David W. Carley

Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential

Overview: pathophysiology of sleep-related breathing disorders in man - unanswered questions. General techniques: instrumentation and methods for chronic studies of sleep and breathing in rodents neurochemical evidence for the cholinergic modulation of sleep and breathing functional anatomical analysis of respiratory circuitry gene and protein expression and regulation in the central nervous system. Experimental sleep-related breathing disorders: intermittent hypoxia computer-controlled airway occlusion. Naturally occurring sleep-related breathing disorders: the pre-term lamb - a unique animal model of neonatal respiratory instability neonatal rat mature rat English bulldog aquatic mammals.

Injection of glutamate into the pedunculopontine tegmental nuclei of anesthetized rat causes respiratory dysrhythmia and alters EEG and EMG power

The pedunculopontine tegmental nucleus (PPT) has been shown to have important functions relevant to the regulation of behavioral states and various motor control systems, including breathing control. Our previous work has shown that the activation of neurons within the PPT, a structure that is typically active during rapid eye movement (REM) sleep, can produce respiratory disturbances in freely moving and anesthetized rats. The aim of this study was to test the hypothesis that respiratory modulation by the PPT in anesthetized rats can be evoked in the absence of other signs of an REM-sleep-like state. We characterized electroencephalogram (EEG) and electromyogram (EMG) changes during respiratory disturbances induced by glutamatergic stimulation of the PPT in spontaneously breathing, adult male Sprague–Dawley rats anesthetized with a ketamine/xylazine combination or with nembutal. Respiratory movements were monitored by a piezoelectric strain gauge. Two-barrel glass pipettes were used to pressure inject glutamate, to probe for respiratory effective sites within the PPT, and to inject oil red dye at the end of the experiments for histological verification of the injection sites. The EEGs were recorded from the sensorimotor cortex, hippocampus, and from the pons contralateral from the injection site. The EMGs were recorded from the genioglossus muscle. The initial response to glutamate injection into the respiratory modulating region of the PPT was always a respiratory pattern disturbance. Subsequent activation of EMG and EEG often occurred in ketamine/xylazine-anesthetized rats, but REM-sleep-like patterns were not observed. Respiratory pattern and EMG power changes in nembutal-anesthetized rats were similar, but EEG activation was never observed. Thus, we conclude that respiratory suppression produced by the local activation of PPT neurons may not necessarily be accompanied by an REM-sleep-like cortical state in this anesthetized model.

Minimal Modeling of Human Respiratory Stability

It is known that periodic breathing (PB), or Cheyne-Stokes respiration, may result from a wide range of pathophysiological, metabolic, or environmental conditions including; congestive heart failure, lesions of the central nervous system, hypoxemia, metabolic alkalosis and prematurity1,2. Klein first suggested that PB may derive from unstable operation of the chemostatic respiratory control system3. It was not until digital computers became widely available, however, that a series of mathematical models was developed to explore Klein’s hypothesis4–11. Early mathematical models of PB were highly-parameterized and non-linear simulation models4–8 which served to support the hypothesis that unstable chemical control of respiration, associated with loop gain magnitudes greater than unity, may be common to the wide range of conditions associated with PB. The large numbers of parameters and the difficulties of their laboratory estimation, however, made these models impractical for correlating respiratory control loop gain with observed breathing patterns in individual patients or subjects. More recently, attempts have been made to linearize9–11 and minimize the parameterization10–11 of mathematical models of PB.