© 2003 American Thoracic Society
Impaired Arousals and Sudden Infant Death SyndromePreexisting Neural Injury?*Department of Neurobiology and the Brain Research Institute David Geffen School of Medicine at UCLA Los Angeles, California In a report on the spontaneous incidence of "full" arousals (those accompanied by electroencephalographic signal changes) and incomplete or "subcortical" arousals (arousals with cardiovascular or momentary muscles signs, but not electroencephalographic desynchronization), Kato and colleagues, in this issue of the Journal (1), raise several important issues in the description of developmental sleep physiology in infants who later succumb to sudden infant death syndrome (SIDS). The dataset examined in this study could only be described as extraordinary; namely, a subset of a very large number of infants who had undergone earlier all-night polysomnographic recording, not just heart rate and respiratory monitoring; this subset later succumbed to SIDS. The recordings were collected from 10 hospitals in Belgium; the database was sufficiently large (more than 20,000 infants) that a large sample of SIDS victims (n = 16) became available for study; a significant achievement, considering the now relatively low incidence of SIDS in the general population. The large numbers of initial recordings also ensured adequate matching with control subjects. The major findings suggest that homeostatic systems that recruit forebrain participation may exert a protective role in restoring vital functions when SIDS-susceptible infants are physiologically challenged. The data indicate a diminished incidence of spontaneous full arousals, those associated with activation of neocortical electroencephalographic signals, during sleep in future victims. Assigning the full arousal process a protective role as a means to maintain respiratory integrity during sleep has been proposed earlier for adult breathing patterns (2), and directs attention to potential failing mechanisms in developing infants. The study of Kato and coworkers (1), however, also demonstrates that arousal processes that do not incorporate neocortical signs, "subarousals," occurred more frequently in later SIDS victims. This finding may be a key to determining pathologic processes in the syndrome. Increased numbers of subarousals suggest processes that are unable to dampen or filter stimuli that normally are suppressed during sleep, and hence trigger muscle or heart rate responses. We could speculate that several mechanisms may underlie the increased incidence of subarousals; however, undampened release of motor, cardiac, and neural signal patterns occur in response to loaded breathing following the cerebellar damage that accompanies disordered breathing in adults (3, 4). Routine stimulation of the body, encountered during sleep, might elicit undampened muscle and cardiovascular responses, a hallmark of cerebellar damage, if similar neural damage occurred in infants. Such damage might emerge after cerebellar maldevelopment, or an earlier undetected hypoxic or ischemic event. Cerebellar structures are especially sensitive to injury from such events (5). In SIDS victims, a principal nucleus which projects to cerebellar structures, the inferior olive, shows prenatal brainstem injury (6); infants who succumb also show delayed cerebellar cortex development (7). The functional deficits shown by Kato and coworkers (1) in future SIDS victims appear to have a basis in structural damage. The cerebellar processes that may mediate the undampened subarousal responses could play a role in diminishing the numbers of full arousals in future SIDS victims. Deficient influences from cerebellar deep nuclei projections to thalamic sites have the potential to modify thalamocortical interactions, and thus alter cortical synchronization. Several other ascending arousal systems, however, affect cortical activation, and some use ventral pathways, bypassing the thalamus, and incorporate input from limbic structures to elicit activation (8). Multiple neural sites, including neocortical and limbic regions regulating arousal-related cardiovascular and electroencephalographic responses, are both structurally and functionally compromised in adults with a history of disordered breathing (3, 4). The potential for involvement of these multiple cortical arousal systems in the fatal events of SIDS remains to be clarified. The findings further demonstrate that arousal deficiencies are present at least six weeks before death, reinforcing a suspicion from multiple sources that, although future SIDS victims present an apparently unremarkable physical condition before the fatal event, subtle physiologic deficits are present much earlier. Indeed, other evidence suggests that abnormalities exist from fetal life: prenatal nicotine exposure is a significant risk factor for the syndrome (9), and aberrant respiratory patterns are present shortly after the first month of life (10). The deficient arousal responses should be viewed in the context that the infants are physiologically compromised for some time before death from SIDS occurs. Any indication of physiologic differences that predict which infants are at risk for SIDS should be of immediate clinical interest. It is important to note, however, that despite the importance of these data in determining failing systems in SIDS, the described deficiencies required assessments of all-night sleep patterns, identification and partitioning of sleep state (quiet sleep or rapid eye movement sleep) and measures of transitions from one state to another, in addition to the physiologic signal evaluation. Such an assessment is not achieved in an acute examination, but requires long-term signal acquisition with multiple physiologic measures, and necessitates evaluation of those changes against a substantial database of normative data. The findings direct attention to potential defective mechanisms underlying the syndrome, suggest that reflexive brainstem compensatory mechanisms for arousal are aberrant, and that processes that recruit neocortical regions are lacking. Examination of processes by which critical challenges incorporate these ascending pathways may be of benefit in evaluating vital functions during sleep. FOOTNOTES Supported by a grant (HD-22695) from the National Institute of Child Health and Human Development. Conflict of Interest Statement: R.M.H. has no declared conflict of interest. REFERENCES
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