Ashley A. Scott-Van Zeeland

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.

Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.

Children who carry one variant of a brain protein associated with autism exhibit fewer long-range connections between the prefrontal cortex and more posterior brain regions. A Window into the Genetic Control of Brain Function Even seemingly simple traits like height are controlled by more than 180 separate genes. Imagine the complexity of the genetic network that determines the structure of the human brain: Billions of neurons connected to one another by at least as many axons. Variations in these links lead to differences among us and, sometimes, to disability, but picking out the key connections is not easy. Now, Scott-van Zeeland and colleagues show that the two versions of a protein that guides growth of the prefrontal cortex—one of which is known to confer risk of autism—generate distinct neural circuits in this region of the brain, possibly explaining the increased risk of autism and other intellectual disabilities in carriers. The protein is contactin-associated protein-like 2 (CNTNAP2), which has turned up in a number of genetic studies as associated with autism and other language-related disorders. Caspr2, the protein encoded by CNTNAP2, participates in cellular migration and in forming the final layered organization of the brain. It is expressed during development in the frontal and temporal lobes, including the frontal cortex and stratum, areas that participate in language and learning. The authors of this study have used functional magnetic resonance imaging (fMRI) of the brain to pinpoint the differences in brain structure and function that result from two variants of CNTNAP2, one of which confers risk of autism. They found in a discovery and a replication cohort of children that carriers of the risky allele showed more neural activity in the medial prefrontal cortex as they performed an assigned task. Moreover, this region was connected only locally in a diffuse bilateral network in the carriers, whereas in those with the nonrisk allele the medial prefrontal cortex conveyed information to more posterior regions via a network on the left side. This left lateralized functional anterior-posterior connection in the noncarriers involves regions of the brain known to control language processing, a skill that is defective in some people with autism. It is possible that the lack of efficient information transfer to these regions from frontal areas in the risk allele–carrying children may contribute to the increased chance that they will be affected by autism or other related disorders. The careful dissection of genetic contributions to discrete aspects of brain structure and function (so-called endophenotypes) such as reported here is one way to begin to untangle the basis of human-to-human variations in cognition and behavior. 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 as autism in part through modulation of frontal lobe connectivity.

Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia

To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).

No Neural Evidence of Statistical Learning During Exposure to Artificial Languages in Children with Autism Spectrum Disorders

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.

Altered integration of speech and gesture in children with autism spectrum disorders

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.

Annotating individual human genomes

Advances in DNA sequencing technologies have made it possible to rapidly, accurately and affordably sequence entire individual human genomes. As impressive as this ability seems, however, it will not likely amount to much if one cannot extract meaningful information from individual sequence data. Annotating variations within individual genomes and providing information about their biological or phenotypic impact will thus be crucially important in moving individual sequencing projects forward, especially in the context of the clinical use of sequence information. In this paper we consider the various ways in which one might annotate individual sequence variations and point out limitations in the available methods for doing so. It is arguable that, in the foreseeable future, DNA sequencing of individual genomes will become routine for clinical, research, forensic, and personal purposes. We therefore also consider directions and areas for further research in annotating genomic variants.

Clinical implications of human population differences in genome-wide rates of functional genotypes

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.

A genome sequencing program for novel undiagnosed diseases

Purpose:The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene–disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study.Methods:A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician–scientist review panel, and 17 patients (14.0%) and their family members were enrolled.Results:60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene–disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings.Conclusion:Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.Genet Med 17 12, 995–1001.

Assessing Bioenergetic Compromise in Autism Spectrum Disorder With 31P Magnetic Resonance Spectroscopy Preliminary Report

We sought to examine, via Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in a case-control design, whether bioenergetic deficits in autism spectrum disorders extend to the brain and muscle. Six cases with autism spectrum disorder with suspected mitochondrial dysfunction (age 6-18 years) and 6 age/sex-matched controls underwent 31P magnetic resonance spectroscopy. The outcomes of focus were muscle resting phosphocreatine and intracellular pH as well as postexercise phosphocreatine recovery time constant and frontal brain phosphocreatine. Intracellular muscle pH was lower in each autism spectrum disorder case than their matched control (6/6, P = .03; P = .0048, paired t test). Muscle phosphocreatine (5/6), brain phosphocreatine (3/4), and muscle phosphocreatine recovery time constant (3/3) trends were in the predicted direction (not all participants completed each). This study introduces 31P magnetic resonance spectroscopy as a noninvasive tool for assessment of mitochondrial function in autism spectrum disorder enabling bioenergetic assessment in brain and provides preliminary evidence suggesting that bioenergetic defects in cases with autism spectrum disorder are present in muscle and may extend to brain.

Project brainstorm: using neuroscience to connect college students with local schools.

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.