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Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

ABSTRACT: Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by ¹²⁵I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in ¹²⁵I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, ¹²⁵I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on ¹²⁵I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

SUBMITTER: Vivekanandarajah A

PROVIDER: S-EPMC7988476 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. Methods:The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. Findings:One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7, p < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83, p = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27, p = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. Interpretation:Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. Funding:National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

Project description:Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

Project description:BackgroundIt is not currently possible to predict which patients will develop chronic disorders of consciousness (DoC) after severe traumatic brain injury (TBI). Although the ascending arousal network (AAN) supports human consciousness, it is unknown which AAN pathways must be preserved for patients to recover consciousness.MethodsSixteen patients with acute traumatic coma and 16 matched healthy controls were scanned with high angular resolution diffusion imaging (HARDI). All patients recovered consciousness (Recovery Cohort). Nine were scanned longitudinally: first in the ICU (Acute), then at ≥5 months post-injury (Follow-up). Six separate patients with post-traumatic DoC were scanned ≥5 months post-injury (Chronic DoC Cohort). For each AAN pathway, we computed the median relative change in Acute-to-Follow-up Connectivity Probability (CP) in the Recovery Cohort. We then used Wilcoxon tests with Bonferroni correction to compare CP in each AAN pathway in the Recovery Cohort at Follow-up versus the Chronic DoC Cohort. In an exploratory analysis, we used principal component analysis (PCA) to determine whether linear combinations of AAN CP values could separate the Chronic DoC Cohort from the Recovery Cohort and the healthy controls.ResultsIn the Recovery Cohort, the largest relative AAN CP changes were in the brainstem-to-thalamus (median [IQR] = 0.7 [0.09, 0.9]) and forebrain-to-occipital lobe (-0.8 [-0.9, -0.8]) pathways. The AAN connections that differed in the cross-sectional analysis between the Recovery Cohort at Follow-up and the Chronic DoC Cohort included brainstem-to-hypothalamus (W = 53, PBonf = 0.02), brainstem-to-temporal lobe (W = 52, PBonf = 0.04), and thalamus-to-temporal lobe (W = 54, PBonf = 0.009). Plotting the first two principal components of AAN connectivity resulted in a linear separation of Chronic DoC patients from other study groups.ConclusionsWe provide evidence for a longitudinal increase in brainstem-thalamic connectivity during recovery of consciousness after traumatic coma. Cross-sectional analyses revealed that brainstem-hypothalamus, brainstem-temporal lobe, and thalamus-temporal lobe connectivity differed between patients who recovered consciousness and those with a chronic DoC. These observations provide the basis for further investigation into AAN connectivity as a biomarker for recovery of consciousness after traumatic coma.

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Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

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