Emily L. Williams

Quantitative analysis of the shape of the corpus callosum in patients with autism and comparison individuals

Multiple studies suggest that the corpus callosum in patients with autism is reduced in size. This study attempts to elucidate the nature of this morphometric abnormality by analyzing the shape of this structure in 17 high-functioning patients with autism and an equal number of comparison participants matched for age, sex, IQ, and handedness. The corpus callosum was segmented from T1 weighted images acquired with a Siemens 1.5 T scanner. Transformed coordinates of the curvilinear axis were aggregated into a parametric map and compared across series to derive regions of statistical significance. Our results indicate that a reduction in size of the corpus callosum occurs over all of its subdivisions (genu, body, splenium) in patients with autism. Since the commissural fibers that traverse the different anatomical compartments of the corpus callosum originate in disparate brain regions our results suggest the presence of widely distributed cortical abnormalities in people with autism.

Above genetics: Lessons from cerebral development in autism

While a distinct minicolumnar phenotype seems to be an underlying factor in a significant portion of cases of autism, great attention is being paid not only to genetics but to epigenetic factors which may lead to development of the conditions. Here we discuss the indivisible role the molecular environment plays in cellular function, particularly the pivotal position which the transcription factor and adhesion molecule, β-catenin, occupies in cellular growth. In addition, the learning environment is not only integral to postnatal plasticity, but the prenatal environment plays a vital role during corticogenesis, neuritogenesis, and synaptogenesis as well. To illustrate these points in the case of autism, we review important findings in genetics studies (e.g., PTEN, TSC1/2, FMRP, MeCP2, Neurexin-Neuroligin) and known epigenetic factors (e.g., valproic acid, estrogen, immune system, ultrasound) which may predispose towards the minicolumnar and connectivity patterns seen in the conditions, showing how one-gene mutational syndromes and exposure to certain CNS teratogens may ultimately lead to comparable phenotypes. This in turn may shed greater light on how environment and complex genetics combinatorially give rise to a heterogenetic group of conditions such as autism.

Autism and dyslexia: a spectrum of cognitive styles as defined by minicolumnar morphometry.

There is a continuum of cognitive styles amongst humans, defined by differences in minicolumnar numbers/width and arcuate/commissural white matter connectivities. Specifically, it is the connectivity within and between modular cortical circuits that defines conditions such as autism and developmental dyslexia. In autism, a model of local hyperconnectivity and long-range hypoconnectivity explains many of the behavioral and cognitive traits present in the condition, while the inverse arrangement of local hypoconnectivity and long-range hyperconnectivity in dyslexia sheds light on that condition as well. We propose that the cognitive styles present in autism and developmental dyslexia typify the extremes of a minicolumnar spectrum in humans.

Potential teratogenic effects of ultrasound on corticogenesis: Implications for autism

The phenotypic expression of autism, according to the Triple Hit Hypothesis, is determined by three factors: a developmental time window of vulnerability, genetic susceptibility, and environmental stressors. In utero exposure to thalidomide, valproic acid, and maternal infections are examples of some of the teratogenic agents which increase the risk of developing autism and define a time window of vulnerability. An additional stressor to genetically susceptible individuals during this time window of vulnerability may be prenatal ultrasound. Ultrasound enhances the genesis and differentiation of progenitor cells by activating the nitric oxide (NO) pathway and related neurotrophins. The effects of this pathway activation, however, are determined by the stage of development of the target cells, local concentrations of NO, and the position of nuclei (basal versus apical), causing consequent proliferation at some stages while driving differentiation and migration at others. Ill-timed activation or overactivation of this pathway by ultrasound may extend proliferation, increasing total cell number, and/or may trigger precipitous migration, causing maldistribution of neurons amongst cortical lamina, ganglia, white matter, and germinal zones. The rising rates of autism coincident with the increased use of ultrasound in obstetrics and its teratogenic/toxic effects on the CNS demand further research regarding a putative correlation.

Corpus Callosum Shape Analysis with Application to Dyslexia.

Morphometric studies of the corpus callosum suggest its involvement in a number of psychiatric conditions. In the present study we introduce a novel pattern recognition technique that offers a point-bypoint shape descriptor of the corpus callosum. The method uses arc lengths of electric field lines in order to avoid discontinuities caused by folding anatomical contours. We tested this technique by comparing the shape of the corpus callosum in a series of dyslexic men (n = 16) and age-matched controls (n = 14). The results indicate a generalized increase in size of the corpus callosum in dyslexia with a concomitant diminution at its rostral and caudal poles. The reported shape analysis and 2D-reconstruction provide information of anatomical importance that would otherwise passed unnoticed when analyzing size information alone.

Spherical harmonic analysis of cortical complexity in autism and dyslexia

Alterations in gyral form and complexity have been consistently noted in both autism and dyslexia. In this present study, we apply spherical harmonics, an established technique which we have exapted to estimate surface complexity of the brain, in order to identify abnormalities in gyrification between autistics, dyslexics, and controls. On the order of absolute surface complexity, autism exhibits the most extreme phenotype, controls occupy the intermediate ranges, and dyslexics exhibit lesser surface complexity. Here, we synthesize our findings which demarcate these three groups and review how factors controlling neocortical proliferation and neuronal migration may lead to these distinctive phenotypes.

Reassessment of teratogenic risk from antenatal ultrasound

Science has shown that risk of cavitation and hyperthermia following prenatal ultrasound exposure is relatively negligible provided intensity, frequency, duration of exposure, and total numbers of exposures are safely limited. However, noncavitational mechanisms have been poorly studied and occur within what are currently considered “safe” levels of exposure. To date, the teratogenic capacity of noncavitational effectors are largely unknown, although studies have shown that different forms of ultrasound-induced hydraulic forces and pressures can alter membrane fluidity, proliferation, and expression of inflammatory and repair markers. Loose regulations, poor end user training, and unreliable ultrasound equipment may also increase the likelihood of cavitation and hyperthermia during prenatal exposure with prolonged durations and increased intensities. The literature suggests a need for tighter regulations on the use of ultrasound and further studies into its teratogenicity.

Ultrasound and Autism: How Disrupted Redox Homeostasis and Transient Membrane Porosity Confer Risk

Autism is a group of heterogenetic conditions, comprised of syndromic and nonsyndromic phenotypes. Its heterogeneity has challenged scientists for decades in the attempt to delimit its etiological origins. In this search, focus has fallen heavily on genetics, although a growing body of research suggests a large portion of cases may have a more complex etiology than genetics can explain. Therefore, greater attention is being paid to epigenetic effectors which may play roles in the development of autism. One such teratogen is prenatal ultrasound. In this chapter, we review the current modes of use and recent deregulations surrounding ultrasound, the primary and secondary bioeffects following exposure, its relevance to the development of the brain as well as to autism, the plasticity of the biological organism and how two separate effectors can lead to a common phenotype, and our hopes for future research in this area.