Autism and Abnormal Development of Brain Connectivity: Figure 1.

Abstract

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...

Vibrotactile adaptation fails to enhance spatial localization in adults with autism

“…For example, parietal cortex in subjects with autism exhibits a ~ 50% reduction in protein levels of the enzymes that synthesize GABA, glutamic acid decarboxylase (GAD) 65 and 67 (Fatemi et al, 2002). Both of these observations appear to be fully consistent with the frequently reported hypersensitivity (Cascio et al, 2007;Blakemore et al, 2006) and abnormally widespread (Belmonte et al, 2004) cerebral cortical response to skin stimulation in autism. If parietal cortical pericolumnar lateral inhibitory interactions are, in fact, deficient in subjects with autism, and if adaptation-induced spatial funneling of the primary somatosensory cortical response to repetitive skin stimulation is achieved via GABA-mediated postsynaptic inhibitory mechanisms intrinsic to primary somatosensory cortex, subjects with autism should not be expected to exhibit the adaptation-induced improvement of tactile spatial localization capacity that occurs reliably in neurologically normal subjects.…”

“…For example, some subjects with autism exhibit hyperarousal to natural sensory input, and a decreased ability to select among competing sensory inputs ( . Although many reports acknowledge a widespread neocortical dysfunction in autism, it is less widely recognized that the dysfunction is non-uniform -e.g., the excessive responsivity of primary sensory cortex to peripheral stimulation is accompanied (in the same subject) by abnormally low activation/responsivity in cortical regions devoted to higher-order information processing (Belmonte et Consideration of the above-described observations, together with the relatively recent demonstration that autism is associated with mutation in regions centered around the GABA A -β3 receptor subunit gene, led some researchers (Belmonte et al, 2004;Polleux and Lauder, 2004) to suggest that the neocortical dysfunction in this disorder may be attributable to a deficiency during early development in GABA-mediated synaptic neurotransmission. According to this view, the excessive excitatory neurotransmission within low-order neocortical processing areas that accompanies insufficient GABA-mediated neocortical inhibition leads to the experience-driven abnormalities in neocortical functional connectivity characteristic of autism.…”

SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

“…47 These results are consistent with the local deregulation of networks involved in working memory and attention, with a possible increase in local connectivity and a selective loss of long-range connectivity. 48 Different expression patterns for human SLC25A12 and its mouse ortholog We found that SLC25A12 was expressed mostly in the brain during human embryonic and fetal development. However, this restricted pattern of expression changes after birth, as high levels of SLC25A12 expression have been reported in skeletal muscle, heart, pancreas and kidney in adults, with low levels of expression observed in the brain.…”

Endocannabinoid Signaling in Autism

“…Autism is neurodevelopmental in nature, and atypical development of neural connectivity has been suggested to underlie its key phenotypic features [125]. A set of genes involved in neurodevelopmental processes that mediate the formation, stabilization, and pruning of synapses has been consistently associated with autism-related phenotypes in animal models [126][127][128].…”