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SIDS Infants Show Abnormalities In Brain Area Controlling Breathing, Heart Rate

     Infants who died from SIDS had significantly more serotonergic neurons (neurons that make and release serotonin) in their brainstem as compared with controls, particularly in the area known as the midline raphé nucleus (blue dots). (Image courtesy David Paterson, Ph.D., Children's Hospital Boston)
Infants who die of sudden infant death syndrome have abnormalities in the brainstem, a part of the brain that helps control heart rate, breathing, blood pressure, temperature and arousal, report researchers funded by the National Institutes of Health. The finding is the strongest evidence to date suggesting that innate differences in a specific part of the brain may place some infants at increased risk for SIDS.

The abnormalities appeared to affect the brainstem's ability to use and recycle serotonin, a brain chemical which also is used in a number of other brain areas and plays a role in communications between brain cells. Serotonin is most well known for its role in regulating mood, but it also plays a role in regulating vital functions like breathing and blood pressure.

The study appears in the November 1 Journal of the American Medical Association and was conducted by researchers in the laboratory of Hannah Kinney, M.D., at Children's Hospital Boston and Harvard Medical School as well as other institutions.

"This finding lends credence to the view that SIDS risk may greatly increase when an underlying predisposition combines with an environmental risk--such as sleeping face down-- at a developmentally sensitive time in early life," said Duane Alexander, M.D., Director of the NIH's National Institute of Child Health and Human Development.

SIDS is the sudden and unexpected death of an infant under 1 year of age, which cannot be explained after a complete autopsy, an investigation of the scene and circumstances of the death, and a review of the medical history of the infant and his or her family. Typically, the infant is found dead after having been put to sleep and shows no signs of having suffered.

In previous studies, researchers have hypothesized that abnormalities in the brainstem may make an infant susceptible to situations in which they re-breathe their own exhaled breath, depriving them of oxygen. This hypothesis holds that certain infants may not be able to detect high carbon dioxide or low oxygen levels during sleep, and do not wake up.

To conduct the current study, researchers examined tissue from the brainstems of 31 infants who died of SIDS and 10 infants who died of other causes. The tissue was provided by the office of the chief medical examiner in San Diego, California, and was collected from infants who died between 1997 and 2005.

The lower brainstem helps control such basic functions as breathing, heart rate, blood pressure, body temperature, and arousal. The researchers found that brainstems from SIDS infants contained more neurons (brain or nerve cells) that manufacture and use serotonin than did the brainstems of the control infants, explained the study's first author, David Paterson, PhD, a researcher at Children's Hospital in Boston.

Serotonin belongs to a class of molecules known as neurotransmitters, which serve to relay messages between neurons. Neurons release neurotransmitters, which fit into special sites, or receptors, on surrounding neurons, somewhat like a key fits into a lock. Once in place, the neurotransmitter either promotes or hinders electrical activity in the receiving neuron--next in line in a particular brain circuit--causing it to release its neurotransmitters, which either excite or inhibit still more neurons, and so on.

Although the brainstem tissue from the SIDS infants contained more serotonin-using neurons, these serotonin-using neurons appeared to contain fewer receptors for serotonin than did the brainstems of control infants. Dr. Paterson noted that there are at least 14 different subtypes of serotonin receptor. In their study, the researchers tested the infants' brainstem tissue for a serotonin receptor known as "subtype 1A."

Tissue from both the SIDS infants and the control infants contained roughly equal amounts of a key brain protein, serotonin transporter protein. This protein recycles serotonin, collecting the neurotransmitter from the surrounding spaces outside the neuron and transporting it back into the neuron so it can be used again. Dr. Paterson explained, however, that because the SIDS infants had proportionately more serotonin-using neurons than did the control infants, they would also be expected to have more serotonin transporter protein. So even though they had equal amounts of serotonin transporter protein, the levels were nevertheless reduced--relative to the increased number of serotonin-using neurons-- and, for this reason, unlikely to meet the needs of these cells.

Dr. Paterson added that from the observations in this study it was not possible to determine how much serotonin the infants' brainstems contained when the infants were alive. He noted, however, that the pattern of abnormalities--more serotonin neurons, an apparent reduction of serotonin 1A receptors, and insufficient serotonin transporter--suggested that the level of serotonin in the brainstems of SIDS infants was abnormal.

"Our hypothesis right now is that we're seeing a compensation mechanism," Dr. Paterson said. "If you have more serotonin neurons, it may be because you have less serotonin and more neurons are recruited to produce and use serotonin to correct this deficiency."

The researchers also found that male SIDS infants had fewer serotonin receptors than did either female SIDS infants or control infants. The finding may provide insight into why SIDS affects roughly twice as many males as females.

"These findings provide evidence that SIDS is not a mystery but a disorder that we can investigate with scientific methods, and some day, may be able to identify and treat," said Dr. Hannah Kinney, the senior author of the paper.

A large body of research has shown that placing an infant to sleep on his or her stomach greatly increases the risk of SIDS. The NICHD-sponsored Back to Sleep campaign urges parents and caregivers to place infants to sleep on their backs, to reduce SIDS risk. The campaign has reduced the number of SIDS deaths by about half since it began in 1994. The campaign also cautions against other practices that increase the risk of SIDS, such as soft bedding, smoking during pregnancy, and smoking around a baby after birth.

Despite the fact that the Back to Sleep Campaign recommendations had been widely distributed by the time the study began, a large proportion of the SIDS cases in the study by Drs. Paterson, Kinney and their coworkers were correlated with known SIDS risk factors: 15 (48 percent) were found sleeping on their stomachs, 9 (29 percent) were found face down, and 7 (23 percent) were sharing a bed, at the time of death.

"The majority (65 percent) of the SIDS cases in this data set, however, were sleeping prone or on their side at the time of death, indicating the need for continued public health messages on safe sleeping practices, the study authors wrote."

Backgrounder: Searching For Those At Greatest Risk For SIDS

The current study, appearing in the November 1 Journal of the American Medical Association, provides additional evidence that brainstem abnormalities may impair an infant's ability to sense high carbon dioxide and low oxygen levels. Such impairment would put an infant at risk in situations in which they breathe in their own exhaled breath, depriving them of oxygen. The study represents the latest in a body of research begun in the mid 1980's and initiated by study senior author, Hannah Kinney, .M.D. Dr. Kinney is a longtime grantee of the NICHD. In 1983, when she was a fellow in pathology, Dr. Kinney published a study describing subtle scarring on the brainstem of a number of infants who died of SIDS, corroborating isolated observations by other researchers at the time. During the 1990s, Dr. Kinney and her coworkers examined brainstem tissue from SIDS infants, comparing them to brainstem tissue from controls, to determine which of 6 neurotransmitter systems might potentially be involved in the disorder.

The researchers learned that a region at the surface of the brainstem using glutamate and acetylcholine--both neurotransmitters thought to be involved in sensing carbon dioxide levels in the blood--were abnormal in SIDS cases. However, the greatest involvement appeared to be with a wider brainstem network relying on the neurotransmitter serotonin, thought to play an even greater role in regulating breathing. Infants who died of SIDS appeared to have fewer serotonin receptors than did infants who died of other causes. At the time, multiple subtypes of the serotonin receptor had not yet been identified.

In the current study, Drs. Kinney, Paterson, and their colleagues took advantage of more refined methods to examine the pattern of the serotonin receptor 1A subtype. They were also able to count serotonin-using cells, and estimate their prevalence in the brainstem, something that had not been possible previously. In future studies, the researchers plan to examine the role of other serotonin receptor subtypes in both lab animals and in SIDS cases.

"Our goal is to find a way--a diagnostic test--to identify these defects in living infants and then find a way to correct these defects by drugs or other means as the infant passes through the first six months of life, the period of greatest risk for SIDS," Dr. Kinney said.

Along with providing funding for Dr. Kinney's laboratory, the NICHD funds a wide range of research projects in sudden infant death syndrome. The Back to Sleep Campaign, which urges parents and caregivers to place infants to sleep on their backs, has greatly reduced the SIDS rate. However, the practice cannot eliminate all SIDS deaths.

"Back sleeping is an intervention for all babies, but we still can't target high risk babies because we can't identify them," said Marian Willinger, PhD. "There are still babies who die of SIDS after being placed on their backs."

The NICHD supports a broad portfolio of SIDS research, which includes research on the brain, biological and behavioral markers of abnormal brain function, along with research on prenatal, genetic, behavioral, and environmental factors that may increase SIDS risk. The NICHD also supports technology development to detect potential abnormalities in infants at risk for SIDS.

"Eventually, we hope to have an understanding of the developmental disease process underlying SIDS, so that we can identify infants at highest risk and provide them with appropriate intervention," Dr. Willinger said.

Source: NIH/National Institute of Child Health and Human Development. October 31, 2006.

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