separate models for each measurement, but there is no clear anatomical or biological interpretation to aid in the selection of the appropriate paradigm. In this paper, we propose a consistent framework for the analysis of longitudinal data by estimating the continuous evolution of shape over time as twice differentiable flows of deformations. In contrast to 1D regression models, one model is chosen to realistically capture the growth of anatomical structures. From the continuous evolution of shape, we can simply extract any clinical measurements of interest. We demonstrate on real anatomical surfaces that volume extracted from a continuous shape evolution is consistent with a 1D regression performed on the discrete measurements. We further show how the visualization of shape progression can aid in the search for significant measurements. Finally, we present an example on a shape complex of the brain (left hemisphere, right hemisphere, cerebellum) that demonstrates a potential clinical application for our framework.
doi:10.1117/12.911721
PMCID: PMC3877317  PMID: 24392201
8.  White Matter Microstructure and Atypical Visual Orienting in 7-Month-Olds at Risk for Autism 
The American journal of psychiatry  2013;170(8):10.1176/appi.ajp.2012.12091150.
Objective
The authors sought to determine whether specific patterns of oculomotor functioning and visual orienting characterize 7-month-old infants who later meet criteria for an autism spectrum disorder (ASD) and to identify the neural correlates of these behaviors.
Method
Data were collected from 97 infants, of whom 16 were high-familial-risk infants later classified as having an ASD, 40 were high-familial-risk infants who did not later meet ASD criteria (high-risk negative), and 41 were low-risk infants. All infants underwent an eye-tracking task at a mean age of 7 months and a clinical assessment at a mean age of 25 months. Diffusion-weighted imaging data were acquired for 84 of the infants at 7 months. Primary outcome measures included average saccadic reaction time in a visually guided saccade procedure and radial diffusivity (an index of white matter organization) in fiber tracts that included corticospinal pathways and the splenium and genu of the corpus callosum.
Results
Visual orienting latencies were longer in 7-month-old infants who expressed ASD symptoms at 25 months compared with both high-risk negative infants and low-risk infants. Visual orienting latencies were uniquely associated with the microstructural organization of the splenium of the corpus callosum in low-risk infants, but this association was not apparent in infants later classified as having an ASD.
Conclusions
Flexibly and efficiently orienting to salient information in the environment is critical for subsequent cognitive and social-cognitive development. Atypical visual orienting may represent an early prodromal feature of an ASD, and abnormal functional specialization of posterior cortical circuits directly informs a novel model of ASD pathogenesis.
doi:10.1176/appi.ajp.2012.12091150
PMCID: PMC3863364  PMID: 23511344
9.  Evidence of a Distinct Behavioral Phenotype in Young Boys with Fragile X Syndrome and Autism 
Objective
How does the behavioral expression of autism in fragile X syndrome (FXS+Aut) compare to idiopathic autism (iAut)? While social impairments and restricted, repetitive behaviors (RRBs) are common to both variants of autism, closer examination of these symptom domains may reveal meaningful similarities and differences. To this end, we profiled the specific behaviors comprising the social and repetitive behavioral domains in young children with FXS+Aut and iAut.
Method
Twenty-three males ages 3–5 years with FXS + Aut were age-matched with a group of 38 boys with iAut. Repetitive behavior was assessed using the RBS-R. Social behavior was evaluated using Autism Diagnostic Observation Schedule (ADOS) social item severity scores.
Results
Rates of stereotypy, self-injury, and sameness behaviors did not differ between groups, whereas compulsive and ritual behavior scores were significantly lower for individuals with FXS + Aut compared to iAut. Those with FXS + Aut scored significantly lower (less severe) than the iAut group on five ADOS measures of social behavior: Gaze Integration, Quality of Social Overtures, Social Smile, Facial Expressions, and Response to Joint Attention.
Conclusions
The behavioral phenotype of FXS + Aut and iAut are most similar with respect to lower-order (motoric) RRBs and social approach, but differ in more complex forms of RRB and some social response behaviors. These findings highlight the phenotypic heterogeneity of autism overall and its unique presentation in an etiologically distinct condition.
doi:10.1016/j.jaac.2012.09.001
PMCID: PMC3513689  PMID: 23200289
fragile X syndrome; autism; repetitive behavior; behavioral phenotype
10.  Trajectories of Early Brain Volume Development in Fragile X and Autism RH: Trajectory of Brain Volume in Fragile X 
Objective
To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared to a comparison group (controls) and a group with idiopathic autism.
Method
The study included 53 boys between 18–42 months of age with FXS, 68 boys with idiopathic autism (ASD), and a comparison group of 50 typically-developing and developmentally-delayed controls. We examined structural brain volumes using magnetic resonance imaging (MRI) across two timepoints between ages 2–3 and 4–5 years and examined total brain volumes and regional (lobar) tissue volumes. Additionally, we studied a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala).
Results
Children with FXS had greater global brain volumes compared to controls, but were not different than children with idiopathic autism, and the rate of brain growth between ages 2 and 5 paralleled that seen in controls. In contrast to the children with idiopathic autism who had generalized cortical lobe enlargement, the children with FXS showed a specific enlargement in temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but significantly smaller amygdala.
Conclusions
This structural longitudinal MRI study of preschoolers with FXS observed generalized brain overgrowth in FXS compared to controls, evident at age 2 and maintained across ages 4–5. We also find different patterns of brain growth that distinguishes boys with FXS from children with idiopathic autism.
doi:10.1016/j.jaac.2012.07.003
PMCID: PMC3428739  PMID: 22917205
fragile X syndrome; autism; children; brain MRI; brain volume
11.  Defining Genetically Meaningful Language and Personality Traits in Relatives of Individuals with Fragile X Syndrome and Relatives of Individuals with Autism 
BACKGROUND
Substantial phenotypic overlap exists between fragile X syndrome (FXS) and autism, suggesting that FMR1 (the gene causing FXS) poses a significant risk for autism. Cross-population comparisons of FXS and autism therefore offer a potentially valuable method for refining the range of phenotypes associated with variation in FMR1. This study adopted a broader phenotype approach, focusing on parents who are at increased genetic liability for autism or FXS. Women who were carriers of FMR1 in its premutation state were compared with mothers of individuals with autism, and controls in an attempt to determine whether subtle features of the broad autism phenotype may express at elevated rates among FMR1 premutation carriers.
METHODS
The principal personality and language features comprising the broad autism phenotype (i.e., rigid and aloof personality, and particular patterns of pragmatic language use) were assessed among 49 premutation carriers who were mothers of individuals with FXS, 89 mothers of individuals with autism, and 23 mothers of typically developing individuals.
RESULTS
Relative to controls, the autism and premutation parent groups showed elevated rates of certain personality and language characteristics which have been described as constituting the broad autism phenotype.
CONCLUSIONS
Findings suggest partially overlapping personality and language profiles among autism and premutation parent groups, with rigid personality style and patterns of pragmatic language use emerging as features most clearly shared between groups. These results provide further evidence for the overlap of autism and FXS, and may implicate FMR1 in some of the subtle features comprising the broad autism phenotype.
doi:10.1002/ajmg.b.32070
PMCID: PMC3740587  PMID: 22693142
Autism; fragile X syndrome; fragile X premutation; FMR1; language; broad autism phenotype
12.  Analysis of Longitudinal Shape Variability via Subject Specific Growth Modeling 
Statistical analysis of longitudinal imaging data is crucial for understanding normal anatomical development as well as disease progression. This fundamental task is challenging due to the difficulty in modeling longitudinal changes, such as growth, and comparing changes across different populations. We propose a new approach for analyzing shape variability over time, and for quantifying spatiotemporal population differences. Our approach estimates 4D anatomical growth models for a reference population (an average model) and for individuals in different groups. We define a reference 4D space for our analysis as the average population model and measure shape variability through diffeomorphisms that map the reference to the individuals. Conducting our analysis on this 4D space enables straightforward statistical analysis of deformations as they are parameterized by momenta vectors that are located at homologous locations in space and time. We evaluate our method on a synthetic shape database and clinical data from a study that seeks to quantify brain growth differences in infants at risk for autism.
PMCID: PMC3744241  PMID: 23285617
13.  Brain Volume Findings in Six Month Old Infants at High Familial Risk for Autism 
The American journal of psychiatry  2012;169(6):601-608.
Objective
Brain enlargement has been observed in individuals with autism as early as two years of age. Studies using head circumference suggest that brain enlargement is a postnatal event that occurs around the latter part of the first year. To date, no brain imaging studies have systematically examined the period prior to age two. In this study we examine MRI brain volume in six month olds at high familial risk for autism.
Method
The Infant Brain Imaging Study (IBIS) is a longitudinal imaging study of infants at high risk for autism. This cross-sectional analysis examines brain volumes at six months of age, in high risk infants (N=98) in comparison to infants without family members with autism (low risk) (N=36). MRI scans are also examined for radiologic abnormalities.
Results
No group differences were observed for intracranial cerebrum, cerebellum, lateral ventricle volumes, or head circumference.
Conclusions
We did not observe significant group differences for head circumference, brain volume, or abnormalities of radiologic findings in a sample of 6 month old infants at high-risk for autism. We are unable to conclude that these changes are not present in infants who later go on to receive a diagnosis of autism, but rather that they were not detected in a large group at high familial risk. Future longitudinal studies of the IBIS sample will examine whether brain volume may differ in those infants who go onto develop autism, estimating that approximately 20% of this sample may be diagnosed with an autism spectrum disorder at age two.
doi:10.1176/appi.ajp.2012.11091425
PMCID: PMC3744332  PMID: 22684595
autism; child psychiatry
14.  QUANTIFYING REGIONAL GROWTH PATTERNS THROUGH LONGITUDINAL ANALYSIS OF DISTANCES BETWEEN MULTIMODAL MR INTENSITY DISTRIBUTIONS 
Quantitative analysis of early brain development through imaging is critical for identifying pathological development, which may in turn affect treatment procedures. We propose a framework for analyzing spatiotemporal patterns of brain maturation by quantifying intensity changes in longitudinal MR images. We use a measure of divergence between a pair of intensity distributions to study the changes that occur within specific regions, as well as between a pair of anatomical regions, over time. The change within a specific region is measured as the contrast between white matter and gray matter tissue belonging to that region. The change between a pair of regions is measured as the divergence between regional image appearances, summed over all tissue classes. We use kernel regression to integrate the temporal information across different subjects in a consistent manner. We applied our method on multimodal MRI data with T1-weighted (T1W) and T2-weighted (T2W) scans of each subject at the approximate ages of 6 months, 12 months, and 24 months. The results demonstrate that brain maturation begins at posterior regions and that frontal regions develop later, which matches previously published histological, qualitative and morphometric studies. Our multimodal analysis also confirms that T1W and T2W modalities capture different properties of the maturation process, a phenomena referred to as T2 time lag compared to T1. The proposed method has potential for analyzing regional growth patterns across different populations and for isolating specific critical maturation phases in different MR modalities.
PMCID: PMC3744339  PMID: 23958630
Early brain development; structural MRI; longitudinal analysis; distribution statistics; MR contrast analysis
15.  Evidence for three subtypes of repetitive behavior in autism that differ in familiality and association with other symptoms 
Background
Restricted repetitive behaviors (RRBs) are a core feature of autism and consist of a variety of behaviors, ranging from motor stereotypies to complex circumscribed interests. The objective of the current study was to examine the structure of RRBs in autism using relevant items from the Autism Diagnostic Interview-Revised in a sample of 316 individuals with autistic disorder.
Methods/Results
Using exploratory factor analysis, three distinct factors were identified: Repetitive Motor Behaviors (RMB), Insistence on Sameness (IS), and Circumscribed Interests (CI). RMB were found to be associated with a variety of subject characteristics such as IQ, age, social/communication impairments, and the presence of regression. IS was associated with social and communication impairments whereas CI appeared to be independent of subject characteristics, suggesting CI may be particularly useful in subsetting samples. Based on sib-pair correlations, IS and CI (but not RMB) appear to be familial. Analysis of the data at the case level suggests that the presence of multiple forms of RRB in an individual is associated with more impairment in the social and communication domains, suggesting a more severe presentation of autistic disorder.
Conclusions
There appears to be considerable structure within repetitive behavior in autism. The finding that these behaviors are differentially related to subject characteristics and familiality adds to their validity.
doi:10.1111/j.1469-7610.2008.01944.x
PMCID: PMC3709850  PMID: 19017031
Autism; repetitive behavior; factor analysis; Autism Diagnostic Interview-Revised
16.  Journal of Neurodevelopmental Disorders reviewer acknowledgement 2012 
Contributing reviewers
The editors of Journal of Neurodevelopmental Disorders would like to thank all of our reviewers who have contributed to the journal in volume 4 (2012). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal.
doi:10.1186/1866-1955-5-5
PMCID: PMC3605391  PMID: 23517765
17.  Autism and the broad autism phenotype: familial patterns and intergenerational transmission 
Background
Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands.
Method
Seven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire.
Results
Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one.
Conclusions
Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics.
doi:10.1186/1866-1955-5-11
PMCID: PMC3651284  PMID: 23639131
Autism; Broad autism phenotype; Endophenotype; Assessment; Genetics; Personality
18.  Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome 
Background
Following from previous work suggesting that neurobehavioral features distinguish fragile X and idiopathic variants of autism, we investigated the relationships between four forms of repetitive behavior (stereotypy, self-injury, compulsivity, ritual behavior) and caudate nuclei volume in two groups: boys with fragile X syndrome, a subset of whom met criteria for autism, and a comparison group of boys with idiopathic autism.
Methods
Bilateral caudate nuclei volumes were measured in boys aged 3 to 6 years with fragile X syndrome (n = 41), the subset of boys with fragile X syndrome and autism (n = 16), and boys with idiopathic autism (n = 30). Repetitive behaviors were measured using the Repetitive Behavior Scales-Revised.
Results
For boys with idiopathic autism, left caudate volume was modestly associated with self-injury, while both compulsive and ritual behaviors showed significant positive correlations with bilateral caudate nuclei volumes, replicating previous results. For boys with fragile X syndrome, there was no such association between caudate volume and compulsive behaviors. However, we did identify significant positive correlations between self-injury total scores and number of self-injury topographies with bilateral caudate nuclei volumes.
Conclusions
These findings suggest a specific role for the caudate nucleus in the early pathogenesis of self-injurious behavior associated with both idiopathic autism and fragile X syndrome. Results further indicate that the caudate may be differentially associated with compulsive behavior, highlighting the utility of isolating discrete brain-behavior associations within and between subtypes of autism spectrum disorder.
doi:10.1186/1866-1955-5-12
PMCID: PMC3651404  PMID: 23639144
Autism; Caudate; Fragile X syndrome; Repetitive behavior; Self-injurious behavior
19.  Prevalence of selected clinical problems in older adults with autism and intellectual disability 
Background
Originally described as a disorder of childhood, evidence now demonstrates the lifelong nature of autism spectrum disorder (ASD). Despite the increase of the population over age 65, older adults with ASD remain a scarcely explored subpopulation. This study set out to investigate the prevalence of clinically relevant behaviors and medical problems in a sample of US adults aged 30 to 59 with ASD and intellectual disability (ID), in comparison to those with ID only.
Methods
A cross-sectional study, with both an exploratory and replication analysis, was conducted using National Core Indicators (NCI) multi-state surveys from 2009 to 2010 and 2010 to 2011. There were 4,989 and 4,261 adults aged 30–59 with ID examined from the 2009 to 2010 and 2010 to 2011 samples, respectively. The two consecutive annual samples consisted of 438 (9%) and 298 (7%) individuals with ASD and ID. Variables were chosen from the NCI data as outcomes, including medication use for behavior problems, severe or aggressive behavior problems and selected medical conditions.
Results
No age-associated disparities were observed between adults with ASD and ID versus adults with ID only in either sample. For the 2009 to 2010 sample, the prevalence of support needed to manage self-injurious, disruptive and destructive behavior in subjects with ASD and ID ranged from 40 to 60%. Similarly, the prevalence estimates of self-injurious, disruptive and destructive behavior were each almost double in adults with ASD and ID relative to those with ID only. These results were replicated in the 2010 to 2011 sample.
Conclusions
The findings of this study highlight the urgent need for research on the nature and treatment of severe behavior problems in the rapidly increasing population of older adults with ASD. They also suggest the importance of developing policies that expand our capacity to care for these individuals.
doi:10.1186/1866-1955-5-27
PMCID: PMC3848965  PMID: 24066979
Autism; ASD; Older adults; Clinical problems; Behavior problems; Intellectual disabilities
20.  A molecular genetic study of autism and related phenotypes in extended pedigrees 
Background
Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD.
Methods
We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior.
Results
Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas 'repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study.
Conclusions
These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.
doi:10.1186/1866-1955-5-30
PMCID: PMC3851306  PMID: 24093601
Autism; Genetics; Linkage; Pedigree; Phenotype; Posterior probability of linkage
21.  UNC-Utah NA-MIC framework for DTI fiber tract analysis 
Diffusion tensor imaging has become an important modality in the field of neuroimaging to capture changes in micro-organization and to assess white matter integrity or development. While there exists a number of tractography toolsets, these usually lack tools for preprocessing or to analyze diffusion properties along the fiber tracts. Currently, the field is in critical need of a coherent end-to-end toolset for performing an along-fiber tract analysis, accessible to non-technical neuroimaging researchers. The UNC-Utah NA-MIC DTI framework represents a coherent, open source, end-to-end toolset for atlas fiber tract based DTI analysis encompassing DICOM data conversion, quality control, atlas building, fiber tractography, fiber parameterization, and statistical analysis of diffusion properties. Most steps utilize graphical user interfaces (GUI) to simplify interaction and provide an extensive DTI analysis framework for non-technical researchers/investigators. We illustrate the use of our framework on a small sample, cross sectional neuroimaging study of eight healthy 1-year-old children from the Infant Brain Imaging Study (IBIS) Network. In this limited test study, we illustrate the power of our method by quantifying the diffusion properties at 1 year of age on the genu and splenium fiber tracts.
doi:10.3389/fninf.2013.00051
PMCID: PMC3885811  PMID: 24409141
neonatal neuroimaging; white matter pathways; magnetic resonance imaging; diffusion tensor imaging; diffusion imaging quality control; DTI atlas building
22.  Early Brain Overgrowth in Autism Associated with an Increase in Cortical Surface Area Before Age 2 
Archives of General Psychiatry  2011;68(5):467-476.
Objective
Brain enlargement has been observed in 2 year old children with autism but the underlying mechanisms are unknown. This longitudinal MRI study investigated early growth trajectories in brain volume and cortical thickness.
Method
Cerebral gray and white matter volumes and cortical thickness in children with autism spectrum disorder and controls were examined. Subjects were seen at approximately 2 years of age (autism = 59, controls = 38) and were rescanned approximately 24 months later at age 4–5 years (autism = 38, controls = 21).
Results
We observed generalized cerebral cortical enlargement in individuals with ASD at both 2 and 4 – 5 years of age. Rate of cerebral cortical growth across multiple brain regions and tissue compartments, in individuals with ASD, was parallel to that seen in controls, indicating that there was no increase in rate of cerebral cortical growth during this interval. No cerebellar differences were observed in ASD. After controlling for TBV, a disproportionate enlargement in temporal lobe white matter was observed in the ASD group. We found no differences in cortical thickness, but an increase in an estimate of surface area in the ASD group compared to controls for all cortical regions measured (temporal, frontal, and parietal-occipital).
Conclusions
Our longitudinal MRI study found generalized cerebral cortical enlargement in children with ASD, with a disproportionate enlargement in temporal lobe white matter. There was no difference from controls in the rate of brain growth for this age interval, indicating brain enlargement in ASD results from an increased rate of brain growth prior to age 2. The presence of increased cortical volume, but not cortical thickness, suggests that early brain enlargement may be associated with increased cortical surface area. Cortical surface area overgrowth in ASD may underlie brain enlargement and implicates a distinct set of pathogenic mechanisms.
doi:10.1001/archgenpsychiatry.2011.39
PMCID: PMC3315057  PMID: 21536976
24.  Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism 
Archives of general psychiatry  2009;66(5):509-516.
Context
Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of sub-regions during this period of development. The amygdala is hypothesized to be abnormal in volume and related to core clinical features in autism.
Objective
To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism.
Design
Longitudinal magnetic resonance imaging study.
Setting
University medical setting.
Participants
Fifty-two autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age.
Main Outcome Measures
Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response scale; group comparisons including total tissue volume, sex, IQ and age as covariates.
Results
Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, though the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism.
Conclusions
The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism.
doi:10.1001/archgenpsychiatry.2009.19
PMCID: PMC3156446  PMID: 19414710
25.  Multi-object Analysis of Volume, Pose, and Shape using Statistical Discrimination 
One goal of statistical shape analysis is the discrimination between two populations of objects. Whereas traditional shape analysis was mostly concerned with studying single objects, analysis of multi-object complexes presents new challenges related to alignment and relative object pose. In this paper, we present a methodology for discriminant analysis of sets multiple shapes. Shapes are represented by sampled medial manifolds including normals to the boundary. Non-Euclidean metrics that describe geodesic distance between sets of sampled representations are used for shape alignment and discrimination. Our choice of discriminant method is the distance weighted discriminant (DWD) because of its generalization ability in high dimensional, low sample size settings. Using an unbiased, soft discrimination score we can associate a statistical hypothesis test with the discrimination results. Furthermore, localization and nature significant differences between populations can be visualized via the average best discriminating axis.
We explore the effectiveness of different choices of features as input to the discriminant analysis, using morphologic measures like volume, pose, shape and the combination of pose and shape. Our method is applied to a longitudinal pediatric autism study with object sets of 10 subcortical brain structures in a population of 70 samples. The results compare group discrimination by volume, pure shape or pose, and combinations thereof. It is shown that the choices of type of global alignment and of intrinsic versus extrinsic shape features, the latter being sensitive to relative pose, are crucial factors for group discrimination and also for explaining the nature of shape change in terms of the application domain.
doi:10.1109/TPAMI.2009.92
PMCID: PMC3118303  PMID: 20224121

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