Respiratory, Autonomic, & Sleep – Disorders of Breathing and Clinical Implications

SIDS remains the leading cause of death among children younger than 1 year of age: 7000 babies/year in the US: nearly one baby every hour of every day. Increasing evidence indicates that children succumb to SIDS because they fail to arouse when exposed to hypoxic/Hypercapnic conditions associated for example with the prone position (see Figure right). Normal children respond to such conditions with sighs, and gasps that trigger the arousal response and autoresuscitation. The Ramirez laboratory unravels the mechanisms underlying this arousal response. We described the neurons and cellular mechanisms responsible for gasping and sighing (Lieske et al. 2000; Pena et al. 2004; Tryba et al. 2008) and demonstrated that specific sodium-dependent pacemaker neurons (Movie link) located in the pre-Bötzinger complex require serotonergic modulation (Tryba and Ramirez, 2006). SIDS children have a disturbance in serotonergic modulation which weakens gasps and arousal. Our laboratory has demonstrated that males have a delayed recovery from hypoxia, a gender-bias that may explain the gender-bias in SIDS (Garcia et al., submitted). Together with Dr. Rubens we also explore the role of the auditory and vestibular system in SIDS (Allen et al. 2010). These mechanisms play critical roles in arousal and seem to be disturbed in SIDS victims. Critical for the Hypercapnic response is the vestibular nucleus which we described in collaboration with the Palmiter laboratory (see Figure below, Quintana et al. 2012). We hope that our discoveries will help prevent SIDS, and identify children that are in danger of succumbing to SIDS.


Sudden Unexplained Death of Epilepsy (SUDEP) & Sudden Unexplained Death of Childhood (SUDC).  Sudden unexplained death is thought to be responsible for up to 18% of all deaths in patients with epilepsy.  It is thought to be caused by epileptic seizures triggering either cardiac or respiratory arrest. The Ramirez laboratory has expertise in characterizing epilepsy and respiratory activity. The knowledge gained in understanding the mechanisms that lead to SIDS will be applied to better understand SUDEP as well as Sudden Unexplained Death of Childhood (SUDC). This effort will be performed in collaboration with Dr. Franck Kalume. One specific project focuses on sodium channel mutations that cause seizures in the neocortex, but the same sodium channels are also critical for the generation of gasping and the arousal response. We hypothesize that mutations in these ion channels will not only cause epilepsy, but will also impair the responsiveness of the respiratory network to the sudden apnea.

The Sigh: Clinical Implications.  Sighs are the first behavioral events that lead to arousal. They are activated by pain, good and bad emotions but also in response to hypoxia and hypercapnia. Sighs are associated with characteristic heart rate changes: an increase in heart rate is followed by a decrease in heart rate. This has important clinical implications: the smaller the heart rate change, the less likely a person arouses, and this cardiorespiratory coupling is often disturbed in breathing disorders. In familial dysautonomia the heart-rate-increase during the sigh is weak (see Figure below). In SIDS, sigh-associated heart rate changes seem to be smaller than in control infants (see papers by Andre Kahn, Belgium).

Rett Syndrome.  Rett Syndrome is a devastating disorder characterized by autonomic nervous system dysfunction/dysregulation. Diagnosis of Rett Syndrome is based on clinical criteria, with more than 85% of identified girls having mutations in MECP2 on the X chromosome. The Rett Syndrome phenotype includes normal development until 6–18 months of age, then regression with slowing of head circumference growth, loss of language, development of stereotypical hand movements, gait and truncal apraxia, EEG abnormalities, seizures, spasticity, and scoliosis. Breathing irregularities consistent with autonomic dysregulation in RS include characteristic patterns variably described as hyperventilation, Valsalva maneuvers, apnea, apneusis, breathholding, and rapid shallow breathing. The Ramirez laboratory focuses on the neuronal basis of Rett Syndrome (Viemari et al. 2005), and together with Dr. Weese-Mayer characterizes the clinical phenotype (Weese-Mayer et al. 2006, 2008).



Prenatal Insults, Prematurity And Respiration.  Globally, prematurity is the leading cause of death for newborns. Each year 2.6 million infants die just minutes or hours before breathing (See GAPPS Foundation: Evidence has long linked prenatal insults such as hypoxic events and infection to negative outcomes for the baby and mother. The Ramirez laboratory is now investigating how these insults affect the postnatal development of respiration and the respiratory network. We hope to characterize changes in brainstem network properties and provide insight into deficits seen in children who were exposed to these prenatal insults. Prematurely born babies typically show apneas of prematurity and often require artificial ventilation. The Ramirez laboratory in collaboration with the laboratory of Dr. “Skip” Smith (Center for Developmental Therapeutics) studies the pre- and postnatal development of the respiratory network using a mouse model. Dr. Jenna Schuster characterizes changes in the respiratory network in prematurely born mice using a variety of electrophysiological and histological approaches. We hope by understanding how prematurity affects the central neuronal networks that control breathing and its neuromodulatory drive we will be able to prevent apneas of prematurity and avoid the need for artificial ventilation and their negative consequences.

Obstructive And Central Sleep Apnea.  Obstructive sleep apnea (OSA) affects 2-4% of the adult population and an increasing number of children. While OSA is caused by airway obstructions, a major contributor to the disorder is the central nervous system. OSA is characterized by recurrent apneas that lead to intermittent hypoxia (IH). Episodic airway obstructions can occur more than 60 times per hour and lead to significant desaturations of hemoglobin to levels as low as 50%. Patients with OSA exhibit substantial memory and executive functional loss, have increased circulating markers of oxidative stress and inflammation and develop regional gray matter loss. Relevant for pediatric research is the finding that both prenatal and early postnatal IH adversely affect gasping and related survival mechanisms, which could be relevant for SIDS. The Ramirez laboratory has two ongoing projects to understand (a) the impact of chronic intermittent hypoxia (mice exposed to IH over several days) and (b) acute intermittent hypoxia (respiratory network exposed directly to IH) on the respiratory network. Of particular interest is the impact of IH on the modulatory response of the respiratory network. We find that norepinephrine which is normally a stabilizer of breathing destabilizes breathing after intermittent hypoxia. Acetylcholine which is excitatory within the respiratory network becomes inhibitory. These changes in the modulatory response can explain why respiratory drive becomes suppressed during sleep states that are characterized by increased cholinergic drive.


Familial Dysautonomia.  Familial Dysautonomia (FD) is a severe neurological disorder characterized by autonomic dysregulation. It is caused by a mutation in the IKBKP gene and it affects the development of the peripheral and central nervous system. Sudden unexplained deaths have been reported in 13% of patients with Familial Dysautonomia. In collaboration with Dr. Weese-Meyer the Ramirez laboratory is interested in understanding the neuronal basis of this devastating disorder. While peripheral nervous system effects are clearly important for the observed autonomic effects, our studies suggest that altered neuronal network functions within the CNS play also critical roles. Disruption of central rhythm generating networks may be responsible for the increased respiratory timing variability in particular during the night. Our investigations demonstrate dramatic reductions in the inspiratory duty cycle during both day and night which leads to long periods of elevated breathing rates (“hyperventilation”, see Figure right. For further information see: Weese-Meyer et al. 2008; Carroll et al. 2011.


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