Structural mechanisms underlying autonomic reactions in pediatric arousal

Sleep Medicine 3 (2002) S53–S56 www.elsevier.com/locate/sleep

Structural mechanisms underlying autonomic reactions in pediatric arousal Ronald M. Harper*, Christopher A. Richard, Luke A. Henderson, Paul M. Macey, Katherine E. Macey Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095-1763, USA

Abstract Arousal provides an essential means to restore homeostasis following a system perturbation during a quiescent state. The classic definition of ‘arousal’ includes a constellation of cardiovascular, respiratory and somatic muscle characteristics, together with activation of the electrocorticogram (ECoG). At least two ascending activating systems, a ventral cholinergic and a serotonergic ascending system, both interacting with other regional neurotransmitter processes, contribute to electrocortical activation, with separate behaviors mediated by each system. A number of ‘arousal’ processes essential for survival operate at local levels, and interact with the systems that mediate cortical activation. These processes include cerebellar compensatory mechanisms which respond to extreme cardiovascular challenges, and limbic structures which respond to hypoxia or hypercarbia and the resultant dyspnea. The local processes show exceptional cortical arousing properties upon recruitment of some structures, such as the amygdala, which has major projections to ascending arousal systems. Components of arousal can emerge without ECoG activation and can be mediated at local levels which interact with ascending systems. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Hippocampus; Cerebellum; Cholinergic; Serotonergic; Sleep; Sudden infant death syndrome

An examination of neural mechanisms underlying arousal must consider that the usual definition of ‘arousal’ includes a constellation of physiologic responses including variation in heart rate, increased blood pressure and muscle tone, a sustained inspiratory effort or breathing pause, and activation of the electrocorticogram (ECoG). Arousal has been considered an essential element for restoration of homeostasis during respiratory and cardiovascular challenges to physiologic systems by providing an excitatory drive to vital processes. Although cortical activation has been a ‘gold standard’ for definition of arousal, it may be also useful to consider a range of responses as ‘sub-arousals’ without such ECoG patterns. Activation of the ECoG represents the classic ‘signature’ of arousal in children. However, somatosensory and auditory stimuli often result in cardiac, respiratory or somatic changes without overt activation [1]. Apneas are frequently terminated without arousal in either children or adults [1–3], with such terminations usually resulting in heart rate acceleration. The concept that arousals include a range of physiologic responses has partially developed from revised descriptions * Corresponding author. Tel.: 11-310-825-5303; fax: 11-310-825-2224. E-mail address: [email protected] (R.M. Harper).

of ascending activation systems underlying cerebral cortical activation and wakefulness. The classic descriptions of the arousal system, with the reticular formation projecting to midline and intralaminar thalamic structures, which in turn activates the cortex [4], are no longer tenable for understanding the full range of physiologic responses associated with arousal, and do not adequately account for the current evidence from lesion, pharmacologic and recording studies [5]. Prominent among this evidence are demonstrations that (a) large thalamic lesions in animal and man do not prevent cortical activation [6,7]; (b) cortical activation returns following removal of the forebrain from the reticular formation (cerveau isole´ preparation) [8]; and (c) cortical activation by thalamic stimulation is dependent on the integrity of more-caudal structures [9]. Vanderwolf and colleagues (see Refs. [10,11] for reviews), in particular have defined arousal roles for a ventral cholinergic system, with neurons sited in the basal forebrain, and a serotonergic ascending projection system which arises from the midline raphe. These systems bypass the thalamus and alter cortical activity directly. Although corticothalamic interactions can result in synchronization and activation, a large body of evidence suggests that many of these responses are partially mediated through interactions with cholinergic and serotonergic ascending systems [11]. Dopamine, histamine and noradrenergic

1389-9457/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 1389-945 7(02)00166-1

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systems can also activate cortical activity, likely by effects on the cholinergic and serotonergic systems, and should be considered within any discussion of arousal systems. Knowledge of systems which contribute to maintain arousal continues to develop; recent findings of peptide roles, e.g. hypocretin influences on motor activation (in addition to the remarkable relationship of this peptide to narcolepsy), represent one such addition [12,13]. Cholinergic and serotonergic projections appear to mediate separate behavioral and electrographic components. Pharmacologic partitioning of neurotransmitter effects can elicit behavioral characteristics associated with aroused behavior, but with the ECoG characteristics of quiet sleep; a classic example is that of the extreme behavioral alertness found after large-dose atropine sulfate administration in animals, a condition that is nevertheless accompanied by very large slow waves on the cortex [14]. Hippocampal patterns typically exhibit rhythmical slow ‘theta’ waves during alert behaviors such as grooming and chewing; this pattern is abolished with cholinergic blockade; but, a higher frequency form of theta returns if the animal voluntarily moves [15]. The cortex becomes activated concurrently with the faster-frequency synchronous theta pattern associated with such movements. Simultaneous blockade of serotonergic and cholinergic systems results in abolition of the higher frequency hippocampal theta and no cortical activation to behaviors [11]. Forebrain influences on brain stem output nuclei mediating autonomic and motor control, such as hypothalamic thermal drive and amygdala central nucleus effects on blood pressure, are lost or greatly diminished during rapid eye movement (REM) sleep [16,17]. The loss of descending influences during REM sleep effectively ‘releases’ medullary structures from modulation by forebrain structures, and places the subject at some risk during certain challenges. An inability to increase respiratory rate during hyperthermia, for example, could have significant consequences for survival unless arousal or transition to quiet sleep (QS) occurs. Other medullary structures appear to become ‘undamped’ during REM sleep; the rostral ventral medullary surface (RVMS) exhibits exaggerated responses to cardiovascular challenges during the REM state [18]. Deficits in the RVMS may result in uncompensated cardiovascular responses if normal modulation by forebrain or other structures is lost during REM sleep. Many of the compensatory efforts taken to overcome prolonged apnea or severe loss of blood pressure during sleep are initially mediated by local neural actions. These local actions have the potential to include an arousal component, and use anatomic properties suited to induce ECoG activation. Baroreflex mechanisms normally serve to maintain blood pressure from momentary variation; significant blood pressure variation results in changes in afferent input that lead to autonomic or somatic responses indistinguishable from patterns occurring during arousals with cortical activation [19]. Less marked changes in arterial

pressure result in similar autonomic and respiratory changes, and alter somatic muscle tone without necessarily eliciting ECoG activation. Lowering of blood pressure evokes increased heart and respiratory rates, while hypertension elicits heart rate slowing and apnea; if the blood pressure elevation is substantial, activation occurs [20]. The physiologic alterations to blood pressure manipulation are partially mediated through RVMS action, which shows dramatic changes in activity with blood pressure alteration; RVMS activity declines to blood pressure elevation and increases to depressor challenges [18]; sub-arousals and overt arousals to blood pressure change cause a sharp rise in activity [19]. Should blood pressure reductions be very large, the normal compensatory mechanisms of increasing heart rate may be inadequate to restore cardiovascular homeostasis. Severe hypotension can develop in cases when the baroreflex is ineffective, such as conditions of shock produced by bacterial infection, deep pain or blood loss. During such extreme blood pressure alterations, cerebellar actions are significant. Cerebellar sites play a role in ‘error correction’ of movement, and particular nuclei, especially the fastigial nucleus, appear to exert similar corrective action in extreme hypotension and prolonged apnea [21,22]. Cerebellar structures have previously been implicated in the expression of arousal reactions [23], and in interacting with vagallymediated respiratory responses [24]. Afferent traffic modifying cardiovascular and respiratory patterns can reach the cerebellum through vagal afferents and through vestibular and other inputs via the inferior olive [25,26]. The latter structure gives rise to climbing fibers to the cerebellar fastigial nucleus and Purkinje cells. The fastigial nucleus projects to the medial reticular formation, intralaminar nuclei of the thalamus, superior colliculus and parasolitary nuclei, and sparsely to the hypothalamus [27–29]; its destruction results in death in response to uncompensated hypotensive challenges [21]. The climbing fibers from the inferior olive are extraordinarily sensitive to ischemia, and when damaged, can result in severe motor deficits [30]; such damage offers a potential mechanism for an inability to respond to severe hypotension from endotoxic or other shock processes [21]. The ‘error correction’ function of cerebellar sites is especially prominent with profound lowering of blood pressure, e.g. by hypovolemia, a challenge which results in extreme activation of somatic musculature and marked changes in breathing, with both tachypnea and exaggerated inspiratory efforts recruited in attempts to overcome the loss of blood pressure [31]. Delayed development, damage, or indications of enhanced apoptosis in cerebellar or cerebellar-related structures (e.g. cerebellar cortex, vermis, inferior olive, vestibular nuclei) are associated with a variety of developmental breathing disturbances during sleep and with the sudden infant death syndrome (SIDS) [32–35]. Vestibular input to the inferior olive differs between the prone and supine positions (input arising from static body

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position sensors) and to body tilt, and offers a means to modulate responses to blood pressure challenges [36]. The vestibular input to cerebellar structures provides a basis for understanding the enhanced risk for SIDS from sleeping in the prone position [37], the position-dependent impaired arousal responses to auditory stimuli [38], and cardiovascular responses to blood pressure challenges evoked by tilt in infants at risk [39]. Infants with incompetent mechanisms to cope with profound drops in blood pressure during sleep may not be able to mount adequate compensatory responses to restore perfusion. Among structures eliciting arousal, an often-overlooked contribution is that from limbic structures, including the cingulate, insula, hippocampus and amygdala; their roles include affective influences, such as dyspnea, but may include more general aspects of chemoreceptor integration. Stimulation, recording and lesion studies demonstrate that these limbic structures play significant roles in breathing and cardiovascular control. Inspiratory efforts are paced by amygdalar stimulation, an effect abolished by entry into QS [40]; extreme, state-dependent elevations in blood pressure are elicited by stimulation in the amygdala [17]; substantial increases in sympathetic tone and arrhythmia develop from insular lesions [41]; and single neuron discharge relationships with the respiratory and cardiac cycles emerge in multiple limbic structures [42]. Electrical stimulation of the amygdala results in pronounced cortical activation [43], an effect apparently mediated by projections to basal forebrain cholinergic systems [11,44]. The hippocampus shows pronounced activity changes to sigh-apnea sequences, a pattern frequently accompanying momentary arousals [45,46]. Examination of children afflicted with the congenital central hypoventilation syndrome provide even further insights into functioning of limbic structures and arousal accompanying breathing challenges. Such children, in addition to their well-known loss of breathing drive during sleep and ventilatory insensitivity to CO2, show little emotional response or dyspnea to low oxygen and high CO2. Functional magnetic resonance imaging data show diminished or absent responses to CO2 challenges in amygdala, hippocampal, insular and anterior cingulate structures as well as portions of the cerebellum [47]. Adults show recruitment of the insula under conditions which induce dyspnea [48,49]. In a similar fashion, multiple limbic sites are recruited to the Valsalva maneuver, a respiratory-induced autonomic challenge which elicits significant cardiovascular patterns [50]. In summary, local processes that mediate reactions to cardiovascular and respiratory challenges during sleep can exert compensatory responses of an arousal nature without ECoG activation. These processes can interact with more recently defined ascending cortical activation systems to produce classic characteristics of arousal. Damage to specific neural structures may alter local network processes, and fail to induce appropriate arousal sequences.

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Acknowledgements This research was supported by HD-22695. We thank Rebecca Harper for assistance.

References [1] Davies RJO, Belt PJ, Roberts SJ, Ali NJ, et al. Arterial blood pressure responses to graded transient arousal from sleep in normal humans. J Appl Physiol 1993;74(3):1123–1130. [2] McNamara F, Issa FG, Sullivan CE. Arousal pattern following central and obstructive breathing abnormalities in infants and children. J Appl Physiol 1996;81(6):2651–2657. [3] Rees K, Spenee DPS, Earis JE, Calverley PMA. Arousal responses from apneic events during non-rapid-eye-movement sleep. Am J Respir Crit Care Med 1995;152:1016–1021. [4] Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. J Neuropsychiatry Clin Neurosci 1949;7:251–267. [5] Blessing WW. The lower brainstem and body homeostasis. Oxford: Oxford University Press, 1997. [6] Villablanca J, Salinas-Zeballos ME. Sleep-wakefulness, EEG and behavioral studies of chronic cats without the thalamus: the ‘athalamic’ cat. Arch Ital Biol 1972;110:383–411. [7] Kinney HC, Korein J, Panigrahy A, Dikkes P, et al. Neuropathological findings in the brain of Karen Ann Quinlan. The role of the thalamus in the persistent vegetative state. N Engl J Med 1994; 330(21):1469–1475. [8] Batsel HL. Electroencephalographic synchronization and desynchronization in the chronic ‘cerveau isole´ ’ of the dog. Electroencephalogr clin Neurophysiol 1960;12:421–430. [9] Schlag J, Chaillet F. Thalamic mechanisms involved in cortical desynchronization and recruiting responses. Electroencephalogr clin Neurophysiol 1963;15:39–62. [10] Vanderwolf CH. Cerebral activity and behavior: control by central eholinergic and serotonergic systems. Int Rev Neurobiol 1988;30: 225–340. [11] Dringenberg HC, Vanderwolf CH. Involvement of direct and indirect pathways in electrocorticographic activation. Neurosci Biobehav Rev 1998;22:243–257. [12] Kiyashchenko LI, Mileykovskiy BY, Maidment N, Lam HA, et al. Release of hypocretin (Orexin) during waking and sleep states. J Neurosci 2002;22(13):5282–5286. [13] Lin L, Faraco J, Kadotani H, Rogers W, et al. The REM sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor gene. Cell 1999;98:365–376. [14] Wikler A. Pharmacologic dissociation of behaviour and EEG ‘sleep patterns’ in dogs: morphine, N-allylnor-morphine and atropine. Proc Soc Exp Biol Med 1952;79:261–265. [15] Vanderwolf CH. Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr clin Neurophysiol 1969;26(4): 407–418. [16] Ni H, Zhang J, Glotzbach S, Schechtman VL, et al. Dynamic respiratory responses to preoptic/anterior hypothalamic warming in the sleeping cat. Sleep 1994;17(8):657–664. [17] Frysinger RC, Marks JD, Trelease RB, Schechtman VL, et al. Sleep states attenuate the pressor response to central amygdala stimulation. Exp Neurol 1984;83:604–617. [18] Rector DM, Richard CA, Staba RJ, Harper RM. Sleep states alter ventral medullary surface responses to blood pressure challenges. Am J Physiol 2000;278:R1090–R1098. [19] Richard CA, Ali N, Macey PM, Rector DM, Harper RM. Arousal responses and ventral medullary surface activity following pressor and depressor challenges. Soc Neurosci Abstr 2001;27:690.10. [20] Trelease RB, Sieck GC, Marks JD, Harper RM. Respiratory inhibition

S56

[21]

[22]

[23]

[24] [25] [26] [27]

[28]

[29]

[30]

[31]

[32]

[33]

[34] [35]

R.M. Harper et al. / Sleep Medicine 3 (2002) S53–S56 induced by transient hypertension during sleep in unrestrained cats. Exp Neurol 1985;90(1):173–186. Lutherer LO, Lutherer BC, Dormer KJ, Janssen HF, et al. Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by hemorrhage or administration of endotoxin. Brain Res 1983;269:251–257. Williams JL, Everse SJ, Lutherer LO. Stimulating fastigial nucleus alters central mechanisms regulating phrenic activity. Respir Physiol 1989;76:215–227. Bradley DJ, Ghelarducci B, La Noce A, Spyer KM. Autonomic and somatic responses evoked by stimulation of the cerebellar uvula in the conscious rabbit. Exp Physiol 1990;75:179–186. Xu F, Frazier DT. Involvement of the fastigial nuclei in vagally mediated respiratory responses. J Appl Physiol 1997;82:1853–1861. Zheng ZH, Dietrichs E, Walberg F. Cerebellar afferent fibres from the dorsal motor vagal nucleus in the cat. Neurosci Lett 1982;32:113–118. Armstrong DM. Functional significance of connections of the inferior olive. Physiol Rev 1974;54:358–417. Andrezik JA, Dormer KJ, Foreman RD, Person RJ. Fastigial nucleus projections to the brain stem in beagles: pathways for autonomic regulation. Neuroscience 1984;11:497–507. Person RJ, Andrezik JA, Dormer KJ, Foreman RD. Fastigial nucleus projections in the midbrain and thalamus in dogs. Neuroscience 1986;18:105–120. Person RJ, Dormer KJ, Bedford TG, Andrezik JA, et al. Fastigial nucleus modulation of medullary parasolitary neurons. Neuroscience 1986;19:1293–1301. Welsh JP, Yuen G, Placantonakis DG, Vu TQ, et al. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol 2002;89:331–359. Harper R, Richard CA, Rector DM. Physiological and ventral medullary surface activity during hypovolemia. Neuroscience 1999;94(2): 579–586. Cruz-Sa´ nchez FF, Lucena J, Ascaso C, Tolosa E, et al. Cerebellar cortex delayed maturation in sudden infant death syndrome. J Neuropathol Exp Neurol 1997;56:340–346. Waters KA, Forbes P, Morielli A, Hum C, et al. Sleep-disordered breathing in children with myelomeningocele. J Pediatr 1998;132: 672–681. Waters KA, Meehan B, Huang JQ, Gravel RA, et al. Neuronal apoptosis in sudden infant death syndrome. Pediatr Res 1999;45:166–172. Kinney HC, McHugh T, Miller K, Belliveau RA, et al. Subtle developmental abnormalities in the inferior olive: an indicator of prenatal brainstem injury in the sudden infant death syndrome. J Neuropathol Exp Neurol 2002;6:427–441.

[36] Doba N, Reis DJ. Role of the cerebellum and vestibular apparatus in regulation of orthostatic reflexes in the cat. Circ Res 1974;34:9–18. [37] Ponsonby A, Dwyer T, Gibbons L, Cochrane J, et al. Factors potentiating the risk of sudden infant death syndrome associated with the prone position. N Engl J Med 1993;329:377–382. [38] Franco P, Pardou A, Hassid S, Lurquin P, et al. Auditory arousal thresholds are higher when infants sleep in the prone position. J Pediatr 1998;132:240–243. [39] Harrington C, Kirjavainen T, Teng A, Sullivan CE. Altered autonomic function and reduced arousability in apparent life-threatening event infants with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:1048–1054. [40] Harper RM, Frysinger RC, Trelease RB, Marks JD. State-dependent alteration of respiratory cycle timing by stimulation of the central nucleus of the amygdala. Brain Res 1984;306:1–8. [41] Oppenheimer SM. Neurogenic cardiac effects of cerebrovascular disease. Curr Opin Neurol 1994;7:20–24. [42] Frysinger RC, Harper RM. Cardiac and respiratory correlations with unit discharge in human amygdala and hippocampus. Electroencephalogr clin Neurophysiol 1989;72:463–470. [43] Feindel W, Gloor P. Comparison of electrographic effects of stimulation of the amygdala and brain stem reticular formation in cats. Electroencephalogr clin Neurophysiol 1954;6:389–402. [44] Dringenberg HC, Vanderwolf CH. Cholinergic activation of the electrocorticogram: an amygdaloid activating system. Exp Brain Res 1996;108:285–296. [45] Poe GR, Kristensen MP, Rector DM, Harper RM. Hippocampal activity during transient respiratory events in the freely behaving cat. Neuroscience 1996;72:39–48. [46] Harper RM, Poe GR, Rector DM, Kristensen MP. Relationships between hippocampal activity and breathing patterns. Neurosci Biobehav Rev 1998;22:233–236. [47] Spriggs D, Saeed MM, Alger JR, Woo MA, et al. Time course of functional magnetic resonance signal changes in response to hypercapnia in congenital central hypoventilation syndrome (CCHS). Soc Neurosci Abstr 1999;25:280. [48] Banzett RB, Mulnier HE, Murphy K, Rosen SD, et al. Breathlessness in humans activates insular cortex. Neuroreport 2000;11:2117–2120. [49] Peiffer C, Poline J-B, Thivard L, Aubier M, et al. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 2001;163(4):951–957. [50] Harper RM, Bandler R, Spriggs D, Alger JR. Lateralized and widespread brain activation during transient blood pressure elevation revealed by magnetic resonance imaging. J Comp Neurol 2000; 417:195–204.