Neurochemical abnormalities in the brainstem of the Sudden Infant Death Syndrome (SIDS).

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Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium

Neurochemical abnormalities in the brainstem of the Sudden Infant Death Syndrome (SIDS) Rita Machaalani 1,2,*, Karen A. Waters 1,2,3 1

Department of Medicine, Room 206, Blackburn Building, D06, The University of Sydney, NSW 2006, Australia The Bosch Institute, Room 206, Blackburn Building, D06, The University of Sydney, NSW 2006, Australia 3 The Childrens’ Hospital, Westmead, NSW 2145, Australia 2

EDUCATIONAL AIMS To understand why the brainstem is a focus of research for causes of SIDS. To provide a comprehensive summary of abnormal neurotransmitter & receptor systems in the SIDS brainstem. To highlight and discuss the implications of patterns emerging in SIDS research for particular brainstem nuclei, including the DMNV, NTS, AN and raphe.

A R T I C L E I N F O

S U M M A R Y

Keywords: Apoptosis Brain Growth factor Neurotransmitter Receptors Sudden infant death

The brainstem has been a focus in Sudden Infant Death Syndrome (SIDS) research for 30 years. Physiological and animal model data show that cardiorespiratory, sleep, and arousal mechanisms are abnormal after exposure to SIDS risk factors or in infants who subsequently die from SIDS. As the brainstem houses the regulatory centres for these functions, it is the most likely site to find abnormalities. True to this hypothesis, data derived over the last 30 years shows that the brainstem of infants who died from SIDS exhibits abnormalities in a number of major neurotransmitter and receptor systems including: catecholamines, neuropeptides, acetylcholinergic, indole amines (predominantly serotonin and its receptors), amino acids (predominantly glutamate), brain derived neurotrophic growth factor (BDNF), and some cytokines. A pattern is emerging of particular brainstem nuclei being consistently affected including the dorsal motor nucleus of the vagus (DMNV), nucleus of the solitary tract (NTS), arcuate nucleus (AN) and raphe. We discuss the implications of these findings and directions that this may lead in future research. ß 2014 Elsevier Ltd. All rights reserved.

INTRODUCTION

in the SIDS brainstem. We highlight emerging patterns that could direct future studies to obtain a better understanding of the role of the brain in the etiology of SIDS.

A leading hypothesis underlying brain research in SIDS, is that the brainstem of SIDS infants is abnormally developed, leading to the loss of cardiorespiratory, arousal and autonomic reflexes in the face of homeostatic stressors, such as hypoxia, ultimately leading to a sleep-related death [40]. It is on this basis that studies of the SIDS brainstem continue. This review will bring together data suggesting the presence of abnormal neurochemical (including neurotransmitters, receptors, growth and cytokine factor) findings

* Corresponding author. Department of Medicine, Room 206, Blackburn Building, DO6, University of Sydney, NSW 2006, Australia. Tel.: +61 2 9351 3851; Fax: +61 2 9550 3851. E-mail address: [email protected] (R. Machaalani).

LITERATURE SEARCH A literature search was conducted in PubMed (NCBI) for relevant journals published from 1980 to December 2013. Search terminologies used were: SIDS and brain; Sudden Infant Death and brain; SIDS and neuropathology. Only papers written in English, with an analysis of the brainstem, including midbrain, pons and medulla, and reporting on neurochemical changes (not structural or architectural such as size or cell numbers) were included. This resulted in a total of 39 papers. Data from these papers are summarized in Table 1 to highlight the neurotransmitter, receptor,

http://dx.doi.org/10.1016/j.prrv.2014.09.008 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Machaalani R, Waters KA. Neurochemical abnormalities in the brainstem of the Sudden Infant Death Syndrome (SIDS). Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.09.008

Catecholamines COMT (catechol-o- methyl transferase) Dopa decarboxylase DBH (Dopamine-beta- hydroxylase)

TH (tyrosine hydroxylase)

PNMT (phenethalolamine-N-methyl transferase)

Norepinephrine 3 H-PAC (Para-amino-clonidine) AR a2A-C

Neuropeptides NPY (Neuropeptide Y)

ME (met enkephalin)

SP (substance-P)

b-endorphin

General Functional significance

Experimental Method & level of brainstem

# of cases SIDS:Controls

Results: SIDS vs Controls

References

Catabolises catacholamines

Respiratory control

RIA; whole brainstem

30:20

No difference

Converts l-dopa to dopamine; dopaminergic Converts dopamine to norepinephrine; dopaminergic

Respiratory control


30:20

No difference

Respiratory control


30:20

No difference

RIA; medulla & pons

28:9

Converts tyrosine to l-dopa: the rate limiting step in dopamine synthesis; dopaminergic

Respiratory control


30:20

# in NA & medullary C2 (area of NTS & DMNV) No difference

Ozand and Tildon 1983 Ozand and Tildon 1983 Ozand and Tildon 1983 Denoroy et al., 1987

IHC; medulla & pons

9:5

No difference

IHC; midbrain, pons & medulla

22:13


37:20

HPLC in raphe obscurus & PGCL. RIA; medulla & pons

35:5

# in DMNV, area reticularis superficialis ventrolateralis, NTS # in DMNV & area reticularis superficialis ventrolateralis No difference

28:9

IHC; medulla & pons

9:5

HPLC in raphe obscurus & PGCL. RLB; medulla

35:5

# in medullary C2 (area of NTS & DMNV), nucleus centralis, NA Absent in the dorsal part of NTS " in PGCL

10:10

No difference


21:17

# a2A in medullary NTS,VLM No difference for a2B &C

Respiratory control

RIA; medulla & pons

12:9

No difference

Bergstrom et al., 1984

Respiratory & autonomic control

RIA; medulla

unknown

No difference

RIA; medulla & pons

12:9

No difference

RIA; medulla & pons

12:9

" in medulla

IHC; pons

20:7

IHC, medulla RLB; medulla IHC; midbrain, pons & medulla IHC; NSTT of medulla IHC; medulla (Cuneate nucleus)

15:8 9:24 26:12

" in trigeminal fibres of the pons " in NTS and NSTT No difference No difference

Kuich et al., 1983 (abstract) Bergstrom et al., 1984 Bergstrom et al., 1984 Yamanouchi et al., 1993 Obonai et al., 1996 Jordan et al., 1997 Sawaguchi et al., 2003 Lavazzi et al., 2011 Hollander 1988

Neurotransmitter; dopaminergic Converts norepinephrine to epinephrine; adrenergic

Neurotransmitter; adrenergic norepinephrine and epinephrine; adrenergic norepinephrine and epinephrine; adrenergic receptor a2A,B,&C Co-transported with other neurotransmitters; No particular receptor Opioid

Co-transported with other neurotransmitters; No particular receptor

opioid

Respiratory control Respiratory control

Respiratory control Respiratory control

Respiratory control & chemoreception

Respiratory & autonomic control

20:11 25:10

# in NSTT Lower proportion of SIDS (8%) had b-endorphin expression compared with controls (80%)

Ozand and Tildon 1983 Kopp et al., 1993 Obonai et al., 1998

Ozawa et al., 1999

Duncan et al., 2010 Denoroy et al., 1987

Kopp et al., 1993 Duncan et al., 2010 Mansouri et al., 2001 Ozawa et al., 2003

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Dopamine

Specific neurotransmitter and receptor system

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Enzyme, transmitter or ligand analysed

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Table 1 Summary of all neurochemical abnormalities identified in the SIDS brainstem 1983-2013.

125

I-Tyr3 I-Somatostatin

[125I-Tyr0,D-Trp8] somatostatine-14 Acetylcholine 3 H-QNB (Quinuclidinyl benzilate)

Neurotensin Somatostatin Somatostatin

Respiratory & autonomic control, opioids as a risk factor Respiratory control Respiratory & blood pressure control Respiratory & blood pressure control

RLB; medulla and pons

45:14 Acute & 15 Chronic Controls

No difference

Kinney et al., 1998

RLB; medulla RLB; medulla

7:6 7:6

" in NTS No difference

Chigr et al., 1992 Chigr et al., 1992


11:6

" in Medial and lateral parabrachial nuclei

Carpentier et al., 1998

# in AN compared to both control groups # number of positive neurons in AN No difference # number of positive neurons in XII & DMNV, # optical density in XII No difference compared to both control groups

Kinney et al., 1995

muscarininc

Chemoreception


mAchR (mucarinic acetyl choline receptor)

muscarininc

Chemoreception

IHC; medulla

45:14 Acute & 18 Chronic Controls unknown

mAchR2 CHAT (choline acetyl transferase)

muscarininc receptor 2 Catalyzes acetylcholine

Chemoreception Chemoreception

IHC; medulla IHC; medulla

14:9 14:9

3

nicotinic

Autonomic control, nicotine as risk factor


45:14 Acute & 15 Chronic Controls

RLB; medulla, pons & midbrain

27:6

H-Nicotine

No difference SIDS cf Controls. Sub-analysis by history of smoke exposure: # in LC, PAG, raphe dorsalis but only in control group. # a7 in NTS, Gracile & cuneate. b2 # in NTS, " in facial

Kubo et al., 1998 (abstract) Mallard et al., 1999 Mallard et al., 1999

Nachmanoff et al., 1998 Duncan et al., 2008

Nicotinic a7 & b2 receptor subunits

Nicotinic receptors a7 & b2

Autonomic control, nicotine as risk factor

IHC; medulla

46:14

Amino acid 3 H-Kainate

Glutamate; kainate

Chemoreception


NR1

Glutamate; N-methyl-Daspartate (NMDA) receptor 1

Respiratory control

Quantitative IHC & nonRISH; medulla and pons

47: 14 Acute & 17 Chronic Controls 15:10

GABA-A & GABAA3

Glutamate; Gabaergic receptor

Chemoreception & respiratory control

GABA-A: RLB; medulla GABAA3: WB; gigantocellularis nucleus

RLB- 34:13# WB- 24:8

Serotonin and its metabolite (5HIAA)

Respiratory, sleep & arousal control

HPLC; medulla and pons raphe HPLC; raphe obscurus & PGCL. IHC; midbrain, pons & medulla IHC; medulla. HPLC; in raphe obscurus & PGCL. WB; in raphe obscurus. RLB; medulla and pons

19:8

No difference

Kopp 1994.

35:5

# 5-HT only

Duncan et al., 2010

26:12

No difference

16:7 35:5

" in Raphe nuclei # TPH2 in raphe obscurus

Sawaguchi et al., 2003 Paterson et al., 2006 Duncan et al., 2010

52: 14 Acute & 17 Chronic Controls

# in AN, ION, nucleus giantocellularis, nucleus raphe obscurus & IRZ # in AN

Panigrahy et al., 2000a

# in DMNV, NTS and VLM, " in PAG

Ozawa and Okado 2002

Indole amine 5HT and 5HIAA

TPH (tryptophan hydroxylase)

3

H-LSD (lysergic acid diethylamide)

Serotonin; converts 5HT to serotonin

Serotonin; serotonergic receptors (5-HT1A-D & 5-HT2)



RLB; medulla and pons 5-HT1A

Serotonin; serotonergic



23:6 northern plain Indian population 31:25

# in AN "mRNA in XII, ION, Cun, Vest, DMNV & NSTT. "protein in DMNV, # in NSTT # RLB in raphe, giantocellularis, XII, NTS, IRZ, dorsal & medial accessory olivary, ION # WB in gigantocellularis

Machaalani et al., 2011

Panigrahy et al., 1997 Machaalani and Waters, 2003

Broadbelt et al., 2011

Kinney et al., 2003

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125

opioid



H-Naloxone


3

3

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18:10

67:25

IHC; medulla

IHC; medulla BDNF & TrkB

IL-2

Cytokine receptor (IL-6R) and signal transducer (gp130) T-immune cell growth factor cytokine Growth factor and receptor. IL-6R & gp130

Abbreviations: 5-HT, serotonin; 5HTT, serotonin transporter; 5-HIAA, 5-hydroxyindoleacetic Acid; AN, arcuate nucleus; DMNV, dorsal motor nucleus of the vagus; IHC, immunohistochemistry; ION, inferior olivary nucleus; IRZ, intermediate reticular zone; NA, nucleus ambiguus; NSTT, nucleus of the spinal trigeminal tract; NTS, nucleus of the tractus solitarus; PAG, periaqueductal grey; PGCL, Paragigantocellularis lateralis; RIA, radioimmunological assay; RLB, radioactive ligand binding; TPH, tryptophan hydroxylase; VLM, ventral lateral medulla; WB, western blotting; XII, hypoglossal nucleus. #Three datasets were studied. This is the maximum of cases in the largest dataset of the study. *Gender specific. References: [1–39]

Tang et al., 2012

25:14 IHC; medulla

# BDNF in DMNV & NTS " TrkB in DMNV & AN*

Kadhim et al., 2010

Rognum et al., 2009

Kadhim et al., 2003 19:8 IHC; medulla Growth factors and immunological (cytokine) markers IL-1b, TNF-a Pro-inflammatory cytokine

Serotonin; 5-HT transporter 5HTT

Respiratory, sleep & arousal control Respiratory, sleep & arousal control Respiratory, sleep & arousal control Respiratory control.

30:7

" IL-1b in DMNV & AN TNF-a: No difference. " IL-6R in AN Gp130- No difference. No difference

Duncan et al., 2010 Ozawa and Okado 2002 Paterson et al., 2006 35:5 31:25

RLB; medulla. IHC; midbrain, pons & medulla RLB; medulla. Serotonin; serotonergic 5-HT2A

Respiratory, sleep & arousal control Respiratory, sleep & arousal control

16:7 RLB; medulla.

# in DMNV, NTS, Vest, Cun, & ION # in raphe, AN, NTS, medial accessory ON, & XII # in XII, DMNV & NTS # in DMNV, NTS and VLM, " in PAG No difference. 53:17 IHC; medulla

Results: SIDS vs Controls # of cases SIDS:Controls Experimental Method & level of brainstem General Functional significance Specific neurotransmitter and receptor system Enzyme, transmitter or ligand analysed

Table 1 (Continued )

Machaalani et al., 2009 Paterson et al., 2006


References

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growth or cytokine system studied, method of experimental procedure and analysis used, number of cases included, and the results of the study [1–39]. NEUROPATHOLOGY OF SIDS The focus on brain abnormalities in SIDS is strong because physiological studies of infants who subsequently died of SIDS indicate abnormalities in cardiopulmonary and sleep waking function. A common pathway to explain the origin of these abnormalities would be altered control of these functions, at the level of brainstem nuclei since it is within these nuclei that pathways that control ventilation, cardiac activity, as well as initiating pathways for sleep and arousal control are located. While SIDS may result from a brain abnormality or maturational delay in brain regions responsible for cardiorespiratory control, it has been very difficult to prove because, using conventional histopathological criteria, the SIDS brain is ‘‘normal’’ or has only non-specific lesions. A major challenge in SIDS brain research is, therefore, to locate and identify specific brain lesions. If a brain abnormality exists to explain the cause for sudden death, more refined analysis with quantitative cellular, neurochemical, and/or molecular tools appears to be necessary for it to be detected. A number of studies have now reported neuropathological findings in SIDS victims using non-standard histological techniques (reviewed [41]), and which taken together, suggest that brain abnormalities are present in SIDS victims. Brainstem Chemical Neuropathology (Table 1) Studies for neurochemical abnormalities in the brainstem of SIDS infants were initiated in the 1980’s. The neurotransmitters selected for study had their functional role in the brainstem established in prior animal studies. For example, serotonin (5HT) and acetylecholine (ACh) were found to facilitate respiration [42,43] whereas epinephrine (Epi), otherwise known as adrenaline, and norepinephrine (NE), also known as noradrenaline, depressed respiration [44]. For blood pressure and cardiac control, 5HT/ACh and Epi/NE interacted in opposition to one another [42,45]. Furthermore, it was shown that 5HT, Epi and NE were also involved in sleep organization [46,47]. Dopamine was found to be involved in stimulating respiration while the peptide neuromodulator substance P (SP) [48], endogenous opioids (endorphins and enkephalins) [49] and growth factor brain derived neurotrophic factor (BDNF) [50] were found to be involved in central control of respiration. More specific roles for these neurotransmitters and modulators according to their particular brainstem location have since been identified and can be found in many recent neuroanatomy text books, but because this is still an evolving field, many more roles are yet to be determined. The first report on neurochemical abnormalities in the SIDS brainstem was in 1983. All neurochemical findings since then are summarised in Table 1. The enzymes, transmitters or ligands, and growth factors or cytokines analysed have been tabulated under one of the following 6 categories: catecholamine, neuropeptide, acetylcholine, indole amine, amino acid, and growth factor and cytokines. The order in which they are presented represents the trend and time sequence in which the neurochemicals were studied over the last 30 years. The specific neurotransmitter and/or receptor analysed has been specified, as has its general functional significance. The experimental methods employed are restricted to one of the following five: 1. Radioimmunological assay (RIA) which involves homogenizing tissue to determine protein content,


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2. Immunohistochemistry (IHC) where tissue sections are stained for the respective protein of interest, and staining is either qualitatively or quantitatively analysed, 3. In-situ hybridisation (ISH) where tissue sections are stained for the respective mRNA of interest, and staining quantitatively analysed, 4. Radioactive ligand binding (RLB) which involves studying a radioactively labelled receptor ligand binding to the receptor of interest. The level of binding is determined by the amount of radioactivity emitted, and 5. High performance liquid chromatography (HPLC) of homogenized tissue to quantitatively determine protein content. Earlier studies mainly employed the RIA method, whereas recent studies have moved to employ RLB, HPLC, IHC and ISH methods (Table 1). Although many of the studies were conducted at the level of the medulla, other parts of the brainstem have been studied. The majority of studies compared SIDS infants to all infants who had died from a known cause and who were denoted as ‘‘controls’’. However some studies by Kinney’s group separated their control group into two; one comprising infants who died of a known cause and who had experienced acute hypoxia (acute controls) while the other comprised infants who had experienced chronic hypoxia (chronic controls) prior to death. The purpose for this separation was to rule out chronic hypoxia prior to death as a contributing factor for the neuropathological changes observed in SIDS infants. The results showed that overall, there was no difference between the two hypoxic groups and if a difference was evident in the SIDS group, it was consistent with both these hypoxic groups [12,13,25,33]. Changes in each of the five neurotransmitter categories have been found in the SIDS brainstem but no definitive conclusion can be made with regards to these findings since most of them have not yet been verified or the results have been inconsistent amongst studies, mostly due to differences in experimental methodologies. An important emerging distinction is whether the abnormalities reflect aetiological factors for SIDS or whether they are also a consequence of the risk factors associated with SIDS. Thus, it seems likely that the changes, which in most of the studies have actually been stated as being present in ‘‘some’’ and not all of the SIDS infants, are caused by associated risk factors. Regardless, there is now a body of evidence to support the contention that neurochemical pathologies exist in the SIDS brainstem, and that these affected regions are known to be involved in respiratory, cardiac, sleep and arousal control. Some of the more convincing findings in the SIDS brainstem compared to non-SIDS (based on the reproducibility of the results and moderate number of cases studied) include: Of the catecholamines, a decrease in tyrosine hydroxylase (TH). Although two studies showed no changes in TH [15,28], two other independent studies found it to be decreased in several nuclei of the medulla including the dorsal motor nucleus of the vagus (DMNV) and nucleus of the solitary tract (NTS) [27,29]. Of the neuropeptides, an increase in substance P. Three out of five studies showed an increase in SP in the medulla [1,26] and pons [39]. This increase seemed to be specific to nuclei of the trigeminal system [26,39]. Of the acetylcholinergic system, a decrease in muscarinic receptor binding [13] and number [17], specifically in the arcuate nucleus (AN). A third study [23] showed there to be no differences but was restricted in that they only studied for one receptor subtype. Of the amino acids, a decrease in kainite [33] and GABAergic receptor binding [2] but an increase in NMDA receptor

5

1 expression [22]. However, these findings are based on one study only per ligand so further studies are required to verify data concerning the amino acids. Of the indole amines, a decrease in serotonin receptor binding [6,14,32] and expression [20,30] in several nuclei of the medulla and pons, including the DMNV, AN and raphe. Of the cytokines and growth factors, an increase in IL-1b [11] and IL-6R [35] and decrease in BDNF in the DMNV, AN and NTS [38].

BRAINSTEM NUCLEI OF INTEREST (FIGURE 1 AND TABLE 2) Of all the brainstem nuclei analysed in the studies summarised in Table 1, the emerging pattern of the main nuclei involved in the pathophysiology of SIDS include the DMNV, NTS, AN and raphe; all nuclei located within the medulla, with the exception of the raphe which extends into the pons (Figure 1). As can be seen in Table 2, more changes have been found in the DMNV and NTS, keeping in mind that the AN and raphe were only studied after the findings of Kinney’s group and the start of 5HT research in SIDS. The DMNV functionally contributes to the efferent parasympathetic function of the vagus nerve. It innervates organs to induce various parasympathetic functions based on the level of the medulla, with the rostral DMNV predominantly involved in respiratory control while the intermediate to caudal level is involved in cardiac control (reviewed [51]). SIDS infants have been reported to have altered heart rate [52] and respiratory responses [53,54], suggesting possible physiological expression of the neurochemical findings in the DMNV of SIDS infants. The NTS is the first central site where cardiovascular reflexes regulating blood pressure and fluid balance are coordinated [55]. The NTS is the primary site of termination of afferent fibres arising from many cardiovascular receptors, including those in the aortic nerve, carotid sinuses and bodies, and is also a major site of termination for second-order neurons receiving inputs from many other visceral and somatic receptors (reviewed in [56]). Centrally, the NTS receives afferent inputs from many brain regions including the cortex, hypothalamus, parabrachial complex nuclei of the pons

Table 2 Summary of the findings predominating in four brainstem regions when comparing SIDS to non-SIDS.

Catecholaminergic DBH TH PNMT AR a2A-C Peptidergic Substance P Neurotensin Cholinergic CHAT mAChR nAChR a7 & b2 Glutamatergic Kainite Receptor GABA-A Receptor NR1; NMDA Receptor Serotonergic TPH 5HT1A receptor 5HT2A receptor LSD binding Cytokine & growth factor IL-1B IL-6R BDNF TrkB

DMNV

NTS

# # # #

# # # #

AN

Raphe

" " # # # # #

#

"

# #

# #

" # "

#

" #

#

#

" " # "


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Fig. 1. The brainstem and representative section at the caudal medulla showing nuclei of interest. A) Lateral view of the brainstem showing the four nuclei of interest in rostral caudal dimension, and B) caudal medulla (obex or closed medulla) at the level of the purple line in figure A. Abbreviations in alphabetical order: Acc olv, accessory olivary nucleus; AN, arcuate nucleus; CC, central canal; Cun, cuneate nucleus; DMNV, dorsal motor nucleus of the vagus; Gr, gracile nucleus; ION, inferior olivary nucleus; NSTT, nucleus of the spinal trigeminal tract; NTS, nucleus of the tractus solitarus; Pyr, pyramids; XII, hypoglossal nucleus.

and the area postrema. In turn, efferent outputs return to the same regions or various other ones. Projection from the NTS to the DMNV are of particular interest since they innervate the preganglionic spinal neurons of the sympathetic system involved in blood pressure regulation [57]. Altered sympatho-vagal balance [58] and prolonged QT interval [59] in subsequent SIDS infants, may be a cause of the abnormal neurochemical expression of at least one marker in all the transmitter system groups that have been studied, with the exception of cytokines that were not altered in the SIDS NTS (Table 2). The AN is located near the surface of the ventrolateral, ventral and ventromedial medulla and believed to have a role in cardiovascular control. It is a well-defined area in the human brainstem but not in experimental animals. In some animal species, like the cat and rat, neurons that occupy locations homologous to the human AN have been given various names depending on species, including the nucleus paragigantocellularis lateralis and ventral raphe pallidus [60]. In the cat brainstem, the homologous region to the AN is involved in protective responses to hypercapnia and asphyxia, and projects to the medullary raphe, the NTS and nucleus ambiguus, evoking hypotension and often bradycardia [61]. The finding that there are abnormalities in the expression of the cholinergic, glutamatergic, serotonergic and cytokine systems of the SIDS AN, supports the findings of abnormal responses to hypercapnia and evidence of bradycardia [62,63] as has been reported in some near miss SIDS infants. The raphe nuclei located along the midline of the medulla extending into the pons, synthesize 5HT and are the source of endogenous 5HT. Serotonin released by neurons of the raphe, modulates respiratory network function, but whether it is an excitatory or inhibitory effect is dependent on the various receptor subtypes 5HT acts on [64]. The raphe also regulates chemoreception [65] and respiratory responses to CO2 [66]. Thus, respiratory abnormalities identified in infants who subsequently died from SIDS, particularly decreased chemoreception and altered hypercapnic responses [62,63], could potentially reflect altered expression of 5-HT and its receptor in the raphe nuclei.

confirmed independently by Oehmichen et al., [69] who also found increased Alz-50 in the medulla of a different SIDS dataset. Using TUNEL as a specific marker for apoptosis, we were the first to report that apoptosis was increased in a Canadian cohort of SIDS compared to non-SIDS infants, in both the medulla of the brainstem, and the hippocampus [71]. Of the 29 SIDS cases, 96% showed an increase in TUNEL positive neurons. The distribution of this increase was mostly in dorsal nuclei of the medulla (nucleus of the spinal trigeminal tract (NSTT) and vestibular nuclei) at both the caudal and rostral levels, and CA1 and CA4 hypoxia sensitive regions of the hippocampus. The distribution of the apoptosis suggested a link between apoptosis and hypoxia. The prone sleeping position is also possible, because the NSTT and vestibular nuclei are involved in sensory relay of body movement and sensation. Soon after, a quantitative analysis of TUNEL staining in glial cells of the periaqueductal gray matter at the midbrain level [70] showed that SIDS infants had a greater number of TUNEL positive glial cells compared to controls. This increase was associated with a high frequency of obstructive apneas documented in the same infants during life. Given that the midbrain periaqueductal gray matter is associated with the ‘‘visceral alerting response’’, this group concluded that their findings indicated a possibility of dysfunction within the arousal pathway. We extended our studies of TUNEL expression in a larger Australian cohort of SIDS infants (67 SIDS vs 25 non-SIDS) [67]and studied an earlier specific marker of apoptosis, active caspase-3 [67,68]. We found that active caspase-3 was increased in the DMNV and hypoglossal (XII) nucleus, and TUNEL in the AN, with additional findings that cigarette smoking increased TUNEL in the DMNV and AN while prone sleeping correlated with increased TUNEL in the cuneate nucleus [68]; this latter being consistent with the findings in the Canadian cohort [71]. Together these studies suggest downstream pathways resulting in apoptosis of physiologically important neurons that lead to the loss of function and cellular death as recently reviewed [51].

CONSEQUENCE OF NEUROCHEMICAL IMBALANCE- APOPTOSIS

Evidence of abnormal neurochemical expression in the brainstem of infants who died from SIDS supports the hypothesis that many SIDS victims have an underlying immaturity, abnormality, or delayed development within the central nervous system. The areas of focus regulate many important physiological parameters. The four nuclei with most consistent abnormalities are the DMNV, NTS, AN and raphe, which have important roles in cardiorespiratory control and chemosensation. Finally, changes appear to culminate at the cellular level in apoptosis.

To date, six studies have looked for changes in neuronal cell death markers in the brainstem of SIDS infants [41,67–71]. Using Alz-50 as a marker, Sparks et al., [72] found an increase in Alz-50 immunoreactive neurons in regions of the dorsal medulla (mid medulla level) in SIDS infants when compared to the controls. They proposed that this increase in Alz-50 reflected an increase in apoptotic neurodegeneration in SIDS. These findings were later

CONCLUSION


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RESEARCH DIRECTIONS Combining new experimental methods with ongoing evaluation of the brain; for example proteomics would allow the study of many proteins simultaneously. Limited studies provide enticing preliminary data Studies of more extensive brain regions that control sleep and arousal (particularly at the level of the pons) with markers including orexin.

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Sudden infant death syndrome (SIDS) and the immune response.

Sudden infant death syndrome (SIDS): a time lag factor.

Sudden infant death syndrome (SIDS) and disordered blood flow.

Cardiac abnormalities and sudden infant death syndrome.

Cardiac and other abnormalities in the sudden infant death syndrome.

Evolution and sudden infant death syndrome (SIDS) : Part I: Infant responsivity to parental contact.

Evolution and the sudden infant death syndrome (SIDS) : Part II: Why human infants?

Hypophosphatemia and sudden infant death syndrome (SIDS)--is ATP the link?

Evolution and the sudden infant death syndrome (SIDS) : Part III: Infant arousal and parent-infant co-sleeping.

Ontogeny of peptides in human hypothalamus in relation to sudden infant death syndrome (SIDS).

Sudden infant death syndrome.

Sudden infant death syndrome.

Sudden infant death syndrome.

Sudden infant death syndrome.

Sudden infant death syndrome.

body weight ratio in sudden infant death syndrome (SIDS).

Maternal substance use and subsequent sudden infant death syndrome (SIDS) in offspring.

Beta-endorphin and neurotensin in brainstem and cerebrospinal fluid in the sudden infant death syndrome.

proton exchanger 3 (NHE3) and sudden infant death syndrome (SIDS).

Child Protection Registration and siblings, diagnosed as sudden infant death syndrome (SIDS)

Sudden infant death syndrome temperament before death.

The sudden infant death syndrome and infant botulism.

Seasonal variation in sudden-infant-death syndrome.

Sudden infant death syndrome in China.