Serotonergic receptor binding in the brainstem in the Sudden Infant Death Syndrome in a high-risk population

Abstract

The Sudden Infant Death Syndrome (SIDS) is a major global health problem, with increased risk among socioeconomically disadvantaged populations. We propose SIDS, or a subset, is due to a defect in the brainstem serotonin system mediating cardiorespiratory integration and arousal. This defect impinges on homeostasis during a critical developmental period in infancy, especially in populations experiencing maternal and infantile stress, resulting in sleep-related sudden death. In the socially disadvantaged cohort of the prospective Safe Passage Study from Cape Town, South Africa, and the Northern Plains of the United States, we tested the hypothesis that: 1) serotonin (5-HT) receptor 1A binding is reduced within the brainstem of SIDS infants compared to controls; and 2) reduced 5-HT1A binding in SIDS is associated with maternal drinking and/or smoking during pregnancy. Using receptor ligand autoradiography for the 5-HT1A receptor, 3H-8-OH-DPAT binding was measured in brainstem nuclei in infants dying of SIDS (n = 14) and controls dying of known causes (n = 10). We found a brainstem serotonin defect in SIDS infants, that is strongly driven by preterm birth, and that likely underlies the pathogenesis of sleep-related sudden death in response to homeostatic stress. The findings replicate studies of US low-to-middle income SIDS cohorts, with key differences related to prematurity, including increased 5-HT1A binding in premature SIDS compared to premature controls. The relationship of the serotonin defect to prenatal smoking and drinking is unclear, owing to the high exposure rates in SIDS cases and controls. SIDS was significantly associated with lack of a phone (proxy for poverty) (p = 0.024) and overcrowded housing (p = 0.047). These data support the concept of a serotonin defect in brainstem nuclei mediating cardiorespiratory control and arousal in SIDS infants. Maternal and/or fetal stress, along with premature birth, may underlie a deflection of normal development of the serotonergic system.

Fig 1. Representative distribution of 5-HT_1A binding in the pons and medulla.

Autoradiograph images display the distribution pattern of 5-HT_1A binding across different nuclei of the medulla and rostral pons. Receptor binding in fmol/mg is indicated with color according to the scale. Measured nuclei of the mid medulla are as follows: RO/RMg, raphe obscurus/raphe magnus; HG, hypoglossal nucleus; DMX, dorsal motor nucleus of the vagus; NTS, nucleus of the solitary tract; CEN, centralis; S5, spinal 5; MAO, medial accessory olive; PIO, principal inferior olive; ARC, arcuate nucleus. Measured nuclei of the rostral medulla are as follows: RO/RMg, raphe obscurus/raphe magnus; GC, gigantocellularis; PGCL, paragigantocellularis lateralis; IRZ, intermediate reticular zone; PIO, principal inferior olive; DAO, dorsal accessory olive; ARC, arcuate nucleus. Measured nuclei of the rostral pons are as follows: MR, median raphe; DR, dorsal raphe; LC, locus coeruleus; PO, nucleus pontis oralis; BP, basis pontis. Cerebellar tissue (CB, rostral pons section only) displays 5-HT_1A binding but was not measured.

Fig 2. Developmental change in 5-HT_1A binding in known cause of death controls (predischarge and postdischarge combined).

Shown are autoradiographic images of 5-HT_1A binding in the rostral medulla in three representative controls at 33, 38, and 52 post conceptional (PC) weeks. Three source nuclei that synthesize 5-HT are delineated with white lines (GC, gigantocellularis; IRZ, intermediate reticular zone; and PGCL, paragigantocellularis). Binding in these nuclei are visually (top row) and quantitatively (bottom row) decreasing with PC age, the latter shown with plots of 5-HT_1A binding vs PC age. The relationship of PC age with binding is statistically significant in each of the nuclei shown. Data include the combined South Africa and Northern Plains cohorts.

Fig 3. 5.HT_1A binding difference between known cause of death (KCOD) controls and SIDS.

Three nuclei measured at the mid-medulla level show abnormalities in SIDS compared to PostKCOD controls (A) and Pre- and PostKCOD controls combined (B). A) When SIDS is compared to PostKCOD controls only, the hypoglossal nucleus (HG) shows a significant increase in binding in SIDS compared to controls while the nucleus of the solitary tract (NTS) and medial accessory olive (MAO) show a significant age-vs-diagnosis interaction. In the NTS and MAO, note the decrease in binding with postconceptional (PC) age in SIDS with no change in binding with age in the controls. B). When SIDS is compared to all KCOD controls, the HG, NTS, and MAO show a significant mean difference in 5-HT_1A receptor binding. Data include the combined South Africa and Northern Plains cohorts.

Fig 4. Significantly different 5-HT_1A receptor binding based on prematurity.

Premature SIDS infants show higher binding compared to premature post-discharge known cause of death (PostKCOD) controls in the nucleus of the solitary tract, the dorsal motor nucleus of vagus, the hypoglossal nucleus, the medial accessory olive, and the centralis [Left column]. There is no difference between term SIDS and term PostKCOD controls in these same nuclei [Middle column]. The localization of each nucleus is indicated by a white boundary line in a representative autoradiograph of a 64 postconceptional week PostKCOD control born at term birth [Right column]. Data include the combined South Africa and Northern Plains cohorts..

Fig 5. Proposed expanded model of the pathogenesis of a medullary serotonopathy in a high-risk population of SIDS.

We propose that serotonergic receptor pathology originates among susceptible circuits involved in homeostatic control of autoresuscitation, sleep, and arousal during development of the brainstem (pons and medulla oblongata) in a subset of SIDS infants in a critical developmental period — a period that extends from the prenatal period into the postnatal period in the first year of life. This receptor pathology is a marker of an underlying brain vulnerability in the infant (serotonopathy) that compromises autoresuscitation during sleep upon confronting a life-threatening asphyxial challenge in the environment, as in unsafe sleep conditions. The expanded model that we are proposing is an elaboration of the original triple risk model for SIDS [105], which was based upon a multi-risk, multi-factorial premise of the pathogenesis of SIDS, involving the interlocking factors of the vulnerable infant, critical developmental period, and exogenous stressor in a three-circle Venn diagram. As shown in this figure, the revised model emphasizes the role of socioeconomic stressors for the mother and infant, incorporates subtypes of SIDS, one of which derives from a serotonopathy, and emphasizes the importance of prenatal risk factors. These new aspects of the model are based on novel information obtained mainly in the SPS, that highlights the vulnerability of high risk, socioeconomically depressed populations, which represent a large proportion of infants worldwide affected by SIDS. The revised model accounts for the high likelihood that the clinicopathologic phenotype of SIDS is due to multiple causes that form subsets of heterogeneous diseases, many yet to be discovered, in the vulnerable infant. In the revised model, medullary serotonopathies represent one such subtype. The revised model also emphasizes a fetal origin of the underlying vulnerability, with its lethal clinical manifestation after birth in the early postnatal period, recognized by the association of multiple prenatal stressors to SIDS in the SPS (see figure for list). A major concept introduced in the revised model of SIDS pathogenesis is the essential burden of stress and the social determinants of health in socially deprived populations transducing susceptible fetal circuits in gestation, disrupting fetal programming, and producing the underlying vulnerability. Postnatal stressors reinforce the burden of prenatal stressors (see list in figure). Thus, SIDS reflects an intricate constellation of internal and external factors, molded, in part, by stress, arising in fetal life and expressed in infancy. The importance of stress in the pathogenesis of SIDS represents a challenge and an opportunity that may require revamping political and scientific policy in SIDS research.