Neurobiological Alterations Of The Substantia Nigra In Sudden Infant Death Syndrome

Abstract

Background - The purpose of this study was to research possible morphological and functional alterations of the substantia nigra in SIDS. Methods - Brainstems of 46 victims of sudden infant death, aged from 1 to 7 months, were investigated. Twenty-six of these cases were diagnosed as SIDS, due to the lack of any pathological finding, while the remaining 20 cases, in which the cause of death was determined at autopsy, served as controls. Maternal smoking was reported in 10% of controls and 77% of SIDS. Histopathological examination of the substantia nigra was done on midbrain 5-µm-thick sections stained with hematoxylin-eosin and Klüver-Barrera. Densitometry, immunohistochemistry and histochemistry were applied to highlight the neuronal concentration, the expression of tyrosine hydroxylase and neuromelanin, respectively. Results - Hypoplasia of the pars compacta of the substantia nigra was observed in SIDS but not in controls. Tyrosine hydroxylase expression in the substantia nigra was significantly higher in controls than in SIDS. Neuromelanin was observed as dark granules only in 4 infants of the control group but never in SIDS. A significant correlation was found between hypoplasia/low neuronal density, low tyrosine hydroxylase expression in the substantia nigra pars compacta and maternal smoking. Conclusion - The substantia nigra pars compacta, that is the main dopamine center in the brain, is involved in the control of many functions, including the sleep-arousal phase, and hence, its structural and/or functional alterations may explain the pathogenesis of SIDS, that often occurs during sleep. This study also indicates that maternal smoking can may have strongly influenced the SN altered development. Trial registration – not applicable for this study

The Mesencephalic Periaqueductal Gray, a Further Structure Involved in Breathing Failure Underlying Sudden Infant Death Syndrome

“…Furthermore, the significant association observed in the present study between the PAGsm and SNpc hypoplasia previously detected (Lavezzi et al, 2020) (15 of the 17 cases with hypoplasia of the PAGsm, in fact, also presented SNpc hypoplasia) leads us to believe that the two mesencephalic structures are connected to each other and joined through synaptic descending ways to lower brainstem nuclei of the respiratory network. This view finds support in the experimental study by Lima et al on animal models (Lima et al, 2018), showing evidence of direct projection from SNpc to PAG and, from here, to the medullary retrotrapezoid nucleus, a group of glutamatergic neurons expressing the transcription factor PHOX2B and involved in activation of breathing (Moreira et al, 2021;Takakura et al, 2014).…”

“…The above results were compared with those of our previous study on the same case series (Lavezzi et al, 2020), among which the most important was the hypoplasia of the substantia nigra, mainly affecting its pars compacta (SNpc) and characterized by a remarkable reduction of neuron number, found in 18 of the 26 SIDS cases. A strong correlation between SNpc hypoplasia and that of the PAGsm was highlighted.…”

“…We investigated the cytoarchitecture of the PAG and the expression of tyrosine hydroxylase (TH), the enzyme involved in the catecholamine synthesis, in its neurons in a cohort of 46 victims of sudden infant death, 26 males and 20 females, aged between 4 and 30 postnatal weeks (approximately 1-7 months), and precisely in the same series of cases in which we previously reported the frequent presence of morphological and functional alterations of the substantia nigra (Lavezzi et al, 2020).…”

“…Given that SIDS has been recognized as a consequence of breathing control disorders, mainly in awakening from sleep (Hunt, 1989;Kahn et al, 2003;Kato et al, 2003), the aim of this study was to verify whether even alterations of the PAG could contribute to death in this syndrome. Then, for this purpose, we reconsidered a large series of SIDS, in which we already highlighted significant morphological and functional alterations of the substantia nigra pars compacta (SNpc), another mesencephalic structure that is involved in the breath and the sleep-wake cycle regulation (Lavezzi et al, 2020). Then, we set out to focus the present study on the PAG, a region that has been quite neglected or not examined in depth in the previous research, correlating the results with the previous ones related to the SN, with the hope to offer a contribution to the current knowledge on the pathogenetic mechanism of SIDS.…”

The Role of Maternal Smoking in Sudden Fetal and Infant Death Pathogenesis

“…These findings can be observed throughout the central nervous system, including the brainstem, cerebellar cortex, and spinal cord, but also in peripheral organ systems (45,56). Hypoplasia of the pars compacta of the substantia nigra has been observed in SIDS victims; 77% of the SIDS victims had been exposed to maternal smoking; the substantia nigra pars compacta is involved in the sleep arousal phase (57).…”