Our unborn children at risk?

T he study by Ang et al. (1) in this issue of PNAS strikes a precautionary note, in that it presents experimental evidence that prolonged continuous ultrasound (US) exposure may cause mild disruption in neuronal migration to the cerebral cortex in fetal mice. The authors (1) suggest that such neuronal heterotopia may result in anomalies in brain circuitry and synaptic activity. Does this study indicate that we should be concerned about human fetal US? First, we will review the essential details of the study by Ang et al. (1). In the mouse, cells of the neocortex are formed and largely complete their migrations from their place of origin in the ventricular zone (VZ) to the cortex during the final week of a 19-day gestation (2). In these experiments, cells completing their final round of division on the 16th day of gestation, corresponding to the time of origin of cells of the outermost layers, were labeled by exposure to BrdU. A total of 146 embryos were exposed transabdominally in utero to a variable dosage schedule of B-mode US [unanesthetized dams; 6.7 MHz; 0.2s US pulse duration; 11 frames per second scanning rate; continuous exposure for between 5 and 35 min in graded schedules for a total exposure of 5, 15, 30, 60, 210, or 420 min; estimated attenuated spatial peak time average intensity (ISPTA) of 0.6 mW per cm2; spatial peak pulse average intensity (ISPPA) of 262 W per cm2; and mechanical index (MI), 0.66]. An exposure to US occurred on each of the final 3 days of gestation, that is, while cells arising on embryonic day 16 (E16) would be migrating. There were 141 sham control embryos and 30 control embryos. The general appearance of the brains, examined on the 10th postnatal day, was unremarkable. There was no difference in brain size or neocortical cytoarchitecture and no histological evidence of tissue cavitation or other signs of tissue injury. In the sham control animals, the majority of neurons born on E16 were in layers II and III. In the experimental set, undergoing total exposures 30 min, a relatively small percentage of E16 neurons were located more deeply at all levels of the cerebral wall. At an exposure time of 30 min, a small subpopulation of heterotopic cells formed a discrete band in the subventricular zone (SVZ), just above the proliferative epithelium in the VZ. With increasing durations of exposure, heterotopic neurons became dispersed throughout the full width of the cerebral wall extending from the VZ through the cortical layers. The heterotopic neurons, including those lying in layer VI, did not stain with FoxP2, a marker for layer VI neurons, but some did stain for Brn1, a marker for outer-layer neurons. That is, with respect to these markers at least, they appeared to retain cell classspecific properties of neurons arising on E16 despite their abnormal positions.