Brainstem immaturity in sudden infant death syndrome: A quantitative rapid Golgi study of dendritic spines in 95 infants

doi:10.1016/0006-8993(85)90300-2

Brain Research

Volume 325, Issues 1–2, 28 January 1985, Pages 39-48

https://doi.org/10.1016/0006-8993(85)90300-2 Get rights and content

Abstract

Quantitative analysis of reticular dendritic spines was performed on rapid Golgi impregnated neurons in 7 brainstem areas from 61 sudden infant death syndrome (SIDS) and 34 control infants. Throughout the first postnatal year, mean spine density in SIDS was significantly greater than the mean density in controls (P < 0.0001). There were significantly higher values of spine density in SIDS compared to controls (P < 0.0001) in both term and preterm infants. Within the SIDS brainstem itself, the density of dendritic spines was significantly different (P < 0.05) between two medullary regions and between reticular and non-reticular formation areas. Among these brainstem areas in controls, there was no significant difference. Our findings indicate an immature developmental pattern of increased dendritic spine density in the SIDS brainstem which may be responsible for abnormal central respiratory and arousal control. These significant quantitative differences in spine density are considered in the present study to represent an anatomical substrate of brainstem immaturity in the multifactorial pathogenesis of SIDS.

Reference (41)

ColonnierM.
Synaptic patterns on different cell types in the different laminae of the cat visual cortex: an electron microscope study
Brain Research
(1968)
ConnorJ.R. et al.
Aging and environmental influences on two types of dendritic spines in the rat occipital cortex
Exp. Neurol.
(1980)
HammerR.P.
The influence of pre- and postnatal under nutrition on the developing brainstem reticular core: a quantitative golgi study
Develop. Brain Res.
(1981)
HammerR.P. et al.
Development of the brainstem reticular core: an assessment of dendritic state and configuration in the perinatal rat
Develop. Brain Res.
(1981)
Marin-PadillaM.
Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a golgi study
Brain Research
(1972)
Marin-PadillaM.
Cortical axo-spinodendritic synapses in man: a golgi study
Brain Research
(1968)
QuattrochiJ. et al.
Sudden infant death syndrome: a preliminary study of reticular dendritic spines in infants with SIDS
Brain Research
(1980)
ScheibelM.E. et al.
Maturation of reticular dendrites: loss of spines and development of bundles
Exp. Neurol.
(1973)
Shammah-LagnadoS.J. et al.
Afferent connections of the mesencephalic reticular formation: a horseradish peroxidase study in the rat
Neuroscience
(1983)
BabaN. et al.
Possible role of the brainstem in sudden infant death syndrome
J. Amer. med. Ass.
(1983)

BennettM.V.L. et al.

Gap junctions, electronic coupling, and intercellular communication

Neurosci. Res. Prog. Bull.

(1978)

BergerA.J. et al.

Regulation of respiration

New Engl. J. Med.

(1977)

BuellS.J.

Golgi cox and rapid golgi methods as applied to autopsied human brain tissue: widely disparate results

J. Neuropath. exp. Neurol.

(1982)

CohenM.I.

Central determinants of respiratory rhythm

Ann. Rev. Physiol.

(1981)

FeldmanM.L. et al.

A technique for estimating total spine numbers on golgi-impregnated dendrites

J. comp. Neurol.

(1979)

FisherJ. et al.

Qualitative and quantitative neurohistological changes produced in the rat brain by prolonged aerogenic hypoxia in early ontogeny

Physiol. bohemoslov.

(1974)

GadsonD.R. et al.

Fatty changes in the brain in perinatal and unexpected death

Arch. Dis. Childh.

(1976)

GlobusA. et al.

Loss of dendritic spines as an index of presynaptic terminal patterns

Nature (Lond.)

(1966)

Gordon, D., Cohen, R. J., Kelly, D., Akselrod, S. and Shannon, D. C., Sudden infant death syndrome: abnormalities in...

GuilleminaultC. et al.

Sleep parameters and respiratory variables in ‘near-miss’ sudden infant death syndrome infants

Pediatrics

(1981)

Cited by (117)

Prenatal intermittent hypoxia sensitizes the laryngeal chemoreflex, blocks serotoninergic shortening of the reflex, and reduces 5-HT<inf>3</inf> receptor binding in the NTS in anesthetized rat pups
2020, Experimental Neurology
Citation Excerpt :
All these pathological changes and risk factors associated with SIDS seem to result from chronic, prenatal events that reduce oxygen delivery to the fetus, and so for many infants, SIDS looks like an acquired, congenital, neuropathological disorder, an idea that was endorsed by the National Institute of Child Health and Human Development SIDS Strategic Plan 2001 (Goldwater, 2011). Pathologists describe the brains of infants who died of SIDS as immature and attribute this to hypoxia-associated developmental delay, and the findings of immature serotonergic neuronal morphology, delayed myelination, and increased numbers of dendritic spines fit this description (Becker, 1990; Bright et al., 2017a; Kinney et al., 1991; Paterson et al., 2006b; Quattrochi et al., 1985; Takashima et al., 1978; Takashima and Becker, 1991; Takashima et al., 1982). Our findings of heightened sensitivity to the LCR, a diminished sensitivity of the LCR to 5-HT, and reduced 5-HT3 receptor binding in younger rat pups exposed to gestational IH can be seen as persistence of fetal patterns of reflex responses and delayed emergence of normal 5-HT3 receptor levels.
We tested the hypothesis that exposure to intermittent hypoxia (IH) during pregnancy would prolong the laryngeal chemoreflex (LCR) and diminish the capacity of serotonin (5-hydroxytryptamine; 5-HT) to terminate the LCR. Prenatal exposure to IH was associated with significant prolongation of the LCR in younger, anesthetized, postnatal day (P) rat pups age P8 to P16 compared to control, room air (RA)-exposed rat pups of the same age. Serotonin microinjected into the NTS shortened the LCR in rat pups exposed to RA during gestation, but 5-HT failed to shorten the LCR in rat pups exposed to prenatal IH. Given these observations, we tested the hypothesis that prenatal hypoxia would decrease binding to 5-HT₃ receptors in the nucleus of the solitary tract (NTS) where 5-HT acts to shorten the LCR. Serotonin 3 receptor binding was reduced in younger rat pups exposed to IH compared to control, RA-exposed rat pups in the age range P8 to P12. Serotonin 3 receptor binding was similar in older animals (P18-P24) regardless of gas exposure during gestation. The failure of the 5-HT injected into the NTS to shorten the LCR was correlated with a developmental decrease in 5-HT₃ receptor binding in the NTS associated with exposure to prenatal IH. In summary, prenatal IH sensitized reflex apnea and blunted processes that terminate reflex apneas in neonatal rat pups, processes that are essential to prevent death following apneas such as those seen in babies who died of SIDS.
On the origins of sex-based differences in respiratory disorders: Lessons and hypotheses from stress neuroendocrinology in developing rats
2017, Respiratory Physiology and Neurobiology
Citation Excerpt :
As discussed in the previous section, the GS protocol reproduces key aspects of this condition both in the dam and the pups. Immaturity of the respiratory control centers, as indicated by increased respiratory instability, apneas with O2 desaturations and reduced responsiveness to hypoxia are associated with SIDS (Quattrochi et al., 1985; Kinney et al., 2009) and these dysfunctions have been observed in GS pups (Table 1). The lower HVR in GS pups is relevant to clinical observations since O2 responsiveness is an important defense system against hypoxia and disruption of this reflex may be threatening to the newborn (Leiter and Böhm, 2007; Kinney, 2009).
The environment plays a critical role in shaping development and function of the brain. Stress, especially when experienced early in life, can interfere with these processes. In the context of respiratory control, perinatal stress can therefore alter the ability to achieve the “fine-tuning” necessary for proper detection of chemosensory stimuli and production of an adequate motor (respiratory) command. Depending on the timing, intensity, and duration, the detrimental consequences of perinatal exposure to adverse conditions on the respiratory network become manifest at various life stages and can persist into adulthood.
During early life, respiratory diseases commonly associated with dysfunction of neural networks include apnea of prematurity (AOP) and cardio-respiratory failure leading to sudden infant death syndrome (SIDS). Sleep disordered breathing (SDB) can occur at various life stages, including adulthood. Regardless of age, a common element of these disorders is their greater prevalence in males. While this sexual dimorphism points to a potential role of sex hormones, our understanding of the neuroendocrine mechanisms remain poorly understood. In addition to their modulatory influence on breathing, gonadal hormones regulate sexual differentiation of the brain. Stress alters these effects, and over the years our laboratory has used various perinatal stress protocols to gain insight into the origins of sex-based differences in respiratory disorders. This review discusses our recent advances with a focus on the sex-specific impact of early life stress on O₂-chemoreflex function both in newborn and adult rats. We conclude by discussing the basic principles emerging from this work, potential mechanisms, and clinical relevance.
The role of the autonomic nervous system in arrhythmias and sudden cardiac death
2017, Autonomic Neuroscience: Basic and Clinical
Citation Excerpt :
Structural and neurotransmitter alterations in the brainstem have been found in SIDS patients, consistent with autonomic dysregulation. These changes include increases in dendritic spine density, a marker of delayed neuronal maturation, and delayed maturation of synapses in medullary respiratory centers (Quattrochi et al., 1985). Polymorphisms in genes that effect ANS development (impaired autonomic regulation) including PHOX2A, RET, ECE1, TLX3, EN1 have been reported in SIDS patients (Weese-Mayer et al., 2004).
The autonomic nervous system (ANS) is complex and plays an important role in cardiac arrhythmia pathogenesis. A deeper understanding of the anatomy and development of the ANS has shed light on its involvement in cardiac arrhythmias. Alterations in levels of Sema-3a and NGF, both growth factors involved in innervation patterning during development of the ANS, leads to cardiac arrhythmias. Dysregulation of the ANS, including polymorphisms in genes involved in ANS development, have been implicated in sudden infant death syndrome. Disruptions in the sympathetic and/or parasympathetic systems of the ANS can lead to cardiac arrhythmias and can vary depending on the type of arrhythmia. Simultaneous stimulation of both the sympathetic and parasympathetic systems is thought to lead to atrial fibrillation whereas increased sympathetic stimulation is thought to lead to ventricular fibrillation or ventricular tachycardia. In inherited arrhythmia syndromes, such as Long QT and Catecholaminergic Polymorphic Ventricular Tachycardia, sympathetic system stimulation is thought to lead to ventricular tachycardia, subsequent arrhythmias, and in severe cases, cardiac death. On the other hand, arrhythmic events in Brugada Syndrome have been associated with periods of high parasympathetic tone. Increasing evidence suggests that modulation of the ANS as a therapeutic strategy in the treatment of cardiac arrhythmias is safe and effective. Further studies investigating the involvement of the ANS in arrhythmia pathogenesis and its modulation for the treatment of cardiac arrhythmias is warranted.
The dorsal motor nucleus of the vagus (DMNV) in sudden infant death syndrome (SIDS): Pathways leading to apoptosis
2013, Respiratory Physiology and Neurobiology
Citation Excerpt :
Abnormalities have been found in a number of medullary nuclei in SIDS infants, and particularly the dorsal motor nucleus of the vagus (DMNV). Amongst the findings affecting this nucleus are an increase in apoptosis in SIDS infants (Machaalani and Waters, 2008), gliosis (Yamanouchi et al., 1993), delayed neuronal maturation (Quattrochi et al., 1985) and decreased neuronal density (Konrat et al., 1992). Such DMNV pathology supports the aforementioned ‘brainstem’ hypothesis as it has been shown to be involved in the efferent control of cardiorespiration (Dampney, 1994; Jordan, 2001).
Sudden infant death syndrome (SIDS) remains the commonest cause of death in the post-neonatal period in the developed world. A leading hypothesis is that an abnormality in the brainstem of infants who succumb to SIDS, either causes or predisposes to failure to respond appropriately to an exogenous stressor. Neuronal apoptosis can lead to loss of cardiorespiratory reflexes, compromise of the infant's ability to respond to stressors such as hypoxia, and ultimately a sleep-related death. The dorsal motor nucleus of the vagus (DMNV) is a medullary autonomic nucleus where abnormalities have regularly been identified in SIDS research. This review collates neurochemical findings documented over the last 30 years, including data from our laboratory focusing on neuronal apoptosis and the DMNV, and provides potential therapeutic interventions targeting neurotransmitters, growth factors and/or genes.
Unexplained stillbirth versus SIDS: Common congenital diseases of the autonomic nervous system-pathology and nosology
2011, Early Human Development
Citation Excerpt :
This alteration was again emphasized by Kinney et al. [21] in 22% of the SIDS victims examined. Subcortical leukomalacia in the white matter [22], developmental delay of dendritic spines and synapses [23], a decreased number of myelinated vagal fibers [24], increased apoptosis in brainstem nuclei [25] and abnormalities in neurotransmitters [26] have all been reported in the SIDS in subsequent research. All these lesions, albeit non-specific, can be attributed to chronic or repeated hypoxia complicating sleep apnea and alveolar hypoventilation, suggesting the possibility that abnormal development of the neuronal circuitry between the brainstem centers that regulate rhythmic breathing and arousal gives rise to cardiorespiratory instability.
To contribute to a more balanced assessment of the morphological substrates underlying unexplained perinatal death and SIDS.
In-depth histological, immunohistochemical and genetic examinations were performed on the autonomic nervous and cardiac conduction systems in 95 unexpected perinatal deaths, 140 SIDS and 78 controls (44 infants and 34 perinatal death victims).
The study revealed the localization and the nature of a variety of specific congenital abnormalities of the autonomic nervous system, central and peripheral, and of the cardiac conduction system that represent the morphological substrates of the pathophysiological mechanism of sudden fetal death and SIDS.
The observation of similar anomalies of the autonomic nervous and the cardiac conduction systems in both unexplained perinatal deaths and SIDS indicates their common congenital nature. Therefore, the definitions of these deaths, currently nosographically distinct, should be unified.
Mechanisms of pathogenesis in the Sudden Infant Death Syndrome
2007, Respiratory Physiology and Neurobiology
The likely processes of the Sudden Infant Death Syndrome (SIDS) were identified many years ago (apnea, failed arousal, failed autoresuscitation, etc.). The neurophysiological basis of these processes and the neurophysiological reasons some infants die of SIDS and others do not are, however, only emerging now. We reviewed recent studies that have shed light on the way in which epidemiological risk factors, genetics, neurotransmitter receptor defects and neonatal cardiorespiratory reflex responses interact to lead to sudden death during sleep in a small number of normal appearing infants. As a result of this review and analysis, we hypothesize that the neurophysiological basis of SIDS resides in a persistence of fetal reflex responses into the neonatal period, amplification of inhibitory cardiorespiratory reflex responses and reduced excitatory cardiorespiratory reflex responses. The hypothesis we developed explores the ways in which multiple subtle abnormalities interact to lead to sudden death and emphasizes the difficulty of ante-mortem identification of infants at risk for SIDS, although identification of infants at risk remains an essential goal of SIDS research.

View all citing articles on Scopus

View full text

Brainstem immaturity in sudden infant death syndrome: A quantitative rapid Golgi study of dendritic spines in 95 infants

Abstract

Brain Research

Exp. Neurol.

Develop. Brain Res.

Develop. Brain Res.

Brain Research

Brain Research

Brain Research

Exp. Neurol.

Neuroscience

Possible role of the brainstem in sudden infant death syndrome

J. Amer. med. Ass.

Gap junctions, electronic coupling, and intercellular communication

Neurosci. Res. Prog. Bull.

Regulation of respiration

New Engl. J. Med.

Golgi cox and rapid golgi methods as applied to autopsied human brain tissue: widely disparate results

J. Neuropath. exp. Neurol.

Central determinants of respiratory rhythm

Ann. Rev. Physiol.

A technique for estimating total spine numbers on golgi-impregnated dendrites

J. comp. Neurol.

Qualitative and quantitative neurohistological changes produced in the rat brain by prolonged aerogenic hypoxia in early ontogeny

Physiol. bohemoslov.

Fatty changes in the brain in perinatal and unexpected death

Arch. Dis. Childh.

Loss of dendritic spines as an index of presynaptic terminal patterns

Nature (Lond.)

Sleep parameters and respiratory variables in ‘near-miss’ sudden infant death syndrome infants

Pediatrics