Introduction

Sudden infant death syndrome (SIDS) has a complex and heterogeneous pathogenesis, with multiple abnormalities in a number of physiological functions and systems including neurological, cardiovascular, respiratory, gastrointestinal, nutritional, endocrine, metabolic, infectious, immunological, environmental, and genetic (1-7). Typically, without warning, an apparently healthy infant is found deceased sometime after being placed to sleep (8). there are many theories involving animal and human studies that have attempted to understand the pathophysiology of SIDS. Unfortunately, to date, there are no biomarkers available to aid in the prevention or definitive diagnosis of SIDS. the aim of much scientific research has been to determine the mechanisms of failure in SIDS infants that are undetectable prior to death and that remain just as unclear following death. While the precise cause of death in infants dying of SIDS has not been identified, there is considerable evidence that the syndrome results from a combination of circumstances involving [1] a cardiorespiratory challenge that occurs in [2] a neurologically compromised infant at [3] a specific period of postnatal development (3, 9, 10). The following chapter will focus on the failure of cardiorespiratory and autonomic control associated with neuropathology of the brainstem in SIDS.

An important step in understanding the complex pathophysiology of SIDS was the establishment of the Triple Risk Model, which successfully conceptualized the epidemiological, physiological, and neuropathological data associated with SIDS. the Triple Risk Model proposes three coinciding factors: [1] an underlying vulnerability of the infant; [2] a critical developmental period in homeostatic control that the infant is transitioning through; and [3] the application of an exogenous stressor/s such as an asphyxiating environment (11). the model implies that an infant may be most at risk of SIDS when all three factors are simultaneously present (8, 11). All three factors contribute to the risk of an adverse event that occurs suddenly in an otherwise “healthy” infant. therefore, consideration of the Triple Risk Model is of key importance to SIDS research, with the model providing a foundation upon which researchers can build in the generation of research hypotheses.

The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life.

Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration.

This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system.

Abstract

Magnesium status is highly associated with stress levels, with both stress and hypomagnesemia potentiating each other's negative effects. Indeed, hypomagnesemia has been associated with stressful conditions such as photosensitive headache, fibromyalgia, chronic fatigue syndrome, audiogenic stress, cold stress, and physical stress, amongst others. The role of magnesium in these conditions is unclear, although a number of potential mechanisms for magnesium's action have been identified including via the glutamatergic, serotonergic, and adrenergic neurotransmitter systems, as well as via several neurohormones. The current review examines the link between magnesium deficiency and stress, focusing on the association between magnesium and various stress pathologies, magnesium's potential interaction with stress pathways, and magnesium's effects on the brain.

Introduction

At the beginning of the twentieth century, Walter Cannon pioneered research concerning the importance of the sympathetic nervous system in adaptation of the body. While Claude Bernard was the first who defined the term of “milieu interieur” as being “the constancy of the internal environment” (see Cameron, 2007), it was Walter Cannon who coined the terms “homeostasis” and “fight-or-flight response” (see Quick, 1994). Subsequently, Hans Selye (see Neylan, 1998) in 1936 adapted a concept from physics describing the resistance of a body to applied pressure in order to define the concept of stress. General adaptation syndrome, as he called it, is the non-specific response of the body to any demand for change.

Abstract

The finding that magnesium levels are reduced in acute and chronic brain diseases has led to a recent surge in interest in the role of magnesium in the normal and injured nervous system, although the mechanisms of magnesium decline in pathological conditions and its availability in the neural tissue after administration are not fully understood. The brain has two main barrier systems: (1) the blood-brain barrier (BBB) formed by brain capillary endothelial cells which separate the blood from the extracellular fluid in the neuropil; and (2) the blood-CSF barrier (BCSFB) formed by choroidal epithelial cells which separate the blood from the CSF. Genetic studies in families with hereditary hypomagnesemia have identified mutations in two genes encoding claudin-16 (paracellin-1) and claudin-19, both localized at tight junctions between nephron epithelial cells and providing passive paracellular conductance for magnesium in the kidney. Endothelial cells of the BBB also express claudins, although whether members of the claudin family expressed at the BBB and BCSFB have similar conductance for magnesium akin to the role of claudin-16 and -19 in the nephron remains to be confirmed. Recently, the transient receptor potential melastatin (TRPM) members TRPM6 and TRPM7 have been identified as cation channels for magnesium transport. Although it is not known if choroidal epithelial cells express TRPM6 and TRPM7, these molecules are expressed by brain endothelial cells and may play a role in magnesium transport. While it is evident that magnesium enters the CNS through the BBB and is actively transported by choroidal epithelial cells into the CSF, the mechanisms of its entry into the brain will require further investigation.