1. Bowler DM, Gaigg SB, Gardiner JM. {{Multiple List Learning in Adults with Autism Spectrum Disorder: Parallels with Frontal Lobe Damage or Further Evidence of Diminished Relational Processing?}} {J Autism Dev Disord};2009 (Aug 13)
To test the effects of providing relational cues at encoding and/or retrieval on multi-trial, multi-list free recall in adults with high-functioning autism spectrum disorder (ASD), 16 adults with ASD and 16 matched typical adults learned a first followed by a second categorised list of 24 words. Category labels were provided at encoding, retrieval, both or not at all. Both groups showed enhanced recall when labels were available during encoding or throughout the task. ASD individuals showed reduced recall of the second list and reduced clustering. Clustering and recall were correlated in both groups, which also showed similar levels of subjective organisation. The findings are discussed in relation to theories of frontal and medial temporal lobe contributions to memory in ASD.
2. Brigham NB, Yoder PJ, Jarzynka MA, Tapp J. {{The Sequential Relationship Between Parent Attentional Cues and Sustained Attention to Objects in Young Children with Autism}}. {J Autism Dev Disord};2009 (Aug 15)
This study examined the sequential relationship between parent attentional cues and sustained attention to objects in young children with autism during a 20 min free-play interaction session. Twenty-five parent-child dyads with a preschool child with autism participated. Results indicated that (a) parent attentional cues that maintained the child’s focus of attention were more likely to support child sustained object attention than parent attentional cues that redirected the child from his or her focus of attention or introduced a new focus of attention (d = 4.46), and (b) parent attentional cues that included three or more parent behaviors were more likely to support child sustained object attention than parent attentional cues that included one or two parent behaviors (d = 1.03).
3. D’Cruz AM, Mosconi MW, Steele S, Rubin LH, Luna B, Minshew N, Sweeney JA. {{Lateralized response timing deficits in autism}}. {Biol Psychiatry};2009 (Aug 15);66(4):393-397.
BACKGROUND: Procedural learning is an implicit process in which a behavioral response is refined through repeated performance. Neural systems supporting this cognitive process include specific frontostriatal systems responsible for the preparation and timing of planned motor responses. Evaluating performance on procedural learning tasks can provide unique information about neurodevelopmental disorders in which frontostriatal disturbances have been reported, such as autism. METHODS: Fifty-two individuals with autism and 54 age-, IQ-, and gender-matched healthy individuals performed an oculomotor serial reaction time task and a sensorimotor control task. RESULTS: Whereas the rate of procedural learning and the precision of planned motor responses were unimpaired in autism, a lateralized alteration in the ability to time predictive responses was observed. Rightward saccadic responses were speeded in individuals with autism relative to healthy control subjects. CONCLUSIONS: Speeded rightward predictive saccades suggest atypical functioning of left hemisphere striatal chronometric systems in autism.
4. De Felice C, Ciccoli L, Leoncini S, Signorini C, Rossi M, Vannuccini L, Guazzi G, Latini G, Comporti M, Valacchi G, Hayek J. {{Systemic oxidative stress in classic Rett syndrome}}. {Free Radic Biol Med};2009 (Aug 15);47(4):440-448.
Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, is a leading cause of mental retardation with autistic features in females. However, its pathogenesis remains incompletely understood, and no effective therapy is available to date. We hypothesized that a systemic oxidative stress may play a key role in the pathogenesis of classic RS. Patients with classic RS (n=59) and control subjects (n=43) were evaluated. Oxidative stress markers included intraerythrocyte non-protein-bound iron (NPBI; i.e., free iron), plasma NPBI, F2-isoprostanes (F2-IsoPs, as free, esterified, and total forms), and protein carbonyls. Lung ventilation/perfusion (V/Q) ratio was assessed using a portable gas analyzer, and RS clinical severity was evaluated using standard scales. Significantly increased intraerythrocyte NPBI (2.73-fold), plasma NPBI (x 6.0), free F(2)-IsoP (x1.85), esterified F2-IsoP (x 1.69), total F2-IsoP (x 1.66), and protein carbonyl (x 4.76) concentrations were evident in RS subjects and associated with reduced (-10.53%) arterial oxygen levels compared to controls. Biochemical evidence of oxidative stress was related to clinical phenotype severity and lower peripheral and arterial oxygen levels. Pulmonary V/Q mismatch was found in the majority of the RS population. These data identify hypoxia-induced oxidative stress as a key factor in the pathogenesis of classic RS and suggest new therapeutic approaches based on oxidative stress modulation.
5. Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, Chaste P, Siffroi JP, Chantot-Bastaraud S, Benyahia B, Trouillard O, Nygren G, Kopp S, Johansson M, Rastam M, Burglen L, Leguern E, Verloes A, Leboyer M, Brice A, Gillberg C, Betancur C. {{Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders}}. {Biol Psychiatry};2009 (Aug 15);66(4):349-359.
BACKGROUND: Maternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD. METHODS: A total of 522 patients belonging to 430 families were screened for deletions, duplications, and methylation abnormalities involving 15q11-q13 with multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified four patients with 15q11-q13 abnormalities: a supernumerary chromosome 15, a paternal interstitial duplication, and two subjects with Angelman syndrome, one with a maternal deletion and the other with a paternal uniparental disomy. CONCLUSIONS: Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening.
6. Freitag CM, Luders E, Hulst HE, Narr KL, Thompson PM, Toga AW, Krick C, Konrad C. {{Total brain volume and corpus callosum size in medication-naive adolescents and young adults with autism spectrum disorder}}. {Biol Psychiatry};2009 (Aug 15);66(4):316-319.
BACKGROUND: Increased total brain volume (TBV) has been reported for children with autism spectrum disorder (ASD) but studies in older ASD subjects have been contradictory. Similarly, studies of corpus callosum (CC) area in ASD differ with regard to inclusion criteria, age, and IQ. METHODS: In the present study, TBV, gray matter (GM), and white matter (WM) volume as well as midsagittal CC area were compared between 15 medication-naive, high-functioning adolescent and young adult ASD subjects and 15 healthy control individuals, and correlations with visuomotor coordination and imitation abilities were explored. In addition, computational surface-based methods were implemented to encode callosal thickness at high spatial resolution. RESULTS: Total brain volume, GM, and WM were increased and CC area was decreased in ASD subjects, a finding that was predominantly due to ASD subjects with lower IQ. Positive correlations of IQ with volume measures were observed only in control subjects. Autism spectrum disorder subjects showed reduced thickness in the posterior part of the CC. White matter volume showed a trend for negative correlation with dynamic balance and imitation abilities across groups. CONCLUSIONS: This study replicates previous structural magnetic resonance imaging (MRI) findings in ASD, emphasizes the role of IQ differences, and adds some evidence for functional implications of structural findings.
7. Hardan AY, Libove RA, Keshavan MS, Melhem NM, Minshew NJ. {{A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism}}. {Biol Psychiatry};2009 (Aug 15);66(4):320-326.
BACKGROUND: Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism. METHODS: MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline. RESULTS: No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology. CONCLUSIONS: Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.
8. Jackson PB, Boccuto L, Skinner C, Collins JS, Neri G, Gurrieri F, Schwartz CE. {{Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with Autistic disorder}}. {Autism Res};2009 (Aug 13)
Previous studies in three independent cohorts have shown that the rs1858830 C allele variant in the promoter region of the MET gene on chromosome 7q31 is associated with autism. Another study has found correlations between other alterations in the MET gene and autism in two unrelated cohorts. This study screened two cohorts, an Autistic Disorder cohort from South Carolina and a Pervasive Developmental Disorder (PDD) cohort from Italy, for the presence of the C allele variant in rs1858830. A significant increase in the C allele variant frequency was found in the South Carolina Autistic Disorder patients as compared to South Carolina Controls (chi(2)=5.8, df=1, P=0.02). In the South Carolina cohort, a significant association with Autistic Disorder was found when comparing the CC and CG genotypes to the GG genotype (odds ratio (OR)=1.64; 95% confidence interval (CI)=1.12-2.40; chi(2)=6.5, df=1, P=0.01) in cases and controls. In the Italian cohort, no significant association with PDD was found when comparing the CC or CG genotype to the GG genotype (OR=1.20; 95% CI=0.56-2.56; chi(2)=0.2, df=1, P=0.64). This study is the third independent study to find the rs1858830 C variant in the MET gene promoter to be associated with autism.
9. Langen M, Schnack HG, Nederveen H, Bos D, Lahuis BE, de Jonge MV, van Engeland H, Durston S. {{Changes in the developmental trajectories of striatum in autism}}. {Biol Psychiatry};2009 (Aug 15);66(4):327-333.
BACKGROUND: Repetitive and stereotyped behavior has been associated with striatum in various neuropsychiatric disorders. However, striatal involvement has not yet been shown conclusively in autism. Issues include the use of neuroleptic medication and differences in mean age between samples, where conflicting results may reflect differences in developmental stage between samples. The objective was to examine brain development in a homogeneous sample of subjects with high-functioning autism. METHODS: Magnetic resonance measures of brain structure of 188 individuals (99 subjects with high-functioning autism and 89 typically developing, matched control subjects) aged between 6 years and 25 years were compared. Measurements included the volume of brain structures, including striatum, as well as voxel-based assessment of gray matter density. RESULTS: Developmental trajectories of the caudate nucleus, putamen, and nucleus accumbens differed between subjects with autism and control subjects. Results were not accounted for by overall changes in brain volume or neuroleptic medication. The development of the caudate nucleus differed from typical most, as its volume increased with age in autism, while it decreased for control subjects. Voxel-based analysis showed that changes in striatum localized to the head of the caudate nucleus. Overall, caudate nucleus volume was associated with repetitive behavior in autism. CONCLUSIONS: We report changes in striatal development in autism, while caudate volume is associated with repetitive behaviors. This emphasizes the importance of striatum in the etiology of autism, in particular in the development of repetitive behavior that characterizes the disorder.
10. Lasgaard M, Nielsen A, Eriksen ME, Goossens L. {{Loneliness and Social Support in Adolescent Boys with Autism Spectrum Disorders}}. {J Autism Dev Disord};2009 (Aug 15)
Loneliness and perceived social support were examined in 39 adolescent boys with autism spectrum disorders (ASD) by means of a self-labeling loneliness measure, the UCLA Loneliness Scale (third version), and the Social Support Scale for Children. Twenty-one percent of the boys with ASD described themselves as often or always feeling lonely. Compared with 199 boys from regular schools in a national probability study, ASD was strongly associated with often or always feeling lonely (OR: 7.08, p < .0005), as well as with a higher degree of loneliness (F(1,229) = 11.1, p < .005). Perceived social support from classmates, parents, and a close friend correlated negatively with loneliness in ASD. The study, therefore, indicates a high occurrence of loneliness among adolescent boys with ASD and points at perceived social support as an important protective factor.
11. Monk CS, Peltier SJ, Wiggins JL, Weng SJ, Carrasco M, Risi S, Lord C. {{Abnormalities of intrinsic functional connectivity in autism spectrum disorders}}. {Neuroimage};2009 (Aug 15);47(2):764-772.
Autism spectrum disorders (ASD) impact social functioning and communication, and individuals with these disorders often have restrictive and repetitive behaviors. Accumulating data indicate that ASD is associated with alterations of neural circuitry. Functional MRI (FMRI) studies have focused on connectivity in the context of psychological tasks. However, even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic or resting connectivity. Notably, the default network, which includes the posterior cingulate cortex, retro-splenial, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus, is strongly active when there is no task. Altered intrinsic connectivity within the default network may underlie offline processing that may actuate ASD impairments. Using FMRI, we sought to evaluate intrinsic connectivity within the default network in ASD. Relative to controls, the ASD group showed weaker connectivity between the posterior cingulate cortex and superior frontal gyrus and stronger connectivity between the posterior cingulate cortex and both the right temporal lobe and right parahippocampal gyrus. Moreover, poorer social functioning in the ASD group was correlated with weaker connectivity between the posterior cingulate cortex and the superior frontal gyrus. In addition, more severe restricted and repetitive behaviors in ASD were correlated with stronger connectivity between the posterior cingulate cortex and right parahippocampal gyrus. These findings indicate that ASD subjects show altered intrinsic connectivity within the default network, and connectivity between these structures is associated with specific ASD symptoms.
12. Pugliese L, Catani M, Ameis S, Dell’Acqua F, de Schotten MT, Murphy C, Robertson D, Deeley Q, Daly E, Murphy DG. {{The anatomy of extended limbic pathways in Asperger syndrome: a preliminary diffusion tensor imaging tractography study}}. {Neuroimage};2009 (Aug 15);47(2):427-434.
It has been suggested that people with autistic spectrum disorder (ASD) have altered development (and connectivity) of limbic circuits. However, direct evidence of anatomical differences specific to white matter pathways underlying social behaviour and emotions in ASD is lacking. We used Diffusion Tensor Imaging Tractography to compare, in vivo, the microstructural integrity and age-related differences in the extended limbic pathways between subjects with Asperger syndrome and healthy controls. Twenty-four males with Asperger syndrome (mean age 23+/-12 years, age range: 9-54 years) and 42 age-matched male controls (mean age 25+/-10 years, age range: 9-54 years) were studied. We quantified tract-specific diffusivity measurements as indirect indexes of microstructural integrity (e.g. fractional anisotropy, FA; mean diffusivity, MD) and tract volume (e.g. number of streamlines) of the main limbic tracts. The dissected limbic pathways included the inferior longitudinal fasciculus, inferior frontal occipital fasciculus, uncinate, cingulum and fornix. There were no significant between-group differences in FA and MD. However, compared to healthy controls, individuals with Asperger syndrome had a significantly higher number of streamlines in the right (p=.003) and left (p=.03) cingulum, and in the right (p=.03) and left (p=.04) inferior longitudinal fasciculus. In contrast, people with Asperger syndrome had a significantly lower number of streamlines in the right uncinate (p=.02). Within each group there were significant age-related differences in MD and number of streamlines, but not FA. However, the only significant age-related between-group difference was in mean diffusivity of the left uncinate fasciculus (Z(obs)=2.05) (p=.02). Our preliminary findings suggest that people with Asperger syndrome have significant differences in the anatomy, and maturation, of some (but not all) limbic tracts.
13. Staples KL, Reid G. {{Fundamental Movement Skills and Autism Spectrum Disorders}}. {J Autism Dev Disord};2009 (Aug 15)
Delays and deficits may both contribute to atypical development of movement skills by children with ASD. Fundamental movement skills of 25 children with autism spectrum disorders (ASD) (ages 9-12 years) were compared to three typically developing groups using the Test of Gross Motor Development (TGMD-2). The group matched on chronological age performed significantly better on the TGMD-2. Another comparison group matched on movement skill demonstrated children with ASD perform similarly to children approximately half their age. Comparisons to a third group matched on mental age equivalence revealed the movement skills of children with ASD are more impaired than would be expected given their cognitive level. Collectively, these results suggest the movement skills of children with ASD reflect deficits in addition to delays.
14. Vaccarino FM, Smith KM. {{Increased brain size in autism–what it will take to solve a mystery}}. {Biol Psychiatry};2009 (Aug 15);66(4):313-315.
