Sleep-disordered breathing (SDB) has emerged as a major public health problem. Indeed, several studies suggest that 2–3% of children between 2 and 8 years of age, 5–7% of male middle-aged adults, and more than 15% of all people aged 65 years or older are affected (1), even when rather restrictive diagnostic criteria are used. Although substantial research over the last two decades has provided invaluable insights on the pathophysiology of SDB, it is becoming increasingly clear that a single mechanism cannot explain the presence or absence of the condition in the average patient. Several putative mechanisms would appear to be operative at the same time to induce the decompensation of naturally occurring and system-embedded redundancies that routinely preserve upper airway patency. In other words, none of the increased mass effect secondary to obesity, reduced upper airway dilator motor tone during sleep, altered chemosensitivity, and reduced mandibular and nasopharyngeal size can singly explain the occurrence and progression of SDB. Therefore, interactions between these pathophysiologic factors, to name just a few, need to occur. Coincidentally, initial genetic population linkage studies suggest the occurrence of multiple genes as being involved in SDB and further reinforce the concept of cross interactions between multiple genetically determined elements in SDB (2).
Is it then possible that genetically related alterations leading to abnormal neuronal proliferation or to premature neuronal cell loss within particular brain regions mediating sleep, upper airway motor control, and/or cardiorespiratory regulation could be implicated in SDB? Could primary abnormalities occurring in brain organogenesis or during postnatal development lead to specific alterations in the functional characteristics of the “upper airway patency module” and provide a unifying link between a primary central nervous system abnormality and the generation of the SDB phenotype?
This provocative possibility is now raised by the study of Macey and colleagues (3) in this issue of AJRCCM (pp. 1382–1387). Indeed, the authors report on the presence of unilateral gray matter losses in regions such as the left ventrolateral frontal cortex, a well-established region modulating upper airway motor function, the anterior cingulate cortex, and the cerebellum, which is a brain structure that plays major roles in cardiovascular and respiratory control. These findings raise the tantalizing possibility that the changes in gray matter hint at mechanisms for the genesis of the SDB syndrome, likely in concert with anatomic features but certainly playing a role in the progression of a compromised oral airway environment leading to a condition of certain upper airway failure. The evidence is inferential and speculative but clearly intriguing. Much of the gray matter loss reported by Macey and colleagues (3) occurred in well-perfused sites, was situated unilaterally, or emerged in discrete, rather than diffuse, regions—a scenario not usually encountered, and certainly not anticipated, with hypoxic damage. The loss also preferentially targeted areas associated with upper airway function, including expressive areas for speech, a particular aspect of interest because 38% of their patients showed stuttering or speech impediments from childhood. The mechanism(s) by which such specific and localized regional targeting was achieved are unclear but direct the search for origins of SDB to an earlier stage of life (4), thereby raising the possibility of developmental contributions or neural insults as major pathophysiologic issues underlying the SDB syndrome.
Is there any evidence to support such a heretic possibility? Most of the now well-established occurrences of neural deficits in SDB patients would suggest otherwise. For example, aberrant sensory processing of stimulation to the upper airway (5, 6), impaired autonomic responses (7), or the recent demonstration of a reduction in apnea by atrial pacing (8) implicates deficits in central neural mechanisms. These neural deficits have thus far been justifiably assumed to represent a consequence of SDB rather than to precede the syndrome. Perhaps the time has come to reverse our thinking.
An additional important implication of this study relates to the potential location of brain regions affected by the typical alterations that accompany SDB, namely, episodic hypoxemia, hypercapnia, and arousal from sleep. These affected regions most likely underlie the prominent neurobehavioral deficits that occur in both pediatric and adult patients with SDB and involve a wide range of behavioral, language, and cognitive skills. The anatomic findings reported by Macey and coworkers (3) suggest dysfunction in Broca's language area, the hippocampus, a structure implicated in recent memory functions, the frontal and cerebellar cortices, associated with a range of cognitive aspects and processes involved in selective inhibition of motor expression, important for Attention Deficit Disorder, and limbic structures, such as the anterior cingulate gyrus, which are involved in emotional expression (9). There is no doubt that some of the gray matter loss, particularly that affecting bilateral structures, may indeed derive from repeated exposure to low oxygen, and the evidence from intermittent hypoxia exposure in animals provides a basis for understanding such processes, particularly in specific sites of the hippocampus and cortex (10).
In conclusion, although anatomic contributions, including obesity, diminished nasal airway or oropharyngeal dimensions, or a recessed mandible, appear be primary features of SDB, certain characteristics of the brain of SDB patients suggest that primary central neural dysfunction contributes to the genesis, maintenance, and progression of the syndrome and that secondary neural deficits may underlie the range of cognitive and behavioral symptoms frequently encountered in afflicted cases. Until we determine what is primary and what is secondary in the brains of SDB patients, we can only speculate on the order of appearance of the chicken and the egg.
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