It has been said that people with autism suffer from a lack of "central coherence," the cognitive ability to bind together a jumble of separate features into a single, coherent object or concept (Frith, 1989). Ironically, the same can be said of the field of autism research, which all too often seems a fragmented tapestry stitched from differing analytical threads and theoretical patterns. Defined and diagnosed by purely behavioral criteria, autism was first described and investigated using the tools of behavioral psychology. More recent years have added brain anatomy and physiology, genetics, and biochemistry, but results from these new domains have not been fully integrated with what is known about autistic behavior. The unification of these many levels of analysis will not only provide therapeutic targets for prevention and remediation of autism but can also provide a test case for theories of normal brain and cognitive development. Autism research therefore has much to learn from and much to offer to the broader neuroscience community. Clinical featuresClinically, autism is defined by a "triad" of deficits comprising impaired social interaction, impaired communication, restricted interests, and repetitive behaviors. Although in some cases speech never develops fully or never develops at all, in other cases, speech may be present but so inflexible and unresponsive to context that it is unusable in normally paced conversation; often, speech is limited to echolalia or confined to narrow topics of expertise in which discourse can proceed without conversational interplay. The communicative impairment extends also to nonverbal signals such as gaze, facial expression, and gesture. Social behaviors, too, are beset by a lack of flexibility and rapid coordination: children with autism do not coordinate attention between objects of mutual interest and the other people who may be interested in them, often engage in "parallel play" at the edge of a group rather than joining in cooperative play, and do not engage in pretend play. Intense and narrowly focused interests tend to concentrate on systems (Baron-Cohen, 2002) that operate deterministically and repeatably according to tractable sets of rules, whether these are abstract and complex systems such as computers or roleplaying games or very concrete and simple systems such as toilets or washing machines. Critical to identifying the causal factors of autism, and key to its relevance to normal development, is the recognition that autism is actually the extreme of a spectrum of abnormalities. Milder phenotypes on this spectrum include Asperger syndrome (Wing, 1981) in which language is relatively unimpaired, and the "Broader Autism Phenotype" in which characteristic cognitive traits are present subclinically . The combination of this broad variation of phenotypes and a 60 -90% concordance rate in identical twins suggests a large number of genetic and environmental biasing factors (Muhle et al., 2004). A basis in neural connectivity?In addition to the central coherence par...

Empathizing is the capacity to predict and to respond to the behavior of agents (usually people) by inferring their mental states and responding to these with an appropriate emotion. Systemizing is the capacity to predict and to respond to the behavior of nonagentive deterministic systems by analyzing input-operation-output relations and inferring the rules that govern such systems. At a population level, females are stronger empathizers and males are stronger systemizers. The “extreme male brain” theory posits that autism represents an extreme of the male pattern (impaired empathizing and enhanced systemizing). Here we suggest that specific aspects of autistic neuroanatomy may also be extremes of typical male neuroanatomy.

New DNA sequencing technologies deliver data at dramatically lower costs but demand new analytical methods to take full advantage of the very short reads that they produce. We provide an initial, theoretical solution to the challenge of de novo assembly from whole-genome shotgun “microreads.” For 11 genomes of sizes up to 39 Mb, we generated high-quality assemblies from 80× coverage by paired 30-base simulated reads modeled after real Illumina-Solexa reads. The bacterial genomes of Campylobacter jejuni and Escherichia coli assemble optimally, yielding single perfect contigs, and larger genomes yield assemblies that are highly connected and accurate. Assemblies are presented in a graph form that retains intrinsic ambiguities such as those arising from polymorphism, thereby providing information that has been absent from previous genome assemblies. For both C. jejuni and E. coli, this assembly graph is a single edge encompassing the entire genome. Larger genomes produce more complicated graphs, but the vast majority of the bases in their assemblies are present in long edges that are nearly always perfect. We describe a general method for genome assembly that can be applied to all types of DNA sequence data, not only short read data, but also conventional sequence reads.

Autism, an entirely behavioral diagnosis with no largely understood etiologies and no population-wide biomarkers, contrasts with fragile X syndrome (FXS), a single-gene disorder with definite alterations of gene expression and neuronal morphology. Nevertheless, the behavioral overlap between autism and FXS suggests some overlapping mechanisms. Understanding how the single-gene alteration in FXS plays out within complex genetic and neural network processes may suggest targets for autism research and illustrate strategies for relating autism to more singular genetic syndromes.

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Although the neurobiological understanding of autism has been increasing exponentially, the diagnosis of autism spectrum conditions still rests entirely on behavioral criteria. Autism is therefore most productively approached using a combination of biological and psychological theory. The triad of behavioral abnormalities in social function, communication, and restricted and repetitive behaviors and interests can be explained psychologically by an impaired capacity for empathizing, or modeling the mental states governing the behavior of people, along with a superior capacity for systemizing, or inferring the rules governing the behavior of objects. This empathizing-systemizing theory explains other psychological models such as impairments of executive function or central coherence, and may have a neurobiological basis in abnormally low activity of brain regions subserving social cognition, along with abnormally high activity of regions subserving lower-level, perceptual processing--a pattern that may result from a skewed balance of local versus long-range functional connectivity.

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Autism involves impairments in communication and social interaction, as well as high levels of repetitive, stereotypic and ritualistic behaviours, and extreme resistance to change. This latter dimension, whilst required for a diagnosis, has received less research attention. We hypothesise that this extreme resistance to change in autism is rooted in atypical processing of unexpected stimuli. We tested this using auditory event-related fMRI to determine regional brain activity associated with passive detection of infrequently occurring frequency-deviant and complex novel sounds in a no-task condition. Participants were twelve 10 to 15-year-old children with autism, and a group of 12 age-and sex-matched healthy controls.During deviance-detection, significant activation common to both groups was located in the superior temporal and inferior frontal gyri. During 'novelty-detection', both groups showed activity in the superior temporal gyrus, the temporo-parietal junction, the superior and inferior frontal gyri and the cingulate gyrus.Children with autism showed reduced activation of the left anterior cingulate cortex during both deviance and novelty detection. During 'novelty-detection' children with autism also showed reduced activation in the bilateral temporo-parietal region, and in the right inferior and middle frontal areas. This study confirms previous evidence from ERP studies of atypical brain function related to automatic change detection in autism. Abnormalities involved a cortical network known to have a role in attention-switching and attentional resource distribution. These results throw light on the neurophysiological processes underlying autistic 'resistance to change'. Change detection in children with autism: an auditory event-related fMRI study Marie Gomot et al: NIMG-05-251Dear Drs Toga and Fletcher, Thank you for inviting us to resubmit this manuscript to NeuroImage. We are grateful to the reviewers for their constructive comments. Especially we would like to thanks reviewer 2 who did insightful criticisms. We did take into account most of the remarks and we feel that the paper is improved as a result. Reviewer 2's observations allowed getting a better definition of the terms and concepts used. We corrected the text according to these criticisms, but we think that some of the modifications required regarding fundamental concepts on deviance processing would not serve the manuscript. We didn't wish for adding to many additional details about these fundamental concepts, in order to keep focus on the main aim of the study which was to study change processing in an autistic population. Moreover, we felt a bit disconcerted by some of the comments (See comments 5, 7, 19, 21, 24, 30 and 34 for example). We look forward to hearing from you about the acceptability of the revised manuscript for publication in NeuroImage. SUMMARY:Autism involves impairments in communication and social interaction, as well as high levels of repetitive, stereotypic and ritualistic behaviours, and extreme resistan...