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1.  Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review 
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
Background
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
Conclusions
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001572.
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
doi:10.1371/journal.pmed.1001572
PMCID: PMC3866092  PMID: 24358029
2.  Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders 
eLife  2014;3:e02917.
Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34–1.44) and 2.19 (95% CI 2.15–2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36–1.58) and 2.70 (95% CI 2.59–2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.
DOI: http://dx.doi.org/10.7554/eLife.02917.001
eLife digest
Children learn to talk, manage their emotions, and control their behavior in a period when the brain is developing rapidly. The first signs of several developmental disorders, such as autism and attention-deficit/hyperactivity disorder (ADHD), may also emerge during this period. Children with autism may have difficulties with social interactions and communication, while those with attention-deficit/hyperactivity disorder may struggle to pay attention to a task and may be more active than other children.
Autism or ADHD are diagnosed based on the child's behavior because the underlying causes of the disorders are not well understood. Both genes and the environment have been linked to the conditions; and it was recently suggested that certain common genetic mutations are more common in children with ADHD or autism. However, as some of the mutations linked to autism are not found in the genes of the affected children's parents, it is likely that they occurred in either of the sperm or the egg cell from the parents.
Exposure to harmful substances in the environment can cause mutations in egg or sperm cells, or alter the expression of genes without changing the gene sequence. Excessive alcohol consumption is one environmental factor that can mutate genes or alter gene expression. Here, Sundquist et al. have looked to see if there is a relationship between a child having a parent with an alcohol use problem and the child's risk of developing autism or ADHD.
Examining national medical registries identified 24,157 people with autism and 49,348 with ADHD in Sweden between 1987 and 2010. Sundquist et al. discovered that autism and ADHD were more common in individuals who had a parent with a history of an alcohol use disorder than in those whose parents had no history of an alcohol use disorder. There was also an even greater risk of either condition if the parent had been diagnosed with an alcohol use problem before the birth of the child.
Adopted children who had a biological parent with an alcohol use disorder were at a greater risk of autism and ADHD than those whose adoptive parent had an alcohol use disorder. However, as very few adopted parents were diagnosed with an alcohol use problem, it is important to be cautious about drawing firm conclusions from this observation.
Sundquist et al. estimate that around 4% of autism cases and 11% of ADHD cases could be avoided if parents abstained from heavy alcohol consumption. Though these findings are consistent with parents with an alcohol use disorder being more likely to pass on mutations to their children, there are also other possible explanations. As such, further research examining the underlying cause is still needed.
DOI: http://dx.doi.org/10.7554/eLife.02917.002
doi:10.7554/eLife.02917
PMCID: PMC4135348  PMID: 25139954
autism; ADHD; alcohol use disorders; human
3.  Constraining Heterogeneity: The Social Brain and its Development in Autism Spectrum Disorder 
The expression of autism spectrum disorder (ASD) is highly heterogeneous, owing to the complex interactions between genes, the brain, and behavior throughout development. Here we present a model of ASD that implicates an early and initial failure to develop the specialized functions of one or more of the set of neuroanatomical structures involved in social information processing (i.e., the “social brain”). From this early and primary disruption, abnormal brain development is canalized because the individual with an ASD must develop in a highly social world without the specialized neural systems that would ordinarily allow him or her to partake in the fabric of social life, which is woven from the thread of opportunities for social reciprocity and the tools of social engagement. This brain canalization gives rise to other characteristic behavioral deficits in ASD including deficits in communication, restricted interests, and repetitive behaviors. We propose that focused efforts to explore the brain mechanisms underlying the core, pathognomic deficits in the development of mechanisms for social engagement in ASD will greatly elucidate our understanding and treatment of this complex, devastating family of neurodevelopmental disorders. In particular, developmental studies (i.e., longitudinal studies of young children with and without ASD, as well as infants at increased risk for being identified with ASD) of the neural circuitry supporting key aspects of social information processing are likely to provide important insights into the underlying components of the full-syndrome of ASD. These studies could also contribute to the identification of developmental brain endophenotypes to facilitate genetic studies. The potential for this kind of approach is illustrated via examples of functional neuroimaging research from our own laboratory implicating the posterior superior temporal sulcus (STS) as a key player in the set of neural structures giving rise to ASD.
doi:10.1111/j.1469-7610.2010.02349.x
PMCID: PMC3096715  PMID: 21244421
4.  Age-Dependent Brain Gene Expression and Copy Number Anomalies in Autism Suggest Distinct Pathological Processes at Young Versus Mature Ages 
PLoS Genetics  2012;8(3):e1002592.
Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism.
Author Summary
Autism is a disorder characterized by aberrant social, communication, and restricted and repetitive behaviors. It develops clinically in the first years of life. Toddlers and children with autism often exhibit early brain enlargement and excess neuron numbers in the prefrontal cortex. Adults with autism generally do not display enlargement but instead may have a smaller brain size. Thus, we investigated DNA and mRNA patterns in prefrontal cortex from young versus adult postmortem individuals with autism to identify age-related gene expression differences as well as possible genetic correlates of abnormal brain enlargement, excess neuron numbers, and abnormal functioning in this disorder. We found abnormalities in genetic pathways governing cell number, neurodevelopment, and cortical lateralization in autism. We also found that the key pathways associated with autism are different between younger and older autistic individuals. These findings suggest that dysregulated gene pathways in the early stages of neurodevelopment could lead to later behavioral and cognitive deficits associated with autism.
doi:10.1371/journal.pgen.1002592
PMCID: PMC3310790  PMID: 22457638
5.  What are infant siblings teaching us about autism in infancy? 
International research to understand infant patterns of development in autism spectrum disorders has recently focused on a research paradigm involving prospective longitudinal studies of infant siblings of children with autism. Such designs use a comparison group of infant siblings without any familial risks (the low- risk group) to gather longitudinal information about developmental skills across the first three years of life, followed by clinical diagnosis of ASD at 36 months. This review focuses on five topics: presence of ASD in the infant sibling groups, patterns and characteristics of motor development, patterns and characteristics of social and emotional development, patterns and characteristics of intentional communication, both verbal and nonverbal, and patterns that mark the onset of behaviors pathognomonic for ASD. Symptoms in all these areas typically begin to be detected during the age period of 12 –24 months in infants who will develop autism. Onset of the symptoms occurs at varying ages and in varying patterns, but the pattern of frank loss of skills and marked regression reported from previous retrospective studies in 20–30% of children is seldom reported in these infant sibling prospective studies. Two surprises involve the very early onset of repetitive and unusual sensory behaviors, and the lack of predictive symptoms at age 6 months. Contrary to current views that autism is a disorder that profoundly affects social development from the earliest months of life, the data from these studies presents a picture of autism as a disorder involving symptoms across multiple domains with a gradual onset that changes both ongoing developmental rate and established behavioral patterns across the first two to three years of life.
doi:10.1002/aur.81
PMCID: PMC2791538  PMID: 19582867
6.  Autism 
Clinical Evidence  2010;2010:0322.
Introduction
Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child’s Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.
Key Points
Autism is one of a group of pervasive developmental disorders, and is characterised by qualitative impairments in communication and social interaction, and by repetitive and stereotyped behaviours and interests. Abnormal development is present before the age of 3 years. A quarter of affected children show developmental regression, with loss of previously acquired skills.One third of children with autism have epilepsy, and three quarters have mental retardation. Only 15% of adults with autism will lead independent lives.Twin and family studies suggest that most cases of autism occur because of a combination of genetic factors. Autism is not caused by perinatal factors or by the MMR vaccine.
It may be difficult to apply the results of research in practice, as improvements in outcomes assessed in RCTs using standardised assessment tools may not correlate with improvements in function in a particular child with autism.
Some interventions are administered by (or in conjunction with) parents, and may be carried out in the home. Consideration of the direct financial costs, indirect costs (through possible lost earnings), and the impact on relationships within the family (to siblings or spouse) must be balanced against likely and possible improvements in outcome for the child with autism.
There is a lack of good-quality evidence on the effectiveness of early multidisciplinary intervention programmes, or for other treatments for children with autism. There is consensus, supported by a systematic review, that early intensive behavioural interventions are likely to be beneficial in children with autism.Attendance at a "More Than Words" training course for parents may improve communication between parents and children, as may participation in Child's Talk. There is consensus that the Autism Preschool Programme and TEACCH may be effective, although no RCTs or cohort studies evaluating these interventions have been found.We don't know whether early intervention using the EarlyBird programme, the Portage scheme, Relationship-Development Intervention, Social stories, music therapy, CBT, facilitated communication or Son-Rise are beneficial in children with autism.
Methylphenidate may reduce hyperactivity in children with autism. Methylphenidate may increase social withdrawal and irritability. Growth and blood pressure monitoring are required.
Risperidone may improve behaviour in children with autism compared with placebo, but its use is limited by adverse effects such as weight gain, drowsiness, prolactinaemia, and tremors.
There is consensus that selective serotonin reuptake inhibitors (SSRIs) improve symptoms in children with autism, although no RCTs have been found. The adverse effects of SSRIs, including possible increases in agitation, hostility, and suicidal ideation, are well documented.
We don't know whether auditory integration training, sensory integration training, chelation, a gluten- and casein-free diet, digestive enzymes, omega-3 fish oil, secretin, vitamin A, vitamin B6 plus magnesium, melatonin, olanzapine, or vitamin C are beneficial for treating children with autism, as few studies have been found.
PMCID: PMC2907623  PMID: 21729335
7.  Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood 
PLoS Medicine  2009;6(3):e1000040.
Background
Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood.
Methods and Findings
A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures.
Conclusions
The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.
Using a sample of children from the US Collaborative Perinatal Project, John McGrath and colleagues show that the offspring of older fathers exhibit subtle impairments on tests of neurocognitive ability during infancy and childhood.
Editors' Summary
Background.
Over the last few decades, changes in society in the developed world have made it increasingly common for couples to wait until their late thirties to have children. In 1993, 25% of live births within marriage in England and Wales were to fathers aged 35–54 years, but by 2003 it was 40%. It is well known that women's fertility declines with age and that older mothers are more likely to have children with disabilities such as Down's syndrome. In contrast, many men can father children throughout their lives, and little attention has been paid to the effects of older fatherhood.
More recent evidence shows that a man's age does affect both fertility and the child's health. “Advanced paternal age” has been linked to miscarriages, birth deformities, cancer, and specific behavioral problems such as autism or schizophrenia.
Rates of autism have increased in recent decades, but the cause is unknown. Studies of twins and families have suggested there may be a complex genetic basis, and it is suspected that damage to sperm, which can accumulate over a man's lifetime, may be responsible. A woman's eggs are formed largely while she is herself in the womb, but sperm-making cells divide throughout a man's lifetime, increasing the chance of mutations in sperm.
Why Was This Study Done?
There is good evidence linking specific disorders with older fathers, but the link between a father's age and a child's more general intelligence is not as clear. A recent study suggested a link between reduced intelligence and both very young and older fathers. The authors wanted to use this large dataset to test the idea that older fathers have children who do worse on tests of intelligence. They also wanted to re-examine others' findings using this same dataset that older mothers have more intelligent children.
What Did the Researchers Do and Find?
The researchers gathered no new data but reanalyzed data on children from the US Collaborative Perinatal Project (CPP), which had used a variety of tests given to children at ages 8 months, 4 years, and 7 years, to measure cognitive ability—the ability to think and reason, including concentration, memory, learning, understanding, speaking, and reading. Some tests included assessments of “motor skills”—physical co-ordination.
The CPP dataset holds information on children of 55,908 expectant mothers who attended 12 university-affiliated hospital clinics in the United States from 1959 to 1965. The researchers excluded premature babies and multiple births and chose one pregnancy at random for each eligible woman, to keep their analysis simpler. This approach reduced the number of children in their analysis to 33,437.
The researchers analyzed the data using two models. In one, they took into account physical factors such as the parents' ages. In the other, they also took into account social factors such as the parents' level of education and income, which are linked to intelligence. In addition, the authors grouped the children by their mother's age and, within each group, looked for a link between the lowest-scoring children and the age of their father.
The researchers found that children with older fathers had lower scores on all of the measures except one measure of motor skills. In contrast, children with older mothers had higher scores. They found that the older the father, the more likely was this result found.
What Do These Findings Mean?
This study is the first to show that children of older fathers perform less well in a range of tests when young, but cannot say whether those children catch up with their peers after the age of 7 years. Results may also be biased because information was more likely to be missing for children whose father's age was not recorded.
Previous researchers had proposed that children of older mothers may perform better in tests because they experience a more nurturing home environment. If this is the case, children of older fathers do not experience the same benefit.
However, further work needs to be done to confirm these findings. Especially in newer datasets, current trends to delay parenthood mean these findings have implications for individuals, couples, and policymakers. Individuals and couples need to be aware that the ages of both partners can affect their ability to have healthy children, though the risks for individual children are small. Policymakers should consider promoting awareness of the risks of delaying parenthood or introducing policies to encourage childbearing at an optimal age.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000040.
Mothers 35+ is a UK Web site with resources and information for older mothers, mothers-to-be, and would-be mothers, including information on the health implications of fathering a child late in life
The American Society for Reproductive Medicine published a Patient Information Booklet on Age and Fertility in 2003, which is available online; it contains a small section called “Fertility in the Aging Male,” but otherwise focuses on women
The online encyclopedia Wikipedia has a short article on the “Paternal age effect” (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
In 2005, the UK Office of National Statistics published a booklet entitled “Perpetual postponers? Women's, men's and couple's fertility intentions and subsequent fertility behaviour” looking at data from the British Household Panel Survey
doi:10.1371/journal.pmed.1000040
PMCID: PMC2653549  PMID: 19278291
8.  Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism 
Lay Abstract
Autism is a behaviorally defined disorder with increasing prevalence rates globally. The disorder is characterized by deficits in several domains including social behaviors, restricted and repetitive behaviors, and deficits in communication. Two regions thought to contribute to deficits in social behavior are the posterior cingulate cortex (PCC) and fusiform gyrus (FFG). The PCC is involved in processing emotionally salient stimuli, and also has a role in processing faces. The FFG is the area responsible for object and face recognition. A potential imbalance between excitatory and inhibitory processing in the brain may contribute to some of the abnormal social behaviors observed in autism. This is supported by previous work suggesting reduced GABA receptors in the autistic brain. The present study used thionin stained section to qualitatively assess cortical patterning and quantitatively assess the density of neurons. Furthermore, immunohistochemistry was used to determine the density of a subset of GABAergic interneurons. In the autistic brain, the PCC displayed several abnormal cortical patterns including irregularly distributed neurons in specific cortical layers, and the presence of increased white matter neurons. In marked contrast, the FFG appeared normal and there were no significant differences in the density of neurons or interneurons in either region. The present study highlights the presence of abnormal findings in the PCC, which appear to have developmental origins and could affect local processing of social-emotional behaviors as well as the function of interrelated cortical areas.
Scientific Abstract
Autism is a developmental disorder with prenatal origins, currently estimated to affect 1 in 91 children in the United States. Social-emotional deficits are a hallmark of autism and early neuropathology studies have indicated involvement of the limbic system. Imaging studies demonstrate abnormal activation of the posterior cingulate cortex (PCC), a component of the limbic system. Abnormal activation has also been noted in the fusiform gyrus (FFG), a region important for facial recognition and a key element in social interaction. A potential imbalance between excitatory and inhibitory interneurons in the cortex may contribute to altered information processing in autism. Furthermore, reduced numbers of GABA receptors have previously been reported in the autistic brain. Thionin stained sections were used to qualitatively assess cytoarchitectonic patterning and quantitatively determine the density of neurons and immunohistochemistry was used to determine the densities of a subset of GABAergic interneurons utilizing parvalbumin- and calbindin- immunoreactivity. In autism, the PCC displayed altered cytoarchitecture with irregularly distributed neurons, poorly demarcated layers IV and V, and increased presence of white matter neurons. In contrast, no neuropathology was observed in the FFG. There was no significant difference in the density of thionin, parvalbumin, or calbindin interneurons in either region and there was a trend towards a reduced density of calbindin neurons in the PCC. This study highlights the presence of abnormal findings in the PCC, which appear to be developmental in nature and could affect the local processing of social-emotional behaviors as well as functioning of interrelated areas.
doi:10.1002/aur.188
PMCID: PMC3110607  PMID: 21360830
9.  Two-year-olds with autism orient to nonsocial contingencies rather than biological motion 
Nature  2009;459(7244):257-261.
Typically-developing human infants preferentially attend to biological motion within the first days of life1. This ability is highly conserved across species2,3 and is believed to be critical for filial attachment and for detection of predators4. The neural underpinnings of biological motion perception are overlapping with brain regions involved in perception of basic social signals such as facial expression and gaze direction5, and preferential attention to biological motion is seen as a precursor to the capacity for attributing intentions to others6. However, in a serendipitous observation7, we recently found that an infant with autism failed to recognize point-light displays of biological motion but was instead highly sensitive to the presence of a non-social, physical contingency that occurred within the stimuli by chance. This observation raised the hypothesis that perception of biological motion may be altered in children with autism from a very early age, with cascading consequences for both social development and for the lifelong impairments in social interaction that are a hallmark of autism spectrum disorders8. Here we show that two-year-olds with autism fail to orient towards point-light displays of biological motion, and that their viewing behavior when watching these point-light displays can be explained instead as a response to non-social, physical contingencies physical contingencies that are disregarded by control children. This observation has far-reaching implications for understanding the altered neurodevelopmental trajectory of brain specialization in autism9.
doi:10.1038/nature07868
PMCID: PMC2758571  PMID: 19329996
10.  Children with Autism Show Reduced Somatosensory Response: An MEG Study 
Lay Abstract
Autism spectrum disorders are reported to affect nearly one out of every one hundred children, with over 90% of these children showing behavioral disturbances related to the processing of basic sensory information. Behavioral sensitivity to light touch, such as profound discomfort with clothing tags and physical contact, is a ubiquitous finding in children on the autism spectrum. In this study, we investigate the strength and timing of brain activity in response to simple, light taps to the fingertip. Our results suggest that children with autism show a diminished early response in the primary somatosensory cortex (S1). This finding is most evident in the left hemisphere. In exploratory analysis, we also show that tactile sensory behavior, as measured by the Sensory Profile, may be a better predictor of the intensity and timing of brain activity related to touch than a clinical autism diagnosis. We report that children with atypical tactile behavior have significantly lower amplitude somatosensory cortical responses in both hemispheres. Thus sensory behavioral phenotype appears to be a more powerful strategy for investigating neural activity in this cohort. This study provides evidence for atypical brain activity during sensory processing in autistic children and suggests that our sensory behavior based methodology may be an important approach to investigating brain activity in people with autism and neurodevelopmental disorders.
Scientific Abstract
The neural underpinnings of sensory processing differences in autism remain poorly understood. This prospective magnetoencephalography (MEG) study investigates whether children with autism show atypical cortical activity in the primary somatosensory cortex (S1) in comparison to matched controls. Tactile stimuli were clearly detectable, painless taps applied to the distal phalanx of the second (D2) and third (D3) fingers of the right and left hands. Three tactile paradigms were administered: an oddball paradigm (standard taps to D3 at an inter-stimulus interval (ISI) of 0.33 and deviant taps to D2 with ISI ranging from 1.32–1.64s); a slow-rate paradigm (D2) with an ISI matching the deviant taps in the oddball paradigm; and a fast-rate paradigm (D2) with an ISI matching the standard taps in the oddball. Study subjects were boys (age 7–11 years) with and without autism disorder. Sensory behavior was quantified using the Sensory Profile questionnaire. Boys with autism exhibited smaller amplitude left hemisphere S1 response to slow and deviant stimuli during the right hand paradigms. In post-hoc analysis, tactile behavior directly correlated with the amplitude of cortical response. Consequently, the children were re-categorized by degree of parent-report tactile sensitivity. This regrouping created a more robust distinction between the groups with amplitude diminution in the left and right hemispheres and latency prolongation in the right hemisphere in the deviant and slow-rate paradigms for the affected children. This study suggests that children with autism have early differences in somatosensory processing, which likely influence later stages of cortical activity from integration to motor response.
doi:10.1002/aur.1247
PMCID: PMC3474892  PMID: 22933354
Cognitive Neuroscience; Event Related Potential; School age; Low-level perception; Magnetoencephalography
11.  The Modifier Model of Autism and Social Development in Higher Functioning Children 
The study of phenotypic variability in social impairments and comorbid emotional disorders in autism is important because it provides information on phenotypic differences that currently complicate diagnosis, research, and treatment of this disorder. Currently, though, relatively little is known about the processes that contribute to individual differences in social impairments and comorbidity in autism. In this paper, we present a model that suggests modifier processes (MPs), which are not necessarily specific to the syndrome refractor alter the expression of autism and contribute to fundamental behavioral and psychological differences in children diagnosed with this disorder. One MPs involves the somewhat surprising tendency of some children with higher functioning autism (HFA) to make attributions about other peoples thoughts, although they have social cognitive deficits Just as in other children, the attributions of children with HFA are linked to some of their behavioral problems Another MP involves the influence of differences in motivation associated with the behavioral activation and inhibition systems that can be assessed with measures of anterior EEG asymmetry. This dimension of motivation may be linked to how active but inappropriate and withdrawn children with HFA may appear. Third, differences in the self-monitoring of errors among children with HFA appear to be related to individual differences in IQ and social symptom severity in these children. The possible role of these MPs in diagnostic subgroups and differences in treatment responses among children with HFA are discussed. In addition, the role of MPs in understanding the effects associated with specific genetic functions in autism, such as those associated with the serotonin transporter gene (5-HTTLPR), is discussed. A conclusion of this paper is that the varied expression of autism may require that we understand how autism interacts with other non-syndrome-specific processes that are related to individual differences in all people.
PMCID: PMC2773555  PMID: 19898685
phenotypic variability; comorbity; self-monitoring; motivation and attributional processes; autism
12.  Heavy Metals and Trace Elements in Hair and Urine of a Sample of Arab Children with Autistic Spectrum Disorder 
Mædica  2011;6(4):247-257.
ABSTRACT
General information: Autism is a severe developmental disorder which involves social withdrawal, communication deficits, and stereotypic/repetitive behavior. The pathophysiological etiologies which precipitate autism symptoms remain elusive and controversial in many cases, but both genetic and environmental factors (and their interactions) have been implicated. While autism is considered multicausal, environmental factors have received significant attention. International discussion has ocused on neurotoxins such as mercury and lead, suggesting that these and other toxic metals contribute to the development of the disorder. An epidemiological study released in 2006 (Palmer et al.) linking Toxic Release Inventory (TRI) data on mercury to special education data in Texas reported a 61% increase in autism prevalence rates (or 17% adjusted) per 1000 pounds of mercury released into the environment (1). We attempted to further evaluate whether exposure to variable environmental contributes to the genesis of autistic spectrum disorder, and thus is a factor increasing the risk for developing autism symptoms in utero or in early childhood.
Purpose: The purpose of this study is to examine possible environmental risk factors and sources of exposure to mercury and other heavy metals in children with autism spectrum disorder versus controls. Through laboratory diagnostics we are able to distinguish between present and past exposure (i.e. hair analysis measurements reflect past exposure), urinary excretion levels of unprovoked urine represent immediate exposure. By assessing a spectrum of trace elements and heavy metals in hair and urine of both autistic and control groups, we focused on the participants≈ past and present exposure.
Methodology: The participants were 25 Autistic Spectrum Disorder (ASD) children (22 boys and 3 girls) between the age of 3 and 9 years. They were either diagnosed previously by other psychiatrist, psychologist, and developmental pediatrician or suspected by their parents as being autistic. All children were attendants to the Child Psychiatric Clinic in Erfan Psychiatric Hospital in Jeddah, KSA. Samples were collected during the period of June 2006 to March 2008. A control group of 25 children without any psychiatric or medical disorders was age-matched and sex-matched. All parents signed informed consent forms. All autistic children were subjected to a full clinical child psychiatric sheet for the diagnosis of autism spectrum disorder and exclusion of other psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) using the Arabic versions. Both groups were subjected to the Questionnaire on Exposure to Heavy Metals, Physical Symptoms, and Child Development. Hair and baseline urine samples (i.e. unprovoked urine) were taken from both groups and sent to the German clinical and environmental laboratory Micro Trace Minerals Gmbh, for the detection of heavy metals and trace elements levels where metal testing was performed via ICP-MS spectroscopy utilizing cell technique.
Results: By comparing the ASD Group to the Control Group, we found a statistically significant difference in the mean hair levels of arsenic, cadmium, barium, cerium and lead (p=0.01, 0.03, 0.003, 0.003, and 0.03 respectively), and in the mean hair levels of magnesium and zinc (p=0.001 and 0.003 respectively). There were also statistically significant differences in the mean urine levels of aluminum, barium, cerium, mercury, and lead (p=0.004, 002, 0.014, 0.006 and 0.004 respectively), and in the mean urine levels of copper and germanium (p=0.049 and 0.02 respectively). An agreement was found in both specimen (hair and urine) for barium and lead. The statistically significant differences in mean hair levels of arsenic, cadmium, and cerium were not supported by urine baseline levels. Also, the statistically significant magnesium and zinc levels of hair were not supported by urine levels. A disagreement was also found with copper and germanium concentrations.
PMCID: PMC3391939  PMID: 22879836
micronucleus; nucleoplasmic bridges; colon cancer
13.  The broad autism phenotype predicts child functioning in autism spectrum disorders 
Background
Broad autism phenotype (BAP) is a milder expression of the social and communication impairments seen in autism spectrum disorders (ASD). While prior studies characterized the BAP in unaffected family members of probands with ASD, the relationship between parental BAP traits and proband symptomatology remains poorly understood. This study utilizes the Broad Autism Phenotype Questionnaire (BAPQ) in parents and the Social Responsiveness Scale (SRS) in children to examine this connection. We hypothesized that in families affected by ASD, elevated maternal and paternal BAPQ scores would correlate with greater autism symptomatology in diagnosed children. In an extension of prior research, we also explored this relationship in families with typically developing children (TDC).
Methods
Two hundred and forty-five children with ASD, 129 TDC and all parents were recruited as part of a larger study investigating relationships between genes, brain and behavior. The Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and expert clinical judgment confirmed ASD diagnoses in children. SRS was collected for all children. Parents completed a self-report BAPQ and an informant report BAPQ for their spouse; an average of self-report and informant report for each parent was used in all analyses.
Results
Mothers and fathers of children with ASD had significantly higher rates of BAP traits as compared to parents of TDC. Maternal and paternal BAPQ total scores were not correlated with child IQ in either group. In the ASD group, 10% of mothers and 21% of fathers scored above the established BAP threshold compared to 4% of TDC parents. Crude regression analyses showed that maternal and paternal BAPQ total scores accounted for significant variance in child SRS scores in both ASD (17.1%) and TDC (19.8%) families.
Conclusions
Our results suggest that broad autism symptomatology in parents is moderately associated with their child’s autism symptomatology. This result extended to TDC families, suggesting that the BAPQ and SRS capture subtle, subclinical social variation in both children and adults. These findings could help define multi-generational social impairments in future phenotypic and genetic studies.
doi:10.1186/1866-1955-5-25
PMCID: PMC3848833  PMID: 24053506
Autism spectrum disorders; Broad autism phenotype; Social functioning
14.  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)
15.  MRI Study of Minor Physical Anomaly in Childhood Autism Implicates Aberrant Neurodevelopment in Infancy 
PLoS ONE  2011;6(6):e20246.
Background
MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective ‘window’ to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism.
Methods
We recruited 91 children aged 7–16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates.
Results
Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles.
Conclusions
Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to “social brain” dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a “fossil record” of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism.
doi:10.1371/journal.pone.0020246
PMCID: PMC3110727  PMID: 21687660
16.  Family function, Parenting Style and Broader Autism Phenotype as Predicting Factors of Psychological Adjustment in Typically Developing Siblings of Children with Autism Spectrum Disorders 
Iranian Journal of Psychiatry  2014;9(2):55-63.
Objective
Siblings of children with autism are at a greater risk of experiencing behavioral and social problems. Previous researches had focused on environmental variables such as family history of autism spectrum disorders (ASDs), behavior problems in the child with an ASD, parental mental health problems, stressful life events and “broader autism phenotype” (BAP), while variables like parenting style and family function that are shown to influence children’s behavioral and psychosocial adjustment are overlooked. The aim of the present study was to reveal how parenting style and family function as well as BAP effect psychological adjustment of siblings of children with autism.
Method
The Participants included 65 parents who had one child with an Autism Spectrum Disorder and one typically developing child. Of the children with ASDs, 40 were boys and 25 were girls; and they were diagnosed with ASDs by a psychiatrist based on DSM-IV-TR criteria and Autism Diagnostic Interview-Revised (ADI-R). The Persian versions of the six scales were used to collect data from the families. Pearson’s correlation test and regression analysis were used to determine which variables were related to the psychological adjustment of sibling of children with ASDs and which variables predicted it better.
Results
Significant relationships were found between Strengths and Difficulties Questionnaire (SDQ) total difficulties, prosocial behaviors and ASDs symptoms severity, parenting styles and some aspects of family function. In addition, siblings who had more BAP characteristics had more behavior problems and less prosocial behavior. Behavioral problems increased and prosocial behavior decreased with permissive parenting style. Besides, both of authoritarian and authoritative parenting styles led to a decrease in behavioral problems and an increase in prosocial behaviors. Our findings revealed that some aspects of family function (affective responsiveness, roles, problem solving and behavior control) were significantly correlated with behavioral problems and prosocial behaviors in typically developing (TD) siblings of children with ASDs.
Conclusion
Siblings of children with ASDs, due to genetic liability, are at a greater risk of psychological maladjustment. Furthermore, environmental factors like parenting styles and family function also have a significant effect on psychological maladjustment.
PMCID: PMC4300466  PMID: 25632281
Autism spectrum disorders (ASDs); broader autism phenotype; sibling; parenting style; psychological adjustment
17.  The Long-Term Health Consequences of Child Physical Abuse, Emotional Abuse, and Neglect: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(11):e1001349.
Rosana Norman and colleagues conduct a systematic review and meta-analysis to assess the relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
Background
Child sexual abuse is considered a modifiable risk factor for mental disorders across the life course. However the long-term consequences of other forms of child maltreatment have not yet been systematically examined. The aim of this study was to summarise the evidence relating to the possible relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
Methods and Findings
A systematic review was conducted using the Medline, EMBASE, and PsycINFO electronic databases up to 26 June 2012. Published cohort, cross-sectional, and case-control studies that examined non-sexual child maltreatment as a risk factor for loss of health were included. All meta-analyses were based on quality-effects models. Out of 285 articles assessed for eligibility, 124 studies satisfied the pre-determined inclusion criteria for meta-analysis. Statistically significant associations were observed between physical abuse, emotional abuse, and neglect and depressive disorders (physical abuse [odds ratio (OR) = 1.54; 95% CI 1.16–2.04], emotional abuse [OR = 3.06; 95% CI 2.43–3.85], and neglect [OR = 2.11; 95% CI 1.61–2.77]); drug use (physical abuse [OR = 1.92; 95% CI 1.67–2.20], emotional abuse [OR = 1.41; 95% CI 1.11–1.79], and neglect [OR = 1.36; 95% CI 1.21–1.54]); suicide attempts (physical abuse [OR = 3.40; 95% CI 2.17–5.32], emotional abuse [OR = 3.37; 95% CI 2.44–4.67], and neglect [OR = 1.95; 95% CI 1.13–3.37]); and sexually transmitted infections and risky sexual behaviour (physical abuse [OR = 1.78; 95% CI 1.50–2.10], emotional abuse [OR = 1.75; 95% CI 1.49–2.04], and neglect [OR = 1.57; 95% CI 1.39–1.78]). Evidence for causality was assessed using Bradford Hill criteria. While suggestive evidence exists for a relationship between maltreatment and chronic diseases and lifestyle risk factors, more research is required to confirm these relationships.
Conclusions
This overview of the evidence suggests a causal relationship between non-sexual child maltreatment and a range of mental disorders, drug use, suicide attempts, sexually transmitted infections, and risky sexual behaviour. All forms of child maltreatment should be considered important risks to health with a sizeable impact on major contributors to the burden of disease in all parts of the world. The awareness of the serious long-term consequences of child maltreatment should encourage better identification of those at risk and the development of effective interventions to protect children from violence.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Child maltreatment—the abuse and neglect of children—is a global problem. There are four types of child maltreatment—sexual abuse (the involvement of a child in sexual activity that he or she does not understand, is unable to give consent to, or is not developmentally prepared for), physical abuse (the use of physical force that harms the child's health, survival, development, or dignity), emotional abuse (the failure to provide a supportive environment by, for example, verbally threatening the child), and neglect (the failure to provide for all aspects of the child's well-being). Most child maltreatment is perpetrated by parents or parental guardians, many of whom were maltreated themselves as children. Other risk factors for parents abusing their children include poverty, mental health problems, and alcohol and drug misuse. Although there is considerable uncertainty about the frequency and severity of child maltreatment, according to the World Health Organization (WHO) about 20% of women and 5%–10% of men report being sexually abused as children, and the prevalence of physical abuse in childhood may be 25%–50%.
Why Was This Study Done?
Child maltreatment has a large public health impact. Sometimes this impact is immediate and direct (injuries and deaths), but, more often, it is long-term, affecting emotional development and overall health. For child sexual abuse, the relationship between abuse and mental disorders in adult life is well-established. Exposure to other forms of child maltreatment has also been associated with a wide range of psychological and behavioral problems, but the health consequences of physical abuse, emotional abuse, and neglect have not been systematically examined. A better understanding of the long-term health effects of child maltreatment is needed to inform maltreatment prevention strategies and to improve treatment for children who have been abused or neglected. In this systematic review and meta-analysis, the researchers quantify the association between exposure to physical abuse, emotional abuse, and neglect in childhood and mental health and physical health outcomes in later life. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 124 studies that investigated the relationship between child physical abuse, emotional abuse, or neglect and various health outcomes. Their meta-analysis of data from these studies provides suggestive evidence that child physical abuse, emotional abuse, and neglect are causally linked to mental and physical health outcomes. For example, emotionally abused individuals had a three-fold higher risk of developing a depressive disorder than non-abused individuals (an odds ratio [OR] of 3.06). Physically abused and neglected individuals also had a higher risk of developing a depressive disorder than non-abused individuals (ORs of 1.54 and 2.11, respectively). Other mental health disorders associated with child physical abuse, emotional abuse, or neglect included anxiety disorders, drug abuse, and suicidal behavior. Individuals who had been non-sexually maltreated as children also had a higher risk of sexually transmitted diseases and/or risky sexual behavior than non-maltreated individuals. Finally, there was weak and inconsistent evidence that child maltreatment increased the risk of chronic diseases and lifestyle risk factors such as smoking.
What Do These Findings Mean?
By providing suggestive evidence of a causal link between non-sexual child maltreatment and mental health disorders, drug use, suicide attempts, and sexually transmitted diseases and risky sexual behavior, these findings contribute to our understanding of the non-injury health impacts of child maltreatment. Although most of the studies included in the meta-analysis were undertaken in high-income countries, the findings suggest that this link occurs in both high- and low-to-middle-income countries. They also suggest that neglect may be as harmful as physical and emotional abuse. However, they need to be interpreted carefully because of the limitations of this meta-analysis, which include the possibility that children who have been abused may share other, unrecognized factors that are actually the cause of their later mental health problems. Importantly, this confirmation that physical abuse, emotional abuse, and neglect in childhood are important risk factors for a range of health problems draws attention to the need to develop evidence-based strategies for preventing child maltreatment both to reduce childhood suffering and to alleviate an important risk factor for later health problems.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001349.
The World Health Organization provides information on child maltreatment and its prevention (in several languages); Preventing Child Maltreatment: A Guide to Taking Action and Generating Evidence is a 2006 report produced by WHO and the International Society for Prevention of Child Abuse and Neglect
The US Centers for Disease Control and Prevention provides information on child maltreatment and links to additional resources
The National Society for the Prevention of Cruelty to Children (NSPCC) is a not-for-profit organization that aims to end all cruelty to children in the UK; Childline is a resource provided by the NSPCC that provides help, information, and support to children who are being abused
The Hideout is a UK-based website that helps children and young people understand domestic abuse
Childhelp is a US not-for-profit organization dedicated to helping victims of child abuse and neglect; its website includes a selection of personal stories about child maltreatment
doi:10.1371/journal.pmed.1001349
PMCID: PMC3507962  PMID: 23209385
18.  Novel copy number variants in children with autism and additional developmental anomalies 
Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.
Electronic supplementary material
The online version of this article (doi:10.1007/s11689-009-9013-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11689-009-9013-z
PMCID: PMC3164008  PMID: 21547721
Autism; Copy number variation; Structural variation; Mental retardation; Dysmorphology; Chromosome 6q24; STXBP5; Chromosome 3p26.3; LRRN1; Chromosome 22q11.2; Chromosome 4q34.2; Chromosome 1q24
19.  Social Approach in Genetically-Engineered Mouse Lines Relevant to Autism 
Genes, brain, and behavior  2008;8(2):129-142.
Profound impairment in social interaction is a core symptom of autism, a severe neurodevelopmental disorder. Deficits can include a lack of interest in social contact and low levels of approach and proximity to other children. In this study, a three-chambered choice task was used to evaluate sociability and social novelty preference in five lines of mice with mutations in genes implicated in autism spectrum disorders. Fmr1tm1Cgr/Y (Fmr1−/y) mice represent a model for fragile X, a mental retardation syndrome that is partially co-morbid with autism. We tested Fmr1−/y mice on two genetic backgrounds, C57BL/6J and FVB/N-129/OlaHsd (FVB/129). Targeted disruption of Fmr1 resulted in low sociability on one measure, but only when the mutation was expressed on FVB/129. Autism has been associated with altered serotonin levels and polymorphisms in SLC6A4 (SERT), the serotonin-transporter gene. Male mice with targeted disruption of Slc6a4 displayed significantly less sociability than wildtype controls. Mice with conditional overexpression of Igf-1 (Insulin-like growth factor-1) offered a model for brain overgrowth associated with autism. Igf-1 transgenic mice engaged in levels of social approach similar to wildtype controls. Targeted disruption in other genes of interest, En2 (Engrailed 2) and Dhcr7, was carried on genetic backgrounds that demonstrated low levels of exploration in the choice task, precluding meaningful interpretations of social behavior scores. Overall, results show that loss of Fmr1 or Slc6a4 gene function can lead to deficits in sociability. Findings from the fragile X-model suggest that the FVB/129 background confers enhanced susceptibility to consequences of Fmr1 mutation on social approach.
doi:10.1111/j.1601-183X.2008.00452.x
PMCID: PMC2659808  PMID: 19016890
autism spectrum disorders; endophenotype; Engrailed; Fmr1; fragile X; Sert; Slc6a4; sociability
20.  Mice Genetically Depleted of Brain Serotonin Display Social Impairments, Communication Deficits and Repetitive Behaviors: Possible Relevance to Autism 
PLoS ONE  2012;7(11):e48975.
Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. A very large number of genes have been linked to autism, many of which encode proteins involved in the development and function of synaptic circuitry. However, the manner in which these mutated genes might participate, either individually or together, to cause autism is not understood. One factor known to exert extremely broad influence on brain development and network formation, and which has been linked to autism, is the neurotransmitter serotonin. Unfortunately, very little is known about how alterations in serotonin neuronal function might contribute to autism. To test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, we analyzed mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2)) for behaviors that are relevant to this disorder. Mice lacking brain serotonin (TPH2−/−) showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2−/− mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism. Our findings should stimulate new studies that focus on determining how brain hyposerotonemia during critical neurodevelopmental periods can alter the maturation of synaptic circuits known to be mis-wired in autism and how prevention of such deficits might prevent this disorder.
doi:10.1371/journal.pone.0048975
PMCID: PMC3490915  PMID: 23139830
21.  Assessment of knowledge about childhood autism among paediatric and psychiatric nurses in Ebonyi state, Nigeria 
Background
There is increasing public and professional awareness of autism spectrum disorders with early recognition, diagnosis and interventions that are known to improve prognosis. Poor knowledge about childhood autism among paediatric and psychiatric nurses who are members of multidisciplinary teams that care for such children may be a major barrier to early interventions that could improve quality of life and prognosis in childhood autism. Factors that influence knowledge about childhood autism among these nurses are not known. This study assessed knowledge about childhood autism among paediatric and psychiatric nurses in Ebonyi state, Nigeria and determined the factors that could be influencing such knowledge.
Methods
Forty specialist paediatric and forty psychiatric nurses, making a total sample of eighty, were randomly selected from all the health care facilities in Ebonyi state, Nigeria. A socio-demographic questionnaire and knowledge about childhood autism among health workers (KCAHW) questionnaire were administered to them and the study was a point survey.
Results
The total mean score on the KCAHW questionnaire among the nurses that participated in the study was 12.56 ± 3.23 out of a total of 19 possible. The mean score for the paediatric nurses was 11.78 ± 3.64 while psychiatric nurses had mean score of 13.35 ± 2.58. The mean scores in Domain 1 were 6.17 ± 1.75 for the paediatric nurses and 6.52 ± 1.43 for the psychiatric nurses. The mean scores in Domain 2 were 0.65 ± 0.48 for the paediatric nurses and 0.80 ± 0.41 for the psychiatric nurses. Domain 3 showed mean scores of 1.97 ± 1.25 for the paediatric nurses while psychiatric nurses scored 2.62 ± 1.23. Domain 4 yielded the mean scores of 2.97 ± 1.54 and 3.42 ± 0.98 for the paediatric and psychiatric nurses respectively.
There was significant relationship between the total mean score on the KCAHW questionnaire for the two groups and the area of specialisation of the nurses (t = -2.23, df = 78, p = 0.03) and there was also significant relationship between previous involvement in managing children with childhood autism as a specialist paediatric or psychiatric nurse and the total mean score on the KCAHW questionnaire (t = 6.90, df = 78, p = 0.00).
Conclusion
The scores reflect deficits in knowledge about childhood autism among the study cohorts. Paediatric and psychiatric nurses as members of multidisciplinary teams that care for children with childhood autism are expected to provide holistic care and adequate counselling to the families of these children. Unfortunately in this environment, they are not fully equipped with enough knowledge about childhood autism. Education on childhood autism is therefore needed and can be provided through continuing medical education and emphasizing childhood autism in their training curriculum. This will enhance early identification and diagnosis of childhood autism with early interventions that are known to improve prognosis.
doi:10.1186/1753-2000-5-1
PMCID: PMC3022827  PMID: 21214953
22.  Trajectories of Emotional Well-Being in Mothers of Adolescents and Adults with Autism 
Developmental psychology  2011;47(2):551-561.
Raising an adolescent or adult child with a developmental disability confers exceptional caregiving challenges on parents. We examined trajectories of two indicators of emotional well-being (depressive symptoms and anxiety) in a sample of primarily Caucasian mothers (N = 379; Mage = 51.22 years at Time 1) of adolescent and adult children with an autism spectrum disorder (ASD; Mage = 21.91 years at Time 1, 73.2% male). We also investigated within-person associations of child context time-varying covariates (autism symptoms, behavior problems, residential status) and maternal context time-varying covariates (social support network size and stressful family events) with the trajectories of emotional well-being. Data were collected on 5 occasions across a 10-year period. Average patterns of stable (depressive symptoms) and improved (anxiety) emotional well-being were evident and well-being trajectories were sensitive to fluctuations in both child and maternal context variables. On occasions when behavior problems were higher, depressive symptoms and anxiety were higher. On occasions after which the grown child moved out of the family home, anxiety was lower. Anxiety was higher on occasions when social support networks were smaller and when more stressful life events were experienced. These results have implications for midlife and aging families of children with an ASD and those who provide services to these families.
doi:10.1037/a0021268
PMCID: PMC3074104  PMID: 21171753
maternal well-being; depressive symptoms; anxiety; autism spectrum disorders; longitudinal
23.  Autism Spectrum Features in Smith-Magenis Syndrome 
Smith-Magenis syndrome (SMS; OMIM 182290) is a neurodevelopmental disorder characterized by a well-defined pattern of anomalies. The majority of cases are due to a common deletion in chromosome 17p11.2 that includes the RAI1 gene. In children with SMS, autistic-like behaviors and symptoms start to emerge around 18 months of age. This study included 26 individuals (15 females and 11 males), with a confirmed deletion (del 17p11.2). Parents/caregivers were asked to complete the Social Responsiveness Scale (SRS) and the Social Communication Questionnaire (SCQ) both current and lifetime versions. The results suggest that 90% of the sample had SRS scores consistent with autism spectrum disorders. Moreover, females showed more impairment in total T-scores (p=0.02) and in the social cognition (p=0.01) and autistic mannerisms (p=0.002) subscales. The SCQ scores are consistent to show that a majority of individuals may meet criteria for autism spectrum disorders at some point in their lifetime. These results suggest that SMS needs to be considered in the differential diagnosis of autism spectrum disorders but also that therapeutic interventions for autism are likely to benefit individuals with SMS. The mechanisms by which the deletion of RAI1 and contiguous genes cause psychopathology remain unknown but they provide a solid starting point for further studies of gene-brain-behavior interactions in SMS and autism spectrum disorders.
doi:10.1002/ajmg.c.30275
PMCID: PMC2967410  PMID: 20981775
del 17p11.2; RAI1; microdeletion syndrome; behavioral phenotype; social communication
24.  The Intense World Syndrome – an Alternative Hypothesis for Autism 
Frontiers in Neuroscience  2007;1(1):77-96.
Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple environmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome.
doi:10.3389/neuro.01.1.1.006.2007
PMCID: PMC2518049  PMID: 18982120
autism; microcircuit; connectivity; plasticity; neocortex; amygdala; valproic acid
25.  Social Peers Rescue Autism-Relevant Sociability Deficits in Adolescent Mice 
Lay Abstract
Limited reciprocal social interactions are central to the diagnosis of autism. Behavioral intervention programs are effective in improving social and communication skills in children with autism. We are employing mouse models to understand the individual components of behavioral interventions which effectively improve social interactions. BTBR T+tf/J (BTBR) is an inbred strain of mice that exhibits multiple social deficits, unusual vocalizations, and high levels of repetitive behaviors, which are relevant to all three diagnostic symptom categories of autism. C57BL/6J (B6) is an inbred strain of mice that exhibits high sociability and low repetitive behaviors. We reasoned that these mouse strains with low versus high social interactions might be useful for evaluating social peer enrichment as a behavioral intervention during adolescence. Juvenile BTBR and B6 of the same sex were placed in a same home cage and lived together as cagemates until they reached young adulthood. The two control groups were juvenile B6 housed together, and juvenile BTBR housed together. B6 controls that lived with B6 cagemates showed their strain-typical high sociability. BTBR controls that lived with BTBR cagemates showed their strain-typical low sociability. Remarkably, BTBR that shared home cages with B6 showed high sociability as young adults. Peer rearing for either 20 days or 40 days were equally effective. These results from a robust mouse model of autism support the strategy of early behavioral intervention for treating the social domain in autism spectrum disorders, including beneficial interactions with social peers.
Scientific Abstract
Behavioral therapies are currently the most effective interventions for treating the diagnostic symptoms of autism. We employed a mouse model of autism to evaluate components of behavioral interventions that improve sociability in mice. BTBR T+tf/J (BTBR) is an inbred mouse strain that exhibits prominent behavioral phenotypes with face validity to all three diagnostic symptom categories of autism, including robust and well-replicated deficits in social approach and reciprocal social interactions. To investigate the role of peer interactions in the development of sociability, BTBR juvenile mice were reared in the same home cage with juvenile mice of a highly social inbred strain, C57BL/6J (B6). Subject mice were tested as young adults for sociability and repetitive behaviors. B6 controls reared with B6 showed their strain-typical high sociability. BTBR controls reared with BTBR cagemates showed their strain-typical lack of sociability. In contrast, BTBR reared with B6 as juveniles showed significant sociability as young adults. A 20-day intervention was as effective as a 40-day intervention for improving social approach behavior. High levels of repetitive self-grooming by BTBR were not rescued by peer-rearing with B6, indicating specificity of the intervention to the social domain. These results from a robust mouse model of autism support the interpretation that social enrichment with juvenile peers is a beneficial intervention for improving adult outcome in the social domain. This novel paradigm may prove useful for discovering factors that are essential for effective behavioral treatments, and biological mechanisms underlying effective behavioral interventions.
doi:10.1002/aur.163
PMCID: PMC3065860  PMID: 20928844
Autism; BTBR inbred strain; mouse model; peer enrichment; social enrichment; behavioral intervention

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