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PROLONGED ULTRASOUND DISRUPTS BRAIN DEVELOPMENT IN FETAL MICE

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Exposure to ultrasound waves at levels beyond those used in obstetrical exams may disrupt the normal migration of neurons in the developing brains of fetal mice, according to a new study by researchers at Yale University.

There is no evidence that this occurs in human fetuses, but the findings should raise concern about unregulated ultrasound services, said senior author Pasko Rakic, MD, Chair of the Department of Neurobiology at Yale Medical School.

The team injected special biomarkers into more than 335 fetal mice at day 16 of gestation. They then tracked neuronal migration after the mice were exposed to ultrasound for 30 minutes or more.

“A small but significant number of neurons did not migrate to their proper positions in the cerebral cortex but were scattered within inappropriate cortical layers and adjacent white matter,” Dr. Rakic told Neurology Today in a telephone interview.

“We don't have any evidence ourselves that ultrasound causes behavioral effects in mice or has any effect on the developing human brain,” he said. “But our findings indicate a need for further study and caution with regard to unnecessary non-medical exposure.”

The findings were reported in the August 7 issue of the Proceedings of the National Academy of Sciences (2006;103:12903–12910).

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Dr. Pasko Rakic: “Ultrasound is a vibration, its a force – its safe but we dont know all the details. What we do know is that ultrasound does not belong in a booth at a mall.”

The American Institute of Ultrasound Medicine has come out strongly against commercially marketed, non-medically indicated fetal imaging, as has the Food and Drug Administration (FDA). In a 2004 report, the FDA cautioned pregnant women to avoid what it called “entertainment ultrasounds” – those typically offered in shopping malls as a “keepsake” photo service, warning that the effects of repeated ultrasound exposures on human fetuses are not known.

The study is believed to be the first to evaluate the effects of ultrasound waves on neuronal migration in mice at a late stage of embryonic brain development, when migratory pathways are longest and most vulnerable. The magnitude of migratory misdirection was highly variable, but increased with the duration of exposure, said Dr. Rakic, who directs the Kavli Institute of Neuroscience at Yale.

Dr. Rakic told Neurology Today that the mouse results may not directly apply to humans for several reasons. First, the mice had much longer exposures to ultrasound than those administered in human prenatal exams, and the sound waves were aimed directly at their brains. Prenatal ultrasound scans may last around 30 minutes, but during that time the entire fetus, as well as the amniotic fluid and the mother's cervix, are being examined.

“I want to emphasize that our study in mice does not mean that use of ultrasound on human fetuses for appropriate diagnostic and medical purposes should be abandoned,” he said. “On the contrary: Ultrasound has been shown to be very beneficial in the medical context. Instead, our study warns against non-medical use.”

Dr. Rakic is currently determining whether exposure has any effect on behavior or cognition in exposed mice as they grow. The researchers will also be conducting similar tests in non-human primates. He said the mouse studies should be completed this year, but the primate studies will take much longer, perhaps years.

SOUND JUDGMENT

The new findings should help reinforce FDA guidelines, said Verne Caviness, MD, Chief of Pediatric Neurology and Joseph and Rose Kennedy Professor of Child Neurology and Mental Retardation at Massachusetts General Hospital in Boston. “The basic guidelines in this country suggest using ultrasound as little as possible,” he said.

In an accompanying editorial, Dr. Caviness explained that a human fetus has a much larger and denser brain, and that scans usually just pass through the brain for only a few seconds. The commentary was co-authored by P. Ellen Grant, MD, Assistant Professor in Radiology at Harvard Medical School and the Department of Radiology at Massachusetts General Hospital.

“The corresponding neurons in the human brain would probably be formed in the 16th week and continue to migrate for at least 1–2 weeks,” Drs. Caviness and Grant noted.

Nonetheless, they added, “Ultrasound is capable of causing deleterious bioeffects to the human fetus, and the paper…reminds us of the need to maintain our vigilance. More fundamentally, the study may illustrate a new consequence of ultrasound where we have little or no understanding of the mechanism.”

But patients and their physicians should have little concern, Dr. Caviness told Neurology Today in a telephone interview.

The human brain is about 1,000 times larger than the mouse brain, and ultrasound scans only a small part of the human brain at once. No area of the human brain is exposed for over a minute during a standard prenatal exam, he noted. He cautioned, however, that the effects of long-term exposure have not been studied well.

“It draws our attention to mechanisms of injury, and disruption [of brain development] by mechanical force such as sound waves is not very well understood,” he said. “Because of this, the lowest possible exposure to ultrasound waves should be observed, not for women to repeatedly visit these photo shops to get pictures for a scrapbook.”

WOMB WITH A VIEW

Steven M. Rothman, MD, the Ernest and Jane G. Stein Professor of Developmental Neurology and Pediatrics at the Washington University School of Medicine in St. Louis and St. Louis Children's Hospital, said the study illustrates the importance of ongoing research to monitor potential effects of biomedical technology after it enters the medical mainstream.

“The technical rigor of this study, which comes from a laboratory that generated much of our understanding of normal cortical development, has to be taken seriously,” he told Neurology Today in a telephone interview.

“It is actually reassuring that many clinical examinations require less than 10 minutes, below the threshold to induce migrational abnormalities in the current study,” he noted. “However, if there was ever any scientific proof needed to halt the expansion of recreational ultrasound, this study provides it.”

While the significance of these migrational anomalies is still unclear, he said, the observation of normal brain size and cytoarchitectonic organization in ultrasound-exposed mice fails to support a link between ultrasound and increased frequency of childhood autism, as some research has suggested.

‘TOM CRUISE LAW’ AND OTHER LEGISLATION

On May 4, the California Assembly passed a law prohibiting anyone but licensed clinicians from offering ultrasound services. The American College of Radiology wanted the so-called “Tom Cruise law” to be even stricter.

Tom Cruise and his then-expectant wife drew media attention when they purchased an ultrasound device to use in their home during the pregnancy.

James P. Borgstede, MD, Chair of the American College of Radiology Board of Chancellors, criticized the law when it passed, saying in a press release that the legislation should have also banned the sale of ultrasound equipment to fetal keepsake studios.

“They most often lack onsite physician supervision, the tests are almost always not the result of a physician prescription, and may cause parents to mistakenly believe that they do not need appropriate medical attention,” he commented.

Several other states are considering similar legislation that would bar such services from being offered to consumers, such as those marketed nationally under such names as “Womb with a View” and “Fetal Photos.”

“This still looks very safe in humans, nothing has changed,” said Dr. Rakic, “But ultrasound is a vibration, it's a force – it's safe but we don't know all the details. What we do know is that ultrasound does not belong in a booth at a mall.”

ARTICLE IN BRIEF

  • ✓ A new study found that ultrasound waves at levels beyond those used in obstetrical exams may disrupt the normal migration of neurons in the developing brain of mice, raising concern about the use of unregulated ultrasound services by pregnant women.

REFERENCE

• Ang ESBC, Gluncic V, Rakic P, et al. Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc Nat Acad Sci 2006;103:12903–12910.