Study of the human hypoglossal nucleus: Normal development and morpho-functional alterations in sudden unexplained late fetal and infant death

Abstract

This study evaluated the development and the involvement in sudden perinatal and infant death of the medullary hypoglossal nucleus, a nucleus that, besides to coordinate swallowing, chewing and vocalization, takes part in inspiration. Through histological, morphometrical and immunohistochemical methods in 65 cases of perinatal and infant victims (29 stillbirths, 7 newborns and 29 infants), who died of both unknown and known cause, the authors observed developmental anomalies of the hypoglossal nucleus (HGN) in high percentage of sudden unexplained fetal and infant deaths. In particular, HGN hypoplasia, hyperplasia, positive expression of somatostatin and absence of interneurons were frequently found particularly in infant deaths, with a significant correlation with maternal smoking.

Introduction

Developmental abnormalities of brainstem centers checking the vital functions have been reported by us in sudden perinatal and infant death victims. These include, in particular in the brainstem, hypoplasia of the arcuate nucleus, pre-Bötzinger nucleus, tractus solitarius nucleus, parafacial complex and parabrachial/Kölliker-Fuse complex [1], [2], [3], [4], [5], [6], [7]. The present study was performed with the purpose to deepen our knowledges by evaluating the development and the involvement in these pathologies even of the hypoglossal nucleus (HGN), a nucleus of the dorsal part of the medulla oblongata that, even if not generally included among the so defined vital centers, takes part in specific phases of breathing. In fact the hypoglossal neurons, besides to coordinate swallowing, chewing and vocalization, have been identified as having a peak of activity during inspiration [8], [9], [10].

The HGN contains two distinct neuronal populations: the first, predominant, is represented by motoneurons, that are large, multipolar and rich in Nissl substance neurons; the second neuronal pool is constituted by small round or oval neurons with poor rough endoplasmatic reticulum, defined as “inhibitory interneurons” [11], [12], [13].

The functional significance of the two neuronal groups in HGN has been explained in relation to tongue control, in particular to control of the genioglossus muscle that is important in maintaining a patent airway, especially during inspiration [14], [15], [16]. Both the HGN motoneurons and interneurons are involved in the generation of excitatory and inhibitory post-synaptic potential during the different above-mentioned functions that require precise coordination of tongue movements.

The current knowledges on the HGN are prevalently obtained from experimental studies. A review of the literature shows that only few authors, and many years ago, have studied the HGN in man, precisely in sudden infant death syndrome (SIDS) [17], [18], [19], [20]. They observed significantly higher incidence of morphopathological features of this nucleus in victims of sudden infant death than in control infants.

Therefore, we aimed to start from these works to evaluate if the HGN shows morpho-functional alterations not only in SIDS but also in sudden unexplained perinatal deaths, like the alterations in nuclei and/or structures of the brainstem and cerebellum checking vital functions, previously observed by us in these pathologies [1], [2], [3], [4], [5], [6], [7], [21], [22], [23].

Thus, we firstly investigated the developmental patterns of the HGN in a wide cohort of fetal and infant death victims aged from the 17th gestational week to 10 months of life, who had died of known and unknown causes, and then we evaluated whether morphofunctional disorders could be present in this nucleus in victims of unexplained death.

The study protocol of the HGN included, in all cases: (1) morphological examination in histological sections of medulla oblongata; (2) morphometrical analysis of nucleus area and neuronal density; (3) immunohistochemical evaluation of the expression of the somatostatin, a neurotransmitter that controls important physiological functions already from the first weeks of gestation.

Finally, the observation in our previous studies of a significantly increased incidence of structural and/or functional alterations of the central autonomic nervous system in victims of unexplained perinatal and infant death with smoker mothers [21], [24], [25], [26], prompted us to determine whether prenatal absorption of nicotine could also interfere with the maturational processes of the HGN.