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1.  Brief Report: Approaches to 31P-MRS in Awake, Non-Sedated Children With and Without Autism Spectrum Disorder 
We piloted a suite of approaches aimed to facilitate a successful series of up to four brain and muscle 31Phosphorus-Magnetic Resonance Spectroscopy (31P-MRS) scans performed in one session in 12 awake, non-sedated subjects (ages 6 – 18), 6 with autism spectrum disorders (ASD) and 6 controls. We targeted advanced preparation, parental input, physical comfort, short scan protocols, allocation of extra time, and subject emotional support. 100% of subjects completed at least one brain scan and one leg muscle scan: 42 of 46 attempted scans were completed (91%), with failures dominated by exercise muscle scans (completed in 6/6 controls but 3/6 cases). One completed scan lacked usable data unrelated to subject/scan procedure (orthodonture affected a frontal brain scan). As a group, these methods provide a foundation for conduct and enhancement of future MR studies in pediatric subjects with ASD.
doi:10.1007/s10803-011-1359-x
PMCID: PMC3668346  PMID: 21979108
Autism; ASD; Magnetic Resonance; energetics; muscle; brain; awake
2.  Clinical Implications of Human Population Differences in Genome-Wide Rates of Functional Genotypes 
Frontiers in Genetics  2012;3:211.
There have been a number of recent successes in the use of whole genome sequencing and sophisticated bioinformatics techniques to identify pathogenic DNA sequence variants responsible for individual idiopathic congenital conditions. However, the success of this identification process is heavily influenced by the ancestry or genetic background of a patient with an idiopathic condition. This is so because potential pathogenic variants in a patient’s genome must be contrasted with variants in a reference set of genomes made up of other individuals’ genomes of the same ancestry as the patient. We explored the effect of ignoring the ancestries of both an individual patient and the individuals used to construct reference genomes. We pursued this exploration in two major steps. We first considered variation in the per-genome number and rates of likely functional derived (i.e., non-ancestral, based on the chimp genome) single nucleotide variants and small indels in 52 individual whole human genomes sampled from 10 different global populations. We took advantage of a suite of computational and bioinformatics techniques to predict the functional effect of over 24 million genomic variants, both coding and non-coding, across these genomes. We found that the typical human genome harbors ∼5.5–6.1 million total derived variants, of which ∼12,000 are likely to have a functional effect (∼5000 coding and ∼7000 non-coding). We also found that the rates of functional genotypes per the total number of genotypes in individual whole genomes differ dramatically between human populations. We then created tables showing how the use of comparator or reference genome panels comprised of genomes from individuals that do not have the same ancestral background as a patient can negatively impact pathogenic variant identification. Our results have important implications for clinical sequencing initiatives.
doi:10.3389/fgene.2012.00211
PMCID: PMC3485509  PMID: 23125845
clinical sequencing; congenital disease; whole genome sequencing; population genetics
3.  Altered integration of speech and gesture in children with autism spectrum disorders 
Brain and Behavior  2012;2(5):606-619.
The presence of gesture during speech has been shown to impact perception, comprehension, learning, and memory in normal adults and typically developing children. In neurotypical individuals, the impact of viewing co-speech gestures representing an object and/or action (i.e., iconic gesture) or speech rhythm (i.e., beat gesture) has also been observed at the neural level. Yet, despite growing evidence of delayed gesture development in children with autism spectrum disorders (ASD), few studies have examined how the brain processes multimodal communicative cues occurring during everyday communication in individuals with ASD. Here, we used a previously validated functional magnetic resonance imaging (fMRI) paradigm to examine the neural processing of co-speech beat gesture in children with ASD and matched controls. Consistent with prior observations in adults, typically developing children showed increased responses in right superior temporal gyrus and sulcus while listening to speech accompanied by beat gesture. Children with ASD, however, exhibited no significant modulatory effects in secondary auditory cortices for the presence of co-speech beat gesture. Rather, relative to their typically developing counterparts, children with ASD showed significantly greater activity in visual cortex while listening to speech accompanied by beat gesture. Importantly, the severity of their socio-communicative impairments correlated with activity in this region, such that the more impaired children demonstrated the greatest activity in visual areas while viewing co-speech beat gesture. These findings suggest that although the typically developing brain recognizes beat gesture as communicative and successfully integrates it with co-occurring speech, information from multiple sensory modalities is not effectively integrated during social communication in the autistic brain.
doi:10.1002/brb3.81
PMCID: PMC3489813  PMID: 23139906
Autism spectrum disorders; fMRI; gesture; language; superior temporal gyrus
4.  Project Brainstorm: Using Neuroscience to Connect College Students with Local Schools 
PLoS Biology  2012;10(4):e1001310.
Neuroscience can be used as a tool to inspire an interest in science in school children as well as to provide teaching experience to college students.
doi:10.1371/journal.pbio.1001310
PMCID: PMC3328426  PMID: 22529746
5.  No Neural Evidence of Statistical Learning During Exposure to Artificial Languages in Children with Autism Spectrum Disorders 
Biological psychiatry  2010;68(4):345-351.
Background
Language delay is a hallmark feature of autism spectrum disorders (ASD). The identification of word boundaries in continuous speech is a critical first step in language acquisition that can be accomplished via statistical learning and reliance on speech cues. Importantly, early word segmentation skills have been shown to predict later language development in typically developing (TD) children.
Methods
Here we investigated the neural correlates of online word segmentation in children with and without ASD with a well-established behavioral paradigm previously validated for functional magnetic resonance imaging. Eighteen high-functioning boys with ASD and 18 age- and IQ-matched TD boys underwent functional magnetic resonance imaging while listening to two artificial languages (containing statistical or statistical + prosodic cues to word boundaries) and a random speech stream.
Results
Consistent with prior findings, in TD control subjects, activity in fronto-temporal-parietal networks decreased as the number of cues to word boundaries increased. The ASD children, however, did not show this facilitatory effect. Furthermore, statistical contrasts modeling changes in activity over time identified significant learning-related signal increases for both artificial languages in basal ganglia and left temporo-parietal cortex only in TD children. Finally, the level of communicative impairment in ASD children was inversely correlated with signal increases in these same regions during exposure to the artificial languages.
Conclusions
This is the first study to demonstrate significant abnormalities in the neural architecture subserving language-related learning in ASD children and to link the communicative impairments observed in this population to decreased sensitivity to the statistical and speech cues available in the language input.
doi:10.1016/j.biopsych.2010.01.011
PMCID: PMC3229830  PMID: 20303070
Autism; implicit learning; language; neuroimaging; speech perception
6.  Reward Processing in Autism 
The social motivation hypothesis of autism posits that infants with autism do not experience social stimuli as rewarding, thereby leading to a cascade of potentially negative consequences for later development. While possible downstream effects of this hypothesis such as altered face and voice processing have been examined, there has not been a direct investigation of social reward processing in autism. Here we use functional magnetic resonance imaging to examine social and monetary rewarded implicit learning in children with and without autism spectrum disorders (ASD). Sixteen males with ASD and sixteen age- and IQ-matched typically developing (TD) males were scanned while performing two versions of a rewarded implicit learning task. In addition to examining responses to reward, we investigated the neural circuitry supporting rewarded learning and the relationship between these factors and social development. We found diminished neural responses to both social and monetary rewards in ASD, with a pronounced reduction in response to social rewards (SR). Children with ASD also demonstrated a further deficit in frontostriatal response during social, but not monetary, rewarded learning. Moreover, we show a relationship between ventral striatum activity and social reciprocity in TD children. Together, these data support the hypothesis that children with ASD have diminished neural responses to SR, and that this deficit relates to social learning impairments.
doi:10.1002/aur.122
PMCID: PMC3076289  PMID: 20437601
functional MRI (fMRI); social cognition; reward; learning
7.  Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2 
Science translational medicine  2010;2(56):56ra80.
Genetic studies are rapidly identifying variants that shape risk for disorders of human cognition, but the question of how such variants predispose to neuropsychiatric disease remains. Noninvasive human brain imaging allows assessment of the brain in vivo, and the combination of genetics and imaging phenotypes remains one of the only ways to explore functional genotype-phenotype associations in human brain. Common variants in contactin-associated protein-like 2 (CNTNAP2), a neurexin superfamily member, have been associated with several allied neurodevelopmental disorders, including autism and specific language impairment, and CNTNAP2 is highly expressed in frontal lobe circuits in the developing human brain. Using functional neuroimaging, we have demonstrated a relationship between frontal lobar connectivity and common genetic variants in CNTNAP2. These data provide a mechanistic link between specific genetic risk for neurodevelopmental disorders and empirical data implicating dysfunction of long-range connections within the frontal lobe in autism. The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such asautism in part through modulation of frontal lobe connectivity.
doi:10.1126/scitranslmed.3001344
PMCID: PMC3065863  PMID: 21048216

Results 1-7 (7)