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1.  Neurodevelopment for syntactic processing distinguishes childhood stuttering recovery versus persistence 
Background
Characterized by the presence of involuntary speech disfluencies, developmental stuttering is a neurodevelopmental disorder of atypical speech-motor coordination. Although the etiology of stuttering is multifactorial, language development during early childhood may influence both the onset of the disorder and the likelihood of recovery. The purpose of this study was to determine whether differences in neural indices mediating language processing are associated with persistence or recovery in school-age children who stutter.
Methods
Event-related brain potentials (ERPs) were obtained from 31 6–7-year-olds, including nine children who do not stutter (CWNS), 11 children who had recovered from stuttering (CWS-Rec), and 11 children who persisted in stuttering (CWS-Per), matched for age, and all with similar socioeconomic status, nonverbal intelligence, and language ability. We examined ERPs elicited by semantic and syntactic (phrase structure) violations within an auditory narrative consisting of English and Jabberwocky sentences. In Jabberwocky sentences, content words were replaced with pseudowords to limit semantic context. A mixed effects repeated measures analysis of variance (ANOVA) was computed for ERP components with four within-subject factors, including condition, hemisphere, anterior/posterior distribution, and laterality.
Results
During the comprehension of English sentences, ERP activity mediating semantic and syntactic (phrase structure) processing did not distinguish CWS-Per, CWS-Rec, and CWNS. Semantic violations elicited a qualitatively similar N400 component across groups. Phrase structure violations within English sentences also elicited a similar P600 component in all groups. However, identical phrase structure violations within Jabberwocky sentences elicited a P600 in CWNS and CWS-Rec, but an N400-like effect in CWS-Per.
Conclusions
The distinguishing neural patterns mediating syntactic, but not semantic, processing provide evidence that specific brain functions for some aspects of language processing may be associated with stuttering persistence. Unlike CWS-Rec and CWNS, the lack of semantic context in Jabberwocky sentences seemed to affect the syntactic processing strategies of CWS-Per, resulting in the elicitation of semantically based N400-like activity during syntactic (phrase structure) violations. This vulnerability suggests neural mechanisms associated with the processing of syntactic structure may be less mature in 6–7-year-old children whose stuttering persisted compared to their fluent or recovered peers.
doi:10.1186/1866-1955-7-4
PMCID: PMC4318174  PMID: 25657823
Stuttering; Event-related potentials; Language processing; Language development; N400; P600; Children
2.  Patterns of autism spectrum symptomatology in individuals with Down syndrome without comorbid autism spectrum disorder 
Background
Prevalence estimates of autism spectrum disorder (ASD) in Down syndrome (DS) are highly varied. This variation is partly due to the difficulty of screening for and diagnosing comorbid ASD in individuals with a syndrome that carries its own set of social communicative and behavioral difficulties that are not well documented. The aim of this study was to identify the typical range of social communicative impairments observed in children, adolescents, and young adults with DS who do not have comorbid ASD.
Methods
We examined patterns of scores from the five subscales of the Social Responsiveness Scale (SRS) in 46 individuals with DS (ages 10–21 years) without comorbid ASD relative to the published normative sample. We also explored the correlations between SRS symptomatology and age, nonverbal cognition, and receptive language.
Results
SRS scores were elevated (i.e., more ASD symptoms endorsed), with mean scores falling into the clinically significant range. Analysis by subscale revealed a specific pattern, with Autistic Mannerisms and Social Cognition scores significantly more elevated than Social Communication scores, which were significantly more elevated than Social Awareness and Social Motivation scores. Correlations between SRS scores and the other measures varied by subscale.
Conclusions
General elevated ASD symptomatology on the SRS indicates the need for developing population-based norms specific to DS. The pattern of scores across subscales should inform clinicians of the typical range of behaviors observed in DS so that individuals with atypical patterns of behavior can be more easily identified and considered for a full ASD evaluation.
doi:10.1186/1866-1955-7-5
PMCID: PMC4318440  PMID: 25657824
Down syndrome; Autism spectrum disorder; Comorbidity; Social communication; Intellectual disability
3.  There is variability in the attainment of developmental milestones in the CDKL5 disorder 
Background
Individuals with the CDKL5 disorder have been described as having severely impaired development. A few individuals have been reported having attained more milestones including walking and running. Our aim was to investigate variation in attainment of developmental milestones and associations with underlying genotype.
Methods
Data was sourced from the International CDKL5 Disorder Database, and individuals were included if they had a pathogenic or probably pathogenic CDKL5 mutation and information on early development. Kaplan-Meier time-to-event analyses investigated the occurrence of developmental milestones. Mutations were grouped by their structural/functional consequence, and Cox regression was used to investigate the relationship between genotype and milestone attainment.
Results
The study included 109 females and 18 males. By 5 years of age, only 75% of the females had attained independent sitting and 25% independent walking whilst a quarter of the males could sit independently by 1 year 3 months. Only one boy could walk independently. No clear relationship between mutation group and milestone attainment was present, although females with a late truncating mutation attained the most milestones.
Conclusion
Attainment of developmental milestones is severely impaired in the CDKL5 disorder, with the majority who did attain skills attaining them at a late age. It appears as though males are more severely impaired than the females. Larger studies are needed to further investigate the role of genotype on clinical variability.
doi:10.1186/1866-1955-7-2
PMCID: PMC4318547  PMID: 25657822
CDKL5 disorder; Developmental disabilities; Epileptic encephalopathy; Early infantile epileptic encephalopathy
4.  The relationship between sleep and behavior in autism spectrum disorder (ASD): a review 
Although there is evidence that significant sleep problems are common in children with autism spectrum disorder (ASD) and that poor sleep exacerbates problematic daytime behavior, such relationships have received very little attention in both research and clinical practice. Treatment guidelines to help manage challenging behaviors in ASD fail to mention sleep at all, or they present a very limited account. Moreover, limited attention is given to children with low-functioning autism, those individuals who often experience the most severe sleep disruption and behavioral problems. This paper describes the nature of sleep difficulties in ASD and highlights the complexities of sleep disruption in individuals with low-functioning autism. It is proposed that profiling ASD children based on the nature of their sleep disruption might help to understand symptom and behavioral profiles (or vice versa) and therefore lead to better-targeted interventions. This paper concludes with a discussion of the limitations of current knowledge and proposes areas that are important for future research. Treating disordered sleep in ASD has great potential to improve daytime behavior and family functioning in this vulnerable population.
doi:10.1186/1866-1955-6-44
PMCID: PMC4271434  PMID: 25530819
Autism spectrum disorder; Low-functioning autism; Sleep difficulties in ASD; Treating sleep in ASD
5.  Social (pragmatic) communication disorder: a research review of this new DSM-5 diagnostic category 
Social (pragmatic) communication disorder (SCD) is a new diagnostic category in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). The purpose of this review is to describe and synthesize the relevant literature from language and autism spectrum disorder (ASD) research relating to pragmatic language impairment and other previously used terms that relate to SCD. The long-standing debate regarding how social communication/pragmatic impairments overlap and/or differ from language impairments, ASD, and other neurodevelopmental disorders is examined. The possible impact of the addition of SCD diagnostic category and directions for future research are also discussed.
doi:10.1186/1866-1955-6-41
PMCID: PMC4258293  PMID: 25484991
Social communication disorder; Pragmatic language impairment; Autism spectrum disorder; DSM-5
6.  EEG hyper-connectivity in high-risk infants is associated with later autism 
Background
It has been previously reported that structural and functional brain connectivity in individuals with autism spectrum disorders (ASD) is atypical and may vary with age. However, to date, no measures of functional connectivity measured within the first 2 years have specifically associated with a later ASD diagnosis.
Methods
In the present study, we analyzed functional brain connectivity in 14-month-old infants at high and low familial risk for ASD using electroencephalography (EEG). EEG was recorded while infants attended to videos. Connectivity was assessed using debiased weighted phase lag index (dbWPLI). At 36 months, the high-risk infants were assessed for symptoms of ASD.
Results
As a group, high-risk infants who were later diagnosed with ASD demonstrated elevated phase-lagged alpha-range connectivity as compared to both low-risk infants and high-risk infants who did not go on to ASD. Hyper-connectivity was most prominent over frontal and central areas. The degree of hyper-connectivity at 14 months strongly correlated with the severity of restricted and repetitive behaviors in participants with ASD at 3 years. These effects were not attributable to differences in behavior during the EEG session or to differences in spectral power.
Conclusions
The results suggest that early hyper-connectivity in the alpha frequency range is an important feature of the ASD neurophysiological phenotype.
Electronic supplementary material
The online version of this article (doi:10.1186/1866-1955-6-40) contains supplementary material, which is available to authorized users.
doi:10.1186/1866-1955-6-40
PMCID: PMC4232695  PMID: 25400705
Autism spectrum disorders; EEG; Connectivity; Alpha; Infants; Siblings
7.  Pre-pulse inhibition and antisaccade performance indicate impaired attention modulation of cognitive inhibition in 22q11.2 deletion syndrome (22q11DS) 
Background
22q11.2 deletion syndrome (22q11DS) is associated with a number of physical anomalies and neuropsychological deficits including impairments in executive and sensorimotor function. It is estimated that 25% of children with 22q11DS will develop schizophrenia and other psychotic disorders later in life. Evidence of genetic transmission of information processing deficits in schizophrenia suggests performance in 22q11DS individuals will enhance understanding of the neurobiological and genetic substrates associated with information processing. In this report, we examine information processing in 22q11DS using measures of startle eyeblink modification and antisaccade inhibition to explore similarities with schizophrenia and associations with neurocognitive performance.
Methods
Startle modification (passive and active tasks; 120- and 480-ms pre-pulse intervals) and antisaccade inhibition were measured in 25 individuals with genetically confirmed 22q11DS and 30 healthy control subjects.
Results
Individuals with 22q11DS exhibited increased antisaccade error as well as some evidence (trend-level effect) of impaired sensorimotor gating during the active condition, suggesting a dysfunction in controlled attentional processing, rather than a pre-attentive dysfunction using this paradigm.
Conclusions
The findings from the present study show similarities with previous studies in clinical populations associated with 22q11DS such as schizophrenia that may indicate shared dysfunction of inhibition pathways in these groups.
doi:10.1186/1866-1955-6-38
PMCID: PMC4182838  PMID: 25279014
Startle modification; PPI; PPF; Antisaccade; Neurocognition
8.  Enhanced parietal cortex activation during location detection in children with autism 
Background
Visuospatial processing has been found to be mediated primarily by two cortical routes, one of which is unique to recognizing objects (occipital-temporal, ventral or “what” pathway) and the other to detecting the location of objects in space (parietal-occipital, dorsal or “where” pathway). Considering previous findings of relative advantage in people with autism in visuospatial processing, this functional MRI study examined the connectivity in the dorsal and ventral pathways in high-functioning children with autism.
Methods
Seventeen high-functioning children and adolescents with autism spectrum disorders (ASD) and 19 age-and-IQ-matched typically developing (TD) participants took part in this study. A simple visual task involving object recognition and location detection was used. In the MRI scanner, participants were shown grey scale pictures of objects (e.g., toys, household items, etc.) and were asked to identify the objects presented or to specify the location of objects relative to a cross at the center of the screen.
Results
Children with ASD, relative to TD children, displayed significantly greater activation in the left inferior parietal lobule (especially the angular gyrus) while detecting the location of objects. However, there were no group differences in brain activity during object recognition. There were also differences in functional connectivity, with the ASD participants showing decreased connectivity of the inferior temporal area with parietal and occipital areas during location detection.
Conclusions
The results of this study underscore previous findings of an increased reliance on visuospatial processing (increased parietal activation) for information processing in ASD individuals. In addition, such processing may be more local, focal, and detailed in ASD as evidenced from the weaker functional connectivity.
Electronic supplementary material
The online version of this article (doi:10.1186/1866-1955-6-37) contains supplementary material, which is available to authorized users.
doi:10.1186/1866-1955-6-37
PMCID: PMC4190580  PMID: 25302083
fMRI; Autism; Dorsal; Ventral; Visual system; Functional connectivity; Object recognition; Location detection
9.  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
10.  Associations of HLA alleles with specific language impairment 
Background
Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment.
Methods
We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types.
Results
Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD).
Conclusion
These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.
doi:10.1186/1866-1955-6-1
PMCID: PMC3906746  PMID: 24433325
Specific language impairment (SLI); HLA; Neurodevelopmental disorders; Genetic association
11.  Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome 
Background
22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS.
Methods
The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment.
Results
Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS.
Conclusions
Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.
doi:10.1186/1866-1955-6-3
PMCID: PMC3923103  PMID: 24517288
Psychosis; Shyness prediction; Temperament; Velocardiofacial syndrome; Williams syndrome
12.  Abnormal late visual responses and alpha oscillations in neurofibromatosis type 1: a link to visual and attention deficits 
Background
Neurofibromatosis type 1 (NF1) affects several areas of cognitive function including visual processing and attention. We investigated the neural mechanisms underlying the visual deficits of children and adolescents with NF1 by studying visual evoked potentials (VEPs) and brain oscillations during visual stimulation and rest periods.
Methods
Electroencephalogram/event-related potential (EEG/ERP) responses were measured during visual processing (NF1 n = 17; controls n = 19) and idle periods with eyes closed and eyes open (NF1 n = 12; controls n = 14). Visual stimulation was chosen to bias activation of the three detection mechanisms: achromatic, red-green and blue-yellow.
Results
We found significant differences between the groups for late chromatic VEPs and a specific enhancement in the amplitude of the parieto-occipital alpha amplitude both during visual stimulation and idle periods. Alpha modulation and the negative influence of alpha oscillations in visual performance were found in both groups.
Conclusions
Our findings suggest abnormal later stages of visual processing and enhanced amplitude of alpha oscillations supporting the existence of deficits in basic sensory processing in NF1. Given the link between alpha oscillations, visual perception and attention, these results indicate a neural mechanism that might underlie the visual sensitivity deficits and increased lapses of attention observed in individuals with NF1.
doi:10.1186/1866-1955-6-4
PMCID: PMC3944002  PMID: 24559228
Visual evoked potentials; Alpha rhythm; Contrast response function; Electroencephalogram (EEG); Neurofibromatosis type 1 (NF1); Paediatric
13.  Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome 
Background
Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS.
Methods
Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles.
Results
MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10.
Conclusions
The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS.
doi:10.1186/1866-1955-6-6
PMCID: PMC3987046  PMID: 24669826
Autism; Fragile X syndrome; Brain structure; Monoamine oxidase A; Polymorphism
14.  Neonatal exposure to permethrin pesticide causes lifelong fear and spatial learning deficits and alters hippocampal morphology of synapses 
Background
During the neurodevelopmental period, the brain is potentially more susceptible to environmental exposure to pollutants. The aim was to determine if neonatal exposure to permethrin (PERM) pesticide, at a low dosage that does not produce signs of obvious abnormalities, could represent a risk for the onset of diseases later in the life.
Methods
Neonatal rats (from postnatal day 6 to 21) were treated daily by gavage with a dose of PERM (34 mg/kg) close to the no-observed-adverse-effect level (NOAEL), and hippocampal morphology and function of synapses were investigated in adulthood. Fear conditioning, passive avoidance and Morris water maze tests were used to assess cognitive skills in rats, whereas electron microscopy analysis was used to investigate hippocampal morphological changes that occurred in adults.
Results
In both contextual and tone fear conditioning tests, PERM-treated rats showed a decreased freezing. In the passive avoidance test, the consolidation of the inhibitory avoidance was time-limited: the memory was not impaired for the first 24 h, whereas the information was not retained 72 h following training. The same trend was observed in the spatial reference memories acquired by Morris water maze. In PERM-treated rats, electron microscopy analysis revealed a decrease of synapses and surface densities in the stratum moleculare of CA1, in the inner molecular layer of the dentate gyrus and in the mossy fibers of the hippocampal areas together with a decrease of perforated synapses in the stratum moleculare of CA1 and in the inner molecular layer of the dentate gyrus.
Conclusions
Early-life permethrin exposure imparts long-lasting consequences on the hippocampus such as impairment of long-term memory storage and synaptic morphology.
doi:10.1186/1866-1955-6-7
PMCID: PMC3994247  PMID: 24678976
Neonatal exposure; permethrin; hippocampus; synapse; fear conditioning
15.  Common and specific impairments in attention functioning in girls with chromosome 22q11.2 deletion, fragile X or Turner syndromes 
Background
Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention.
Methods
Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices.
Results
Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system.
Conclusions
These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory.
doi:10.1186/1866-1955-6-5
PMCID: PMC3995552  PMID: 24628892
Attention networks test; Visuospatial cognition; Cognitive development; Developmental disorder; Chromosome 22q11.2 deletion syndrome; Velocardiofacial syndrome; DiGeorge syndrome; Fragile X syndrome; Turner syndrome
16.  Self-injury and aggression in tuberous sclerosis complex: cross syndrome comparison and associated risk markers 
Background
Research reporting prevalence rates of self-injurious and aggressive behaviour in people with tuberous sclerosis complex (TSC) is limited. No studies have compared rates of these behaviours in TSC with those in other syndrome groups matched for degree of disability or investigated risk markers for these behaviours in TSC.
Methods
Data from the Challenging Behaviour Questionnaire were collected for 37 children, aged 4 to 15 years, with TSC. Odds ratios were used to compare rates of self-injury and aggression in children with TSC with children with idiopathic autism spectrum disorder (ASD), fragile X, Cornelia de Lange and Down syndromes. Characteristics were measured using the Mood Interest and Pleasure Questionnaire, the Activity Questionnaire, the Social Communication Questionnaire, the Repetitive Behaviour Questionnaire, the Wessex Behaviour Schedule and the revised Non-communicating Children Pain Checklist. Mann-Whitney U analyses were used to compare characteristics between individuals with self-injury and aggression and those not showing these behaviours.
Results
Rates of self-injury and aggression in TSC were 27% and 50%, respectively. These are high but not significantly different from rates in children with Down syndrome or other syndrome groups. Both self-injury and aggression were associated with stereotyped and pain-related behaviours, low mood, hyperactivity, impulsivity and repetitive use of language. Children who engaged in self-injury also had lower levels of interest and pleasure and showed a greater degree of ‘insistence on sameness’ than children who did not self-injure. Aggression was associated with repetitive behaviour. The majority of these associations remained significant when the association with level of adaptive functioning was controlled for.
Conclusions
Behavioural profiles can be used to identify those most at risk of developing self-injury and aggression. Further research is warranted to understand the influence of such internal factors as mood, ASD symptomatology and pain on challenging behaviour in people with intellectual disability.
doi:10.1186/1866-1955-6-10
PMCID: PMC4017702  PMID: 24822087
Aggression; ASD; Impulsivity; Pain; Repetitive/stereotyped behaviour; Self-injury; Tuberous sclerosis complex
17.  CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems 
Background
The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.
Methods
We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.
Results
Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.
Conclusions
The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.
doi:10.1186/1866-1955-6-9
PMCID: PMC4022362  PMID: 24834135
Autism spectrum disorder; CHD2; Developmental delay; Epilepsy; Learning disability
18.  Differences in age-related effects on brain volume in Down syndrome as compared to Williams syndrome and typical development 
Background
Individuals with Down Syndrome (DS) are reported to experience early onset of brain aging. However, it is not well understood how pre-existing neurodevelopmental effects versus neurodegenerative processes might be contributing to the observed pattern of brain atrophy in younger adults with DS. The aims of the current study were to: (1) to confirm previous findings of age-related changes in DS compared to adults with typical development (TD), (2) to test for an effect of these age-related changes in a second neurodevelopmental disorder, Williams syndrome (WS), and (3) to identify a pattern of regional age-related effects that are unique to DS.
Methods
High-resolution T1-weighted MRI of the brains of subjects with DS, WS, and TD controls were segmented, and estimates of regional brain volume were derived using FreeSurfer. A general linear model was employed to test for age-related effects on volume between groups. Secondary analyses in the DS group explored the relationship between brain volume and neuropsychological tests and APOE.
Results
Consistent with previous findings, the DS group showed significantly greater age-related effects relative to TD controls in total gray matter and in regions of the orbitofrontal cortex and the parietal cortex. Individuals with DS also showed significantly greater age-related effects on volume of the left and right inferior lateral ventricles (LILV and RILV, respectively). There were no significant differences in age-related effects on volume when comparing the WS and TD groups. In the DS group, cognitive tests scores measuring signs of dementia and APOE ϵ4 carrier status were associated with LILV and RILV volume.
Conclusions
Individuals with DS demonstrated a unique pattern of age-related effects on gray matter and ventricular volume, the latter of which was associated with dementia rating scores in the DS group. Results may indicate that early onset of brain aging in DS is primarily due to DS-specific neurodegenerative processes, as opposed to general atypical neurodevelopment.
doi:10.1186/1866-1955-6-8
PMCID: PMC4022321  PMID: 24713364
Down syndrome; Williams syndrome; Neurodevelopmental disorder; Brain volume; APOE; MRI; Accelerated aging; Neuroimaging genetics; Alzheimer’s disease
19.  Motor function and perception in children with neuropsychiatric and conduct problems: results from a population based twin study 
Background
Children with early symptomatic psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) have been found to have high rates of motor and/or perception difficulties. However, there have been few large-scale studies reporting on the association between Conduct Disorder (CD) and motor/perception functions. The aim of the present study was to investigate how motor function and perception relate to measures of ADHD, ASD, and CD.
Methods
Parents of 16,994 Swedish twins (ages nine and twelve years) were interviewed using the Autism-Tics, ADHD and other Comorbidities inventory (A-TAC), which has been validated as a screening instrument for early onset child psychiatric disorders and symptoms. Associations between categorical variables of scoring above previously validated cut-off values for diagnosing ADHD, ASD, and CD on the one hand and motor and/or perception problems on the other hand were analysed using cross-tabulations, and the Fisher exact test. Associations between the continuous scores for ADHD, ASD, CD, and the subdomains Concentration/Attention, Impulsiveness/Activity, Flexibility, Social Interaction and Language, and the categorical factors age and gender, on the one hand, and the dependent dichotomic variables Motor control and Perception problems, on the other hand, were analysed using binary logistic regression in general estimated equation models.
Results
Male gender was associated with increased risk of Motor control and/or Perception problems. Children scoring above the cut-off for ADHD, ASD, and/or CD, but not those who were ‘CD positive’ but ‘ADHD/ASD negative’, had more Motor control and/or Perception problems, compared with children who were screen-negative for all three diagnoses. In the multivariable model, CD and Impulsiveness/Activity had no positive associations with Motor control and/or Perception problems.
Conclusions
CD symptoms or problems with Impulsiveness/Activity were associated with Motor control or Perception problems only in the presence of ASD symptoms and/or symptoms of inattention. Our results indicate that children with CD but without ASD or inattention do not show a deviant development of motor and perceptual functions. Therefore, all children with CD should be examined concerning motor control and perception. If problems are present, a suspicion of ADHD and/or ASD should be raised.
doi:10.1186/1866-1955-6-11
PMCID: PMC4035850  PMID: 24872861
Conduct Disorder; Attention-Deficit/Hyperactivity Disorder; Autism Spectrum Disorder; Motor control; Perception; A-TAC
20.  Inaugural Christianson Syndrome Association conference: families meeting for the first time 
Christianson syndrome (CS) is an X-linked neurodevelopmental disorder caused by deleterious mutations in SLC9A6. Affected families organized the inaugural Christianson Syndrome Association conference to advance CS knowledge and develop questions that may be prioritized in future research.
doi:10.1186/1866-1955-6-13
PMCID: PMC4038054  PMID: 25273398
Christianson syndrome; Intellectual disability; NHE6; SLC9A6; X-linked developmental disorder
21.  Robust features for the automatic identification of autism spectrum disorder in children 
Background
It is commonly reported that children with autism spectrum disorder (ASD) exhibit hyper-reactivity or hypo-reactivity to sensory stimuli. Electroencephalography (EEG) is commonly used to study neural sensory reactivity, suggesting that statistical analysis of EEG recordings is a potential means of automatic classification of the disorder. EEG recordings taken from children, however, are frequently contaminated with large amounts of noise, making analysis difficult. In this paper, we present a method for the automatic extraction of noise-robust EEG features, which serve to quantify neural sensory reactivity. We show the efficacy of a system for the classification of ASD using these features.
Methods
An oddball paradigm was used to elicit event-related potentials from a group of 19 ASD children and 30 typically developing children. EEG recordings were taken and robust features were extracted. A support vector machine, logistic regression, and a naive Bayes classifier were used to classify the children as having ASD or being typically developing.
Results
A classification accuracy of 79% was achieved, making our method competitive with other automatic diagnosis methods based on EEG. Additionally, we found that classification performance is reduced if eye blink artifacts are removed during preprocessing.
Conclusions
This study shows that robust EEG features that quantify neural sensory reactivity are useful for the classification of ASD. We showed that noise-robust features are crucial for our analysis, and observe that traditional preprocessing methods may lead to poor classification performance in the face of a large amount of noise. Further exploration of alternative preprocessing methods is warranted.
doi:10.1186/1866-1955-6-12
PMCID: PMC4039057  PMID: 24936212
Autism spectrum disorder; Event-related potential; EEG; Classification
22.  Neural synchrony examined with magnetoencephalography (MEG) during eye gaze processing in autism spectrum disorders: preliminary findings 
Background
Gaze processing deficits are a seminal, early, and enduring behavioral deficit in autism spectrum disorder (ASD); however, a comprehensive characterization of the neural processes mediating abnormal gaze processing in ASD has yet to be conducted.
Methods
This study investigated whole-brain patterns of neural synchrony during passive viewing of direct and averted eye gaze in ASD adolescents and young adults (M Age  = 16.6) compared to neurotypicals (NT) (M Age  = 17.5) while undergoing magnetoencephalography. Coherence between each pair of 54 brain regions within each of three frequency bands (low frequency (0 to 15 Hz), beta (15 to 30 Hz), and low gamma (30 to 45 Hz)) was calculated.
Results
Significantly higher coherence and synchronization in posterior brain regions (temporo-parietal-occipital) across all frequencies was evident in ASD, particularly within the low 0 to 15 Hz frequency range. Higher coherence in fronto-temporo-parietal regions was noted in NT. A significantly higher number of low frequency cross-hemispheric synchronous connections and a near absence of right intra-hemispheric coherence in the beta frequency band were noted in ASD. Significantly higher low frequency coherent activity in bilateral temporo-parieto-occipital cortical regions and higher gamma band coherence in right temporo-parieto-occipital brain regions during averted gaze was related to more severe symptomology as reported on the Autism Diagnostic Interview-Revised (ADI-R).
Conclusions
The preliminary results suggest a pattern of aberrant connectivity that includes higher low frequency synchronization in posterior cortical regions, lack of long-range right hemispheric beta and gamma coherence, and decreased coherence in fronto-temporo-parietal regions necessary for orienting to shifts in eye gaze in ASD; a critical behavior essential for social communication.
doi:10.1186/1866-1955-6-15
PMCID: PMC4072845  PMID: 24976870
Autism spectrum disorder; Eye gaze; Neural synchrony; Coherence; Magnetoencephalography; Social cognition
23.  Reactivity to fearful expressions of familiar and unfamiliar people in children with autism: an eye-tracking pupillometry study 
Background
Individuals with autism are often reported to have difficulty with emotion processing. However, clinical and experimental data show that they are sensitive to familiarity; for example, they show normative attachment to familiar people, and have normative brain activity in response to familiar faces. To date, no study has measured their reactivity to the emotions of familiar vs. unfamiliar people. Thus, our aim was to determine whether individuals with autism would show normative reactivity to emotion in familiar people.
Methods
Participants were 21 children with autism and 21 children with typical development, aged two to five years, matched on age and gender. The children observed videos of familiar people (their child-care teachers) and unfamiliar people expressing fear, whilst their visual attention and pupillary reactions were recorded (the latter as an index of emotional reactivity), using eye tracking technology.
Results
The children with autism showed normative pupillary reactions (peak magnitude) to fear expressed by familiar people, but a reduced response to fear expressed by unfamiliar people. However, across familiarity conditions, the children with autism had longer latency peak responses than the typically developing children. This pattern of findings was independent of cognitive factors or visual attention as visual attention by group was not related to familiarity condition. The children with autism had reduced visual attention to neutral faces; however, on fearful faces there were no group differences. Abnormalities in pupillary reactivity in the autism group were related to less prosocial behaviour and more severe play and communication deficits.
Conclusions
Children with autism were less atypical in their responses to fearful expressions of people they know, arguing against a pervasive emotional impairment in autism, but rather one that may be mediated by familiarity.
doi:10.1186/1866-1955-6-14
PMCID: PMC4064262  PMID: 24982695
Autism; Emotion; Familiarity; Physiological reactivity; Pupillometry; Eye-tracking; Response latency
24.  A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder 
Background
Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution.
Methods
We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse.
Results
The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development.
Conclusion
The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
doi:10.1186/1866-1955-6-17
PMCID: PMC4104741  PMID: 25050139
Autism spectrum disorder (ASD); CTNNA3; αT-catenin; Alpha T-catenin; Cell adhesion; DNA copy number variants
25.  The neural correlates of visuo-spatial working memory in children with autism spectrum disorder: effects of cognitive load 
Background
Research on the neural bases of cognitive deficits in autism spectrum disorder (ASD) has shown that working memory (WM) difficulties are associated with abnormalities in the prefrontal cortex. However, cognitive load impacts these findings, and no studies have examined the relation between WM load and neural underpinnings in children with ASD. Thus, the current study determined the effects of cognitive load on WM, using a visuo-spatial WM capacity task in children with and without ASD with functional magnetic resonance imaging (fMRI).
Methods
We used fMRI and a 1-back colour matching task (CMT) task with four levels of difficulty to compare the cortical activation patterns associated with WM in children (7–13 years old) with high functioning autism (N = 19) and matched controls (N = 17) across cognitive load.
Results
Performance on CMT was comparable between groups, with the exception of one difficulty level. Using linear trend analyses, the control group showed increasing activation as a function of difficulty level in frontal and parietal lobes, particularly between the highest difficulty levels, and decreasing activation as a function of difficulty level in the posterior cingulate and medial frontal gyri. In contrast, children with ASD showed increasing activation only in posterior brain regions and decreasing activation in the posterior cingulate and medial frontal gyri, as a function of difficulty level. Significant differences were found in the precuneus, dorsolateral prefrontal cortex and medial premotor cortex, where control children showed greater positive linear relations between cortical activity and task difficulty level, particularly at the highest difficulty levels, but children with ASD did not show these trends.
Conclusions
Children with ASD showed differences in activation in the frontal and parietal lobes—both critical substrates for visuo-spatial WM. Our data suggest that children with ASD rely mainly on posterior brain regions associated with visual and lower level processing, whereas controls showed activity in frontal lobes related to the classic WM network. Findings will help guide future work by localizing areas of vulnerability to developmental disturbances.
doi:10.1186/1866-1955-6-19
PMCID: PMC4107490  PMID: 25057329
Working memory; Autism spectrum disorder; Functional magnetic resonance imaging; Executive function; Cognitive load; Frontal lobe; Parietal lobe

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