1. Amaral DG. {{The promise and the pitfalls of autism research: An introductory note for new autism researchers}}. {Brain Res};2011 (Mar 22);1380:3-9.
The last decade has seen an enormous growth in the quantity of research directed at understanding the biological underpinnings of autism spectrum disorders. This increase has been spurred on, in part, by research funding provided through private, parent advocacy groups. While increased funding and entry into autism research by scientists from many disciplines has facilitated the speed of discoveries germane to establishing the etiologies of autism, there remain a number of roadblocks to understanding autism sufficiently well to foster new treatments. This short article provides a brief overview of some of the achievements and some of the difficulties in conducting autism research.
2. Bernardi S, Anagnostou E, Shen J, Kolevzon A, Buxbaum JD, Hollander E, Hof PR, Fan J. {{In vivo (1)H-magnetic resonance spectroscopy study of the attentional networks in autism}}. {Brain Res};2011 (Mar 22);1380:198-205.
Attentional dysfunction is one of the most consistent findings in individuals with autism spectrum disorders (ASD). However, the significance of such findings for the pathophysiology of autism is unclear. In this study, we investigated cellular neurochemistry with proton magnetic resonance spectroscopy imaging ((1)H-MRS) in brain regions associated with networks subserving alerting, orienting, and executive control of attention in patients with ASD. Concentrations of cerebral N-acetyl-aspartate (NAA), creatinine+phosphocreatinine, choline-containing compounds, myo-inositol (Ins) and glutamate+glutamine (Glx) were determined by 3T (1)H-MRS examinations in 14 high-functioning medication-free adults with a diagnosis of ASD and 14 age- and IQ-matched healthy controls (HC) in the anterior cingulate cortex (ACC), thalamus, temporoparietal junction (TPJ), and areas near or along the intraparietal sulcus (IPS). Compared to HC group, the ASD group showed significantly lower Glx concentration in right ACC and reduced Ins concentration in left TPJ. This study provides evidence of abnormalities in neurotransmission related to networks subserving executive control and alerting of attention, functions which have been previously implicated in ASD pathogenesis.
3. Betancur C. {{Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting}}. {Brain Res};2011 (Mar 22);1380:42-77.
There is increasing evidence that autism spectrum disorders (ASDs) can arise from rare highly penetrant mutations and genomic imbalances. The rare nature of these variants, and the often differing orbits of clinical and research geneticists, can make it difficult to fully appreciate the extent to which we have made progress in understanding the genetic etiology of autism. In fact, there is a persistent view in the autism research community that there are only a modest number of autism loci known. We carried out an exhaustive review of the clinical genetics and research genetics literature in an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD. We provide data on 103 disease genes and 44 genomic loci reported in subjects with ASD or autistic behavior. These genes and loci have all been causally implicated in intellectual disability, indicating that these two neurodevelopmental disorders share common genetic bases. A genetic overlap between ASD and epilepsy is also apparent in many cases. Taken together, these findings clearly show that autism is not a single clinical entity but a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders. Increased recognition of the etiological heterogeneity of ASD will greatly expand the number of target genes for neurobiological investigations and thereby provide additional avenues for the development of pathway-based pharmacotherapy. Finally, the data provide strong support for high-resolution DNA microarrays as well as whole-exome and whole-genome sequencing as critical approaches for identifying the genetic causes of ASDs.
4. Buxbaum JD, Hof PR. {{The emerging neuroscience of autism spectrum disorders}}. {Brain Res};2011 (Mar 22);1380:1-2.
5. Carter AS, Messinger DS, Stone WL, Celimli S, Nahmias AS, Yoder P. {{A randomized controlled trial of Hanen’s ‘More Than Words’ in toddlers with early autism symptoms}}. {J Child Psychol Psychiatry};2011 (Mar 22)
Background: This randomized controlled trial compared Hanen’s ‘More than Words’ (HMTW), a parent-implemented intervention, to a ‘business as usual’ control group. Methods: Sixty-two children (51 boys and 11 girls; M age = 20 months; SD = 2.6) who met criteria for autism spectrum disorders (ASD) and their parents participated in the study. The HMTW intervention was provided over 3.5 months. There were three measurement periods: prior to randomization (Time 1) and at 5 and 9 months post enrollment (Times 2 and 3). Children’s communication and parental responsivity were measured at each time point. Children’s object interest, a putative moderator, was measured at Time 1. Results: There were no main effects of the HMTW intervention on either parental responsivity or children’s communication. However, the effects on residualized gains in parental responsivity from Time 1 to both Times 2 and 3 yielded noteworthy effect sizes (Glass’s Delta = .71, .50 respectively). In contrast, there were treatment effects on child communication gains to Time 3 that were moderated by children’s Time 1 object interest. Children with lower levels of Time 1 object interest exhibited facilitated growth in communication; children with higher levels of object interest exhibited growth attenuation. Conclusions: The HMTW intervention showed differential effects on child communication depending on a baseline child factor. HMTW facilitated communication in children with lower levels of Time 1 object interest. Parents of children who evidence higher object interest may require greater support to implement the HMTW strategies, or may require different strategies than those provided by the HMTW curriculum.
6. Charman T, Jones CR, Pickles A, Simonoff E, Baird G, Happe F. {{Defining the cognitive phenotype of autism}}. {Brain Res};2011 (Mar 22);1380:10-21.
Although much progress has been made in determining the cognitive profile of strengths and weaknesses that characterise individuals with autism spectrum disorders (ASDs), there remain a number of outstanding questions. These include how universal strengths and deficits are; whether cognitive subgroups exist; and how cognition is associated with core autistic behaviours, as well as associated psychopathology. Several methodological factors have contributed to these limitations in our knowledge, including: small sample sizes, a focus on single domains of cognition, and an absence of comprehensive behavioural phenotypic information. To attempt to overcome some of these limitations, we assessed a wide range of cognitive domains in a large sample (N=100) of 14- to 16-year-old adolescents with ASDs who had been rigorously behaviourally characterised. In this review, we will use examples of some initial findings in the domains of perceptual processing, emotion processing and memory, both to outline different approaches we have taken to data analysis and to highlight the considerable challenges to better defining the cognitive phenotype(s) of ASDs. Enhanced knowledge of the cognitive phenotype may contribute to our understanding of the complex links between genes, brain and behaviour, as well as inform approaches to remediation.
7. Courchesne E, Campbell K, Solso S. {{Brain growth across the life span in autism: Age-specific changes in anatomical pathology}}. {Brain Res};2011 (Mar 22);1380:138-145.
Autism is marked by overgrowth of the brain at the earliest ages but not at older ages when decreases in structural volumes and neuron numbers are observed instead. This has led to the theory of age-specific anatomic abnormalities in autism. Here we report age-related changes in brain size in autistic and typical subjects from 12months to 50years of age based on analyses of 586 longitudinal and cross-sectional MRI scans. This dataset is several times larger than the largest autism study to date. Results demonstrate early brain overgrowth during infancy and the toddler years in autistic boys and girls, followed by an accelerated rate of decline in size and perhaps degeneration from adolescence to late middle age in this disorder. We theorize that underlying these age-specific changes in anatomic abnormalities in autism, there may also be age-specific changes in gene expression, molecular, synaptic, cellular, and circuit abnormalities. A peak age for detecting and studying the earliest fundamental biological underpinnings of autism is prenatal life and the first three postnatal years. Studies of the older autistic brain may not address original causes but are essential to discovering how best to help the older aging autistic person. Lastly, the theory of age-specific anatomic abnormalities in autism has broad implications for a wide range of work on the disorder including the design, validation, and interpretation of animal model, lymphocyte gene expression, brain gene expression, and genotype/CNV-anatomic phenotype studies.
8. Devlin B, Melhem N, Roeder K. {{Do common variants play a role in risk for autism? Evidence and theoretical musings}}. {Brain Res};2011 (Mar 22);1380:78-84.
Both rare and common genetic variants underlie risk for almost any complex disease. Over the past few years a common tool for identifying common risk variants is genome-wide association or GWA. Our analyses focus on results from GWA targeting common variants affecting risk for autism spectrum disorders (ASD). Thus far three large GWA studies have been published, each of which highlights a single, non-overlapping risk locus. Evaluation of these studies suggests that combination of their data would diminish evidence for all of these loci, making none of them significant. Despite this paucity of findings, statistical theory can be used to infer a plausible distribution of effect sizes for SNPs affecting risk for ASD. We lay out this theory, calculate plausible distributions, and discuss the results in the context of results from GWA studies for schizophrenia.
9. Frankel F, Whitham C. {{Parent-assisted group treatment for friendship problems of children with autism spectrum disorders}}. {Brain Res};2011 (Mar 22);1380:240-245.
Children with Asperger’s Disorder or High Functioning Autism are included in regular education classes but find themselves excluded from the social lives of their classmates. This paper briefly reviews studies which attempt to provide them with training to overcome their social difficulties. These interventions have had limited success and have not systematically incorporated the child’s parents into the intervention. Children’s Friendship Training is a manualized parent-assisted group treatment which teaches social skill through learning and practicing sets of rules of etiquette for key social situations. The treatment approach has been demonstrated to have success in improving friendships of children with autism spectrum disorders. The content of Children’s Friendship Training is briefly described and results of controlled studies are reviewed. Limitations of previous research and future directions are also described.
10. Gauthier J, Siddiqui TJ, Huashan P, Yokomaku D, Hamdan FF, Champagne N, Lapointe M, Spiegelman D, Noreau A, Lafreniere RG, Fathalli F, Joober R, Krebs MO, Delisi LE, Mottron L, Fombonne E, Michaud JL, Drapeau P, Carbonetto S, Craig AM, Rouleau GA. {{Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia}}. {Hum Genet};2011 (Mar 22)
Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.
11. Ghahramani Seno MM, Hu P, Gwadry FG, Pinto D, Marshall CR, Casallo G, Scherer SW. {{Gene and miRNA expression profiles in autism spectrum disorders}}. {Brain Res};2011 (Mar 22);1380:85-97.
Accumulating data indicate that there is significant genetic heterogeneity underlying the etiology in individuals diagnosed with autism spectrum disorder (ASD). Some rare and highly-penetrant gene variants and copy number variation (CNV) regions including NLGN3, NLGN4, NRXN1, SHANK2, SHANK3, PTCHD1, 1q21.1, maternally-inherited duplication of 15q11-q13, 16p11.2, amongst others, have been identified to be involved in ASD. Genome-wide association studies have identified other apparently low risk loci and in some other cases, ASD arises as a co-morbid phenotype with other medical genetic conditions (e.g. fragile X). The progress studying the genetics of ASD has largely been accomplished using genomic analyses of germline-derived DNA. Here, we used gene and miRNA expression profiling using cell-line derived total RNA to evaluate possible transcripts and networks of molecules involved in ASD. Our analysis identified several novel dysregulated genes and miRNAs in ASD compared with controls, including HEY1, SOX9, miR-486 and miR-181b. All of these are involved in nervous system development and function and some others, for example, are involved in NOTCH signaling networks (e.g. HEY1). Further, we found significant enrichment in molecules associated with neurological disorders such as Rett syndrome and those associated with nervous system development and function including long-term potentiation. Our data will provide a valuable resource for discovery purposes and for comparison to other gene expression-based, genome-wide DNA studies and other functional data.
12. Hagebeuk EE, Koelman JH, Duran M, Abeling NG, Vyth A, Poll-The BT. {{Clinical and Electroencephalographic Effects of Folinic Acid Treatment in Rett Syndrome Patients}}. {J Child Neurol};2011 (Mar 22)
Rett syndrome is characterized by the development of stereotypic hand movements and seizures, which are often difficult to treat. Previous studies have shown conflicting results during add-on folinic acid. Here, the authors reevaluate the response to folinic acid in terms of epilepsy control and electroencephalography features. They performed a randomized, placebo-controlled, double-blind crossover trial, with a follow-up of more than 2 years. Twelve girls with Rett syndrome participated, comparable in clinical stage and disease severity. The Rett syndrome patients were given either folinic acid or placebo, for 1 year each. Only 3 girls benefited to some extent: 2 had a reduction and/or decrease in seizures, and all 3 showed some decreased epileptiform activity on electroencephalography during the addition of folinic acid. Despite this, antiepileptic drugs were adjusted. Because the effect of added folinic acid was limited and did not prevent antiepileptic drug increase, the authors do not recommend adding on folinic acid in Rett syndrome girls with epilepsy.
13. King BH, Lord C. {{Is schizophrenia on the autism spectrum?}}. {Brain Res};2011 (Mar 22);1380:34-41.
With the ongoing consideration of the diagnostic criteria for mental disorders that is active in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and International Classification of Diseases (ICD-11) revision processes, it is timely to review the phenomenological overlap between autism and schizophrenia. These disorders have at various times been regarded alternatively as closely related and as non-overlapping and incompatible. Nevertheless, there are several reports in the literature that have described individuals with both autism and schizophrenia, and the broader phenotypes of these disorders clearly intersect. Recent studies reveal theory of mind deficits in both disorders, and mirror neuron impairments also appear to be shared. There also may be similar connectivity deficits emerging in functional imaging studies, and both disorders share several genetic signals that are being identified through detection of copy number variants. Taken together, these data suggest that it may be time to revisit the possibility that these disorders are related.
14. Kolevzon A, Cai G, Soorya L, Takahashi N, Grodberg D, Kajiwara Y, Willner JP, Tryfon A, Buxbaum JD. {{Analysis of a purported SHANK3 mutation in a boy with autism: Clinical impact of rare variant research in neurodevelopmental disabilities}}. {Brain Res};2011 (Mar 22);1380:98-105.
There is strong evidence for rare, highly penetrant genetic variants playing an etiological role in multiple neurodevelopmental disabilities, including autism spectrum disorders. The rate of discovery of such rare variants is increasing with the advent of larger sample collections, chromosome microarray analyses, and high-throughput sequencing. As the variants that are being discovered can be highly penetrant, they lead immediately to model systems with construct validity, critical for understanding the underlying neurobiology of these conditions, which in turn can provide leads for novel therapeutic targets. Moreover, these discoveries can benefit families with information about recurrence risk, resolve concerns about etiology, provide information about associated medical issues, and engender directed advocacy for specific genetic conditions. For these reasons, diagnostic laboratories are taking advantage of research data as they are produced. In the current report, we present our molecular analysis of a child with a purported disruptive mutation in SHANK3 identified by a commercial genetic testing laboratory and we provide evidence that this was not an etiological variant. The variant was a 1-bp insertion in exon 11 of the RefSeq gene, which we then determined was inherited from a healthy mother and found in ~1% of controls. Since the variant would be predicted to disrupt the reference gene, and the penetrance of SHANK3 mutations is very high, we did follow up molecular and bioinformatic analyses and concluded that the presumptive exon containing the variant is not likely to be present in most or all SHANK3 transcripts. The results highlight difficulties that can arise with rapid translation of research findings to clinical practice. Researchers are in a unique position to generate resources with collated and curated information that can inform research, genetic testing, clinicians, and families about the best practices as pertains to rare genetic variants in neurodevelopmental disabilities. Of immediate importance would be a well-curated database of gene variation identified in large numbers of typically developing individuals and in individuals affected with neurodevelopmental disabilities. Such a database would reduce false-positive results in clinical settings, would be helpful in structure-function analyses, and would direct translational research to pathways most likely to benefit families.
15. Lundstrom S, Chang Z, Kerekes N, Gumpert CH, Rastam M, Gillberg C, Lichtenstein P, Anckarsater H. {{Autistic-like traits and their association with mental health problems in two nationwide twin cohorts of children and adults}}. {Psychol Med};2011 (Mar 22):1-11.
BACKGROUND: Autistic-like traits (ALTs), that is restrictions in intuitive social interaction, communication and flexibility of interests and behaviors, were studied in two population-based Swedish twin studies, one in children and one in adults: (1) to examine whether the variability in ALTs is a meaningful risk factor for concomitant attention deficit hyperactivity disorder (ADHD), anxiety, conduct problems, depression and substance abuse, and (2) to assess whether common genetic and environmental susceptibilities can help to explain co-existence of ALTs and traits associated with such concomitant problems.MethodTwo nationwide twin cohorts from Sweden (consisting of 11 222 children and 18 349 adults) were assessed by DSM-based symptom algorithms for autism. The twins were divided into six groups based on their degree of ALTs and the risk for concomitant mental health problems was calculated for each group. Genetic and environmental susceptibilities common to ALTs and the other problem types were examined using bivariate twin modeling. RESULTS: In both cohorts, even the lowest degree of ALTs increased the risk for all other types of mental health problems, and these risk estimates increased monotonically with the number of ALTs. For all conditions, common genetic and environmental factors could be discerned. Overall, the phenotypic correlation between ALTs and the traits examined were less pronounced in adulthood than in childhood and less affected by genetic compared with environmental factors. CONCLUSIONS: Even low-grade ALTs are relevant to clinical psychiatry as they increase the risk for several heterotypical mental health problems. The association is influenced partly by common genetic and environmental susceptibilities. Attention to co-existing ALTs is warranted in research on a wide range of mental disorders.
16. Mejias R, Adamczyk A, Anggono V, Niranjan T, Thomas GM, Sharma K, Skinner C, Schwartz CE, Stevenson RE, Fallin MD, Kaufmann W, Pletnikov M, Valle D, Huganir RL, Wang T. {{Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism}}. {Proc Natl Acad Sci U S A};2011 (Mar 22);108(12):4920-4925.
Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P < 0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n = 480) and matched controls (n = 480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P = 0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype.
17. Murphy DG, Beecham J, Craig M, Ecker C. {{Autism in adults. New biologicial findings and their translational implications to the cost of clinical services}}. {Brain Res};2011 (Mar 22);1380:22-33.
There is increasing evidence that children with autism spectrum disorder (ASD) have differences in brain growth trajectory. However, the neurobiological basis of ASD in adults is poorly understood. We report evidence that brain anatomy and aging in people with ASD is significantly different as compared to controls-so that in adulthood they no longer have a significantly larger overall brain volume, but they do have anatomical and functional abnormalities in frontal lobe, basal ganglia and the limbic system. Further we present preliminary evidence that females have significantly greater abnormalities in brain than males to express the same symptom severity of ASD (i.e. the female brain is « protective » against developing ASD). Also we present preliminary evidence that, in adults, clinical services for autism in the United Kingdom are experiencing very significantly increased demand; but that just over 50% of people seeking a diagnosis from one expert service do not have ASD. This consumes very significant health care resources, and so we need to identify new cost-effective methods to aid current diagnostic practice. We present initial evidence offering proof of concept that brain anatomy can be used to accurately distinguish adults with autism from healthy controls, and from some other neurodevelopmental disorders (ADHD). Hence further studies are required to determine if sMRI can become an aid to current diagnostic practice in young adults with ASD. Lastly we report evidence that differences in serotonin, glutamate and GABA may partially explain neuroanatomical and neurofunctional abnormalities in people with ASD, and that genetic influences on brain maturation vary across the lifespan (with 5-HT transporter polymorphisms having significant modulatory effects in children but not adults).
18. Oblak AL, Gibbs TT, Blatt GJ. {{Reduced GABA(A) receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism}}. {Brain Res};2011 (Mar 22);1380:218-228.
Individuals with autism display deficits in the social domain including the proper recognition of faces and interpretations of facial expressions. There is an extensive network of brain regions involved in face processing including the fusiform gyrus (FFG) and posterior cingulate cortex (PCC). Functional imaging studies have found that controls have increased activity in the PCC and FFG during face recognition tasks, and the FFG has differential responsiveness in autism when viewing faces. Multiple lines of evidence have suggested that the GABAergic system is disrupted in the brains of individuals with autism and it is likely that altered inhibition within the network influences the ability to perceive emotional expressions. On-the-slide ligand binding autoradiography was used to determine if there were alterations in GABA(A) and/or benzodiazepine binding sites in the brain in autism. Using (3)H-muscimol and (3)H-flunitrazepam we could determine whether the number (B(max)), binding affinity (K(d)), and/or distribution of GABA(A) receptors and benzodiazepine binding sites (BZD) differed from controls in the FFG and PCC. Significant reductions were found in the number of GABA(A) receptors and BZD binding sites in the superficial layers of the PCC and FFG, and in the number of BZD binding sites in the deep layers of the FFG. In addition, the autism group had a higher binding affinity in the superficial layers of the GABA(A) study. Taken together, these findings suggest that the disruption in inhibitory control in the cortex may contribute to the core disturbances of socio-emotional behaviors in autism.
19. Pierce K. {{Early functional brain development in autism and the promise of sleep fMRI}}. {Brain Res};2011 (Mar 22);1380:162-174.
Functional magnetic resonance imaging (fMRI) is a powerful tool for examining brain function but has yet to be systematically applied to the study of brain development in autism. Recently, however, scientists have begun to apply fMRI during natural sleep as a mechanism to study function in the developing brain. When considering the study of autism, this method opens considerable doors because it eliminates biases of past studies which only sampled from high-functioning, older populations. This paper describes the application of sleep fMRI as a way to study both extrinsic and intrinsic brain functions in autism between 12 and 36months. Preliminary studies that use sleep fMRI method show that defects in the superior temporal gyrus (STG) in response to language are early emerging in autism and can be found in as young as 14months in age. As such indices of abnormal early development of the STG may prove useful in the search for a biomarker of autism detectable during the infancy period. From a theoretical standpoint, examining sleep fMRI studies in autism gains some clarity when placed in context of the more established literature on structural brain development of autism which suggests that autism involves early brain overgrowth. Studies of plasticity in autism have yet to be done, but it is likely that the window of opportunity for altering the course of brain development in autism begins within the first year of life. The ability to do so relies on improving and streamlining early identification and thus early treatment efforts.
20. Reaven J. {{The treatment of anxiety symptoms in youth with high-functioning autism spectrum disorders: Developmental considerations for parents}}. {Brain Res};2011 (Mar 22);1380:255-263.
Anxiety symptoms are one of the most common mental health conditions in childhood. Children and adolescents with Autism Spectrum Disorders (ASD) are at risk for developing mental health symptoms and anxiety in particular, especially when compared with their peers – both in the general population as well as when compared to youth with other developmental disabilities. Cognitive behavior therapy (CBT) has been identified as the treatment of choice in addressing anxiety symptoms in the general population, and an emerging body of literature indicates that modified CBT for youth with ASD can be effective in reducing anxiety symptoms. In a review of these modified treatment protocols, parent involvement is emphasized as an important component of interventions for youth with ASD and anxiety. However, the majority of these studies only briefly describe the parent’s role, and little mention is made with regard to how the parent’s role evolves over time as children age into adolescence. In this paper, the parent’s role in the treatment of anxiety symptoms in children and adolescents with high-functioning ASD will be discussed with a particular emphasis on considerations for parents of teenagers. Specific recommendations for parent involvement will be provided.
21. Rodgers J, Riby DM, Janes E, Connolly B, McConachie H. {{Anxiety and Repetitive Behaviours in Autism Spectrum Disorders and Williams Syndrome: A Cross-Syndrome Comparison}}. {J Autism Dev Disord};2011 (Mar 22)
Children with Autism Spectrum Disorder or Williams syndrome are vulnerable to anxiety. The factors that contribute to this risk remain unclear. This study compared anxiety in autism spectrum disorder and Williams Syndrome and examined the relationship between repetitive behaviours and anxiety. Thirty-four children with autism and twenty children with Williams Syndrome were assessed with measures of anxiety and repetitive behaviours. Children with autism had higher levels of anxiety. Within the autism sample higher levels of repetitive behaviours were associated with more anxiety. This was not replicated in the Williams Syndrome sample, indicating a differential role for restricted and repetitive behaviours in relation to anxiety. Understanding the links between repetitive behaviours and anxiety is essential for effective intervention.
22. Santos M, Uppal N, Butti C, Wicinski B, Schmeidler J, Giannakopoulos P, Heinsen H, Schmitz C, Hof PR. {{von Economo neurons in autism: A stereologic study of the frontoinsular cortex in children}}. {Brain Res};2011 (Mar 22);1380:206-217.
The presence of von Economo neurons (VENs) in the frontoinsular cortex (FI) has been linked to a possible role in the integration of bodily feelings, emotional regulation, and goal-directed behaviors. They have also been implicated in fast intuitive evaluation of complex social situations. Several studies reported a decreased number of VENs in neuropsychiatric diseases in which the « embodied » dimension of social cognition is markedly affected. Neuropathological analyses of VENs in patients with autism are few and did not report alterations in VEN numbers. In this study we re-evaluated the possible presence of changes in VEN numbers and their relationship with the diagnosis of autism. Using a stereologic approach we quantified VENs and pyramidal neurons in layer V of FI in postmortem brains of four young patients with autism and three comparably aged controls. We also investigated possible autism-related differences in FI layer V volume. Patients with autism consistently had a significantly higher ratio of VENs to pyramidal neurons (p=0.020) than control subjects. This result may reflect the presence of neuronal overgrowth in young patients with autism and may also be related to alterations in migration, cortical lamination, and apoptosis. Higher numbers of VENs in the FI of patients with autism may also underlie a heightened interoception, described in some clinical observations.
23. Schumann CM, Nordahl CW. {{Bridging the gap between MRI and postmortem research in autism}}. {Brain Res};2011 (Mar 22);1380:175-186.
Autism is clearly a disorder of neural development, but when, where, and how brain pathology occurs remain elusive. Typical brain development is comprised of several stages, including proliferation and migration of neurons, creation of dendritic arbors and synaptic connections, and eventually dendritic pruning and programmed cell death. Any deviation at one or more of these stages could produce catastrophic downstream effects. MRI studies of autism have provided important clues, describing an aberrant trajectory of growth during early childhood that is both present in the whole brain and marked in specific structures such as the amygdala. However, given the coarse resolution of MRI, the field must also look towards postmortem human brain research to help elucidate the neurobiological underpinnings of MRI volumetric findings. Likewise, studies of postmortem tissue may benefit by looking to the findings from MRI studies to narrow hypotheses and target specific brain regions and subject populations. In this review, we discuss the strengths, limitations, and major contributions of each approach to autism research. We then describe how they relate and what they can learn from each other. Only by integrating these approaches will we be able to fully explain the neuropathology of autism.
24. Shic F, Bradshaw J, Klin A, Scassellati B, Chawarska K. {{Limited activity monitoring in toddlers with autism spectrum disorder}}. {Brain Res};2011 (Mar 22);1380:246-254.
This study used eye-tracking to examine how 20-month-old toddlers with autism spectrum disorder (ASD) (n=28), typical development (TD) (n=34), and non-autistic developmental delays (DD) (n=16) monitored the activities occurring in a context of an adult-child play interaction. Toddlers with ASD, in comparison to control groups, showed less attention to the activities of others and focused more on background objects (e.g., toys). In addition, while all groups spent the same time overall looking at people, toddlers with ASD looked less at people’s heads and more at their bodies. In ASD, these patterns were associated with cognitive deficits and greater autism severity. These results suggest that the monitoring of the social activities of others is disrupted early in the developmental progression of autism, limiting future avenues for observational learning.
25. Spratt EG, Nicholas JS, Brady KT, Carpenter LA, Hatcher CR, Meekins KA, Furlanetto RW, Charles JM. {{Enhanced Cortisol Response to Stress in Children in Autism}}. {J Autism Dev Disord};2011 (Mar 22)
Children with Autism often show difficulties in adapting to change. Previous studies of cortisol, a neurobiologic stress hormone reflecting hypothalamic-pituitary-adrenal (HPA) axis activity, in children with autism have demonstrated variable results. This study measured cortisol levels in children with and without Autism: (1) at rest; (2) in a novel environment; and (3) in response to a blood draw stressor. A significantly higher serum cortisol response was found in the group of children with autism. Analysis showed significantly higher peak cortisol levels and prolonged duration and recovery of cortisol elevation following the blood-stick stressor in children with autism. This study suggests increased reactivity of the HPA axis to stress and novel stimuli in children with autism.
26. Stahmer AC, Schreibman L, Cunningham AB. {{Toward a technology of treatment individualization for young children with autism spectrum disorders}}. {Brain Res};2011 (Mar 22);1380:229-239.
Although the etiology of autism spectrum disorders (ASD) and early development of the ASD are not yet well understood, recent research in the field of autism has heavily emphasized the importance of early intervention (i.e. treatment before the age of 4years). Currently, several methods have been demonstrated to be efficacious with some children however no treatment completely ameliorates the symptoms of ASD or works for all children with the disorder. The heterogeneity and developmental nature of the disorder make it unlikely that one specific treatment will be best for all children, or will work for any one child throughout his or her educational career. Thus, this paper examines early research validating different technologies for individualizing treatment. A discussion of current research on pre-treatment characteristics associated with differential outcomes in treatment, including child, family, and practitioner variables; and how specific intervention techniques address each of those pre-treatment characteristics is provided. The ultimate goal of this line of research is to enable practitioners to prospectively tailor treatments to specific children and increase the overall rate of positives outcomes for children with autism. Research that furthers understanding of how to match clients with efficacious treatments will decrease the outcome variability that characterizes early intervention research at present, and provide for the most efficient allocation of resources during the critical early intervention time-period. This type of research is in its infancy, but is imperative if we are to determine a priori which treatment method will be most effective for a specific child.
27. Stigler KA, McDonald BC, Anand A, Saykin AJ, McDougle CJ. {{Structural and functional magnetic resonance imaging of autism spectrum disorders}}. {Brain Res};2011 (Mar 22);1380:146-161.
The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter have been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default-mode network during the resting state have also been identified. Overall, structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.
28. Tuchman R, Cuccaro M. {{Epilepsy and Autism: Neurodevelopmental Perspective}}. {Curr Neurol Neurosci Rep};2011 (Mar 22)
Epilepsy and autism coexist in up to 20% of children with either disorder. Current studies suggest that a frequent co-occurring condition in epilepsy and autism is intellectual disability, which shows a very high prevalence in those with both autism and epilepsy. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. In this review we discuss recent advances in the conceptualization of shared anatomical and molecular mechanisms that may account for the coexistence of epilepsy, autism, and intellectual disability. A major contribution to our improved understanding of the relationship among these three phenotypes is the discovery of multiple genomic variants that cut across them as well as other neurobehavioral phenotypes. As these discoveries continue they are very likely to elucidate causal mechanisms for the various phenotypes and pinpoint biologic pathways that may be amenable to therapeutic interventions for this group of neurodevelopmental disorders.
29. Van Adel JM, Dunn Geier J, Perry A, Reitzel JA. {{Credible Knowledge: A pilot evaluation of a modified GRADE method using parent-implemented interventions for children with autism}}. {BMC Health Serv Res};2011 (Mar 22);11(1):60.
ABSTRACT: BACKGROUND: Decision-making in child and youth mental health (CYMH) care requires recommendations that are developed through an efficient and effective method and are based on credible knowledge. Credible knowledge is informed by two sources: scientific evidence, and practice-based evidence, that reflects the « real world » experience of service providers. Current approaches to developing these recommendations in relation to CYMH will typically include evidence from one source or the other but do not have an objective method to combine the two. To this end, a modified version of the Grading Recommendations Assessment, Development and Evaluation (GRADE) approach, a novel method for the CYMH field, was pilot-tested. METHODS: GRADE has an explicit methodology that relies on input from scientific evidence as well as a panel of experts. The panel established the quality of evidence and derived detailed recommendations regarding the organization and delivery of mental health care for children and youth or their caregivers. In this study a modified GRADE method was used to provide precise recommendations based on a specific CYMH question (i.e. What is the current credible knowledge concerning the effects of parent-implemented, early intervention with their autistic children?). RESULTS: Overall, it appeared that early, parent-implemented interventions for autism result in positive effects that outweigh any undesirable effects. However, as opposed to overall recommendations, the heterogeneity of the evidence required that recommendations be specific to particular interventions, based on the questions of whether the benefits of a particular intervention outweighs its harms. CONCLUSIONS: This pilot project provided evidence that a modified GRADE method may be an effective and practical approach to making recommendations in CYMH, based on credible knowledge. Key strengths of the process included separating the assessments of the quality of the evidence and the strength of recommendations, transparency in decision-making, and the objectivity of the methods. Most importantly, this method combined the evidence and clinical experience in a more timely, explicit and simple process as compared to previous approaches. The strengths, limitations and modifications of the approach as they pertain to CYMH, are discussed.
30. Wiggins JL, Peltier SJ, Ashinoff S, Weng SJ, Carrasco M, Welsh RC, Lord C, Monk CS. {{Using a self-organizing map algorithm to detect age-related changes in functional connectivity during rest in autism spectrum disorders}}. {Brain Res};2011 (Mar 22);1380:187-197.
Healthy individuals show robust functional connectivity during rest, which is stronger in adults than in children. Connectivity occurs between the posterior and anterior portions of the default network, a group of structures active in the absence of a task, including the posterior cingulate cortex and the superior frontal gyrus. Previous studies found weaker posterior-anterior connectivity in the default network in adults and adolescents with autism spectrum disorders (ASD). However, these studies used small a priori regions of interest (« seeds ») to calculate connectivity. Since seed location for all participants was chosen based on controls’ brains, these studies’ analyses are more tailored to controls than individuals with ASD. An alternative is to use a data-driven approach, such as self-organizing maps (SOM), to create a reference for each participant to calculate connectivity. We used individualized resting-state clusters identified by an SOM algorithm to corroborate previous findings of weaker posterior-anterior connectivity in the ASD group and examine age-related changes in the ASD and control groups. Thirty-nine adolescents with ASD and 41 controls underwent a 10-minute, eyes-open, resting-state functional MRI scan. The SOM analysis revealed that adolescents with ASD versus controls have weaker connectivity between the posterior hub of the default network and the right superior frontal gyrus. Additionally, controls have larger increases in connectivity with age compared to the ASD group. These findings indicate that SOM is a complementary method for calculating connectivity in a clinical population. Additionally, adolescents with ASD have a different developmental trajectory of the default network compared to controls.
