A widely held hypothesis of sudden infant death syndrome (SIDS) is that it represents fatal sleep apnea due to a maturational defect in brainstem neural circuits controlling respiration during sleep. This hypothesis is based upon the consistent association of silent death to sleep periods in SIDS victims. Developmental mechanisms are implied by the unique age range of SIDS, with a peak at 2 - 4 months, a critical time in the maturation of respiratory and sleep patterns. Yet, proof of a brainstem defect is not forthcoming, because qualitative abnormalities have not been detected and quantitative abnormalities have not been consistent. We propose that the developmental brainstem defect in SIDS is quantitative and requires sophisticated morphometrics for its proof.
Our aim i s to test this hypothesis through the rigorous quantitation of morphological and neurochemical parameters of astrocyte and neuron maturation. We will use quantitative cytoarchitectonics to assess the number of reactive astrocytes and number and size of neuron subclasses in brainstem nuclei related and unrelated to the control of respiration and sleep. Formalin-fixed paraffin embedded brainstems, primarily from the Valdes-Dapena/Tildon collaborative study of the seven tissue markers of chronic hypoxemia, will be used in these studies. Sophisticated computer programs for quantitation and analysis of the number and size of cell subtypes in serial sections in 2- and 3-dimensions will be employed. We will use quantitative autoradiography to map the distribution of postsynaptic receptors as a probe of neurochemical development for neurotransmitters postulated to play a major role in respiratory and sleep regulation. Frozen brainstem specimens collected by us from a network of donating pathologists and medical examiners will be used in these studies. Autoradiographic and computer methodologies will be used for quantifying and analysing the anatomical distribution of receptor densities in 2- and 3-dimensions and correlating these findings with the results from the quantitative cytoarchitectonics. The rigorous quantitative methods proposed here have the potential to resolve many of the controversies concerning claims of morphologic and neurochemical abnormalities in the SIDS brainstem. While not directly explaining the cause of SIDS, a rigorously verified brainstem abnormality would provide a crucial lead. The establishment of normative standards about human brainstem maturation based upon the control specimens form a significant part of this study.
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